Title of Invention	4,4-DIFLUORO-1,2,3,4-TETRAHYDRO-5H-1-BENZAZEPINE DERIVATIVE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEROF
Abstract	4,4-Difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives represented by the general formula (I), which have excellent arginine vasopressin V2 activity and are useful in the treatment of central diabetes insipidus and/or night pollakisuria: (I) wherein R1 is -OH, -O-lower alkyl, or optionally substituted amino; R2 is lower alkyl which may be substituted with one or more halogen atoms, or halogeno; one of R3 and R4 is -H, lower alkyl, or halogeno, and the other is optionally substituted nonaromatic cyclic amino or optionally substituted aromatic cyclic amino; and R5 is -H, lower alkyl, or halogeno. (FIG.nil

Title of Invention

4,4-DIFLUORO-1,2,3,4-TETRAHYDRO-5H-1-BENZAZEPINE DERIVATIVE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEROF

Abstract

4,4-Difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives represented by the general formula (I), which have excellent arginine vasopressin V2 activity and are useful in the treatment of central diabetes insipidus and/or night pollakisuria: (I) wherein R1 is -OH, -O-lower alkyl, or optionally substituted amino; R2 is lower alkyl which may be substituted with one or more halogen atoms, or halogeno; one of R3 and R4 is -H, lower alkyl, or halogeno, and the other is optionally substituted nonaromatic cyclic amino or optionally substituted aromatic cyclic amino; and R5 is -H, lower alkyl, or halogeno. (FIG.nil

