Title of Invention	NOVEL SPIRO COMPOUNDS
Abstract	Spiro compounds of the general formula (1): wherein Ar1 represents an optionally substituted ary) or beteroaryl; n represents 0 or 1; T, U, V and W each represent a nitrogen atom or an optionally substituted methane group, wherein at least two of which represent said methane group; X represents nitrogen; Y represents an optionally substituted imino or oxygen atom, which exhibit neuropeptide Y receptor (NPY) antagonistic activities and are useful as agents for the treatment of various diseases related to NPY, for example, cardiovascular disorders, central nervous system disorders, metabolic diseases and the like.

Title of Invention

NOVEL SPIRO COMPOUNDS

Abstract

Spiro compounds of the general formula (1): wherein Ar1 represents an optionally substituted ary) or beteroaryl; n represents 0 or 1; T, U, V and W each represent a nitrogen atom or an optionally substituted methane group, wherein at least two of which represent said methane group; X represents nitrogen; Y represents an optionally substituted imino or oxygen atom, which exhibit neuropeptide Y receptor (NPY) antagonistic activities and are useful as agents for the treatment of various diseases related to NPY, for example, cardiovascular disorders, central nervous system disorders, metabolic diseases and the like.

Full Text	DESCRIPTION Novel Spiro Compounds Technical Field The present invention is useful in medical fields. In more detail, novel spiro compounds of this invention are useful as neuropeptide Y receptor antagonists and as agents for the treatment of various kinds of cardiovascular disorders, central nervous system disorders, metabolic diseases, and the like. Background Art Neuropeptide Y (hereinafter referred to as NPY), a peptide consisting of 36 amino acids, was first isolated from porcine brain by Tatemoto et al. in 1982 [Nature, 296: 659 (1982)]. NPY is widely distributed in central nervous system and peripheral nervous system and plays various roles as one of the most abundant peptide in the nervous system. That is, NPY acts as an orexigenic substance in the central nervous system and markedly promotes fat accumulation via the mediation of the secretion of various hormones or the action of the nervous system. It is known that the- continuous intracerebroventricular administration of NPY induces obesity and insulin resistance based on these actions (International Journal of Obesity, vol.19: 517 (1995); Endocrinology, vol.133: 1753 (1993)). It is also known that NPY has central effects, such as depression, anxiety, schizophrenia, pain, dementia and the like (Drugs, vol. 52, 371(1996). Further, in the periphery, NPY coexists with norepinephrine in sympathetic ending and is involved in the tonicity of the sympathetic nervous system. It is known that peripheral administration of NPY causes vasoconstriction and enhances the activities of other vasoconstrictive substances such as norepinephrine (British Journal of Pharmacology, vol.95: 419 (1988)). It is also reported that NPY could participate in the development of cardiac hypertrophy as a result of the sympathic stimulation (Proceeding National Academic Science USA, Vol. 97, 1595(2000)). On the other hand, it is reported that NPY is also involved in the secretory function of sexual hormones and growth hormone, sexual behavior and reproductive function, gastro-intestinal motility, bronchoconstriction, inflammation and alcohol preference (Life Science, vol. 55, 551(1994); The Journal of Allergy and Immunology, vol. 101, S345(1998); Nature, vol. 396, 366(1998)). NPY has a variety of pharmacological effects which result from NPY binding to the NPY receptors. Other NPY related peptides, including peptide YY and pancreatic polypeptide also bind to the NPY receptors. It is known that these pharmacological effects are mediated by the action of, at least, five receptor subtypes with or without synergistic interactions. (Trends in Neuroscience, vol. 20, 294(1997)). Y1: It is reported that the central effect mediated by NPY Y1 receptor includes the remarkable orexigenic effect (Endocrinology, vol. 137, 3177(1996); Endocrinology, vol. 141, 1011(2000)). Further, the Y1 receptor is reported to be involved in anxiety and pain (Nature, vol. 259, 528(1993); Brain Research, vol. 859, 361(2000)). In addition, the pressor effects mediated by the strong action of vasoconstriction in the periphery by NPY is also reported to be mediated by Y1 (FEBS Letters, vol. 362, 192(1995); Nature Medicine, vol. 4, 722(1998)). Y2: It is known that the inhibitory effect on the release of various neurotransmitters in the sympathetic nerve endings is mediated by the NPY Y2 receptor (British Journal of Pharmacology, vol. 102, 41(1991); Synapse, vol. 2, 299(1988) ). In periphery, NPY causes constriction of blood vessel or vas def erens directly or via the control of release of various neurotransmitters (The Journal of Pharmacology and Experimental Therapeutics, vol. 261, 863(1992); British Journal of Pharmacology, vol. 100, 190(1990)). In addition, inhibition of lipolysis in adipose tissues is known (Endocrinology, vol. 131, 1970(1992)). Further, the inhibition of ion secretion in the gastro-intestinal tract is reported (British Journal of Pharmacology, vol. 101 247(1990) ). On the other hand, the inhibitory effect on the central nervous system functions such as memory and anxiety is also reported (Brain Research, vol. 503, 73(1989); Peptides, vol. 19, 359(1998)). Y3: It is reported that NPY Y3 receptor is mainly located at brainstem and in the heart and is related to regulation of blood pressure and heart rate (The Journal of Pharmacology and Experimental Therapeutics, vol. 258, 633(1991); Peptides, vol. 11, 545(1990)). Further, it is known that the Y3 receptor is involved in the control of catecholamine secretion in adrenal gland ( (The Journal of Pharmacology and Experimental Therapeutics, vol. 244, 468(1988); Life Science, vol. 50, PL7(1992)). Y4: NPY Y4 receptor has high affinity for pancreatic polypeptide. The related pharmacological effects reported to be mediated by the Y4 receptor include the inhibition of pancreatic secretion and the gastro-intestinal motility (Gastroenterology, vol.85, 1411(1983)). Further, it is reported that NPY enhances the secretion of the sexual hormone in the central nervous system (Endocrinology, vol. 140, 5171(1999)). Y5: The effect mediated by NPY Y5 receptor includes feeding stimulation and accumulation of fat: (Nature, vol. 382, 168(1996)); American Journal of Physiology, vol. 277, R1428(1999) ). It is reported that the NPY Y5 receptor also mediates some CNS effects, such as seizure and epilepsy, or pain and the morphine withdrawal symptoms (Natural Medicine, vol. 3, 761(1997); Proceeding Academic Science USA, vol. 96, 13518(1999); The Journal of Pharmacology and Experimental Therapetlcs, vol. 284, 633(1998)). In the periphery, the Y5 receptor is reported to be involved in diuresis and hypoglicemic effect caused by NPY (British Journal of Pharmacology, vol. 120, 1335(1998); Endocrinology, vol. 139, 3018(1998)). NPY is also reported to enhance cardiac hypertrophy as a result of the sympathic accentuation (Proceeding National Academic Science USA, Vol. 97, 1595(2000) ). The effects of NPY occur by binding to the NPY receptors in the central or peripheral nervous system. Therefore, the action of NPY can be prevented by blocking the binding to NPY receptors. Substances antagonize NPY binding to NPY receptors may be useful for the prophylaxis or treatment of various diseases related to NPY, such as cardiovascular disorders (for example hypertension, nephropathy, heart disease, vasospasm), central nervous system disorders (for example bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal), metabolic diseases (for example obesity, diabetes, hormone abnormality), sexual and reproductive dysfunction, gastro-intestinal motility disorder, respiratory disorder, inflammation or glaucoma and the like (Trends in Pharmacological Sciences, 15: 153 (1994); Life Science,. 55, 551(1994); Drugs, vol. 52, 371(1996); The Journal of Allergy and Immunology, vol. 101, S345(1998); Nature, vol. 396, 366(1998); The Journal of Pharmacology and Experimental Therapeutics, vol. 284, 633(1998); Trends in Pharmacological Science, vol. 20, 104(1999); Proceeding National Academic Science USA, vol. 97, 1595(2000)). Recently, according to the investigation of the present inventors, it has been found that some kind of NPY receptor antagonist is useful in the prophylaxis or treatment of hypercholesterolemia, hyperlipidemia and arteriosclerosis [International application publication WO99/27965]. Disclosure of Invention The object of the present invention is to provide novel medicines which exhibit NPY antagonistic activities. The present inventors have discovered that the compounds of the general formula (I} : wherein Ar1 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, lower alkyl, halo(lower )alkyl, hydroxy(lower)alky1, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene optionally substituted with oxo, and a group represented by formula of-Q-Ar2; Ar2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; n represents 0 orl; Q represents a single bond or carbonyl; T, U, V and W represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxy and lower alkoxy, where at least two of them represent the said methine group; X represents methine group or nitrogen; Y represents imino which may be substituted with lower alkyl, or oxygen; exhibit NPY antagonistic activities and is useful as a therapeutic agent for treatment of various diseases associated with NPY, thereby completing the present invention. Compounds of the present invention (I) are useful as agents for the treatment of various diseases related to NPY, that is, for example cardiovascular disorders (for example hypertension, nephropathy, heart disease, vasospasm, arteriosclerosis), central nervous system disorders (for example bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal), metabolic diseases (for example obesity, diabetes, hormone abnormality, hypercholesterolemia, hyperllpidemia), sexual and reproductive dysfunction, gastro-lntestinal disorder, respiratory disorder, inflammation, or glaucoma, and the like. More particulary, compounds of this invention (I) is useful as agents for the treatment of bulimia, obesity, diabetes, and the like. The present invention refers to compounds of the general formula (I), the salts or esters thereof, and the process for production and use. In another embodiment, the present invention is related to the intermediate for producing the compound represented by the general formula (I). Specifically, it is related to the compound represented by the general formula (VI-1): wherein t, u, v and w represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy and optionally protected hydroxy, where at least two of them represent the said methine group. The means of terms used in the present specification are defined and more detailed description of this invention is shown in the following. "Halogen atom" refers to fluorine atom, chlorine atom, bromine atom and iodine atom. "Lower alkyl" refers to a straight- or branched-chain alkyl group of Cl to C6, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like. "Halo(lower)alkyl" refers to the aforesaid lower alkyl substituted with 1 or more than 2, preferably 1 to 3 aforesaid halogen atoms identically or differently at the substitutable, arbitrary positions, for example. fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 1,2-difluoroethyl, chloromethyl, 2- chloroethyl, 1,2-dichloroethyl, broraomethyl, iodomethyl, and the like. "Hydroxy(lower)alkyl" refers to the aforesaid lower alkyl substituted with 1 or more than 2, preferably 1 or 2 hydroxy groups at the substitutable, arbitrary positions, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1- methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, and the like. "Cyclo(lower)alkyl" refers to a cycloalkyl group of C3 to C6, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. "Lower alkenyl" refers to a straight- or branched-chain alkenyl group of C2 to C6, for example, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, l-methyl-2-propenyl, 1-methyl-l-propenyl, 1- ethyl-1-ethenyl, 2-methyl-2-propenyl,, 2-methyl-l-propenyl, 3-methyl-2-butenyl, 4-pentenyl, and the like. "Lower alkoxy" refers to a straight- or branched- chain alkoxy group of Cl to C6, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, lsobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, and the like. "Halo(lower)alkoxy" refers to the aforesaid lower alkoxy substituted with 1 or more thcin 2, preferably 1 to 3 aforesaid halogen atoms identically or differently at the substitutable, arbitrary positions, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2- fluoroethoxy, 1, 2-difluoroethoxy, chloromethoxy, 2- chloroethoxy, 1, 2-dichloroethoxy, bromomethoxy, iodomethoxy, and the like. "Lower alkylthio" refers to a straight- or branched-chain alkylthio group of Cl to C6, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthlo, sec-butylthio, isobutylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, and the like. "Lower alkanoyl" refers to an alkanoyl group containing the aforesaid lower alkyl, that is, an alkanoyl group of C2 to C7, for example acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, plvaloyl, and the like. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group containing the aforesaid lower alkoxy, that is, an alkoxycarbonyl group of C2 to C7, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and the like. "Lower alkylene optionally substituted with oxo" refers to a straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1 or more than 2, preferably 1 oxo group at a substitutable, arbitrary position, for example, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1- oxoethylene, 1-oxotrimethylene, 2-oxotrimethylene, 1- oxotetramethylene, 2-oxotetramethylene, and the like. "Aryl" includes phenyl, naphthyl, and the like. "Heteroaryl" refers to 5- or 6-membered monocylic heteroaromatic group which contains 1 or more than 2, preferably 1 to 3 hetero atoms identically or differently selected from the group of oxygen atom, nitrogen atom and sulfur atom; or condensed heteroaromatic group, where the aforesaid monocylic heteroaromatic group is condensed with the aforesaid aryl group, or with the identified or different aforesaid monocylic heteroaromatic group each other, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,3- triazolyl, 1, 2,4-triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4- thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl, and the like. "Lower alkylamino" refers to an amino group mono- substituted with the aforesaid lower alkyl, for example, methylamino, ethylamino, propylami.no, isopropylamino, butylamino, sec-butylamino, tert-butylamino, and the like. "Di-lower alkylamino" refers to an amino group di-substituted with identical or different aforesaid lower alkyl, for example, dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino, diisopropylamino, and the like. The salts of compounds of formula (I) refer to the pharmaceutically acceptable and common salts, for example. base addition salt to carboxyl group when the compound has a carboxyl group, or acid addition salt to amino or basic heterocyclyl when the compound has an amino or basic heterocyclyl group, and the like. Aforesaid base addition salts include salts with alkali metals (for example sodium, potassium); alkaline earth metals (for example calcium, magnesium); ammonium or organic amines (for example trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, dlethanolamine, triethanolamine, procaine, N,N'-dibenzylethylenediamine), and the like. Aforesaid acid addition salts include salts with inorganic acids (for example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid), organic acids (for example maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, trifluoroacetic acid), sulfonic acids (for example methanesulfonic acid, Isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid), and the like. The esters of compounds of formula (I) refer to, for example, the pharmaceutically acceptable, common esters on carboxyl group when the compound has a carboxyl group, for example, esters with lower alkyls ( for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl), aralkyls (for example benzyl, phenethyl), lower alkenyls (for example allyl, 2-butenyl), lower alkoxy (lower) alkyls (for example methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl), lower alkanoyloxy (lower) alkyls (for example acetoxymethyl, pivaloyloxy-methyl, 1- pivaloyloxyethyl), lower alkoxycarbonyl (lower) alkyls (for example methoxycarbonylmethyl, isopropoxycarbonylmethyl), carboxy-(lower)alkyls (for example carboxymethyl), lower alkoxycarbonyloxy-(lower)alkyls (for example 1- (ethoxycarbonyloxy)ethyl, 1-(cyclohexyl- oxycarbonyloxy)ethyl), carbamoyloxy(lower)alkyls (for example carbamoyloxymethyl), phthalidyl group, (5- substituted-2-oxo-l,3-dioxol-4-yl)methyl (for example (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl), and the like. "An agent for treatment" refers to a medicament which is employed for the treatment and/or prophylaxis of various diseases. In order to disclose the aforesaid compounds of the general formula (I) more detailed, the various symbols used in the formula (I) are explained in more detail by the use of preferred embodiments. Ar1 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo (lower )alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene optionally substituted with oxo, and a group represented by formula of-Q-Ar2. "Aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl. lower alkoxy, halo (lower )alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene optionally substituted with oxo, and a group represented by formula of-Q-Ar2" refers to unsubstituted aforesaid aryl or aforesaid heteroaryl, or the aforesaid aryl or aforesaid heteroaryl which has substituent(s) at the substitutable, arbitrary position(s). The aforesaid substituent can be. Identically or differently, one or more than 2, preferably 1 or 2 selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alky1, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene optionally substituted with oxo, and a group of formula:-Q-Ar2. Halogen atom as the aforesaid substituent includes fluorine atom, chlorine atom, and the like preferably. Lower alkyl as the aforesaid substituent includes methyl, ethyl, propyl, isopropyl, and the like preferably. Halo(lower)alkyl as the aforesaid substituent includes difluoromethyl, trifluoromethyl, and the like preferably. Hydroxy(lower)alkyl as the aforesaid substituent includes hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-l- methylethyl, and the like preferably. Cyclo(lower)alkyl as the aforesaid substituent includes cyclopropyl, cyclobutyl, and the like preferably. Lower alkenyl as the aforesaid substituent includes vinyl, 1-propenyl, 2-methyl-1-propenyl, and the like preferably. Lower alkoxy as the aforesaid substituent includes methoxy, ethoxy, and the like preferably. Halo(lower)alkoxy as the aforesaid substituents includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, and the like preferably. Lower alkylthio as the aforesaid substituent includes methylthio, ethylthio, and the like preferably. Lower alkanoyl as the aforesaid substituent includes acetyl, propionyl, and the like preferably. Lower alkoxycarbonyl as the aforesaid substituent includes methoxycarbonyl, ethoxycarbonyl, and the like preferably. Lower alkylene optionally substituted with oxo as the aforesaid substituent includes 1-oxotetramethylene, and the like preferably. In a group of formula:-Q-Ar2 as the aforesaid substituent, Ar2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q represents a single bond or carbonyl. "Aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl" refers to unsubstituted aforesaid aryl or aforesaid heteroaryl, or the aforesaid aryl or aforesaid heteroaryl which has substituent(s) at the substitutable, arbitrary position!s). The aforesaid substituent can be, identically or differently, one or not less than 2, preferably 1 or 2 selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl. Halogen atom as the aforesaid substituent includes, preferably, fluorine atom, chlorine atom, and the like. Lower alkyl as the aforesaid substituent includes, preferably, methyl, ethyl, propyl, isopropyl, and the like. Halo(lower)alkyl as the aforesaid substituent includes, preferably, difluoromethyl, trifluoromethyl, and the like. Hydroxy(lower)alkyl as the aforesaid substituent includes, preferably, hydroxymethyl, 2-hydroxyethyl, 1- hydroxy-1-methylethyl, and the like. Lower alkoxy as the aforesaid substituent includes, preferably, methoxy, ethoxy, and the like. Halo(lower)alkoxy as the aforesaid substituent includes, preferably, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and the like. Lower alkylamino as the aforesaid substituent includes, preferably, methylamino, ethylamino, and the like. Di-lower alkylamino as the aforesaid substituent includes, preferably, dimethylamino, diethylamino, and the like. Lower alkanoyl as the aforesaid substituent includes, preferably, acetyl, propionyl, and the like. Aryl as the aforesaid substituent includes, preferably, phenyl, and the like. The substituent(s) of Ar2 include, preferably, halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alky1, hydroxy, halo(lower)alkoxy, and the like. Aryl in Ar2 includes, preferably, phenyl, and the like and heteroaryl includes imidazolyl, pyridyl, benzofuranyl, quinolyl, and the like. Consequently, a group of formula:-Q-Ar2 includes, for example, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4- chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- fluoro-5-methylphenyl, 3-fluoromethylphenyl, 2- trifluoromethylphenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3- fluoromethoxyphenyl, 3-difluoromethoxyphenyl, 3-(2- hydroxyethyl)phenyl, 3-hydroxymethylphenyl, 3-(l- hydroxy-1-methylethyl)phenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 2-imidazolyl, 1-ethyl-2-imidazolyl, l,2,4-thiadiazol-5-yl, 1,3,4-thiadiaol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-ethyl-4-pyridyl, 4-pyrimidlnyl, 5-pyrimidinyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 7- benzo[b]furanyl, 2-quinolyl, 3-guinolyl, 4-quinolyl, 5- qulnolyl, 6-quinolyl, 8-quinolyl, benzoyl, 2- pyridylcarbonyl, and the like, and preferably, phenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-cyanophenyl, 3- trlfluoromethylphenyl, 3-difluoromethoxyphenyl, 3-(2- hydroxyethyl)phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 1-ethyl-2-imidazolyl, 2-pyridyl, 7-benzo[b]furanyl, 2- quinolyl, 3-qulnolyl, benzoyl, 2-pyridylcarbonyl, and the like. The substltuent of Ar1 includes, preferably, halogen, lower alkyl, halo(lower)alkyl, lower alkenyl, lower alkanoyl, lower alkylene optionally substituted with oxo, and a group of formula:-Q-Ar2, and the like. Aryl in Ar1 includes, preferably, phenyl, and the like and heteroaryl of Ar1 includes pyrrolyl, lmidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3- triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, quinolyl, pyrido[3,2-b]pyridyl, and the like. Consequently, Ar1 includes, for example, 3- fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4- acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl, 4- acetyl-3-trifluoromethylphenyl, 4-(l-ethyl-2- imidazolyl)phenyl, 3-(2-pyridyl)phenyl, 3-(4- pyridyl)phenyl, 4-(2-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 4-(2-ethyl-4-pyridyl)phenyl, 4-(4-pyrimidinyl)phenyl, 4- benzoylphenyl, 4-(2-pyridylcarbonyl)phenyl, 1-phenyl-3- pyrrolyl, l-phenyl-4-imidazolyl, 1-(2-fluorophenyl)-4- imidazolyl, 1-(3-fluorophenyl)-4-imidazolyl, l-(4- fluorophenyl)-4-imidazolyl, 1-(2,3-difluorophenyl)-4- imidazolyl. 1-(2,4-dlfluorophenyl)-4-imidazolyl, l-(3,5- difluorophenyl)-4-imidazolyl, 1-(3-chlorophenyl)-4- imidazolyl, 1-(2-cyanophenyl)-4-imidazolyl, l-(3- cyanophenyl)-4-imidazolyl, 1-(4-cyanophenyl)-4- imidazolyl, 1-(3-trifluoromethylphenyl)-4-imidazolyl, 1- [3-(2-hydroxyethyl)phenyl]-4-imidazolyl, 1-[ 3-(1- hydroxy-1-methylethyl)phenyl]-4-imidazolyl, 1-(3- methoxyphenyl)-4-imidazolyl, 1-(2- difluoromethoxyphenyl)- 4-imidazolyl, 1-(3- difluoromethoxyphenyl)- 4-imidazolyl, 1-(4- difluoromethoxy-phenyl)-4-imidazolyl, 1-(2-pyrldyl)-4- imidazolyl, 1-(4-benzo[b]furanyl)-4-imidazolyl, l-(5- benzo[b]furanyl)-4-imidazolyl, 1-(7-benzo[b]furanyl)-4- imidazolyl, 1-(2-quinolyl)-4-imidazolyl, 1-(3-quinolyl)- 4-imidazolyl, 1-(4-quinolyl)-4-imidazolyl, l-(5- quinolyl)-4-imidazolyl, 1-(6-quinolyl)-4-imidazolyl, 1- (8-quinolyl)-4-imldazolyl, l-phenyl-3-pyrazolyl, 5- phenyl-3-pyrazolyl, 1-phenyl-4-pyrazolyl, l-(2- fluorophenyl)-3-pyrazolyl, 5-(2-fluorophenyl)-3- pyrazolyl, 5-(3-fluorophenyl)-3-pyrazolyl, l-(3- fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-3- pyrazolyl, 5-(4-fluorophenyl)-3-pyrazolyl, 5-(2- chlorophenyl)-3-pyrazolyl, 5-(3-chlorophenyl)-3- pyrazolyl, 5-(4-chlorophenyl)-3-pyrazolyl, 5-(2- difluoromethoxyphenyl)-3-pyrazolyl, 5-(3- difluoromethoxyphenyl)- 3-pyrazolyl, 2-methyl- 5-phenyl- 3- pyrazolyl, 5-(2-pyridyl)-3-pyrazolyl, 5-(2-qulnolyl)-3- pyrazolyl, 5-(3-quinolyl)-3-pyrazolyl, 4-phenyl-2- thiazolyl, 5-phenyl-2-thiazolyl, 5-(3-chlorophenyl)-2- thiazolyl, 5-(4-chlorophenyl)-2-thiazolyl, 5-(4- methoxyphenyl)-2-thiazolyl, 5-(2-pyridyl)-2-thiazolyl, 2-phenyl-4-thiazolyl, 4-phenyl-2-oxazolyl, 5-phenyl-2- oxazolyl, 4-(2-fluoromethoxyphenyl)-2-oxazolyl, 4-(3- fluoromethoxyphenyl)- 2-oxazolyl, 5-phenyl-3-isoxazolyl, 3-phenyl-5-isoxazolyl, 3-(2-chlorophenyl)-5-isoxazolyl, 3-(3-chlorophenyl)-5-isoxazolyl, 3-(4-chlorophenyl)-5- isoxazolyl, 3-(2-pyridyl)-5-isoxazolyl, 2-phenyl-l,2,3- triazol-4-yl, 5-phenyl-l,2,4-thiadlazol-3-yl, 5-phenyl- 1,3,4-thiadiazol-2-yl, 5-(3-chlorophenyl)-1,3,4- thiadiazol-2-yl, 5-(2-pyridyl)-1.3,4-thiadlazol-2-yl, 5- (2-ethyl-4-pyridyl)-l,3,4-thiadiazol-2-yl, 5-phenyl-2- pyridyl, 6-phenyl-3-pyridyl, 2-phenyl-4-pyridyl, 5-(2- pyridyl)-2-pyridyl, 5-benzoyl-2-pyridyl, 6-benzoyl-3- pyridyl, 5-chloro-2-pyrazinyl, 5-(2-methyl-1-propenyl)- 2-pyrazinyl, 5-acetyl-2-pyrazinyl, 5-propionyl-2- pyrazinyl, 5-phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2- pyrazlnyl, 5-(4-hydroxyphenyl)-2-pyrazinyl, 5-(1,2,4- thiadiazol-5-yl)-2-pyrazinyl, 5-(1,3,4-thiadiazol-2-yl)- 2-pyrazinyl, 5-(2-pyridyl)-2-pyrazinyl, 5-(3-pyridyl)-2- pyrazinyl, 5-(5-pyrimidinyl)-2-pyrazinyl, 5-(3- quinolyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl, 5-(2- pyridylcarbonyl)-2-pyrazinyl, 5-acetyl-2-pyrimidinyl, 5- acetyl-3-methyl-2-pyrimidinyl, 4-phenyl-2-pyrimidinyl, 5-phenyl-2-pyrimidinyl, 6-phenyl-4-pyrimidinyl, 2- phenyl-5-pyrimldinyl, 5-(2-fluorophenyl)-2-pyrimidinyl, 5-(3-fluorophenyl)-2-pyrimidinyl, 5-(4-fluorophenyl)-2- pyrimidinyl, 5-(2-chlorophenyl)-2-pyrimldinyl, 5-(3- chlorophenyl)-2-pyrimidinyl, 5-(4-chlorophenyl)-2- pyrimidinyl, 5-(2-methylphenyl)-2-pyrimidinyl, 5-(3- methylphenyl)-2-pyrimidinyl, 5-(2-fluoromethylphenyl)-2- pyrimidinyl, 5-(3-fluoromethylphenyl)-2-pyrimidinyl, 5- (2-trifluoromethylphenyl)-2-pyrimidinyl, 5-(3- trifluoromethylphenyl)-2-pyrimidinyl, 5-(4- trif luoromethylphenyl)-2-pyrimidinyl., 5-( 2- hydroxymethylphenyl)-2-pyrimidiny1, 5-(3- hydroxymethylphenyl)-2-pyrimidinyl, 5-(2-hydroxyphenyl)- 2-pyrimidinyl, 5-(3-hydroxyphenyl)-2-pyrimidinyl, 5-(2- methoxyphenyl)-2-pyrimidinyl, 5-(3-methoxyphenyl)-2- pyrimldinyl, 5-(4-methoxyphenyl)-2-pyrimidinyl, 5-(2- fluoromethoxyphenyl)-2-pyrimidinyl, 5-(3- fluoromethoxyphenyl)-2-pyrimidinyl, 5-(2-fluoro-5- methylphenyl)-2-pyrimidinyl, 5-(3-fluoro-5- methoxyphenyl)-2-pyrimidinyl, 6-phenyl-3-pyridazinyl, 6- phenyl-1,2,4-triazin-3-yl, 5-chloro-2-benzoxazolyl, 5- fluoro-2-benzothiazolyl, 4-methyl-2-benzothiazolyl, 2- methyl-5-benzothiazolyl, 4-methoxy-2-benzothiazolyl, 3- quinolyl, 6-quinolyl, 7-methyl-2-quinolyl, 2-methyl-6- quinolyl, 6-chloro-2-quinoxalinyl, pyrido[3,2-b]pyridin- 2-yl, 7-chloropyrido[3,2-b]pyridin-2-yl, 7- methylpyrido[3,2-b]pyridin-2-yl, 7- trlfluoromethylpyrido[3,2-b]pyridin-2-yl, 7- difluoromethoxypyrido[3,2-b]pyridin-2-yl, 7- acetylpyrido[3,2-b]pyridin-2-yl, and the like, preferably 3,4-dichlorophenyl, 4-acetylphenyl, 5-oxo-5,6,7,8- tetrahydro-2-naphthyl, 4-acetyl-3-trifluoromethylphenyl, 4-(l-ethyl-2-imidazolyl)phenyl, 4-benzoylphenyl, 4-(2- pyridylcarbonyl)phenyl, l-phenyl-3-pyrrolyl, 1-phenyl- 4-iraidazolyl, 1-(2-fluorophenyl)-4-imidazolyl, l-(3,5- difluorophenyl)- 4-imidazolyl, 1-(3-chlorophenyl)-4- imidazolyl, 1-(3-cyanophenyl)-4-imidazolyl, l-[3-(2- hydroxyethyl)phenyl]-4-imidazolyl, 1-(3- difluoromethoxyphenyl)-4-imidazolyl, 1-(7- benzo[b]furanyl)-4-imidazolyl, 1-(2-quinolyl)-4- imidazolyl, 1-(3-quinolyl)-4-imidazolyl, l-phenyl-3- pyrazolyl, 5-phenyl-3-pyrazolyl, l-phenyl-4-pyrazolyl, 1-(3-fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-3- pyrazolyl, 5-(4-chlorophenyl)-3-pyrazolyl, 5-(3- quinolyl)-3-pyrazolyl, 5-phenyl-2-thiazolyl, 3-phenyl-5- isoxazolyl, 5-(2-methyl-l-propenyl)-2-pyrazinyl, 5- phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2-pyrazinyl, 5- (4-hydroxyphenyl)-2-pyrazinyl, 5-(2-pyridyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl, 5-phenyl-2-pyrimidinyl, 5-(2- fluorophenyl)-2-pyrimidinyl, 5-(3-fluorophenyl)-2- pyrimidinyl, 5-(3-chlorophenyl)-2-pyrimidinyl, 5-(3- trifluoromethyl-phenyl)-2-pyrimidinyl, 5-chloro-2- benzoxazolyl, 4-methyl-2-benzothia-zolyl, 7-methyl-2- quinolyl, 7-trifluoromethylpyrido[3,2-b]pyridin-2-yl, and the like, especially 1-phenyl-3-pyrazolyl, 5-phenyl-3- pyrazolyl, 5-phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2- pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl, 5-phenyl-2- pyrimidlnyl, 5-(2-fluorophenyl)-2-pyrimidinyl, 5-(3- fluorophenyl)-2-pyrimidinyl, 7-trifluoro- methylpyrido[3,2-b]pyridin-2-yl, and the like. n represents 0 or 1, 0 is preferable. T, U, V and W represent independently nitrogen atom or methine which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxy and lower alkoxy, where at least two of them represent the said methine group. "Methine which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxy and lower alkoxy" refers to unsubstituted methine or methine having a substituent which can be selected from the group consisting of halogen, lower alkyl, hydroxy and lower alkoxy. Halogen atom as the aforesaid substituent Includes preferably fluorine atom, chlorine atom, and the like. Lower alkyl as the aforesaid substituent includes preferably methyl, ethyl, and the like. Lower alkoxy as the aforesaid substituent includes preferably methoxy, ethoxy, and the like. The aforesaid substituent include preferably halogen, and the like. The preferred mode of T, U, V and W includes, for example, T, U, V and W are independently methine optionally having the aforesaid substituent, preferably halogen; or one of T, U, V and W is nitrogen atom. X represents methine or nitrogen. Y represents imino which may be substituted with lower alkyl, or oxygen. "Imino which may be substituted with lower alkyl" refers to unsubstituted imino or iraino substituted with lower alkyl. The aforesaid lower alkyl includes, preferably, methyl, ethyl, and the like. Y is preferably unsubstituted imino or oxygen, especially oxygen. In more detail, a group of formula (15): includes a group of formula (16): and the like. Preferred compounds of the general formula (I) are, for example, compounds of the general formula (I-a): wherein R1 represents hydrogen atom or halogen, Ar1 has the aforesaid meaning; or compounds of the general formula (I-b): wherein Ar1, T, U, V and W have the aforesaid meanings. With regard to the compound represented by the general formula (I-a), the preferred compounds are, for example, the compounds, wherein the aryl group in Ar1 is phenyl, or the heteroaryl group in Ar1 is imidazolyl, pyrazolyl, lsoxazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyrimidinyl, quinolyl or pyrido[3,2-b]pyridyl. With regard to the compound represented by the general formula (I-b), the preferred compounds; are, for example, the compounds, wherein the aryl group in Ar1 is phenyl, or the heteroaryl group in Ar1 is pyrrolyl, imidazolyl, pyrazolyl, thlazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4- thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or 1,2,4- triazinyl. Further, with regard to the compound represented by the general formula (I-b), the preferred compounds are, for example, the compounds, wherein one of T, U, V and W is a nitrogen atom and the more preferred compounds are, for example, the compounds wherein V is a nitrogen atom and T,U as well as W are an unsubstituted methine group. Compounds of this invention may include stereoisomers such as optical isomers, diastereoisomers and geometrical isomers, or tautomers depending upon the mode of substltuents. Compounds of this invention include all the stereoisomers, tautomers and their mixtures. For example, compounds of the general formula (I- b) include stereoisomers such as trans-form compound of the general formula (I-lb): and cis-form compound of the general formula (I-2b): trans form is preferable. Also included within the scope of the invention are polymorphs, hydrates and solvates of the compounds of the instant invention. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present Invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu. The specific compound represented by the general formula (I) is, for example, N-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4'- piperidine]-1'-carboxamide, 3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4'- piperidine]-1'-carboxamide, N-(7-methyl-2-quinolyl)- 3-oxospiro[isoindoline-1, 4'- piperidine]-1'-carboxamide, N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline- 1,4'-piperidine]-1'-carboxamide, N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline- 1(2H),4'-piperidine]-1'-carboxamide, 3,4-dihydro-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isoquinoline-1(2H),4'-piperidine]-1'- carboxamide, 3,4-dlhydro-N-(7-methyl-2-quinolyl)-3- oxospirotisoquinoline-1(2H),4'-piperidine]-1'- carboxamide, N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline- 1(2H),4'-piperidine]-1'-carboxamide. 3,4-dihydro-3-oxo-N-[l-(2-quinolyl)-4- imidazolyl]spiro[isoquinoline-1(2H),4'-piperidine]-1'- carboxamide, 3,4-dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2- naphthyl)spiro[isoquinoline-1(2H),4'-piperidine]-1'- carboxamide, 3,4-dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3- oxospiro[isoquinoline-l(2H), 4'-piperidine]-1'- carboxamide, 3,4-dihydro-3-oxo-N-(3-phenyl-5- isoxazolyl)spiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3- oxospiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4- dihydro-3-oxospiro[isoquinoline-l(2H),4'-piperidine]-1' carboxamide, 3,4-dihydro-3-oxo-N-[4-(2- pyridylcarbonyl)phenyl]spiro[isoquinoline-l(2H),4'- piperidine]-1'-carboxamide, N-(3,4-dichlorophenyl)-3,4-dihydro-3- oxospiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, N-[1-(3-chlorophenyl)-4-imidazolyl]- 3,4-dihydro-3- oxospiro[isoquinollne-l(2H),4'-piperidine]-1'- carboxamide, 3,4-dihydro-3-oxo-N-(5-phenyl-2- thiazolyl)spiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, 3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2- pyrazinyl]spiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, 3,4-dihydro-N-(4-methyl-2-benzothiazolyl)-3- oxospiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3- oxosplro[isoquinoline-1(2H),4'-piperidine]-1'- carboxamide, N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-l(3H),4'- piperidine]-1'-carboxamide, 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, 3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, 3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2- yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, 3-oxo-N-[l-(3-quinolyl)-4- imidazolyl]spiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, N-[5-(4-chlorophenyl)-3-pyrazolyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-[5-(3-quinolyl)- 3-pyrazolyl]spiro[isobenzofuran 1(3H),4'-piperidine]-1'-carboxamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3- oxospiro[lsobenzofuran-l(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-[5-(3-trifluoromethylphenyl)-2- pyrimidinyl]spiro[isobenzofuran-l(3H),4'-piperidine]-1' carboxamide, N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, N-(7-difluoromethoxypyridot3,2-b]pyridin-2-yl)-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-(5-phenyl-l,2,4-thiadiazol-3- yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, N-{1-[3-(2-hydroxyethyl)phenyl]- 4-imidazoly}- 3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, N-[4-(l-ethyl-2-imidazolyl)phenyl]-3- oxospiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide, N-[1-(3-methoxyphenyl)-4-imidazolyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 6-fluoro-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 6-fluoro-3-oxo-N-(5-phenyl-2- pyrimldinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1' carboxamide, 5-fluoro-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l( 3H),, 4'-plperidlne]-1'- carboxamide, 5-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl)spiro[isobenzofuran-l(3H),4'-plperidlne]-1' carboxamide, N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2- benzopyran-1,4'-piperidine]-1'-carboxamide, 3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2- benzopyran-1,4'-piperidine]-1'-carboxamide, N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxosplro[1H-2- benzopyran-1,4'-piperidine]-1'-carboxamide, trans-N-(4-benzoylphenyl)-3'-oxospiro[cyclohexane- 1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-3'-oxo-N-(5-phenyl-2-pyrazinyl)spiro t cyclohexane- 1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-3'-oxo-N-(1-phenyl-4-imidazolyl)splro[cyclohexane 1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-3'-oxo-N-(5-phenyl-2- pyrimidinyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]- 4-carboxamide, trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3'- oxospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4- carboxamide, trans-3'-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane- 1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3'- oxospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4- carboxamide. trans-N-(4-acetyl-3-trifluoromethylphenyl)-3'- oxospiro[cyclohexane-l,1'(3'H)-isobenzofuran]-4- carboxamide, trans-3'-oxo-N-[1-(3-quinolyl)-4- imidazolyl]spiro[cyclohexane-l,1'(3'H)-isobenzofuran]-4- carboxamide, trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3'- oxospiro[cyclohexane-l, 1'(3'H)-isobenzofuran]-4- carboxamide, trans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran- 1(3H),1'- cyclohexane]- 4'-carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spirot 4- azaisobenzofuran-1(3H),1'-cyclohexane]- 4'-carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran- 1(3H),1'- cyclohexane]-4'-carboxamide, trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran- 1(3H),1'- cyclohexane]- 4'-carboxamide, N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 4-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1' carboxamide, 7-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide, 6-ethyl-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide, 6-hydroxy-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-1(3H), 1'-cyclohexane]- 4'-carboxamide, trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5 azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(3-methylphenyl)-2-pyrimldinyl]-3-oxospiro[5 azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'- carboxamlde, trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamlde, trans-N-[4-(3-fluoromethoxyphenyl)-2-oxazolyl]-3- oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3- oxosplro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3- oxospirot 6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3- oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamlde, trans-3-oxo-N-(6-phenyl-1,2,4-triazln-3-yl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3- oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3- oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxosplro[6- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-N-(4-benzoylphenyl)-3-oxospirc>[7-azaisobenzofuran- 1(3H),1'-cyclohexane]- 4'-carboxamide, trans-N-[l-(3.5-dlfluorophenyl)-4-imidazolyl]-3- oxospiro[7-azaisobenzofuran-l(3H), 1'-cyclohexane]-4'- carboxamide, trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(l-phenyl-4-pyrazolyl)splro[7- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(l-phenyl-3-pyrazolyl)spiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(5-phenyl-l,2,4-thiad:Lazol-3-yl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(2-phenyl-3-thiazolyl)splro[6- azalsobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide or trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide. Among these compounds, the preferable compound is, for example, 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, 3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2- yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, trans-3'-oxo-N-(5-phenyl-2- pyrimidinyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]- 4-carboxamide, trans-3'-oxo-N-[1-(3-quinolyl)-4- imidazolyl]spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4- carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(3-fluorophenyl)-2-pyrimldinyl]-3-oxospiro[5- azalsobenzofuran-1(3H), 1'-cyclohexane]-4'-carboxamide, trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[l-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(l-phenyl-3-pyrazolyl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide or trans-3-oxo-N-(2-phenyl-l,2,3-triazol-4-yl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide. The process for producing compounds of this invention is illustrated as follows. Compounds of this invention (I) can be synthesized, for example, by the following processes for production or the processes shown in examples, but these embodiments are not intended to restrict the process for producing compounds of this invention (I). Production Process 1 A compound of the general formula (II): wherein Ar1p represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy. halo(lower)alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, a group of formula:-Qp-Ar2p, and an optionally protected, lower alkylene optionally substituted with oxo, hydroxy(lower)alkyl or carboxyl group; Ar2p represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, di-lower alkylamino, lower alkanoyl, aryl, and an optionally protected hydroxy(lowerJalkyl, hydroxy or lower alkyl amino group; Ar3 represents phenyl which may be substituted by halogen or nitro; Qp represents a single bond or optionally protected carbonyl; is reacted with a compound of the general formula (III): wherein n, t, u, v, w and Y have the same meanings as mentioned above; to provide a compound of the general formula (IV-1): wherein Arlp, n, t, u, v, w and Y have the same meanings as mentioned above; optionally followed by elimination of a protective group to give a compound of the general formula (I-1): wherein Ar1, n, T, U, V, W and Y have the same meanings as mentioned above. This production process refers to the process for producing a compound of the general formula (I), wherein X is nitrogen, that is, a compound of the general formula (I-1). When a reactant has an amino, hydroxy, carboxyl, oxo, carbonyl, or the like group which does not participate in the reaction, the reaction may be carried out after protecting the amino, hydroxy, carboxyl, oxo, carbonyl, or the like group with an amino protecting group, hydroxy protecting group, carboxyl protecting group, or oxo- or carbonyl-protecting group, followed by deprotection after completion of the reaction. "Amino protecting group" includes aralkyl (for example benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o- nitrobenzyl, p-nitrobenzyl, benzhydryl, trityl); lower alkanoyl (for example formyl, acetyl, propionyl, butyryl, pivaloyl); benzoyl; arylalkanoyl (for example phenylacetyl, phenoxyacetyl); lower alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, tert-butoxycarbonyl); aralkyloxycarbonyl (for example benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl); lower alkylsilyl (for example trimethylsilyl, tert-butyldimethylsilyl); and the like, especially acetyl, pivaloyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like. "Hydroxy protectiing group" includes lower alkyl (for example methyl, ethyl, propyl, isopropyl, tert-butyl); lower alkylsilyl (for example trimethylsilyl, tert- butyldimethylsilyl); lower alkoxymethyl (for example methoxymethyl, 2-methoxyethoxymethyl); tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl (for example benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p- nitrobenzyl, trityl); acyl (for example formyl, acetyl), and the like, especially methyl, methoxymethyl, tetrahydropyranyl, trityl, trimethylsilylethoxymethyl. tert-butyldimethylsilyl, acetyl, and the like. "Carboxyl protecting group" includes lower alkyl (for example methyl, ethyl, propyl, isopropyl, tert-butyl); lower haloalkyl (for example 2,2,2-trichloroethyl); lower alkenyl (for example 2-propenyl); aralkyl (for example benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl, trityl); and the like, especially methyl, ethyl, tert-butyl, 2-propenyl, benzyl, p-methoxybenzyl, benzhydryl, and the like. "Oxo- or carbonyl-protecting group" includes acetal or ketal (for example ethylene ketal, trimethylene ketal, dimethyl ketal), and the like. The reaction between a compound of the general formula (II) and a compound of the general formula (III) is usually carried out by employing an equivalent to excessive mole, preferably an equivalent to 1. 5 moles of compound (III) based on 1 mole of compound (II). The reaction is usually carried out in an inert solvent, and as the inert solvent, made is use of, for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or the mixture, and the like, preferably. The aforesaid reaction may be preferably carried out in the presence of base, including organic bases (for example triethylamine, diisopropylethylamine, pyridine, 4- dimethylaminopyridine) or inorganic bases (for example sodium hydroxide, potassium hydroxide), and the like. The amount of the aforesaid base employed is usually an equivalent to excessive mole, preferably 1 to 5 moles based on 1 mole of a compound of the general formula (II). Reaction temperature is usually-30 t to 200 oC, preferably 20oC to lOOoC. Reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours. At the conclusion of the reaction, the crude product of a compound of the general formula (IV-1) can be obtained by usual treatment. Thus obtained compound (IV-1) is purified by the conventional method, or not purified, if necessary followed by optional combination of elimination reaction of amino-, hydroxy-, carboxyl-, oxo- and carbonyl-protecting group to give a compound of the general formula (1-1). The elimination of protecting groups may be carried out depending upon the kinds of the aforesaid protecting groups, the stability of a desired compound (1-1) and so on, for example, by the manner described in the literature [Protective Groups in Organic Synthesis, T.W.Greene, John Wiley & Sons, (1981)] or its similar manner, for example, solvolysis using acid or base, that is, for example 0.01 mole to a large excess of acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid, or the like, or an equivalent mole to a large excess of base, preferably potassium hydroxide, calcium hydroxide, or the like; chemical reduction using metallic complex hydride, or the like; or catalytic reduction using palladium-carbon catalyst, Raney nickel catalyst, or the like. Production Process 2 A compound of the general formula (V): wherein Arlp has the same meaning as mentioned above; is reacted with a carboxylic acid of the general formula (VI): wherein n, t, u, v, w and Y have the same meanings as mentioned above; or its reactive derivative to provide a compound of the general formula (IV-2): wherein Arlp, n, t, u, v, w and Y have the same meanings as mentioned above; optionally followed by elimination of a protecting group to give a compound of the general formula (I-2): wherein Ar1, n, T, U, V, W and Y have the same meanings as mentioned above. This production process refers to the process for producing compounds of the general formula (I), wherein X is methine, that is, a compound of the general formula (I-2). Reaction between a compound of the general formula (V) and a carboxylic acid of the general formula (VI) is usually carried out by employing 0. 5 mole to excessive moles, preferably 1 mole to 1.5 mole of carboxylic acid (VI) based on 1 mole of compound (V). The reaction is usually carried out in an inert solvent, and preferable examples of the inert solvent include methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine or a mixture thereof, and the like. The aforesaid reaction is preferably carried out in the presence of condensing agents, for example N, N'- dicyclohexylcarbodiimide, N,N'-diisopropylcarbodlimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris- pyrrolidlnophosphonium hexafluorophosphate, bromotris- (dimethylamino)phosphonium hexafluorophosphate, diphenylphosphoryl azide, 1,1'-carbonyldiimidazole, or the like. The aforesaid condensing agent: is usually employed at 1 mole to excessive mole, preferably 1 mole to 1.5 moles based on 1 mole of compound (VI). Reaction temperature is usually-50 oC to 100oC, preferably-20oC to 50oC. Reaction time is usually 30 minutes to 7 days, preferably 1 hour to 24 hours. A compound of formula (I-2) is also produced by reacting a compound of the general formula (V) with a reactive derivative of the carboxylic acid (VI) instead of the carboxylic acid (VI). The reactive derivatives of carboxylic acid of the general formula (VI) include acid halides, mixed acid anhydrides, activated esters, activated amides, and the like. The acid halides of carboxylic: acid of the general formula (VI) may be obtained by reacting a carboxylic acid of the general formula (VI) with a halogenating agent according to the conventional method. Halogenating agent includes thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, phosgene, and the like. The mixed acid anhydrides of carboxylic acid of the general formula (VI) may be obtained by reacting a carboxylic acid of the general formula (VI) with alkyl chlorocarbonate (for example ethyl chlorocarbonate); aliphatic carboxylic acid chloride (for example pivaloyl chloride), and the like according to the conventional method. The activated esters of carboxylic acid of the general formula (VI) may be obtained by reacting a carboxylic acid of the general formula (VI) with N-hydroxy compound (for example N-hydroxysuccinimide, N-hydroxyphthalimide, 1- hydroxybenzotriazole); phenol compound (for example 4- nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol), or the like in the presence of a condensing agent (for example N, N'- dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3- ethylcarbodl-imide) according to the conventional method. The activated amides of carboxylic acid of the general formula (VI) may be obtained by reacting a carboxylic acid of the general formula (VI) with for example 1,1'- carbonyldiimidazole, 1,1'-carbonylbis(2-methylimidazole), or the like according to the conventional method. Reaction between a compound of the general formula (V) and a reactive derivative of the carboxylic acid of the general formula (VI) is usually carried out by employing 0.5 mole to excessive mole, preferably 1 mole to 1.5 moles of the reactive derivative of carboxylic acid (VI) based on 1 mole of compound (V). The reaction is usually carried out in an inert solvent, and preferable examples of the inert solvent include methylene chloride, chloroform, tetrahydrofuran, dlmethylformamide, pyridine or a mixture thereof, and the like. The aforesaid reaction proceeds in the absence of bases, but it is preferable to carry out the reaction in the presence of bases to promote the reaction smoothly. The aforesaid bases include organic bases (for example triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganic bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate), and the like. It is preferable to employ 1 mole to excessive mole of the aforesaid base to 1 mole of a compound of the general formula (V). When the aforesaid base is liquid, the aforesaid base can also be used as a solvent. Reaction temperature is usually-50 oC to 100 oC, preferably-20oC to 50oC. Reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours. A compound of the general formula (I-2) can be produced by treating a reaction mixture in the usual way after deprotection if the product has a protecting group at the conclusion of the reaction, or by treating the mixture directly in the usual way if the protective group is absent. Elimination of the protecting groups and post- treatment, and the like can be carried out according to the method described in the aforesaid production process 1. Compounds of the general formula (I-1) or (I-2) may readily be isolated and purified by the conventional separation technique, for example, solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography, or/and the like. These compounds may be converted into the pharmaceutically acceptable salts or esters by the conventional method, on the contrary, the conversion of the salts or esters into free compounds may also be carried out according to the conventional method. Compounds of the general formula (II), (III), (V) or (VI) are commercially available, or are prepared according to the methods described in the literature [Japanese Patent Unexamined Publication No.94/263737-A, U.S. Patent No.3301857, J. Org. Chem, 40: 1427 (1975), International Patent Publication WO95/28389 or the like], or analogous methods thereto or the methods shown below or in Examples, optionally in combination. Production Process A wherein L1 represents halogen; Arlp and Ar3 have the same meanings as given above; This process refers to a process for producing a compound of the general formula (II). Compound (II) is prepared by reacting a compound of the general formula (V) with a compound of the general formula 1 according to this process. The reaction between a compound (V) and a compound 1 is usually carried out by employing 0.5 mole to excessive mole, preferably an equivalent to 1.5 moles of compound 1 based on 1 mole of compound (V). The reaction is usually carried out in an inert solvent, and the preferable examples of the inert solvent include methylene chloride, chloroform, tetrahydrofuran, ethyl ether, benzene, toluene, dimethylformamlde or a mixture thereof, and the like. It is preferable to carry out the reaction in the presence of bases. The aforesaid bases include organic bases (for example triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganic bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate), and the like. It is preferable to employ an equivalent to excessive mole of the aforesaid base to 1 mole of a compound (V). When the aforesaid base is liquid, the aforesaid base can be used also as a solvent. Reaction temperature is usually-78 oC to 100 oC, preferably-20oC to 50oC. Reaction time is usually 5 minutes to 7 days. preferably 30 minutes to 24 hours. Compounds of formula 1 are commercially available, or are prepared according to the conventional method, the methods described in Examples, or the like methods, optionally in combination. Production Process B wherein P1 represents an amino protecting group; R10 represents hydrogen, nitro, lower alkyl or lower alkoxy; L1, t, u, v and w have the same meanings as given above. This process refers to a process for producing compounds of the general formula (III-l). Compound (III- 1) may so be prepared by the present process that a compound of the general formula 2 is subjected to dehydrogenated condensation with a compound of the general formula 2. to give a compound of the general formula A, which is subjected to reaction with a compound of the general formula 5. in the presence of a base to yield a compound of the general formula 6 and then the compound £ is cyclized by an intra-molecular Heck reaction to give a compound of the general formula 7, and then the compound 1 is subjected to reduction, optionally followed by elimination of amino protecting group P1. Amino protecting group P1 includes the amino protecting groups described in the aforesaid production process 1. A step for preparing compound A by dehydrogenated condensation of compound 2 with compound 2. is usually carried out in an inert solvent, for example benzene, toluene, or the like. Reaction temperature is preferably from room temperature to the boiling point of a solvent used and reaction time is preferably from 30 minutes to 24 hours. A step for preparing compound 6 from compound A is usually carried out in an inert solvent (for example benzene, toluene, methylene chloride, chloroform, acetonitrile, dimethylformamide) in the presence of base (for example triethylamine, diisopropylethylamlne, pyridine, 4- dimethylaminopyridine). Reaction temperature is preferably from 0oC to the boiling point of a solvent used and reaction time is preferably from 30 minutes to 24 hours. So-called intramolecular Heck reaction well known in the field of organic chemistry can be applied to the step for preparing compound 2 from compound 6. The aforesaid step is usually carried out in an inert solvent (for example benzene, toluene, tetrahydrofuran, acetonitrile, dimethylformamide, N-methylpyrrolidone) in the presence of palladium catalyst (for example palladium acetate, palladium chloride), phosphine ligand (for example triphenylphosphine, tri-2-furylphosphine) and base (for example potassium carbonate, triethylamine), optionally additives (for example tetraethylammonium chloride). Reaction temperature is preferably from room temperature to the boiling point of a solvent used in reaction and reaction time is preferably from 30 minutes to 24 hours. As a method for reduction in the step for preparing compound (III-l) from compound 2, for example catalytic reduction is preferable. The catalytic reduction is usually carried out in an inert solvent (for example methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, acetic acid) in the presence of a catalyst such as palladium-carbon at 1 to 50 atmospheric pressure of hydrogen. Reaction temperature is preferably from room temperature to the boiling point of a solvent used and reaction time is preferably from 30 minutes to 24 hours. At the conclusion of the reaction, if a reaction product has a protecting group, compound (III-l) can be prepared by elimination of the protecting group. Elimination of a protecting group can be carried out according to the method described in the aforesaid production process 1. This step may also be carried out by elimination of the protecting group of compound 1, followed by reduction of the resulting compound. Compounds of the general formula 2, 2. or 5. are commercially available, or may be prepared according to the conventional method, the methods shown in Examples, or the like methods, optionally in combination. Production Process C wherein L2 represents hydrogen or halogen; Ph represents phenyl; Y1 represents oxygen or imino substituted with lower alkyl or aryl; t, u, v and w have the same meanings as given above. This production process refers to the process for preparing compound of the general formula (VI-1). The compound represented by the general formula of (VI-1) is novel compound, which is not disclosed in the literature. The compound can be produced according to the present production process, that is, a compound of the general formula 8 is subjected to lithiation, reaction with compound 9 and lactonization with an acid, followed by deketalation to yield a compound of the general formula 10; and 1) methylene group is introduced to the compound 1H, which is followed by hydroboration to give a compound of the general formula H, and the compound is subjected to oxidation reaction, or 2) the compound 10. is reduced to give a compound of the general formula 12.. which is subjected to introduction of a leaving group and then cyanization to give a compound of the general formula 13, followed by hydrolysis of the compound 13 at the cyano group. Lithiation in the step preparing compound 10 from compound 8 is usually carried out by allowing compound 8 to be acted on by an organic lithium reagent (for example n-butyllithium, lithium 2,2,6,6-tetramethyl-piperidide) in an inert solvent (for example tetrahydrofuran, diethyl ether). Reaction temperature is usually from-120oC to 0oC, preferably from-100 oC to-50 oC and reaction time is preferably from 1 hour to 4 hours. Reaction between the resulting lithio type and a ketone of the general formula £ is usually carried out in an inert solvent (for example tetrahydrofuran, dlethyl ether). Reaction temperature is preferably from-100oC to room temperature and reaction time is preferably from 10 minutes to 2 hours. The resulting compound can be lactonized by treating with an acid (for example hydrochloric acid, sulfuric acid). Reaction temperature is preferably from 0oC to the boiling point of a solvent used and reaction time is preferably from 30 minutes to 8 hours. Compound 10. can be prepared by subjecting the resulting lactone type to deketalatlon according to the conventional method. Reaction temperature is preferably from 50oC to the boiling point of a solvent used and reaction time is preferably from 1 hour to 24 hours. The method used for converting oxo group to hydroxymethyl group, which is well known in the field of organic chemistry, can be applied to the step for preparing compound 11 from compound 10 and the step is usually carried out by reacting compound 10 with for example methylenetrlphenylphosphorane to Introduce a methylene group, followed by hydroboration in an inert solvent (for example benzene, toluene, methylene chloride, chloroform. acetonitrile, tetrahydrofuran, dimethylformamide). In both steps for Introducing methylene group and for hydroboration, reaction temperature Is preferably from 0oC to the boiling point of a solvent used and reaction time is preferably from 30 minutes to 8 hours. The method used for oxidizing hydroxymethyl group to carboxyl group, which is well known in the field of organic chemistry, can be applied to the step for preparing compound (VI-1) from compound 11 and the step is usually carried out by using an oxidizing agent such as sodium periodate and a catalytic amount of ruthenium chloride, in an inert solvent (for example benzene, toluene, methylene chloride, chloroform, acetonitrile, dimethylformamide). Reaction temperature is preferably from OoC to the boiling point of a solvent used and reaction time is preferably from 30 minutes to 8 hours. The method used for reducing oxo group to hydroxyl group, which is well known in the field of organic chemistry, can be applied to the step for preparing compound 12. from compound 10 and the step is usually carried out by using a reducing agent (for example sodium borohydride, lithium borohydride), in an inert solvent (for example water, methanol, ethanol, tetrahydrofuran or a mixture thereof). Reaction temperature is preferably from-20oC to 50oC and reaction time is preferably from 10 minutes to 4 hours. The method used for converting hydroxy group to cyano group, which is well known in the field of organic chemistry, can be applied to the step for preparing compound 13 from compound 12 and the step is usually carried out by reacting compound 12 with for example methanesulfonyl chloride, p-toluenesulfonyl chloride, or the like to convert hydroxy group to a leaving group in the presence of base (for example triethylamine, pyridine), followed by reacting the resulting compound with a cyanide (for example sodium cyanide, potassium cyanide, tetraethylammonium cyanide, tetrabutylammonium cyanide). The step for converting hydroxy group to a leaving group is usually carried out in an inert solvent (for example methylene chloride, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide). Reaction temperature is preferably from-20oC to room temperature and reaction time is preferably from 10 minutes to 8 hours. The step for reacting with a cyanide is usually carried out in an inert solvent (for example tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide). Reaction temperature is preferably from 50oC to 120oC and reaction time is preferably from 2 to 24 hours. Hydrolysis of cyano group, which is well known in the field of organic chemistry, can be applied to the step for preparing compound (VI-1) by hydrolysis of the cyano group of compound 13. and the step is usually carried out by using an acid (for example hydrochloric acid, sulfuric acid) or a base (for example sodium hydroxide, potassium hydroxide, calcium hydroxide), in a solvent (for example methanol, ethanol, tetrahydrofuran, dioxane, water or a mixture thereof). Reaction temperature is preferably from 50oC to the boiling point of a solvent used and reaction time is preferably from 1 to 48 hours. Compounds of the general formula (VI-1) have two kinds of stereolsomers represented by the general formula (VI- 1-a) or (VI-1-b): wherein t, u, v and w have the same meanings as given above. These stereoisomers can be separated from the mixture by the conventional method such as chromatography, fractional recrystallization, and the like. Compounds of the general formula (VI-1-a) or (VI- 1-b) can be prepared by using an intermediate product which is obtained by separation of the stereoisomers of the general compound 11. 12. or 13.. Compounds of the general formula & or 3. are commercially available, or are prepared according to the conventional method, the methods described in Examples, or the like methods, optionally in combination. The utility of compounds of the present invention as a medicament is proved by describing NPY antagonistic activity, for example, in the following pharmacological tests. Pharmacological Test 1 (NPY binding inhibition test) cDNA sequence encoding human NPY Y5 receptor [International patent publication number WO96/16542] was cloned into expression vectors pcDNA3, pRc/RSV (made by Invitrogen Inc.) and pCI-neo (made by Promega Inc.). This obtained expression vectors were transfected to host cells COS-7, CHO and LM(tk-) (American Type Culture Collection) by cationic lipid method [Proceedings of the National Academy of Sciences of the United States of America, 84: 7413(1987)] to give NPY Y5 receptor expression cells. A membrane sample prepared from the cells which expressed NPY Y5 receptor was incubated together with a test compound and [125I]peptideYY (NEN) (20,000cpm) in an assay buffer (25mMTris buffer, pH7.4, containing lOmM magnesium chloride, lmM phenylmethylsulfonyl fluoride, 0.1% bacitracin and 0. 5% bovine serum albumin) at 25oC for 2 hours, then filtered through a glass filter GF/C and washed with 5mM Tris buffer (pH7.4) containing 0.3% BSA. The radioactivity of the cake on the glass filter was measured. Nonspecific binding was measured in the presence of 1MM peptldeYY and a 50% Inhibitory Concentration (IC50) of the test compound against specific peptideYY binding was determined [Endocrinology, 131: 2090(1992)]. The results are summarized in Table 1. [Table 1] Inhibitory activities on NPY receptor binding As shown above, compounds of this invention potently inhibited peptideYY (NPY homologue) binding to NPY Y5 receptors. Pharmacological Test 2 (Antagonistic effect on bPP-lnduced feeding behavior) A guide cannula (external diameter 0.8mm, internal diameter 0. 5mm, length 10mm) was inserted stereotaxicly into the right lateral ventricle of male SD rats (7-8 weeks old, 200-300g) anesthetized with pentobarbital (single intraperitoneal administration of 50mg/kg) and fixed by dental resin. The top of the cannula was located 0.9mm behind bregma, 1.2mm to the right of median line and 1.5mm depth from the brain surface so that, when injection needle is inserted into the guide cannula, the needle extends 2 mm beyond the tip of the guide cannula and reaches the lateral ventricle. After about 1-week recovery period, bovine pancreatic polypeptide (bPP, 5 m g/10mL/head, 0.01M, pH7.4 phosphate buffered saline solution containing 0.05% bovine serum albumin) was injected into the lateral ventricle. A test compound suspended in aqueous 0.5% methylcellulose was administered orally 2 hours before the administration of bPP and the food consumption was measured 2 hours after administration of bPP. Compounds of this invention significantly inhibited the increase in food consumption induced by bPP (NPY homologue) which was administered to the lateral ventricle. Compounds of the general formula (I) can be administered orally or parenterally and may be formulated in the form suitable for administration to provide an agent for treatment of various diseases related to NPY, which include, for example, cardiovascular disorders (for example hypertension, nephropathy, heart disease, vasospasm, arteriosclerosis), central nervous system disorders (for example bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal), metabolic diseases (for example obesity, diabetes, hormone abnormality, hypercholesterolemia, hyperlipidemia), sexual and reproductive dysfunction, gastro-intestinal motility disorder, respiratory disorder, inflammation or glaucoma and the like, preferably, bulimia, obesity, diabetes and the like. In clinical use, compounds of this Invention can be administered after being formulated, together with pharmaceutically acceptable additives, into an appropriate preparation according to the mode of administration. For said additives, those which are usually used in the field of pharmaceutical formulation may be used, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium methasillcate alumlnate. anhydrous calcium phosphate, citric acid, sodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin or hydroxypropyl cyclodextrin. A mixture with said additives may be formulated in the form of solid preparations (for example tablets, capsules, granules, powder, suppositories); or liquid preparations (for example syrups, elixirs, injections). Such preparations may be formulated according to techniques well-known in the art of pharmaceutical formulation. Liquid preparations may be in the form of preparations which are dissolved or suspended in water or other appropriate media when used and especially injectable preparations may be dissolved or suspended in physiological saline or glucose solution if necessary, optionally together with a buffer and preservative. Such preparations may contain 0.1 to 100 wt. %, preferably 1.0 to 60 wt. % of compounds of this invention and may also contain therapeutically effective other compounds. The compounds of the present invention can be used in combination with other agents useful for treating metabolic and/or feeding disorders. The Individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The Instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating metabolic and/or feeding disorders includes in principle any combination with any pharmaceutical composition useful for treating metabolic and/or feeding disorders. When compounds of this invention are used clinically, the dose and frequency of dosage may be varied depending upon the sex, age, body weight, the degree of symptoms and the kind and range of the desired treatment effects. A daily dose for an adult is 0.01-100mg/kg, preferably 0.03-3mg/kg orally, or 0.001-10mg/kg, preferably 0.001-0.lmg/kg parenterally, preferably in a single dose or in divided doses. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Best Mode for Carrying Out the Invention The following examples are provided so that the present invention may be more concretely illustrated but they should not be construed as limiting the invention in any way. Unless otherwise noted, melting point was measured by MP-S3 Model (manufactured by Yanagimoto Selsakusho) and disclosed in this specification without correction. Example 1 Preparation of N-(4-benzoylphenyl)-3- oxospiro[isoindoline-1.4'-piperldine1-1'-carboxamlde (1) Preparation of N-benzyl-N-(1-tert-butoxycarbonyl- 1,2,3,6-tetrahydropyridln-4-yl)-2-iodobenzamide A mixture of N-tert-butoxycarbonyl-4-piperldone (1.llg) and benzylamlne (597mg) dissolved in toluene (20mL) was stirred at 100oC for 3 hours and then concentrated. Toluene (30mL), o-iodobenzoyl chloride (1.13g) and triethylamine (0.70g) were added to the residue and the mixture was stirred at 80oC for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) to give the subject compound (2.44g). (2) Preparation of 2-benzyl-l'-tert-butoxycarbonyl- 1',6'-dihydro-spiro[lH-isoindole-1,4'(5'H)-pyridine]- 3(2H)-one To N-benzyl-N-(1-tert-butoxycarbonyl-l,2,3,6- tetrahydropyridln-4-yl)-2-iodobenzamide (2.4g) dissolved in acetonltrile, palladium acetate (80mg), triphenylphosphine (187mg), anhydrous K2CO3 (987mg) and tetraethylammonium chloride (591mg) were added and stirred at 80oC for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) to give the subject compound (1.64g). (3) Preparation of 2-benzyl-l'-tert- butoxycarbonylspiro[lH-isoindole-1,4'-piperidine]-3(2H)- one To a solution of 2-benzyl-l'-tert-butoxycarbonyl- 1', 6'-dihydrospiro[lH-isoindole-1,4'(5'H)-pyridine]- 3(2H)-one (l.Og) in chloroform (20mL), trifluoroacetic acid (20mL) was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated. The residue was dissolved in methanol and hydrogenated with 4M hydrogen chloride/ethyl acetate in the presence of 20% palladium carbon at 1 atm of hydrogen for 14 hours. The catalyst was removed by filtration and the filtrate was concentrated. To the residue, aqueous IN sodium hydroxide (5mL), di-tert- butyl dicarbonate (655mg) and dioxane (10mL) were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) to give the subject compound (200mg). (4) Preparation of spiro[lH-isoindole-1,4'-piperidine]- 3(2H)-one hydrochloride 2-Benzyl-l'-tert-butoxycarbonylsplro[1H- lsoindole-1,4'-piperidine]-3(2H)-one (200mg) was added to metallic sodium (235mg) in liquid ammonia (lOmL) and the mixture was stirred for 30 minutes. To the reaction mixture was added methanol, neutralized with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue dissolved in methanol was stirred together with 4M hydrogen chloride/ethyl acetate at SO'C for 1 hour. The reaction solution was concentrated to give the subject compound (591mg). XH-NMR (300MHz, DMSO-d6, 6ppm): 1.70-1.90 (2H, m), 2.00-2.20 (2H,m), 3.00-3.20 (2H,m), 4.20-4.40 (2H, m), 7.40 (1H, d, J=7.5Hz), 7.51 (1H, t, J = 7.5Hz), 7.59 (1H, t, J=7.5Hz). 7.84 (1H, d, J=7.5Hz). (5) Preparation of phenyl N-(4-benzoylphenyl)carbamate To 4-aminobenzophenone (1.97g) dissolved in pyridine (50mL), phenyl chlorocarbonate (1.38g) was added at 0oC and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) to give the subject compound (3.1g). (6) Preparation of N-(4-benzoylphenyl)-3- oxospiro[lsoindoline-l,4'-piperidine]-1'-carboxamide A mixture of spiro[lH-isoindole-1,4'-piperidine]- 3(2H)-one hydrochloride (48mg), triethylamlne (0.14mL) and phenyl N-(4-benzoylphenyl)carbamate (58mg) was stirred in chloroform at 80oC for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) and crystallized from ethyl ether-hexane to give the subject compound (49mg) as colorless crystals (melting point 2530). Compounds of Example 2 and 3 were obtained in the similar manner as Example l-(6) by replacing phenyl N- (4-benzoylphenyl)carbamate used in Example l-(6) by the corresponding materials, respectively. Example 2 3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1.4'- piperldine]-1'-carboxamlde melting point 286-287oC Example 3 N-(7-methyl-2-quinolyl)- 3-oxospiro [isoindoline-1.4'- piperidine1-1'-carboxamlde melting point 194-196oC Example 4 Preparation of N-(4-benzoylphenyl)-2-methyl-3- oxosplro FIsoindoline-1.4'-piperidine1-1'-carboxamlde The subject compound was obtained in the similar manner as Example l-(6) by replacing spiro[lH-isolndole- 1,4'-piperidine]-3(2H)-one hydrochloride by 2- methylspiro[lH-isoindole-1,4'-piperidine]-3(2H)-one hydrochloride. melting point 154-156oC Example 5 Preparation of N-(4-benzoylphanyl)-3.4-dihydro-3- oxospiro [iso-qui noline-1(2H). 4'-piperidinel-1'- carboxamide Spiro[lsoqulnollne-1(2H),4'-piperidine]-3(4H)-one hydrochloride (30mg) and phenyl N-(4- benzoylphenyl)carbamate (3 7mg) were dissolved in dimethyl sulfoxide (2mL) and stirred together with aqueous ION sodium hydroxide (12 mL) at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (20mL). The organic layer was washed with water (20mL) and saturated saline solution (20mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) and recrystallized from chloroform-acetone (1:3) to give the subject compound (81mg) as colorless crystals (melting point 241-243oC). Compounds of Example 6 to 21 were obtained in the similar manner as Example l-(6) or Example 5 by using splro[isoquinoline-l(2H),4'-piperidine]-3(4H)-one hydrochloride and phenyl carbamate derivatives corresponding to the desired compounds. Example 6 3,4-Dlhydro-3-oxo-N-(5-phenyl-2- pyrazlnyl)spiro [Isoquinoline-1(2H).4'-piperidine1-1'- carboxamide melting point 237-239oC Example 7 3.4-Dihydro-N-(7-methyl-2-quinoly1)-3- oxospiro[isoqulnoline-1(2H).4'-piperidinel-1'- carboxamide melting point 216-218oC Example 8 N-(4-acetylphenyl)-3.4-dlhydro-3-oxosplroFlsoquinoline- 1(2H).4'-piperidine1-1'-carboxamlde melting point>300oC Example 9 3.4-Dihydro-3-oxo-N-[1-(2-quinolyl)-4- imidazolyllspiro[lsoquinoline-1(2H).4'-piperidinel-1'- carboxainlde melting point 264-266^ Example 10 3.4-Dihydro-3-oxo-N-(5-oxo-5.6.7.8-tetrahydro-2- naphthyl)spiro [isoquinoline-1(2H).4'-piperidinel-1'- carboxainlde melting point 220.5-222. 2°C Example 11 3.4-Dlhydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3- oxospiro[isoquinoline-1(2H).4'-piperidine]-1'- carboxamide melting point 232.9-236.5oC Example 12 3.4-Dihydro-3-oxo-N-(3-phenyl-5- isoxazolyl)spiro [isoquinoline-l(2H). 4'-piperidine1-1'- carboxamide melting point 239-24loC Example 13 N-[1-(7-benzo[blfurany])-4-imidazoly]1-3.4-dihydro-3- oxosplro[isoqulnollne-l(2H).4'-piperidinel-1'- carboxamide melting point 192-194oC Example 14 N-F1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3.4- dihydro-3-oxospiro[isoqulnoline-1(2H).4'-piperidinel-1'- carboxamide melting point 161-163oC Example 15 3,4-Dihydro-3-oxo-N-[4-(2- pyridylcarbonyl)phenyl]spiro [lsoqulnoline-1(2H).4'- piperidinel-1'-carboxamide melting point 162-164oC Example 16 N-(3.4-dichlorophenyl)-3,4-dlhydro-3- oxospiro[isoqulnoline-1(2H).4'-piperidinel-1'- carboxamide melting point>300oC Example 17 N-[1-(3-chlorophenyl)-4-imidazolyl]-3.4-dihydro-3- oxospiro [isoquinoline-1 (2H), 4'-piperidine]-1'- carboxamide melting point 255-258oC Example 18 3,4-Dihydro-3-oxo-N-(5-phenyl-2- thiazolyl)spiro [isoquinoline-1(2H).4'-piperidine]-1' carboxamide melting point>300 Example 19 3.4-Dihydro-3-oxo-N-[5-(2-pyridyl)-2- pyrazinyl1spiro [isoquinoline-1(2H).4'-piperidine1-1' carboxamide melting point 223-225oC Example 20 3.4-Dihydro-N-(4-methyl-2-benzothlazolyl)- 3- oxospiro[isoqulnoline-1(2H).4'-piperidine1-1'- carboxamide melting point 144-146oC Example 21 N-(5-chloro-2-benzoxazolyl)-3.4-Dihydro-3- oxospiro [isoquinoline-1(2H), 4'-piperidinel-1'- carboxamide melting point 256-258oC Example 22 Preparation of N-(4-benzoylphenyl)-3- oxospiro [isobenzofuran-1 ( 3H), 4'-piperidine]-1'- carboxamide A mixture of spiro[isobenzofuran-1(3H),4'- piperidine]-3-one hydrochloride (48mg), phenyl N-(4- benzoylphenyl)carbamate (58mg) and triethylamine (0.14mL) in chloroform (5mL) was stirred at 80oC for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20mL). The organic layer was washed with saturated saline solution (20mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) and recrystalllzed from ethyl ether-hexane to give the subject compound (81mg) as colorless crystals (melting point 161-163oC). Example 23 Preparation of 3-oxo-N-(5-phenyl-2-pyrazlnyl)- spiro[isobenzofuran-1(3H).4'-piperidinel-1'-carboxamide (l)Preparation of phenyl N-(5-phenyl-2- pyrazlnyl)carbamate Phenyl chlorocarbonate (15.05 mL) was added at ooC to a solution of 2-amino-5-phenylpyrazine (17.12 g) in pyridine (200 mL). The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water (200 mL) and ethyl ether (200 mL). The whole was stirred to provide a suspension containing the subject compound as a crystal. The crystal was collected by filtration and further washed with ethyl ether (50 mL) and then dried under reduced pressure to provide the subject compound (24.57 g) as colorless crystals (melting point 192-198oC, decomposed ). (2preparation of 3-oxo-N-(5-phenyl-2-pyrazinyl)- spiro[isobenzofuran-l(3H),4'-piperidine]-1'-carboxamide (Crystal Form A) A mixture of spiro[isobenzofuran-l(3H),4'- piperidine]-3-one hydrochloride (6.24 g, 26.6 mmol), phenyl N-(5-phenyl-2-pyrazinyl)carbamate(7.59 g, 26.0 mmol) and triethylamine (18 mL, 180 mmol) in chloroform (200 mL) was stirred at SO'C for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (100 mL). After the organic layer was washed with 10% citric acid aqueous solution (100 mL), IN aqueous sodium hydroxide (100 mL) and then saturated saline solution (100 mL), the organic layer was dried over anhydrous Na2SO4 and then concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=l/2) to provide the subject compound as a colorless solid. The solid was washed with diethyl ether (30 mL) to provide the subject compound (8.23g) as a crude crystal. The crystal was dissolved in hot ethyl acetate (300 mL). After removal of about 100 mL of ethyl acetate by distillation, the white suspension began to occur. At this point the distillation was stopped and the whole was cooled and then kept at room temperature for 14 hours. The colorless prisms formed was collected by filtration, which was washed with heptane (20 mL). The obtained crystal was dried at 50oC in vacuo for 6 hours to provide the subject compound (Crystal Form A) (5.17 g) as colorless prisms (melting point 210-211oC). Powder X-ray diffraction Above powder X-ray diffraction analysis data were measured by RINT1100 (manufactured by Rigaku International Corporation) and analysis methods were as follows: X-ray radiation source : Cu, tube voltage : 40kV, tube current : 30mA, monochromater : automatic monochromater, monoreceiving slit : 0.60 mm, goniometer : Wide angle goniometer, scan step : 0.02 deg., scan speed : 2.00 deg./mln., divergence sllt(DS) : 1 deg., scattering slit : 1 deg., receiving slit (RS) : 0.15 mm, measured temperature : ambient temperature. (3) Preparation of 3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide (Crystal Form A)-an alternative method for preparation- Crude crystals (2 g) prepared by the above procedure (2) was dissolved under heating into tetrahydrofuran (20 mL). After confirming complete dissolution, the mixture was cooled to the room temperature by standing it at room temperature. Heptane (27 mL) was dropwise added to the tetrahydrofuran solution, followed by stirring at room temperature for 15 hours. The yielded colorless crystals were collected by filtration, washed with heptane (5 mL) and dried in vacuum at 30oC for 15 hours to obtain the above-Identified compound in crystal form A (1.82 g). (4) Preparation of 3-oxo-N-(5-phenyl-2- pyrazlnyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide (Crystal Form B) Crude crystals (2 g) prepared by the above procedure (2) was dissolved under heating into dimethylformamide (6 mL). After confirming complete dissolution, water (13 mL) was dropwise added at 80oC and the resultant mixture was cooled to room temperature, followed by stirring for 15 hours. The yielded colorless crystals were collected by filtration at room temperature, washed with heptane (5 mL) and dried in vacuum for 15 hours at room temperature to obtain 1.78 g of the above-identified compound in the crystal form B as colorless prisms (melting point; 208oC measured without correction by the use of Melting Point B-545 distributed by Buchi Company). Powder X-ray diffraction Above powder X-ray diffraction analysis data were measured by the same conditions as Example 23(2). (5) Preparation of 3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[lsobenzofuran-1(3H),4'-piperidine]-1'- carboxamide (Crystal Form C) Crude crystals (2 g) prepared by the above procedure (2) was dissolved under heating into tetrahydrof uran (20 mL). After confirming complete dissolution, the solution was cooled to-30oC. Heptane (30 mL) was dropwise added to the tetrahydrofuran solution, followed by stirring at-30oC for one hour. The yielded colorless crystals were collected by filtration, washed with heptane (5 mL) and dried in vacuum at room temperature for 15 hours to obtain 1.90 g of the above-identified product (monotetrahydrofuran solvate, the crystal form C) as colorless fine granules. Powder X-ray diffraction Above powder X-ray diffraction analysis data were measured by the same conditions as Example 23(2). (6) Preparation of 3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide (Crystal Form D) Spiro[isobenzofuran-1(3H),4'-piperidine]-3-one hydrochloride (515 mg) and phenyl N-(5-phenyl-2- pyrazlnyl)carbamate (583 mg) were dissolved into dimethyl sulfoxide (2.6 mL), followed by dropwise addition of dimethylbenzylamine (0.33 mL). The temperature of the resultant mixture was raised up to 50 °C, and the mixture was stirred for one hour. The reaction mixture was cooled to room temperature, and acetonltrlle/water (1:2) mixture solution (7.8 mL) was dropwise added. At the time when 0.2 mL of the mixture solution was added, seed crystal was added. The resultant mixture was stirred at room temperature for 6 hours. The yielded colorless crystals were collected by filtration, washed with acetonitrlle/water (1:1) and dried in vacuum at room temperature for 15 hours to obtain the above-identified compound (793 mg) as crude colorless crystals. Crude crystals (26 g) prepared by the repetition of the above procedure were suspended in water-saturated lsopropyl acetate (143 mL). The mixture was seeded with seed crystal and stirred at room temperature for 18 hours. The yielded crystals were collected by filtration, washed with isopropyl acetate (20 mL) and dried in vacuum at 30°C for 15 hours to obtain the above-identified compound in the crystal form D (25.2 g) as colorless crystals (melting point ; 206oC measured without correction by the use of Melting Point B-545 distributed by Buchi Company). Powder X-ray diffraction Above powder X-ray diffraction analysis data were measured by the same conditions as Example 23(2). (7) Preparation of 3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[lsobenzofuran-l(3H),4'-piperidine]-1'- carboxamide (Crystal Form B)-an alternative method for preparation- Crude crystals (26g) prepared by the above procedure (6) was suspended in acetonitrile (260 mL). The mixture was seeded with the seed crystal prepared by the above procedure (4) and stirred at room temperature for 24 hours. The yielded crystals were collected by filtration, washed with acetonitrile (50 mL) and dried in vacuum at 30oC for 15 hours to obtain the above-identified product in the crystal form B (25.5 g). Compounds of Example 24 to 39 were obtained in the similar manner as Example 22 by replacing phenyl N-(4- benzoylphenyl)carbamate used in Example 2 2 by the corresponding materials, respectively. Example 24 N-(7-methyl-2-quinolyl)-3-oxospiro\isobenzofuran-1(3H), 4'-piperidine1-1'-carboxamide melting point 178-180 Example 25 3-Oxo-N-(3-phenyl-5-isoxazolyl)-spiro Flsobenzofuran- K3H). 4'-piperidinel-1'-carboxamide melting point 239-242^ Example 26 3-Oxo-N-(7-trifluoromethylpyrido[3.2-b]pyridin-2-yl)- spiro[isobenzofuran-1(3H).4'-piperidine1-1'-carboxamide melting point 246-248oC Example 27 3-Oxo-N-(5-Phenyl-2-Pyrimidinyl)-spirorisobenzofuran- 1(3H).4'-piperidinel-1'-carboxamide melting point 211-214oC Example 28 3-Oxo-N-[1-(3-quinolyl)-4- imidazolyl] spiro[isobenzofuran-1(3H).4'-piperidine1-1'- carboxamide melting point 251-254oC Example 2 9 3-Oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran- 1(3H)- 4'-piperidine1-1'-carboxamide melting point 160-165 Example 30 N- [5-(4-chlorophenyl)-3-pyrazolyl]-3- oxospiro [isobenzofuran-1(3H),4'-piperidinel-l'- carboxamide melting point 255-258oC Example 31 3-qxo-N-[5-(3-quinolyl)-3-pyrazolylispiro [isobenzofuran 1(3H), 4'-piperidine1-1'-carboxamide melting point 253-257oC Example 32 N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3- oxospiro [isobenzofuran-1(3H).4'-piperidine1-1'- carboxamide melting point 122-125oC Powder X-ray diffraction Above powder X-ray diffraction analysis data were measured by RINT2100 Ultima+ System(2 KW) (manufactured by Rigaku International Corporation) and analysis methods were as follows: X-ray radiation source : Cu, tube voltage : 40kV, tube current : 30mA, monochromater : automatic monochromater, monoreceiving slit : 0.15 mm, goniometer : Horizontal goniometer I, scan step : 0.02 deg., scan speed : 2.00 deg./min., divergence sllt(DS) : 1 deg., scattering slit : 1 deg., receiving slit (RS) : 0.15 mm, measured temperature : ambient temperature. Example 33 3-Oxo-N-[5-(3-trifluoromethylphenyl)-2- pyrimidinyl) spiro [isobenzofuran- 1 ( 3H), 4'-piperidinel-1'- carboxamide melting point 190-192oC Example 34 N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3- oxospiro [isobenzofuran-1(3H).4'-piperidine1-1'- carboxamide melting point 126-128oC Example 35 N- ( 7-difluoromethoxypyrido [3, 2-b]pyridin-2-yl)-3- oxospiro [isobenzofuran-1 (3H).4'-piperidine1-1'- carboxamide melting point 1930 Example 36 3-Oxo-N-(5-phenyl-l,2,4-thiadlazol-3- yl)spiro[isobenzofuran-1(3H).4'-piperidine1-1'- carboxamide melting point 239-243X Example 37 N-{1-F 3-(2-hydroxyethyl)phenyl]-4-imidazolyl]-3- oxospiro fIsobenzofuran-1(3H).4'-piperidine1-1'- carboxamide melting point 99-100'C Example 38 N-[4-(l-ethyl-2-imidazolyl)phenyl]-3- oxospiro [isobenzofuran-1(3H).4'-piperidinel-1'- carboxamide melting point 221-223 Example 39 N-[1-(3-methoxyphenyl)-4-imidazolyl]-3- oxospiro [isobenzofuran-1(3H).4'-piperidine1-1'- carboxamide melting point 208-210oC Example 40 Preparation of 6-fluoro-3-oxo-N-(5-phanyl-2- pyrazinyl)spiro-[isobenzofuran-1(3H), 4'-piperidiNEL-1'- carboxamide A mixture of 6-fluorospiro[isobenzofuran-l(3H),4'- piperidine]-3-one hydrochloride (64mg), phenyl N-(5- phenyl-2-pyrazinyl)carbamate (73mg) and triethylamine (174 m L) in chloroform (5mL) was stirred at 80oC for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20mL). The organic layer was washed with saturated saline solution (20mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) and recrystallized from ethyl ether-hexane to give the subject compound (101mg) as colorless crystals (melting point 222-224oC). Example 41 Preparation of 6-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl)spiro[iso-benzofuran-l(3H).4'-Piperidinel- 1'-carboxamide The subject compound was obtained in the similar manner as Example 40 by replacing phenyl N-(5-phenyl-2- pyrazinyl)carbamate used in Example 40 by phenyl N-(5- phenyl-2-pyrimidinyl)carbamate. melting point 176-178oC Example 42 Preparation of 5-fluoro-3-oxo-N-(5-phenyl-2- carboxamide A mixture of 5-fluorospiro[isobenzofuran-1(3H),4'- piperidine]-3-one hydrochloride (64mg), phenyl N-(5- phenyl-2-pyrazlnyl)carbamate (73mg) and triethylamlne (174 Uh) in chloroform (5mL) was stirred at 80"C for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20mL). The organic layer was washed with saturated saline solution (20mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) and recrystallized from ethyl ether-hexane to give the subject compound (100mg) as colorless crystals (melting point 236-238T;). Example 43 preparation of 5-fluorp-3-oxo-N-(5-phenyl-2- pyrimidinyl)spirof iso-benzofuran-1(3H)4'-piperidinel- 1'-carboxamide The subject compound was obtained in the similar manner as Example 42 by replacing phenyl N-(5-phenyl-2- pyrazinyUcarbamate used in Example 4 2 by phenyl N-(5- phenyl-2-pyrimidinyl)carbamate. melting point 255-257^ Example 44 preparation of N-(4-benzoylphenyl)-3,4-Dihydro-3- oxospiro[1H-2-benzopyran-1,4'-piperidinel-1'-carboxamide Spiro[lH-2-benzopyran-l,4'-piperidine]-3(4H)-one hydrochloride (50.6mg) and phenyl N-(4- benzoylphenyl)carbamate (63.4mg) were suspended In dimethyl sulfoxide (l.OmL) and the suspension was vigorously stirred together with aqueous 10M sodium hydroxide (30 ML) for 5 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over anhydrous Na2SO4 and concentrated. The residue was crystallized from methanol-diisopropyl ether to give the subject compound (68.0mg) as colorless crystals (melting point 138-146^). Compounds of Example 45 and 46 were obtained in the similar manner as Example 44 by replacing phenyl N-(4- benzoylphenyl)carbamate used in Example 44 by the corresponding materials, respectively. Example 4 5 3.4-Dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro [1H-2- benzopyran-1.4'-piperj dine 1-1'-carboxamide melting point 221CC Example 46 N-(5-benzoyl-2-pyrazinyl)-3.4-dihydro-3-oxospiro [1H- 2- benzopyran-1.4'-piperidine1-1'-carboxamide melting point 128-13loC Example 4 7 Preparation of trans-N-(4-benzoylphenyl)-3'- oxospiro[cyclohexane-1.1'(3'H)-lsobenzofuran]-4- carboxamide (1) Preparation of spiro[cyclohexane-l,1'(3'H)- isobenzofuran]-3',4-dione A solution of 2-bromobenzoic acid (4.77g) in anhydrous tetrahydrofuran (lOOmL) was cooled to-78oC under an atmosphere of nitrogen, to which n-butyllithium (1.53M solution inhexane, 31mL) was dropwise added while being kept the internal temperature below-55oC. After being stirred for 1 hour, a solution of 1, 4-cyclohexanedione monoethylene ketal (5.18g) in anhydrous tetrahydrofuran (10mL) was added dropwise to the mixture while being kept the internal temperature below-67oC. After the temperature was raised to room temperature, the reaction solution was partitioned between water (150mL) and hexane (100mL). The aqueous layer was acidified with concentrated hydrochloric acid and refluxed together with acetone (lOmL) for 2 hours. After cooling, thus obtained mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over anhydrous Na2SO4 and evaporated. The residue was crystallized from ethyl acetate-hexane to give the subject compound (2.42g). (2) Preparation of 4-methylenespiro[cyclohexane- 1,1'(3'H)-isobenzofuran]-3-one A suspension of methyltriphenylphosphonlum bromide (715mg) in anhydrous tetrahydrofuran (7.0mL) was cooled to 0oC under an atmosphere of nitrogen, to which n-butyllithium (1. 53M solution in hexane, 1. 3mL) was added, stirred at that temperature for 20 minutes and then cooled to-78oC. A solution of spiro[cyclohexane-l,1'(3'H)- isobenzofuran]-3',4-dione (216mg) in anhydrous tetrahydrofuran (3mL) was added to the reaction mixture and the temperature was raised to 0oC. After stirring for 20 minutes, aqueous ammonium chloride was added to thus obtained mixture and the resulting crude product was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l) to give the subject compound (196mg). (3) Preparation of 4-hydroxymethylspiro[cyclohexane- 1,1'(3'H)-Isobenzofuran]-3'-one A solution of 4-methylenespiro[cyclohexane- 1,1'(3'H)-Isobenzofuran]-3-one (196mg) in anhydrous tetrahydrofuran (5.0mL) was cooled to 0oC, to which borane-dimethyl sulfide complex (2M tetrahydrofuran solution, 690 ML) was added and the mixture was stirred at that temperature for 1.5 hours, then additional 20 minutes together with aqueous 2M sodium hydroxide (5.0mL) and aqueous 30% hydroperoxlde (5.0mL). The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated saline solution, then dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/l) to give the subject compound (190mg) as dlastereomers. (4) Preparation of trans-3'-oxospiro[cyclohexane- 1,1'(3'H)-Isobenzofuran]-4-carboxylic acid A mixture of 4-hydroxymethylspiro[cyclohexane- 1,1'(3'H)-isobenzofuran]-3'-one (190mg), chloroform (2.0mL), acetonitrile (2.0mL) and sodium phosphate buffer (pH6.5, 2.0mL) was cooled to 0oC, to which sodium periodate (612mg) and ruthenium(III) chloride n-hydrate (10mg) were added and the mixture was stirred for 30 minutes. The reaction mixture was stirred together with 1N hydrochloric acid (2.0mL) for 30 minutes and partitioned between water (50mL) and ethyl acetate (50mL). The organic layer was washed with saturated saline solution, dried over anhydrous Na2SO4 and then concentrated. The residue was purified by column chromatography on silica gel (chloroform/methanol=100/l) to give the subject compound (98.6mg). (5) Preparation of trans-N-(4-benzoylphenyl)-3'- oxospiro[cyclohexane-l,1'(3'H)-isobenzofuran]-4- carboxamide To a solution of trans-3'-oxospirofcyclohexane- 1,1'(3'H)-isobenzofuran]-4-carboxyllc acid (24.6mg) in pyridine (500 ML), 4-amlnobenzophenone (19.8mg) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5mg) were added and the mixture was stirred at 50 "C for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with aqueous potassium hydrogen sulfate, aqueous sodium hydrogen carbonate, and saturated saline solution and then dried over anhydrous Na2SO4 and evaporated. The residue was crystallized from ethyl acetate-hexane to give the subject compound (31.2mg) as colorless crystals (melting point 194oC). Compounds of Example 48 to 56 were obtained in the similar manner as Example 47-(5) by replacing 4- aminobenzophenone used in Example 47-(5) by the corresponding materials, respectively. Example 48 Trans-3'-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane- 1.1'(3'H)-isobenzofuran]-4-carboxamide melting point 223oC Example 49 Trans-3'-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane- 1.1'(3'H)-isobenzofuran1-4-carboxamide melting point 264oC Example 50 Trans-3'-oxo-N-(5-phenyl-2- pyrlmidinyl)spiro{cyclohexane-1.1'(3'H)-isobenzofuran1- 4-carboxamide melting point 184oC Example 51 Trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3'- oxospiro [cyclohexane-1.1'(3'H)-isobenzofuran]-4- carboxamide melting point 294oC Example 52 Trans-3'-oxo-N-(5-phenyl-3-pyrazolyl)spiro (cyclohexane- 1.1'(3'H)-isobenzofuran]-4-carboxamide melting point 238oC Example 53 Trans-N-F1- (2-fluorophenyl)-4-imidazolyl1-3'- oxospiro[cyclohexane-1.1'(3'H)-lsobenzofuran1-4- carboxamide melting point 258oC Example 54 Trans-N-(4-acetyl-3-trifluoromethylphenyl)-3'- oxospiro[cyclohexane-1.1'(3'H)-lsobenzofuran]- 4- carboxamide melting point 274-275oC Example 55 Trans-3'-oxo-N-F1-( 3-qulnolyl)-4- lmidazolyl1spiro\cyclohexane-1.1'(3'H)-lsobenzofuran]- 4 carboxamide melting point>300oC Example 56 Trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3'- oxospiro[cyclohexane-1.1'(3'H)-isobenzofuran]-4- carboxamide melting point 268-270oC Example 57 Preparation of trans-N-(4-benzoylphenyl)-3-oxospiro[4- azaisobenzofuran-1(3H), 1'-cvclohexane]-4'-carboxamide (1) Preparation of dispiro[4-azaisobenzofuran-l(3H),1'- cyclohexane-4',2"-l",3"-dioxolane]-3-one A solution of N-methyl-2-pyridinecarboxamide (9.53g) in anhydrous tetrahydrofuran (400mL) was cooled to-78oC under an atmosphere of nitrogen, to which n-butyllithlum (1. 54M solution in hexane, 100mL) was dropwise added. After being stirred for 1.5 hours at the some temperature, a solution of 1,4-cyclohexanedione monoethylene ketal (10.93g) in anhydrous tetrahydrofuran (100mL) was added dropwise to the mixture. After the temperature was raised to room temperature, the reaction mixture was partitioned between water (300mL) and ethyl ether (lOOmL). The aqueous layer was acidified with 2N hydrochloric acid, stirred for 30 minutes, neutralized with potassium carbonate and then left overnight. The resulting precipitate was collected by filtration and dried to give the subject compound (6.84g). (2) Preparation of spiro[4-azaisobenzofuran-l(3H),1'- cyclohexane]-3,4'-dione A mixture of dispiro[4-azalsobenzofuran- 1(3H).1'-cyclohexane-4',2"-l",3"-dioxolane]-3-one (6.8g), 2N hydrochloric acid (20mL) and acetone (5mL) was heated under reflux for 13 hours. After cooling, the mixture was neutralized with potassium carbonate and stirred together with isopropyl ether (5mL) for 3 hours. The resulting precipitate was collected by filtration, washed with water and isopropyl ether and then dried to give the subject compound (3.39g). (3) Preparation of cis-4'-hydroxyspiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-3-one Spiro[4-azaisobenzofuran-1(3H),1'-cyclohexane]- 3,4'-dione (5.7g) was dissolved in tetrahydrofuran (50mL) and water (lOmL) and cooled to 00. The solution was stirred together with sodium borohydride (993mg) for 20 minutes, acidified with 10% sulfuric acid, adjusted to pH7.4 with saturated sodium hydrogen carbonate aqueous solution and extracted with chloroform-ethanol and chloroform- tetrahydrofuran. The organic layer was dried over anhydrous Na2S04 and concentrated. The residue was crystallized from ethyl acetate-isopropyl ether to give the subject compound (2.02g). (4) Preparation of trans-3-oxospiro[4-azaisobenzofuran- 1(3H),1'-cyclohexane]-4'-carbonitrile To a solution of cis-4'-hydroxyspiro[4- azaisobenzofuran-l(3H),1'-cyclohexane]-3-one (2.02g) in anhydrous tetrahydrofuran (60mL), triethylamine (3.08mL) was added and cooled to 00. Methanesulf onyl chloride (1. 3mL) was added dropwise to the mixture and stirred at that temperature for 1 hour. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous Na2SO4 and evaporated. The residue was crystallized from ethyl acetate-isopropyl ether to give mesylate (2.47g). Thus obtained mesylate was dissolved in dimethylformamide (2 5mL) and stirred together with tetraethylammonlum cyanide (3.25g) at 100oC for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over anhydrous Na2SO4 and then concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/3) to give the subject compound (l.Og). (5) Preparation of trans-3-oxospirot4-azaisobenzofuran- 1(3H),1'-cyclohexane]- 4'-carboxylic acid A solution of trans-3-oxospiro[4-azaisobenzofuran- 1(3H),1'-cyclohexane]-4'-carbonitrile (l.Og) in 30% sulfuric acid was heated under reflux for 11 hours. After cooling, the reaction mixture was diluted with water and adjusted to pH6 with potassium carbonate. The resulting precipitate was collected by filtration, washed with water and air-dried to give the subject compound (974mg). (6) Preparation of trans-N-(4-benzoylphenyl)-3- oxospiro[4-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide To a solution of trans-3-oxospiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxylic acid (66mg) in pyridine (lmL), 4-aminobenzophenone (52.6mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153mg) were added and the mixture was stirred at 40"C for 2 hours. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na2SO4 and then concentrated. The residue was crystallized from ethyl acetate-hexane to give the subject compound (94.4mg) as colorless crystals (melting point 237oC). Compounds of Example 58 to 60 were obtained in the similar manner as Example 57-(6) by replacing 4- aminobenzophenone used in Example 57-(6) by the corresponding materials, respectively. Example 58 Trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 203oC Example 59 Trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4- azaisobenzofuran-1f 3H).1'-cyclohexane1-4'-carboxamide melting point 217oC Example 60 Trans-3-oxo-N-(5-phenyl-2-pyrlmidinyl)spiro [4- azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 237oC Example 61 Preparation of trans-N-(4-benzoylphenyl)-3-oxospiro[5- azaisobenzofuran-1(3H).1'- cyclohexane1-4'-carboxamide (1) Preparation of dispiro[5-azaisobenzofuran-l(3H),1'- cyclohexane-4', 2"-l",3"-dloxolane]-3-one 2,2,6,6-Tetramethylpiperidine (41.1mL) was dissolved in anhydrous tetrahydrofuran (400mL) and cooled to-50"C, to which n-butylllthium (1. 50M solution in hexane, 217mL) and nicotinic acid (lO.Og) were added successively. After being stirred at-SO'C for 1 hour, a solution of 1,4-cyclohexanedione monoethylene ketal (13.9g) in anhydrous tetrahydrofuran (2 5mL) was added and then the mixture was stirred at-50'C for 1 hour. After the temperature was raised to room temperature, the reaction mixture was poured into water (800mL) and extracted with hexane-ether (1:1, 500mL). The aqueous layer was adjusted to pH3 with 6N hydrochloric acid and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and washed with water. Thus obtained solid was dissolved in chloroform (300mL), washed with saturated sodium bicarbonate aqueous solution (150mL), dried and then concentrated. The residue was recrystallized from ethyl acetate-hexane to give the subject compound (4.2 9 g). (2) Preparation of spiro[5-azaisobenzofuran-l(3H),1'- cyclohexane]-3,4'-dione Dispiro[5-azaisobenzofuran-l(3H),1'-cyclohexane- 4',2"-l",3"-dioxolane]-3-one (4.29g) and p- toluenesulfonic acid monohydrate (3.74g) were dissolved in acetone (80mL) and water (8mL) and the solution was heated under reflux for 3 hours. After cooling, acetone was evaporated off and chloroform (lOOmL) was added to the residue. The mixture was washed with saturated sodium bicarbonate aqueous solution (50mL X 2), dried over anhydrous Na2SO4 and then evaporated. The resulting crystals were recrystallized from ethyl acetate-hexane to give the subject compound (2.68g). (3) Preparation of cis-4'-hydroxyspiro[5- azaisobenzofuran-l(3H),1'-cyclohexane]-3-one A suspension of spiro[5-azaisobenzofuran-l(3H),1'- cyclohexane]-3,4'-dlone (167mg) in tetrahydrofuran-water (10:1, 4mL) was cooled to o'C and stirred together with sodium borohydride (32mg) at O'C for 30 minutes. The reaction mixture was poured into water ( 5mL), stirred at room temperature for 30 minutes and then extracted with chloroform (20mLX3). The extract was dried over anhydrous Na2SO4 and concentrated. The residue was recrystallized from ethyl acetate-hexane to give the subject compound (77.7mg). (4) Preparation of trans-3-oxospiro[5-azaisobenzofuran- 1(3H),1'- cyclohexane]-4'-carbonitrile A solution of cis-4'-hydroxyspiro[5- azaisobenzofuran-1(3H),1'-cyclohexane]-3-one (1.31g) and triethylamine (1.17mL) in anhydrous tetrahydrofuran (20mL) was cooled to O'C and stirred together with methanesulf onyl chloride (0.555mL) at o'C for 1 hour. The reaction mixture was poured into water (50mL), extracted with ethyl acetate (100mLX2), dried over anhydrous Na2SO4 and concentrated to give crude mesylate (1.87g). The mesylate was dissolved in anhydous dimethylformamide (30mL) and stirred together with triethylammonium cyanide (2.98g) at 100oC for 5 hours. The reaction mixture was poured into water (100mL) and extracted with ether (150mLX3), and ether-ethyl acetate (2:1, 200mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated. The resulting oily residue was purified by column chromatography on silica gel (hexane/ethyl acetate/methanol=2/l/0 to 1/1/0 to 30/30/1) and the obtained solid was recrystallized from ethyl acetate-hexane to give the subject compound (631mg). (5) Preparation of trans-3-oxosp±ro[5-azaisobenzofuran -1(3H),1'- cyclohexane]-4'-carboxylic acid A mixture of trans-3-oxospiro[5-azaisobenzofuran- 1(3H),1'-cyclohexane]-4'-carbonitrile (lOOmg), water (0.7mL) and concentrated sulfuric acid (0.3mL) was refluxed for 11 hours. The reaction mixture was cooled to room temperature and adjusted to pH4 with aqueous 4N sodium hydroxide. The resulting precipitate was collected by filtration, washed successively with water, ethanol and dllsopropyl ether and then dried to give the subject compound (78mg). 1H-NMR (200MHz, DMSO-d6, 6ppm) : 1.63-1.87 (2H, m), 1.88-2.20 (6H, m), 2.70 (1H, m), 7.76 (1H, dd, J = 5.2, l.lHz), 8.86 (1H, d, J=5.2Hz), 9.06 (1H, d, J=l.lHz). (6) Preparation of trans-N-(4-benzoylphenyl)-3- oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide A solution of trans-3-oxospiro[5- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxylic acid (20mg) and 4-aminobenzophenone (16mg) in anhydrous pyridine (0.5mL) was stirred together with l-(3- dimethylamlnopropyl)-3-ethylcarbodilmide hydrochloride (20mg) at 600 for 2 hours. The reaction mixture was poured into water (lOmL) and extracted with ethyl acetate (30mL X 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The resulting oily residue was purified by column chromatography on silica gel (hexane/ethyl acetate =1/1 to 1/2) and the obtained solid was recrystalllzed from ethyl acetate-hexane to give the subject compound (10mg) as colorless crystals (melting point 256-257t:). Example 62 Preparation of trans-N-(4-benzoylphenyl)-3-oxospj.rof6- azalsobenzofuran-1(3H).1'- cyclohexane1-4'-carboxamide (1) Preparation of dispiro[6-azaisobenzofuran- 1(3H),1'-cyclohexane-4', 2"-l",3"-dioxolane]-3-one 2,2,6,6-Tetramethylpiperidine (50mL) was dissolved in anhydrous tetrahydrofuran (500mL) and the solution was cooled to-50oC, to which n-butyllithium (1.50M solution in hexane, 270.7mL) and isonicotinic acid (12.5g) were added successively. The reaction mixture was stirred at-50oC for 10 minutes and the temperature was raised to 25oC over 30 minutes. The reaction mixture was further stirred at 25oC for 10 minutes and then cooled to-65oC. 1,4- Cyclohexanedione monoethylene ketal (19g) was added and the reaction mixture was stirred at-65oC for 10 minutes. The temperature of the reaction mixture was raised to-15oC over 1 hour, then to 0oC over 30 minutes. Then the mixture was poured into water (300mL), from which the aqueous layer was separated. The organic layer was extracted with aqueous 2N sodium hydroxide. The combined aqueous layers were adjusted to pH3 with concentrated hydrochloric acid and extracted with ethyl acetate ( 500mL). The organic layer was washed with saturated aqueous sodium bicarbonate (200mL), and saturated saline solution, then dried over anhydrous MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate =1/0 to 4/1 to 3/2) and recrystallized from ethyl acetate-hexane to give the subject compound (7.20g). (2) Preparation of spiro[6-azalsobenzofuran-l(3H),1'- cyclohexane]-3, 4'-dione Dlspiro[6-azaisobenzofuran-l(3H),1'-cyclohexane- 4',2"-l",3"-dioxolane]-3-one (7.20g) and p- toluenesulfonic acid monohydrate (5.80g) were dissolved in acetone (150mL) and water (15mL) and the solution was heated under reflux for 5.5 hours. After cooling, acetone was evaporated off and the residue was extracted with ethyl acetate (100mL X 3). The combined organic layers were washed with saturated saline solution (50mL), dried over anhydrous MgSO4 and then evaporated. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give the subject compound (1.96g). (3) Preparation of cis-4'-hydroxyspiro[6- azaisobenzofuran-l(3H),1'-cyclohexane]-3-one A solution of spiro[6-azaisobenzofuran- 1(3H),1'-cyclohexane]-3,4'-dione (1.0g) in ethanol(100mL) was cooled to 0oC and stirred together with sodium borohydride (174mg) at 0oC for 1 hour. The reaction mixture was adjusted to pH4 with 10% sulfuric acid, rendered basic with aqueous saturated sodium bicarbonate and then extracted with chloroform (200mLX2). The extract was dried over anhydrous MgSO4 and concentrated. The residue was recrystallized from ethyl acetate-hexane to give the subject compound (954.5mg). (4) Preparation of trans-3-oxospiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carbonltrile A solution of cis-4'-hydroxyspiro[6- azaisobenzofuran-l(3H),1'-cyclohexane]-3-one (954mg) and triethylamlne (0.91mL) in dimethylformamide (lOmL) was cooled to 00 and stirred together with methanesulfonyl chloride (0.40mL) at 00 for 1 hour. The reaction mixture was diluted with ethyl acetate (100mL), washed with aqueous saturated sodium bicarbonate (50mL X 2), and saturated saline solution (50mL), then dried over anhydrous MgSO4 and concentrated. The residue was recrystallized from ethyl acetate-diisopropyl ether to give mesylate (995mg). This mesylate was dissolved in anhydrous dimethylformamide (30mL) and stirred together with triethylammonium cyanide (1.57g) at 100oC for 1.5 hours. The reaction mixture was diluted with ethyl acetate (200mL) and washed successively with water (200mL), aqueous saturated sodium bicarbonate (200mL), and saturated saline solution (100mL). The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was recrystallized from ethyl acetate- diisopropyl ether to give the subject compound (447mg). (5) Preparation of trans-3-oxospiro[6- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxylic acid A mixture of trans-3-oxospiro[6-azaisobenzofuran- 1(3H),1'-cyclohexane]-4'-carbonitrile (445mg), water (3.5mL) and concentrated sulfuric acid (1.5mL) was refluxed for 6 hours. The reaction mixture was cooled to room temperature and adjusted to pH8 with aqueous 5N sodium hydroxide, then to pH4 with concentrated hydrochloric acid. The resulting crystals were collected by filtration, washed with water and dried to give the subject compound (416mg) as colorless crystals (melting point 222-223oC). 1H-NMR (300MHz, DMSO-d6, 6ppm) : 1.7-2.2 (6H, m), 2.65-2.75 (1H, m). 7.83 (1H, dd, J=1.2Hz, 4. 9Hz), 8.86 (1H, d, J=4.9Hz), 9.05 (1H, d, J=1.2Hz), 12.3 (1H, brs). (6) Preparation of trans-N-(4-benzoylphenyl)-3- oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide A solution of trans-3-oxospiro[6-azaisobenzofuran- l(3H),l'- cyclohexane]-4'-carboxylic acid (50mg) and 4- aminobenzophenone (51.6mg) in anhydrous pyridine (1mL) was stirred together with 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (48. 