Full Text	DESCRIPTION 4,4-Difluoro-l,2,3,4-Tetrahydro-5H-l-Benzazepine Derivative or Salt Thereof Technical Field of the Invention The present invention relates to a novel 4,4-difluoro-l,2,3,4- tetrahydro-5H-1-benzazepine derivative or a salt thereof, which is useful as a medicament, especially as a drug for the treatment of central diabetes insipidus or nocturia, and to a medicament comprising the compound as an active ingredient. Background Art Arginine vasopressin (AVP) is a peptide consisting of 9 amino acids, which is biosynthesized and secreted from the hypothalamus/ pituitary gland. AVP receptors are classified into three subtypes, i.e. V1a, V1b, and V2. It is known that the main pharmaceutical effects of AVP in peripheral are vasoconstriction through the V1a receptor, and antidiuresis through the V2 receptor. As a medicament for selectively stimulating V2 receptors, desmopressin has been synthesized (by deleting the amino acid of cystein in position 1 of AVP, and converting arginine of position 8 into a d form) and is used in the treatment of central diabetes insipidus (Journal of Japanese Academy of Endocrinology, 54, 676-691, 1978). However, an oral agent of desmopressin has very low biological availability and requires a high dose. Thus, desmopressin formulation is expensive, and side effect based on variation of absorption according to individuals is often recognized. Therefore, there is a demand for the development of a nonpeptide antidiuretic agent, which selectively stimulates V2 receptors and has high biological availability. In addition, according to diversified medical treatment and aging population, it has become rare to employ a single medicine, and in most cases, plural kinds of medicines are administrated simultaneously or at intervals. The same applies to the field of medicament for stimulating AVP. A medicine is inactivated by the action of a medicine metabolism enzyme in the liver and is converted into a metabolite, and among these enzymes, cytochrome P450 (CYP) is most important. Several types of molecular species of CYP exist, but if plural kinds of medicines that are metabolized by the same molecular species of CYP compete on the metabolism enzyme, it is believed that metabolism is somewhat inhibited, although the extent of the inhibition varies depending on affinity of each of the medicines for CYP. As a result, interactions between medicines such as blood concentration increase or blood half life prolongation, etc. are expressed. Such interactions between medicines are not desirable, except in a case where synergism is intended, and often result in unexpected side effect. Therefore, there is a demand for the development of Pharmaceuticals that have low affinity for CYP and between which causes little concern about interactions between other medicines. As conventional nonpeptide compounds that selectively stimulate V2 receptor and show antidiuretic effects, tricyclic compounds represented by the general Formula (A), general Formula (B), or general Formula (C) are disclosed in WO 99/06409, WO 99/06403, and WO 00/46224. (Each symbol is as defined in the above publications.) Additionally, condensed azepine derivatives represented by the general Formula (D) are disclosed in WO 01/49682. (Each symbol is as defined in the above publication.) Also, benzazepine derivatives represented by the general Formula (E) are disclosed in WO 97/22591 and Japanese Patent No. 2926335, and benzoheterocyclic compounds represented by the general Formula (F) or general Formula (G) axe disclosed in Japanese Patent No. 3215910, and Japanese Patent Publication Nos. tokkaihei 11-349570 and tokkai 2000 351768. (Each symbol is as defined in the above publications.) However, none of the publications discloses 4,4-difluoro-l,2,3,4- tetrahydro-5H-l-benzazepine derivatives. In addition, although WO95/06035 and WO 98/39325, and Japanese Patent Publication No. tokkaihei 9-221475 disclose 4,4-difluorol,2,3,4- tetrahydro-5H-1-benzazepine derivatives that have AVP receptor antagonist effects or oxytocin receptor antagonist effects, none of them discloses V2 receptor agonist effects and efficacy in treating central diabetes insipidus and nocturia. Accordingly, there is a demand for the development of a nonpeptide antidiuretic agent that is useful in the treatment of central diabetes insipidus and/or nocturia, and has high biological availability. Disclosure of the Invention The inventors, as a result of assiduous studies on compounds having V2 receptor agonist effects and efficacy in treating central diabetes insipidus and/or nocturia, discovered that 4,4-difluoro-1,2,3,4-tetrahydro-5H-1- benzazepin derivatives have such effects, and completed the present invention. Additionally, the inventors discovered that the compound of the present invention has a very low inhibitory activity against medicine metabolism enzymes of CYP3A4 and CYP2C9, compared with known benzazepine derivatives having V2 receptor agonist activity, and completed the present invention. The object of the present invention is to provide a novel 4,4-difluoro- l,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by the following general Formula (I) or a pharmaceutically acceptable salt thereof, which are useful for a drug for the treatment of central diabetes insipidus and/or nocturia; and a drug comprising the compound, as an active ingredient, particularly a drug for the treatment of central diabetes insipidus or nocturia, or a drug as arginine vasopressin V2 receptor agonist. wherein each symbol has the following meaning: R1: -OH, -Olower alkyl, or an optionally substituted amino; R2: a lower alkyl which may be substituted with one or more halogen, or a halogen; R3,R4:- one is -H, a lower alkyl, or a halogen, and the other is an optionally substituted nonaromatic cyclic amino, or an optionally substituted aromatic cyclic amino; and R5: -H, a lower alkyl, or a halogen. The compound of the present invention is characterized by having two fluoro groups on a carbon atom in a benzazepine ring, which carbon atom is adjacent to a carbon atom substituted by substituted methylidene group in the ring. Further, since the double bond conjugated with a carbonyl group is not isomerized due to the two fluoro groups, the compound of the invention has a sufficient stability even in a living body. Preferred is a novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1- benzazepine derivative represented by the general Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is a group represented by the general Formula (II), or a group represented by the general Formula (III). wherein each symbol has the following meaning: A:- a single bond, lower alkylene, or -lower alkylene-C(=O)-; R11- a lower alkyl which may be substituted with a group selected from the group consisting of -OH, -Olower alkyl, -CO2H-, -CO2-lower alkyl, and carbamoyl which may be substituted with one or two lower alkyl, or -H; R12: (1) when A is a single bond or lower alkylene, R12 is aryl, cycloalkyl, aromatic heterocycle, or nonaromatic heterocycle, each of which may be substituted, or -H, -OH, -Olower alkyl, -CO2H, -CO2-lower alkyl, or carbamoyl which may be substituted with one or two lower alkyl. (2) when A is -lower alkylene-C(=O)-, R12 is a group represented by the general Formula (III), or a group represented by the general Formula (IV); B- a single bond or lower alkylene; R13, R14: optionally substituted nonaromatic cyclic amino group bonded together with an adjacent nitrogen atom. More preferred is a novel 4,4-difluoro-l,2,3,4-tetrahydro-5H-l- benzazepine derivative represented by the general Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is a group represented by the general Formula (II), or a group represented by the general Formula (III); R3 is an optionally substituted nonaromatic cyclic amino group, or an optionally substituted aromatic cyclic amino group; R4 is -H, a lower alkyl, or a halogen; and R5 is -H. Still more preferred is a novel 4,4-difluoro-l,2,3,4-tetrahydro-5H-l- benzazepine derivative represented by the general Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is a group represented by the general Formula (II), or a group represented by the general Formula (III); R3 is an optionally substituted nonaromatic cyclic amino, or an optionally substituted aromatic cyclic aminol R4 is -H; and R5 is -H. Most preferred is a novel 4,4-difluoro-l,2,3,4-tetrahydro-5H-l- benzazepine derivative represented by the general Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is a group represented by the general Formula (II), or a group represented by the general Formula (III); R3 is methylpyrazolyl, pyrrolidinyl, or methylpyrrolidinyl; R4 is -H; and R5 is -H. Among these compounds, a compound or a pharmaceutically acceptable salt thereof selected from the compound group A and the compound group B are particularly preferable, and a compound or a pharmaceutically salt thereof selected from the compound group A are more preferable. The compound group A includes: (2Z)-2-{1-[2-chloro-4-(3-methyl-lH-pyrazoly-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(pyridin-2- ylmethyl) acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-[l-(2-chloro-4-pyrrolidin-l-ylbenzoyl)- 4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene]acetamide; (2Z)-2-{4,4-difluoro-l-[4-(3-methyl-lH-pyrazol-l-yl)-2- (trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-l-[4-(3R)-3- methylpyrrolidin-l-yl]-2-(trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l- benzazepin-5-ylidene}acetamide; (2Z)-2-{4,4-difluoro-l-[4-[(3R)-3-methylpyrrolidm-lyl]-2- (trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N- (2-hydroxy ethyl)acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-l-[4-(3S)-3- methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4- tetrahydro-5H-1- benzazepin-5-ylidene}acetamide; (2Z)-2-{4,4-difluoro-l-[4-[(3-methyl-lH-pyrazol-l-yl)-2- (trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene]-N- (2-hydroxyethyl) acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-(l-{2-chloro-4-[(3R)-3- methylpyrrolidin-l-yl]benzoyl}-4,4-difluoro-l,2,3,4-tetrahydro-5H-l- benzazepin-5-ylidene)acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-(l-{2-chloro-4-[(3S)-3- methylpyrrolidin-l-yl]benzoyl}-4,4-difluoro-l,2,3,4-tetrahydro-5H-l- benzazepin-5-ylidene)acetamide; (2Z)-2-{4,4-difluoro-l-[4-(4-methyl-lH-pyrazoM-yl)-2- (trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-{l-[4-(3,4-dimethylpyrrolidin-l-yl)-2- (trifluoromethyl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin- 5-ylidene}acetamide; and (2Z)-2-{4,4-difluoro-l-[2-methyl-4-(3-methyl-1H-pyrazol-l- yl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}acetamide. The compound group B includes- (2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazoM-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3- (hydroxymethyl)phenyl] acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazoM-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[4- (hydroxymethyl)phenyl] acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-1H-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[(6-methylpyridin-2- yl) methyl] acetamide; 3-[((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetyl)amino]benzamide; 4-[((2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4- difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetyl)amino]benzamide; 4-{[((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetyl)amino]methyl}benzamide; (2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3- (methoxymethyl)phenyl]acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3-(l- hydroxyethyDphenyl] acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3- (methylsulfonyl)phenyl]acetamide; (2Z)-N-(3-acetylphenyl)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l- yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(3- methylphenyl)acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(3- fluorophenyl) acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazol-1-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3-(2- hydroxyethyl)phenyl] acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(2-hydroxyl,l- dimethyletyl) acetamide; l-((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}acetyl)piperidine-3- carboxamide; (2Z)-N-[4-(aminosulfonyl)benzyl]-2-{l-[2-chloro-4-(3-methyl-lH- pyrazol-l-yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazoM-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(2- hydroxycyclohexyl)acetamide; (2Z)-N-[3-(2-amino-2-oxoethyl)phenyl]-2-{l-[2-chloro-4-(3-methyl- lH-pyrazoM-yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- yliende}acetamide; 3-{3-[((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- yliende}acetyl)amino]phenyl}propanamide; (2E)-3-{3-[((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]- 4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- yliende}acetyl)amino]phenyl}acrylamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(2-oxopyrrolidin-3- yl)acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(2-oxotetrahydrofuran-3- yl)acetamide; 3-[((2Z)-2-{l-[2-chloro-4-(3-methyl-1H-pyrazol-l-yl)benzoyl]-4,4- difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetyl)amino]-N- methylbenzamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-{2-[2- (hydroxymethyl)piperidin-l-yl]-2-oxoethyl}acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-{2-[3- (hydroxymethyl)piperidin-1-yl]-2-oxoethyl}acetamide; (2Z)-N-[3-(acetylamino)phenyl]-2-{l-[2-chloro-4-(3-methyl-1H- pyrazol-1-yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- yliende}acetamide; (2Z)-2-{l-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(2-oxotetrahydrothiophen- 3-yl)acetamide; (2Z)-2-{l-[2-chloro-4-(3,3-dimethylpyrrolidin-l-yl)benzoyl]-4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(pyridine-2- ylmethyl)acetamide; (2Z)-2-{l-[2-chloro-4-(3,3-dimethylpyrrolidin-l-yl)benzoyl]-4,4- difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-{l-[2-chloro-4-(3-ethyl-3- methylpyrrolidin-l-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-l- benzazepin-5-yliende}acetamide; (2Z)-N-(2-amino-2-oxoethylyl)-2-{l-[2-chloro-4-(3,3- dimethylpyrrolidin-l-yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l- benzazepin-5-yliende}acetamide; (2Z)-N-(2-amino-2-oxoethylyl)-2-{l-[2-chloro-4-(3-phenylpyrrolidin-l- yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- yliende}acetamide; (2Z)-2-{l-[2-chloro-4-(3,3-dimethylpyrrolidin-l-yl)benzoyl]-4,4- difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(2- hy droxyethy 1) acetamide; (2Z)-2-{l-[2-chloro-4-(3-phenylpyrrolidin-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetamide; (2Z)-2-{l-[2-chloro-4-(3-ethyl-3-methylpyrrolidin-l-yl)benzoyl]-4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetamide; (2Z)-2-{4,4-difluoro-l-[4-[(3R)-3-methylpyrrolidin-l-yl]-2- (trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1 -benzazepin- 5-yliende}- N- (2 -hydroxyethyl) acetamide; (2Z)-2-{4,4-difluoro-l-[4-[(3R)-3-methylpyrrolidin-l-yl]-2- (trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5- yliende}acetamide; (2Z)-2-{l-[2-chloro-5-fluoro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetamide; and (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-[4-(l,2- dihydroxyethyl)phenyl]acetamide. Another object of the present invention is to provide a novel 4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepine derivative represented by the following general Formula (V) or a pharmaceutically acceptable salt thereof, which is a useful intermediate in the preparation of the 4,4-difluoro-1,2,3,4- tetrahydro-5H-l-benzazepine derivative represented by the above general Formula (I) or a pharmaceutically acceptable salt thereof, which is useful in the treatment of central diabetes insipidus and/or nocturia. wherein each symbol has the following meaning, R21: lower alkyl, R22: chloro or trifluoromethyl, R23, R24: one is -H, and the other is an optionally protected hydrazino group, and R21 is preferably methyl or ethyl, more preferably methyl. The present invention will be explained in detail herein below. In the definition of the general formula for the compound of the present invention, the term "lower alkyl" means a monovalent group of a straight or branched carbon chain having 1 to 6 carbon atoms, and its examples include methyl, ethyl, propyl, butyl, pentyl, and hexyl, and structural isomers thereof such as isopropyl, tert-butyl, and the like, of which alkyl having 1 to 3 carbon atoms such as methyl, ethyl, propyl, and isopropyl are preferred. The term "lower alkenyl" means a monovalent group of a straight or branched unsaturated carbon chain having 2 to 6 carbon atoms, and its examples include vinyl, allyl, 1-butenyl, 2-butenyl, 1-hexenyl, and 3- hexenyl, and structural isomers thereof such as 2-methylallyl, and the like, of which vinyl and allyl are preferred. The term "lower alkylene" means a divalent group of a straight or branched carbon chain having 1 to 6 carbon atoms, and its examples include methylene, ethylene, trimethylene, methylmethylene, methylethylene, dimethylmethylene, and the like. The "cycloalkyl" means a monovalent group of a nonaromatic hydrocarbon ring having 3 to 8 carbon atoms, which may have a partial unsaturation, and its examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctandienyl, and the like. The term "aryl" means a monovalent group of a mono- to tri-cyclic aromatic hydrocarbon ring having 6 to 14 carbon atoms, and its examples include phenyl, naphthyl, and the like, of which phenyl is preferred. The term "aromatic heterocycle" means a monovalent group of a mono- to tri-cyclic aromatic ring having a hetero atom such as a nitrogen atom, an oxygen atom, a sulfur atom, and the like, and its examples include pyridyl, thienyl, furyl, benzimidazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrimidinyl, benzothiazoyl, pyrazolyl, indazolyl, pyrrolyl, oxazoyl, triazoyl, tetrazoyl, indolyl, quinolyl, isothiazolyl, isooxazoyl, imidazoyl, and the like, of which pyridyl is preferred. The term "nonaromatic heterocycle" means a monovalent group of a five- to seven-membered ring having a hetero atom such as a nitrogen atom, an oxygen atom, a sulfur atom, and the like, which may have a partial unsaturation and may be condensed with an aryl or aromatic heterocycle, and its examples include pyrrolidinyl, imidazolydinyl, piperidinyl, piperazinyl, azepinyl, morphonyl, thiomorphonyl, tetrahydrofuryl, tetrahydrothienyl, and the like, of which pyrrolidinyl, tetrahydrofuryl, and tetrahydrothienyl are preferred. The term "aromatic cyclic amino" means a monovalent group of a five- to seven-membered aromatic cyclic amine, which may contain a nitrogen, an oxygen, or a sulfur atom, and its examples include benzimidazolyl, indolyl, pyrazolyl, indazolyl, pyrrolyl, imidazolyl, and the like, of which pyrazolyl is preferred. The term "nonaromatic cyclic amino" means a monovalent group of a three- to ten-membered, preferably a five- to seven-membered nonaromatic cyclic amine, which may have a partial unsaturation and comprise a nitrogen, an oxygen or a sulfur atom, and its examples include pyrrolidinyl, piperidinyl, azepinyl, morphonyl, thiomorphonyl, piperazinyl, pyrazolidinyl, indolinyl, isoindolinyl, dihydropyrrolyl, pyrrolinyl, dihydropyrrolinyl, and the like, of which pyrrolidinyl, piperidinyl, and dihydropyrrolyl are preferred. The term "halogen" means a monovalent group of a halogen atom, and its examples include fluoro, chloro, bromo, iodo, and the like. As the substituent group that can be used for the term "optionally substituted" or "which may be substituted", those which are commonly used as a substituent group for each corresponding group can be used, and each group may have one or more substituent groups. In the definition of R1, the "optionally substituted amino group" includes the groups represented by the above general Formulae (II) and (III). As the substituent groups that can be used for "aryl, cycloalkyl, aromatic heterocycle, or nonaromatic heterocycle, each of which may be substituted" in the definition of R12, and "optionally substituted nonaromatic cyclic amino group" and "optionally substituted aromatic cyclic amino group" in the definition of R13, R14, R3, and R4, the following groups (a) to (h) can be exemplified. RA is a lower alkyl group which may be substituted with one or more groups selected from the group consisting of- OH, -Olower alkyl, an amino which may be substituted with one or two lower alkyls, a carbamoyl which may be substituted with one or two lower alkyls, an aryl, an aromatic heterocycle and a halogen. (a) halogen, (b) -OH, -O-RA -O-aryl, -OCO-RA, OXO(=O); (c) -SH, -S-RA, -S-aryl, -SO-RA, -SO-aryl, SO2-RA, -SO2aryl, sulfamoyl which may be substituted with one or two RA; (d) amino which may be substituted with one or two RA, -NHCORA, NHCO-aryl, -NHSO2-RA -NHSO2-aryl, nitro; (e) -CHO, -CO-RA, -CO2H, -CO2-RA, carbamoyl which may be substituted with one or two RA, cyano; (f) aryl or cycloalkyl, each of which may be substituted with one or more groups selected from the group consisting of -OH, -O-lower alkyl, amino which may be substituted with one or two lower alkyls, carbamoyl which may be substituted with one or two lower alkyls, aryl, aromatic heterocycle, halogen and RA; (g) aromatic heterocycle or nonaromatic heterocycle, each of which may be substituted with one or more groups selected from the group consisting of- OH, -O-lower alkyl, amino which may be substituted with one or two lower alkyls, carbamoyl which may be substituted with one or two lower alkyls, aryl, aromatic heterocycle, halogen and RA; (h) lower alkyl or lower alkenyl, each of which may be substituted with one or more groups selected from the substituent groups described in (a) to (g). As a protection group that can be used for "optionally protected hydrazino group" in the definition of R23 and R24, those; which are commonly used as a protection group for an amino group can be used, and those described in "Protective Groups in Organic Synthesis", third edition, edited by Greene and Wuts, can be exemplified. Its examples include acetyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, phthalimide, and the like, of which tert-butyloxycarbonyl is preferred. The compound represented by the general Formula (I) may comprise asymmetric carbon atoms according to the kinds of substituent groups, and optical isomers based on the asymmetric carbon atom may exist. The compound of the present invention includes a mixture of these optical isomers or isolated ones. Also, tautomers may be included in the compound of the present invention, and the compound of the present invention includes these isomers as a mixture or as an isolated one. In addition, the compound of the present invention may form a salt, which is included in the present invention as long as pharmaceutically acceptable. Examples of the salt include addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like; salts with an inorganic base such as sodium, potassium, magnesium, calcium, and the like, or an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like; and ammonium salts, and the like. And, a hydrate and a solvate of the compound and its pharmaceutically acceptable salt of the present invention, and those having polymorphism, are also included in the present invention. In addition, the compound of the present invention also includes a compound which is metabolized in a living organism to be converted into the compound of the general Formula (I) or the salt thereof, a so-called prodrug. As a group for forming the prodrug, those described in Prog. Med., 5; 2157-2161, 1985. and Hirokawa Shoten, 1990, "Development of medicine" Vol. 7, Molecular Design, pp 163-198 can be exemplified. (Production Methods) The compound and its pharmaceutically acceptable salt can be prepared by various known synthesis methods, using characteristics based on its basic backbone or the kinds of substituent groups. The Representative preparation methods will be explained in detail. And, according to the kinds of functional groups, it is advantageous in some cases in terms of preparation technique to substitute a functional group with a suitable protection group, i.e., a group that can be easily converted into the functional group, in the step of a preparation of raw material or intermediate. Then, if necessary, the protection group is removed to obtain a desired compound. Examples of the functional group include hydroxyl, carboxy, and amino groups, and examples of the protection group include those described in "Protective Groups in Organic Synthesis ", third edition, edited by Greene and Wuts. It is preferable to suitably use them depending on reaction conditions. (wherein R2, R3, and R4 are as defined in the foregoing; and one of X and Y is -H, a lower alkyl, or a halogen, and the other is a leaving group or an amino group.) In this step, a leaving group of X or Y in the compound (la) is substituted with an optionally substituted nonaromatic cyclic amine or aromatic cyclic amine ("(1b)") to prepare a compound (1c), or an amino group of X or Y is converted into a pyrrol- 1-yl group. Examples of the leaving group of X or Y include a halogen atom, methylsulfonyl, 1H- benzotriazoM-yloxy, methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethane sulfonyloxy. When one of R3 and R4 is pyrrole, one of X and Y is an amino group, and in this case, the compound (lc) can be synthesized with reference to J. Med. Chem., 28(10), 1405, 1985. And, when X or Y is a leaving group, preferably I, Br, or trifluoromethanesulfonyloxy, the compound (lc) can be synthesized by a coupling reaction using Pd(0). The coupling reaction can be conducted with reference to Tetrahedron Letters, Vol. 38, No. 66, pp. 6359-662, 1997. And, when X is a leaving group, preferably F or Cl, the compound (lc) can be synthesized by a substitution reaction. The reaction can be carried out free of a solvent or in an inert solvent including an aromatic hydrocarbon such as benzene, toluene, xylene, and the like; an ether such as diethylether, tetrahydrofuran (THF), dioxane, and the like; a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chloroform, and the like; N,N-dimethylformamide (DMF); dimethylacetamide (DMA); N-methylpyrrolidone; dimethylsulfoxide (DMSO); an ester such as ethyl acetic acid (EtOAc); acetonitrile, and the like, or an alcohol solvent such as methanol (MeOH), ethanol (EtOH), 2- propanol, and the like, at room temperature or while heating under reflux, using equal moles of the compound (la) and the compound (1b) or an excess amount of any one of them. Depending on the compounds to be produced, it is advantageous to carry out the reaction in the presence of an organic base (preferably, triethylamine, diisopropylethylamine, N-methylmorpholin, pyridine, 4- (N,N-dimethylamino)pyridine), or a basic metal salt (preferably potassium carbonate, cesium carbonate, sodium hydroxide, or sodium hydride). And, when one- of R3 and R4 is an optionally substituted pyrazolyl group, the substitution reaction may be carried out using an optionally protected hydrazine, preferably a hydrazine protected with mono tert-butyl oxycarbonyl instead of the compound (lb), and then, if necessary, the protection group is removed to react the aldehyde protected form of acylacetaldehyde (e.g., acetylacetaldehyde dimethylacetal) to form an optionally substituted pyrazol ring. The formation of the pyrazol ring is advantageously carried out in the presence of acid, preferably hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like), under room temperature or with heating. (Second step) In this step, the compound (1c) obtained in the first step of the first production method is hydrolyzed to prepare a compound (1d). The reaction can be carried out in a solvent inert to the compound (lc), such as an aromatic hydrocarbon, an ether, a halogenated hydrocarbon, an alcohol, DMF, DMA, DMSO, pyridine, water, and the like, in the presence of a mineral acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, an organic acid such as formic acid, acetic acid, and the like, or a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, or ammonia, under a cooling to a heat refluxing environment. Reaction temperature can be appropriately selected depending on the compounds. (Third step) (wherein R5 is as defined in the foregoing.) In this step, a compound (1f) of the present invention is prepared by the amidation of the compound (1d) obtained in the second step of the first production method or its reactive derivative with a compound (1e). As the reactive derivative of the compound (1d), a common ester such as methylester, ethylester, tert-butyl ester, and the like; an acid halide such as acid chloride, acid bromide, and the like; an acid azide; an active ester with N-hydroxybenzotriazole, p-nitrophenol, or N-hydroxysuccinimide, and the like; a symmetrical acid anhydride; an acid anhydride mixture of an alkyl halide carbonate, and the like, and an halocarboxylic acid alkylester, pivaloyl halide, p-toluenesulfonic acid chloride, and the like; and a phosphate-type acid anhydride mixture obtained by the reaction of diphenylphosphoryl chloride and N-methylmorpholin can be used. And, when the compound (1d) is used in its free acid form or an active ester without isolation, it is preferable to use a condensing agent such as dicyclohexylcarbodiimide (DCC), l,l"-carbonylbis-1H- imidazole(CDI), diphenylphosphorylazide (DPPA), diethylphosphorylcyanide, and 1-ethyl-3-(3- dimehtylaminopropyl)carbodiimide hydrochloride (EDCI HC1), and the like. Particularly, in the present invention, an acid chloride method, a method of carrying out the reaction in the presence of both an active esterification agent and a condensing agent, or a method of treating a common ester with an amine is convenient because it is easy to prepare the compound of the present invention therewith. The reaction is, although it varies depending on the employed reactive derivative or condensing agent, carried out in an inert organic solvent such as a halogenated hydrocarbon, an aromatic hydrocarbon, an ether, an ester, acetonitrile, DMF, or DMSO, and the like, under a cooling, a cooling to room temperature, or a room temperature to heating environment. In carrying out the reaction, in order to progress the reaction smoothly, it is advantageous in some cases to use the compound (1e) in an excess amount or to carry out the reaction in the presence of a base such as N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, lutidine, and the like. And, a salt consisting of a strong acid and a weak base such as pyridine hydrochloride, pyridine, p-toluenesulfonate, N,N- dimethylaniline hydrochloride, and the like can be used. Pyridine can also be used as a solvent. Particularly, it is preferable to carry out the reaction in a solvent such as acetonitrile, DMF, and the like, in the presence of a base such as pyridine, N,N-dimethylaniline, and the like, or a salt such as pyridine hydrochloride, and the like. (Fourth step) (wherein NRR" is an optionally substituted amino, preferably a group represented by the general Formula (II) or (III).) In this step, a compound (1f) of the present invention obtained in the third step of the first production method is hydrolyzed to prepare a compound (1g) of the present invention, and then the compound (I) of the present invention is prepared by the amidation of the compound (lg) or its reactive derivative with a compound (1h). Each reaction can be carried out in accordance with the second step or third step of the first production method. In this method, a compound (1e) is hydrolyzed in a first step to prepare a compound (2a), a compound (2b) is prepared by the amidation of the compound (2a) or its reactive derivative with a compound (1h) in a second step, and then the compound (I) is prepared by the amidation of the compound (2b) with a compound (1d) or its reactive derivative in a third step. The reaction in the first step can be carried out in accordance with the second step of the first production method, and the reactions in the second and third steps in accordance with the third step of the first production method. In this method, a compound (3b) is prepared by the amidation of the compound (2b) obtained in the second step of the second production method with a compound (3a) or its reactive derivative in a first step, and in a second step, a leaving group of X or Y of the obtained compound (3b) is substituted with a compound (1b) or an optionally substituted hydrazine to form an optionally substituted pyrazole ring, as shown in the first step of the first production method, thereby forming a compound (I) of the present invention. The leaving group of X or Y is as defined in the first step of the first production method. The reaction in the first step can be carried out in accordance with the third step of the first production method, and the reaction in the second step in accordance with the first step of the first production method. In this method, a compound (4a) is prepared by the amidation of a compound (1e) with a compound (3a) or its reactive derivative in a first step, the obtained compound (4a) is hydrolyzed to prepare a compound (4b) in a second step, and a compound (3b) is prepared by the amidation of the obtained compound (4b) or its reactive derivative with a compound (1h) in a third step, and then, in a fourth step, the leaving group of X or Y of the obtained compound (3b) is substituted with a compound (1b) or an optionally substituted hydrazine to form an optionally substituted pyrazole ring, as shown in the first step of the first production method, thereby preparing a compound (I) of the present invention. The leaving group of X or Y is as defined in the first step of the first production method. The reactions in the first and third steps can be carried out in accordance with the third step of the first production method, the reaction in the second step in accordance with the second step of the first production method, and the reaction in the fourth step in accordance with the first step of the first production method. In this method, in a first step, the leaving group of X or Y of the compound (4a) obtained in the first step of the fourth production method is substituted with a compound (1b) or an optionally substituted hydrazine to form an optionally substituted pyrazole ring, as shown in the first step of the first production method, thereby forming a compound (1f) of the present invention, which is hydrolyzed to prepare a compound (1g) of the present invention in a second step, and then the compound (I) of the present invention is prepared by the amidation of the compound (1g) or its reactive derivative with a compound (1h) in a third step. The leaving group of X or Y is as defined in the first step of the first production method. The reaction in the first step can be carried out in accordance with the first step of the first production method, the reaction in the second step in accordance with the second step of the first production method, and the reaction in the third step in accordance with the third step of the first production method. The thus produced compound of the present invention is isolated and purified as its free form or as a salt thereof. A salt of the compound (I) can be produced by subjecting it to a usual salt formation reaction. The isolation and purification are carried out by usual chemical manipulations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography, and the like. Various types of isomers can be separated by usual method using the difference in physicochemical properties among isomers. For example, racemic compounds can be separated by a general racemic compound resolution method, e.g., a method in which racemic compounds are converted into diastereomer salts with an optically active base such as tartaric acid, and the like and then subjected to optical resolution. And, diastereomers can be separated by fraction crystallization or various types of chromatography or the like. Also, optically active compounds can be prepared using appropriate optically active starting materials. The compound and its salt of the present invention have excellent stimulation effects for arginine vasopressin V2 receptors. Thus, the compound of the present invention has antidiuretic effects and effects of releasing blood coagulating agents VIII factor and von Willebrand factor, is useful for treating various urination disorders, polyuria, or hemorrhage conditions, and is effective in the diagnosis, prevention, and treatment of polyuria, urinary incontinence, central diabetes insipidus, nocturia, nocturnal enuresis, spontanous hemorrhage, hemophilia, von Willebrand disease, uremia, congenital or acquired platelet dysfunction, traumatic or surgical hemorrhage, hepatocirrhosis, and the like. Since the compound of the present invention has little inhibition effects against medicine metabolism enzymes CYP3A4 and CYP2C9, there is less concern for interaction with other medicines metabolized by CYP3A4 or CYP2C9, compared with known benzazepine derivatives having arginine vasopressin V2 receptor agonist effects, and it can be safely used in combined therapy with various preparations. Examples of medicines metabolized by CYP3A4 include simvastatin, lovastatin, fluvastatin, midazolam, niphedipine, amlodipine, nicardipine, and the like, and example of medicines metabolized by CYP2C9 include diclofenac, ibuprofen, indomethacin, tolbutamide, glibenclamide, losartan, and the like (General Clinic, 48(6), 1427-1431, 1999). Pharmaceutical efficacy of the compound of the present invention was confirmed by the following assays, (l) V2 receptor binding assay A human V2 expression CHO cell membrane sample was prepared in accordance with a method of Tahara, et al. (British Journal of Pharmacology. Vol 125, p. 1463-1470, 1998). 2 µg of the membrane sample were incubated in a total of 250 µl of 50 mM tris-chloric acid buffer solution (pH=7.4) containing 10 mM MgCl2 and 0.1% bovine serum albumin (BSA), together with [3H]-Arginine-Vasopressin (hereinafter referred to as "[3H]- Vasopressin") (0.5 nM, Specific activity = 75 Ci / mmol) and a test compound (10-10~10-5 M) at 25oC for 60 minutes. Then, free [3H]-Vasopressin and receptor binding [3H]-Vasopressin were separated using a cell harvester, and the receptor binding [3H]-Vasopressin was adsorbed on a Unifilter Plate GF/B glass filter, sufficiently dried, and then mixed with a microplate scintillation cocktail. The amount of receptor binding [3H]-Vasopressin was measured using a top count, and inhibition rate was calculated by the following equation. Inhibition Rate(%) = 100-(C1-B1)/(Co-B1) X 100 C1: the amount of [3H]-Vasopressin bound to the membrane sample, when the receptor membrane sample is treated in the coexistence of a test compound of known concentration and [3H]-Vasopressin Co: the amount of [3H]-Vasopressin bound to the membrane sample, when the receptor membrane sample is treated with [3H]-Vasopressin, in the absence of a test compound B1- the amount of [3H]-Vasopressin bound to the membrane sample, when the receptor membrane sample is treated in the coexistence of an excess amount of Vasopressin (106 M) and [3H] -Vasopressin From the above equation, concentration of the test compound corresponding to the inhibition rate of 50% (IC50) was calculated, from which affinity of the test compound for a receptor, i.e., dissociation coefficient (Ki) was calculated by the following equation. Dissociation Coefficient (Ki) = IC5o/(l+[L]/Kd) [L] : the concentration of [3H]-Vasopressin Kd: dissociation coefficient of [3H]-Vasopressin for the receptor, calculated from saturation binding assay (Table 1) [Affinity for V2 receptor] As the control, the compound of Example 32 described in WO 97/22591 (Compound name: 2-[(5R)-l-(2-chloro-4-pyrrolidin-l-ylbenzoyl)- 2,3,4,5-tetrahydro-lH-l-benzazepin-5-yl]-N-isopropyacetamide) was used. As shown in Table 1, it has been verified that the compound of the present invention has high affinity for the V2 receptor. (2) Antidiuresis assay (intravenous administration) For the assay, 5 Wistar male rats (1O~12 weeks of age) were employed for each group. For group A, 0.3 mg/kg of the compound of Example 135, for group B, 0.3 mg/kg of the compound of Example 201, and for group C, 1 ml/kg of physiological saline solution comprising DMSO as a control were intravenously administrated. After 15 minutes, 30 ml/kg of distilled water were orally administrated (water load). Until 2 hours after the water load, urine was collected in a metabolism cage, and the amount of urine when the water load is set to 100% was calculated as the urinary excretion rate. For the assay, the average value in each group of urinary excretion rate until 1 hour after the water load and that until 2 hours after the water load was employed. The results are described in the following Table 2. (Table 2) [Antidiuretic effects (intravenous administration)] As shown in Table 2, it has been verified that the compound of the present invention has excellent antidiuretic effects. (3) Antidiuresis assay (oral administration) For the assay, Wistar male rats (10~12 weeks of age) were employed. The test compound was orally administrated, and after 15 minutes, 30 ml/kg of distilled water were orally administrated (water load). Until 4 hours after the water load, urine was collected in a metabolism cage, and the amount of urine when the water load was set to 100% was calculated as the urinary excretion rate. For the assay, the amount of the test compound required for decreasing urinary excretion rate by 50% (ED50) was employed. The results are described in the following Table 3. (Table 3) [Antidiuretic effects (oral administration)] As shown in Table 3, it has been verified that the compound of the present invention has excellent antidiuretic effects by oral administration as well as by intravenous administration. (4) Cytochrome P450 (3A4) enzyme inhibition assay The assay was carried out in accordance with a method of Crespi, et al. (Analytical Biochemistry, 248, 188-190, 1997). A 96 well plate was employed, and 7-benzyloxy-4- (trifluoromethyl)coumarin (5 x 10-5 M) as a substrate, a test compound (4.9 x 10-8 ~ 5 x 105 M), and an enzyme (5 x 10~9 M) were incubated in a total of 200 µl of a 200 mM phosphate buffer solution (pH=7.4) comprising 8.2 µM NADP+, 0.41 mM glucose-6-phosphate, 0.41 mM MgCl2, and 0.4 Units/ml glucose-6-phosphate dehydrogenase, at 37°C for 30 minutes. Then, 0.5 M aqueous solution of 2-amino-2-hydroxymethyl-l,3-propanediol containing 80% acetonitrile was added thereto to stop the reaction, and fluorescence intensity was measured with a fluorescent plate reader (excited wavelength: 409 nm, fluorescent wavelength: 530 nm). Inhibition rate was calculated by the following equation, and the concentration of the test compound corresponding to an inhibition rate of 50% (IC50) was calculated. The results are described in the following Table 4. Inhibition Rate (%) = 100-(C1-B1)/(C0-B1) x 100 C1: fluorescence intensity in the presence of a known concentration of test compound, enzyme, and a substrate C0: fluorescence intensity in the presence of an enzyme and a substrate, in the absence of a test compound B1-" fluorescence intensity of a blank well (5) Cytochrome P450 (2C9) enzyme inhibition effects The assay was carried out in accordance with a method of Crespi, et al. (Analytical Biochemistry, 248, 188-190, 1997). A 96 well plate was employed, and 7-methoxy4- (trifluoromethyl)coumarin (7.5 x 10-5 M) as a substrate, a test compound (4.9 x 10-8 ~ 5 x 10-5 M), and an enzyme (108 M) were incubated in a total of 200 µL of a 200 mM phosphate buffer solution (pH=7.4) comprising 8.2 µM NADP+, 0.41 mM glucose-6-phosphate, 0.41 mM MgCl2, and 0.4 Units/ml glucose-6-phosphate dehydrogenase, at 37°C for 45 minutes. Then, 0.5 M aqueous solution of 2-amino-2-hydroxymethyl-1,3-propanediol containing 80% acetonitrile was added thereto to stop the reaction, and fluorescence intensity was measured with a fluorescent plate reader (excited wavelength: 409 nm, fluorescent wavelength: 530 nm). Inhibition rate was calculated from the above equation in (4), and the concentration of the test compound corresponding to an inhibition rate of 50% (IC50) was calculated. The results are described in the following Table 4. (Table 4) [CYP(3A4 and 2C9) inhibition effects] As shown in Table 4, the compound of the present invention showed very low inhibition effects for the medicine metabolism enzymes CYP3A4 and CYP2C9. The control was the same as in Table 1. A pharmaceutical composition of the present invention can be prepared by generally used methods using one or more kinds of the compound of the present invention and pharmaceutical carriers, fillers, and other additives generally used in the preparation of medicaments. It may be administrated either by oral administration through tablets, pills, capsules, granules, powders, solutions, and the like, or by parenteral administration through injections such as intravenous injection, intramuscular injection, and the like, or through suppositories, or pernasal, permucosal, or percutaneous preparations, and the like. The solid composition for use in the oral administration according to the present invention is used in the forms of tablets, powders, granules, and the like. In such a solid composition, one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, metasilicate, or magnesium aluminate. In the usual way, the composition may contain additives other than the inert diluent, which include a lubricant such as magnesium stearate, a disintegrating agent such as calcium cellulose glycolate, a stabilizing agent such as lactose, and a solubilization-assisting agent such as glutamic acid or aspartic acid. As occasion demands, tablets or pills may be coated with a sugar coat or a film of gastrosoluble or enterosoluble substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or the like. The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and it contains a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents such as a moistening agent and a suspending agent, as well as a sweetener, a flavoring agent, an aromatic, and an antiseptic. The injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solutions and suspensions include distilled water for injection use, and physiological saline. Examples of the non-aqueous solutions and suspensions include plant oil such as propylene glycol, polyethylene glycol, olive oil or the like, alcohol such as ethanol, polysorbate 80 (trade name), and the like. Such a composition may further contain auxiliary agents such as an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose), and a solubilization- assisting agent (e.g., glutamic acid or aspartic acid. These compositions are sterilized, for example by filtration through a bacteria retaining filter, blending of a germicide, or irradiation. Alternatively, they may be used by firstly making into sterile solid compositions and dissolving them in sterile water or a sterile solvent for injection use, prior to their use. In the case of oral administration, a daily dose is approximately 0.0001~50 mg/kg of body weight, preferably approximately 0.001~10 mg/kg, and more preferably approximately 0.01-1 mg/kg, and the daily dose is administered once a day or by dividing it into 2 to 4 doses per day. In the case of intravenous administration, a daily dose is approximately 0.0001~l mg/kg of body weight, preferably approximately 0.0001~0.1 mg/kg, and the daily dose is administered once a day or by dividing it into plural doses per day. The dose is appropriately determined by taking symptoms, age, the sex of the patient to be treated, and the like into consideration. Since the dose is varied depending on various conditions, a smaller dose is sufficient in some cases. Best Mode for Carrying Out the Invention The following describes the invention more illustratively with reference to examples, but the present invention is not limited to these examples. In this connection, novel materials are included in the starting materials to be used in the examples, and production methods of the starting materials from known materials are described as reference examples. Reference Example 1 20.85 g of methyl 2-chloro-4-fluorobenzoate were dissolved in 150 ml of N-methylpyrrolidone, 30.68 g of potassium carbonate and 9.38 ml of 3- methylpyrazole were added thereto, and the mixture was stirred at 120 °C for 3 hours. Additionally, thereto was added 1.79 ml of 3-methylpyrazole, and the mixture was stirred at 120 °C for 3 hours. The reaction solution was cooled, mixed with water, and extracted with EtOAc. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (hexane-EtOAc (20:1)) to obtain 9.25 g of methyl 2-chloro-4-(3-metyl-1H-pyrazol-1-yl)benzoate. The compounds of Reference Examples 2 -40 were synthesized in the same manner as described in Reference Example 1. Reference Example 41 2.0 g of methyl 4-amino-2-chlorobenzoate were dissolved in 10 ml of acetic acid, 2.0 ml of 2,5-dimethoxytetrahydrofuran were added thereto, and the mixture was heated under reflux for 15 minutes. After cooling the reaction solution, the solvent was evaporated. The obtained residue was mixed with EtOAc and saturated NaHCO3 aq. and extracted. The organic layer was washed with brine, and dried over sodium sulfate anhydride. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (4:1)) to obtain 2.1 g of methyl 2-chloro-4- (lH-pyrrol-l-yl)benzoate. The compound of Reference Example 42 was synthesized in the same manner as described in Reference Example 41. Reference Example 43 2.0 g of methyl 4-bromo-2-methylbenzoate were dissolved in 20 ml of toluene, and 1.08 ml of pyrrolidine, 4.0 g of cesium carbonate, 200mg of tris(dibenzylideneacetone)-dipalladium (0) and 200 mg of (R)-(+)-2,2"- bis(diphenylphosphino)-l,l"-binaphthyl were added thereto, and then the mixture was heated under reflux for 6 hours. The reaction solution was cooled, mixed with water and EtOAc, and extracted. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (25:l)) to obtain 0.784 g of methyl 2- methyl-4-pyrrolidin-l-ylbenzoate. The compound of Reference Example 44 was synthesized in the same manner as described in Reference Example 43. Reference Example 45 9.25 g of the compound of the Reference Example 1 were dissolved in 10 ml of acetic acid and 10 ml of 6M HC1 aq., and then the mixture was heated under reflux for 13 hours. The reaction solution was cooled, and then poured into ice water, and the thus precipitated crystals were collected by filtration to obtain 8.56 g of 2-chloro-4-(3-methylpyrazol-1-yl) benzoic acid. Reference Example 46 10.7 g of the compound of Reference Example 2 were dissolved in 60 ml of MeOH and 20 ml of 5M NaOH aq., and the mixture was heated under reflux for 2 hours. The reaction solution was cooled, and then neutralized with 2M HC1 aq., and the solvent was evaporated. To the obtained residue, water was added, and the thus precipitated crystals were collected by filtration to obtain 10.17g of 2-chloro-4-pyrrolidin-l-ylbenzoic acid. The compounds of Reference Examples 47-88 were synthesized in the same manner as described in Reference Example 46. The structures and physical data of the compounds of Reference Examples are shown in Tables 5 to 8. Symbol meanings in the Tables are as follows. Rf Reference Example number MS: Mass spectrometry data (FAB-MS(M+H)+ unless otherwise noted, and MM, MN, and ME respectively indicate FAB-MS(M)+, FAB-MS(M-H)+, and EI-MS(M)+). Rb, Rc, Rd: substituent group in the general formula (Me: methyl, Et: ethyl, iPr: isopropyl, cPr: cyclopropyl, tBu: tert-butyl, Ph: phenyl, pra: pyrazolyl, pyrr: pyrrolinidyl, mor: morpholinyl, the: thienyl, imid: imidazolyl, bimid: benzoimidazolyl, pipe: piperidyl, di: di), The number before the substituent group indicates location of substitution. Thus, for example, 3-Me-1-pra indicates 3-methylpyrazol-1-yl, 3,3-diMe-l-pyrr indicates 3,3- dimethylpyrrolidin-l-yl, and 3-(2-the)-1-pra indicates 3-thiophene-2- ylpyrazol-1-yl. (Table 5) (Table 5 contd) (Table 6) (Table 7) (Table 7 contd) (Table 8) Reference Example 89 8.0 g of methyl (2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H-1- benzazepin-5-ylidene) acetate were dissolved in 20 ml of MeOH and 20 ml of THF. 45 ml of 1M NaOH aq. were added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was neutralized with 1M HC1 aq.. The reaction solution was mixed with chloroform and extracted. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated to obtain 4.57 g of carboxylic acid intermediate. 4.57 g of the carboxylic acid intermediate were dissolved in 45 ml of DMF. 2.22 ml of 2-picolyl amine, 3.6 g of 1-hydroxybenzoimidazol (HOBt), and 5.6 g of l-ethyl-3-(3"-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCI) were added thereto, and the mixture was stirred at room temperature for 18 hours. The reaction solution was mixed with water and EtOAc and extracted therewith. The organic layer was washed with brine, and dried over sodium sulfate anhydride. After evaporation of the solvent, the residue was purified by silica gel column chromatography (chloroform-MeOH (25:1)) to obtain 6.849 g of (2Z)-2-(4,4-difluoro-1,2,3,4- tetrahydro-5H-l-benzazepin-5-ylidene)-N-(pyridine-2-ylmethyl)acetamide. FAB-MS; 330. ([M+H]+) Reference Example 90 To a solution of 1.37 g of the compound of Example 6, 0.45 g of HOBt, and 0.63 g of EDCI HC1 in 15 ml of DMF, 0.46 g of sarcosinic methylester hydrochloride and 0.47g of triethylamine were added, and the mixture was stirred at room temperature overnight. The reaction solution was mixed with NaHCO3 aq. and EtOAc and extracted. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the obtained ester intermediate was dissolved in 20 ml of MeOH, 5 ml of 1M NaOH aq. was added thereto, and the mixture was stirred at room temperature for 1 hour. To the crude product obtained by the evaporation of the solvent, 1M HC1 aq. was added, and the thus precipitated white crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 1.43 g of [((2Z)-2-{l-[2-chloro-4-(3-methyl-1H-pyrazol-l-yl)benzoyl]-4,4- difluoro-l,2,3,4"tetrahydro-5H-l-benzazpine-5- ylidene}acetyl(methyl)amino)acetic acid. FAB-MS; 529. ([M+H]+) Example 1 To a suspension of 21.0 g of 2-chloro-4-(3-methyl-1H-pyrazol-1- yl)benzoic acid in 200 ml of 1,2-dichloroethane, 15 ml of thionyl chloride and 3 drops of DMF were added at room temperature, and the mixture was stirred at 70oC for 2 hours. The reaction solution was cooled to room temperature, the solvent was evaporated, and the residue was dried to obtain acid chloride form. 22.5 g of methyl (2Z)-(4,4-difluoro-l,2,3,4- tetrahydro-5H-l-benzazepin-5-ylidene)acetate were added thereto, 200 ml of pyridine was added thereto under ice cooling, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the solvent was evaporated, and the residue was mixed with diluted hydrochloric acid water and EtOAc and extracted. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (9:1 ~ 4:1)) to obtain 38.0 g of methyl (2Z)- {l-[2-chloro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4-difluoro-1,2,3,4- tetrahydro-5H-1-benzazepin-5-ylidene}acetate. Example 2 To a solution of 3.0 g of 4-bromo-2-methylbenzoic acid in 20 ml of THF and 1 drop of DMF, 1.9 ml of oxalyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was mixed with 3 ml of toluene and concentrated again. The obtained residue was mixed with 20 ml of pyridine and 3.5 g of methyl (2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H- l-benzazepin-5-ylidene)acetate and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, then to the mixture was added chloroform and 1M aqueous NaOH and was extracted. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (6:1)) to obtain 5.94 g of methyl (2Z)-[l-(4-bromo-2-methylbenzoyl)-4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene]acetate. Example 3 To a solution of 4.62 g of 2-(trifluoromethyl)benzoic acid in 30 ml of sulfuric acid, 3.48 g of l,3-dibromo-5,5-dimethylhydantoin were added. The mixture was stirred at room temperature for 15 hours, and then added to ice water dropwise. 5M NaOH aq. were added to the reaction solution to control pH of the solution to 12, and then the reaction solution was extracted with chloroform. To the aqueous layer, concentrated hydrochloric acid was added to control the pH of the solution to 1, and then the reaction solution was extracted with chloroform. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, 20 ml of THF and 1 drop of DMF were added to the residue, and 2.5 ml of oxalyl chloride were added thereto under ice cooling, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was mixed with 10 ml of toluene and concentrated again. To the obtained residue, 20 ml of pyridine and 6.2 g of methyl (2Z)-(4,4- difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene)acetate were added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the residue was mixed with chloroform and 1M HC1 aq. and extracted. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc(6:1)). And, the residue obtained by concentration under reduced pressure was crystallized from EtOH to obtain 3.66 g of methyl (2Z)-{l-[4-bromo-2-(trifluoromethyl)benzoyl]-4,4-difluoro- 1,2,3,4-tetrahydro- 5H-1-benzazepin-5-ylidene}acetate. Example 4 To a solution of 2.0 g of the compound of Example 2 in 30 ml of toluene, 22.35 g of tert-butyl hydrazine carboxylate, 1.43 g of cesium carbonate, 400 mg of tris(dibenzylideneacetone)dipalladium (0), and 740 mg of 1,1"-bis(diphenylphosphine)ferrocene were added, and the mixture was stirred at 100°C for 4 hours. After cooling the reaction solution, insoluble matter was filtered, and EtOAc and 10% citric acid aqueous solution were added to the filtrate to extract it. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate anhydride. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (2:1)) to obtain 1.0 g of tert-butyl 1- (4-{[(5Z)-4,4-difluoro-5-(2-methyl-2-oxoethylidene)-2,3,4,5-tetrahydro-lH-l- benzazepin-l-yl]carbonyl}-3-methylphenyl)hydrazine carboxylate. Example 5 To a solution of 1.0 g of the compound of Example 4 in 10 ml of EtOAc, 10 ml of 4M HCl-EtOAc were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was mixed with saturated NaHCC>3 aq. and chloroform and extracted. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, 40 ml of MeOH and 275 mg of acetylacetaldehyde dimethylacetal were added to the residue, and the mixture was heated under reflux for 1.5 hours. To the reaction solution, 3 drops of cone, hydrochloric acid were added, and the mixture was heated under reflux for 30 minutes again. The reaction solution was cooled, and then concentrated under reduced pressure. The residue was mixed with saturated sodium hydrogen carbonate aqueous solution and chloroform and extracted. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (4:1)) to obtain 561 mg of methyl (2Z)-{4,4-difluoro-l-[2-methyl-4-(3-methyl- lH-pyrazol-l-yl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetate. Example 6 38.0 g of the compound of Example 1 were dissolved in 120 ml of MeOH and 120 ml of THF, 100 ml of 1M NaOH aq. was added at room temperature, and the mixture was stirred for 10 hours. Approximately 200 ml of the solvent were evaporated under reduced pressure, 0.5M HC1 aq. were added to the residue under ice cooling, and the mixture was stirred for 1 hour. Thus formed white precipitations were filtered and dried to obtain 36.5 g of (2Z)-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-lH-1-benzazepin-5-ylidene}acetic acid in the form of powder. Example 7 To a solution of 229 mg of the compound of Example 6, 71 mg of HOBt and 101 mg of EDCI HCl in 3 ml of DMF, 35 mg of thiophen-2- ylmethylamine were added, and the mixture was stirred at room temperature overnight. The reaction solution was mixed with saturated sodium bicarbonate aqueous solution and chloroform, and extracted. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified by silica gel column chromatography (chloroform-MeOH (30:1)). The residue obtained by concentration under reduced pressure was crystallized from a 2-propanol- diisopropyl ether solvent mixture to obtain 61 mg of (2Z)-2-{l-[2-chloro-4-(3- methyl-lH-pyrazol-l-yl]benzoyl}-4,4-difluoro-l,2,3,4,-tetrahydro-5H-l- benzazepin-5-ylidene}-N-(thiophen-2-ylmethyl)acetamide. Example 8 210 mg of the compound of Example 6 were dissolved in 20 ml of dichloroethane, 2 ml of thionyl chloride were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was mixed with toluene and concentrated again. The obtained acid chloride form were dissolved in 30 ml of acetonitrile, and added dropwise to 30 ml of ammonia water at room temperature. After stirring at room temperature for 12 hours, the formed white precipitations were filtered and dried to obtain 259 mg of (2Z)-2-{l-[2-ehloro-4-(3-methyl-lH-pyrazol- l-yl)benzoyl]-4,4-difluoro- l,2,3,4-tetrahydro-5H-benzazepine}acetamide in the form of powder. Example 9 915 mg of the compound of Example 14 were dissolved in 20 ml of MeOH, 3 ml of 1M NaOH aq. were added, and the mixture was stirred at room temperature for 15.5 hours. The solvent was evaporated under reduced pressure, and then the residue was acidified with 1M HC1 aq. and extracted with chloroform. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the obtained carboxylic acid intermediate was dissolved in 10 ml of DMF, 0.24 ml of 2-picolyl amine, 0.39 g of HOBt and 0.61 g of EDCI HC1 were added thereto, and the mixture was stirred at room temperature for 84 hours. The reaction solution was mixed with water and EtOAc, and extracted. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (chloroform-MeOH (35:1)). The residue obtained by concentration under reduced pressure was dissolved in EtOAc, 0.4 ml of 4M HCl-EtOAc solution was added thereto, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from EtOH to obtain 0.456 g of (2Z)-2-[l-(2-chloro- 4-pyrrolidin-l-ylbenzoyl)-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene]-N-(pyridin-2-ylmethyl)acetamide hydrochloride. Example 10 0.25 g of the compound of Example 93 were dissolved in 10 ml of MeOH, 10 ml of 1M NaOH were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was neutralized with 1M HC1 aq., and extracted with chloroform. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was crystallized from an EtOAc-hexane solvent mixture to obtain 116 mg of [((2Z)-2-{l-[2-chloro-4-(3- methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-l- benzazepin-5-ylidene}acetyl)amino]acetic acid. Example 11 To a solution of 258 mg of the compound of Example 10, 71 mg of HOBt and 101 mg of EDCI HC1 in 5 ml of THF, and 0.5 ml of 2.0 M methylamine-THF solution were added, and the mixture was stirred at room temperature overnight. The reaction solution was mixed with saturated NaHCO3 aq. and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by evaporation of the solvent was purified by silica gel column chromatography (chloroform-MeOH (30:1)). The residue obtained by concentration under reduced pressure was crystallized from a 2-propanol- hexane solvent mixture to obtain 51 mg of (2Z)-2-{l-[2chloro-4-(3-methyl- lH-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}-N-[2-(methylamino)-2-oxoethyl]acetamide. Example 12 To a solution of 265 mg of the compound of Reference Example 90 in 5 ml of THF, 82 mg of l,l"-carbonylbis-lH-imidazole were added, and the mixture was stirred at room temperature for 1 hour. Then, ammonia water was added to the reaction solution, and the mixture was stirred at room temperature for 22 hours. The reaction solution was mixed with water and EtOAc, and extracted therewith. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporation of the solvent was purified by silica gel column chromatography (chloroform-MeOH(100:1)). The residue obtained by concentration under reduced pressure was crystallized from a 2-propnaol-diisopropyl ether solvent mixture to obtain 41 mg of (2Z)-N-[2- amino-2-oxoethyl]-N-methyl-2-{l-[2-chloro-4-(3-methyMH-pyrazol-l- yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetamide. Example 13 To a solution of 0.35 g of the compound of Reference Example 85 in 10 ml of THF and 1 drop of DMF, 0.22 ml of thionylchloride were added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was mixed with 3 ml of toluene and concentrated again. The obtained residue was dissolved in 20 ml of acetonitrile, 0.4 g of the compound of Reference Example 89 and 0.4 ml of pyridine were added, and the mixture was stirred at 80°C for 17 hours. After cooling the reaction solution, the solvent was evaporated, and the residue was mixed with chloroform and 10% citric acid aqueous solution, and extracted therewith. The organic layer was washed with saturated sodium bicarbonate aqueous solution, water, and brine, and the dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (chloroform-MeOH-ammonia water (25:0:0.1)). The residue obtained by concentration under reduced pressure was dissolved in EtOAc, 0.18 ml of 4M HCl-EtOAc solution was added thereto, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from EtOH to obtain 0.176 g of (2Z)-2-[l-(2-chloro- 4-piperidin-l-ylbenzoyl)-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene]-N-(pyridine-2-ylmethyl)acetainide hydrochloride. The structures and physicochemical data of the compounds of Examples are shown in Tables 9. Additionally, the structures and physicochemical data of the compounds obtained by the same production method are also shown in Tables 9 to 16. The symbols in the Tables have the following meanings. Ex: number of Example Salt: salt (HC1: hydrochloride, inorganic material: free form) Syn: synthesis method (The number indicates the number of Example of which method is applied) RA, RB, Rc, RD, R1A: substituent group in the general formula (nPen: normal pentyl, cHex: cyclohexyl, Ac: acetyl, Ms: mesyl, Boc: tert-butyloxycarbony, py: pyridyl, fur:furyl, thia: thiazolyl, bthia: benzothiazolyl. Thus, as examples, -NH2CH2-(2-py) indicates pyridine-2-ylmethylamino, -NH2CH2- (4-HO-3-MeO-Ph) indicates 4-hydroxy3-methoxybenzylamino, and 2- HOCH2-l-pipe indicates 2-hydroxymethylpiperidin-l-yl.) (Table 9) (Table 10 contd) (Table 10 contd) (Table 11) (Table 11 contd) (Table 11 contd) (Table 11 contd) (Table 12) (Table 13) (Table 14) (Table 15) (Table 16) NMR data of the compounds of some Examples are shown in Table 17. The term "NMR" indicates 8(ppm) of the peaks in ^-NMR employing DMSOofeas a measuring solvent unless otherwise indicated, using (CH^Si as an internal standard. (Table 17 contd) (Table 17 contd) The structures of the compounds of the present invention are shown in Table 18. These compounds can be easily synthesized by methods that are self-evident to an ordinarily skilled person, or with modified methods. The "No" in the Table indicates compound number. (Table 18) (Table 18 contd) (Table 18 contd) (Table 18 contd) (Table 18 contd) (Table 18 contd) We Claim: 1. 4,4-difluoro-1,2,3,4-tetrahydro-5H-l-benzazepine derivative represented by the general Formula (I) or a pharmaceutically acceptable salt thereof: wherein the symbols have the following meanings: R1: a group represented by the following general formula (II), or a group represented by the following general formula (III): wherein the symbols have the following meanings: A: a single bond, (C1-C6) alkylene, or -(C1-C6) alkylene- C(=O)-; R11: (C1-C6) alkyl which may be substituted with a group selected from the group consisting of -OH, -O-(C1-C6) alkyl, - CO2H, -CO2H, -CO2-(C1-C6) alkyl, and carbamoyl which may be substituted with one or two (C1-C6) alkyl, or -H; R10 : (1) when A is a single bond or (C1-C6) alkylene, R12 is aryl, cycloalkyl, aromatic heterocycle, or nonaromatic heterocycle, each of which may be substituted by one or more groups selected from the group consisting of (a) to (h), or -H, -OH, -O-(C1-C6) alkyl, -CO2-H, -CO2-(C1-C6) alkyl, or carbamoyl which may be substituted with one or two (C1-C6) alkyls; and (2) when A is -(C1-C6) alkylene-C(=O)-, R12 Is a group represented by the above general formula (HI), or a group represented by the following general formula (IV), B: a single bond, or (C1-C6) alkylene; and R13 and R14: nonaromatic cyclic amino, bonded together with an adjacent nitrogen atom, which may be substituted by one or more groups selected from the group consisting of (a) to (h); R2: (C1-C6) alkyl which may be substituted with one or more halogen, or halogen; R3 and R4: one is -H, (C1-C6) alkyl, or halogen, and the other is nonaromatic cyclic amino which may be substituted by one or more groups selected from the group consisting of (a) to (h), or an aromatic cyclic amino which may be substituted by one or more groups selected from the group consisting of (a) to (h); R5: -H, (C1-C6) alkyl, or halogen; (a) halogen; (b) -OH, -O-RA, -O-aryl, -OCO-RA, oxo(=O); (c) -SH, -S-RA, -S-aryl, -SO-RA, -SO-aryl, -SO2-RA, -SO2-aryl, sulfamoyl which may be substituted with one or two RA; (d) amino which may be substituted with one or more RA, - NHCO-RA, -NHCO-aryl, -NHSO2-RA, -NHSO2-aryl, nitro; (e) -CHO, -CO-RA, -CO2-H, -CO2-RA, carbamoyl which may be substituted with one or two RA, cyano; (f) aryl or cycloalkyl, each of which may be substituted with one or more groups selected from the group consisting of -OH, -O-(C1-C6) alkyl, amino which may be substituted with one or two (C1-C6) alkyls, carbamoyl which may be substituted with one or more (C1-C6) alkyls, aryl, aromatic heterocycle, halogen and RA; (g) aromatic heterocycle or nonaromatic heterocycle, each of which may be substituted with one or more groups selected from the group consisting of-OH, -O-(C1-C6) alkyl, amino which may be substituted with one or two (C1-C6) alkyls, carbamoyl which may be substituted with one or two (C1-C6) alkyls, aryl, aromatic heterocycle, halogen and RA; (h) (C1-C6) alkyl or (C1-C6) alkenyl, each of which may be substituted with one or more groups selected from the substituent groups described in (a) to (g); and RA: (C1-C6) alkyl group which may be substituted with one or more groups selected from the group consisting of-OH, -O-(C1- C6) alkyl, amino which may be substituted with one or two (C1-C6) alkyls, carbamoyl which may be substituted with one or two (C1- C6) alkyls, aryl, aromatic heterocycle and halogen. 2. The compound s claimed in claim 1, wherein R3, is nonaromatic cyclic amino which may be substituted by one or more groups selected from the group consisting of (a) to (h) described in claim 1, or aromatic cyclic amino which may be substituted by one or more groups selected from the group consisting of (a) to (h) described in claim 1; R4 is -H, (C1-C6) alkyl, or halogen; and R5 is -H. 3. The compound as claimed in claim 2, wherein R4 is -H. 4. The compound as claimed in claim 1, wherein the compound is selected from the group consisting of: (2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4- difluoro-1,2,3,4-tetrahydro-5H-1 -benzazepin- 5-ylidene} -N- (pyridin-2-ylmethyl) acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-[1-(2-chloro-4-pyrrolidin-1 - ylbenzoyl)-4,4-difluoro-1,2,3,4-tetrahydro-5H-1 -benzazepin-5- ylidene]acetamide; (2Z)-2- {4,4-difluoro-1 -[4-(3-methyl-1H-pyrazol-1-yl)-2- (trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-l-[4-[(3R)-3- methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4- tetrahydro-5-H-1 -benzazepin-5-ylidene} acetamide; (2Z)-2-{4,4-difluoro-l-[4-(3R)-3-methylpyrrolidin-l-yl]-2- (trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-l-benzazepin-5- ylidene}-N-(2-hydroxehtyl)acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-l-[4-(3S)-3- methylpyrrolidin-1 -yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4- tetrahydro-5H-1 -benzazepin-5-ylidene} acetamide; (2Z)-2-{4,4-difluoro-1-[4- [(3-methyl-1H-pyrazol-1-yl)-2- (trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5- ylidene]-N-(2-hydroxyethyl)acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3R)-3 - methylpyrrolidin-1-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro- 5H-1-benzazepin-5-ylidene)acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-(1- {2-chloro-4-[(3S)-3 - methylpyrrolidin-l-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro- 5H-1-benzazepin-5-ylidene)acetamide; (2Z)-2-{4,4-difluoro-1-[4-(4-methyl-1H-pyrazol-1-yl)-2- (trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5- ylidene}acetamide; (2Z)-N-(2-amino-2-oxoethyl)-2-{1-[4-(3,4-dimethylpyrrolidin-1- yl)-2-(trifluoromethyl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro- 5H-l-benzazepin-5-ylidene}acetamide; (2Z)-2- {4,4-difluoro-1-[2-methyl-4-(3-metyl-1H-pyrazol-1- yl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepine-5- ylidene}acetamide; and a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient. 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives, which have excellent arginine vasopressin V2 activity and are useful for a drug for the treatment of central diabetes insipidus and/or nocturia.