7mg) at 60oC for 2 hours. The reaction mixture was diluted with ethyl acetate (20mL) and washed successively with water (20mL), 10% citric acid aqueous solution (20mL X 2), aqueous saturated sodium bicarbonate, and saturated saline solution. The organic layer was dried over anhydrous MgSO4 and concentrated. The resulting oily residue was purified by column chromatography on silica gel (hexane/ethyl acetate =3/2 to 1/4) and the obtained solid was recrystallized from ethyl acetate-hexane to give the subject compound (62.7mg) as colorless crystals (melting point 147-149^). Example 63 Preparation of N-F5-(4-hydroxyphenyl)-2-pyrazinyl]- 3-oxospiro[isobenzofuran-1(3H).4'-piperidine 1-1'- narhoxamide (1) Preparation of 2-amlno-5-(4-hydroxyphenyl)pyrazine To a solution of 2-amino-5-bromopyrazine (366 mg) in dimethoxyethane (20 mL) was added 4-hydroxyphenylboronic acid (320 mL), 1. 5N sodium carbonate aqueous solution (2.5 mL) and tetrakis (triphenylphosphine) palladium (0) (54 mg). The mixture was stirred at 80oC for 3 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethyl acetate (50 mL x 3). The extract was washed with saturated saline solution, then dried over anhydrous Na2SO4. The removal of the solvent provided crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (305 mg). (2) Preparat ion of pheny1 N-[5-(4-hydroxypheny1)-2- pyrazinyl]carbamate To a solution of 2-amino-5-(4-hydroxyphenyl)pyrazlne (283 mg) in pyridine (20 mL) was added under ice-cooling phenyl chlorof ormate (199 mL) and the mixture was stirred for 1 hour. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate ( 20 mL x 3). The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (314 mg). (3) Preparation of N-[5-(4-hydroxyphenyl)-2-pyrazinyl]- 3-oxospiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide A mixture of spiro[isobenzofuran-l(3H),4'- piperidine]-3-one hydrochloride (96 mg), phenyl N-5-[(4- hydroxyphenyl)-2-pyrazinyl]carbamate (128 mg) and triethylamine (279 mL) in chloroform (5 mL) was stirred at 80oC for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20mL) and then dried over anhydrous Na2SO4 The concentration of the solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) followed by recrystallization from ethyl ether-hexane to give the subject compound (114 mg) as colorless crystals (melting point 263-2650). Example 64 Preparation of N-[5-(3-hydroxyphenyl)-2-pyrazinyl1- 3-oxospirof isobenzofuran-1(3H).4'-piperidine]-1'- carboxamide (1) Preparation of 2-amlno-5-(3-methoxyphenyl)pyrazine To a solution of 2-amino-5-bromopyrazine (642 mg) in dimethoxyethane (40 mL) was added 3-methoxyphenylboronic acid (560 mg), 1. 5N aqueous sodium carbonate solution (4mL) and tetrakis(triphenylphosphine) palladium (0) (86 mg). The mixture was stirred at 80oC for 6 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethyl acetate (50 mL x 3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4 The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (760 mg). (2) Preparation of 2-amino-5-(3-hydroxyphenyl)pyrazine 2-amino-5-(3-methoxyphenyl)pyrazine (566 mg) was dissolved in methylene chloride (10 mL). To this mixture was added under ice-cooling boron tribromide (530 U L) and the whole was stirred at room temperature for 14 hours. To the reaction mixture was added IN aqueous sodium hydroxide. The whole was extracted with ethyl acetate ( 30 mL x 2). The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4 The concentration of the solvent provides the subject compound (94 mg) as a yellow solid. (3) Preparation of Phenyl N-[5-(3-hydroxyphenyl)-2- pyrazinyl]carbamate To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine (89 mg) in pyridine (10 mL) was added under ice-cooling phenyl chloroformate (63 UL). The mixture was stirred for 1 hour and then poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (51 mg). (4) Preparation of N-[5-(3-hydroxyphenyl)-2- pyrazinyl]-3-oxospiro[isobenzofuran-l(3H),4'- piperidine]-1'-carboxamide A mixture of spiro[isobenzofuran-l(3H),4'- piperidine]-3-one hydrochloride (40 mg), phenyl N-[5- (3-hydroxyphenyl)-2-pyrazinyl]carbamate (51 mg) and triethylamine (119 ££L) in chloroform (5 mL) was stirred at 80oC for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL) and then dried over anhydrous Na2SO4 The concentration of the solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 1/2) followed by recrystallization from ethyl ether-hexane to give the subject compound (24 mg) as colorless crystals (melting point 257-259^). Example 6 5 Preparation of 4-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl)spiro flsobenzofuran-1f3H).4'-piperidinei-1'- carboxamide A mixture of 4-fluorospiro[isobenzofuran-l(3H),4'- piperidine]-3-one hydrochloride (150 mg), phenyl N-(5- phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60 hours. The concentration of the reaction mixture left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/methanol=l/l/0~8/8/1~ 6/6/1) followed by recrystallization from ethyl acetate- hexane to give the subject compound (190 mg) as colorless crystals (melting point 247-249oC). Example 66 Preparation of 7-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl1spiro flsohenzofuran-1f 3H).4'-piperidine1-1'- carboxamide A mixture of 7-fluorospiro[isobenzofuran-1(3H),4'- piperidine]-3-one hydrochloride (150 tng), phenyl N-(5- phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine (0.24 mL) In chloroform (2 mL) was stirred at 60oC for 2 hours. The reaction mixture was diluted with ethyl acetate. The whole was washed with 10% citric acid aqueous solution, saturated aqueous sodium bicarbonate and saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the reaction mixture left a residue, which was recrystallized from ethyl acetate to give the subject compound (202 mg) as colorless crystals (melting point 244-246T;). Example 6 7 Preparation of 6-ethyl-3-oxo-N-(5-phenyl-2- pyrazlnyl)spiro\isobenzofuran-1(3H).4'-piperidine1-1'- carboxamide (1) Preparation of 2-(4-ethylphenyl)-4,4-dimethyl-2- oxazoline To a solution of 4-ethylbenzoic acid (3.80 g) in anhydrous acetonitrile (100 mL) was added under a nitrogen atmosphere, triphenylphosphine (20 g), 2-amino-2-methyl- 1-propanol (2.74 mL) and triethylamine (28.2 mL). The mixture was cooled on an ice bath and then tetrachloromethane (5.36 mL) was added. The reaction mixture was allowed to stand at room temperature and stirred for 18 hours. To the reaction mixture was added ethyl acetate and hexane and the precipitate was removed by filtration. The concentration of the filtrate left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/ = 9/l/ to 6/1) to give the subject compound (1.15 g). (2) Preparation of 1'-benzyl-6-ethylspiro[isobenzofuran- 1(3H),4'-piperidine]-3-one hydrochloride Under a nitrogen atmosphere, a solution of 2-(4- ethylphenyl)-4,4-dimethyl-2-oxazoline (1.15 g) in anhydrous tetrahydrofuran (100 mL) was cooled to-78'C. To this solution was added 1.5 M butyl lithium hexane solution (4.53 mL). After being stirred for 1 hour, l-benzyl-4- piperidone (1.05 mL) was added dropwise. After the reaction temperature was allowed to rise up to room temperature, 2N hydrochloric acid was added to the reaction mixture to make the mixture acidic. The whole was refluxed for 2 hours. After cooling, sodium hydroxide aqueous solution was added to make the reaction mixture basic. The mixture was extracted with ethyl ether. The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the organic solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/=3/2) to give the subject compound (409 mg). (3) Preparation of 6-ethylspiro[isobenzofuran-l(3H),4'- piperidine]-3-one hydrochloride 1'-benzyl-6-ethylspiro[isobenzofuran-1(3H),4'- piperidine]-3-one hydrochloride(400 mg) was dissolved in methanol (10 mL) and 10% palladium carbon was added. The mixture was stirred under a hydrogen atmosphere for 1. 5 hours. After the palladium carbon was removed by filtration, the filtrate was concentrated to give a residue, which was subjected to crystallization with methanol-ethyl ether to give the subject compound (222 mg). (4) Prepartation of 6-ethyl-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide To a suspension of 6-ethylspiro[isobenzofuran- 1(3H), 4'-piperidine]-3-one hydrochloride (53 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) in dimethyl sulfoxide (1 mL) was added 10 M sodium hydroxide aqueous solution (0.02 mL). The mixture was vigorously stirred for 5 minutes followed by partition between water and ethyl acetate. The organic layer was separated and then washed with saturated saline solution and then dried over anhydrous Na2SO4 The concentration of the organic solvent left a residue, which was subjected to the crystallization from ethyl acetate to give the subject compound (46 mg) as crystals (melting point 176-178oC). Example 68 Preparation of 6-hydroxy-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-1(3H).4'-piperidinei-1'- carboxamide (1) Preparation of 2-(4-methoxyphenyl)-4,4-dimethyl-2- oxazoline To a solution of 2-amino-2-methyl-l-propanol (14.4 g) and triethylamlne (23 mL) in dried THF (200 mL) was added dropwise under ice-cooling a solution of 4-methoxybenzoyl chloride ( 25 g) in dried THF ( 20 mL). The mixture was stirred at room temperature for 1 hour and then water (200 mL) was added. The reaction mixture was extracted with ethyl acetate (100 mL) twice. The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4 The concentration of the organic solvent provided the subject compound (29.5 g) as a white solid. Thionyl chloride (25 mL) was added to the above white solid compound, and the reaction was carried out at room temperature for one hour. The reaction mixture was made alkaline by the addition of 5N sodium hydroxide aqueous solution and was extracted twice each with ethyl acetate (100 mL). The combined organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate. The solvent was evaporated off to give the above-identified compound (22 g) as colorless oil. (2) Preparation of l'-benzyl-6- methoxyspiro[isobenzofuran-1(3H),4'-piperidine]-3-one Under a nitrogen atmosphere, to a solution of 2- (4-methoxyphenyl)-4,4-dimethyl-2-oxazoline (7.9 g) in anhydrous toluene (100 mL) was added dropwise under ice- cooling 1. 5M butyl lithium hexane solution (28 mL). After being stirred for 3 hours at the same temperature, 1- benzyl-4-piperidone (8 g) in anhydrous toluene (20 mL) was added dropwise. After the reaction mixture was stirred at room temperature for 14 hours, a saturated ammonium chloride aqueous solution (50 mL) was added. The mixture was extracted with ethyl acetate (100 mL) twice. The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4 The concentration of the organic solvent provided the compound (8.3 g) as a white solid. This compound was dissolved in methanol (50 mL) and concentrated sulfuric acid (4 mL) was added. The mixture was stirred at room temperature for 1 hour. To the reaction mixture was added IN sodium hydroxide aqueous solution to make the reaction mixture basic. The mixture was extracted with ethyl acetate (100 mL) twice. The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4 The concentration of the organic solvent provided the subject compound (6.6 g) as a yellow solid. (3) Preparation of 6-hydroxyspiro[isobenzofuran-l(3H),4'- piperidine]-3-one hydrochloride 1'-benzyl-6-methoxyspirofisobenzofuran-1(3H), 4'- piperidine]-3-one (1.8 g) was dissolved in methylene chloride (20 mL). To this solution was added under ice- cooling boron tribromide (1.3 mL). After the reaction mixture was stirred at room temperature for 14 hours, IN sodium hydroxide aqueous solution was added. The mixture was extracted with ethyl acetate (30 mL) twice. The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the organic solvent provided the compound (1.2 g) as a yellow solid, which was dissolved in methanol (30 mL). To this solution was added 4N hydrogen chloride-ethyl acetate ( 5 mL), 20% palladium hydroxide-carbon (300 mg). The mixture was stirred under a hydrogen atmosphere for 14 hours. After the catalyst was removed by filtration, the filtrate was concentrated to give the subject compound (891 mg) as a white solid. (4) Prepartation of 6-hydroxy-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide A mixture of 6-hydroxyspiro[isobenzofuran- 1(3H),4'-piperidine]-3-one hydrochloride (51 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) and triethylamine (119 U L) in chloroform (5 mL) was stirred at 80oC for 2 hours. The reaction mixture was poured into water, and then extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL) and then dried over anhydrous Na2SO4 The concentration of the organic solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/=4/l to 1/2) followed by the recrystallization from ethyl ether- hexane to give the subject compound (29 mg) as colorless crystals (melting point 206-208'C). The compounds from Example 69 to Example 79 were prepared, according to the same preparation procedure described in Example 61 by using the corresponding starting material in place of 4-aminobenzophenon used in the Example 61. Example 69 trans-3-oxo-N-(5-phenyl-2-pyrimidiny1)spirof5- azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide. melting point 215-217T: Example 70 trans-N-F 5- (3-fluorophenyl)-2-pyrimidinyl1-3-oxospiro [5- azaisobenzofuran-1(3H). 1'-cyclohexane1-4'-carboxamide melting point 205-207oC Example 71 trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro [5- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 226-228oC Powder X-ray diffraction Above powder X-ray diffraction analysis data were measured by the same conditions as Example 32. Example 72 trans-3-oxo-N-L4-phenvl-2-oxazolyl)spiro [5- azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 273-275"€ Example 73 trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]- 3-oxospiro [5- azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 213-215T: Example 74 trans-N-[5-(3-methylphenyl)- 2-pyrimidinyl1-3-oxospiro [5- azaisobenzofuran-3(3H).1'-cyclohexane1-4'-carboxamide melting point 145-147oC Example 75 trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl1-3- oxospiro [5-azaisobenzofuran-1(3H),1'-cyclohexane1-4'- carboxamide melting point 157-159oC Example 76 trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl1-3- oxospiro [5-azaisobenzofuran-1(3H).1'-cyclohexane]-4'- carboxamide melting point lSS-lSSt: Example 77 trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl1-3- oxospiro [5-azaisobenzofuran-1(3H).1'-cyclohexane1-4'- carboxamide melting point 218-220oC Example 78 trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrlmidinyl1-3- oxospiro [5-azalsobenzofuran-1(3H).1'-cyclohexane]-4'- carboxamide melting point 151-153T; Example 7 9 trans-N-[4-(3-fluoromethoxylphenyl)-2-oxazolyli-3- oxospiro[5-azaisobenzofuran-1 ( 3H). 1'-cyclohexane]-4'- carboxamide melting point 214-217oC Example 80 Preparation of trans-N-[5-(3-hydroxymethylphenyl)-2- pyrimidinyl1-3-oxospiro[5-azalsobenzofuran-1(3H).1'- cyclohexansl-4'-carboxamide To a solution of 2-chloro-l,3-dimethylimidazollum chloride (613 mg) in chloroform (10 mL) was added pyridine (0.489 mL), trans-3-oxospiro[5-azaisobenzofuran- 1(3H),1'-cyclohexane]-4'-carboxylic acid (300 mg) and 2- amino-5-bromopyrimidine (211 mg). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The whole was washed with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the organic solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate = l/l to 1/3 to 1/4 to 1/5) followed by the crystallization from ethyl acetate to give the desired amide (210 mg). This amide was suspended in ethyleneglycol dimethyl ether (3.5 mL), and water (0.5 mL), 3-hydroxymethylphenylboronic acid (95 mg), 2M sodium carbonate aqueous solution (0.31 mL) and tetrakistrlphenylphosphinepalladium (30 mg) was added thereto. The mixture was refluxed for 2 hours and then diluted with water. The whole was extracted with ethyl acetate and then dried over anhydrous Na2SO4 The concentration of the organic solvent left a residue, which was purified by column chromatography on silica gel (ethyl acetate/methanol=l/0 to 30/1 to 20/1 to 15/1) to give the subject compound (151 mg) as light yellow crystals (melting point 207-2090). Example 81 Preparation of trans-N-[5-(3-hydrpxyphenyl)-2- pyrlmidinyl]-3-oxospiro[5-azalsobenzofuran-1(3H).1'- cyclohexane]-4'-carboxaniide To a solution of 2-chloro-l,3-dimethylimidazolium chloride (622 mg) in chloroform (7 mL) was added pyridine (0.50 mL), trans-3- oxospiro[5-azaisobenzofuran-l(3H),1'- cyclohexane]-4'-carboxylic acid (303 mg) and 2-amino-5- (3-benzyloxyphenyl)pyrimidine (340 mg). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The whole was washed with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, saturated saline solution and then dried over anhydrous Na2SO4 The concentration of the organic solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=l/l to 1/2 to 1/4 to 1/5 to 1/6) followed by the crystallization from ethyl acetate to give the desired amide (210 mg). This amide was dissolved in methanol (5mL) and tetrahydrofuran (5 mL), and 10% palladium-carbon (120 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The catalyst was removed by filtration. The filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel (chlorof orm/methanol=50/l to 30/1) to give a solid compound. The solid compound was washed with ethanol and then recrystallized from ethyl acetate to give the subject compound (95 mg) as light yellow crystals (melting point 260-262oC). The compounds from Example 82 to Example 89 were prepared, according to the same preparation procedure described in Example 62 by using the corresponding starting material in place of 4-aminobenzophenon used in the Example 62. Example 82 trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro [6- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 189-191oC Example 83 trans-N-[5-(3-fluoromethylphenyl)- 2-pyrimidinyl"I-3- oxospiroT 6-azaisobenzofuran-1(3H).1'-cyclohexane1-4'- carboxamidfi melting point 199-200cC Example 84 trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrlmidinyll-3- oxospiroF 6-azaisobenzofuran-1(3H).1'-cyclohexane1-4'- carboxamida melting point 198-200 Example 85 trans- 3-oxo-N-(6-phenyl-1.2 r 4-triazin-3-yl) spiro [6- azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 272-275^ Example 86 trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl1-3- oxospirof 6-azaisobenzofuran-1(3H).1'-cyclohexane1-4'- carboxamide melting point 239-240oC Example 87 trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl1-3- oxospiro[6-azaisobenzofuran-1(3H).1'-cyclohexane1-4'- carboxamide melting point 183-185oC Example 88 trans-N-[5-(3-fluorophenyl)-3-pyrazolyl1-3-oxospiro\6- azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 182-184CC Example 89 trans-N-F5-(4-fluorophenyl)- 3-pyrazolyl1-3-oxospiro[6- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 228-229^ Example 90 Preparation of trans-N-(4-benzoylphenyl)-3- oxospiro[7-azaisobenzofuran-1(3H).1'-cyclohexane1-4'- carboxamide (1) Preparation of 3-cyano-2-hydroxypyridine To malonaldehyde bisdimethylacetal (16.4 g) was added 0.5 N hydrochloric acid (40 mL). The mixture was stirred at 500 for 20 minutes and then cooled to room temperature. To the reaction mixture was added triethylamine (16 mL) followed by 2-cyanoacetoamide (9 g). The whole was stirred at room temperature for 30 minutes and further heated at eo'C for 90 minutes as well as lOO'C for 2 hours. After cooling, the reaction mixture was concentrated to give a residue, which was recrystallized from ethanol-ethyl ether to give the subject compound (7.49 g). (2) Preparation of 2-bromo-3-cyanopyridine Tetrabutylammonium bromide (35.4 g) and diphosphorus pentaoxide (15.58 g) was suspended in toluene (100 mL). After the mixture was stirred at 70oC for 30 minutes, 3- cyano-2-hydroxypyridine (6.59 g) was added thereto. The mixture was refluxed for 4 hours. The reaction mixture was poured into the ice water (200 g) and extracted with ethyl acetate (200mL x 2). The organic layer was dried over anhydrous Na2SO4 The concentration of the solvent gave a oily residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=4/l to 3/1) to give a solid compound. The solid compound was recrystallized from ethyl acetate-hexane to give the subject compound (5.16 g). (3) Preparation of spiro[7-azaisobenzofuran-1(3H),1'- cyclohexane]-3,4'-dione 2-bromo-3-cyanopyridine (2.96 g) and 1,4- cyclohexanedione monoethyleneketal (3.47 g) were dissolved in anhydrous tetrahydrofuran (38 mL). After being cooled to-78oC, n-butyl lithium (1.5 M hexane solution, 12.64 mL) was added and the mixture was stirred at-78oC for 30 minutes. The reaction temperature was allowed to rise up to the room temperature. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous MgSO4 The concentration of the solvent gave a residue, which was recrystallized from ethyl ether-hexane to give iminoether compound (2.93 g). This compound was dissolved in acetone (5 mL) and 2N hydrochloric acid (30 mL). The solution was refluxed for 2 hours. After cooling, 2N sodium hydroxide aqueous solution was added to the reaction mixture to adjust pH to 4. The whole was extracted with ethyl acetate (100mL x 3). The organic layer was dried over anhydrous MgSO4. The concentration of the solvent gave a residue, which was recrystallized from ether-hexane to give the subject compound (1.07 g). (4)Preparation of cis-4'-hydroxyspiro[7-azaisobenzofuran- 1(3H), 1'-cyclohexane]-3-one Spiro[7-azaisobenzofuran-l(3H),1'-cyclohexane]- 3,4'-dione (1.6 g) was suspended in tetrahydrofuran (37 mL). After being cooled to O'C, lithium tert-butoxyaluminium hydride (1.0M tetrahydrofuran solution, 9.58 mL) was added dropwise to the mixture. After the mixture was stirred at O'C for 90 minutes, IN hydrochloric acid was added to adjust pH to 2. The mixture was extracted with ethyl acetate (100 mL x 4). The organic layer was dried over anhydrous MgSO4 The concentration of the solvent gave the subject compound (1.58 g). (5) Preparation of trans-3-oxospiro[7-azaisobenzofuran- 1(3H),1'-cyclohexane]-4'-carbonitrile Cis-4'-hydroxyspiro[7-azaisobenzofuran-1(3H), 1'- cyclohexane]-3-one (1.58 g) and triethylamine (1.81 mL) were dissolved in chloroform (28 mL). After being cooled to OoC, methanesulfonyl chloride (0.67 mL) was added thereto. The mixture was stirred at room temperature for 2 hours and then poured into the saturated sodium bicarbonate aqueous solution (50 mL). The whole was extracted with chloroform (100 mL x 3). The organic layer was dried over anhydrous MgSO4 The concentration of the solvent gave a oily residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=2/l to 1/2) to give a solid compound. The solid compound was recrystallized from ethyl acetate-hexane to give the desired mesylate compound (2.03 g). This compound was dissolved in anhydrous dimethylformamide (30 mL), and triethylammonium cyanide (3.2 g) was added thereto. The mixture was stirred at 100oC for 3 hours. After being cooled, the reaction mixture was poured into water (100 mL). The whole was extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous MgSO4. The concentration of the solvent gave a oily residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=3/l to 2/1) to give a solid compound. The solid compound was further recrystallized from ethyl ether-hexane to give the subject compound (515 mg). (6) Preparation of trans-3-oxospiro[7-azalsobenzofuran- 1(3H),1'-cyclohexane]-4'-carboxylic acid Water (6.6 mL) and concentrated sulfuric acid (2.2 mL) were added to trans-3-oxospiro[7-azaisobenzofuran- 1(3H),1'-cyclohexane]-4'-carbonitrile (515 mg). The mixture was refluxed for 13 hours. After the reaction mixture was cooled to 0t, 4N sodium hydroxide aqueous solution was added to adjust pH to 4. The crystal precipitated was collected by filtration. The crystal was washed with water, ethanol as well as diisopropyl ether and then dried. The subject compound (500 mg) was obtained. 1H-NMR (300 MHz, DMSO-d6, 6ppm): 1.73-1.80(2H, m), 1.81-1.94(2H, m), 1.99-2.08(2H, m), 2.14-2.22(2H, m), 2.64-2.68(lH, m), 7.63(1H, dd, J = 7.8, 4.8Hz), 8.28(1H. dd, J=7.8, 1.5HZ), 8.89(1H, dd, J=4.8, 1.5Hz). (7) Preparation of trans-N-(4-benzoylphenyl)-3-oxospiro- [7-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide trans-3-oxospiro[7-azaisobenzofuran-l(3H),1'- cyclohexane]-4'-carboxylic acid (26 mg) and 4- aminobenzophenone (20 mg) were dissolved in anhydrous pyridine (1 mL). 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (29 mg) was added thereto. The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (10 mL). The whole was extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous MgSO4 The concentration of the solvent gave an oily residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=3/l to 2/1) to give a solid compound. The solid compound was further recrystallized from ethyl acetate-hexane to give the subject compound (30 mg) as colorless crystals (melting point 214-216 Employing the procedure substantially as described in Example 90-(7), but substituting the appropriate amines for 4-aminobenzophenone used in Example 90-(7), compounds of Examples 91 to 95 were prepared. Example 91 trans-N-f1-(3 r5-difluorophenyl)-4-lmidazolyl1-3- oxospiroT 7-azaisobenzofuran-l(3H).1'-cyclohexane1-4'- carboxamide melting point 269-271T; Powder X-ray diffraction Above powder X-ray diffraction analysis data were measured by the same conditions as Example 32. Example 92 trans-3-oxo-N-[2-phenyl-4-pyridylIspiror7- azaisobenzofuran-1(3H),1'-cyclohexane1-4'-carboxamide melting point 221-223oC Example 93 trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 240-242oC Example 94 trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spirof 7- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 214-217oC Example 9 5 trans-N-[1-(4-fluorophenyl)-3-pyrazolyl1-3-oxospiro[7- azaisobenzofuran-1(3H), 1'-cyclohexane1-4'-carboxamide melting point 210-212oC Employing the procedure substantially as described in Example 57-(6), but substituting the appropriate amines for 4-aminobenzophenone used in Example 57-(6), compounds of Examples 96 to 98 were prepared. Example 96 trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro [4- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 200-202oC Example 97 trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiror4- azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 223-225oC Powder X-ray diffraction Above powder X-ray diffraction analysis data were measured by the same conditions as Example 32. Example 98 trans-N-F1-(3-fluorophenyl)-4-pyrazolyli-3-oxospiro[4- azaisobenzofuran-l(3H).1'-cyclohexane]-4'-carboxamide melting point 176-178oC Employing the procedure substantially as described in Example 62-(6), but substituting the appropriate amines for 4-aminobenzophenone used in Example 62-(6), compounds of Examples 99 to 106 were prepared. Example 99 trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 249-250oC Example 100 trans-N-F1-(4-fluorophenyl)-3-pyrazolyl1-3-oxospiro[6- azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 254-257 C Example 101 trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 239-24lt: Example 102 trans-3-oxo-N-(5-phenyl-1.2.4-thladlazol-3-yl)spiro[6- azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide melting point 221-223oC Example 103 trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6- azaisobenzofuran-1(3H) 1'-cyclohexane1-4'-carboxamide melting point 259-26l"€ Example 104 trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6- azaisobenzofuran-1f 3H).1'-cyclohexanel-4'-carboxamide melting point 249-251oC Example 105 trans-3-oxo-N-(2-phenyl-3-thiazolyl)spirof 6- azalsobenzofuran-1(3H), 1'-cyclohexane]- 4'-carboxamide melting point 278-280T: Example 106 trans-3-oxo-N-(2-phenyl-1.2.3-triazol-4-yl)spiro[6- azalsobenzofuran-1(3H),1'-cyclohexane]- 4'-carboxamide melting point 232-233oC Formulation example 1 20.0 grams of compound of Example 1, 417 grams of lactose, 80 grams of crystalline cellulose and 80 grams of partial a-starch were blended with a V-cone blender. To the mixture was added 3.0 grams of magnesium stearate and the whole was blended. The blended powder was compressed into 3000 tablets by conventional procedure so that each tablet has a weight of 150 mg and 7.0 mm in diameter. The content of one tablet with a weight of 150 mg the compound of Example 1 5.0mg 135 lactose 104.25 mg crystalline cellulose 20.0 mg partial a-starch 20.0 mg magnesium stearate 0.75 mg Formulation example 2 10.8 grams of hydroxypropylcellulose 2910 and 2.1 grams of polyethylene glycol 6000 were dissolved in 172.5 grams of purified water. To the solution was dispersed 2.1 grams of titanium oxide to provide a coating liquid. 2500 tablets prepared in Formulation example 1, was subjected to spray-coating with the coating liquid using HICOATER-MINI to provide a film coated tablet with a weight of 155 mg. The content of one tablet (155 mg) the tablet prepared in the Formulation example 1 150 mg hydroxypropylcellulose 2910 3.6 mg Polyethylene glycol 6000 0.7 mg titanium dioxide 0. 7 mg Industrial Applicability Compounds of the present Invention exhibit NPY antagonistic activities and are useful as agents for the treatment of various diseases related to NPY, for example, cardiovascular disorders such as hypertension, nephropathy, heart disease, vasospasm, arteriosclerosis and the like, central nervous system disorders such as bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal and the like, metabolic diseases such as obesity, diabetes, hormone abnormality. hypercholesterolemia, hyperlipidemia and the like, sexual and reproductive dysfunction, gastro-intestinal disorder, respiratory disorder, inflammation or glaucoma, and the like. WE CLAIM 1. A spiro compound represented by the general formula wherein Ar represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of C1 to C6, straight- or branched- chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, cycloalkyl group of C3 to C6, straight-or branched-chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of Cl to C6, straight- or branched-chain alkoxy group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of Cl to C6, carboxyl, alkanoyl group containing straight- or branched-chain alkyl group of Cl to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of Cl to C6, straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1,2 or more than 2 oxo groups at a substitutable, arbitrary positions, and a group represented by formula of-Q- Ar2; Ar2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or branched-chain alkoxy group of Cl to C6, straight- or branched-chain alkoxy group of Cl to C6 susbstituted with 1, 2 more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group mono-substituted with straight- or branched-chain alkyl group of Cl to C6, amino group di-substituted with identical or different straight-or branched-chain alkyl group of Cl to C6, alkanoyl group containing straight- or branched-chain alkyl group of Cl to C6 and aryl; n represents 0 or 1; Q represents a single bond or carbonyl; T, U, V and W represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of Cl to C6, hydroxy and straight- or branched-chain alkoxy group of Cl to C6, where at least two of them represent the said methine group; X represents methine or nitrogen; Y represents imino which may be substituted with straight- or branched- chain alkyl group of Cl to C6, or oxygen; a salt or ester thereof. 2. The compound as claimed in claim 1, wherein the aryl in Ar1 is phenyl. 3. The compound as claimed in claim 1, wherein the heteroaryl in Ar1 is pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1, 2, 3- triazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1, 2, 4- triazinyl, benzoxazolyl, benzothiazolyl, quinolyl or pyrido [3, 2-b] pyridyl. 4. The compound as claimed in claim 1, wherein T, U, V and W are independently methine which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of Cl to C6, hydroxy and straight- or branched-chain alkoxy group of Cl to C6. 5. The compound as claimed in claim 1, wherein T, U, V and W are independently methine which may be substituted with halogen. 6. The compound as claimed in claim 1, wherein one of T, U, V and W is nitrogen. 7. The compound as claimed in claim 1, wherein Y is unsubstituted imino or oxygen. 8. The compound as claimed in claim 1, wherein Y is oxygen. 9. The compound as claimed in claim 1 which is represented by the general formula (I-a ) : wherein Ar1 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of Cl to C6, straight- or branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of Cl to C6, straight- or branched- chain alkoxy group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of Cl to C6, carboxyl, alkanoyl group containing straight- or branched-chain alkyl group of Cl to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of Cl to C6, straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1, 2 or more than 2 oxo groups at a substitutable, arbitrary positions, and a group represented by formula of-Q-Ar2 ; At2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-chain alkyl group of Cl to C6, straight- or branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or branched-chain alkoxy group of Cl to C6, straight- or branched-chain alkoxy group of Cl to C6 substituted with 1,2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group mono-substituted with straight- or branched-chain alkyl group of C1 to C6, amino group di-substituted with identical or different straight- or branched-chain alkyl group of Cl to C6, alkanoyl group containing straight- or branched-chain alkyl group of Cl to C6 and aryl; Q represents a single bond or carbonyl; R1 represents hydrogen or halogen. 10. The compound as claimed in claim 9, wherein the aryl in Ar1 is phenyl. 11. The compound as claimed in claim 9, wherein the heteroaryl in Ar1 is imidazolyl, pyrazolyl, isoxazolyl, 1, 2, 4-thiadiazolyl, pyrazinyl, pyrimidinyl, quinolyl or pyrido [3,2-b] pyridyl. 12. The compound as claimed in claim 1 which is represented by the general formula (I-b): wherein Ar1 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of Cl to C6, straight- or branched- chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1,2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1, 2 or more than 2 oxo groups at a substitutable, arbitrary positions, and a group represented by formula of-Q- Ar2; Ar2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group mono-substituted with straight- or branched-chain alkyl group of C1 to C6, amino group di-substituted with identical or different straight- or branched-chain alkyl group of C1 to C6, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6 and aryl; Q represents a single bond or carbonyl; T, U, V and W represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of C1 to C6, hydroxy and straight- or branched-chain alkoxy group of C1 to C6, where at least two of them represent the said methine group. 13. The compound as claimed in claim 12, wherein the aryl in Ar1 is phenyl. 14. The compound as claimed in claim 12, wherein the heteroaryl in Ar1 is pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1, 2, 3- triazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or 1, 2, 4- triazinyl. 15. The compound as claimed in claim 12, wherein one of T, U, V and W is nitrogen. 16. The compound as claimed in claim 12, wherein V is nitrogen and each of T, U and W is unsubstituted methine group. 17. The compound of claim 1, which is N- (4-benzoylphenyl)-3-oxospiro[isoindoline-l,4'- piperidine]-1'-carboxamide, 3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-l,4'- piperidine]-1'-carboxamide, N- ( 7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1, 4'- piperidine]-1'-carboxamide, N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-l,4'-piperidine]-1'-carboxamide, N- (4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline- 1(2H),4'-piperidine]-1'-carboxamide, 3,4-dihydro-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, 3,4-dihydro-N-(7-methyl-2-quinolyl)-3- oxospiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, N- ( 4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline- 1(2H),4'-piperidine]-1'-carboxamide, 3,4-dihydro-3-oxo-N-[1-(2-quinolyl)-4- imidazolyl]spiro [isoquinoline-1 ( 2H), 4'-piperidine]-1'-carboxamide, 3,4-dihydro-3-oxo-N-(5-oxo-5, 6,7,8-tetrahydro-2- naphthyl)spiro[isoquinoline-l( 2H), 4'-piperidine]-1'-carboxamide, 3, 4-dihydro-N-[5- ( 2-methyl- 1-propenyl)-2-pyrazinyl ]-3- oxospirof isoquinoline-1(2H),4'-piperidine]-1'-carboxamide, 3,4-dihydro-3-oxo-N-(3-phenyl-5- is oxazolyl)spiro[ is oquinoline-1 ( 2H), 4'-piperidine]-1'- carboxamide, N-[l-(7-benzo[b]furanyl)-4-imidazolyl]-3, 4-dihydro-3- oxospiro[isoquinoline-l ( 2H), 4'-piperidine]-1'- carboxamide, N-[1- (3-difluoromethoxyphenyl)-4-imidazolyl]-3,4- dihydro-3-oxospiro[isoquinoline-l(2H), 4'-piperidine]-1'- carboxamide, 3,4-dihydro-3-oxo-N-[4-(2- pyridylcarbonyl)phenyl]spiro[isoquinoline-l( 2H), 4'- piperidine)-1'-carboxamide, N-(3,4-dichlorophenyl)-3,4-dihydro-3- oxospiro[isoquinoline-1(2H),4'-piperidine]-1'- carboxamide, N-[1-(3-chlorophenyl)-4-imidazolyl ]-3, 4-dihydro-3- oxospiro[isoquinoline-l(2H),4'-piperidine]-1'- carboxamide, 3,4-dihydro-3-oxo-N-(5-phenyl-2- thiazolyl)spiro[isoquinoline-1( 2H), 4'-piperidine]-1'- carboxamide, 3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2- pyrazinyl]spiro[ isoquinoline-1( 2H), 4'-piperidine]-1'- carboxamide, 3, 4-dihydro-N-( 4-methyl-2-benzothiazolyl)-3- oxospiro[isoquinoline-1( 2H), 4'-piperidine]-1'- carboxamide, N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3- oxospiro[isoquinoline-1 ( 2H),4'-piperidine]-1'- carboxamide, N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H), 4'- piperidine]-1'-carboxamide, 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, 3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, 3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2- yl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, 3-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran -1(3H),4'-piperidine]-1'-carboxamide, 3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, N-[5-(4-chlorophenyl)-3-pyrazolyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran- 1(3H),4'-piperidine]-1'-carboxamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-[5-(3-trifluoromethylphenyl)-2- pyrimidinyl]spiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, N-[5-(3-chlorophenyl)- 2-pyrimidinyl]-3- oxospiro[isobenzofuran-l(3H),4'-piperidine]-1'- carboxamide, N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 3-oxo-N-(5-phenyl-l,2,4-thiadiazol-3- yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, N-{l-[3-(2-hydroxyethyl)phenyl]-4-imidazoly}-3- oxospiro[isobenzofuran-1 (3H), 4'-piperidine]-1'- carboxamide, N-[4-(1-ethyl-2-imidazolyl)phenyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, N- [l-(3-methoxyphenyl)-4-imidazolyl]-3- oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'- carboxamide, 6-fluoro-3-oxo-N-(5-phenyl-2- pyrazinyl) spiro[isobenzof uran-1 ( 3H), 4'-piperidine ]-1'- carboxamide, 6-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl) spiro [isobenzof uran-1(3H),4'-piperidine]-1' carboxamide, 5-fluoro-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l ( 3H), 4'-piperidine]-1'- carboxamide, 5-flubro-3-oxo-N-(5-phenyl-2- pyrimidinyl) spiro [isobenzof uran- 1 ( 3H), 4'-piperidine]-1' carboxamide, N-(4-benzoylphenyl)-3, 4-dihydro-3-oxospiro[1H-2- benzopyran-1,4'-piperidine]-1'-carboxamide, 3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)sp±ro[ 1H-2- benzopyran-1, 4'-piperidine]-1'-carboxamide, N- ( 5-benzoyl-2-pyrazinyl)-3, 4-dihydro-3-oxospiro[ 1H-2- benzopyran-1, 4'-piperidine]-1'-carboxamide, trans-N- (4-benzoylphenyl)-3'-oxospiro[cyclohexane- 1,1' (3'H)-isobenzofuran]-4-carboxamide, trans-3'-oxo-N- (5-phenyl-2-pyrazinyl) spiro[cyclohexane- 1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-3'-oxo-N- (l-phenyl-4-imidazolyl) spiro[cyclohexane- 1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-3'-oxo-N- (5-phenyl-2-pyrimidinyl)spiro [cyclohexane -1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-N-[1-(3, 5-dif luorophenyl)-4-imidazolyl ]-3'- oxospiro[cyclohexane-1,1' (3'H)-isobenzofuran]-4- carboxamide, trans-3'-oxo-N- (5-phenyl- 3-pyrazolyl) spiro[cyclohexane- 1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-N-[l-(2- fluorophenyl)-4-imidazolyl ]-3'- oxospiro[cyclohexane-1,1' (3'H)-isobenzofuran]-4- carboxamide, trans-N- ( 4-acetyl-3-trif luoromethylphenyl)-3'- oxospiro[cyclohexane-1,1' (3'H)-isobenzofuran]-4- carboxamide, trans-3'-oxo-N-[1-(3-quinolyl)-4- imidazolyl] spiro [cyclohexane- 1, 1' ( 3' H)-isobenzofuran ]-4- carboxamide, trans-N-[1- ( 3-cyanophenyl)-'4-imidazolyl ]-3'- oxospirotcyclohexane-1.1'(3'H)-isobenzofuran]-4- carboxamide, trans-N- (4-benzoylphenyl)-3-oxospiro[4-azaisobenzof uran- 1(3H),1'- cyclohexane]-4'-carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4- azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4- azaisobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N- (5-phenyl-2-pyrimidinyl) spiro[4- azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide, trans-N- (4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran- 1(3H),1'- cyclohexane]-4'-carboxamide, trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran- 1(3H),1'- cyclohexane]-4'-carboxamide, N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3- oxospiro[isobenzofuran-1 ( 3H),4'-piperidine]-1'- carboxamide, N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3- oxospiro[isobenzofuran-1 ( 3H), 4'-piperidine ]-1'- carboxamide, 4-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl) spiro[isobenzofuran-1( 3H), 4'-piperidine]-1'- carboxamide, 7-fluoro-3-oxo-N-(5-phenyl-2- pyrimidinyl) spiro[isobenzofuran-1( 3H), 4'-piperidine]-1'- carboxamide, 6-ethyl-3-oxo-N-(5-phenyl-2- pyrazinyl) spiro[isobenzofuran-1 ( 3H), 4'-piperidine]-1'- carboxamide. 6-hydroxy-3-oxo-N-(5-phenyl-2- pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide, trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-1(3H), 1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide, trans-N-[5- ( 3-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide, trans-N-[5- (3-[luoromethoxyphenyl)-2-pyrimidinyl]-3- oxospiro[ 5-azaisobenzof uran-1 ( 3H), 1'-cyclohexane]-4'- carboxamide, trans-N-[5- (3-[luoromethylphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzof uran-1 ( 3H), 1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-[luoro-5-methoxyphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzof uran-1 ( 3H), 1'-cyclohexane ]-4'- carboxamide, trans-N-[5- ( 2-[luoro-5-methylphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzof uran- 1 ( 3H), 1'-cyclohexane]-4'- carboxamide, trans-N-[4- ( 3-[luoromethoxyphenyl)-2-oxazolyl ]-3- oxospiro[5-azaisobenzof uran-1 ( 3H),1'-cyclohexane]-4'- carboxamide, ' trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3- oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'- carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6- azaisobenzofuran-l(3H)»1'-cyclohexane]-4'-carboxamide, trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3- oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3- oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'- carboxamide, trans-3-oxo-N-(6-phenyl-1,2,4-triazin-3-yl)spiro[6- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3- oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'- carboxamide, trans-N- [5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3- oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'- carboxamide, trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N- ( 4-benzoylphenyl)-3-oxospiro[7-azaisobenzofuran- 1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3- oxospiro[7-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7- azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-az aisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(5-phenyl-1, 2,4-thiadiazol-3-yl)spiro[6-az aisobenzofuran-1(3H),1'-cyclohexane]- 4'-carboxamide, trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzo furan-1(3H),1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azaisobenzofur an-1(3H), 1'-cyclohexane]-4'-carboxamide, trans-3-oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-l (3H), 1'- cyclohexane]-4'-carboxamide or trans-3-oxo-N-(2-phenyl-l, 2, 3-triazol-4-yl)spiro[6-azaisobenzofuran- 1(3H), 1'-cyclohexane]-4'-carboxamide. 18. The compound as claimed in claim 1, which is 3-oxo-N-(5-phenyl-2- pyrazinyl)-spiro[isobenzofuran-l(3H), 4'-piperidine]-r-carboxamide. 19. The compound as claimed in claim 1, which is 3-oxo-N-(7- txifluoromethylpyrido[3, 2-b]pyridin-2-yl)spiro[isobenzofuran-l(3H), 4'- piperidine]-r-carboxamide. 20. The compound as claimed in claim 1, which is N-[5(3-fluorophenyl)- 2-pyrimidinyl]-3-oxospiro[isobenzofuran-l(3H),4'-piperidine]-r- carboxamide. 21. The compound as claimed in claim 1, which is trans-3'-oxo-N-(5- phenyl-2-pyrimidinyl)spiro[cyclohexane-1, 1'(3'H)-isobenzofuran]-4- carboxamide. 22. The compound as claimed in claim 1, which is trans-3'-oxo-N-[l-(3- quinolyl)-4-imidazolyl]spiro[cyclohexane-1, l'(3'H)-isobenzofuran]-4- carboxamide. 23. The compound as claimed in claim 1, which is trans-3-oxo-N-(5- phenyl-2-pyrazinyl)spiro[4-a2jaisobenzoniran-l(3H), 1'-cyclohexane]-4'- carboxamide. 24. The compound as claimed in claim 1, which is trans-N-[5-(3- fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1 (3H), 1'- cyclohexane]-4-'-carboxamide. 25. The compound as claimed in claim 1, which is trans-N-[5-(2- fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1 (3H), 1'- cyclohexane]-4'-carboxamide. 26. The compound as claimed in claim 1, which is trans-N-[l-(3, 5- difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1 (3H), 1'- cyclohexane]-4'-carboxamide. 27. The compound as claimed in claim 1, which is trans-3-oxo-N-(l- phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-l(3H), 1'-cyclohexane]-4'- carboxamide. 28. The compound as claimed in claim 1, which is trans-3-oxo-N-(l- phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-l(3H), 1'-cyclohexane]-4'- carboxamide. 29. The compound as claimed in claim 1, which is trans-3-oxo-N-(2- phenyl-1, 2, 3-triazol-4-yl)spiro[6-azaisobenzofuran-l(3H), 1'- cyclohexane]-4'-carboxamide. 30. A process for producing a spiro compound of the general formula (I-1): wherein Ar1 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of C1 to C6, straight- or branched- chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1, 2 or more than 2 oxo groups at a substitutable, arbitrary positions, and a group represented by formula of-Q- V; Ar2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group mono-substituted with straight- or branched-chain alkyl group of C1 to C6, amino group di-substituted with identical or different straight- or branched-chain alkyl group of C1 to C6, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6 and aryl; Q represents a single bond or carbonyl; T, U, V and W represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of C1 to C6, hydroxy and straight- or branched-chain alkoxy group of C1 to C6, where at least two of them represent the said methine group; n and Y have the same meanings as described hereinafter; a salt or ester thereof, which comprises reacting a compound of the general formula (II): wherein Arlp represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of C1 to C6, straight- or branched- chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of C1 to C6 straight- or branched-chain alkoxy of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of C1 to C6, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of C1 to C6, a group of formula:-QpAr2p, and an optionally protected, (i) straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1, 2 or more than 2 oxo groups, (ii) straight- or branched- chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, or (iii) carboxyl group; Ar2p represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group di-substituted with identical or different straight- or branched-chain alkyl group of C1 to C6, alkanoyl group containing straight- or branched- chain alkyl group of C1 to C6, aryl, and an optionally protected, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy or amino group mono-substituted with straight- or branched-chain alkyl group of C1 toC6; Ar3 represents phenyl which may be substituted by halogen or nitro; Qp represents a single bond or optionally protected carbonyl; with a compound of formula (HI): wherein n represents 0 or 1; t, u, v and w represent independently nitrogen atom methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of C1 to C6, straight- or branched- chain alkoxy group of C1 to C6 and optionally protected hydroxy, where at least two of them represent the said methine group; Y represents imino which may be substituted with straight- or branched- chain alkyl group of C1 to C6, or oxygen atom; to provide a compound of formula (IV-1): wherein Arlp, n, t, u, v, w and Y have the same meanings as described above; optionally followed by elimination of a protecting group. 31. A process for producing a spiro compound of the general formula (1-2): wherein Ar1 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of C1 to C6, straight- or branched- chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, cycloalkyl group of C3 of C6, straight- or branched-chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1, 2, or more than 2 oxo groups at a substitutable, arbitrary positions, and a group represented by formula of-Q- Ar2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group mono-substituted with straight- or branched-chain alkyl group of C1 to C6, amino group di-substituted with identical or different straight- or branched-chain alkyl group of C1 to C6, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6 and aryl; Q represents a single bond or carbonyl; T, U, V and W represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of C1 to C6, hydroxy and straight- or branched-chain alkoxy group of C1 to C6, where at least two of them represent the said methine group; n and Y have the same meanings as described hereinafter; a salt or ester thereof, which comprises reacting a compound of formula (V): Ar1p —NH2 (V) wherein Arlp represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of C1 to C6, straight- or branched- chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of C1 to C6, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of C1 to C6, a group of formula:-Qp-Ar2p, and an optionally protected, (i) straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1, 2 or more than 2 oxo groups, (ii) straight- or branched- chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, or (iii) carboxyl group; Ar2p represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1,2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group di-substituted with identical or different straight- or branched-chain alkyl group of C1 to C6, alkanoyl group containing straight- or branched- chain alkyl group of C1 to C6, aryl, and an optionally protected, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy or amino group mono-substituted with straight- or branched-chain alkyl group of C1 toC6; Qp represents a single bond or optionally protected carbonyl; with a carboxylic acid of the general formula (VI): wherein n represents 0 orl; t, u, v and w represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of C1 to C6, straight- or branched- chain alkoxy group of C1 to C6 and optionally protected hydroxy, where at least two of them represent the said methine group; Y represents imino which may be substituted with straight- or branched- chain alkyl group of C1 to C6, or oxygen atom; or a reactive derivative thereof to provide a compound of the general formula (IV-2): wherein Ar1p, n, t, u, v, w and Y have the same meanings as described above; optionally followed by elimination of a protecting group. 32. Neuropeptide Y receptor antagonist which contains a compound of the general formula (I) : wherein Ar1 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of C1 to C6, straight- or branched- chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1, 2 or more than 2 oxo groups at a substitutable, arbitrary positions, and a group represented by formula of-Q- Ar2; Ar2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group mono-substituted with straight- or branched-chain alkyl group of C1 to C6, amino group di-substituted with identical or different straight- or branched-chain alkyl group of C1 to C6, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6 and aryl; n represents 0 orl; Q represents a single bond or carbonyl; T, U, V and W represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of C1 to C6, hydroxy and straight- or branched-chain alkoxy group of C1 to C6, where at least two of them represent the said methine group; X represents methine or nitrogen; Y represents imino which may be substituted with straight- or branched- chain alkyl group of C1 to C6, or oxygen; a salt or ester thereof as an active ingredient. 33. An agent for the treatment of bulimia, obesity or diabetes which contains a spiro compound of the general formula (I) : wherein Ar1 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, nitro, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, cycloalkyl group of C3 to C6, straight- or branched- chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6 which may be substituted with 1, 2 or more than 2 oxo groups at a substitutable, arbitrary positions, and a group represented by formula of-Q-Ar2; Ar2 represents aryl or heteroaryl which may be substituted, the substituent being selected from the group consisting of halogen, cyano, straight- or branched-'Chain alkyl group of C1 to C6, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or branched-chain alkoxy group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms identically or differently at the substitutable, arbitrary positions, amino group mono- substituted with straight- or branched-chain alkyl group of C1 to C6, amino group di-substituted with identical or different straight- or branched-chain alkyl group of C1 to C6, alkanoyl group containing straight- or branched-chain alkyl group of C1 to C6 and aryl; n represents 0 or 1; Q represents a single bond or carbonyl; T, U, V and W represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of C1 to C6, hydroxy or straight- or branched-chain alkoxy group of C1 to C6, where at least two of them represent the said methine group; X represents methine or nitrogen; Y represents imino which may be substituted with straight- or branched-chain alkyl group of C1 to C6, or oxygen; a salt or ester thereof as an active ingredient. 34. A spiro compound of the general formula (VI-1) : wherein t, u, v and w represent independently nitrogen atom or methine group which may have a substituent selected from the group consisting of halogen, straight- or branched-chain alkyl group of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6 and optionally protected hydroxy, where at least two of them represent the said methine group. 35. The compound of the present product as claimed in claim 1, which is trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenz ofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide. 36. The compound of the present product as claimed in claim 1, which is trans-N-[5-(2-methylphenyI)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide. 37. The compound of the present product as claimed in claim 1, which is trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6- azaisobenzofuran-1 (3H),1'-cyclohexane]-4'-carboxamide. 38. The compound of the present product as claimed in claim 1, which is trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiro[7- azaisobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide. 39. The compound of the present product as claimed in claim 1, which is trans-N-[l-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4- azaisobenzofuran-l(3H),r-cyclohexane]-4'-carboxamide. 40. The compound of the present product as claimed in claim 1, which is trans-N-[l-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azaisobenzofuran-l(3H),l'-cyclohexan e]-4'-carboxamide. Spiro compounds of the general formula (1): wherein Ar1 represents an optionally substituted ary) or beteroaryl; n represents 0 or 1; T, U, V and W each represent a nitrogen atom or an optionally substituted methane group, wherein at least two of which represent said methane group; X represents nitrogen; Y represents an optionally substituted imino or oxygen atom, which exhibit neuropeptide Y receptor (NPY) antagonistic activities and are useful as agents for the treatment of various diseases related to NPY, for example, cardiovascular disorders, central nervous system disorders, metabolic diseases and the like.

Full Text

DESCRIPTION
Novel Spiro Compounds
Technical Field
The present invention is useful in medical fields.
In more detail, novel spiro compounds of this invention are
useful as neuropeptide Y receptor antagonists and as agents
for the treatment of various kinds of cardiovascular
disorders, central nervous system disorders, metabolic
diseases, and the like.
Background Art
Neuropeptide Y (hereinafter referred to as NPY), a
peptide consisting of 36 amino acids, was first isolated from
porcine brain by Tatemoto et al. in 1982 [Nature, 296: 659
(1982)]. NPY is widely distributed in central nervous
system and peripheral nervous system and plays various roles
as one of the most abundant peptide in the nervous system.
That is, NPY acts as an orexigenic substance in the central
nervous system and markedly promotes fat accumulation via
the mediation of the secretion of various hormones or the
action of the nervous system. It is known that the-
continuous intracerebroventricular administration of NPY
induces obesity and insulin resistance based on these
actions (International Journal of Obesity, vol.19: 517
(1995); Endocrinology, vol.133: 1753 (1993)). It is also
known that NPY has central effects, such as depression,
anxiety, schizophrenia, pain, dementia and the like (Drugs,
vol. 52, 371(1996). Further, in the periphery, NPY coexists
with norepinephrine in sympathetic ending and is involved
in the tonicity of the sympathetic nervous system. It is
known that peripheral administration of NPY causes
vasoconstriction and enhances the activities of other
vasoconstrictive substances such as norepinephrine (British
Journal of Pharmacology, vol.95: 419 (1988)). It is also
reported that NPY could participate in the development of
cardiac hypertrophy as a result of the sympathic stimulation
(Proceeding National Academic Science USA, Vol. 97,
1595(2000)).
On the other hand, it is reported that NPY is also
involved in the secretory function of sexual hormones and
growth hormone, sexual behavior and reproductive function,
gastro-intestinal motility, bronchoconstriction,
inflammation and alcohol preference (Life Science, vol. 55,
551(1994); The Journal of Allergy and Immunology, vol. 101,
S345(1998); Nature, vol. 396, 366(1998)).
NPY has a variety of pharmacological effects which
result from NPY binding to the NPY receptors. Other NPY
related peptides, including peptide YY and pancreatic
polypeptide also bind to the NPY receptors. It is known
that these pharmacological effects are mediated by the
action of, at least, five receptor subtypes with or without
synergistic interactions. (Trends in Neuroscience, vol. 20,
294(1997)).
Y1: It is reported that the central effect mediated by NPY
Y1 receptor includes the remarkable orexigenic effect
(Endocrinology, vol. 137, 3177(1996); Endocrinology, vol.
141, 1011(2000)). Further, the Y1 receptor is reported to
be involved in anxiety and pain (Nature, vol. 259, 528(1993);
Brain Research, vol. 859, 361(2000)). In addition, the
pressor effects mediated by the strong action of
vasoconstriction in the periphery by NPY is also reported
to be mediated by Y1 (FEBS Letters, vol. 362, 192(1995);
Nature Medicine, vol. 4, 722(1998)).
Y2: It is known that the inhibitory effect on the release
of various neurotransmitters in the sympathetic nerve
endings is mediated by the NPY Y2 receptor (British Journal
of Pharmacology, vol. 102, 41(1991); Synapse, vol. 2,
299(1988) ). In periphery, NPY causes constriction of blood
vessel or vas def erens directly or via the control of release
of various neurotransmitters (The Journal of Pharmacology
and Experimental Therapeutics, vol. 261, 863(1992); British
Journal of Pharmacology, vol. 100, 190(1990)). In addition,
inhibition of lipolysis in adipose tissues is known
(Endocrinology, vol. 131, 1970(1992)). Further, the
inhibition of ion secretion in the gastro-intestinal tract
is reported (British Journal of Pharmacology, vol. 101
247(1990) ).
On the other hand, the inhibitory effect on the central
nervous system functions such as memory and anxiety is also
reported (Brain Research, vol. 503, 73(1989); Peptides, vol.
19, 359(1998)).
Y3: It is reported that NPY Y3 receptor is mainly located
at brainstem and in the heart and is related to regulation
of blood pressure and heart rate (The Journal of Pharmacology
and Experimental Therapeutics, vol. 258, 633(1991);
Peptides, vol. 11, 545(1990)). Further, it is known that
the Y3 receptor is involved in the control of catecholamine
secretion in adrenal gland ( (The Journal of Pharmacology and
Experimental Therapeutics, vol. 244, 468(1988); Life
Science, vol. 50, PL7(1992)).
Y4: NPY Y4 receptor has high affinity for pancreatic
polypeptide. The related pharmacological effects reported
to be mediated by the Y4 receptor include the inhibition of
pancreatic secretion and the gastro-intestinal motility
(Gastroenterology, vol.85, 1411(1983)). Further, it is
reported that NPY enhances the secretion of the sexual
hormone in the central nervous system (Endocrinology, vol.
140, 5171(1999)).
Y5: The effect mediated by NPY Y5 receptor includes feeding
stimulation and accumulation of fat: (Nature, vol. 382,
168(1996)); American Journal of Physiology, vol. 277,
R1428(1999) ). It is reported that the NPY Y5 receptor also
mediates some CNS effects, such as seizure and epilepsy, or
pain and the morphine withdrawal symptoms (Natural Medicine,
vol. 3, 761(1997); Proceeding Academic Science USA, vol. 96,
13518(1999); The Journal of Pharmacology and Experimental
Therapetlcs, vol. 284, 633(1998)). In the periphery, the
Y5 receptor is reported to be involved in diuresis and
hypoglicemic effect caused by NPY (British Journal of
Pharmacology, vol. 120, 1335(1998); Endocrinology, vol. 139,
3018(1998)). NPY is also reported to enhance cardiac
hypertrophy as a result of the sympathic accentuation
(Proceeding National Academic Science USA, Vol. 97,
1595(2000) ).
The effects of NPY occur by binding to the NPY
receptors in the central or peripheral nervous system.
Therefore, the action of NPY can be prevented by blocking
the binding to NPY receptors. Substances antagonize NPY
binding to NPY receptors may be useful for the prophylaxis
or treatment of various diseases related to NPY, such as
cardiovascular disorders (for example hypertension,
nephropathy, heart disease, vasospasm), central nervous
system disorders (for example bulimia, depression, anxiety,
seizure, epilepsy, dementia, pain, alcoholism, drug
withdrawal), metabolic diseases (for example obesity,
diabetes, hormone abnormality), sexual and reproductive
dysfunction, gastro-intestinal motility disorder,
respiratory disorder, inflammation or glaucoma and the like
(Trends in Pharmacological Sciences, 15: 153 (1994); Life
Science,. 55, 551(1994); Drugs, vol. 52, 371(1996); The
Journal of Allergy and Immunology, vol. 101, S345(1998);
Nature, vol. 396, 366(1998); The Journal of Pharmacology and
Experimental Therapeutics, vol. 284, 633(1998); Trends in
Pharmacological Science, vol. 20, 104(1999); Proceeding
National Academic Science USA, vol. 97, 1595(2000)).
Recently, according to the investigation of the
present inventors, it has been found that some kind of NPY
receptor antagonist is useful in the prophylaxis or
treatment of hypercholesterolemia, hyperlipidemia and
arteriosclerosis [International application publication
WO99/27965].
Disclosure of Invention
The object of the present invention is to provide novel
medicines which exhibit NPY antagonistic activities.
The present inventors have discovered that the
compounds of the general formula (I} :
wherein Ar1 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, nitro, lower alkyl, halo(lower )alkyl,
hydroxy(lower)alky1, cyclo(lower)alkyl, lower alkenyl,
lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl,
lower alkanoyl, lower alkoxycarbonyl, lower alkylene
optionally substituted with oxo, and a group represented by
formula of-Q-Ar2;
Ar2 represents aryl or heteroaryl which may be substituted,
the substituent being selected from the group consisting of
halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy,
halo(lower)alkoxy, lower alkylamino, di-lower alkylamino,
lower alkanoyl and aryl;
n represents 0 orl;
Q represents a single bond or carbonyl;
T, U, V and W represent independently nitrogen atom or
methine group which may have a substituent selected from the
group consisting of halogen, lower alkyl, hydroxy and lower
alkoxy, where at least two of them represent the said methine
group;
X represents methine group or nitrogen;
Y represents imino which may be substituted with lower alkyl,
or oxygen;
exhibit NPY antagonistic activities and is useful as a
therapeutic agent for treatment of various diseases
associated with NPY, thereby completing the present
invention.
Compounds of the present invention (I) are useful as
agents for the treatment of various diseases related to NPY,
that is, for example cardiovascular disorders (for example
hypertension, nephropathy, heart disease, vasospasm,
arteriosclerosis), central nervous system disorders (for
example bulimia, depression, anxiety, seizure, epilepsy,
dementia, pain, alcoholism, drug withdrawal), metabolic
diseases (for example obesity, diabetes, hormone
abnormality, hypercholesterolemia, hyperllpidemia),
sexual and reproductive dysfunction, gastro-lntestinal
disorder, respiratory disorder, inflammation, or glaucoma,
and the like.
More particulary, compounds of this invention (I) is
useful as agents for the treatment of bulimia, obesity,
diabetes, and the like.
The present invention refers to compounds of the
general formula (I), the salts or esters thereof, and the
process for production and use.
In another embodiment, the present invention is
related to the intermediate for producing the compound
represented by the general formula (I). Specifically, it is
related to the compound represented by the general formula
(VI-1):