Full Text

DESCRIPTION
4,4-Difluoro-l,2,3,4-Tetrahydro-5H-l-Benzazepine Derivative
or Salt Thereof
Technical Field of the Invention
The present invention relates to a novel 4,4-difluoro-l,2,3,4-
tetrahydro-5H-1-benzazepine derivative or a salt thereof, which is useful as
a medicament, especially as a drug for the treatment of central diabetes
insipidus or nocturia, and to a medicament comprising the compound as an
active ingredient.
Background Art
Arginine vasopressin (AVP) is a peptide consisting of 9 amino acids,
which is biosynthesized and secreted from the hypothalamus/ pituitary
gland. AVP receptors are classified into three subtypes, i.e. V1a, V1b, and
V2. It is known that the main pharmaceutical effects of AVP in peripheral
are vasoconstriction through the V1a receptor, and antidiuresis through the
V2 receptor. As a medicament for selectively stimulating V2 receptors,
desmopressin has been synthesized (by deleting the amino acid of cystein in
position 1 of AVP, and converting arginine of position 8 into a d form) and is
used in the treatment of central diabetes insipidus (Journal of Japanese
Academy of Endocrinology, 54, 676-691, 1978). However, an oral agent of

desmopressin has very low biological availability and requires a high dose.
Thus, desmopressin formulation is expensive, and side effect based on
variation of absorption according to individuals is often recognized.
Therefore, there is a demand for the development of a nonpeptide
antidiuretic agent, which selectively stimulates V2 receptors and has high
biological availability.
In addition, according to diversified medical treatment and aging
population, it has become rare to employ a single medicine, and in most
cases, plural kinds of medicines are administrated simultaneously or at
intervals. The same applies to the field of medicament for stimulating
AVP. A medicine is inactivated by the action of a medicine metabolism
enzyme in the liver and is converted into a metabolite, and among these
enzymes, cytochrome P450 (CYP) is most important. Several types of
molecular species of CYP exist, but if plural kinds of medicines that are
metabolized by the same molecular species of CYP compete on the
metabolism enzyme, it is believed that metabolism is somewhat inhibited,
although the extent of the inhibition varies depending on affinity of each of
the medicines for CYP. As a result, interactions between medicines such
as blood concentration increase or blood half life prolongation, etc. are
expressed.
Such interactions between medicines are not desirable, except in a
case where synergism is intended, and often result in unexpected side effect.
Therefore, there is a demand for the development of Pharmaceuticals that

have low affinity for CYP and between which causes little concern about
interactions between other medicines.
As conventional nonpeptide compounds that selectively stimulate V2
receptor and show antidiuretic effects, tricyclic compounds represented by
the general Formula (A), general Formula (B), or general Formula (C) are
disclosed in WO 99/06409, WO 99/06403, and WO 00/46224.

(Each symbol is as defined in the above publications.)
Additionally, condensed azepine derivatives represented by the
general Formula (D) are disclosed in WO 01/49682.

(Each symbol is as defined in the above publication.)
Also, benzazepine derivatives represented by the general Formula
(E) are disclosed in WO 97/22591 and Japanese Patent No. 2926335, and
benzoheterocyclic compounds represented by the general Formula (F) or
general Formula (G) axe disclosed in Japanese Patent No. 3215910, and

Japanese Patent Publication Nos. tokkaihei 11-349570 and tokkai 2000
351768.