wherein t, u, v and w represent independently nitrogen atom
or methine group which may have a substituent selected from
the group consisting of halogen, lower alkyl, lower alkoxy
and optionally protected hydroxy, where at least two of them
represent the said methine group.
The means of terms used in the present specification
are defined and more detailed description of this invention
is shown in the following.
"Halogen atom" refers to fluorine atom, chlorine atom,
bromine atom and iodine atom.
"Lower alkyl" refers to a straight- or branched-chain
alkyl group of Cl to C6, for example, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, hexyl, isohexyl, and the like.
"Halo(lower)alkyl" refers to the aforesaid lower
alkyl substituted with 1 or more than 2, preferably 1 to 3
aforesaid halogen atoms identically or differently at the
substitutable, arbitrary positions, for example.
fluoromethyl, difluoromethyl, trifluoromethyl, 2-
fluoroethyl, 1,2-difluoroethyl, chloromethyl, 2-
chloroethyl, 1,2-dichloroethyl, broraomethyl, iodomethyl,
and the like.
"Hydroxy(lower)alkyl" refers to the aforesaid lower
alkyl substituted with 1 or more than 2, preferably 1 or 2
hydroxy groups at the substitutable, arbitrary positions,
for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-
methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, and the
like.
"Cyclo(lower)alkyl" refers to a cycloalkyl group of
C3 to C6, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and the like.
"Lower alkenyl" refers to a straight- or
branched-chain alkenyl group of C2 to C6, for example, vinyl,
1-propenyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl,
1-butenyl, l-methyl-2-propenyl, 1-methyl-l-propenyl, 1-
ethyl-1-ethenyl, 2-methyl-2-propenyl,, 2-methyl-l-propenyl,
3-methyl-2-butenyl, 4-pentenyl, and the like.
"Lower alkoxy" refers to a straight- or branched-
chain alkoxy group of Cl to C6, for example, methoxy, ethoxy,
propoxy, isopropoxy, butoxy, sec-butoxy, lsobutoxy,
tert-butoxy, pentyloxy, isopentyloxy, hexyloxy,
isohexyloxy, and the like.
"Halo(lower)alkoxy" refers to the aforesaid lower
alkoxy substituted with 1 or more thcin 2, preferably 1 to
3 aforesaid halogen atoms identically or differently at the
substitutable, arbitrary positions, for example,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-
fluoroethoxy, 1, 2-difluoroethoxy, chloromethoxy, 2-
chloroethoxy, 1, 2-dichloroethoxy, bromomethoxy,
iodomethoxy, and the like.
"Lower alkylthio" refers to a straight- or
branched-chain alkylthio group of Cl to C6, for example,
methylthio, ethylthio, propylthio, isopropylthio,
butylthlo, sec-butylthio, isobutylthio, tert-butylthio,
pentylthio, isopentylthio, hexylthio, isohexylthio, and the
like.
"Lower alkanoyl" refers to an alkanoyl group
containing the aforesaid lower alkyl, that is, an alkanoyl
group of C2 to C7, for example acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, plvaloyl, and the like.
"Lower alkoxycarbonyl" refers to an alkoxycarbonyl
group containing the aforesaid lower alkoxy, that is, an
alkoxycarbonyl group of C2 to C7, for example,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl, pentyloxycarbonyl, and the like.
"Lower alkylene optionally substituted with oxo"
refers to a straight- or branched-chain alkylene group of
C2 to C6 which may be substituted with 1 or more than 2,
preferably 1 oxo group at a substitutable, arbitrary
position, for example, ethylene, trimethylene,
tetramethylene, pentamethylene, hexamethylene, 1-
oxoethylene, 1-oxotrimethylene, 2-oxotrimethylene, 1-
oxotetramethylene, 2-oxotetramethylene, and the like.
"Aryl" includes phenyl, naphthyl, and the like.
"Heteroaryl" refers to 5- or 6-membered monocylic
heteroaromatic group which contains 1 or more than 2,
preferably 1 to 3 hetero atoms identically or differently
selected from the group of oxygen atom, nitrogen atom and
sulfur atom; or condensed heteroaromatic group, where the
aforesaid monocylic heteroaromatic group is condensed with
the aforesaid aryl group, or with the identified or different
aforesaid monocylic heteroaromatic group each other, for
example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,3-
triazolyl, 1, 2,4-triazolyl, tetrazolyl, oxadiazolyl,
1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-
thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
1,2,4- triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl,
benzothienyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, purinyl, quinolyl, isoquinolyl, phthalazyl,
naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl,
pteridinyl, pyrido[3,2-b]pyridyl, and the like.
"Lower alkylamino" refers to an amino group mono-
substituted with the aforesaid lower alkyl, for example,
methylamino, ethylamino, propylami.no, isopropylamino,
butylamino, sec-butylamino, tert-butylamino, and the like.
"Di-lower alkylamino" refers to an amino group
di-substituted with identical or different aforesaid lower
alkyl, for example, dimethylamino, diethylamino,
ethylmethylamino, dipropylamino, methylpropylamino,
diisopropylamino, and the like.
The salts of compounds of formula (I) refer to the
pharmaceutically acceptable and common salts, for example.
base addition salt to carboxyl group when the compound has
a carboxyl group, or acid addition salt to amino or basic
heterocyclyl when the compound has an amino or basic
heterocyclyl group, and the like.
Aforesaid base addition salts include salts with
alkali metals (for example sodium, potassium); alkaline
earth metals (for example calcium, magnesium); ammonium or
organic amines (for example trimethylamine, triethylamine,
dicyclohexylamine, ethanolamine, dlethanolamine,
triethanolamine, procaine, N,N'-dibenzylethylenediamine),
and the like.
Aforesaid acid addition salts include salts with
inorganic acids (for example hydrochloric acid, sulfuric
acid, nitric acid, phosphoric acid, perchloric acid),
organic acids (for example maleic acid, fumaric acid,
tartaric acid, citric acid, ascorbic acid, trifluoroacetic
acid), sulfonic acids (for example methanesulfonic acid,
Isethionic acid, benzenesulfonic acid, p-toluenesulfonic
acid), and the like.
The esters of compounds of formula (I) refer to, for
example, the pharmaceutically acceptable, common esters on
carboxyl group when the compound has a carboxyl group, for
example, esters with lower alkyls ( for example methyl, ethyl,
propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, cyclopropyl, cyclobutyl,
cyclopentyl), aralkyls (for example benzyl, phenethyl),
lower alkenyls (for example allyl, 2-butenyl), lower alkoxy
(lower) alkyls (for example methoxymethyl, 2-methoxyethyl,
2-ethoxyethyl), lower alkanoyloxy (lower) alkyls (for
example acetoxymethyl, pivaloyloxy-methyl, 1-
pivaloyloxyethyl), lower alkoxycarbonyl (lower) alkyls (for
example methoxycarbonylmethyl, isopropoxycarbonylmethyl),
carboxy-(lower)alkyls (for example carboxymethyl), lower
alkoxycarbonyloxy-(lower)alkyls (for example 1-
(ethoxycarbonyloxy)ethyl, 1-(cyclohexyl-
oxycarbonyloxy)ethyl), carbamoyloxy(lower)alkyls (for
example carbamoyloxymethyl), phthalidyl group, (5-
substituted-2-oxo-l,3-dioxol-4-yl)methyl (for example
(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl), and the like.
"An agent for treatment" refers to a medicament which
is employed for the treatment and/or prophylaxis of various
diseases.
In order to disclose the aforesaid compounds of the
general formula (I) more detailed, the various symbols used
in the formula (I) are explained in more detail by the use
of preferred embodiments.
Ar1 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, nitro, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl,
lower alkoxy, halo (lower )alkoxy, lower alkylthio, carboxyl,
lower alkanoyl, lower alkoxycarbonyl, lower alkylene
optionally substituted with oxo, and a group represented by
formula of-Q-Ar2.
"Aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of
halogen, nitro, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl.
lower alkoxy, halo (lower )alkoxy, lower alkylthio, carboxyl,
lower alkanoyl, lower alkoxycarbonyl, lower alkylene
optionally substituted with oxo, and a group represented by
formula of-Q-Ar2" refers to unsubstituted aforesaid aryl
or aforesaid heteroaryl, or the aforesaid aryl or aforesaid
heteroaryl which has substituent(s) at the substitutable,
arbitrary position(s). The aforesaid substituent can be.
Identically or differently, one or more than 2, preferably
1 or 2 selected from the group consisting of halogen, nitro,
lower alkyl, halo(lower)alkyl, hydroxy(lower)alky1,
cyclo(lower)alkyl, lower alkenyl, lower alkoxy,
halo(lower)alkoxy, lower alkylthio, carboxyl, lower
alkanoyl, lower alkoxycarbonyl, lower alkylene optionally
substituted with oxo, and a group of formula:-Q-Ar2.
Halogen atom as the aforesaid substituent includes
fluorine atom, chlorine atom, and the like preferably.
Lower alkyl as the aforesaid substituent includes
methyl, ethyl, propyl, isopropyl, and the like preferably.
Halo(lower)alkyl as the aforesaid substituent
includes difluoromethyl, trifluoromethyl, and the like
preferably.
Hydroxy(lower)alkyl as the aforesaid substituent
includes hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-l-
methylethyl, and the like preferably.
Cyclo(lower)alkyl as the aforesaid substituent
includes cyclopropyl, cyclobutyl, and the like preferably.
Lower alkenyl as the aforesaid substituent includes
vinyl, 1-propenyl, 2-methyl-1-propenyl, and the like
preferably.
Lower alkoxy as the aforesaid substituent includes
methoxy, ethoxy, and the like preferably.
Halo(lower)alkoxy as the aforesaid substituents
includes fluoromethoxy, difluoromethoxy, trifluoromethoxy,
and the like preferably.
Lower alkylthio as the aforesaid substituent includes
methylthio, ethylthio, and the like preferably.
Lower alkanoyl as the aforesaid substituent includes
acetyl, propionyl, and the like preferably.
Lower alkoxycarbonyl as the aforesaid substituent
includes methoxycarbonyl, ethoxycarbonyl, and the like
preferably.
Lower alkylene optionally substituted with oxo as the
aforesaid substituent includes 1-oxotetramethylene, and the
like preferably.
In a group of formula:-Q-Ar2 as the aforesaid
substituent, Ar2 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy,
halo(lower)alkoxy, lower alkylamino, di-lower alkylamino,
lower alkanoyl and aryl;
Q represents a single bond or carbonyl.
"Aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of
halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy,
halo(lower)alkoxy, lower alkylamino, di-lower alkylamino,
lower alkanoyl and aryl" refers to unsubstituted aforesaid
aryl or aforesaid heteroaryl, or the aforesaid aryl or
aforesaid heteroaryl which has substituent(s) at the
substitutable, arbitrary position!s). The aforesaid
substituent can be, identically or differently, one or not
less than 2, preferably 1 or 2 selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy,
halo(lower)alkoxy, lower alkylamino, di-lower alkylamino,
lower alkanoyl and aryl.
Halogen atom as the aforesaid substituent includes,
preferably, fluorine atom, chlorine atom, and the like.
Lower alkyl as the aforesaid substituent includes,
preferably, methyl, ethyl, propyl, isopropyl, and the like.
Halo(lower)alkyl as the aforesaid substituent
includes, preferably, difluoromethyl, trifluoromethyl, and
the like.
Hydroxy(lower)alkyl as the aforesaid substituent
includes, preferably, hydroxymethyl, 2-hydroxyethyl, 1-
hydroxy-1-methylethyl, and the like.
Lower alkoxy as the aforesaid substituent includes,
preferably, methoxy, ethoxy, and the like.
Halo(lower)alkoxy as the aforesaid substituent
includes, preferably, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, and the like.
Lower alkylamino as the aforesaid substituent
includes, preferably, methylamino, ethylamino, and the
like.
Di-lower alkylamino as the aforesaid substituent
includes, preferably, dimethylamino, diethylamino, and the
like.
Lower alkanoyl as the aforesaid substituent includes,
preferably, acetyl, propionyl, and the like.
Aryl as the aforesaid substituent includes,
preferably, phenyl, and the like.
The substituent(s) of Ar2 include, preferably,
halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alky1, hydroxy, halo(lower)alkoxy, and the
like.
Aryl in Ar2 includes, preferably, phenyl, and the like
and heteroaryl includes imidazolyl, pyridyl, benzofuranyl,
quinolyl, and the like.
Consequently, a group of formula:-Q-Ar2 includes, for
example, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-
fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,
3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-
chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-
fluoro-5-methylphenyl, 3-fluoromethylphenyl, 2-
trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-
trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3-
fluoromethoxyphenyl, 3-difluoromethoxyphenyl, 3-(2-
hydroxyethyl)phenyl, 3-hydroxymethylphenyl, 3-(l-
hydroxy-1-methylethyl)phenyl, 3-hydroxyphenyl, 4-
hydroxyphenyl, 2-imidazolyl, 1-ethyl-2-imidazolyl,
l,2,4-thiadiazol-5-yl, 1,3,4-thiadiaol-2-yl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-ethyl-4-pyridyl, 4-pyrimidlnyl,
5-pyrimidinyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 7-
benzo[b]furanyl, 2-quinolyl, 3-guinolyl, 4-quinolyl, 5-
qulnolyl, 6-quinolyl, 8-quinolyl, benzoyl, 2-
pyridylcarbonyl, and the like, and preferably, phenyl,
2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 3-
chlorophenyl, 4-chlorophenyl, 3-cyanophenyl, 3-
trlfluoromethylphenyl, 3-difluoromethoxyphenyl, 3-(2-
hydroxyethyl)phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
1-ethyl-2-imidazolyl, 2-pyridyl, 7-benzo[b]furanyl, 2-
quinolyl, 3-qulnolyl, benzoyl, 2-pyridylcarbonyl, and the
like.
The substltuent of Ar1 includes, preferably, halogen,
lower alkyl, halo(lower)alkyl, lower alkenyl, lower
alkanoyl, lower alkylene optionally substituted with oxo,
and a group of formula:-Q-Ar2, and the like.
Aryl in Ar1 includes, preferably, phenyl, and the like
and heteroaryl of Ar1 includes pyrrolyl, lmidazolyl,
pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-
triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, 1,2,4-triazinyl, benzoxazolyl,
benzothiazolyl, quinolyl, pyrido[3,2-b]pyridyl, and the
like.
Consequently, Ar1 includes, for example, 3-
fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-
chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-
acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl, 4-
acetyl-3-trifluoromethylphenyl, 4-(l-ethyl-2-
imidazolyl)phenyl, 3-(2-pyridyl)phenyl, 3-(4-
pyridyl)phenyl, 4-(2-pyridyl)phenyl, 4-(3-pyridyl)phenyl,
4-(2-ethyl-4-pyridyl)phenyl, 4-(4-pyrimidinyl)phenyl, 4-
benzoylphenyl, 4-(2-pyridylcarbonyl)phenyl, 1-phenyl-3-
pyrrolyl, l-phenyl-4-imidazolyl, 1-(2-fluorophenyl)-4-
imidazolyl, 1-(3-fluorophenyl)-4-imidazolyl, l-(4-
fluorophenyl)-4-imidazolyl, 1-(2,3-difluorophenyl)-4-
imidazolyl. 1-(2,4-dlfluorophenyl)-4-imidazolyl, l-(3,5-
difluorophenyl)-4-imidazolyl, 1-(3-chlorophenyl)-4-
imidazolyl, 1-(2-cyanophenyl)-4-imidazolyl, l-(3-
cyanophenyl)-4-imidazolyl, 1-(4-cyanophenyl)-4-
imidazolyl, 1-(3-trifluoromethylphenyl)-4-imidazolyl, 1-
[3-(2-hydroxyethyl)phenyl]-4-imidazolyl, 1-[ 3-(1-
hydroxy-1-methylethyl)phenyl]-4-imidazolyl, 1-(3-
methoxyphenyl)-4-imidazolyl, 1-(2-
difluoromethoxyphenyl)- 4-imidazolyl, 1-(3-
difluoromethoxyphenyl)- 4-imidazolyl, 1-(4-
difluoromethoxy-phenyl)-4-imidazolyl, 1-(2-pyrldyl)-4-
imidazolyl, 1-(4-benzo[b]furanyl)-4-imidazolyl, l-(5-
benzo[b]furanyl)-4-imidazolyl, 1-(7-benzo[b]furanyl)-4-
imidazolyl, 1-(2-quinolyl)-4-imidazolyl, 1-(3-quinolyl)-
4-imidazolyl, 1-(4-quinolyl)-4-imidazolyl, l-(5-
quinolyl)-4-imidazolyl, 1-(6-quinolyl)-4-imidazolyl, 1-
(8-quinolyl)-4-imldazolyl, l-phenyl-3-pyrazolyl, 5-
phenyl-3-pyrazolyl, 1-phenyl-4-pyrazolyl, l-(2-
fluorophenyl)-3-pyrazolyl, 5-(2-fluorophenyl)-3-
pyrazolyl, 5-(3-fluorophenyl)-3-pyrazolyl, l-(3-
fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-3-
pyrazolyl, 5-(4-fluorophenyl)-3-pyrazolyl, 5-(2-
chlorophenyl)-3-pyrazolyl, 5-(3-chlorophenyl)-3-
pyrazolyl, 5-(4-chlorophenyl)-3-pyrazolyl, 5-(2-
difluoromethoxyphenyl)-3-pyrazolyl, 5-(3-
difluoromethoxyphenyl)- 3-pyrazolyl, 2-methyl- 5-phenyl- 3-
pyrazolyl, 5-(2-pyridyl)-3-pyrazolyl, 5-(2-qulnolyl)-3-
pyrazolyl, 5-(3-quinolyl)-3-pyrazolyl, 4-phenyl-2-
thiazolyl, 5-phenyl-2-thiazolyl, 5-(3-chlorophenyl)-2-
thiazolyl, 5-(4-chlorophenyl)-2-thiazolyl, 5-(4-
methoxyphenyl)-2-thiazolyl, 5-(2-pyridyl)-2-thiazolyl,
2-phenyl-4-thiazolyl, 4-phenyl-2-oxazolyl, 5-phenyl-2-
oxazolyl, 4-(2-fluoromethoxyphenyl)-2-oxazolyl, 4-(3-
fluoromethoxyphenyl)- 2-oxazolyl, 5-phenyl-3-isoxazolyl,
3-phenyl-5-isoxazolyl, 3-(2-chlorophenyl)-5-isoxazolyl,
3-(3-chlorophenyl)-5-isoxazolyl, 3-(4-chlorophenyl)-5-
isoxazolyl, 3-(2-pyridyl)-5-isoxazolyl, 2-phenyl-l,2,3-
triazol-4-yl, 5-phenyl-l,2,4-thiadlazol-3-yl, 5-phenyl-
1,3,4-thiadiazol-2-yl, 5-(3-chlorophenyl)-1,3,4-
thiadiazol-2-yl, 5-(2-pyridyl)-1.3,4-thiadlazol-2-yl, 5-
(2-ethyl-4-pyridyl)-l,3,4-thiadiazol-2-yl, 5-phenyl-2-
pyridyl, 6-phenyl-3-pyridyl, 2-phenyl-4-pyridyl, 5-(2-
pyridyl)-2-pyridyl, 5-benzoyl-2-pyridyl, 6-benzoyl-3-
pyridyl, 5-chloro-2-pyrazinyl, 5-(2-methyl-1-propenyl)-
2-pyrazinyl, 5-acetyl-2-pyrazinyl, 5-propionyl-2-
pyrazinyl, 5-phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2-
pyrazlnyl, 5-(4-hydroxyphenyl)-2-pyrazinyl, 5-(1,2,4-
thiadiazol-5-yl)-2-pyrazinyl, 5-(1,3,4-thiadiazol-2-yl)-
2-pyrazinyl, 5-(2-pyridyl)-2-pyrazinyl, 5-(3-pyridyl)-2-
pyrazinyl, 5-(5-pyrimidinyl)-2-pyrazinyl, 5-(3-
quinolyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl, 5-(2-
pyridylcarbonyl)-2-pyrazinyl, 5-acetyl-2-pyrimidinyl, 5-
acetyl-3-methyl-2-pyrimidinyl, 4-phenyl-2-pyrimidinyl,
5-phenyl-2-pyrimidinyl, 6-phenyl-4-pyrimidinyl, 2-
phenyl-5-pyrimldinyl, 5-(2-fluorophenyl)-2-pyrimidinyl,
5-(3-fluorophenyl)-2-pyrimidinyl, 5-(4-fluorophenyl)-2-
pyrimidinyl, 5-(2-chlorophenyl)-2-pyrimldinyl, 5-(3-
chlorophenyl)-2-pyrimidinyl, 5-(4-chlorophenyl)-2-
pyrimidinyl, 5-(2-methylphenyl)-2-pyrimidinyl, 5-(3-
methylphenyl)-2-pyrimidinyl, 5-(2-fluoromethylphenyl)-2-
pyrimidinyl, 5-(3-fluoromethylphenyl)-2-pyrimidinyl, 5-
(2-trifluoromethylphenyl)-2-pyrimidinyl, 5-(3-
trifluoromethylphenyl)-2-pyrimidinyl, 5-(4-
trif luoromethylphenyl)-2-pyrimidinyl., 5-( 2-
hydroxymethylphenyl)-2-pyrimidiny1, 5-(3-
hydroxymethylphenyl)-2-pyrimidinyl, 5-(2-hydroxyphenyl)-
2-pyrimidinyl, 5-(3-hydroxyphenyl)-2-pyrimidinyl, 5-(2-
methoxyphenyl)-2-pyrimidinyl, 5-(3-methoxyphenyl)-2-
pyrimldinyl, 5-(4-methoxyphenyl)-2-pyrimidinyl, 5-(2-
fluoromethoxyphenyl)-2-pyrimidinyl, 5-(3-
fluoromethoxyphenyl)-2-pyrimidinyl, 5-(2-fluoro-5-
methylphenyl)-2-pyrimidinyl, 5-(3-fluoro-5-
methoxyphenyl)-2-pyrimidinyl, 6-phenyl-3-pyridazinyl, 6-
phenyl-1,2,4-triazin-3-yl, 5-chloro-2-benzoxazolyl, 5-
fluoro-2-benzothiazolyl, 4-methyl-2-benzothiazolyl, 2-
methyl-5-benzothiazolyl, 4-methoxy-2-benzothiazolyl, 3-
quinolyl, 6-quinolyl, 7-methyl-2-quinolyl, 2-methyl-6-
quinolyl, 6-chloro-2-quinoxalinyl, pyrido[3,2-b]pyridin-
2-yl, 7-chloropyrido[3,2-b]pyridin-2-yl, 7-
methylpyrido[3,2-b]pyridin-2-yl, 7-
trlfluoromethylpyrido[3,2-b]pyridin-2-yl, 7-
difluoromethoxypyrido[3,2-b]pyridin-2-yl, 7-
acetylpyrido[3,2-b]pyridin-2-yl, and the like, preferably
3,4-dichlorophenyl, 4-acetylphenyl, 5-oxo-5,6,7,8-
tetrahydro-2-naphthyl, 4-acetyl-3-trifluoromethylphenyl,
4-(l-ethyl-2-imidazolyl)phenyl, 4-benzoylphenyl, 4-(2-
pyridylcarbonyl)phenyl, l-phenyl-3-pyrrolyl, 1-phenyl-
4-iraidazolyl, 1-(2-fluorophenyl)-4-imidazolyl, l-(3,5-
difluorophenyl)- 4-imidazolyl, 1-(3-chlorophenyl)-4-
imidazolyl, 1-(3-cyanophenyl)-4-imidazolyl, l-[3-(2-
hydroxyethyl)phenyl]-4-imidazolyl, 1-(3-
difluoromethoxyphenyl)-4-imidazolyl, 1-(7-
benzo[b]furanyl)-4-imidazolyl, 1-(2-quinolyl)-4-
imidazolyl, 1-(3-quinolyl)-4-imidazolyl, l-phenyl-3-
pyrazolyl, 5-phenyl-3-pyrazolyl, l-phenyl-4-pyrazolyl,
1-(3-fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-3-
pyrazolyl, 5-(4-chlorophenyl)-3-pyrazolyl, 5-(3-
quinolyl)-3-pyrazolyl, 5-phenyl-2-thiazolyl, 3-phenyl-5-
isoxazolyl, 5-(2-methyl-l-propenyl)-2-pyrazinyl, 5-
phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2-pyrazinyl, 5-
(4-hydroxyphenyl)-2-pyrazinyl, 5-(2-pyridyl)-2-pyrazinyl,
5-benzoyl-2-pyrazinyl, 5-phenyl-2-pyrimidinyl, 5-(2-
fluorophenyl)-2-pyrimidinyl, 5-(3-fluorophenyl)-2-
pyrimidinyl, 5-(3-chlorophenyl)-2-pyrimidinyl, 5-(3-
trifluoromethyl-phenyl)-2-pyrimidinyl, 5-chloro-2-
benzoxazolyl, 4-methyl-2-benzothia-zolyl, 7-methyl-2-
quinolyl, 7-trifluoromethylpyrido[3,2-b]pyridin-2-yl, and
the like, especially 1-phenyl-3-pyrazolyl, 5-phenyl-3-
pyrazolyl, 5-phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2-
pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl, 5-phenyl-2-
pyrimidlnyl, 5-(2-fluorophenyl)-2-pyrimidinyl, 5-(3-
fluorophenyl)-2-pyrimidinyl, 7-trifluoro-
methylpyrido[3,2-b]pyridin-2-yl, and the like.
n represents 0 or 1, 0 is preferable.
T, U, V and W represent independently nitrogen atom
or methine which may have a substituent selected from the
group consisting of halogen, lower alkyl, hydroxy and lower
alkoxy, where at least two of them represent the said methine
group.
"Methine which may have a substituent selected from
the group consisting of halogen, lower alkyl, hydroxy and
lower alkoxy" refers to unsubstituted methine or methine
having a substituent which can be selected from the group
consisting of halogen, lower alkyl, hydroxy and lower
alkoxy.
Halogen atom as the aforesaid substituent Includes
preferably fluorine atom, chlorine atom, and the like.
Lower alkyl as the aforesaid substituent includes
preferably methyl, ethyl, and the like.
Lower alkoxy as the aforesaid substituent includes
preferably methoxy, ethoxy, and the like.
The aforesaid substituent include preferably halogen,
and the like.
The preferred mode of T, U, V and W includes, for
example, T, U, V and W are independently methine optionally
having the aforesaid substituent, preferably halogen; or one
of T, U, V and W is nitrogen atom.
X represents methine or nitrogen.
Y represents imino which may be substituted with lower
alkyl, or oxygen.
"Imino which may be substituted with lower alkyl"
refers to unsubstituted imino or iraino substituted with
lower alkyl.
The aforesaid lower alkyl includes, preferably,
methyl, ethyl, and the like.
Y is preferably unsubstituted imino or oxygen,
especially oxygen.
In more detail, a group of formula (15):

includes a group of formula (16):
and the like.
Preferred compounds of the general formula (I) are,
for example, compounds of the general formula (I-a):

wherein R1 represents hydrogen atom or halogen, Ar1 has the
aforesaid meaning;
or compounds of the general formula (I-b):

wherein Ar1, T, U, V and W have the aforesaid meanings.
With regard to the compound represented by the general
formula (I-a), the preferred compounds are, for example, the
compounds, wherein the aryl group in Ar1 is phenyl, or the
heteroaryl group in Ar1 is imidazolyl, pyrazolyl, lsoxazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyrimidinyl, quinolyl or
pyrido[3,2-b]pyridyl.
With regard to the compound represented by the general
formula (I-b), the preferred compounds; are, for example, the
compounds, wherein the aryl group in Ar1 is phenyl, or the
heteroaryl group in Ar1 is pyrrolyl, imidazolyl, pyrazolyl,
thlazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-
thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or 1,2,4-
triazinyl.
Further, with regard to the compound represented by
the general formula (I-b), the preferred compounds are, for
example, the compounds, wherein one of T, U, V and W is a
nitrogen atom and the more preferred compounds are, for
example, the compounds wherein V is a nitrogen atom and T,U
as well as W are an unsubstituted methine group.
Compounds of this invention may include stereoisomers
such as optical isomers, diastereoisomers and geometrical
isomers, or tautomers depending upon the mode of
substltuents. Compounds of this invention include all the
stereoisomers, tautomers and their mixtures.
For example, compounds of the general formula (I-
b) include stereoisomers such as trans-form compound of the
general formula (I-lb):
and cis-form compound of the general formula (I-2b):

trans form is preferable.
Also included within the scope of the invention are
polymorphs, hydrates and solvates of the compounds of the
instant invention.
The present invention includes within its scope
prodrugs of the compounds of this invention. In general,
such prodrugs will be functional derivatives of the
compounds of this invention which are readily convertible
in vivo into the required compound. Thus, in the methods
of treatment of the present Invention, the term
"administering" shall encompass the treatment of the various
conditions described with the compound specifically
disclosed or with a compound which may not be specifically
disclosed, but which converts to the specified compound in
vivo after administration to the patient. Conventional
procedures for the selection and preparation of suitable
prodrug derivatives are described, for example, in "Design
of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is
incorporated by reference herein in its entirety.
Metabolites of these compounds include active species
produced upon introduction of compounds of this invention
into the biological milieu.
The specific compound represented by the general
formula (I) is, for example,
N-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4'-
piperidine]-1'-carboxamide,
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4'-
piperidine]-1'-carboxamide,
N-(7-methyl-2-quinolyl)- 3-oxospiro[isoindoline-1, 4'-
piperidine]-1'-carboxamide,
N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-
1,4'-piperidine]-1'-carboxamide,
N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-
1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isoquinoline-1(2H),4'-piperidine]-1'-
carboxamide,
3,4-dlhydro-N-(7-methyl-2-quinolyl)-3-
oxospirotisoquinoline-1(2H),4'-piperidine]-1'-
carboxamide,
N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-
1(2H),4'-piperidine]-1'-carboxamide.
3,4-dihydro-3-oxo-N-[l-(2-quinolyl)-4-
imidazolyl]spiro[isoquinoline-1(2H),4'-piperidine]-1'-
carboxamide,
3,4-dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-
naphthyl)spiro[isoquinoline-1(2H),4'-piperidine]-1'-
carboxamide,
3,4-dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-
oxospiro[isoquinoline-l(2H), 4'-piperidine]-1'-
carboxamide,
3,4-dihydro-3-oxo-N-(3-phenyl-5-
isoxazolyl)spiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3-
oxospiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-
dihydro-3-oxospiro[isoquinoline-l(2H),4'-piperidine]-1'
carboxamide,
3,4-dihydro-3-oxo-N-[4-(2-
pyridylcarbonyl)phenyl]spiro[isoquinoline-l(2H),4'-
piperidine]-1'-carboxamide,
N-(3,4-dichlorophenyl)-3,4-dihydro-3-
oxospiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
N-[1-(3-chlorophenyl)-4-imidazolyl]- 3,4-dihydro-3-
oxospiro[isoquinollne-l(2H),4'-piperidine]-1'-
carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-
thiazolyl)spiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2-
pyrazinyl]spiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
3,4-dihydro-N-(4-methyl-2-benzothiazolyl)-3-
oxospiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-
oxosplro[isoquinoline-1(2H),4'-piperidine]-1'-
carboxamide,
N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-l(3H),4'-
piperidine]-1'-carboxamide,
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-
yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-[l-(3-quinolyl)-4-
imidazolyl]spiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-[5-(3-quinolyl)- 3-pyrazolyl]spiro[isobenzofuran
1(3H),4'-piperidine]-1'-carboxamide,
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-
oxospiro[lsobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-[5-(3-trifluoromethylphenyl)-2-
pyrimidinyl]spiro[isobenzofuran-l(3H),4'-piperidine]-1'
carboxamide,
N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
N-(7-difluoromethoxypyridot3,2-b]pyridin-2-yl)-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-(5-phenyl-l,2,4-thiadiazol-3-
yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
N-{1-[3-(2-hydroxyethyl)phenyl]- 4-imidazoly}- 3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
N-[4-(l-ethyl-2-imidazolyl)phenyl]-3-
oxospiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide,
N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
6-fluoro-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
6-fluoro-3-oxo-N-(5-phenyl-2-
pyrimldinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'
carboxamide,
5-fluoro-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l( 3H),, 4'-plperidlne]-1'-
carboxamide,
5-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl)spiro[isobenzofuran-l(3H),4'-plperidlne]-1'
carboxamide,
N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2-
benzopyran-1,4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-
benzopyran-1,4'-piperidine]-1'-carboxamide,
N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxosplro[1H-2-
benzopyran-1,4'-piperidine]-1'-carboxamide,
trans-N-(4-benzoylphenyl)-3'-oxospiro[cyclohexane-
1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N-(5-phenyl-2-pyrazinyl)spiro t cyclohexane-
1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N-(1-phenyl-4-imidazolyl)splro[cyclohexane
1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N-(5-phenyl-2-
pyrimidinyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-
4-carboxamide,
trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3'-
oxospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-
carboxamide,
trans-3'-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane-
1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3'-
oxospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-
carboxamide.
trans-N-(4-acetyl-3-trifluoromethylphenyl)-3'-
oxospiro[cyclohexane-l,1'(3'H)-isobenzofuran]-4-
carboxamide,
trans-3'-oxo-N-[1-(3-quinolyl)-4-
imidazolyl]spiro[cyclohexane-l,1'(3'H)-isobenzofuran]-4-
carboxamide,
trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3'-
oxospiro[cyclohexane-l, 1'(3'H)-isobenzofuran]-4-
carboxamide,
trans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-
1(3H),1'- cyclohexane]- 4'-carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spirot 4-
azaisobenzofuran-1(3H),1'-cyclohexane]- 4'-carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-
1(3H),1'- cyclohexane]-4'-carboxamide,
trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-
1(3H),1'- cyclohexane]- 4'-carboxamide,
N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
4-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'
carboxamide,
7-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide,
6-ethyl-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide,
6-hydroxy-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-
azaisobenzofuran-1(3H), 1'-cyclohexane]- 4'-carboxamide,
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-methylphenyl)-2-pyrimldinyl]-3-oxospiro[5
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-
carboxamlde,
trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamlde,
trans-N-[4-(3-fluoromethoxyphenyl)-2-oxazolyl]-3-
oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3-
oxosplro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-
oxospirot 6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-
oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamlde,
trans-3-oxo-N-(6-phenyl-1,2,4-triazln-3-yl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3-
oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-
oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxosplro[6-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-(4-benzoylphenyl)-3-oxospirc>[7-azaisobenzofuran-
1(3H),1'-cyclohexane]- 4'-carboxamide,
trans-N-[l-(3.5-dlfluorophenyl)-4-imidazolyl]-3-
oxospiro[7-azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-
carboxamide,
trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(l-phenyl-4-pyrazolyl)splro[7-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(l-phenyl-3-pyrazolyl)spiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-l,2,4-thiad:Lazol-3-yl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(2-phenyl-3-thiazolyl)splro[6-
azalsobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide
or
trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide.
Among these compounds, the preferable compound is,
for example,
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-
yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
trans-3'-oxo-N-(5-phenyl-2-
pyrimidinyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-
4-carboxamide,
trans-3'-oxo-N-[1-(3-quinolyl)-4-
imidazolyl]spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-
carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluorophenyl)-2-pyrimldinyl]-3-oxospiro[5-
azalsobenzofuran-1(3H), 1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[l-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(l-phenyl-3-pyrazolyl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide or
trans-3-oxo-N-(2-phenyl-l,2,3-triazol-4-yl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide.
The process for producing compounds of this invention
is illustrated as follows.
Compounds of this invention (I) can be synthesized,
for example, by the following processes for production or
the processes shown in examples, but these embodiments are
not intended to restrict the process for producing compounds
of this invention (I).
Production Process 1
A compound of the general formula (II):

wherein Ar1p represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, nitro, lower alkyl, halo(lower)alkyl,
cyclo(lower)alkyl, lower alkenyl, lower alkoxy.
halo(lower)alkoxy, lower alkylthio, lower alkanoyl, lower
alkoxycarbonyl, a group of formula:-Qp-Ar2p, and an
optionally protected, lower alkylene optionally substituted
with oxo, hydroxy(lower)alkyl or carboxyl group;
Ar2p represents aryl or heteroaryl which may be substituted,
the substituent being selected from the group consisting of
halogen, cyano, lower alkyl, halo(lower)alkyl, lower alkoxy,
halo(lower)alkoxy, di-lower alkylamino, lower alkanoyl,
aryl, and an optionally protected hydroxy(lowerJalkyl,
hydroxy or lower alkyl amino group;
Ar3 represents phenyl which may be substituted by halogen
or nitro;
Qp represents a single bond or optionally protected carbonyl;
is reacted with a compound of the general formula (III):

wherein n, t, u, v, w and Y have the same meanings as mentioned
above;
to provide a compound of the general formula (IV-1):

wherein Arlp, n, t, u, v, w and Y have the same meanings as
mentioned above;
optionally followed by elimination of a protective group to
give a compound of the general formula (I-1):

wherein Ar1, n, T, U, V, W and Y have the same meanings as
mentioned above.
This production process refers to the process for
producing a compound of the general formula (I), wherein X
is nitrogen, that is, a compound of the general formula
(I-1).
When a reactant has an amino, hydroxy, carboxyl, oxo,
carbonyl, or the like group which does not participate in
the reaction, the reaction may be carried out after
protecting the amino, hydroxy, carboxyl, oxo, carbonyl, or
the like group with an amino protecting group, hydroxy
protecting group, carboxyl protecting group, or oxo- or
carbonyl-protecting group, followed by deprotection after
completion of the reaction.
"Amino protecting group" includes aralkyl (for
example benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-
nitrobenzyl, p-nitrobenzyl, benzhydryl, trityl); lower
alkanoyl (for example formyl, acetyl, propionyl, butyryl,
pivaloyl); benzoyl; arylalkanoyl (for example phenylacetyl,
phenoxyacetyl); lower alkoxycarbonyl (for example
methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl,
tert-butoxycarbonyl); aralkyloxycarbonyl (for example
benzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
phenethyloxycarbonyl); lower alkylsilyl (for example
trimethylsilyl, tert-butyldimethylsilyl); and the like,
especially acetyl, pivaloyl, benzoyl, ethoxycarbonyl,
tert-butoxycarbonyl, and the like.
"Hydroxy protectiing group" includes lower alkyl (for
example methyl, ethyl, propyl, isopropyl, tert-butyl);
lower alkylsilyl (for example trimethylsilyl, tert-
butyldimethylsilyl); lower alkoxymethyl (for example
methoxymethyl, 2-methoxyethoxymethyl); tetrahydropyranyl;
trimethylsilylethoxymethyl; aralkyl (for example benzyl,
p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-
nitrobenzyl, trityl); acyl (for example formyl, acetyl), and
the like, especially methyl, methoxymethyl,
tetrahydropyranyl, trityl, trimethylsilylethoxymethyl.
tert-butyldimethylsilyl, acetyl, and the like.
"Carboxyl protecting group" includes lower alkyl (for
example methyl, ethyl, propyl, isopropyl, tert-butyl);
lower haloalkyl (for example 2,2,2-trichloroethyl); lower
alkenyl (for example 2-propenyl); aralkyl (for example
benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl,
trityl); and the like, especially methyl, ethyl, tert-butyl,
2-propenyl, benzyl, p-methoxybenzyl, benzhydryl, and the
like.
"Oxo- or carbonyl-protecting group" includes acetal
or ketal (for example ethylene ketal, trimethylene ketal,
dimethyl ketal), and the like.
The reaction between a compound of the general formula
(II) and a compound of the general formula (III) is usually
carried out by employing an equivalent to excessive mole,
preferably an equivalent to 1. 5 moles of compound (III) based
on 1 mole of compound (II).
The reaction is usually carried out in an inert solvent,
and as the inert solvent, made is use of, for example,
methylene chloride, chloroform, tetrahydrofuran,
dimethylformamide, dimethyl sulfoxide or the mixture, and
the like, preferably.
The aforesaid reaction may be preferably carried out
in the presence of base, including organic bases (for example
triethylamine, diisopropylethylamine, pyridine, 4-
dimethylaminopyridine) or inorganic bases (for example
sodium hydroxide, potassium hydroxide), and the like.
The amount of the aforesaid base employed is usually
an equivalent to excessive mole, preferably 1 to 5 moles
based on 1 mole of a compound of the general formula (II).
Reaction temperature is usually-30 t to 200 oC,
preferably 20oC to lOOoC.
Reaction time is usually 5 minutes to 7 days,
preferably 30 minutes to 24 hours.
At the conclusion of the reaction, the crude product
of a compound of the general formula (IV-1) can be obtained
by usual treatment. Thus obtained compound (IV-1) is
purified by the conventional method, or not purified, if
necessary followed by optional combination of elimination
reaction of amino-, hydroxy-, carboxyl-, oxo- and
carbonyl-protecting group to give a compound of the general
formula (1-1).
The elimination of protecting groups may be carried
out depending upon the kinds of the aforesaid protecting
groups, the stability of a desired compound (1-1) and so on,
for example, by the manner described in the literature
[Protective Groups in Organic Synthesis, T.W.Greene, John
Wiley & Sons, (1981)] or its similar manner, for example,
solvolysis using acid or base, that is, for example 0.01 mole
to a large excess of acid, preferably trifluoroacetic acid,
formic acid, hydrochloric acid, or the like, or an equivalent
mole to a large excess of base, preferably potassium
hydroxide, calcium hydroxide, or the like; chemical
reduction using metallic complex hydride, or the like; or
catalytic reduction using palladium-carbon catalyst, Raney
nickel catalyst, or the like.
Production Process 2
A compound of the general formula (V):

wherein Arlp has the same meaning as mentioned above;
is reacted with a carboxylic acid of the general formula
(VI):

wherein n, t, u, v, w and Y have the same meanings as mentioned
above;
or its reactive derivative to provide a compound of the
general formula (IV-2):

wherein Arlp, n, t, u, v, w and Y have the same meanings
as mentioned above;
optionally followed by elimination of a protecting group to
give a compound of the general formula (I-2):
wherein Ar1, n, T, U, V, W and Y have the same meanings as
mentioned above.
This production process refers to the process for
producing compounds of the general formula (I), wherein X
is methine, that is, a compound of the general formula (I-2).
Reaction between a compound of the general formula
(V) and a carboxylic acid of the general formula (VI) is
usually carried out by employing 0. 5 mole to excessive moles,
preferably 1 mole to 1.5 mole of carboxylic acid (VI) based
on 1 mole of compound (V).
The reaction is usually carried out in an inert solvent,
and preferable examples of the inert solvent include
methylene chloride, chloroform, tetrahydrofuran,
dimethylformamide, pyridine or a mixture thereof, and the
like.
The aforesaid reaction is preferably carried out in
the presence of condensing agents, for example N, N'-
dicyclohexylcarbodiimide, N,N'-diisopropylcarbodlimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1- (3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium
hexafluorophosphate, benzotriazol-1-yloxy-tris-
pyrrolidlnophosphonium hexafluorophosphate, bromotris-
(dimethylamino)phosphonium hexafluorophosphate,
diphenylphosphoryl azide, 1,1'-carbonyldiimidazole, or the
like.
The aforesaid condensing agent: is usually employed
at 1 mole to excessive mole, preferably 1 mole to 1.5 moles
based on 1 mole of compound (VI).
Reaction temperature is usually-50 oC to 100oC,
preferably-20oC to 50oC.
Reaction time is usually 30 minutes to 7 days,
preferably 1 hour to 24 hours.
A compound of formula (I-2) is also produced by
reacting a compound of the general formula (V) with a
reactive derivative of the carboxylic acid (VI) instead of
the carboxylic acid (VI).
The reactive derivatives of carboxylic acid of the
general formula (VI) include acid halides, mixed acid
anhydrides, activated esters, activated amides, and the
like.
The acid halides of carboxylic: acid of the general
formula (VI) may be obtained by reacting a carboxylic acid
of the general formula (VI) with a halogenating agent
according to the conventional method. Halogenating agent
includes thionyl chloride, phosphorus trichloride,
phosphorus pentachloride, phosphorus oxychloride,
phosphorus tribromide, oxalyl chloride, phosgene, and the
like.
The mixed acid anhydrides of carboxylic acid of the
general formula (VI) may be obtained by reacting a carboxylic
acid of the general formula (VI) with alkyl chlorocarbonate
(for example ethyl chlorocarbonate); aliphatic carboxylic
acid chloride (for example pivaloyl chloride), and the like
according to the conventional method.
The activated esters of carboxylic acid of the general
formula (VI) may be obtained by reacting a carboxylic acid
of the general formula (VI) with N-hydroxy compound (for
example N-hydroxysuccinimide, N-hydroxyphthalimide, 1-
hydroxybenzotriazole); phenol compound (for example 4-
nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol,
pentachlorophenol), or the like in the presence of a
condensing agent (for example N, N'-
dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-
ethylcarbodl-imide) according to the conventional method.
The activated amides of carboxylic acid of the general
formula (VI) may be obtained by reacting a carboxylic acid
of the general formula (VI) with for example 1,1'-
carbonyldiimidazole, 1,1'-carbonylbis(2-methylimidazole),
or the like according to the conventional method.
Reaction between a compound of the general formula
(V) and a reactive derivative of the carboxylic acid of the
general formula (VI) is usually carried out by employing 0.5
mole to excessive mole, preferably 1 mole to 1.5 moles of
the reactive derivative of carboxylic acid (VI) based on 1
mole of compound (V).
The reaction is usually carried out in an inert solvent,
and preferable examples of the inert solvent include
methylene chloride, chloroform, tetrahydrofuran,
dlmethylformamide, pyridine or a mixture thereof, and the
like.
The aforesaid reaction proceeds in the absence of
bases, but it is preferable to carry out the reaction in the
presence of bases to promote the reaction smoothly.
The aforesaid bases include organic bases (for
example triethylamine, diisopropylethylamine, pyridine,
4-dimethylaminopyridine) or inorganic bases (for example
sodium hydroxide, potassium hydroxide, sodium carbonate,
potassium carbonate, sodium hydrogen carbonate), and the
like.
It is preferable to employ 1 mole to excessive mole
of the aforesaid base to 1 mole of a compound of the general
formula (V). When the aforesaid base is liquid, the
aforesaid base can also be used as a solvent.
Reaction temperature is usually-50 oC to 100 oC,
preferably-20oC to 50oC.
Reaction time is usually 5 minutes to 7 days,
preferably 30 minutes to 24 hours.
A compound of the general formula (I-2) can be produced
by treating a reaction mixture in the usual way after
deprotection if the product has a protecting group at the
conclusion of the reaction, or by treating the mixture
directly in the usual way if the protective group is absent.
Elimination of the protecting groups and post-
treatment, and the like can be carried out according to the
method described in the aforesaid production process 1.
Compounds of the general formula (I-1) or (I-2) may
readily be isolated and purified by the conventional
separation technique, for example, solvent extraction,
recrystallization, column chromatography, preparative thin
layer chromatography, or/and the like.
These compounds may be converted into the
pharmaceutically acceptable salts or esters by the
conventional method, on the contrary, the conversion of the
salts or esters into free compounds may also be carried out
according to the conventional method.
Compounds of the general formula (II), (III), (V) or
(VI) are commercially available, or are prepared according
to the methods described in the literature [Japanese Patent
Unexamined Publication No.94/263737-A, U.S. Patent
No.3301857, J. Org. Chem, 40: 1427 (1975), International
Patent Publication WO95/28389 or the like], or analogous
methods thereto or the methods shown below or in Examples,
optionally in combination.
Production Process A

wherein L1 represents halogen; Arlp and Ar3 have the same
meanings as given above;
This process refers to a process for producing a
compound of the general formula (II). Compound (II) is
prepared by reacting a compound of the general formula (V)
with a compound of the general formula 1 according to this
process.
The reaction between a compound (V) and a compound
1 is usually carried out by employing 0.5 mole to excessive
mole, preferably an equivalent to 1.5 moles of compound 1
based on 1 mole of compound (V).
The reaction is usually carried out in an inert solvent,
and the preferable examples of the inert solvent include
methylene chloride, chloroform, tetrahydrofuran, ethyl
ether, benzene, toluene, dimethylformamlde or a mixture
thereof, and the like.
It is preferable to carry out the reaction in the
presence of bases. The aforesaid bases include organic bases
(for example triethylamine, diisopropylethylamine,
pyridine, 4-dimethylaminopyridine) or inorganic bases (for
example sodium hydroxide, potassium hydroxide, sodium
carbonate, potassium carbonate, sodium hydrogen carbonate),
and the like.
It is preferable to employ an equivalent to excessive
mole of the aforesaid base to 1 mole of a compound (V). When
the aforesaid base is liquid, the aforesaid base can be used
also as a solvent.
Reaction temperature is usually-78 oC to 100 oC,
preferably-20oC to 50oC.
Reaction time is usually 5 minutes to 7 days.
preferably 30 minutes to 24 hours.
Compounds of formula 1 are commercially available,
or are prepared according to the conventional method, the
methods described in Examples, or the like methods,
optionally in combination.
Production Process B
wherein P1 represents an amino protecting group;
R10 represents hydrogen, nitro, lower alkyl or lower alkoxy;
L1, t, u, v and w have the same meanings as given above.
This process refers to a process for producing
compounds of the general formula (III-l). Compound (III-
1) may so be prepared by the present process that a compound
of the general formula 2 is subjected to dehydrogenated
condensation with a compound of the general formula 2. to give
a compound of the general formula A, which is subjected to
reaction with a compound of the general formula 5. in the
presence of a base to yield a compound of the general formula
6 and then the compound £ is cyclized by an intra-molecular
Heck reaction to give a compound of the general formula 7,
and then the compound 1 is subjected to reduction, optionally
followed by elimination of amino protecting group P1.
Amino protecting group P1 includes the amino
protecting groups described in the aforesaid production
process 1.
A step for preparing compound A by dehydrogenated
condensation of compound 2 with compound 2. is usually carried
out in an inert solvent, for example benzene, toluene, or
the like.
Reaction temperature is preferably from room
temperature to the boiling point of a solvent used and
reaction time is preferably from 30 minutes to 24 hours.
A step for preparing compound 6 from compound A is
usually carried out in an inert solvent (for example benzene,
toluene, methylene chloride, chloroform, acetonitrile,
dimethylformamide) in the presence of base (for example
triethylamine, diisopropylethylamlne, pyridine, 4-
dimethylaminopyridine).
Reaction temperature is preferably from 0oC to the
boiling point of a solvent used and reaction time is
preferably from 30 minutes to 24 hours.
So-called intramolecular Heck reaction well known in
the field of organic chemistry can be applied to the step
for preparing compound 2 from compound 6.
The aforesaid step is usually carried out in an inert
solvent (for example benzene, toluene, tetrahydrofuran,
acetonitrile, dimethylformamide, N-methylpyrrolidone) in
the presence of palladium catalyst (for example palladium
acetate, palladium chloride), phosphine ligand (for example
triphenylphosphine, tri-2-furylphosphine) and base (for
example potassium carbonate, triethylamine), optionally
additives (for example tetraethylammonium chloride).
Reaction temperature is preferably from room
temperature to the boiling point of a solvent used in
reaction and reaction time is preferably from 30 minutes to
24 hours.
As a method for reduction in the step for preparing
compound (III-l) from compound 2, for example catalytic
reduction is preferable.
The catalytic reduction is usually carried out in an
inert solvent (for example methanol, ethanol, methylene
chloride, chloroform, tetrahydrofuran, dimethylformamide,
acetic acid) in the presence of a catalyst such as
palladium-carbon at 1 to 50 atmospheric pressure of
hydrogen.
Reaction temperature is preferably from room
temperature to the boiling point of a solvent used and
reaction time is preferably from 30 minutes to 24 hours.
At the conclusion of the reaction, if a reaction
product has a protecting group, compound (III-l) can be
prepared by elimination of the protecting group.
Elimination of a protecting group can be carried out
according to the method described in the aforesaid
production process 1.
This step may also be carried out by elimination of
the protecting group of compound 1, followed by reduction
of the resulting compound.
Compounds of the general formula 2, 2. or 5. are
commercially available, or may be prepared according to the
conventional method, the methods shown in Examples, or the
like methods, optionally in combination.
Production Process C
wherein L2 represents hydrogen or halogen;
Ph represents phenyl;
Y1 represents oxygen or imino substituted with lower alkyl
or aryl;
t, u, v and w have the same meanings as given above.
This production process refers to the process for
preparing compound of the general formula (VI-1). The
compound represented by the general formula of (VI-1) is
novel compound, which is not disclosed in the literature.
The compound can be produced according to the present
production process, that is, a compound of the general
formula 8 is subjected to lithiation, reaction with compound
9 and lactonization with an acid, followed by deketalation
to yield a compound of the general formula 10; and 1)
methylene group is introduced to the compound 1H, which is
followed by hydroboration to give a compound of the general
formula H, and the compound is subjected to oxidation
reaction, or 2) the compound 10. is reduced to give a compound
of the general formula 12.. which is subjected to introduction
of a leaving group and then cyanization to give a compound
of the general formula 13, followed by hydrolysis of the
compound 13 at the cyano group.
Lithiation in the step preparing compound 10 from
compound 8 is usually carried out by allowing compound 8 to
be acted on by an organic lithium reagent (for example
n-butyllithium, lithium 2,2,6,6-tetramethyl-piperidide)
in an inert solvent (for example tetrahydrofuran, diethyl
ether).
Reaction temperature is usually from-120oC to 0oC,
preferably from-100 oC to-50 oC and reaction time is
preferably from 1 hour to 4 hours.
Reaction between the resulting lithio type and a
ketone of the general formula £ is usually carried out in
an inert solvent (for example tetrahydrofuran, dlethyl
ether).
Reaction temperature is preferably from-100oC to
room temperature and reaction time is preferably from 10
minutes to 2 hours.
The resulting compound can be lactonized by treating
with an acid (for example hydrochloric acid, sulfuric acid).
Reaction temperature is preferably from 0oC to the
boiling point of a solvent used and reaction time is
preferably from 30 minutes to 8 hours.
Compound 10. can be prepared by subjecting the
resulting lactone type to deketalatlon according to the
conventional method.
Reaction temperature is preferably from 50oC to the
boiling point of a solvent used and reaction time is
preferably from 1 hour to 24 hours.
The method used for converting oxo group to
hydroxymethyl group, which is well known in the field of
organic chemistry, can be applied to the step for preparing
compound 11 from compound 10 and the step is usually carried
out by reacting compound 10 with for example
methylenetrlphenylphosphorane to Introduce a methylene
group, followed by hydroboration in an inert solvent (for
example benzene, toluene, methylene chloride, chloroform.
acetonitrile, tetrahydrofuran, dimethylformamide).
In both steps for Introducing methylene group and for
hydroboration, reaction temperature Is preferably from 0oC
to the boiling point of a solvent used and reaction time is
preferably from 30 minutes to 8 hours.
The method used for oxidizing hydroxymethyl group to
carboxyl group, which is well known in the field of organic
chemistry, can be applied to the step for preparing compound
(VI-1) from compound 11 and the step is usually carried out
by using an oxidizing agent such as sodium periodate and a
catalytic amount of ruthenium chloride, in an inert solvent
(for example benzene, toluene, methylene chloride,
chloroform, acetonitrile, dimethylformamide).
Reaction temperature is preferably from OoC to the
boiling point of a solvent used and reaction time is
preferably from 30 minutes to 8 hours.
The method used for reducing oxo group to hydroxyl
group, which is well known in the field of organic chemistry,
can be applied to the step for preparing compound 12. from
compound 10 and the step is usually carried out by using a
reducing agent (for example sodium borohydride, lithium
borohydride), in an inert solvent (for example water,
methanol, ethanol, tetrahydrofuran or a mixture thereof).
Reaction temperature is preferably from-20oC to 50oC
and reaction time is preferably from 10 minutes to 4 hours.
The method used for converting hydroxy group to cyano
group, which is well known in the field of organic chemistry,
can be applied to the step for preparing compound 13 from
compound 12 and the step is usually carried out by reacting
compound 12 with for example methanesulfonyl chloride,
p-toluenesulfonyl chloride, or the like to convert hydroxy
group to a leaving group in the presence of base (for example
triethylamine, pyridine), followed by reacting the
resulting compound with a cyanide (for example sodium
cyanide, potassium cyanide, tetraethylammonium cyanide,
tetrabutylammonium cyanide).
The step for converting hydroxy group to a leaving
group is usually carried out in an inert solvent (for example
methylene chloride, chloroform, ethyl acetate, acetonitrile,
tetrahydrofuran, dimethylformamide). Reaction temperature
is preferably from-20oC to room temperature and reaction
time is preferably from 10 minutes to 8 hours.
The step for reacting with a cyanide is usually carried
out in an inert solvent (for example tetrahydrofuran,
dioxane, dimethylformamide, N-methylpyrrolidone, dimethyl
sulfoxide). Reaction temperature is preferably from 50oC
to 120oC and reaction time is preferably from 2 to 24 hours.
Hydrolysis of cyano group, which is well known in the
field of organic chemistry, can be applied to the step for
preparing compound (VI-1) by hydrolysis of the cyano group
of compound 13. and the step is usually carried out by using
an acid (for example hydrochloric acid, sulfuric acid) or
a base (for example sodium hydroxide, potassium hydroxide,
calcium hydroxide), in a solvent (for example methanol,
ethanol, tetrahydrofuran, dioxane, water or a mixture
thereof).
Reaction temperature is preferably from 50oC to the
boiling point of a solvent used and reaction time is
preferably from 1 to 48 hours.
Compounds of the general formula (VI-1) have two kinds
of stereolsomers represented by the general formula (VI-
1-a) or (VI-1-b):