(Each symbol is as defined in the above publications.)
However, none of the publications discloses 4,4-difluoro-l,2,3,4-
tetrahydro-5H-l-benzazepine derivatives.
In addition, although WO95/06035 and WO 98/39325, and Japanese
Patent Publication No. tokkaihei 9-221475 disclose 4,4-difluorol,2,3,4-
tetrahydro-5H-1-benzazepine derivatives that have AVP receptor
antagonist effects or oxytocin receptor antagonist effects, none of them
discloses V2 receptor agonist effects and efficacy in treating central diabetes
insipidus and nocturia.
Accordingly, there is a demand for the development of a nonpeptide
antidiuretic agent that is useful in the treatment of central diabetes
insipidus and/or nocturia, and has high biological availability.
Disclosure of the Invention
The inventors, as a result of assiduous studies on compounds having
V2 receptor agonist effects and efficacy in treating central diabetes insipidus
and/or nocturia, discovered that 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-

benzazepin derivatives have such effects, and completed the present
invention. Additionally, the inventors discovered that the compound of the
present invention has a very low inhibitory activity against medicine
metabolism enzymes of CYP3A4 and CYP2C9, compared with known
benzazepine derivatives having V2 receptor agonist activity, and completed
the present invention.
The object of the present invention is to provide a novel 4,4-difluoro-
l,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by the
following general Formula (I) or a pharmaceutically acceptable salt thereof,
which are useful for a drug for the treatment of central diabetes insipidus
and/or nocturia; and a drug comprising the compound, as an active
ingredient, particularly a drug for the treatment of central diabetes
insipidus or nocturia, or a drug as arginine vasopressin V2 receptor agonist.

wherein each symbol has the following meaning:
R1: -OH, -Olower alkyl, or an optionally substituted amino;
R2: a lower alkyl which may be substituted with one or more
halogen, or a halogen;

R3,R4:- one is -H, a lower alkyl, or a halogen, and the other is an
optionally substituted nonaromatic cyclic amino, or an optionally
substituted aromatic cyclic amino; and
R5: -H, a lower alkyl, or a halogen.
The compound of the present invention is characterized by having
two fluoro groups on a carbon atom in a benzazepine ring, which carbon
atom is adjacent to a carbon atom substituted by substituted methylidene
group in the ring. Further, since the double bond conjugated with a
carbonyl group is not isomerized due to the two fluoro groups, the
compound of the invention has a sufficient stability even in a living body.
Preferred is a novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-
benzazepine derivative represented by the general Formula (I) or a
pharmaceutically acceptable salt thereof, wherein R1 is a group represented
by the general Formula (II), or a group represented by the general Formula
(III).

wherein each symbol has the following meaning:
A:- a single bond, lower alkylene, or -lower alkylene-C(=O)-;
R11- a lower alkyl which may be substituted with a group selected
from the group consisting of -OH, -Olower alkyl, -CO2H-, -CO2-lower alkyl,
and carbamoyl which may be substituted with one or two lower alkyl, or -H;
R12: (1) when A is a single bond or lower alkylene, R12 is aryl,

cycloalkyl, aromatic heterocycle, or nonaromatic heterocycle, each of which
may be substituted, or -H, -OH, -Olower alkyl, -CO2H, -CO2-lower alkyl, or
carbamoyl which may be substituted with one or two lower alkyl.
(2) when A is -lower alkylene-C(=O)-, R12 is a group
represented by the general Formula (III), or a group represented by the
general Formula (IV);

B- a single bond or lower alkylene;
R13, R14: optionally substituted nonaromatic cyclic amino group
bonded together with an adjacent nitrogen atom.
More preferred is a novel 4,4-difluoro-l,2,3,4-tetrahydro-5H-l-
benzazepine derivative represented by the general Formula (I) or a
pharmaceutically acceptable salt thereof, wherein R1 is a group represented
by the general Formula (II), or a group represented by the general Formula
(III); R3 is an optionally substituted nonaromatic cyclic amino group, or an
optionally substituted aromatic cyclic amino group; R4 is -H, a lower alkyl,
or a halogen; and R5 is -H.
Still more preferred is a novel 4,4-difluoro-l,2,3,4-tetrahydro-5H-l-
benzazepine derivative represented by the general Formula (I) or a
pharmaceutically acceptable salt thereof, wherein R1 is a group represented
by the general Formula (II), or a group represented by the general Formula
(III); R3 is an optionally substituted nonaromatic cyclic amino, or an

optionally substituted aromatic cyclic aminol R4 is -H; and R5 is -H.
Most preferred is a novel 4,4-difluoro-l,2,3,4-tetrahydro-5H-l-
benzazepine derivative represented by the general Formula (I) or a
pharmaceutically acceptable salt thereof, wherein R1 is a group represented
by the general Formula (II), or a group represented by the general Formula
(III); R3 is methylpyrazolyl, pyrrolidinyl, or methylpyrrolidinyl; R4 is -H;
and R5 is -H.
Among these compounds, a compound or a pharmaceutically
acceptable salt thereof selected from the compound group A and the
compound group B are particularly preferable, and a compound or a
pharmaceutically salt thereof selected from the compound group A are more
preferable.
The compound group A includes:
(2Z)-2-{1-[2-chloro-4-(3-methyl-lH-pyrazoly-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(pyridin-2-
ylmethyl) acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-[l-(2-chloro-4-pyrrolidin-l-ylbenzoyl)-
4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene]acetamide;
(2Z)-2-{4,4-difluoro-l-[4-(3-methyl-lH-pyrazol-l-yl)-2-
(trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-l-[4-(3R)-3-
methylpyrrolidin-l-yl]-2-(trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-

benzazepin-5-ylidene}acetamide;
(2Z)-2-{4,4-difluoro-l-[4-[(3R)-3-methylpyrrolidm-lyl]-2-
(trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-
(2-hydroxy ethyl)acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-l-[4-(3S)-3-
methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4- tetrahydro-5H-1-
benzazepin-5-ylidene}acetamide;
(2Z)-2-{4,4-difluoro-l-[4-[(3-methyl-lH-pyrazol-l-yl)-2-
(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene]-N-
(2-hydroxyethyl) acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-(l-{2-chloro-4-[(3R)-3-
methylpyrrolidin-l-yl]benzoyl}-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-
benzazepin-5-ylidene)acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-(l-{2-chloro-4-[(3S)-3-
methylpyrrolidin-l-yl]benzoyl}-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-
benzazepin-5-ylidene)acetamide;
(2Z)-2-{4,4-difluoro-l-[4-(4-methyl-lH-pyrazoM-yl)-2-
(trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-{l-[4-(3,4-dimethylpyrrolidin-l-yl)-2-
(trifluoromethyl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-
5-ylidene}acetamide; and
(2Z)-2-{4,4-difluoro-l-[2-methyl-4-(3-methyl-1H-pyrazol-l-

yl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}acetamide.
The compound group B includes-
(2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazoM-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3-
(hydroxymethyl)phenyl] acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazoM-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[4-
(hydroxymethyl)phenyl] acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-1H-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[(6-methylpyridin-2-
yl) methyl] acetamide;
3-[((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetyl)amino]benzamide;
4-[((2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4-
difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetyl)amino]benzamide;
4-{[((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetyl)amino]methyl}benzamide;
(2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3-
(methoxymethyl)phenyl]acetamide;

(2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3-(l-
hydroxyethyDphenyl] acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3-
(methylsulfonyl)phenyl]acetamide;
(2Z)-N-(3-acetylphenyl)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-
yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(3-
methylphenyl)acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(3-
fluorophenyl) acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyMH-pyrazol-1-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-[3-(2-
hydroxyethyl)phenyl] acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(2-hydroxyl,l-
dimethyletyl) acetamide;
l-((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}acetyl)piperidine-3-

carboxamide;
(2Z)-N-[4-(aminosulfonyl)benzyl]-2-{l-[2-chloro-4-(3-methyl-lH-
pyrazol-l-yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazoM-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene}-N-(2-
hydroxycyclohexyl)acetamide;
(2Z)-N-[3-(2-amino-2-oxoethyl)phenyl]-2-{l-[2-chloro-4-(3-methyl-
lH-pyrazoM-yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
yliende}acetamide;
3-{3-[((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
yliende}acetyl)amino]phenyl}propanamide;
(2E)-3-{3-[((2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-
4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
yliende}acetyl)amino]phenyl}acrylamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(2-oxopyrrolidin-3-
yl)acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(2-oxotetrahydrofuran-3-
yl)acetamide;
3-[((2Z)-2-{l-[2-chloro-4-(3-methyl-1H-pyrazol-l-yl)benzoyl]-4,4-

difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetyl)amino]-N-
methylbenzamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-1-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-{2-[2-
(hydroxymethyl)piperidin-l-yl]-2-oxoethyl}acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-{2-[3-
(hydroxymethyl)piperidin-1-yl]-2-oxoethyl}acetamide;
(2Z)-N-[3-(acetylamino)phenyl]-2-{l-[2-chloro-4-(3-methyl-1H-
pyrazol-1-yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
yliende}acetamide;
(2Z)-2-{l-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(2-oxotetrahydrothiophen-
3-yl)acetamide;
(2Z)-2-{l-[2-chloro-4-(3,3-dimethylpyrrolidin-l-yl)benzoyl]-4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(pyridine-2-
ylmethyl)acetamide;
(2Z)-2-{l-[2-chloro-4-(3,3-dimethylpyrrolidin-l-yl)benzoyl]-4,4-
difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-{l-[2-chloro-4-(3-ethyl-3-
methylpyrrolidin-l-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-l-
benzazepin-5-yliende}acetamide;
(2Z)-N-(2-amino-2-oxoethylyl)-2-{l-[2-chloro-4-(3,3-

dimethylpyrrolidin-l-yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-
benzazepin-5-yliende}acetamide;
(2Z)-N-(2-amino-2-oxoethylyl)-2-{l-[2-chloro-4-(3-phenylpyrrolidin-l-
yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
yliende}acetamide;
(2Z)-2-{l-[2-chloro-4-(3,3-dimethylpyrrolidin-l-yl)benzoyl]-4,4-
difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-(2-
hy droxyethy 1) acetamide;
(2Z)-2-{l-[2-chloro-4-(3-phenylpyrrolidin-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetamide;
(2Z)-2-{l-[2-chloro-4-(3-ethyl-3-methylpyrrolidin-l-yl)benzoyl]-4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetamide;
(2Z)-2-{4,4-difluoro-l-[4-[(3R)-3-methylpyrrolidin-l-yl]-2-
(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1 -benzazepin- 5-yliende}- N-
(2 -hydroxyethyl) acetamide;
(2Z)-2-{4,4-difluoro-l-[4-[(3R)-3-methylpyrrolidin-l-yl]-2-
(trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
yliende}acetamide;
(2Z)-2-{l-[2-chloro-5-fluoro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}acetamide; and
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-l-benzazepin-5-yliende}-N-[4-(l,2-
dihydroxyethyl)phenyl]acetamide.

Another object of the present invention is to provide a novel 4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepine derivative represented by the
following general Formula (V) or a pharmaceutically acceptable salt thereof,
which is a useful intermediate in the preparation of the 4,4-difluoro-1,2,3,4-
tetrahydro-5H-l-benzazepine derivative represented by the above general
Formula (I) or a pharmaceutically acceptable salt thereof, which is useful in
the treatment of central diabetes insipidus and/or nocturia.

wherein each symbol has the following meaning,
R21: lower alkyl,
R22: chloro or trifluoromethyl,
R23, R24: one is -H, and the other is an optionally protected
hydrazino group, and
R21 is preferably methyl or ethyl, more preferably methyl.
The present invention will be explained in detail herein below.
In the definition of the general formula for the compound of the
present invention, the term "lower alkyl" means a monovalent group of a
straight or branched carbon chain having 1 to 6 carbon atoms, and its

examples include methyl, ethyl, propyl, butyl, pentyl, and hexyl, and
structural isomers thereof such as isopropyl, tert-butyl, and the like, of
which alkyl having 1 to 3 carbon atoms such as methyl, ethyl, propyl, and
isopropyl are preferred.
The term "lower alkenyl" means a monovalent group of a
straight or branched unsaturated carbon chain having 2 to 6 carbon atoms,
and its examples include vinyl, allyl, 1-butenyl, 2-butenyl, 1-hexenyl, and 3-
hexenyl, and structural isomers thereof such as 2-methylallyl, and the like,
of which vinyl and allyl are preferred.
The term "lower alkylene" means a divalent group of a straight or
branched carbon chain having 1 to 6 carbon atoms, and its examples include
methylene, ethylene, trimethylene, methylmethylene, methylethylene,
dimethylmethylene, and the like.
The "cycloalkyl" means a monovalent group of a nonaromatic
hydrocarbon ring having 3 to 8 carbon atoms, which may have a partial
unsaturation, and its examples include cyclopropyl, cyclopentyl, cyclohexyl,
cyclooctyl, cyclohexenyl, cyclooctandienyl, and the like.
The term "aryl" means a monovalent group of a mono- to tri-cyclic
aromatic hydrocarbon ring having 6 to 14 carbon atoms, and its examples
include phenyl, naphthyl, and the like, of which phenyl is preferred.
The term "aromatic heterocycle" means a monovalent group of a
mono- to tri-cyclic aromatic ring having a hetero atom such as a nitrogen
atom, an oxygen atom, a sulfur atom, and the like, and its examples include

pyridyl, thienyl, furyl, benzimidazolyl, pyrazinyl, pyridazinyl, thiazolyl,
pyrimidinyl, benzothiazoyl, pyrazolyl, indazolyl, pyrrolyl, oxazoyl, triazoyl,
tetrazoyl, indolyl, quinolyl, isothiazolyl, isooxazoyl, imidazoyl, and the like,
of which pyridyl is preferred.
The term "nonaromatic heterocycle" means a monovalent group of a
five- to seven-membered ring having a hetero atom such as a nitrogen atom,
an oxygen atom, a sulfur atom, and the like, which may have a partial
unsaturation and may be condensed with an aryl or aromatic heterocycle,
and its examples include pyrrolidinyl, imidazolydinyl, piperidinyl,
piperazinyl, azepinyl, morphonyl, thiomorphonyl, tetrahydrofuryl,
tetrahydrothienyl, and the like, of which pyrrolidinyl, tetrahydrofuryl, and
tetrahydrothienyl are preferred.
The term "aromatic cyclic amino" means a monovalent group of a
five- to seven-membered aromatic cyclic amine, which may contain a
nitrogen, an oxygen, or a sulfur atom, and its examples include
benzimidazolyl, indolyl, pyrazolyl, indazolyl, pyrrolyl, imidazolyl, and the
like, of which pyrazolyl is preferred.
The term "nonaromatic cyclic amino" means a monovalent group of
a three- to ten-membered, preferably a five- to seven-membered
nonaromatic cyclic amine, which may have a partial unsaturation and
comprise a nitrogen, an oxygen or a sulfur atom, and its examples include
pyrrolidinyl, piperidinyl, azepinyl, morphonyl, thiomorphonyl, piperazinyl,
pyrazolidinyl, indolinyl, isoindolinyl, dihydropyrrolyl, pyrrolinyl,

dihydropyrrolinyl, and the like, of which pyrrolidinyl, piperidinyl, and
dihydropyrrolyl are preferred.
The term "halogen" means a monovalent group of a halogen atom,
and its examples include fluoro, chloro, bromo, iodo, and the like.
As the substituent group that can be used for the term "optionally
substituted" or "which may be substituted", those which are commonly used
as a substituent group for each corresponding group can be used, and each
group may have one or more substituent groups.
In the definition of R1, the "optionally substituted amino group"
includes the groups represented by the above general Formulae (II) and
(III).
As the substituent groups that can be used for "aryl, cycloalkyl,
aromatic heterocycle, or nonaromatic heterocycle, each of which may be
substituted" in the definition of R12, and "optionally substituted
nonaromatic cyclic amino group" and "optionally substituted aromatic cyclic
amino group" in the definition of R13, R14, R3, and R4, the following groups
(a) to (h) can be exemplified. RA is a lower alkyl group which may be
substituted with one or more groups selected from the group consisting of-
OH, -Olower alkyl, an amino which may be substituted with one or two
lower alkyls, a carbamoyl which may be substituted with one or two lower
alkyls, an aryl, an aromatic heterocycle and a halogen.
(a) halogen,
(b) -OH, -O-RA -O-aryl, -OCO-RA, OXO(=O);

(c) -SH, -S-RA, -S-aryl, -SO-RA, -SO-aryl, SO2-RA, -SO2aryl, sulfamoyl
which may be substituted with one or two RA;
(d) amino which may be substituted with one or two RA, -NHCORA,
NHCO-aryl, -NHSO2-RA -NHSO2-aryl, nitro;
(e) -CHO, -CO-RA, -CO2H, -CO2-RA, carbamoyl which may be substituted
with one or two RA, cyano;
(f) aryl or cycloalkyl, each of which may be substituted with one or more
groups selected from the group consisting of -OH, -O-lower alkyl, amino
which may be substituted with one or two lower alkyls, carbamoyl which
may be substituted with one or two lower alkyls, aryl, aromatic heterocycle,
halogen and RA;
(g) aromatic heterocycle or nonaromatic heterocycle, each of which may be
substituted with one or more groups selected from the group consisting of-
OH, -O-lower alkyl, amino which may be substituted with one or two lower
alkyls, carbamoyl which may be substituted with one or two lower alkyls,
aryl, aromatic heterocycle, halogen and RA;
(h) lower alkyl or lower alkenyl, each of which may be substituted with one
or more groups selected from the substituent groups described in (a) to (g).
As a protection group that can be used for "optionally protected
hydrazino group" in the definition of R23 and R24, those; which are commonly
used as a protection group for an amino group can be used, and those
described in "Protective Groups in Organic Synthesis", third edition, edited
by Greene and Wuts, can be exemplified. Its examples include acetyl,

methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl,
phthalimide, and the like, of which tert-butyloxycarbonyl is preferred.
The compound represented by the general Formula (I) may comprise
asymmetric carbon atoms according to the kinds of substituent groups, and
optical isomers based on the asymmetric carbon atom may exist. The
compound of the present invention includes a mixture of these optical
isomers or isolated ones. Also, tautomers may be included in the
compound of the present invention, and the compound of the present
invention includes these isomers as a mixture or as an isolated one.
In addition, the compound of the present invention may form a salt,
which is included in the present invention as long as pharmaceutically
acceptable. Examples of the salt include addition salts with a mineral acid
such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
nitric acid, phosphoric acid, and the like, or an organic acid such as formic
acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,
fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic
acid, glutamic acid, and the like; salts with an inorganic base such as
sodium, potassium, magnesium, calcium, and the like, or an organic base
such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the
like; and ammonium salts, and the like. And, a hydrate and a solvate of
the compound and its pharmaceutically acceptable salt of the present
invention, and those having polymorphism, are also included in the present

invention. In addition, the compound of the present invention also
includes a compound which is metabolized in a living organism to be
converted into the compound of the general Formula (I) or the salt thereof,
a so-called prodrug. As a group for forming the prodrug, those described in
Prog. Med., 5; 2157-2161, 1985. and Hirokawa Shoten, 1990, "Development
of medicine" Vol. 7, Molecular Design, pp 163-198 can be exemplified.
(Production Methods)
The compound and its pharmaceutically acceptable salt can be
prepared by various known synthesis methods, using characteristics based
on its basic backbone or the kinds of substituent groups. The
Representative preparation methods will be explained in detail. And,
according to the kinds of functional groups, it is advantageous in some cases
in terms of preparation technique to substitute a functional group with a
suitable protection group, i.e., a group that can be easily converted into the
functional group, in the step of a preparation of raw material or
intermediate. Then, if necessary, the protection group is removed to obtain
a desired compound. Examples of the functional group include hydroxyl,
carboxy, and amino groups, and examples of the protection group include
those described in "Protective Groups in Organic Synthesis ", third edition,
edited by Greene and Wuts. It is preferable to suitably use them
depending on reaction conditions.

(wherein R2, R3, and R4 are as defined in the foregoing; and one of X
and Y is -H, a lower alkyl, or a halogen, and the other is a leaving group or
an amino group.)
In this step, a leaving group of X or Y in the compound (la) is
substituted with an optionally substituted nonaromatic cyclic amine or
aromatic cyclic amine ("(1b)") to prepare a compound (1c), or an amino
group of X or Y is converted into a pyrrol- 1-yl group. Examples of the
leaving group of X or Y include a halogen atom, methylsulfonyl, 1H-
benzotriazoM-yloxy, methanesulfonyloxy, p-toluenesulfonyloxy, and
trifluoromethane sulfonyloxy.
When one of R3 and R4 is pyrrole, one of X and Y is an amino group,
and in this case, the compound (lc) can be synthesized with reference to J.
Med. Chem., 28(10), 1405, 1985.
And, when X or Y is a leaving group, preferably I, Br, or
trifluoromethanesulfonyloxy, the compound (lc) can be synthesized by a
coupling reaction using Pd(0). The coupling reaction can be conducted
with reference to Tetrahedron Letters, Vol. 38, No. 66, pp. 6359-662, 1997.
And, when X is a leaving group, preferably F or Cl, the compound
(lc) can be synthesized by a substitution reaction. The reaction can be
carried out free of a solvent or in an inert solvent including an aromatic

hydrocarbon such as benzene, toluene, xylene, and the like; an ether such
as diethylether, tetrahydrofuran (THF), dioxane, and the like; a
halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane,
chloroform, and the like; N,N-dimethylformamide (DMF);
dimethylacetamide (DMA); N-methylpyrrolidone; dimethylsulfoxide
(DMSO); an ester such as ethyl acetic acid (EtOAc); acetonitrile, and the
like, or an alcohol solvent such as methanol (MeOH), ethanol (EtOH), 2-
propanol, and the like, at room temperature or while heating under reflux,
using equal moles of the compound (la) and the compound (1b) or an excess
amount of any one of them.
Depending on the compounds to be produced, it is advantageous to
carry out the reaction in the presence of an organic base (preferably,
triethylamine, diisopropylethylamine, N-methylmorpholin, pyridine, 4-
(N,N-dimethylamino)pyridine), or a basic metal salt (preferably potassium
carbonate, cesium carbonate, sodium hydroxide, or sodium hydride). And,
when one- of R3 and R4 is an optionally substituted pyrazolyl group, the
substitution reaction may be carried out using an optionally protected
hydrazine, preferably a hydrazine protected with mono tert-butyl
oxycarbonyl instead of the compound (lb), and then, if necessary, the
protection group is removed to react the aldehyde protected form of
acylacetaldehyde (e.g., acetylacetaldehyde dimethylacetal) to form an
optionally substituted pyrazol ring. The formation of the pyrazol ring is
advantageously carried out in the presence of acid, preferably hydrochloric

acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like), under room
temperature or with heating.
(Second step)

In this step, the compound (1c) obtained in the first step of the first
production method is hydrolyzed to prepare a compound (1d).
The reaction can be carried out in a solvent inert to the compound
(lc), such as an aromatic hydrocarbon, an ether, a halogenated hydrocarbon,
an alcohol, DMF, DMA, DMSO, pyridine, water, and the like, in the
presence of a mineral acid such as sulfuric acid, hydrochloric acid,
hydrobromic acid, an organic acid such as formic acid, acetic acid, and the
like, or a base such as sodium hydroxide, potassium hydroxide, potassium
carbonate, sodium carbonate, cesium carbonate, or ammonia, under a
cooling to a heat refluxing environment. Reaction temperature can be
appropriately selected depending on the compounds.
(Third step)

(wherein R5 is as defined in the foregoing.)
In this step, a compound (1f) of the present invention is prepared by
the amidation of the compound (1d) obtained in the second step of the first
production method or its reactive derivative with a compound (1e).
As the reactive derivative of the compound (1d), a common ester
such as methylester, ethylester, tert-butyl ester, and the like; an acid halide
such as acid chloride, acid bromide, and the like; an acid azide; an active
ester with N-hydroxybenzotriazole, p-nitrophenol, or N-hydroxysuccinimide,
and the like; a symmetrical acid anhydride; an acid anhydride mixture of an
alkyl halide carbonate, and the like, and an halocarboxylic acid alkylester,
pivaloyl halide, p-toluenesulfonic acid chloride, and the like; and a
phosphate-type acid anhydride mixture obtained by the reaction of
diphenylphosphoryl chloride and N-methylmorpholin can be used.
And, when the compound (1d) is used in its free acid form or an
active ester without isolation, it is preferable to use a condensing agent
such as dicyclohexylcarbodiimide (DCC), l,l"-carbonylbis-1H-
imidazole(CDI), diphenylphosphorylazide (DPPA),

diethylphosphorylcyanide, and 1-ethyl-3-(3-
dimehtylaminopropyl)carbodiimide hydrochloride (EDCI HC1), and the like.
Particularly, in the present invention, an acid chloride method, a
method of carrying out the reaction in the presence of both an active
esterification agent and a condensing agent, or a method of treating a
common ester with an amine is convenient because it is easy to prepare the
compound of the present invention therewith. The reaction is, although it
varies depending on the employed reactive derivative or condensing agent,
carried out in an inert organic solvent such as a halogenated hydrocarbon,
an aromatic hydrocarbon, an ether, an ester, acetonitrile, DMF, or DMSO,
and the like, under a cooling, a cooling to room temperature, or a room
temperature to heating environment.
In carrying out the reaction, in order to progress the reaction
smoothly, it is advantageous in some cases to use the compound (1e) in an
excess amount or to carry out the reaction in the presence of a base such as
N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline,
lutidine, and the like. And, a salt consisting of a strong acid and a weak
base such as pyridine hydrochloride, pyridine, p-toluenesulfonate, N,N-
dimethylaniline hydrochloride, and the like can be used. Pyridine can also
be used as a solvent.
Particularly, it is preferable to carry out the reaction in a solvent
such as acetonitrile, DMF, and the like, in the presence of a base such as
pyridine, N,N-dimethylaniline, and the like, or a salt such as pyridine

hydrochloride, and the like.
(Fourth step)

(wherein NRR" is an optionally substituted amino, preferably a
group represented by the general Formula (II) or (III).)
In this step, a compound (1f) of the present invention obtained in
the third step of the first production method is hydrolyzed to prepare a
compound (1g) of the present invention, and then the compound (I) of the
present invention is prepared by the amidation of the compound (lg) or its
reactive derivative with a compound (1h).
Each reaction can be carried out in accordance with the second step
or third step of the first production method.

In this method, a compound (1e) is hydrolyzed in a first step to
prepare a compound (2a), a compound (2b) is prepared by the amidation of
the compound (2a) or its reactive derivative with a compound (1h) in a
second step, and then the compound (I) is prepared by the amidation of the
compound (2b) with a compound (1d) or its reactive derivative in a third
step.
The reaction in the first step can be carried out in accordance with
the second step of the first production method, and the reactions in the
second and third steps in accordance with the third step of the first
production method.

In this method, a compound (3b) is prepared by the amidation of the
compound (2b) obtained in the second step of the second production method
with a compound (3a) or its reactive derivative in a first step, and in a
second step, a leaving group of X or Y of the obtained compound (3b) is
substituted with a compound (1b) or an optionally substituted hydrazine to
form an optionally substituted pyrazole ring, as shown in the first step of
the first production method, thereby forming a compound (I) of the present
invention. The leaving group of X or Y is as defined in the first step of the
first production method.
The reaction in the first step can be carried out in accordance with
the third step of the first production method, and the reaction in the second
step in accordance with the first step of the first production method.

In this method, a compound (4a) is prepared by the amidation of a
compound (1e) with a compound (3a) or its reactive derivative in a first step,
the obtained compound (4a) is hydrolyzed to prepare a compound (4b) in a
second step, and a compound (3b) is prepared by the amidation of the
obtained compound (4b) or its reactive derivative with a compound (1h) in a
third step, and then, in a fourth step, the leaving group of X or Y of the

obtained compound (3b) is substituted with a compound (1b) or an
optionally substituted hydrazine to form an optionally substituted pyrazole
ring, as shown in the first step of the first production method, thereby
preparing a compound (I) of the present invention. The leaving group of X
or Y is as defined in the first step of the first production method.
The reactions in the first and third steps can be carried out in
accordance with the third step of the first production method, the reaction
in the second step in accordance with the second step of the first production
method, and the reaction in the fourth step in accordance with the first step
of the first production method.

In this method, in a first step, the leaving group of X or Y of the
compound (4a) obtained in the first step of the fourth production method is
substituted with a compound (1b) or an optionally substituted hydrazine to
form an optionally substituted pyrazole ring, as shown in the first step of
the first production method, thereby forming a compound (1f) of the present
invention, which is hydrolyzed to prepare a compound (1g) of the present
invention in a second step, and then the compound (I) of the present
invention is prepared by the amidation of the compound (1g) or its reactive
derivative with a compound (1h) in a third step. The leaving group of X or
Y is as defined in the first step of the first production method.

The reaction in the first step can be carried out in accordance with the
first step of the first production method, the reaction in the second step in
accordance with the second step of the first production method, and the
reaction in the third step in accordance with the third step of the first
production method.
The thus produced compound of the present invention is isolated and
purified as its free form or as a salt thereof. A salt of the compound (I) can
be produced by subjecting it to a usual salt formation reaction. The
isolation and purification are carried out by usual chemical manipulations
such as extraction, concentration, evaporation, crystallization, filtration,
recrystallization, various types of chromatography, and the like.
Various types of isomers can be separated by usual method using the
difference in physicochemical properties among isomers. For example,
racemic compounds can be separated by a general racemic compound
resolution method, e.g., a method in which racemic compounds are
converted into diastereomer salts with an optically active base such as
tartaric acid, and the like and then subjected to optical resolution. And,
diastereomers can be separated by fraction crystallization or various types
of chromatography or the like. Also, optically active compounds can be
prepared using appropriate optically active starting materials.
The compound and its salt of the present invention have excellent
stimulation effects for arginine vasopressin V2 receptors. Thus, the
compound of the present invention has antidiuretic effects and effects of

releasing blood coagulating agents VIII factor and von Willebrand factor, is
useful for treating various urination disorders, polyuria, or hemorrhage
conditions, and is effective in the diagnosis, prevention, and treatment of
polyuria, urinary incontinence, central diabetes insipidus, nocturia,
nocturnal enuresis, spontanous hemorrhage, hemophilia, von Willebrand
disease, uremia, congenital or acquired platelet dysfunction, traumatic or
surgical hemorrhage, hepatocirrhosis, and the like.
Since the compound of the present invention has little inhibition
effects against medicine metabolism enzymes CYP3A4 and CYP2C9, there
is less concern for interaction with other medicines metabolized by CYP3A4
or CYP2C9, compared with known benzazepine derivatives having arginine
vasopressin V2 receptor agonist effects, and it can be safely used in
combined therapy with various preparations.
Examples of medicines metabolized by CYP3A4 include simvastatin,
lovastatin, fluvastatin, midazolam, niphedipine, amlodipine, nicardipine,
and the like, and example of medicines metabolized by CYP2C9 include
diclofenac, ibuprofen, indomethacin, tolbutamide, glibenclamide, losartan,
and the like (General Clinic, 48(6), 1427-1431, 1999).
Pharmaceutical efficacy of the compound of the present invention was
confirmed by the following assays,
(l) V2 receptor binding assay
A human V2 expression CHO cell membrane sample was prepared in
accordance with a method of Tahara, et al. (British Journal of

Pharmacology. Vol 125, p. 1463-1470, 1998). 2 µg of the membrane sample
were incubated in a total of 250 µl of 50 mM tris-chloric acid buffer solution
(pH=7.4) containing 10 mM MgCl2 and 0.1% bovine serum albumin (BSA),
together with [3H]-Arginine-Vasopressin (hereinafter referred to as "[3H]-
Vasopressin") (0.5 nM, Specific activity = 75 Ci / mmol) and a test compound
(10-10~10-5 M) at 25oC for 60 minutes. Then, free [3H]-Vasopressin and
receptor binding [3H]-Vasopressin were separated using a cell harvester,
and the receptor binding [3H]-Vasopressin was adsorbed on a Unifilter Plate
GF/B glass filter, sufficiently dried, and then mixed with a microplate
scintillation cocktail. The amount of receptor binding [3H]-Vasopressin
was measured using a top count, and inhibition rate was calculated by the
following equation.
Inhibition Rate(%) = 100-(C1-B1)/(Co-B1) X 100
C1: the amount of [3H]-Vasopressin bound to the membrane sample, when
the receptor membrane sample is treated in the coexistence of a test
compound of known concentration and [3H]-Vasopressin
Co: the amount of [3H]-Vasopressin bound to the membrane sample, when
the receptor membrane sample is treated with [3H]-Vasopressin, in the
absence of a test compound
B1- the amount of [3H]-Vasopressin bound to the membrane sample, when
the receptor membrane sample is treated in the coexistence of an excess
amount of Vasopressin (106 M) and [3H] -Vasopressin
From the above equation, concentration of the test compound

corresponding to the inhibition rate of 50% (IC50) was calculated, from
which affinity of the test compound for a receptor, i.e., dissociation
coefficient (Ki) was calculated by the following equation.
Dissociation Coefficient (Ki) = IC5o/(l+[L]/Kd)
[L] : the concentration of [3H]-Vasopressin
Kd: dissociation coefficient of [3H]-Vasopressin for the receptor, calculated
from saturation binding assay
(Table 1)
[Affinity for V2 receptor]

As the control, the compound of Example 32 described in WO
97/22591 (Compound name: 2-[(5R)-l-(2-chloro-4-pyrrolidin-l-ylbenzoyl)-
2,3,4,5-tetrahydro-lH-l-benzazepin-5-yl]-N-isopropyacetamide) was used.
As shown in Table 1, it has been verified that the compound of the
present invention has high affinity for the V2 receptor.
(2) Antidiuresis assay (intravenous administration)
For the assay, 5 Wistar male rats (1O~12 weeks of age) were employed
for each group. For group A, 0.3 mg/kg of the compound of Example 135,
for group B, 0.3 mg/kg of the compound of Example 201, and for group C, 1
ml/kg of physiological saline solution comprising DMSO as a control were
intravenously administrated. After 15 minutes, 30 ml/kg of distilled water
were orally administrated (water load). Until 2 hours after the water load,

urine was collected in a metabolism cage, and the amount of urine when the
water load is set to 100% was calculated as the urinary excretion rate. For
the assay, the average value in each group of urinary excretion rate until 1
hour after the water load and that until 2 hours after the water load was
employed. The results are described in the following Table 2.
(Table 2)
[Antidiuretic effects (intravenous administration)]

As shown in Table 2, it has been verified that the compound of the
present invention has excellent antidiuretic effects.
(3) Antidiuresis assay (oral administration)
For the assay, Wistar male rats (10~12 weeks of age) were employed.
The test compound was orally administrated, and after 15 minutes, 30
ml/kg of distilled water were orally administrated (water load). Until 4
hours after the water load, urine was collected in a metabolism cage, and
the amount of urine when the water load was set to 100% was calculated as
the urinary excretion rate. For the assay, the amount of the test
compound required for decreasing urinary excretion rate by 50% (ED50) was
employed. The results are described in the following Table 3.
(Table 3)
[Antidiuretic effects (oral administration)]

As shown in Table 3, it has been verified that the compound of the
present invention has excellent antidiuretic effects by oral administration
as well as by intravenous administration.
(4) Cytochrome P450 (3A4) enzyme inhibition assay
The assay was carried out in accordance with a method of Crespi, et al.
(Analytical Biochemistry, 248, 188-190, 1997).
A 96 well plate was employed, and 7-benzyloxy-4-
(trifluoromethyl)coumarin (5 x 10-5 M) as a substrate, a test compound (4.9
x 10-8 ~ 5 x 105 M), and an enzyme (5 x 10~9 M) were incubated in a total of
200 µl of a 200 mM phosphate buffer solution (pH=7.4) comprising 8.2 µM
NADP+, 0.41 mM glucose-6-phosphate, 0.41 mM MgCl2, and 0.4 Units/ml
glucose-6-phosphate dehydrogenase, at 37°C for 30 minutes. Then, 0.5 M
aqueous solution of 2-amino-2-hydroxymethyl-l,3-propanediol containing
80% acetonitrile was added thereto to stop the reaction, and fluorescence
intensity was measured with a fluorescent plate reader (excited
wavelength: 409 nm, fluorescent wavelength: 530 nm). Inhibition rate was
calculated by the following equation, and the concentration of the test
compound corresponding to an inhibition rate of 50% (IC50) was calculated.
The results are described in the following Table 4.
Inhibition Rate (%) = 100-(C1-B1)/(C0-B1) x 100
C1: fluorescence intensity in the presence of a known concentration of test

compound, enzyme, and a substrate
C0: fluorescence intensity in the presence of an enzyme and a substrate, in
the absence of a test compound
B1-" fluorescence intensity of a blank well
(5) Cytochrome P450 (2C9) enzyme inhibition effects
The assay was carried out in accordance with a method of Crespi, et al.
(Analytical Biochemistry, 248, 188-190, 1997).
A 96 well plate was employed, and 7-methoxy4-
(trifluoromethyl)coumarin (7.5 x 10-5 M) as a substrate, a test compound
(4.9 x 10-8 ~ 5 x 10-5 M), and an enzyme (108 M) were incubated in a total of
200 µL of a 200 mM phosphate buffer solution (pH=7.4) comprising 8.2 µM
NADP+, 0.41 mM glucose-6-phosphate, 0.41 mM MgCl2, and 0.4 Units/ml
glucose-6-phosphate dehydrogenase, at 37°C for 45 minutes. Then, 0.5 M
aqueous solution of 2-amino-2-hydroxymethyl-1,3-propanediol containing
80% acetonitrile was added thereto to stop the reaction, and fluorescence
intensity was measured with a fluorescent plate reader (excited
wavelength: 409 nm, fluorescent wavelength: 530 nm). Inhibition rate was
calculated from the above equation in (4), and the concentration of the test
compound corresponding to an inhibition rate of 50% (IC50) was calculated.
The results are described in the following Table 4.
(Table 4)
[CYP(3A4 and 2C9) inhibition effects]