wherein t, u, v and w have the same meanings as given above.
These stereoisomers can be separated from the mixture
by the conventional method such as chromatography,
fractional recrystallization, and the like.
Compounds of the general formula (VI-1-a) or (VI-
1-b) can be prepared by using an intermediate product which
is obtained by separation of the stereoisomers of the general
compound 11. 12. or 13..
Compounds of the general formula & or 3. are
commercially available, or are prepared according to the
conventional method, the methods described in Examples, or
the like methods, optionally in combination.
The utility of compounds of the present invention as
a medicament is proved by describing NPY antagonistic
activity, for example, in the following pharmacological
tests.
Pharmacological Test 1 (NPY binding inhibition test)
cDNA sequence encoding human NPY Y5 receptor
[International patent publication number WO96/16542] was
cloned into expression vectors pcDNA3, pRc/RSV (made by
Invitrogen Inc.) and pCI-neo (made by Promega Inc.). This
obtained expression vectors were transfected to host cells
COS-7, CHO and LM(tk-) (American Type Culture Collection)
by cationic lipid method [Proceedings of the National
Academy of Sciences of the United States of America, 84:
7413(1987)] to give NPY Y5 receptor expression cells.
A membrane sample prepared from the cells which
expressed NPY Y5 receptor was incubated together with a test
compound and [125I]peptideYY (NEN) (20,000cpm) in an assay
buffer (25mMTris buffer, pH7.4, containing lOmM magnesium
chloride, lmM phenylmethylsulfonyl fluoride, 0.1%
bacitracin and 0. 5% bovine serum albumin) at 25oC for 2 hours,
then filtered through a glass filter GF/C and washed with
5mM Tris buffer (pH7.4) containing 0.3% BSA. The
radioactivity of the cake on the glass filter was measured.
Nonspecific binding was measured in the presence of 1MM
peptldeYY and a 50% Inhibitory Concentration (IC50) of the
test compound against specific peptideYY binding was
determined [Endocrinology, 131: 2090(1992)]. The results
are summarized in Table 1.
[Table 1]
Inhibitory activities on NPY receptor binding
As shown above, compounds of this invention potently
inhibited peptideYY (NPY homologue) binding to NPY Y5
receptors.
Pharmacological Test 2 (Antagonistic effect on bPP-lnduced
feeding behavior)
A guide cannula (external diameter 0.8mm, internal
diameter 0. 5mm, length 10mm) was inserted stereotaxicly into
the right lateral ventricle of male SD rats (7-8 weeks old,
200-300g) anesthetized with pentobarbital (single
intraperitoneal administration of 50mg/kg) and fixed by
dental resin. The top of the cannula was located 0.9mm
behind bregma, 1.2mm to the right of median line and 1.5mm
depth from the brain surface so that, when injection needle
is inserted into the guide cannula, the needle extends 2 mm
beyond the tip of the guide cannula and reaches the lateral
ventricle. After about 1-week recovery period, bovine
pancreatic polypeptide (bPP, 5 m g/10mL/head, 0.01M, pH7.4
phosphate buffered saline solution containing 0.05% bovine
serum albumin) was injected into the lateral ventricle. A
test compound suspended in aqueous 0.5% methylcellulose was
administered orally 2 hours before the administration of bPP
and the food consumption was measured 2 hours after
administration of bPP.
Compounds of this invention significantly inhibited
the increase in food consumption induced by bPP (NPY
homologue) which was administered to the lateral ventricle.
Compounds of the general formula (I) can be
administered orally or parenterally and may be formulated
in the form suitable for administration to provide an agent
for treatment of various diseases related to NPY, which
include, for example, cardiovascular disorders (for example
hypertension, nephropathy, heart disease, vasospasm,
arteriosclerosis), central nervous system disorders (for
example bulimia, depression, anxiety, seizure, epilepsy,
dementia, pain, alcoholism, drug withdrawal), metabolic
diseases (for example obesity, diabetes, hormone
abnormality, hypercholesterolemia, hyperlipidemia),
sexual and reproductive dysfunction, gastro-intestinal
motility disorder, respiratory disorder, inflammation or
glaucoma and the like, preferably, bulimia, obesity,
diabetes and the like. In clinical use, compounds of this
Invention can be administered after being formulated,
together with pharmaceutically acceptable additives, into
an appropriate preparation according to the mode of
administration. For said additives, those which are
usually used in the field of pharmaceutical formulation may
be used, for example, gelatin, lactose, sucrose, titanium
oxide, starch, crystalline cellulose, hydroxypropyl
methylcellulose, carboxymethylcellulose, corn starch,
microcrystalline wax, white petrolatum, magnesium
methasillcate alumlnate. anhydrous calcium phosphate,
citric acid, sodium citrate, hydroxypropyl cellulose,
sorbitol, sorbitan fatty acid ester, polysorbate, sucrose
fatty acid ester, polyoxyethylene, hydrogenated castor oil,
polyvinylpyrrolidone, magnesium stearate, light silicic
anhydride, talc, vegetable oil, benzyl alcohol, gum arabic,
propylene glycol, polyalkylene glycol, cyclodextrin or
hydroxypropyl cyclodextrin.
A mixture with said additives may be formulated in
the form of solid preparations (for example tablets,
capsules, granules, powder, suppositories); or liquid
preparations (for example syrups, elixirs, injections).
Such preparations may be formulated according to techniques
well-known in the art of pharmaceutical formulation. Liquid
preparations may be in the form of preparations which are
dissolved or suspended in water or other appropriate media
when used and especially injectable preparations may be
dissolved or suspended in physiological saline or glucose
solution if necessary, optionally together with a buffer and
preservative.
Such preparations may contain 0.1 to 100 wt. %,
preferably 1.0 to 60 wt. % of compounds of this invention and
may also contain therapeutically effective other compounds.
The compounds of the present invention can be used
in combination with other agents useful for treating
metabolic and/or feeding disorders. The Individual
components of such combinations can be administered
separately at different times during the course of therapy
or concurrently in divided or single combination forms. The
Instant invention is therefore to be understood as embracing
all such regimes of simultaneous or alternating treatment
and the term "administering" is to be interpreted
accordingly. It will be understood that the scope of
combinations of the compounds of this invention with other
agents useful for treating metabolic and/or feeding
disorders includes in principle any combination with any
pharmaceutical composition useful for treating metabolic
and/or feeding disorders.
When compounds of this invention are used clinically,
the dose and frequency of dosage may be varied depending upon
the sex, age, body weight, the degree of symptoms and the
kind and range of the desired treatment effects. A daily
dose for an adult is 0.01-100mg/kg, preferably 0.03-3mg/kg
orally, or 0.001-10mg/kg, preferably 0.001-0.lmg/kg
parenterally, preferably in a single dose or in divided
doses.
An ordinarily skilled physician, veterinarian or
clinician can readily determine and prescribe the effective
amount of the drug required to prevent, counter or arrest
the progress of the condition.
Best Mode for Carrying Out the Invention
The following examples are provided so that the
present invention may be more concretely illustrated but
they should not be construed as limiting the invention in
any way.
Unless otherwise noted, melting point was measured
by MP-S3 Model (manufactured by Yanagimoto Selsakusho) and
disclosed in this specification without correction.
Example 1
Preparation of N-(4-benzoylphenyl)-3-
oxospiro[isoindoline-1.4'-piperldine1-1'-carboxamlde
(1) Preparation of N-benzyl-N-(1-tert-butoxycarbonyl-
1,2,3,6-tetrahydropyridln-4-yl)-2-iodobenzamide
A mixture of N-tert-butoxycarbonyl-4-piperldone
(1.llg) and benzylamlne (597mg) dissolved in toluene (20mL)
was stirred at 100oC for 3 hours and then concentrated.
Toluene (30mL), o-iodobenzoyl chloride (1.13g) and
triethylamine (0.70g) were added to the residue and the
mixture was stirred at 80oC for 2 hours. The reaction
mixture was poured into water and extracted with ethyl
acetate. The ethyl acetate layer was dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l to
1/2) to give the subject compound (2.44g).
(2) Preparation of 2-benzyl-l'-tert-butoxycarbonyl-
1',6'-dihydro-spiro[lH-isoindole-1,4'(5'H)-pyridine]-
3(2H)-one
To N-benzyl-N-(1-tert-butoxycarbonyl-l,2,3,6-
tetrahydropyridln-4-yl)-2-iodobenzamide (2.4g) dissolved
in acetonltrile, palladium acetate (80mg),
triphenylphosphine (187mg), anhydrous K2CO3 (987mg) and
tetraethylammonium chloride (591mg) were added and stirred
at 80oC for 6 hours. The reaction mixture was poured into
water and extracted with ethyl acetate. The ethyl acetate
layer was dried over anhydrous Na2SO4 and concentrated. The
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate=4/l to 1/2) to give the subject
compound (1.64g).
(3) Preparation of 2-benzyl-l'-tert-
butoxycarbonylspiro[lH-isoindole-1,4'-piperidine]-3(2H)-
one
To a solution of 2-benzyl-l'-tert-butoxycarbonyl-
1', 6'-dihydrospiro[lH-isoindole-1,4'(5'H)-pyridine]-
3(2H)-one (l.Og) in chloroform (20mL), trifluoroacetic acid
(20mL) was added and the mixture was stirred for 1 hour. The
reaction mixture was concentrated. The residue was
dissolved in methanol and hydrogenated with 4M hydrogen
chloride/ethyl acetate in the presence of 20% palladium
carbon at 1 atm of hydrogen for 14 hours. The catalyst was
removed by filtration and the filtrate was concentrated. To
the residue, aqueous IN sodium hydroxide (5mL), di-tert-
butyl dicarbonate (655mg) and dioxane (10mL) were added and
the mixture was stirred at room temperature for 4 hours. The
reaction mixture was poured into water and extracted with
ethyl acetate. The organic layer was dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l to
1/2) to give the subject compound (200mg).
(4) Preparation of spiro[lH-isoindole-1,4'-piperidine]-
3(2H)-one hydrochloride
2-Benzyl-l'-tert-butoxycarbonylsplro[1H-
lsoindole-1,4'-piperidine]-3(2H)-one (200mg) was added to
metallic sodium (235mg) in liquid ammonia (lOmL) and the
mixture was stirred for 30 minutes. To the reaction mixture
was added methanol, neutralized with a saturated ammonium
chloride aqueous solution and extracted with ethyl acetate.
The organic layer was dried over anhydrous Na2SO4 and
concentrated. The residue dissolved in methanol was stirred
together with 4M hydrogen chloride/ethyl acetate at SO'C for
1 hour. The reaction solution was concentrated to give the
subject compound (591mg).
XH-NMR (300MHz, DMSO-d6, 6ppm): 1.70-1.90 (2H, m),
2.00-2.20 (2H,m), 3.00-3.20 (2H,m), 4.20-4.40 (2H, m), 7.40
(1H, d, J=7.5Hz), 7.51 (1H, t, J = 7.5Hz), 7.59 (1H, t,
J=7.5Hz). 7.84 (1H, d, J=7.5Hz).
(5) Preparation of phenyl N-(4-benzoylphenyl)carbamate
To 4-aminobenzophenone (1.97g) dissolved in pyridine
(50mL), phenyl chlorocarbonate (1.38g) was added at 0oC and
the mixture was stirred at room temperature for 1 hour. The
reaction mixture was poured into water and extracted with
ethyl acetate. The organic layer was dried over anhydrous
Na2SO4 and evaporated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l to
1/2) to give the subject compound (3.1g).
(6) Preparation of N-(4-benzoylphenyl)-3-
oxospiro[lsoindoline-l,4'-piperidine]-1'-carboxamide
A mixture of spiro[lH-isoindole-1,4'-piperidine]-
3(2H)-one hydrochloride (48mg), triethylamlne (0.14mL) and
phenyl N-(4-benzoylphenyl)carbamate (58mg) was stirred in
chloroform at 80oC for 2 hours. The reaction mixture was
poured into water and extracted with chloroform. The
organic layer was dried over anhydrous Na2SO4 and
concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l to
1/2) and crystallized from ethyl ether-hexane to give the
subject compound (49mg) as colorless crystals (melting point
253*0).
Compounds of Example 2 and 3 were obtained in the
similar manner as Example l-(6) by replacing phenyl N-
(4-benzoylphenyl)carbamate used in Example l-(6) by the
corresponding materials, respectively.
Example 2
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1.4'-
piperldine]-1'-carboxamlde
melting point 286-287oC
Example 3
N-(7-methyl-2-quinolyl)- 3-oxospiro [isoindoline-1.4'-
piperidine1-1'-carboxamlde
melting point 194-196oC
Example 4
Preparation of N-(4-benzoylphenyl)-2-methyl-3-
oxosplro FIsoindoline-1.4'-piperidine1-1'-carboxamlde
The subject compound was obtained in the similar
manner as Example l-(6) by replacing spiro[lH-isolndole-
1,4'-piperidine]-3(2H)-one hydrochloride by 2-
methylspiro[lH-isoindole-1,4'-piperidine]-3(2H)-one
hydrochloride.
melting point 154-156oC
Example 5
Preparation of N-(4-benzoylphanyl)-3.4-dihydro-3-
oxospiro [iso-qui noline-1(2H). 4'-piperidinel-1'-
carboxamide
Spiro[lsoqulnollne-1(2H),4'-piperidine]-3(4H)-one
hydrochloride (30mg) and phenyl N-(4-
benzoylphenyl)carbamate (3 7mg) were dissolved in dimethyl
sulfoxide (2mL) and stirred together with aqueous ION sodium
hydroxide (12 mL) at room temperature for 30 minutes. The
reaction mixture was poured into water and extracted with
ethyl acetate (20mL). The organic layer was washed with
water (20mL) and saturated saline solution (20mL), then
dried over anhydrous Na2SO4 and concentrated. The residue
was purified by column chromatography on silica gel
(hexane/ethyl acetate=4/l to 1/2) and recrystallized from
chloroform-acetone (1:3) to give the subject compound (81mg)
as colorless crystals (melting point 241-243oC).
Compounds of Example 6 to 21 were obtained in the
similar manner as Example l-(6) or Example 5 by using
splro[isoquinoline-l(2H),4'-piperidine]-3(4H)-one
hydrochloride and phenyl carbamate derivatives
corresponding to the desired compounds.
Example 6
3,4-Dlhydro-3-oxo-N-(5-phenyl-2-
pyrazlnyl)spiro [Isoquinoline-1(2H).4'-piperidine1-1'-
carboxamide
melting point 237-239oC
Example 7
3.4-Dihydro-N-(7-methyl-2-quinoly1)-3-
oxospiro[isoqulnoline-1(2H).4'-piperidinel-1'-
carboxamide
melting point 216-218oC
Example 8
N-(4-acetylphenyl)-3.4-dlhydro-3-oxosplroFlsoquinoline-
1(2H).4'-piperidine1-1'-carboxamlde
melting point>300oC
Example 9
3.4-Dihydro-3-oxo-N-[1-(2-quinolyl)-4-
imidazolyllspiro[lsoquinoline-1(2H).4'-piperidinel-1'-
carboxainlde
melting point 264-266^
Example 10
3.4-Dihydro-3-oxo-N-(5-oxo-5.6.7.8-tetrahydro-2-
naphthyl)spiro [isoquinoline-1(2H).4'-piperidinel-1'-
carboxainlde
melting point 220.5-222. 2°C
Example 11
3.4-Dlhydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-
oxospiro[isoquinoline-1(2H).4'-piperidine]-1'-
carboxamide
melting point 232.9-236.5oC
Example 12
3.4-Dihydro-3-oxo-N-(3-phenyl-5-
isoxazolyl)spiro [isoquinoline-l(2H). 4'-piperidine1-1'-
carboxamide
melting point 239-24loC
Example 13
N-[1-(7-benzo[blfurany])-4-imidazoly]1-3.4-dihydro-3-
oxosplro[isoqulnollne-l(2H).4'-piperidinel-1'-
carboxamide
melting point 192-194oC
Example 14
N-F1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3.4-
dihydro-3-oxospiro[isoqulnoline-1(2H).4'-piperidinel-1'-
carboxamide
melting point 161-163oC
Example 15
3,4-Dihydro-3-oxo-N-[4-(2-
pyridylcarbonyl)phenyl]spiro [lsoqulnoline-1(2H).4'-
piperidinel-1'-carboxamide
melting point 162-164oC
Example 16
N-(3.4-dichlorophenyl)-3,4-dlhydro-3-
oxospiro[isoqulnoline-1(2H).4'-piperidinel-1'-
carboxamide
melting point>300oC
Example 17
N-[1-(3-chlorophenyl)-4-imidazolyl]-3.4-dihydro-3-
oxospiro [isoquinoline-1 (2H), 4'-piperidine]-1'-
carboxamide
melting point 255-258oC
Example 18
3,4-Dihydro-3-oxo-N-(5-phenyl-2-
thiazolyl)spiro [isoquinoline-1(2H).4'-piperidine]-1'
carboxamide
melting point>300 Example 19
3.4-Dihydro-3-oxo-N-[5-(2-pyridyl)-2-
pyrazinyl1spiro [isoquinoline-1(2H).4'-piperidine1-1'
carboxamide
melting point 223-225oC
Example 20
3.4-Dihydro-N-(4-methyl-2-benzothlazolyl)- 3-
oxospiro[isoqulnoline-1(2H).4'-piperidine1-1'-
carboxamide
melting point 144-146oC
Example 21
N-(5-chloro-2-benzoxazolyl)-3.4-Dihydro-3-
oxospiro [isoquinoline-1(2H), 4'-piperidinel-1'-
carboxamide
melting point 256-258oC
Example 22
Preparation of N-(4-benzoylphenyl)-3-
oxospiro [isobenzofuran-1 ( 3H), 4'-piperidine]-1'-
carboxamide
A mixture of spiro[isobenzofuran-1(3H),4'-
piperidine]-3-one hydrochloride (48mg), phenyl N-(4-
benzoylphenyl)carbamate (58mg) and triethylamine (0.14mL)
in chloroform (5mL) was stirred at 80oC for 2 hours. The
reaction mixture was poured into water and extracted with
chloroform (20mL). The organic layer was washed with
saturated saline solution (20mL), then dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l to
1/2) and recrystalllzed from ethyl ether-hexane to give the
subject compound (81mg) as colorless crystals (melting point
161-163oC).
Example 23
Preparation of 3-oxo-N-(5-phenyl-2-pyrazlnyl)-
spiro[isobenzofuran-1(3H).4'-piperidinel-1'-carboxamide
(l)Preparation of phenyl N-(5-phenyl-2-
pyrazlnyl)carbamate
Phenyl chlorocarbonate (15.05 mL) was added at ooC to
a solution of 2-amino-5-phenylpyrazine (17.12 g) in pyridine
(200 mL). The mixture was stirred at room temperature for
2 hours. To the reaction mixture was added water (200 mL)
and ethyl ether (200 mL). The whole was stirred to provide
a suspension containing the subject compound as a crystal.
The crystal was collected by filtration and further washed
with ethyl ether (50 mL) and then dried under reduced
pressure to provide the subject compound (24.57 g) as
colorless crystals (melting point 192-198oC, decomposed ).
(2preparation of 3-oxo-N-(5-phenyl-2-pyrazinyl)-
spiro[isobenzofuran-l(3H),4'-piperidine]-1'-carboxamide
(Crystal Form A)
A mixture of spiro[isobenzofuran-l(3H),4'-
piperidine]-3-one hydrochloride (6.24 g, 26.6 mmol), phenyl
N-(5-phenyl-2-pyrazinyl)carbamate(7.59 g, 26.0 mmol) and
triethylamine (18 mL, 180 mmol) in chloroform (200 mL) was
stirred at SO'C for 3 hours. The reaction mixture was washed
with saturated aqueous sodium bicarbonate (100 mL). After
the organic layer was washed with 10% citric acid aqueous
solution (100 mL), IN aqueous sodium hydroxide (100 mL) and
then saturated saline solution (100 mL), the organic layer
was dried over anhydrous Na2SO4 and then concentrated. The
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate=l/2) to provide the subject compound
as a colorless solid. The solid was washed with diethyl
ether (30 mL) to provide the subject compound (8.23g) as a
crude crystal. The crystal was dissolved in hot ethyl
acetate (300 mL). After removal of about 100 mL of ethyl
acetate by distillation, the white suspension began to occur.
At this point the distillation was stopped and the whole was
cooled and then kept at room temperature for 14 hours. The
colorless prisms formed was collected by filtration, which
was washed with heptane (20 mL). The obtained crystal was
dried at 50oC in vacuo for 6 hours to provide the subject
compound (Crystal Form A) (5.17 g) as colorless prisms
(melting point 210-211oC).
Powder X-ray diffraction
Above powder X-ray diffraction analysis data were
measured by RINT1100 (manufactured by Rigaku International
Corporation) and analysis methods were as follows:
X-ray radiation source : Cu,
tube voltage : 40kV,
tube current : 30mA,
monochromater : automatic monochromater,
monoreceiving slit : 0.60 mm,
goniometer : Wide angle goniometer,
scan step : 0.02 deg.,
scan speed : 2.00 deg./mln.,
divergence sllt(DS) : 1 deg.,
scattering slit : 1 deg.,
receiving slit (RS) : 0.15 mm,
measured temperature : ambient temperature.
(3) Preparation of 3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide (Crystal Form A)-an alternative method for
preparation-
Crude crystals (2 g) prepared by the above procedure
(2) was dissolved under heating into tetrahydrofuran (20 mL).
After confirming complete dissolution, the mixture was
cooled to the room temperature by standing it at room
temperature. Heptane (27 mL) was dropwise added to the
tetrahydrofuran solution, followed by stirring at room
temperature for 15 hours. The yielded colorless crystals
were collected by filtration, washed with heptane (5 mL)
and dried in vacuum at 30oC for 15 hours to obtain the
above-Identified compound in crystal form A (1.82 g).
(4) Preparation of 3-oxo-N-(5-phenyl-2-
pyrazlnyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide (Crystal Form B)
Crude crystals (2 g) prepared by the above procedure
(2) was dissolved under heating into dimethylformamide (6
mL). After confirming complete dissolution, water (13 mL)
was dropwise added at 80oC and the resultant mixture was
cooled to room temperature, followed by stirring for 15 hours.
The yielded colorless crystals were collected by filtration
at room temperature, washed with heptane (5 mL) and dried
in vacuum for 15 hours at room temperature to obtain 1.78
g of the above-identified compound in the crystal form B as
colorless prisms (melting point; 208oC measured without
correction by the use of Melting Point B-545 distributed by
Buchi Company).
Powder X-ray diffraction
Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 23(2).
(5) Preparation of 3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[lsobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide (Crystal Form C)
Crude crystals (2 g) prepared by the above procedure
(2) was dissolved under heating into tetrahydrof uran (20 mL).
After confirming complete dissolution, the solution was
cooled to-30oC. Heptane (30 mL) was dropwise added to the
tetrahydrofuran solution, followed by stirring at-30oC for
one hour. The yielded colorless crystals were collected by
filtration, washed with heptane (5 mL) and dried in vacuum
at room temperature for 15 hours to obtain 1.90 g of the
above-identified product (monotetrahydrofuran solvate, the
crystal form C) as colorless fine granules.
Powder X-ray diffraction
Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 23(2).
(6) Preparation of 3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide (Crystal Form D)
Spiro[isobenzofuran-1(3H),4'-piperidine]-3-one
hydrochloride (515 mg) and phenyl N-(5-phenyl-2-
pyrazlnyl)carbamate (583 mg) were dissolved into dimethyl
sulfoxide (2.6 mL), followed by dropwise addition of
dimethylbenzylamine (0.33 mL). The temperature of the
resultant mixture was raised up to 50 °C, and the mixture
was stirred for one hour. The reaction mixture was cooled
to room temperature, and acetonltrlle/water (1:2) mixture
solution (7.8 mL) was dropwise added. At the time when 0.2
mL of the mixture solution was added, seed crystal was added.
The resultant mixture was stirred at room temperature for
6 hours. The yielded colorless crystals were collected by
filtration, washed with acetonitrlle/water (1:1) and dried
in vacuum at room temperature for 15 hours to obtain the
above-identified compound (793 mg) as crude colorless
crystals. Crude crystals (26 g) prepared by the repetition
of the above procedure were suspended in water-saturated
lsopropyl acetate (143 mL). The mixture was seeded with
seed crystal and stirred at room temperature for 18 hours.
The yielded crystals were collected by filtration, washed
with isopropyl acetate (20 mL) and dried in vacuum at 30°C
for 15 hours to obtain the above-identified compound in the
crystal form D (25.2 g) as colorless crystals (melting point ;
206oC measured without correction by the use of Melting Point
B-545 distributed by Buchi Company).
Powder X-ray diffraction
Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 23(2).
(7) Preparation of 3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[lsobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide (Crystal Form B)-an alternative method for
preparation-
Crude crystals (26g) prepared by the above procedure
(6) was suspended in acetonitrile (260 mL). The mixture was
seeded with the seed crystal prepared by the above procedure
(4) and stirred at room temperature for 24 hours. The
yielded crystals were collected by filtration, washed with
acetonitrile (50 mL) and dried in vacuum at 30oC for 15 hours
to obtain the above-identified product in the crystal form
B (25.5 g).
Compounds of Example 24 to 39 were obtained in the
similar manner as Example 22 by replacing phenyl N-(4-
benzoylphenyl)carbamate used in Example 2 2 by the
corresponding materials, respectively.
Example 24
N-(7-methyl-2-quinolyl)-3-oxospiro\isobenzofuran-1(3H),
4'-piperidine1-1'-carboxamide
melting point 178-180 Example 25
3-Oxo-N-(3-phenyl-5-isoxazolyl)-spiro Flsobenzofuran-
K3H). 4'-piperidinel-1'-carboxamide
melting point 239-242^
Example 26
3-Oxo-N-(7-trifluoromethylpyrido[3.2-b]pyridin-2-yl)-
spiro[isobenzofuran-1(3H).4'-piperidine1-1'-carboxamide
melting point 246-248oC
Example 27
3-Oxo-N-(5-Phenyl-2-Pyrimidinyl)-spirorisobenzofuran-
1(3H).4'-piperidinel-1'-carboxamide
melting point 211-214oC
Example 28
3-Oxo-N-[1-(3-quinolyl)-4-
imidazolyl] spiro[isobenzofuran-1(3H).4'-piperidine1-1'-
carboxamide
melting point 251-254oC
Example 2 9
3-Oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-
1(3H)- 4'-piperidine1-1'-carboxamide
melting point 160-165 Example 30
N- [5-(4-chlorophenyl)-3-pyrazolyl]-3-
oxospiro [isobenzofuran-1(3H),4'-piperidinel-l'-
carboxamide
melting point 255-258oC
Example 31
3-qxo-N-[5-(3-quinolyl)-3-pyrazolylispiro [isobenzofuran
1(3H), 4'-piperidine1-1'-carboxamide
melting point 253-257oC
Example 32
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-
oxospiro [isobenzofuran-1(3H).4'-piperidine1-1'-
carboxamide
melting point 122-125oC
Powder X-ray diffraction
Above powder X-ray diffraction analysis data were
measured by RINT2100 Ultima+ System(2 KW) (manufactured by
Rigaku International Corporation) and analysis methods were
as follows:
X-ray radiation source : Cu,
tube voltage : 40kV,
tube current : 30mA,
monochromater : automatic monochromater,
monoreceiving slit : 0.15 mm,
goniometer : Horizontal goniometer I,
scan step : 0.02 deg.,
scan speed : 2.00 deg./min.,
divergence sllt(DS) : 1 deg.,
scattering slit : 1 deg.,
receiving slit (RS) : 0.15 mm,
measured temperature : ambient temperature.
Example 33
3-Oxo-N-[5-(3-trifluoromethylphenyl)-2-
pyrimidinyl) spiro [isobenzofuran- 1 ( 3H), 4'-piperidinel-1'-
carboxamide
melting point 190-192oC
Example 34
N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-
oxospiro [isobenzofuran-1(3H).4'-piperidine1-1'-
carboxamide
melting point 126-128oC
Example 35
N- ( 7-difluoromethoxypyrido [3, 2-b]pyridin-2-yl)-3-
oxospiro [isobenzofuran-1 (3H).4'-piperidine1-1'-
carboxamide
melting point 193*0
Example 36
3-Oxo-N-(5-phenyl-l,2,4-thiadlazol-3-
yl)spiro[isobenzofuran-1(3H).4'-piperidine1-1'-
carboxamide
melting point 239-243X
Example 37
N-{1-F 3-(2-hydroxyethyl)phenyl]-4-imidazolyl]-3-
oxospiro fIsobenzofuran-1(3H).4'-piperidine1-1'-
carboxamide
melting point 99-100'C
Example 38
N-[4-(l-ethyl-2-imidazolyl)phenyl]-3-
oxospiro [isobenzofuran-1(3H).4'-piperidinel-1'-
carboxamide
melting point 221-223 Example 39
N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-
oxospiro [isobenzofuran-1(3H).4'-piperidine1-1'-
carboxamide
melting point 208-210oC
Example 40
Preparation of 6-fluoro-3-oxo-N-(5-phanyl-2-
pyrazinyl)spiro-[isobenzofuran-1(3H), 4'-piperidiNEL-1'-
carboxamide
A mixture of 6-fluorospiro[isobenzofuran-l(3H),4'-
piperidine]-3-one hydrochloride (64mg), phenyl N-(5-
phenyl-2-pyrazinyl)carbamate (73mg) and triethylamine (174
m L) in chloroform (5mL) was stirred at 80oC for 2 hours.
The reaction mixture was poured into water and extracted with
chloroform (20mL). The organic layer was washed with
saturated saline solution (20mL), then dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l to
1/2) and recrystallized from ethyl ether-hexane to give the
subject compound (101mg) as colorless crystals (melting
point 222-224oC).
Example 41
Preparation of 6-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl)spiro[iso-benzofuran-l(3H).4'-Piperidinel-
1'-carboxamide
The subject compound was obtained in the similar
manner as Example 40 by replacing phenyl N-(5-phenyl-2-
pyrazinyl)carbamate used in Example 40 by phenyl N-(5-
phenyl-2-pyrimidinyl)carbamate.
melting point 176-178oC
Example 42
Preparation of 5-fluoro-3-oxo-N-(5-phenyl-2-
carboxamide
A mixture of 5-fluorospiro[isobenzofuran-1(3H),4'-
piperidine]-3-one hydrochloride (64mg), phenyl N-(5-
phenyl-2-pyrazlnyl)carbamate (73mg) and triethylamlne (174
Uh) in chloroform (5mL) was stirred at 80"C for 2 hours.
The reaction mixture was poured into water and extracted with
chloroform (20mL). The organic layer was washed with
saturated saline solution (20mL), then dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l to
1/2) and recrystallized from ethyl ether-hexane to give the
subject compound (100mg) as colorless crystals (melting
point 236-238T;).
Example 43
preparation of 5-fluorp-3-oxo-N-(5-phenyl-2-
pyrimidinyl)spirof iso-benzofuran-1(3H)4'-piperidinel-
1'-carboxamide
The subject compound was obtained in the similar
manner as Example 42 by replacing phenyl N-(5-phenyl-2-
pyrazinyUcarbamate used in Example 4 2 by phenyl N-(5-
phenyl-2-pyrimidinyl)carbamate.
melting point 255-257^
Example 44
preparation of N-(4-benzoylphenyl)-3,4-Dihydro-3-
oxospiro[1H-2-benzopyran-1,4'-piperidinel-1'-carboxamide
Spiro[lH-2-benzopyran-l,4'-piperidine]-3(4H)-one
hydrochloride (50.6mg) and phenyl N-(4-
benzoylphenyl)carbamate (63.4mg) were suspended In dimethyl
sulfoxide (l.OmL) and the suspension was vigorously stirred
together with aqueous 10M sodium hydroxide (30 ML) for 5
minutes. The reaction mixture was diluted with water and
extracted with ethyl acetate. The organic layer was washed
with saturated saline solution, then dried over anhydrous
Na2SO4 and concentrated. The residue was crystallized from
methanol-diisopropyl ether to give the subject compound
(68.0mg) as colorless crystals (melting point 138-146^).
Compounds of Example 45 and 46 were obtained in the
similar manner as Example 44 by replacing phenyl N-(4-
benzoylphenyl)carbamate used in Example 44 by the
corresponding materials, respectively.
Example 4 5
3.4-Dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro [1H-2-
benzopyran-1.4'-piperj dine 1-1'-carboxamide
melting point 221CC
Example 46
N-(5-benzoyl-2-pyrazinyl)-3.4-dihydro-3-oxospiro [1H- 2-
benzopyran-1.4'-piperidine1-1'-carboxamide
melting point 128-13loC
Example 4 7
Preparation of trans-N-(4-benzoylphenyl)-3'-
oxospiro[cyclohexane-1.1'(3'H)-lsobenzofuran]-4-
carboxamide
(1) Preparation of spiro[cyclohexane-l,1'(3'H)-
isobenzofuran]-3',4-dione
A solution of 2-bromobenzoic acid (4.77g) in
anhydrous tetrahydrofuran (lOOmL) was cooled to-78oC under
an atmosphere of nitrogen, to which n-butyllithium (1.53M
solution inhexane, 31mL) was dropwise added while being kept
the internal temperature below-55oC. After being stirred
for 1 hour, a solution of 1, 4-cyclohexanedione monoethylene
ketal (5.18g) in anhydrous tetrahydrofuran (10mL) was added
dropwise to the mixture while being kept the internal
temperature below-67oC. After the temperature was raised
to room temperature, the reaction solution was partitioned
between water (150mL) and hexane (100mL). The aqueous layer
was acidified with concentrated hydrochloric acid and
refluxed together with acetone (lOmL) for 2 hours. After
cooling, thus obtained mixture was neutralized with
potassium carbonate and extracted with ethyl acetate. The
organic layer was washed with saturated saline solution,
then dried over anhydrous Na2SO4 and evaporated. The residue
was crystallized from ethyl acetate-hexane to give the
subject compound (2.42g).
(2) Preparation of 4-methylenespiro[cyclohexane-
1,1'(3'H)-isobenzofuran]-3-one
A suspension of methyltriphenylphosphonlum bromide
(715mg) in anhydrous tetrahydrofuran (7.0mL) was cooled to
0oC under an atmosphere of nitrogen, to which n-butyllithium
(1. 53M solution in hexane, 1. 3mL) was added, stirred at that
temperature for 20 minutes and then cooled to-78oC. A
solution of spiro[cyclohexane-l,1'(3'H)-
isobenzofuran]-3',4-dione (216mg) in anhydrous
tetrahydrofuran (3mL) was added to the reaction mixture and
the temperature was raised to 0oC. After stirring for 20
minutes, aqueous ammonium chloride was added to thus
obtained mixture and the resulting crude product was
extracted with ethyl acetate. The organic layer was washed
with saturated saline solution, then dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l) to
give the subject compound (196mg).
(3) Preparation of 4-hydroxymethylspiro[cyclohexane-
1,1'(3'H)-Isobenzofuran]-3'-one
A solution of 4-methylenespiro[cyclohexane-
1,1'(3'H)-Isobenzofuran]-3-one (196mg) in anhydrous
tetrahydrofuran (5.0mL) was cooled to 0oC, to which
borane-dimethyl sulfide complex (2M tetrahydrofuran
solution, 690 ML) was added and the mixture was stirred at
that temperature for 1.5 hours, then additional 20 minutes
together with aqueous 2M sodium hydroxide (5.0mL) and
aqueous 30% hydroperoxlde (5.0mL). The reaction mixture
was diluted with water, extracted with ethyl acetate, washed
with saturated saline solution, then dried over anhydrous
Na2SO4 and evaporated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=2/l) to
give the subject compound (190mg) as dlastereomers.
(4) Preparation of trans-3'-oxospiro[cyclohexane-
1,1'(3'H)-Isobenzofuran]-4-carboxylic acid
A mixture of 4-hydroxymethylspiro[cyclohexane-
1,1'(3'H)-isobenzofuran]-3'-one (190mg), chloroform
(2.0mL), acetonitrile (2.0mL) and sodium phosphate buffer
(pH6.5, 2.0mL) was cooled to 0oC, to which sodium periodate
(612mg) and ruthenium(III) chloride n-hydrate (10mg) were
added and the mixture was stirred for 30 minutes. The
reaction mixture was stirred together with 1N hydrochloric
acid (2.0mL) for 30 minutes and partitioned between water
(50mL) and ethyl acetate (50mL). The organic layer was
washed with saturated saline solution, dried over anhydrous
Na2SO4 and then concentrated. The residue was purified by
column chromatography on silica gel
(chloroform/methanol=100/l) to give the subject compound
(98.6mg).
(5) Preparation of trans-N-(4-benzoylphenyl)-3'-
oxospiro[cyclohexane-l,1'(3'H)-isobenzofuran]-4-
carboxamide
To a solution of trans-3'-oxospirofcyclohexane-
1,1'(3'H)-isobenzofuran]-4-carboxyllc acid (24.6mg) in
pyridine (500 ML), 4-amlnobenzophenone (19.8mg) and 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (57.5mg) were added and the mixture was
stirred at 50 "C for 2 hours. The reaction mixture was
partitioned between water and ethyl acetate. The organic
layer was washed with aqueous potassium hydrogen sulfate,
aqueous sodium hydrogen carbonate, and saturated saline
solution and then dried over anhydrous Na2SO4 and evaporated.
The residue was crystallized from ethyl acetate-hexane to
give the subject compound (31.2mg) as colorless crystals
(melting point 194oC).
Compounds of Example 48 to 56 were obtained in the
similar manner as Example 47-(5) by replacing 4-
aminobenzophenone used in Example 47-(5) by the
corresponding materials, respectively.
Example 48
Trans-3'-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-
1.1'(3'H)-isobenzofuran]-4-carboxamide
melting point 223oC
Example 49
Trans-3'-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane-
1.1'(3'H)-isobenzofuran1-4-carboxamide
melting point 264oC
Example 50
Trans-3'-oxo-N-(5-phenyl-2-
pyrlmidinyl)spiro{cyclohexane-1.1'(3'H)-isobenzofuran1-
4-carboxamide
melting point 184oC
Example 51
Trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3'-
oxospiro [cyclohexane-1.1'(3'H)-isobenzofuran]-4-
carboxamide
melting point 294oC
Example 52
Trans-3'-oxo-N-(5-phenyl-3-pyrazolyl)spiro (cyclohexane-
1.1'(3'H)-isobenzofuran]-4-carboxamide
melting point 238oC
Example 53
Trans-N-F1- (2-fluorophenyl)-4-imidazolyl1-3'-
oxospiro[cyclohexane-1.1'(3'H)-lsobenzofuran1-4-
carboxamide
melting point 258oC
Example 54
Trans-N-(4-acetyl-3-trifluoromethylphenyl)-3'-
oxospiro[cyclohexane-1.1'(3'H)-lsobenzofuran]- 4-
carboxamide
melting point 274-275oC
Example 55
Trans-3'-oxo-N-F1-( 3-qulnolyl)-4-
lmidazolyl1spiro\cyclohexane-1.1'(3'H)-lsobenzofuran]- 4
carboxamide
melting point>300oC
Example 56
Trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3'-
oxospiro[cyclohexane-1.1'(3'H)-isobenzofuran]-4-
carboxamide
melting point 268-270oC
Example 57
Preparation of trans-N-(4-benzoylphenyl)-3-oxospiro[4-
azaisobenzofuran-1(3H), 1'-cvclohexane]-4'-carboxamide
(1) Preparation of dispiro[4-azaisobenzofuran-l(3H),1'-
cyclohexane-4',2"-l",3"-dioxolane]-3-one
A solution of N-methyl-2-pyridinecarboxamide (9.53g)
in anhydrous tetrahydrofuran (400mL) was cooled to-78oC
under an atmosphere of nitrogen, to which n-butyllithlum
(1. 54M solution in hexane, 100mL) was dropwise added. After
being stirred for 1.5 hours at the some temperature, a
solution of 1,4-cyclohexanedione monoethylene ketal
(10.93g) in anhydrous tetrahydrofuran (100mL) was added
dropwise to the mixture. After the temperature was raised
to room temperature, the reaction mixture was partitioned
between water (300mL) and ethyl ether (lOOmL). The aqueous
layer was acidified with 2N hydrochloric acid, stirred for
30 minutes, neutralized with potassium carbonate and then
left overnight. The resulting precipitate was collected by
filtration and dried to give the subject compound (6.84g).
(2) Preparation of spiro[4-azaisobenzofuran-l(3H),1'-
cyclohexane]-3,4'-dione
A mixture of dispiro[4-azalsobenzofuran-
1(3H).1'-cyclohexane-4',2"-l",3"-dioxolane]-3-one (6.8g),
2N hydrochloric acid (20mL) and acetone (5mL) was heated
under reflux for 13 hours. After cooling, the mixture was
neutralized with potassium carbonate and stirred together
with isopropyl ether (5mL) for 3 hours. The resulting
precipitate was collected by filtration, washed with water
and isopropyl ether and then dried to give the subject
compound (3.39g).
(3) Preparation of cis-4'-hydroxyspiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-3-one
Spiro[4-azaisobenzofuran-1(3H),1'-cyclohexane]-
3,4'-dione (5.7g) was dissolved in tetrahydrofuran (50mL)
and water (lOmL) and cooled to 0*0. The solution was stirred
together with sodium borohydride (993mg) for 20 minutes,
acidified with 10% sulfuric acid, adjusted to pH7.4 with
saturated sodium hydrogen carbonate aqueous solution and
extracted with chloroform-ethanol and chloroform-
tetrahydrofuran. The organic layer was dried over anhydrous
Na2S04 and concentrated. The residue was crystallized from
ethyl acetate-isopropyl ether to give the subject compound
(2.02g).
(4) Preparation of trans-3-oxospiro[4-azaisobenzofuran-
1(3H),1'-cyclohexane]-4'-carbonitrile
To a solution of cis-4'-hydroxyspiro[4-
azaisobenzofuran-l(3H),1'-cyclohexane]-3-one (2.02g) in
anhydrous tetrahydrofuran (60mL), triethylamine (3.08mL)
was added and cooled to 0*0. Methanesulf onyl chloride (1. 3mL)
was added dropwise to the mixture and stirred at that
temperature for 1 hour. The reaction mixture was diluted
with water and extracted with chloroform. The organic layer
was dried over anhydrous Na2SO4 and evaporated. The residue
was crystallized from ethyl acetate-isopropyl ether to give
mesylate (2.47g). Thus obtained mesylate was dissolved in
dimethylformamide (2 5mL) and stirred together with
tetraethylammonlum cyanide (3.25g) at 100oC for 3 hours.
After cooling, the reaction mixture was diluted with water
and extracted with ethyl acetate. The organic layer was
washed with water and saturated saline solution, dried over
anhydrous Na2SO4 and then concentrated. The residue was
purified by column chromatography on silica gel
(hexane/ethyl acetate=2/3) to give the subject compound
(l.Og).
(5) Preparation of trans-3-oxospirot4-azaisobenzofuran-
1(3H),1'-cyclohexane]- 4'-carboxylic acid
A solution of trans-3-oxospiro[4-azaisobenzofuran-
1(3H),1'-cyclohexane]-4'-carbonitrile (l.Og) in 30%
sulfuric acid was heated under reflux for 11 hours. After
cooling, the reaction mixture was diluted with water and
adjusted to pH6 with potassium carbonate. The resulting
precipitate was collected by filtration, washed with water
and air-dried to give the subject compound (974mg).
(6) Preparation of trans-N-(4-benzoylphenyl)-3-
oxospiro[4-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide
To a solution of trans-3-oxospiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxylic
acid (66mg) in pyridine (lmL), 4-aminobenzophenone (52.6mg)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (153mg) were added and the mixture was stirred
at 40"C for 2 hours. The reaction mixture was concentrated
and the residue was partitioned between water and ethyl
acetate. The organic layer was washed with saturated saline
solution, dried over anhydrous Na2SO4 and then concentrated.
The residue was crystallized from ethyl acetate-hexane to
give the subject compound (94.4mg) as colorless crystals
(melting point 237oC).
Compounds of Example 58 to 60 were obtained in the
similar manner as Example 57-(6) by replacing 4-
aminobenzophenone used in Example 57-(6) by the
corresponding materials, respectively.
Example 58
Trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 203oC
Example 59
Trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4-
azaisobenzofuran-1f 3H).1'-cyclohexane1-4'-carboxamide
melting point 217oC
Example 60
Trans-3-oxo-N-(5-phenyl-2-pyrlmidinyl)spiro [4-
azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 237oC
Example 61
Preparation of trans-N-(4-benzoylphenyl)-3-oxospiro[5-
azaisobenzofuran-1(3H).1'- cyclohexane1-4'-carboxamide
(1) Preparation of dispiro[5-azaisobenzofuran-l(3H),1'-
cyclohexane-4', 2"-l",3"-dloxolane]-3-one
2,2,6,6-Tetramethylpiperidine (41.1mL) was
dissolved in anhydrous tetrahydrofuran (400mL) and cooled
to-50"C, to which n-butylllthium (1. 50M solution in hexane,
217mL) and nicotinic acid (lO.Og) were added successively.
After being stirred at-SO'C for 1 hour, a solution of
1,4-cyclohexanedione monoethylene ketal (13.9g) in
anhydrous tetrahydrofuran (2 5mL) was added and then the
mixture was stirred at-50'C for 1 hour. After the
temperature was raised to room temperature, the reaction
mixture was poured into water (800mL) and extracted with
hexane-ether (1:1, 500mL). The aqueous layer was adjusted
to pH3 with 6N hydrochloric acid and stirred at room
temperature for 2 hours. The resulting precipitate was
collected by filtration and washed with water. Thus
obtained solid was dissolved in chloroform (300mL), washed
with saturated sodium bicarbonate aqueous solution (150mL),
dried and then concentrated. The residue was
recrystallized from ethyl acetate-hexane to give the subject
compound (4.2 9 g).
(2) Preparation of spiro[5-azaisobenzofuran-l(3H),1'-
cyclohexane]-3,4'-dione
Dispiro[5-azaisobenzofuran-l(3H),1'-cyclohexane-
4',2"-l",3"-dioxolane]-3-one (4.29g) and p-
toluenesulfonic acid monohydrate (3.74g) were dissolved in
acetone (80mL) and water (8mL) and the solution was heated
under reflux for 3 hours. After cooling, acetone was
evaporated off and chloroform (lOOmL) was added to the
residue. The mixture was washed with saturated sodium
bicarbonate aqueous solution (50mL X 2), dried over
anhydrous Na2SO4 and then evaporated. The resulting crystals
were recrystallized from ethyl acetate-hexane to give the
subject compound (2.68g).
(3) Preparation of cis-4'-hydroxyspiro[5-
azaisobenzofuran-l(3H),1'-cyclohexane]-3-one
A suspension of spiro[5-azaisobenzofuran-l(3H),1'-
cyclohexane]-3,4'-dlone (167mg) in tetrahydrofuran-water
(10:1, 4mL) was cooled to o'C and stirred together with
sodium borohydride (32mg) at O'C for 30 minutes. The
reaction mixture was poured into water ( 5mL), stirred at room
temperature for 30 minutes and then extracted with
chloroform (20mLX3). The extract was dried over anhydrous
Na2SO4 and concentrated. The residue was recrystallized
from ethyl acetate-hexane to give the subject compound
(77.7mg).
(4) Preparation of trans-3-oxospiro[5-azaisobenzofuran-
1(3H),1'- cyclohexane]-4'-carbonitrile
A solution of cis-4'-hydroxyspiro[5-
azaisobenzofuran-1(3H),1'-cyclohexane]-3-one (1.31g) and
triethylamine (1.17mL) in anhydrous tetrahydrofuran (20mL)
was cooled to O'C and stirred together with methanesulf onyl
chloride (0.555mL) at o'C for 1 hour. The reaction mixture
was poured into water (50mL), extracted with ethyl acetate
(100mLX2), dried over anhydrous Na2SO4 and concentrated to
give crude mesylate (1.87g). The mesylate was dissolved in
anhydous dimethylformamide (30mL) and stirred together with
triethylammonium cyanide (2.98g) at 100oC for 5 hours. The
reaction mixture was poured into water (100mL) and extracted
with ether (150mLX3), and ether-ethyl acetate (2:1, 200mL).
The combined extracts were dried over anhydrous Na2SO4 and
concentrated. The resulting oily residue was purified by
column chromatography on silica gel (hexane/ethyl
acetate/methanol=2/l/0 to 1/1/0 to 30/30/1) and the obtained
solid was recrystallized from ethyl acetate-hexane to give
the subject compound (631mg).
(5) Preparation of trans-3-oxosp±ro[5-azaisobenzofuran
-1(3H),1'- cyclohexane]-4'-carboxylic acid
A mixture of trans-3-oxospiro[5-azaisobenzofuran-
1(3H),1'-cyclohexane]-4'-carbonitrile (lOOmg), water
(0.7mL) and concentrated sulfuric acid (0.3mL) was refluxed
for 11 hours. The reaction mixture was cooled to room
temperature and adjusted to pH4 with aqueous 4N sodium
hydroxide. The resulting precipitate was collected by
filtration, washed successively with water, ethanol and
dllsopropyl ether and then dried to give the subject compound
(78mg).
1H-NMR (200MHz, DMSO-d6, 6ppm) : 1.63-1.87 (2H, m),
1.88-2.20 (6H, m), 2.70 (1H, m), 7.76 (1H, dd, J = 5.2, l.lHz),
8.86 (1H, d, J=5.2Hz), 9.06 (1H, d, J=l.lHz).
(6) Preparation of trans-N-(4-benzoylphenyl)-3-
oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide
A solution of trans-3-oxospiro[5-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxylic
acid (20mg) and 4-aminobenzophenone (16mg) in anhydrous
pyridine (0.5mL) was stirred together with l-(3-
dimethylamlnopropyl)-3-ethylcarbodilmide hydrochloride
(20mg) at 60*0 for 2 hours. The reaction mixture was poured
into water (lOmL) and extracted with ethyl acetate (30mL
X 2). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated. The resulting oily residue was
purified by column chromatography on silica gel
(hexane/ethyl acetate =1/1 to 1/2) and the obtained solid
was recrystalllzed from ethyl acetate-hexane to give the
subject compound (10mg) as colorless crystals (melting point
256-257t:).
Example 62
Preparation of trans-N-(4-benzoylphenyl)-3-oxospj.rof6-
azalsobenzofuran-1(3H).1'- cyclohexane1-4'-carboxamide
(1) Preparation of dispiro[6-azaisobenzofuran-
1(3H),1'-cyclohexane-4', 2"-l",3"-dioxolane]-3-one
2,2,6,6-Tetramethylpiperidine (50mL) was dissolved
in anhydrous tetrahydrofuran (500mL) and the solution was
cooled to-50oC, to which n-butyllithium (1.50M solution in
hexane, 270.7mL) and isonicotinic acid (12.5g) were added
successively. The reaction mixture was stirred at-50oC for
10 minutes and the temperature was raised to 25oC over 30
minutes. The reaction mixture was further stirred at 25oC
for 10 minutes and then cooled to-65oC. 1,4-
Cyclohexanedione monoethylene ketal (19g) was added and the
reaction mixture was stirred at-65oC for 10 minutes. The
temperature of the reaction mixture was raised to-15oC over
1 hour, then to 0oC over 30 minutes. Then the mixture was
poured into water (300mL), from which the aqueous layer was
separated. The organic layer was extracted with aqueous 2N
sodium hydroxide. The combined aqueous layers were
adjusted to pH3 with concentrated hydrochloric acid and
extracted with ethyl acetate ( 500mL). The organic layer was
washed with saturated aqueous sodium bicarbonate (200mL),
and saturated saline solution, then dried over anhydrous
MgSO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate =1/0 to
4/1 to 3/2) and recrystallized from ethyl acetate-hexane to
give the subject compound (7.20g).
(2) Preparation of spiro[6-azalsobenzofuran-l(3H),1'-
cyclohexane]-3, 4'-dione
Dlspiro[6-azaisobenzofuran-l(3H),1'-cyclohexane-
4',2"-l",3"-dioxolane]-3-one (7.20g) and p-
toluenesulfonic acid monohydrate (5.80g) were dissolved in
acetone (150mL) and water (15mL) and the solution was heated
under reflux for 5.5 hours. After cooling, acetone was
evaporated off and the residue was extracted with ethyl
acetate (100mL X 3). The combined organic layers were washed
with saturated saline solution (50mL), dried over anhydrous
MgSO4 and then evaporated. The resulting crystals were
recrystallized from ethyl acetate-diisopropyl ether to give
the subject compound (1.96g).
(3) Preparation of cis-4'-hydroxyspiro[6-
azaisobenzofuran-l(3H),1'-cyclohexane]-3-one
A solution of spiro[6-azaisobenzofuran-
1(3H),1'-cyclohexane]-3,4'-dione (1.0g) in ethanol(100mL)
was cooled to 0oC and stirred together with sodium
borohydride (174mg) at 0oC for 1 hour. The reaction mixture
was adjusted to pH4 with 10% sulfuric acid, rendered basic
with aqueous saturated sodium bicarbonate and then extracted
with chloroform (200mLX2). The extract was dried over
anhydrous MgSO4 and concentrated. The residue was
recrystallized from ethyl acetate-hexane to give the subject
compound (954.5mg).
(4) Preparation of trans-3-oxospiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carbonltrile
A solution of cis-4'-hydroxyspiro[6-
azaisobenzofuran-l(3H),1'-cyclohexane]-3-one (954mg) and
triethylamlne (0.91mL) in dimethylformamide (lOmL) was
cooled to 0*0 and stirred together with methanesulfonyl
chloride (0.40mL) at 0*0 for 1 hour. The reaction mixture
was diluted with ethyl acetate (100mL), washed with aqueous
saturated sodium bicarbonate (50mL X 2), and saturated
saline solution (50mL), then dried over anhydrous MgSO4 and
concentrated. The residue was recrystallized from ethyl
acetate-diisopropyl ether to give mesylate (995mg). This
mesylate was dissolved in anhydrous dimethylformamide
(30mL) and stirred together with triethylammonium cyanide
(1.57g) at 100oC for 1.5 hours. The reaction mixture was
diluted with ethyl acetate (200mL) and washed successively
with water (200mL), aqueous saturated sodium bicarbonate
(200mL), and saturated saline solution (100mL). The
organic layer was dried over anhydrous MgSO4 and concentrated.
The residue was recrystallized from ethyl acetate-
diisopropyl ether to give the subject compound (447mg).
(5) Preparation of trans-3-oxospiro[6-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxylic
acid
A mixture of trans-3-oxospiro[6-azaisobenzofuran-
1(3H),1'-cyclohexane]-4'-carbonitrile (445mg), water
(3.5mL) and concentrated sulfuric acid (1.5mL) was refluxed
for 6 hours. The reaction mixture was cooled to room
temperature and adjusted to pH8 with aqueous 5N sodium
hydroxide, then to pH4 with concentrated hydrochloric acid.
The resulting crystals were collected by filtration, washed
with water and dried to give the subject compound (416mg)
as colorless crystals (melting point 222-223oC).
1H-NMR (300MHz, DMSO-d6, 6ppm) : 1.7-2.2 (6H, m),
2.65-2.75 (1H, m). 7.83 (1H, dd, J=1.2Hz, 4. 9Hz), 8.86 (1H,
d, J=4.9Hz), 9.05 (1H, d, J=1.2Hz), 12.3 (1H, brs).
(6) Preparation of trans-N-(4-benzoylphenyl)-3-
oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide
A solution of trans-3-oxospiro[6-azaisobenzofuran-
l(3H),l'- cyclohexane]-4'-carboxylic acid (50mg) and 4-
aminobenzophenone (51.6mg) in anhydrous pyridine (1mL) was
stirred together with 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (48. 7mg) at 60oC for 2 hours.
The reaction mixture was diluted with ethyl acetate (20mL)
and washed successively with water (20mL), 10% citric acid
aqueous solution (20mL X 2), aqueous saturated sodium
bicarbonate, and saturated saline solution. The organic
layer was dried over anhydrous MgSO4 and concentrated. The
resulting oily residue was purified by column chromatography
on silica gel (hexane/ethyl acetate =3/2 to 1/4) and the
obtained solid was recrystallized from ethyl acetate-hexane
to give the subject compound (62.7mg) as colorless crystals
(melting point 147-149^).
Example 63
Preparation of N-F5-(4-hydroxyphenyl)-2-pyrazinyl]-
3-oxospiro[isobenzofuran-1(3H).4'-piperidine 1-1'-
narhoxamide
(1) Preparation of 2-amlno-5-(4-hydroxyphenyl)pyrazine
To a solution of 2-amino-5-bromopyrazine (366 mg) in
dimethoxyethane (20 mL) was added 4-hydroxyphenylboronic
acid (320 mL), 1. 5N sodium carbonate aqueous solution (2.5
mL) and tetrakis (triphenylphosphine) palladium (0) (54 mg).
The mixture was stirred at 80oC for 3 hours. To the reaction
mixture was added water (20 mL) and the whole was extracted
with ethyl acetate (50 mL x 3). The extract was washed with
saturated saline solution, then dried over anhydrous Na2SO4.
The removal of the solvent provided crystal residue, which
was washed with diethyl ether (10 mL) to give the subject
compound (305 mg).
(2) Preparat ion of pheny1 N-[5-(4-hydroxypheny1)-2-
pyrazinyl]carbamate
To a solution of 2-amino-5-(4-hydroxyphenyl)pyrazlne
(283 mg) in pyridine (20 mL) was added under ice-cooling
phenyl chlorof ormate (199 mL) and the mixture was stirred
for 1 hour. The reaction mixture was poured into water (30
mL) and extracted with ethyl acetate ( 20 mL x 3). The organic
layer was washed with saturated saline solution and then
dried over anhydrous Na2SO4. The concentration of the
solvent left a crystal residue, which was washed with diethyl
ether (10 mL) to give the subject compound (314 mg).
(3) Preparation of N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-
3-oxospiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide
A mixture of spiro[isobenzofuran-l(3H),4'-
piperidine]-3-one hydrochloride (96 mg), phenyl N-5-[(4-
hydroxyphenyl)-2-pyrazinyl]carbamate (128 mg) and
triethylamine (279 mL) in chloroform (5 mL) was stirred at
80oC for 2 hours.
The reaction mixture was poured into water and
extracted with chloroform (20 mL). The organic layer was
washed with saturated saline solution (20mL) and then dried
over anhydrous Na2SO4
The concentration of the solvent left a residue, which
was purified by column chromatography on silica gel
(hexane/ethyl acetate=4/l to 1/2) followed by
recrystallization from ethyl ether-hexane to give the
subject compound (114 mg) as colorless crystals (melting
point 263-265*0).
Example 64
Preparation of N-[5-(3-hydroxyphenyl)-2-pyrazinyl1-
3-oxospirof isobenzofuran-1(3H).4'-piperidine]-1'-
carboxamide
(1) Preparation of 2-amlno-5-(3-methoxyphenyl)pyrazine
To a solution of 2-amino-5-bromopyrazine (642 mg) in
dimethoxyethane (40 mL) was added 3-methoxyphenylboronic
acid (560 mg), 1. 5N aqueous sodium carbonate solution (4mL)
and tetrakis(triphenylphosphine) palladium (0) (86 mg).
The mixture was stirred at 80oC for 6 hours. To the reaction
mixture was added water (20 mL) and the whole was extracted
with ethyl acetate (50 mL x 3). The extract was washed with
saturated saline solution and then dried over anhydrous
Na2SO4 The concentration of the solvent left a crystal
residue, which was washed with ethyl ether (10 mL) to give
the subject compound (760 mg).
(2) Preparation of 2-amino-5-(3-hydroxyphenyl)pyrazine
2-amino-5-(3-methoxyphenyl)pyrazine (566 mg) was
dissolved in methylene chloride (10 mL). To this mixture
was added under ice-cooling boron tribromide (530 U L) and
the whole was stirred at room temperature for 14 hours. To
the reaction mixture was added IN aqueous sodium hydroxide.
The whole was extracted with ethyl acetate ( 30 mL x 2). The
organic layer was washed with saturated saline solution and
then dried over anhydrous Na2SO4 The concentration of the
solvent provides the subject compound (94 mg) as a yellow
solid.
(3) Preparation of Phenyl N-[5-(3-hydroxyphenyl)-2-
pyrazinyl]carbamate
To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine
(89 mg) in pyridine (10 mL) was added under ice-cooling
phenyl chloroformate (63 UL). The mixture was stirred for
1 hour and then poured into water (30 mL) and extracted with
ethyl acetate (20 mL x 3). The extract was washed with
saturated saline solution and then dried over anhydrous
Na2SO4. The concentration of the solvent left a crystal
residue, which was washed with ethyl ether (10 mL) to give
the subject compound (51 mg).
(4) Preparation of N-[5-(3-hydroxyphenyl)-2-
pyrazinyl]-3-oxospiro[isobenzofuran-l(3H),4'-
piperidine]-1'-carboxamide
A mixture of spiro[isobenzofuran-l(3H),4'-
piperidine]-3-one hydrochloride (40 mg), phenyl N-[5-
(3-hydroxyphenyl)-2-pyrazinyl]carbamate (51 mg) and
triethylamine (119 ££L) in chloroform (5 mL) was stirred
at 80oC for 2 hours. The reaction mixture was poured into
water and extracted with chloroform (20 mL). The organic
layer was washed with saturated saline solution (20 mL) and
then dried over anhydrous Na2SO4 The concentration of the
solvent left a residue, which was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/l to
1/2) followed by recrystallization from ethyl ether-hexane
to give the subject compound (24 mg) as colorless crystals
(melting point 257-259^).
Example 6 5
Preparation of 4-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl)spiro flsobenzofuran-1f3H).4'-piperidinei-1'-
carboxamide
A mixture of 4-fluorospiro[isobenzofuran-l(3H),4'-
piperidine]-3-one hydrochloride (150 mg), phenyl N-(5-
phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine
(0.24 mL) in chloroform (2 mL) was stirred at 60 hours. The concentration of the reaction mixture left a
residue, which was purified by column chromatography on
silica gel (hexane/ethyl acetate/methanol=l/l/0~8/8/1~
6/6/1) followed by recrystallization from ethyl acetate-
hexane to give the subject compound (190 mg) as colorless
crystals (melting point 247-249oC).
Example 66
Preparation of 7-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl1spiro flsohenzofuran-1f 3H).4'-piperidine1-1'-
carboxamide
A mixture of 7-fluorospiro[isobenzofuran-1(3H),4'-
piperidine]-3-one hydrochloride (150 tng), phenyl N-(5-
phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine
(0.24 mL) In chloroform (2 mL) was stirred at 60oC for 2
hours. The reaction mixture was diluted with ethyl acetate.
The whole was washed with 10% citric acid aqueous solution,
saturated aqueous sodium bicarbonate and saturated saline
solution and then dried over anhydrous Na2SO4. The
concentration of the reaction mixture left a residue, which
was recrystallized from ethyl acetate to give the subject
compound (202 mg) as colorless crystals (melting point
244-246T;).
Example 6 7
Preparation of 6-ethyl-3-oxo-N-(5-phenyl-2-
pyrazlnyl)spiro\isobenzofuran-1(3H).4'-piperidine1-1'-
carboxamide
(1) Preparation of 2-(4-ethylphenyl)-4,4-dimethyl-2-
oxazoline
To a solution of 4-ethylbenzoic acid (3.80 g) in
anhydrous acetonitrile (100 mL) was added under a nitrogen
atmosphere, triphenylphosphine (20 g), 2-amino-2-methyl-
1-propanol (2.74 mL) and triethylamine (28.2 mL). The
mixture was cooled on an ice bath and then tetrachloromethane
(5.36 mL) was added. The reaction mixture was allowed to
stand at room temperature and stirred for 18 hours. To the
reaction mixture was added ethyl acetate and hexane and the
precipitate was removed by filtration. The concentration
of the filtrate left a residue, which was purified by column
chromatography on silica gel (hexane/ethyl acetate/ = 9/l/ to
6/1) to give the subject compound (1.15 g).
(2) Preparation of 1'-benzyl-6-ethylspiro[isobenzofuran-
1(3H),4'-piperidine]-3-one hydrochloride
Under a nitrogen atmosphere, a solution of 2-(4-
ethylphenyl)-4,4-dimethyl-2-oxazoline (1.15 g) in
anhydrous tetrahydrofuran (100 mL) was cooled to-78'C. To
this solution was added 1.5 M butyl lithium hexane solution
(4.53 mL). After being stirred for 1 hour, l-benzyl-4-
piperidone (1.05 mL) was added dropwise. After the reaction
temperature was allowed to rise up to room temperature, 2N
hydrochloric acid was added to the reaction mixture to make
the mixture acidic. The whole was refluxed for 2 hours.
After cooling, sodium hydroxide aqueous solution was added
to make the reaction mixture basic. The mixture was
extracted with ethyl ether. The organic layer was washed
with saturated saline solution and then dried over anhydrous
Na2SO4. The concentration of the organic solvent left a
residue, which was purified by column chromatography on
silica gel (hexane/ethyl acetate/=3/2) to give the subject
compound (409 mg).
(3) Preparation of 6-ethylspiro[isobenzofuran-l(3H),4'-
piperidine]-3-one hydrochloride
1'-benzyl-6-ethylspiro[isobenzofuran-1(3H),4'-
piperidine]-3-one hydrochloride(400 mg) was dissolved in
methanol (10 mL) and 10% palladium carbon was added. The
mixture was stirred under a hydrogen atmosphere for 1. 5 hours.
After the palladium carbon was removed by filtration, the
filtrate was concentrated to give a residue, which was
subjected to crystallization with methanol-ethyl ether to
give the subject compound (222 mg).
(4) Prepartation of 6-ethyl-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide
To a suspension of 6-ethylspiro[isobenzofuran-
1(3H), 4'-piperidine]-3-one hydrochloride (53 mg) and phenyl
N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) in dimethyl
sulfoxide (1 mL) was added 10 M sodium hydroxide aqueous
solution (0.02 mL). The mixture was vigorously stirred for
5 minutes followed by partition between water and ethyl
acetate. The organic layer was separated and then washed
with saturated saline solution and then dried over anhydrous
Na2SO4 The concentration of the organic solvent left a
residue, which was subjected to the crystallization from
ethyl acetate to give the subject compound (46 mg) as
crystals (melting point 176-178oC).
Example 68
Preparation of 6-hydroxy-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-1(3H).4'-piperidinei-1'-
carboxamide
(1) Preparation of 2-(4-methoxyphenyl)-4,4-dimethyl-2-
oxazoline
To a solution of 2-amino-2-methyl-l-propanol (14.4
g) and triethylamlne (23 mL) in dried THF (200 mL) was added
dropwise under ice-cooling a solution of 4-methoxybenzoyl
chloride ( 25 g) in dried THF ( 20 mL). The mixture was stirred
at room temperature for 1 hour and then water (200 mL) was
added. The reaction mixture was extracted with ethyl
acetate (100 mL) twice. The organic layer was washed with
saturated saline solution and then dried over anhydrous
Na2SO4 The concentration of the organic solvent provided
the subject compound (29.5 g) as a white solid. Thionyl
chloride (25 mL) was added to the above white solid compound,
and the reaction was carried out at room temperature for one
hour. The reaction mixture was made alkaline by the
addition of 5N sodium hydroxide aqueous solution and was
extracted twice each with ethyl acetate (100 mL). The
combined organic layer was washed with saturated sodium
chloride aqueous solution and dried with anhydrous sodium
sulfate. The solvent was evaporated off to give the
above-identified compound (22 g) as colorless oil.
(2) Preparation of l'-benzyl-6-
methoxyspiro[isobenzofuran-1(3H),4'-piperidine]-3-one
Under a nitrogen atmosphere, to a solution of 2-
(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline (7.9 g) in
anhydrous toluene (100 mL) was added dropwise under ice-
cooling 1. 5M butyl lithium hexane solution (28 mL). After
being stirred for 3 hours at the same temperature, 1-
benzyl-4-piperidone (8 g) in anhydrous toluene (20 mL) was
added dropwise. After the reaction mixture was stirred at
room temperature for 14 hours, a saturated ammonium chloride
aqueous solution (50 mL) was added. The mixture was
extracted with ethyl acetate (100 mL) twice. The organic
layer was washed with saturated saline solution and then
dried over anhydrous Na2SO4 The concentration of the
organic solvent provided the compound (8.3 g) as a white
solid. This compound was dissolved in methanol (50 mL) and
concentrated sulfuric acid (4 mL) was added. The mixture
was stirred at room temperature for 1 hour. To the reaction
mixture was added IN sodium hydroxide aqueous solution to
make the reaction mixture basic. The mixture was extracted
with ethyl acetate (100 mL) twice. The organic layer was
washed with saturated saline solution and then dried over
anhydrous Na2SO4 The concentration of the organic solvent
provided the subject compound (6.6 g) as a yellow solid.
(3) Preparation of 6-hydroxyspiro[isobenzofuran-l(3H),4'-
piperidine]-3-one hydrochloride
1'-benzyl-6-methoxyspirofisobenzofuran-1(3H), 4'-
piperidine]-3-one (1.8 g) was dissolved in methylene
chloride (20 mL). To this solution was added under ice-
cooling boron tribromide (1.3 mL). After the reaction
mixture was stirred at room temperature for 14 hours, IN
sodium hydroxide aqueous solution was added. The mixture
was extracted with ethyl acetate (30 mL) twice. The organic
layer was washed with saturated saline solution and then
dried over anhydrous Na2SO4. The concentration of the
organic solvent provided the compound (1.2 g) as a yellow
solid, which was dissolved in methanol (30 mL). To this
solution was added 4N hydrogen chloride-ethyl acetate ( 5 mL),
20% palladium hydroxide-carbon (300 mg). The mixture was
stirred under a hydrogen atmosphere for 14 hours. After the
catalyst was removed by filtration, the filtrate was
concentrated to give the subject compound (891 mg) as a white
solid.
(4) Prepartation of 6-hydroxy-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide
A mixture of 6-hydroxyspiro[isobenzofuran-
1(3H),4'-piperidine]-3-one hydrochloride (51 mg), phenyl
N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) and
triethylamine (119 U L) in chloroform (5 mL) was stirred at
80oC for 2 hours. The reaction mixture was poured into water,
and then extracted with chloroform (20 mL). The organic
layer was washed with saturated saline solution (20 mL) and
then dried over anhydrous Na2SO4 The concentration of the
organic solvent left a residue, which was purified by column
chromatography on silica gel (hexane/ethyl acetate/=4/l to
1/2) followed by the recrystallization from ethyl ether-
hexane to give the subject compound (29 mg) as colorless
crystals (melting point 206-208'C).
The compounds from Example 69 to Example 79 were prepared,
according to the same preparation procedure described in
Example 61 by using the corresponding starting material in
place of 4-aminobenzophenon used in the Example 61.
Example 69
trans-3-oxo-N-(5-phenyl-2-pyrimidiny1)spirof5-
azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide.
melting point 215-217T:
Example 70
trans-N-F 5- (3-fluorophenyl)-2-pyrimidinyl1-3-oxospiro [5-
azaisobenzofuran-1(3H). 1'-cyclohexane1-4'-carboxamide
melting point 205-207oC
Example 71
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro [5-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 226-228oC
Powder X-ray diffraction
Above powder X-ray diffraction analysis data were
measured by the same conditions as Example 32.
Example 72
trans-3-oxo-N-L4-phenvl-2-oxazolyl)spiro [5-
azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 273-275"€
Example 73
trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]- 3-oxospiro [5-
azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 213-215T:
Example 74
trans-N-[5-(3-methylphenyl)- 2-pyrimidinyl1-3-oxospiro [5-
azaisobenzofuran-3(3H).1'-cyclohexane1-4'-carboxamide
melting point 145-147oC
Example 75
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl1-3-
oxospiro [5-azaisobenzofuran-1(3H),1'-cyclohexane1-4'-
carboxamide
melting point 157-159oC
Example 76
trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl1-3-
oxospiro [5-azaisobenzofuran-1(3H).1'-cyclohexane]-4'-
carboxamide
melting point lSS-lSSt:
Example 77
trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl1-3-
oxospiro [5-azaisobenzofuran-1(3H).1'-cyclohexane1-4'-
carboxamide
melting point 218-220oC
Example 78
trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrlmidinyl1-3-
oxospiro [5-azalsobenzofuran-1(3H).1'-cyclohexane]-4'-
carboxamide
melting point 151-153T;
Example 7 9
trans-N-[4-(3-fluoromethoxylphenyl)-2-oxazolyli-3-
oxospiro[5-azaisobenzofuran-1 ( 3H). 1'-cyclohexane]-4'-
carboxamide
melting point 214-217oC
Example 80
Preparation of trans-N-[5-(3-hydroxymethylphenyl)-2-
pyrimidinyl1-3-oxospiro[5-azalsobenzofuran-1(3H).1'-
cyclohexansl-4'-carboxamide
To a solution of 2-chloro-l,3-dimethylimidazollum
chloride (613 mg) in chloroform (10 mL) was added pyridine
(0.489 mL), trans-3-oxospiro[5-azaisobenzofuran-
1(3H),1'-cyclohexane]-4'-carboxylic acid (300 mg) and 2-
amino-5-bromopyrimidine (211 mg). The mixture was stirred
at room temperature overnight. The reaction mixture was
diluted with ethyl acetate.
The whole was washed with 10% citric acid aqueous
solution, saturated sodium bicarbonate aqueous solution,
saturated saline solution and then dried over anhydrous
Na2SO4. The concentration of the organic solvent left a
residue, which was purified by column chromatography on
silica gel (hexane/ethyl acetate = l/l to 1/3 to 1/4 to 1/5)
followed by the crystallization from ethyl acetate to give
the desired amide (210 mg). This amide was suspended in
ethyleneglycol dimethyl ether (3.5 mL), and water (0.5 mL),
3-hydroxymethylphenylboronic acid (95 mg), 2M sodium
carbonate aqueous solution (0.31 mL) and
tetrakistrlphenylphosphinepalladium (30 mg) was added
thereto.
The mixture was refluxed for 2 hours and then diluted
with water. The whole was extracted with ethyl acetate and
then dried over anhydrous Na2SO4 The concentration of the
organic solvent left a residue, which was purified by column
chromatography on silica gel (ethyl acetate/methanol=l/0 to
30/1 to 20/1 to 15/1) to give the subject compound (151
mg) as light yellow crystals (melting point 207-209*0).
Example 81
Preparation of trans-N-[5-(3-hydrpxyphenyl)-2-
pyrlmidinyl]-3-oxospiro[5-azalsobenzofuran-1(3H).1'-
cyclohexane]-4'-carboxaniide
To a solution of 2-chloro-l,3-dimethylimidazolium
chloride (622 mg) in chloroform (7 mL) was added pyridine
(0.50 mL), trans-3- oxospiro[5-azaisobenzofuran-l(3H),1'-
cyclohexane]-4'-carboxylic acid (303 mg) and 2-amino-5-
(3-benzyloxyphenyl)pyrimidine (340 mg). The mixture was
stirred at room temperature overnight. The reaction
mixture was diluted with ethyl acetate. The whole was
washed with 10% citric acid aqueous solution, saturated
sodium bicarbonate aqueous solution, saturated saline
solution and then dried over anhydrous Na2SO4 The
concentration of the organic solvent left a residue, which
was purified by column chromatography on silica gel
(hexane/ethyl acetate=l/l to 1/2 to 1/4 to 1/5 to 1/6)
followed by the crystallization from ethyl acetate to give
the desired amide (210 mg). This amide was dissolved in
methanol (5mL) and tetrahydrofuran (5 mL), and 10%
palladium-carbon (120 mg) was added. The mixture was
stirred at room temperature under a hydrogen atmosphere
overnight. The catalyst was removed by filtration. The
filtrate was concentrated to give a residue, which was
purified by column chromatography on silica gel
(chlorof orm/methanol=50/l to 30/1) to give a solid compound.
The solid compound was washed with ethanol and then
recrystallized from ethyl acetate to give the subject
compound (95 mg) as light yellow crystals (melting point
260-262oC).
The compounds from Example 82 to Example 89 were
prepared, according to the same preparation procedure
described in Example 62 by using the corresponding starting
material in place of 4-aminobenzophenon used in the Example
62.
Example 82
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro [6-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 189-191oC
Example 83
trans-N-[5-(3-fluoromethylphenyl)- 2-pyrimidinyl"I-3-
oxospiroT 6-azaisobenzofuran-1(3H).1'-cyclohexane1-4'-
carboxamidfi
melting point 199-200cC
Example 84
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrlmidinyll-3-
oxospiroF 6-azaisobenzofuran-1(3H).1'-cyclohexane1-4'-
carboxamida
melting point 198-200 Example 85
trans- 3-oxo-N-(6-phenyl-1.2 r 4-triazin-3-yl) spiro [6-
azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 272-275^
Example 86
trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl1-3-
oxospirof 6-azaisobenzofuran-1(3H).1'-cyclohexane1-4'-
carboxamide
melting point 239-240oC
Example 87
trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl1-3-
oxospiro[6-azaisobenzofuran-1(3H).1'-cyclohexane1-4'-
carboxamide
melting point 183-185oC
Example 88
trans-N-[5-(3-fluorophenyl)-3-pyrazolyl1-3-oxospiro\6-
azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 182-184CC
Example 89
trans-N-F5-(4-fluorophenyl)- 3-pyrazolyl1-3-oxospiro[6-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 228-229^
Example 90
Preparation of trans-N-(4-benzoylphenyl)-3-
oxospiro[7-azaisobenzofuran-1(3H).1'-cyclohexane1-4'-
carboxamide
(1) Preparation of 3-cyano-2-hydroxypyridine
To malonaldehyde bisdimethylacetal (16.4 g) was added
0.5 N hydrochloric acid (40 mL). The mixture was stirred
at 50*0 for 20 minutes and then cooled to room temperature.
To the reaction mixture was added triethylamine (16 mL)
followed by 2-cyanoacetoamide (9 g). The whole was stirred
at room temperature for 30 minutes and further heated at
eo'C for 90 minutes as well as lOO'C for 2 hours. After
cooling, the reaction mixture was concentrated to give a
residue, which was recrystallized from ethanol-ethyl ether
to give the subject compound (7.49 g).
(2) Preparation of 2-bromo-3-cyanopyridine
Tetrabutylammonium bromide (35.4 g) and diphosphorus
pentaoxide (15.58 g) was suspended in toluene (100 mL).
After the mixture was stirred at 70oC for 30 minutes, 3-
cyano-2-hydroxypyridine (6.59 g) was added thereto. The
mixture was refluxed for 4 hours. The reaction mixture was
poured into the ice water (200 g) and extracted with ethyl
acetate (200mL x 2). The organic layer was dried over
anhydrous Na2SO4 The concentration of the solvent gave a
oily residue, which was purified by column chromatography
on silica gel (hexane/ethyl acetate=4/l to 3/1) to give a
solid compound. The solid compound was recrystallized from
ethyl acetate-hexane to give the subject compound (5.16 g).
(3) Preparation of spiro[7-azaisobenzofuran-1(3H),1'-
cyclohexane]-3,4'-dione
2-bromo-3-cyanopyridine (2.96 g) and 1,4-
cyclohexanedione monoethyleneketal (3.47 g) were dissolved
in anhydrous tetrahydrofuran (38 mL). After being cooled
to-78oC, n-butyl lithium (1.5 M hexane solution, 12.64 mL)
was added and the mixture was stirred at-78oC for 30 minutes.
The reaction temperature was allowed to rise up to the room
temperature. The reaction mixture was poured into water (40
mL) and extracted with ethyl acetate (100 mL x 3). The
organic layer was dried over anhydrous MgSO4 The
concentration of the solvent gave a residue, which was
recrystallized from ethyl ether-hexane to give iminoether
compound (2.93 g). This compound was dissolved in acetone
(5 mL) and 2N hydrochloric acid (30 mL). The solution was
refluxed for 2 hours. After cooling, 2N sodium hydroxide
aqueous solution was added to the reaction mixture to adjust
pH to 4. The whole was extracted with ethyl acetate (100mL
x 3). The organic layer was dried over anhydrous MgSO4. The
concentration of the solvent gave a residue, which was
recrystallized from ether-hexane to give the subject
compound (1.07 g).
(4)Preparation of cis-4'-hydroxyspiro[7-azaisobenzofuran-
1(3H), 1'-cyclohexane]-3-one
Spiro[7-azaisobenzofuran-l(3H),1'-cyclohexane]-
3,4'-dione (1.6 g) was suspended in tetrahydrofuran (37 mL).
After being cooled to O'C, lithium tert-butoxyaluminium
hydride (1.0M tetrahydrofuran solution, 9.58 mL) was added
dropwise to the mixture. After the mixture was stirred at
O'C for 90 minutes, IN hydrochloric acid was added to adjust
pH to 2. The mixture was extracted with ethyl acetate (100
mL x 4). The organic layer was dried over anhydrous MgSO4
The concentration of the solvent gave the subject compound
(1.58 g).
(5) Preparation of trans-3-oxospiro[7-azaisobenzofuran-
1(3H),1'-cyclohexane]-4'-carbonitrile
Cis-4'-hydroxyspiro[7-azaisobenzofuran-1(3H), 1'-
cyclohexane]-3-one (1.58 g) and triethylamine (1.81 mL) were
dissolved in chloroform (28 mL). After being cooled to OoC,
methanesulfonyl chloride (0.67 mL) was added thereto. The
mixture was stirred at room temperature for 2 hours and then
poured into the saturated sodium bicarbonate aqueous
solution (50 mL). The whole was extracted with chloroform
(100 mL x 3). The organic layer was dried over anhydrous
MgSO4 The concentration of the solvent gave a oily residue,
which was purified by column chromatography on silica gel
(hexane/ethyl acetate=2/l to 1/2) to give a solid compound.
The solid compound was recrystallized from ethyl
acetate-hexane to give the desired mesylate compound (2.03
g). This compound was dissolved in anhydrous
dimethylformamide (30 mL), and triethylammonium cyanide
(3.2 g) was added thereto. The mixture was stirred at 100oC
for 3 hours. After being cooled, the reaction mixture was
poured into water (100 mL). The whole was extracted with
ethyl acetate (100 mL x 3). The organic layer was dried over
anhydrous MgSO4. The concentration of the solvent gave a oily
residue, which was purified by column chromatography on
silica gel (hexane/ethyl acetate=3/l to 2/1) to give a solid
compound. The solid compound was further recrystallized
from ethyl ether-hexane to give the subject compound (515
mg).
(6) Preparation of trans-3-oxospiro[7-azalsobenzofuran-
1(3H),1'-cyclohexane]-4'-carboxylic acid
Water (6.6 mL) and concentrated sulfuric acid (2.2
mL) were added to trans-3-oxospiro[7-azaisobenzofuran-
1(3H),1'-cyclohexane]-4'-carbonitrile (515 mg). The
mixture was refluxed for 13 hours. After the reaction
mixture was cooled to 0t, 4N sodium hydroxide aqueous
solution was added to adjust pH to 4. The crystal
precipitated was collected by filtration. The crystal was
washed with water, ethanol as well as diisopropyl ether and
then dried. The subject compound (500 mg) was obtained.
1H-NMR (300 MHz, DMSO-d6, 6ppm): 1.73-1.80(2H, m),
1.81-1.94(2H, m), 1.99-2.08(2H, m), 2.14-2.22(2H, m),
2.64-2.68(lH, m), 7.63(1H, dd, J = 7.8, 4.8Hz), 8.28(1H. dd,
J=7.8, 1.5HZ), 8.89(1H, dd, J=4.8, 1.5Hz).
(7) Preparation of trans-N-(4-benzoylphenyl)-3-oxospiro-
[7-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide
trans-3-oxospiro[7-azaisobenzofuran-l(3H),1'-
cyclohexane]-4'-carboxylic acid (26 mg) and 4-
aminobenzophenone (20 mg) were dissolved in anhydrous
pyridine (1 mL). 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (29 mg) was added thereto.
The mixture was stirred at room temperature for 18 hours.
The reaction mixture was poured into water (10 mL).
The whole was extracted with ethyl acetate (30 mL x 3). The
combined organic layer was dried over anhydrous MgSO4 The
concentration of the solvent gave an oily residue, which was
purified by column chromatography on silica gel
(hexane/ethyl acetate=3/l to 2/1) to give a solid compound.
The solid compound was further recrystallized from ethyl
acetate-hexane to give the subject compound (30 mg) as
colorless crystals (melting point 214-216 Employing the procedure substantially as described
in Example 90-(7), but substituting the appropriate amines
for 4-aminobenzophenone used in Example 90-(7), compounds
of Examples 91 to 95 were prepared.
Example 91
trans-N-f1-(3 r5-difluorophenyl)-4-lmidazolyl1-3-
oxospiroT 7-azaisobenzofuran-l(3H).1'-cyclohexane1-4'-
carboxamide
melting point 269-271T;
Powder X-ray diffraction
Above powder X-ray diffraction analysis data were
measured by the same conditions as Example 32.
Example 92
trans-3-oxo-N-[2-phenyl-4-pyridylIspiror7-
azaisobenzofuran-1(3H),1'-cyclohexane1-4'-carboxamide
melting point 221-223oC
Example 93
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 240-242oC
Example 94
trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spirof 7-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 214-217oC
Example 9 5
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl1-3-oxospiro[7-
azaisobenzofuran-1(3H), 1'-cyclohexane1-4'-carboxamide
melting point 210-212oC
Employing the procedure substantially as described
in Example 57-(6), but substituting the appropriate amines
for 4-aminobenzophenone used in Example 57-(6), compounds
of Examples 96 to 98 were prepared.
Example 96
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro [4-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 200-202oC
Example 97
trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiror4-
azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 223-225oC
Powder X-ray diffraction
Above powder X-ray diffraction analysis data were
measured by the same conditions as Example 32.
Example 98
trans-N-F1-(3-fluorophenyl)-4-pyrazolyli-3-oxospiro[4-
azaisobenzofuran-l(3H).1'-cyclohexane]-4'-carboxamide
melting point 176-178oC
Employing the procedure substantially as described
in Example 62-(6), but substituting the appropriate amines
for 4-aminobenzophenone used in Example 62-(6), compounds
of Examples 99 to 106 were prepared.
Example 99
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 249-250oC
Example 100
trans-N-F1-(4-fluorophenyl)-3-pyrazolyl1-3-oxospiro[6-
azaisobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 254-257 *C
Example 101
trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 239-24lt:
Example 102
trans-3-oxo-N-(5-phenyl-1.2.4-thladlazol-3-yl)spiro[6-
azalsobenzofuran-1(3H).1'-cyclohexane1-4'-carboxamide
melting point 221-223oC
Example 103
trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-
azaisobenzofuran-1(3H) 1'-cyclohexane1-4'-carboxamide
melting point 259-26l"€
Example 104
trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-
azaisobenzofuran-1f 3H).1'-cyclohexanel-4'-carboxamide
melting point 249-251oC
Example 105
trans-3-oxo-N-(2-phenyl-3-thiazolyl)spirof 6-
azalsobenzofuran-1(3H), 1'-cyclohexane]- 4'-carboxamide
melting point 278-280T:
Example 106
trans-3-oxo-N-(2-phenyl-1.2.3-triazol-4-yl)spiro[6-
azalsobenzofuran-1(3H),1'-cyclohexane]- 4'-carboxamide
melting point 232-233oC
Formulation example 1
20.0 grams of compound of Example 1, 417 grams of
lactose, 80 grams of crystalline cellulose and 80 grams of
partial a-starch were blended with a V-cone blender. To
the mixture was added 3.0 grams of magnesium stearate and
the whole was blended. The blended powder was compressed
into 3000 tablets by conventional procedure so that each
tablet has a weight of 150 mg and 7.0 mm in diameter.
The content of one tablet with a weight of 150 mg
the compound of Example 1 5.0mg
135
lactose 104.25 mg
crystalline cellulose 20.0 mg
partial a-starch 20.0 mg
magnesium stearate 0.75 mg
Formulation example 2
10.8 grams of hydroxypropylcellulose 2910 and 2.1
grams of polyethylene glycol 6000 were dissolved in 172.5
grams of purified water. To the solution was dispersed 2.1
grams of titanium oxide to provide a coating liquid. 2500
tablets prepared in Formulation example 1, was subjected to
spray-coating with the coating liquid using HICOATER-MINI
to provide a film coated tablet with a weight of 155 mg.
The content of one tablet (155 mg)
the tablet prepared in the Formulation example 1 150 mg
hydroxypropylcellulose 2910 3.6 mg
Polyethylene glycol 6000 0.7 mg
titanium dioxide 0. 7 mg
Industrial Applicability
Compounds of the present Invention exhibit NPY
antagonistic activities and are useful as agents for the
treatment of various diseases related to NPY, for example,
cardiovascular disorders such as hypertension, nephropathy,
heart disease, vasospasm, arteriosclerosis and the like,
central nervous system disorders such as bulimia, depression,
anxiety, seizure, epilepsy, dementia, pain, alcoholism,
drug withdrawal and the like, metabolic diseases such as
obesity, diabetes, hormone abnormality.
hypercholesterolemia, hyperlipidemia and the like, sexual
and reproductive dysfunction, gastro-intestinal disorder,
respiratory disorder, inflammation or glaucoma, and the
like.
WE CLAIM
1. A spiro compound represented by the general formula
wherein Ar represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro,
straight- or branched-chain alkyl group of C1 to C6, straight- or branched-
chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 halogen
atoms identically or differently at the substitutable, arbitrary positions,
straight- or branched-chain alkyl group of Cl to C6 substituted with 1, 2 or
more than 2 hydroxy groups at the substitutable, arbitrary positions,
cycloalkyl group of C3 to C6, straight-or branched-chain alkenyl group of
C2 to C6, straight- or branched-chain alkoxy group of Cl to C6, straight- or
branched-chain alkoxy group of Cl to C6 substituted with 1, 2 or more than
2 halogen atoms identically or differently at the substitutable, arbitrary
positions, straight- or branched-chain alkylthio group of Cl to C6, carboxyl,
alkanoyl group containing straight- or branched-chain alkyl group of Cl to
C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy
group of Cl to C6, straight- or branched-chain alkylene group of C2 to C6
which may be substituted with 1,2 or more than 2 oxo groups at a
substitutable, arbitrary positions, and a group represented by formula of-Q-
Ar2;
Ar2 represents aryl or heteroaryl which may be substituted, the substituent
being selected from the group consisting of halogen, cyano, straight- or
branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl
group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or
branched-chain alkoxy group of Cl to C6, straight- or branched-chain
alkoxy group of Cl to C6 susbstituted with 1, 2 more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, amino
group mono-substituted with straight- or branched-chain alkyl group of Cl
to C6, amino group di-substituted with identical or different straight-or
branched-chain alkyl group of Cl to C6, alkanoyl group containing straight-
or branched-chain alkyl group of Cl to C6 and aryl;
n represents 0 or 1;
Q represents a single bond or carbonyl;
T, U, V and W represent independently nitrogen atom or methine group
which may have a substituent selected from the group consisting of halogen,
straight- or branched-chain alkyl group of Cl to C6, hydroxy and straight- or
branched-chain alkoxy group of Cl to C6, where at least two of them
represent the said methine group;
X represents methine or nitrogen;
Y represents imino which may be substituted with straight- or branched-
chain alkyl group of Cl to C6, or oxygen;
a salt or ester thereof.
2. The compound as claimed in claim 1, wherein the aryl in Ar1 is
phenyl.
3. The compound as claimed in claim 1, wherein the heteroaryl in Ar1 is
pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1, 2, 3-
triazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1, 2, 4-
triazinyl, benzoxazolyl, benzothiazolyl, quinolyl or pyrido [3, 2-b] pyridyl.
4. The compound as claimed in claim 1, wherein T, U, V and W are
independently methine which may have a substituent selected from the
group consisting of halogen, straight- or branched-chain alkyl group of Cl to
C6, hydroxy and straight- or branched-chain alkoxy group of Cl to C6.
5. The compound as claimed in claim 1, wherein T, U, V and W are
independently methine which may be substituted with halogen.
6. The compound as claimed in claim 1, wherein one of T, U, V and W
is nitrogen.
7. The compound as claimed in claim 1, wherein Y is unsubstituted
imino or oxygen.
8. The compound as claimed in claim 1, wherein Y is oxygen.
9. The compound as claimed in claim 1 which is represented by the
general formula (I-a ) :
wherein Ar1 represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro, straight-
or branched-chain alkyl group of Cl to C6, straight- or branched-chain alkyl
group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, cycloalkyl group of C3
to C6, straight- or branched-chain alkenyl group of C2 to C6, straight- or
branched-chain alkoxy group of Cl to C6, straight- or branched- chain alkoxy
group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkylthio group of Cl to C6, carboxyl, alkanoyl group
containing straight- or branched-chain alkyl group of Cl to C6, alkoxycarbonyl
group containing straight- or branched-chain alkoxy group of Cl to C6,
straight- or branched-chain alkylene group of C2 to C6 which may be
substituted with 1, 2 or more than 2 oxo groups at a substitutable, arbitrary
positions, and a group represented by formula of-Q-Ar2 ;
At2 represents aryl or heteroaryl which may be substituted, the substituent
being selected from the group consisting of halogen, cyano, straight- or
branched-chain alkyl group of Cl to C6, straight- or branched-chain alkyl
group of Cl to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or
branched-chain alkoxy group of Cl to C6, straight- or branched-chain
alkoxy group of Cl to C6 substituted with 1,2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, amino
group mono-substituted with straight- or branched-chain alkyl group of C1
to C6, amino group di-substituted with identical or different straight- or
branched-chain alkyl group of Cl to C6, alkanoyl group containing straight-
or branched-chain alkyl group of Cl to C6 and aryl;
Q represents a single bond or carbonyl;
R1 represents hydrogen or halogen.
10. The compound as claimed in claim 9, wherein the aryl in Ar1 is
phenyl.
11. The compound as claimed in claim 9, wherein the heteroaryl in Ar1 is
imidazolyl, pyrazolyl, isoxazolyl, 1, 2, 4-thiadiazolyl, pyrazinyl,
pyrimidinyl, quinolyl or pyrido [3,2-b] pyridyl.
12. The compound as claimed in claim 1 which is represented by the
general formula (I-b):

wherein Ar1 represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro,
straight- or branched-chain alkyl group of Cl to C6, straight- or branched-
chain alkyl group of Cl to C6 substituted with 1, 2 or more than 2 halogen
atoms identically or differently at the substitutable, arbitrary positions,
straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or
more than 2 hydroxy groups at the substitutable, arbitrary positions,
cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of
C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or
branched-chain alkoxy group of C1 to C6 substituted with 1,2 or more than
2 halogen atoms identically or differently at the substitutable, arbitrary
positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl,
alkanoyl group containing straight- or branched-chain alkyl group of C1 to
C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy
group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6
which may be substituted with 1, 2 or more than 2 oxo groups at a
substitutable, arbitrary positions, and a group represented by formula of-Q-
Ar2;
Ar2 represents aryl or heteroaryl which may be substituted, the substituent
being selected from the group consisting of halogen, cyano, straight- or
branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl
group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or
branched-chain alkoxy group of C1 to C6, straight- or branched-chain
alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, amino
group mono-substituted with straight- or branched-chain alkyl group of C1
to C6, amino group di-substituted with identical or different straight- or
branched-chain alkyl group of C1 to C6, alkanoyl group containing straight-
or branched-chain alkyl group of C1 to C6 and aryl;
Q represents a single bond or carbonyl;
T, U, V and W represent independently nitrogen atom or methine group
which may have a substituent selected from the group consisting of halogen,
straight- or branched-chain alkyl group of C1 to C6, hydroxy and straight- or
branched-chain alkoxy group of C1 to C6, where at least two of them
represent the said methine group.
13. The compound as claimed in claim 12, wherein the aryl in Ar1 is
phenyl.
14. The compound as claimed in claim 12, wherein the heteroaryl in Ar1 is
pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1, 2, 3-
triazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or 1, 2, 4-
triazinyl.
15. The compound as claimed in claim 12, wherein one of T, U, V and W
is nitrogen.
16. The compound as claimed in claim 12, wherein V is nitrogen and each
of T, U and W is unsubstituted methine group.
17. The compound of claim 1, which is
N- (4-benzoylphenyl)-3-oxospiro[isoindoline-l,4'-
piperidine]-1'-carboxamide,
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-l,4'-
piperidine]-1'-carboxamide,
N- ( 7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1, 4'-
piperidine]-1'-carboxamide,
N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-l,4'-piperidine]-1'-carboxamide,
N- (4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-
1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
3,4-dihydro-N-(7-methyl-2-quinolyl)-3-
oxospiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
N- ( 4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-
1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-[1-(2-quinolyl)-4-
imidazolyl]spiro [isoquinoline-1 ( 2H), 4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-oxo-5, 6,7,8-tetrahydro-2-
naphthyl)spiro[isoquinoline-l( 2H), 4'-piperidine]-1'-carboxamide,
3, 4-dihydro-N-[5- ( 2-methyl- 1-propenyl)-2-pyrazinyl ]-3-
oxospirof isoquinoline-1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(3-phenyl-5-
is oxazolyl)spiro[ is oquinoline-1 ( 2H), 4'-piperidine]-1'-
carboxamide,
N-[l-(7-benzo[b]furanyl)-4-imidazolyl]-3, 4-dihydro-3-
oxospiro[isoquinoline-l ( 2H), 4'-piperidine]-1'-
carboxamide,
N-[1- (3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-
dihydro-3-oxospiro[isoquinoline-l(2H), 4'-piperidine]-1'-
carboxamide,
3,4-dihydro-3-oxo-N-[4-(2-
pyridylcarbonyl)phenyl]spiro[isoquinoline-l( 2H), 4'-
piperidine)-1'-carboxamide,
N-(3,4-dichlorophenyl)-3,4-dihydro-3-
oxospiro[isoquinoline-1(2H),4'-piperidine]-1'-
carboxamide,
N-[1-(3-chlorophenyl)-4-imidazolyl ]-3, 4-dihydro-3-
oxospiro[isoquinoline-l(2H),4'-piperidine]-1'-
carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-
thiazolyl)spiro[isoquinoline-1( 2H), 4'-piperidine]-1'-
carboxamide,
3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2-
pyrazinyl]spiro[ isoquinoline-1( 2H), 4'-piperidine]-1'-
carboxamide,
3, 4-dihydro-N-( 4-methyl-2-benzothiazolyl)-3-
oxospiro[isoquinoline-1( 2H), 4'-piperidine]-1'-
carboxamide,
N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-
oxospiro[isoquinoline-1 ( 2H),4'-piperidine]-1'-
carboxamide,
N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H), 4'-
piperidine]-1'-carboxamide,
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-
yl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran
-1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-
1(3H),4'-piperidine]-1'-carboxamide,
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-[5-(3-trifluoromethylphenyl)-2-
pyrimidinyl]spiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
N-[5-(3-chlorophenyl)- 2-pyrimidinyl]-3-
oxospiro[isobenzofuran-l(3H),4'-piperidine]-1'-
carboxamide,
N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
3-oxo-N-(5-phenyl-l,2,4-thiadiazol-3-
yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
N-{l-[3-(2-hydroxyethyl)phenyl]-4-imidazoly}-3-
oxospiro[isobenzofuran-1 (3H), 4'-piperidine]-1'-
carboxamide,
N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
N- [l-(3-methoxyphenyl)-4-imidazolyl]-3-
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-
carboxamide,
6-fluoro-3-oxo-N-(5-phenyl-2-
pyrazinyl) spiro[isobenzof uran-1 ( 3H), 4'-piperidine ]-1'-
carboxamide,
6-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl) spiro [isobenzof uran-1(3H),4'-piperidine]-1'
carboxamide,
5-fluoro-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l ( 3H), 4'-piperidine]-1'-
carboxamide,
5-flubro-3-oxo-N-(5-phenyl-2-
pyrimidinyl) spiro [isobenzof uran- 1 ( 3H), 4'-piperidine]-1'
carboxamide,
N-(4-benzoylphenyl)-3, 4-dihydro-3-oxospiro[1H-2-
benzopyran-1,4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)sp±ro[ 1H-2-
benzopyran-1, 4'-piperidine]-1'-carboxamide,
N- ( 5-benzoyl-2-pyrazinyl)-3, 4-dihydro-3-oxospiro[ 1H-2-
benzopyran-1, 4'-piperidine]-1'-carboxamide,
trans-N- (4-benzoylphenyl)-3'-oxospiro[cyclohexane-
1,1' (3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N- (5-phenyl-2-pyrazinyl) spiro[cyclohexane-
1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N- (l-phenyl-4-imidazolyl) spiro[cyclohexane-
1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N- (5-phenyl-2-pyrimidinyl)spiro [cyclohexane
-1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-N-[1-(3, 5-dif luorophenyl)-4-imidazolyl ]-3'-
oxospiro[cyclohexane-1,1' (3'H)-isobenzofuran]-4-
carboxamide,
trans-3'-oxo-N- (5-phenyl- 3-pyrazolyl) spiro[cyclohexane-
1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-N-[l-(2- fluorophenyl)-4-imidazolyl ]-3'-
oxospiro[cyclohexane-1,1' (3'H)-isobenzofuran]-4-
carboxamide,
trans-N- ( 4-acetyl-3-trif luoromethylphenyl)-3'-
oxospiro[cyclohexane-1,1' (3'H)-isobenzofuran]-4-
carboxamide,
trans-3'-oxo-N-[1-(3-quinolyl)-4-
imidazolyl] spiro [cyclohexane- 1, 1' ( 3' H)-isobenzofuran ]-4-
carboxamide,
trans-N-[1- ( 3-cyanophenyl)-'4-imidazolyl ]-3'-
oxospirotcyclohexane-1.1'(3'H)-isobenzofuran]-4-
carboxamide,
trans-N- (4-benzoylphenyl)-3-oxospiro[4-azaisobenzof uran-
1(3H),1'- cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-
azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4-
azaisobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N- (5-phenyl-2-pyrimidinyl) spiro[4-
azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide,
trans-N- (4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-
1(3H),1'- cyclohexane]-4'-carboxamide,
trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-
1(3H),1'- cyclohexane]-4'-carboxamide,
N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-
oxospiro[isobenzofuran-1 ( 3H),4'-piperidine]-1'-
carboxamide,
N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-
oxospiro[isobenzofuran-1 ( 3H), 4'-piperidine ]-1'-
carboxamide,
4-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl) spiro[isobenzofuran-1( 3H), 4'-piperidine]-1'-
carboxamide,
7-fluoro-3-oxo-N-(5-phenyl-2-
pyrimidinyl) spiro[isobenzofuran-1( 3H), 4'-piperidine]-1'-
carboxamide,
6-ethyl-3-oxo-N-(5-phenyl-2-
pyrazinyl) spiro[isobenzofuran-1 ( 3H), 4'-piperidine]-1'-
carboxamide.
6-hydroxy-3-oxo-N-(5-phenyl-2-
pyrazinyl)spiro[isobenzofuran-l(3H),4'-piperidine]-1'-carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-
azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-
azaisobenzofuran-1(3H), 1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-
azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide,
trans-N-[5- ( 3-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-
azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide,
trans-N-[5- (3-[luoromethoxyphenyl)-2-pyrimidinyl]-3-
oxospiro[ 5-azaisobenzof uran-1 ( 3H), 1'-cyclohexane]-4'-
carboxamide,
trans-N-[5- (3-[luoromethylphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzof uran-1 ( 3H), 1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-[luoro-5-methoxyphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzof uran-1 ( 3H), 1'-cyclohexane ]-4'-
carboxamide,
trans-N-[5- ( 2-[luoro-5-methylphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzof uran- 1 ( 3H), 1'-cyclohexane]-4'-
carboxamide,
trans-N-[4- ( 3-[luoromethoxyphenyl)-2-oxazolyl ]-3-
oxospiro[5-azaisobenzof uran-1 ( 3H),1'-cyclohexane]-4'-
carboxamide, '
trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3-
oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-
carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-
azaisobenzofuran-l(3H)»1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-
oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-
oxospiro[6-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-
carboxamide,
trans-3-oxo-N-(6-phenyl-1,2,4-triazin-3-yl)spiro[6-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3-
oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N- [5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-
oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-
carboxamide,
trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N- ( 4-benzoylphenyl)-3-oxospiro[7-azaisobenzofuran-
1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-
oxospiro[7-azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-
azaisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-
azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-az
aisobenzofuran-l(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-1, 2,4-thiadiazol-3-yl)spiro[6-az
aisobenzofuran-1(3H),1'-cyclohexane]- 4'-carboxamide,
trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzo
furan-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azaisobenzofur
an-1(3H), 1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-l (3H), 1'-
cyclohexane]-4'-carboxamide
or
trans-3-oxo-N-(2-phenyl-l, 2, 3-triazol-4-yl)spiro[6-azaisobenzofuran-
1(3H), 1'-cyclohexane]-4'-carboxamide.
18. The compound as claimed in claim 1, which is 3-oxo-N-(5-phenyl-2-
pyrazinyl)-spiro[isobenzofuran-l(3H), 4'-piperidine]-r-carboxamide.
19. The compound as claimed in claim 1, which is 3-oxo-N-(7-
txifluoromethylpyrido[3, 2-b]pyridin-2-yl)spiro[isobenzofuran-l(3H), 4'-
piperidine]-r-carboxamide.
20. The compound as claimed in claim 1, which is N-[5(3-fluorophenyl)-
2-pyrimidinyl]-3-oxospiro[isobenzofuran-l(3H),4'-piperidine]-r-
carboxamide.
21. The compound as claimed in claim 1, which is trans-3'-oxo-N-(5-
phenyl-2-pyrimidinyl)spiro[cyclohexane-1, 1'(3'H)-isobenzofuran]-4-
carboxamide.
22. The compound as claimed in claim 1, which is trans-3'-oxo-N-[l-(3-
quinolyl)-4-imidazolyl]spiro[cyclohexane-1, l'(3'H)-isobenzofuran]-4-
carboxamide.
23. The compound as claimed in claim 1, which is trans-3-oxo-N-(5-
phenyl-2-pyrazinyl)spiro[4-a2jaisobenzoniran-l(3H), 1'-cyclohexane]-4'-
carboxamide.
24. The compound as claimed in claim 1, which is trans-N-[5-(3-
fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1 (3H), 1'-
cyclohexane]-4-'-carboxamide.
25. The compound as claimed in claim 1, which is trans-N-[5-(2-
fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1 (3H), 1'-
cyclohexane]-4'-carboxamide.
26. The compound as claimed in claim 1, which is trans-N-[l-(3, 5-
difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1 (3H), 1'-
cyclohexane]-4'-carboxamide.
27. The compound as claimed in claim 1, which is trans-3-oxo-N-(l-
phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-
carboxamide.
28. The compound as claimed in claim 1, which is trans-3-oxo-N-(l-
phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-
carboxamide.
29. The compound as claimed in claim 1, which is trans-3-oxo-N-(2-
phenyl-1, 2, 3-triazol-4-yl)spiro[6-azaisobenzofuran-l(3H), 1'-
cyclohexane]-4'-carboxamide.
30. A process for producing a spiro compound of the general formula
(I-1):
wherein Ar1 represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro,
straight- or branched-chain alkyl group of C1 to C6, straight- or branched-
chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen
atoms identically or differently at the substitutable, arbitrary positions,
straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or
more than 2 hydroxy groups at the substitutable, arbitrary positions,
cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of
C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or
branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than
2 halogen atoms identically or differently at the substitutable, arbitrary
positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl,
alkanoyl group containing straight- or branched-chain alkyl group of C1 to
C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy
group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6
which may be substituted with 1, 2 or more than 2 oxo groups at a
substitutable, arbitrary positions, and a group represented by formula of-Q-
V;
Ar2 represents aryl or heteroaryl which may be substituted, the substituent
being selected from the group consisting of halogen, cyano, straight- or
branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl
group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or
branched-chain alkoxy group of C1 to C6, straight- or branched-chain
alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, amino
group mono-substituted with straight- or branched-chain alkyl group of C1
to C6, amino group di-substituted with identical or different straight- or
branched-chain alkyl group of C1 to C6, alkanoyl group containing straight-
or branched-chain alkyl group of C1 to C6 and aryl;
Q represents a single bond or carbonyl;
T, U, V and W represent independently nitrogen atom or methine group
which may have a substituent selected from the group consisting of halogen,
straight- or branched-chain alkyl group of C1 to C6, hydroxy and straight- or
branched-chain alkoxy group of C1 to C6, where at least two of them
represent the said methine group;
n and Y have the same meanings as described hereinafter;
a salt or ester thereof, which comprises reacting a compound of the general
formula (II):
wherein Arlp represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro,
straight- or branched-chain alkyl group of C1 to C6, straight- or branched-
chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen
atoms identically or differently at the substitutable, arbitrary positions,
cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of
C2 to C6, straight- or branched-chain alkoxy group of C1 to C6* straight- or
branched-chain alkoxy of C1 to C6 substituted with 1, 2 or more than 2
halogen atoms identically or differently at the substitutable, arbitrary
positions, straight- or branched-chain alkylthio group of C1 to C6, alkanoyl
group containing straight- or branched-chain alkyl group of C1 to C6,
alkoxycarbonyl group containing straight- or branched-chain alkoxy group
of C1 to C6, a group of formula:-QpAr2p, and an optionally protected,
(i) straight- or branched-chain alkylene group of C2 to C6 which may be
substituted with 1, 2 or more than 2 oxo groups, (ii) straight- or branched-
chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy
groups at the substitutable, arbitrary positions, or (iii) carboxyl group;
Ar2p represents aryl or heteroaryl which may be substituted, the substituent
being selected from the group consisting of halogen, cyano, straight- or
branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl
group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkoxy group of C1 to C6, straight- or branched-chain
alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, amino
group di-substituted with identical or different straight- or branched-chain
alkyl group of C1 to C6, alkanoyl group containing straight- or branched-
chain alkyl group of C1 to C6, aryl, and an optionally protected, straight- or
branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, hydroxy or amino
group mono-substituted with straight- or branched-chain alkyl group of C1 toC6;
Ar3 represents phenyl which may be substituted by halogen or nitro;
Qp represents a single bond or optionally protected carbonyl;
with a compound of formula (HI):

wherein n represents 0 or 1;
t, u, v and w represent independently nitrogen atom methine group which
may have a substituent selected from the group consisting of halogen,
straight- or branched-chain alkyl group of C1 to C6, straight- or branched-
chain alkoxy group of C1 to C6 and optionally protected hydroxy, where at
least two of them represent the said methine group;
Y represents imino which may be substituted with straight- or branched-
chain alkyl group of C1 to C6, or oxygen atom;
to provide a compound of formula (IV-1):

wherein Arlp, n, t, u, v, w and Y have the same meanings as described
above;
optionally followed by elimination of a protecting group.
31. A process for producing a spiro compound of the general formula
(1-2):
wherein Ar1 represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro,
straight- or branched-chain alkyl group of C1 to C6, straight- or branched-
chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen
atoms identically or differently at the substitutable, arbitrary positions,
straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or
more than 2 hydroxy groups at the substitutable, arbitrary positions,
cycloalkyl group of C3 of C6, straight- or branched-chain alkenyl group of
C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or
branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than
2 halogen atoms identically or differently at the substitutable, arbitrary
positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl,
alkanoyl group containing straight- or branched-chain alkyl group of C1 to
C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy
group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6
which may be substituted with 1, 2, or more than 2 oxo groups at a
substitutable, arbitrary positions, and a group represented by formula of-Q-
Ar2 represents aryl or heteroaryl which may be substituted, the substituent
being selected from the group consisting of halogen, cyano, straight- or
branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl
group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or
branched-chain alkoxy group of C1 to C6, straight- or branched-chain
alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, amino
group mono-substituted with straight- or branched-chain alkyl group of C1
to C6, amino group di-substituted with identical or different straight- or
branched-chain alkyl group of C1 to C6, alkanoyl group containing straight-
or branched-chain alkyl group of C1 to C6 and aryl;
Q represents a single bond or carbonyl;
T, U, V and W represent independently nitrogen atom or methine group
which may have a substituent selected from the group consisting of halogen,
straight- or branched-chain alkyl group of C1 to C6, hydroxy and straight- or
branched-chain alkoxy group of C1 to C6, where at least two of them
represent the said methine group;
n and Y have the same meanings as described hereinafter;
a salt or ester thereof, which comprises reacting a compound of formula (V):
Ar1p —NH2 (V)
wherein Arlp represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro,
straight- or branched-chain alkyl group of C1 to C6, straight- or branched-
chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen
atoms identically or differently at the substitutable, arbitrary positions,
cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of
C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or
branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than
2 halogen atoms identically or differently at the substitutable, arbitrary
positions, straight- or branched-chain alkylthio group of C1 to C6, alkanoyl
group containing straight- or branched-chain alkyl group of C1 to C6,
alkoxycarbonyl group containing straight- or branched-chain alkoxy group
of C1 to C6, a group of formula:-Qp-Ar2p, and an optionally protected,
(i) straight- or branched-chain alkylene group of C2 to C6 which may be
substituted with 1, 2 or more than 2 oxo groups, (ii) straight- or branched-
chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 hydroxy
groups at the substitutable, arbitrary positions, or (iii) carboxyl group;
Ar2p represents aryl or heteroaryl which may be substituted, the substituent
being selected from the group consisting of halogen, cyano, straight- or
branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl
group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkoxy group of C1 to C6, straight- or branched-chain
alkoxy group of C1 to C6 substituted with 1,2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, amino
group di-substituted with identical or different straight- or branched-chain
alkyl group of C1 to C6, alkanoyl group containing straight- or branched-
chain alkyl group of C1 to C6, aryl, and an optionally protected, straight- or
branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, hydroxy or amino
group mono-substituted with straight- or branched-chain alkyl group of C1 toC6;
Qp represents a single bond or optionally protected carbonyl;
with a carboxylic acid of the general formula (VI):

wherein n represents 0 orl;
t, u, v and w represent independently nitrogen atom or methine group which
may have a substituent selected from the group consisting of halogen,
straight- or branched-chain alkyl group of C1 to C6, straight- or branched-
chain alkoxy group of C1 to C6 and optionally protected hydroxy, where at
least two of them represent the said methine group;
Y represents imino which may be substituted with straight- or branched-
chain alkyl group of C1 to C6, or oxygen atom;
or a reactive derivative thereof to provide a compound of the general
formula (IV-2):
wherein Ar1p, n, t, u, v, w and Y have the same meanings as described
above;
optionally followed by elimination of a protecting group.
32. Neuropeptide Y receptor antagonist which contains a compound of
the general formula (I) :
wherein Ar1 represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro,
straight- or branched-chain alkyl group of C1 to C6, straight- or branched-
chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2 halogen
atoms identically or differently at the substitutable, arbitrary positions,
straight- or branched-chain alkyl group of C1 to C6 substituted with 1, 2 or
more than 2 hydroxy groups at the substitutable, arbitrary positions,
cycloalkyl group of C3 to C6, straight- or branched-chain alkenyl group of
C2 to C6, straight- or branched-chain alkoxy group of C1 to C6, straight- or
branched-chain alkoxy group of C1 to C6 substituted with 1, 2 or more than
2 halogen atoms identically or differently at the substitutable, arbitrary
positions, straight- or branched-chain alkylthio group of C1 to C6, carboxyl,
alkanoyl group containing straight- or branched-chain alkyl group of C1 to
C6, alkoxycarbonyl group containing straight- or branched-chain alkoxy
group of C1 to C6, straight- or branched-chain alkylene group of C2 to C6
which may be substituted with 1, 2 or more than 2 oxo groups at a
substitutable, arbitrary positions, and a group represented by formula of-Q-
Ar2;
Ar2 represents aryl or heteroaryl which may be substituted, the substituent
being selected from the group consisting of halogen, cyano, straight- or
branched-chain alkyl group of C1 to C6, straight- or branched-chain alkyl
group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, straight- or
branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more than 2
hydroxy groups at the substitutable, arbitrary positions, hydroxy, straight- or
branched-chain alkoxy group of C1 to C6, straight- or branched-chain
alkoxy group of C1 to C6 substituted with 1, 2 or more than 2 halogen atoms
identically or differently at the substitutable, arbitrary positions, amino
group mono-substituted with straight- or branched-chain alkyl group of C1
to C6, amino group di-substituted with identical or different straight- or
branched-chain alkyl group of C1 to C6, alkanoyl group containing straight-
or branched-chain alkyl group of C1 to C6 and aryl;
n represents 0 orl;
Q represents a single bond or carbonyl;
T, U, V and W represent independently nitrogen atom or methine group
which may have a substituent selected from the group consisting of halogen,
straight- or branched-chain alkyl group of C1 to C6, hydroxy and straight- or
branched-chain alkoxy group of C1 to C6, where at least two of them
represent the said methine group;
X represents methine or nitrogen;
Y represents imino which may be substituted with straight- or branched-
chain alkyl group of C1 to C6, or oxygen;
a salt or ester thereof as an active ingredient.
33. An agent for the treatment of bulimia, obesity or diabetes which
contains a spiro compound of the general formula (I) :
wherein Ar1 represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, nitro,
straight- or branched-chain alkyl group of C1 to C6, straight- or
branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more
than 2 halogen atoms identically or differently at the substitutable,
arbitrary positions, straight- or branched-chain alkyl group of C1 to C6
substituted with 1, 2 or more than 2 hydroxy groups at the substitutable,
arbitrary positions, cycloalkyl group of C3 to C6, straight- or branched-
chain alkenyl group of C2 to C6, straight- or branched-chain alkoxy
group of C1 to C6, straight- or branched-chain alkoxy group of C1 to
C6 substituted with 1, 2 or more than 2 halogen atoms identically or
differently at the substitutable, arbitrary positions, straight- or
branched-chain alkylthio group of C1 to C6, carboxyl, alkanoyl group
containing straight- or branched-chain alkyl group of C1 to C6,
alkoxycarbonyl group containing straight- or branched-chain alkoxy
group of C1 to C6, straight- or branched-chain alkylene group of C2 to
C6 which may be substituted with 1, 2 or more than 2 oxo groups at a
substitutable, arbitrary positions, and a group represented by formula of-Q-Ar2;
Ar2 represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen, cyano,
straight- or branched-'Chain alkyl group of C1 to C6, straight- or
branched-chain alkyl group of C1 to C6 substituted with 1, 2 or more
than 2 halogen atoms identically or differently at the substitutable,
arbitrary positions, straight- or branched-chain alkyl group of C1 to C6
substituted with 1, 2 or more than 2 hydroxy groups at the substitutable,
arbitrary positions, hydroxy, straight- or branched-chain alkoxy group
of C1 to C6, straight- or branched-chain alkoxy group of C1 to C6
substituted with 1, 2 or more than 2 halogen atoms identically or
differently at the substitutable, arbitrary positions, amino group mono-
substituted with straight- or branched-chain alkyl group of C1 to C6,
amino group di-substituted with identical or different straight- or
branched-chain alkyl group of C1 to C6, alkanoyl group containing
straight- or branched-chain alkyl group of C1 to C6 and aryl;
n represents 0 or 1;
Q represents a single bond or carbonyl;
T, U, V and W represent independently nitrogen atom or methine group
which may have a substituent selected from the group consisting of
halogen, straight- or branched-chain alkyl group of C1 to C6, hydroxy
or straight- or branched-chain alkoxy group of C1 to C6, where at least
two of them represent the said methine group;
X represents methine or nitrogen;
Y represents imino which may be substituted with straight- or
branched-chain alkyl group of C1 to C6, or oxygen;
a salt or ester thereof as an active ingredient.
34. A spiro compound of the general formula (VI-1) :
wherein t, u, v and w represent independently nitrogen atom or methine
group which may have a substituent selected from the group consisting
of halogen, straight- or branched-chain alkyl group of C1 to C6,
straight- or branched-chain alkoxy group of C1 to C6 and optionally
protected hydroxy, where at least two of them represent the said
methine group.
35. The compound of the present product as claimed in claim 1,
which is trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenz
ofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide.
36. The compound of the present product as claimed in claim 1,
which is trans-N-[5-(2-methylphenyI)-2-pyrimidinyl]-3-oxospiro[5-
azaisobenzofuran-l(3H), 1'-cyclohexane]-4'-carboxamide.
37. The compound of the present product as claimed in claim 1,
which is trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-
azaisobenzofuran-1 (3H),1'-cyclohexane]-4'-carboxamide.
38. The compound of the present product as claimed in claim 1,
which is trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiro[7-
azaisobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide.
39. The compound of the present product as claimed in claim 1,
which is trans-N-[l-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4-
azaisobenzofuran-l(3H),r-cyclohexane]-4'-carboxamide.
40. The compound of the present product as claimed in claim 1,
which is trans-N-[l-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-
azaisobenzofuran-l(3H),l'-cyclohexan e]-4'-carboxamide.
Spiro compounds of the general formula (1):
wherein Ar1 represents an optionally substituted ary) or beteroaryl; n represents 0
or 1; T, U, V and W each represent a nitrogen atom or an optionally substituted
methane group, wherein at least two of which represent said methane group; X
represents nitrogen; Y represents an optionally substituted imino or oxygen atom,
which exhibit neuropeptide Y receptor (NPY) antagonistic activities and are
useful as agents for the treatment of various diseases related to NPY, for
example, cardiovascular disorders, central nervous system disorders, metabolic
diseases and the like.

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Patent Number

225461

Indian Patent Application Number

IN/PCT/2002/00125/KOL

PG Journal Number

46/2008

Publication Date

14-Nov-2008

Grant Date

12-Nov-2008

Date of Filing

25-Jan-2002

Name of Patentee

BANYU PHARMACEUTICAL CO. LTD

Applicant Address

2-3, NIHONBASHI NONCHO, 2-CHOME, CHUO-KU, TOKYO

Inventors:

#	Inventor's Name	Inventor's Address
1	ITOH TAKAHIRO	C/O BANYU PHARMACEUTICAL CO. LTD. OKAZAKI SITE 9-1, KAMIMUTSUNA 3-CHOME, OKAZAKI-SHI, AICHI 444-0858
2	FUKAMI TAKEHIRO	C/O BANYU PHARMACEUTICAL CO. LTD. TSUKUBA RESEARCH INSTITUTE 3, OKUBO, TSUKUBA-SHI, IBARAKI 300-2611
3	KANATANI AKIO	C/O BANYU PHARMACEUTICAL CO. LTD. TSUKUBA RESEARCH INSTITUTE 3, OKUBO, TSUKUBA-SHI, IBARAKI 300-2611
4	ISHIHARA AKANE	C/O BANYU PHARMACEUTICAL CO. LTD. TSUKUBA RESEARCH INSTITUTE 3, OKUBO, TSUKUBA-SHI, IBARAKI 300-2611
5	ISHII YASUYUKI	C/O BANYU PHARMACEUTICAL CO. LTD. TSUKUBA RESEARCH INSTITUTE 3, OKUBO, TSUKUBA-SHI, IBARAKI 300-2611
6	TAKAHASHI TOSHIYUKI	C/O BANYU PHARMACEUTICAL CO. LTD. TSUKUBA RESEARCH INSTITUTE 3, OKUBO, TSUKUBA-SHI, IBARAKI 300-2611
7	HAGA YUJI	C/O BANYU PHARMACEUTICAL CO. LTD. TSUKUBA RESEARCH INSTITUTE 3, OKUBO, TSUKUBA-SHI, IBARAKI 300-2611
8	SAKAMOTO TOSHIHIRO	C/O BANYU PHARMACEUTICAL CO. LTD. TSUKUBA RESEARCH INSTITUTE 3, OKUBO, TSUKUBA-SHI, IBARAKI 300-2611

PCT International Classification Number

C07D 471/10

PCT International Application Number

PCT/JP00/05427

PCT International Filing date

2000-08-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	11/233573	1999-08-20	Japan
2	2000/137692	2000-05-10	Japan