As shown in Table 4, the compound of the present invention showed
very low inhibition effects for the medicine metabolism enzymes CYP3A4
and CYP2C9. The control was the same as in Table 1.
A pharmaceutical composition of the present invention can be
prepared by generally used methods using one or more kinds of the
compound of the present invention and pharmaceutical carriers, fillers, and
other additives generally used in the preparation of medicaments.
It may be administrated either by oral administration through tablets,
pills, capsules, granules, powders, solutions, and the like, or by parenteral
administration through injections such as intravenous injection,
intramuscular injection, and the like, or through suppositories, or pernasal,
permucosal, or percutaneous preparations, and the like.
The solid composition for use in the oral administration according to
the present invention is used in the forms of tablets, powders, granules, and
the like. In such a solid composition, one or more active substances are
mixed with at least one inert diluent such as lactose, mannitol, glucose,
hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl
pyrrolidone, metasilicate, or magnesium aluminate. In the usual way, the
composition may contain additives other than the inert diluent, which
include a lubricant such as magnesium stearate, a disintegrating agent
such as calcium cellulose glycolate, a stabilizing agent such as lactose, and

a solubilization-assisting agent such as glutamic acid or aspartic acid. As
occasion demands, tablets or pills may be coated with a sugar coat or a film
of gastrosoluble or enterosoluble substance such as sucrose, gelatin,
hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or the like.
The liquid composition for oral administration includes
pharmaceutically acceptable emulsions, solutions, suspensions, syrups,
elixirs, and the like, and it contains a generally used inert diluent such as
purified water or ethanol. In addition to the inert diluent, this composition
may also contain auxiliary agents such as a moistening agent and a
suspending agent, as well as a sweetener, a flavoring agent, an aromatic,
and an antiseptic.
The injections for parenteral administration include aseptic aqueous
or non-aqueous solutions, suspensions, and emulsions. Examples of the
aqueous solutions and suspensions include distilled water for injection use,
and physiological saline. Examples of the non-aqueous solutions and
suspensions include plant oil such as propylene glycol, polyethylene glycol,
olive oil or the like, alcohol such as ethanol, polysorbate 80 (trade name),
and the like. Such a composition may further contain auxiliary agents
such as an antiseptic, a moistening agent, an emulsifying agent, a
dispersing agent, a stabilizing agent (e.g., lactose), and a solubilization-
assisting agent (e.g., glutamic acid or aspartic acid. These compositions
are sterilized, for example by filtration through a bacteria retaining filter,
blending of a germicide, or irradiation. Alternatively, they may be used by

firstly making into sterile solid compositions and dissolving them in sterile
water or a sterile solvent for injection use, prior to their use.
In the case of oral administration, a daily dose is approximately
0.0001~50 mg/kg of body weight, preferably approximately 0.001~10 mg/kg,
and more preferably approximately 0.01-1 mg/kg, and the daily dose is
administered once a day or by dividing it into 2 to 4 doses per day. In the
case of intravenous administration, a daily dose is approximately 0.0001~l
mg/kg of body weight, preferably approximately 0.0001~0.1 mg/kg, and the
daily dose is administered once a day or by dividing it into plural doses per
day. The dose is appropriately determined by taking symptoms, age, the
sex of the patient to be treated, and the like into consideration. Since the
dose is varied depending on various conditions, a smaller dose is sufficient
in some cases.
Best Mode for Carrying Out the Invention
The following describes the invention more illustratively with
reference to examples, but the present invention is not limited to these
examples. In this connection, novel materials are included in the starting
materials to be used in the examples, and production methods of the
starting materials from known materials are described as reference
examples.
Reference Example 1
20.85 g of methyl 2-chloro-4-fluorobenzoate were dissolved in 150 ml

of N-methylpyrrolidone, 30.68 g of potassium carbonate and 9.38 ml of 3-
methylpyrazole were added thereto, and the mixture was stirred at 120 °C
for 3 hours. Additionally, thereto was added 1.79 ml of 3-methylpyrazole,
and the mixture was stirred at 120 °C for 3 hours. The reaction solution
was cooled, mixed with water, and extracted with EtOAc. The organic
layer was washed with water and brine, and then dried over magnesium
sulfate. The solvent was evaporated, and then the residue was purified by
silica gel column chromatography (hexane-EtOAc (20:1)) to obtain 9.25 g of
methyl 2-chloro-4-(3-metyl-1H-pyrazol-1-yl)benzoate.
The compounds of Reference Examples 2 -40 were synthesized in
the same manner as described in Reference Example 1.
Reference Example 41
2.0 g of methyl 4-amino-2-chlorobenzoate were dissolved in 10 ml of
acetic acid, 2.0 ml of 2,5-dimethoxytetrahydrofuran were added thereto, and
the mixture was heated under reflux for 15 minutes. After cooling the
reaction solution, the solvent was evaporated. The obtained residue was
mixed with EtOAc and saturated NaHCO3 aq. and extracted. The organic
layer was washed with brine, and dried over sodium sulfate anhydride.
After evaporating the solvent, the residue was purified by silica gel column
chromatography (hexane-EtOAc (4:1)) to obtain 2.1 g of methyl 2-chloro-4-
(lH-pyrrol-l-yl)benzoate.
The compound of Reference Example 42 was synthesized in the
same manner as described in Reference Example 41.

Reference Example 43
2.0 g of methyl 4-bromo-2-methylbenzoate were dissolved in 20 ml of
toluene, and 1.08 ml of pyrrolidine, 4.0 g of cesium carbonate, 200mg of
tris(dibenzylideneacetone)-dipalladium (0) and 200 mg of (R)-(+)-2,2"-
bis(diphenylphosphino)-l,l"-binaphthyl were added thereto, and then the
mixture was heated under reflux for 6 hours. The reaction solution was
cooled, mixed with water and EtOAc, and extracted. The organic layer was
washed with water and brine, and dried over anhydrous sodium sulfate.
After evaporating the solvent, the residue was purified by silica gel column
chromatography (hexane-EtOAc (25:l)) to obtain 0.784 g of methyl 2-
methyl-4-pyrrolidin-l-ylbenzoate.
The compound of Reference Example 44 was synthesized in the
same manner as described in Reference Example 43.
Reference Example 45
9.25 g of the compound of the Reference Example 1 were dissolved
in 10 ml of acetic acid and 10 ml of 6M HC1 aq., and then the mixture was
heated under reflux for 13 hours. The reaction solution was cooled, and
then poured into ice water, and the thus precipitated crystals were collected
by filtration to obtain 8.56 g of 2-chloro-4-(3-methylpyrazol-1-yl) benzoic
acid.
Reference Example 46
10.7 g of the compound of Reference Example 2 were dissolved in 60
ml of MeOH and 20 ml of 5M NaOH aq., and the mixture was heated under

reflux for 2 hours. The reaction solution was cooled, and then neutralized
with 2M HC1 aq., and the solvent was evaporated. To the obtained residue,
water was added, and the thus precipitated crystals were collected by
filtration to obtain 10.17g of 2-chloro-4-pyrrolidin-l-ylbenzoic acid.
The compounds of Reference Examples 47-88 were synthesized in
the same manner as described in Reference Example 46.
The structures and physical data of the compounds of Reference
Examples are shown in Tables 5 to 8. Symbol meanings in the Tables are
as follows.
Rf Reference Example number
MS: Mass spectrometry data (FAB-MS(M+H)+ unless otherwise noted, and
MM, MN, and ME respectively indicate FAB-MS(M)+, FAB-MS(M-H)+, and
EI-MS(M)+).
Rb, Rc, Rd: substituent group in the general formula (Me: methyl, Et: ethyl,
iPr: isopropyl, cPr: cyclopropyl, tBu: tert-butyl, Ph: phenyl, pra: pyrazolyl,
pyrr: pyrrolinidyl, mor: morpholinyl, the: thienyl, imid: imidazolyl, bimid:
benzoimidazolyl, pipe: piperidyl, di: di), The number before the substituent
group indicates location of substitution. Thus, for example, 3-Me-1-pra
indicates 3-methylpyrazol-1-yl, 3,3-diMe-l-pyrr indicates 3,3-
dimethylpyrrolidin-l-yl, and 3-(2-the)-1-pra indicates 3-thiophene-2-
ylpyrazol-1-yl.

(Table 5)

(Table 5 contd)
(Table 6)

(Table 7)

(Table 7 contd)

(Table 8)

Reference Example 89
8.0 g of methyl (2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H-1-
benzazepin-5-ylidene) acetate were dissolved in 20 ml of MeOH and 20 ml of
THF. 45 ml of 1M NaOH aq. were added thereto, and the mixture was
stirred at room temperature for 15 hours. The reaction solution was
concentrated under reduced pressure, and the residue was neutralized with
1M HC1 aq.. The reaction solution was mixed with chloroform and
extracted. The organic layer was washed with brine, dried over sodium
sulfate, and the solvent was evaporated to obtain 4.57 g of carboxylic acid
intermediate. 4.57 g of the carboxylic acid intermediate were dissolved in

45 ml of DMF. 2.22 ml of 2-picolyl amine, 3.6 g of 1-hydroxybenzoimidazol
(HOBt), and 5.6 g of l-ethyl-3-(3"-dimethylaminopropyl)carbodiimide
hydrochloride (EDCI HCI) were added thereto, and the mixture was stirred
at room temperature for 18 hours. The reaction solution was mixed with
water and EtOAc and extracted therewith. The organic layer was washed
with brine, and dried over sodium sulfate anhydride. After evaporation of
the solvent, the residue was purified by silica gel column chromatography
(chloroform-MeOH (25:1)) to obtain 6.849 g of (2Z)-2-(4,4-difluoro-1,2,3,4-
tetrahydro-5H-l-benzazepin-5-ylidene)-N-(pyridine-2-ylmethyl)acetamide.
FAB-MS; 330. ([M+H]+)
Reference Example 90
To a solution of 1.37 g of the compound of Example 6, 0.45 g of
HOBt, and 0.63 g of EDCI HC1 in 15 ml of DMF, 0.46 g of sarcosinic
methylester hydrochloride and 0.47g of triethylamine were added, and the
mixture was stirred at room temperature overnight. The reaction
solution was mixed with NaHCO3 aq. and EtOAc and extracted. The
organic layer was washed with water and brine, and dried over anhydrous
magnesium sulfate. After evaporation of the solvent, the obtained ester
intermediate was dissolved in 20 ml of MeOH, 5 ml of 1M NaOH aq. was
added thereto, and the mixture was stirred at room temperature for 1 hour.
To the crude product obtained by the evaporation of the solvent, 1M HC1 aq.
was added, and the thus precipitated white crystals were collected by
filtration, washed with water, and dried under reduced pressure to obtain

1.43 g of [((2Z)-2-{l-[2-chloro-4-(3-methyl-1H-pyrazol-l-yl)benzoyl]-4,4-
difluoro-l,2,3,4"tetrahydro-5H-l-benzazpine-5-
ylidene}acetyl(methyl)amino)acetic acid.
FAB-MS; 529. ([M+H]+)
Example 1
To a suspension of 21.0 g of 2-chloro-4-(3-methyl-1H-pyrazol-1-
yl)benzoic acid in 200 ml of 1,2-dichloroethane, 15 ml of thionyl chloride and
3 drops of DMF were added at room temperature, and the mixture was
stirred at 70oC for 2 hours. The reaction solution was cooled to room
temperature, the solvent was evaporated, and the residue was dried to
obtain acid chloride form. 22.5 g of methyl (2Z)-(4,4-difluoro-l,2,3,4-
tetrahydro-5H-l-benzazepin-5-ylidene)acetate were added thereto, 200 ml
of pyridine was added thereto under ice cooling, and the mixture was
stirred at room temperature for 20 hours. After completion of the reaction,
the solvent was evaporated, and the residue was mixed with diluted
hydrochloric acid water and EtOAc and extracted. The organic layer was
washed with brine, and dried over anhydrous magnesium sulfate. After
evaporation of the solvent, the residue was purified by silica gel column
chromatography (hexane-EtOAc (9:1 ~ 4:1)) to obtain 38.0 g of methyl (2Z)-
{l-[2-chloro-4-(3-methyMH-pyrazol-l-yl)benzoyl]-4,4-difluoro-1,2,3,4-
tetrahydro-5H-1-benzazepin-5-ylidene}acetate.
Example 2
To a solution of 3.0 g of 4-bromo-2-methylbenzoic acid in 20 ml of

THF and 1 drop of DMF, 1.9 ml of oxalyl chloride was added under ice
cooling, and the mixture was stirred at room temperature for 2 hours. The
reaction solution was concentrated, and the residue was mixed with 3 ml of
toluene and concentrated again. The obtained residue was mixed with 20
ml of pyridine and 3.5 g of methyl (2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H-
l-benzazepin-5-ylidene)acetate and the mixture was stirred at room
temperature for 12 hours. The reaction mixture was concentrated, then to
the mixture was added chloroform and 1M aqueous NaOH and was
extracted. The organic layer was washed with water and brine, and dried
over anhydrous sodium sulfate. After evaporation of the solvent, the
residue was purified by silica gel column chromatography (hexane-EtOAc
(6:1)) to obtain 5.94 g of methyl (2Z)-[l-(4-bromo-2-methylbenzoyl)-4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene]acetate.
Example 3
To a solution of 4.62 g of 2-(trifluoromethyl)benzoic acid in 30 ml of
sulfuric acid, 3.48 g of l,3-dibromo-5,5-dimethylhydantoin were added.
The mixture was stirred at room temperature for 15 hours, and then added
to ice water dropwise. 5M NaOH aq. were added to the reaction solution to
control pH of the solution to 12, and then the reaction solution was
extracted with chloroform. To the aqueous layer, concentrated
hydrochloric acid was added to control the pH of the solution to 1, and then
the reaction solution was extracted with chloroform. The organic layer
was washed with water and brine, and dried over anhydrous sodium sulfate.

After evaporation of the solvent, 20 ml of THF and 1 drop of DMF were
added to the residue, and 2.5 ml of oxalyl chloride were added thereto under
ice cooling, and then the mixture was stirred at room temperature for 2
hours. The reaction solution was concentrated under reduced pressure,
and the residue was mixed with 10 ml of toluene and concentrated again.
To the obtained residue, 20 ml of pyridine and 6.2 g of methyl (2Z)-(4,4-
difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-ylidene)acetate were added,
and the mixture was stirred at room temperature for 12 hours. The
reaction solution was concentrated, and the residue was mixed with
chloroform and 1M HC1 aq. and extracted. The organic layer was washed
with water and brine, and dried over anhydrous sodium sulfate. After
evaporation of the solvent, the residue was purified by silica gel column
chromatography (hexane-EtOAc(6:1)). And, the residue obtained by
concentration under reduced pressure was crystallized from EtOH to obtain
3.66 g of methyl (2Z)-{l-[4-bromo-2-(trifluoromethyl)benzoyl]-4,4-difluoro-
1,2,3,4-tetrahydro- 5H-1-benzazepin-5-ylidene}acetate.
Example 4
To a solution of 2.0 g of the compound of Example 2 in 30 ml of
toluene, 22.35 g of tert-butyl hydrazine carboxylate, 1.43 g of cesium
carbonate, 400 mg of tris(dibenzylideneacetone)dipalladium (0), and 740 mg
of 1,1"-bis(diphenylphosphine)ferrocene were added, and the mixture was
stirred at 100°C for 4 hours. After cooling the reaction solution, insoluble
matter was filtered, and EtOAc and 10% citric acid aqueous solution were

added to the filtrate to extract it. The organic layer was washed with
water and brine, and dried over anhydrous sodium sulfate anhydride.
After evaporation of the solvent, the residue was purified by silica gel
column chromatography (hexane-EtOAc (2:1)) to obtain 1.0 g of tert-butyl 1-
(4-{[(5Z)-4,4-difluoro-5-(2-methyl-2-oxoethylidene)-2,3,4,5-tetrahydro-lH-l-
benzazepin-l-yl]carbonyl}-3-methylphenyl)hydrazine carboxylate.
Example 5
To a solution of 1.0 g of the compound of Example 4 in 10 ml of
EtOAc, 10 ml of 4M HCl-EtOAc were added, and the mixture was stirred at
room temperature for 4 hours. The reaction solution was concentrated
under reduced pressure, and the residue was mixed with saturated
NaHCC>3 aq. and chloroform and extracted. The organic layer was washed
with water and brine, and dried over anhydrous sodium sulfate. After
evaporation of the solvent, 40 ml of MeOH and 275 mg of
acetylacetaldehyde dimethylacetal were added to the residue, and the
mixture was heated under reflux for 1.5 hours. To the reaction solution, 3
drops of cone, hydrochloric acid were added, and the mixture was heated
under reflux for 30 minutes again. The reaction solution was cooled, and
then concentrated under reduced pressure. The residue was mixed with
saturated sodium hydrogen carbonate aqueous solution and chloroform and
extracted. The organic layer was washed with water and brine, and dried
over anhydrous sodium sulfate. After evaporation of the solvent, the
residue was purified by silica gel column chromatography (hexane-EtOAc

(4:1)) to obtain 561 mg of methyl (2Z)-{4,4-difluoro-l-[2-methyl-4-(3-methyl-
lH-pyrazol-l-yl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetate.
Example 6
38.0 g of the compound of Example 1 were dissolved in 120 ml of
MeOH and 120 ml of THF, 100 ml of 1M NaOH aq. was added at room
temperature, and the mixture was stirred for 10 hours. Approximately 200
ml of the solvent were evaporated under reduced pressure, 0.5M HC1 aq.
were added to the residue under ice cooling, and the mixture was stirred for
1 hour. Thus formed white precipitations were filtered and dried to obtain
36.5 g of (2Z)-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-lH-1-benzazepin-5-ylidene}acetic acid in the form of
powder.
Example 7
To a solution of 229 mg of the compound of Example 6, 71 mg of
HOBt and 101 mg of EDCI HCl in 3 ml of DMF, 35 mg of thiophen-2-
ylmethylamine were added, and the mixture was stirred at room
temperature overnight. The reaction solution was mixed with saturated
sodium bicarbonate aqueous solution and chloroform, and extracted. The
organic layer was dried over anhydrous magnesium sulfate, and the solvent
was evaporated. Then, the residue was purified by silica gel column
chromatography (chloroform-MeOH (30:1)). The residue obtained by
concentration under reduced pressure was crystallized from a 2-propanol-

diisopropyl ether solvent mixture to obtain 61 mg of (2Z)-2-{l-[2-chloro-4-(3-
methyl-lH-pyrazol-l-yl]benzoyl}-4,4-difluoro-l,2,3,4,-tetrahydro-5H-l-
benzazepin-5-ylidene}-N-(thiophen-2-ylmethyl)acetamide.
Example 8
210 mg of the compound of Example 6 were dissolved in 20 ml of
dichloroethane, 2 ml of thionyl chloride were added, and the mixture was
stirred at room temperature for 30 minutes. The reaction solution was
concentrated under reduced pressure, and the residue was mixed with
toluene and concentrated again. The obtained acid chloride form were
dissolved in 30 ml of acetonitrile, and added dropwise to 30 ml of ammonia
water at room temperature. After stirring at room temperature for 12
hours, the formed white precipitations were filtered and dried to obtain 259
mg of (2Z)-2-{l-[2-ehloro-4-(3-methyl-lH-pyrazol- l-yl)benzoyl]-4,4-difluoro-
l,2,3,4-tetrahydro-5H-benzazepine}acetamide in the form of powder.
Example 9
915 mg of the compound of Example 14 were dissolved in 20 ml of
MeOH, 3 ml of 1M NaOH aq. were added, and the mixture was stirred at
room temperature for 15.5 hours. The solvent was evaporated under
reduced pressure, and then the residue was acidified with 1M HC1 aq. and
extracted with chloroform. The organic layer was washed with water and
brine, and dried over anhydrous sodium sulfate. After evaporation of the
solvent, the obtained carboxylic acid intermediate was dissolved in 10 ml of
DMF, 0.24 ml of 2-picolyl amine, 0.39 g of HOBt and 0.61 g of EDCI HC1

were added thereto, and the mixture was stirred at room temperature for
84 hours. The reaction solution was mixed with water and EtOAc, and
extracted. The organic layer was washed with brine, and dried over
anhydrous sodium sulfate. After evaporation of the solvent, the residue
was purified by silica gel column chromatography (chloroform-MeOH (35:1)).
The residue obtained by concentration under reduced pressure was
dissolved in EtOAc, 0.4 ml of 4M HCl-EtOAc solution was added thereto,
and the solvent was evaporated under reduced pressure. The obtained
residue was crystallized from EtOH to obtain 0.456 g of (2Z)-2-[l-(2-chloro-
4-pyrrolidin-l-ylbenzoyl)-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene]-N-(pyridin-2-ylmethyl)acetamide hydrochloride.
Example 10
0.25 g of the compound of Example 93 were dissolved in 10 ml of
MeOH, 10 ml of 1M NaOH were added, and the mixture was stirred at
room temperature for 16 hours. The reaction solution was neutralized
with 1M HC1 aq., and extracted with chloroform. The organic layer was
washed with water and brine, and dried over anhydrous magnesium sulfate.
After evaporation of the solvent, the residue was crystallized from an
EtOAc-hexane solvent mixture to obtain 116 mg of [((2Z)-2-{l-[2-chloro-4-(3-
methyl-lH-pyrazol-l-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-l-
benzazepin-5-ylidene}acetyl)amino]acetic acid.
Example 11
To a solution of 258 mg of the compound of Example 10, 71 mg of

HOBt and 101 mg of EDCI HC1 in 5 ml of THF, and 0.5 ml of 2.0 M
methylamine-THF solution were added, and the mixture was stirred at
room temperature overnight. The reaction solution was mixed with
saturated NaHCO3 aq. and extracted with chloroform. The organic layer
was dried over anhydrous magnesium sulfate. The crude product obtained
by evaporation of the solvent was purified by silica gel column
chromatography (chloroform-MeOH (30:1)). The residue obtained by
concentration under reduced pressure was crystallized from a 2-propanol-
hexane solvent mixture to obtain 51 mg of (2Z)-2-{l-[2chloro-4-(3-methyl-
lH-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}-N-[2-(methylamino)-2-oxoethyl]acetamide.
Example 12
To a solution of 265 mg of the compound of Reference Example 90 in
5 ml of THF, 82 mg of l,l"-carbonylbis-lH-imidazole were added, and the
mixture was stirred at room temperature for 1 hour. Then, ammonia
water was added to the reaction solution, and the mixture was stirred at
room temperature for 22 hours. The reaction solution was mixed with
water and EtOAc, and extracted therewith. The organic layer was washed
with water and brine, and dried over anhydrous magnesium sulfate. The
crude product obtained by evaporation of the solvent was purified by silica
gel column chromatography (chloroform-MeOH(100:1)). The residue
obtained by concentration under reduced pressure was crystallized from a
2-propnaol-diisopropyl ether solvent mixture to obtain 41 mg of (2Z)-N-[2-

amino-2-oxoethyl]-N-methyl-2-{l-[2-chloro-4-(3-methyMH-pyrazol-l-
yl)benzoyl]-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetamide.
Example 13
To a solution of 0.35 g of the compound of Reference Example 85 in
10 ml of THF and 1 drop of DMF, 0.22 ml of thionylchloride were added
under ice cooling, and the mixture was stirred at room temperature for 2.5
hours. The reaction solution was concentrated under reduced pressure,
and the residue was mixed with 3 ml of toluene and concentrated again.
The obtained residue was dissolved in 20 ml of acetonitrile, 0.4 g of the
compound of Reference Example 89 and 0.4 ml of pyridine were added, and
the mixture was stirred at 80°C for 17 hours. After cooling the reaction
solution, the solvent was evaporated, and the residue was mixed with
chloroform and 10% citric acid aqueous solution, and extracted therewith.
The organic layer was washed with saturated sodium bicarbonate aqueous
solution, water, and brine, and the dried over anhydrous sodium sulfate.
After evaporation of the solvent, the residue was purified by silica gel
column chromatography (chloroform-MeOH-ammonia water (25:0:0.1)).
The residue obtained by concentration under reduced pressure was
dissolved in EtOAc, 0.18 ml of 4M HCl-EtOAc solution was added thereto,
and the solvent was evaporated under reduced pressure. The obtained
residue was crystallized from EtOH to obtain 0.176 g of (2Z)-2-[l-(2-chloro-
4-piperidin-l-ylbenzoyl)-4,4-difluoro-l,2,3,4-tetrahydro-5H-l-benzazepin-5-

ylidene]-N-(pyridine-2-ylmethyl)acetainide hydrochloride.
The structures and physicochemical data of the compounds of
Examples are shown in Tables 9. Additionally, the structures and
physicochemical data of the compounds obtained by the same production
method are also shown in Tables 9 to 16. The symbols in the Tables have
the following meanings.
Ex: number of Example
Salt: salt (HC1: hydrochloride, inorganic material: free form)
Syn: synthesis method (The number indicates the number of Example of
which method is applied)
RA, RB, Rc, RD, R1A: substituent group in the general formula (nPen: normal
pentyl, cHex: cyclohexyl, Ac: acetyl, Ms: mesyl, Boc: tert-butyloxycarbony,
py: pyridyl, fur:furyl, thia: thiazolyl, bthia: benzothiazolyl. Thus, as
examples, -NH2CH2-(2-py) indicates pyridine-2-ylmethylamino, -NH2CH2-
(4-HO-3-MeO-Ph) indicates 4-hydroxy3-methoxybenzylamino, and 2-
HOCH2-l-pipe indicates 2-hydroxymethylpiperidin-l-yl.)

(Table 9)

(Table 10 contd)

(Table 10 contd)

(Table 11)

(Table 11 contd)

(Table 11 contd)

(Table 11 contd)

(Table 12)

(Table 13)

(Table 14)

(Table 15)

(Table 16)

NMR data of the compounds of some Examples are shown in Table
17. The term "NMR" indicates 8(ppm) of the peaks in ^-NMR employing
DMSOofeas a measuring solvent unless otherwise indicated, using (CH^Si
as an internal standard.

(Table 17 contd)

(Table 17 contd)

The structures of the compounds of the present invention are shown
in Table 18. These compounds can be easily synthesized by methods that
are self-evident to an ordinarily skilled person, or with modified methods.
The "No" in the Table indicates compound number.

(Table 18)

(Table 18 contd)

(Table 18 contd)

(Table 18 contd)

(Table 18 contd)

(Table 18 contd)

We Claim:
1. 4,4-difluoro-1,2,3,4-tetrahydro-5H-l-benzazepine derivative
represented by the general Formula (I) or a pharmaceutically
acceptable salt thereof:

wherein the symbols have the following meanings:
R1: a group represented by the following general formula
(II), or a group represented by the following general formula (III):

wherein the symbols have the following meanings:
A: a single bond, (C1-C6) alkylene, or -(C1-C6) alkylene-
C(=O)-;
R11: (C1-C6) alkyl which may be substituted with a group
selected from the group consisting of -OH, -O-(C1-C6) alkyl, -
CO2H, -CO2H, -CO2-(C1-C6) alkyl, and carbamoyl which may be
substituted with one or two (C1-C6) alkyl, or -H;
R10 : (1) when A is a single bond or (C1-C6) alkylene, R12 is
aryl, cycloalkyl, aromatic heterocycle, or nonaromatic heterocycle,
each of which may be substituted by one or more groups selected
from the group consisting of (a) to (h), or -H, -OH, -O-(C1-C6)
alkyl, -CO2-H, -CO2-(C1-C6) alkyl, or carbamoyl which may be
substituted with one or two (C1-C6) alkyls; and
(2) when A is -(C1-C6) alkylene-C(=O)-, R12 Is a group represented
by the above general formula (HI), or a group represented by the
following general formula (IV),

B: a single bond, or (C1-C6) alkylene; and
R13 and R14: nonaromatic cyclic amino, bonded together with
an adjacent nitrogen atom, which may be substituted by one or
more groups selected from the group consisting of (a) to (h);
R2: (C1-C6) alkyl which may be substituted with one or
more halogen, or halogen;
R3 and R4: one is -H, (C1-C6) alkyl, or halogen, and the other
is nonaromatic cyclic amino which may be substituted by one or
more groups selected from the group consisting of (a) to (h), or an
aromatic cyclic amino which may be substituted by one or more
groups selected from the group consisting of (a) to (h);
R5: -H, (C1-C6) alkyl, or halogen;
(a) halogen;
(b) -OH, -O-RA, -O-aryl, -OCO-RA, oxo(=O);
(c) -SH, -S-RA, -S-aryl, -SO-RA, -SO-aryl, -SO2-RA,
-SO2-aryl, sulfamoyl which may be substituted with one
or two RA;

(d) amino which may be substituted with one or more RA, -
NHCO-RA, -NHCO-aryl, -NHSO2-RA, -NHSO2-aryl,
nitro;
(e) -CHO, -CO-RA, -CO2-H, -CO2-RA, carbamoyl which
may be substituted with one or two RA, cyano;
(f) aryl or cycloalkyl, each of which may be substituted with
one or more groups selected from the group consisting of
-OH, -O-(C1-C6) alkyl, amino which may be substituted
with one or two (C1-C6) alkyls, carbamoyl which may be
substituted with one or more (C1-C6) alkyls, aryl,
aromatic heterocycle, halogen and RA;
(g) aromatic heterocycle or nonaromatic heterocycle, each of
which may be substituted with one or more groups
selected from the group consisting of-OH, -O-(C1-C6)
alkyl, amino which may be substituted with one or two
(C1-C6) alkyls, carbamoyl which may be substituted with
one or two (C1-C6) alkyls, aryl, aromatic heterocycle,
halogen and RA;

(h) (C1-C6) alkyl or (C1-C6) alkenyl, each of which may be
substituted with one or more groups selected from the
substituent groups described in (a) to (g); and
RA: (C1-C6) alkyl group which may be substituted with one or
more groups selected from the group consisting of-OH, -O-(C1-
C6) alkyl, amino which may be substituted with one or two (C1-C6)
alkyls, carbamoyl which may be substituted with one or two (C1-
C6) alkyls, aryl, aromatic heterocycle and halogen.
2. The compound s claimed in claim 1, wherein R3, is nonaromatic
cyclic amino which may be substituted by one or more groups
selected from the group consisting of (a) to (h) described in claim
1, or aromatic cyclic amino which may be substituted by one or
more groups selected from the group consisting of (a) to (h)
described in claim 1; R4 is -H, (C1-C6) alkyl, or halogen; and R5 is
-H.
3. The compound as claimed in claim 2, wherein R4 is -H.

4. The compound as claimed in claim 1, wherein the compound is
selected from the group consisting of:
(2Z)-2-{l-[2-chloro-4-(3-methyl-lH-pyrazol-l-yl)benzoyl]-4,4-
difluoro-1,2,3,4-tetrahydro-5H-1 -benzazepin- 5-ylidene} -N-
(pyridin-2-ylmethyl) acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-[1-(2-chloro-4-pyrrolidin-1 -
ylbenzoyl)-4,4-difluoro-1,2,3,4-tetrahydro-5H-1 -benzazepin-5-
ylidene]acetamide;
(2Z)-2- {4,4-difluoro-1 -[4-(3-methyl-1H-pyrazol-1-yl)-2-
(trifluoromethyl)benzoyl]-l,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-l-[4-[(3R)-3-
methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-
tetrahydro-5-H-1 -benzazepin-5-ylidene} acetamide;
(2Z)-2-{4,4-difluoro-l-[4-(3R)-3-methylpyrrolidin-l-yl]-2-
(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-l-benzazepin-5-
ylidene}-N-(2-hydroxehtyl)acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-l-[4-(3S)-3-
methylpyrrolidin-1 -yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-
tetrahydro-5H-1 -benzazepin-5-ylidene} acetamide;

(2Z)-2-{4,4-difluoro-1-[4- [(3-methyl-1H-pyrazol-1-yl)-2-
(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-
ylidene]-N-(2-hydroxyethyl)acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3R)-3 -
methylpyrrolidin-1-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro-
5H-1-benzazepin-5-ylidene)acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-(1- {2-chloro-4-[(3S)-3 -
methylpyrrolidin-l-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro-
5H-1-benzazepin-5-ylidene)acetamide;
(2Z)-2-{4,4-difluoro-1-[4-(4-methyl-1H-pyrazol-1-yl)-2-
(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-
ylidene}acetamide;
(2Z)-N-(2-amino-2-oxoethyl)-2-{1-[4-(3,4-dimethylpyrrolidin-1-
yl)-2-(trifluoromethyl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-
5H-l-benzazepin-5-ylidene}acetamide;
(2Z)-2- {4,4-difluoro-1-[2-methyl-4-(3-metyl-1H-pyrazol-1-
yl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepine-5-
ylidene}acetamide; and
a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound of claim
1 as an active ingredient.
4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives, which
have excellent arginine vasopressin V2 activity and are useful for a drug for
the treatment of central diabetes insipidus and/or nocturia.

Documents:

615-kolnp-2004-granted-abstract.pdf

615-kolnp-2004-granted-claims.pdf

615-kolnp-2004-granted-correspondence.pdf

615-kolnp-2004-granted-description (complete).pdf

615-kolnp-2004-granted-examination report.pdf

615-kolnp-2004-granted-form 1.pdf

615-kolnp-2004-granted-form 13.pdf

615-kolnp-2004-granted-form 18.pdf

615-kolnp-2004-granted-form 2.pdf

615-kolnp-2004-granted-form 3.pdf

615-kolnp-2004-granted-form 5.pdf

615-kolnp-2004-granted-letter patent.pdf

615-kolnp-2004-granted-pa.pdf

615-kolnp-2004-granted-reply to examination report.pdf

615-kolnp-2004-granted-specification.pdf

615-kolnp-2004-granted-translated copy of priority document.pdf

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Patent Number

214989

Indian Patent Application Number

00615/KOLNP/2004

PG Journal Number

08/2008

Publication Date

22-Feb-2008

Grant Date

20-Feb-2008

Date of Filing

12-May-2004

Name of Patentee

ASTELLAS PHARMA INC

Applicant Address

3-11 NIHONBASHI-HONCHO 2-CHOME,CHUO-KU, TOKYO, JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	KOSHIO HIROYUIKI	C/O. YAMANOUCHYI PHARMACEUTICAL CO., LTD 21, MUIYUKIGAOKA, TSUKUGA-SHI IBARAKI 305-8585 JAPAN
2	TSUKAMOTO ISSEI	C/O. YAMANOUCHYI PHARMACEUTICAL CO., LTD 21, MUIYUKIGAOKA, TSUKUGA-SHI IBARAKI 305-8585 JAPAN
3	KURAMOCHI TAKAHIRO	C/O. YAMANOUCHYI PHARMACEUTICAL CO., LTD 21, MUIYUKIGAOKA, TSUKUGA-SHI IBARAKI 305-8585 JAPAN
4	AKAMATSU SEIJIRO	C/O. YAMANOUCHYI PHARMACEUTICAL CO., LTD 21, MUIYUKIGAOKA, TSUKUGA-SHI IBARAKI 305-8585 JAPAN
5	SAITOH CHIKASHI	C/O. YAMANOUCHYI PHARMACEUTICAL CO., LTD 21, MUIYUKIGAOKA, TSUKUGA-SHI IBARAKI 305-8585 JAPAN

PCT International Classification Number

B/61 22/00

PCT International Application Number

PCT/JP02/11842

PCT International Filing date

2002-11-13

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2001-350909	2001-11-16	Japan