Indian Patents
Title of Invention

NOVEL PYROLE AND IMIDAZOLE DERIVATIVES AND A PROCESS FOR THE MANUFACTURE OF THE SAME
Abstract The present invention relates to compounds of formula (I) wherein R<SUP>1</SUP>, R<SUP>2</SUP> R<SUP>3</SUP>, R<SUP>4</SUP>, R<SUP>5</SUP>, R<SUP>6</SUP>, m and X are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment . and/or prophylaxis of diseases which are associated with the modulation of CB 1 receptors.
Full Text FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
^ COMPLETE
g SPECIFICATION
OJ
! —'
y
(See Section 10)
TITLE
LLI "NOVEL CB 1 RECEPTOR INVERSE AGONISTS"
H
?T APPLICANT
"""J F. HOFFMANN-LA ROCHE AG
*TT* 124 Grenzacherstrasse
D- CH-4070 Basel
Z-D Switzerland
f) Nationality : a Swiss company
The following specification particularly describes the nature of this invention and the manner in which
it is to be performed
to o
o
c\/
3
CD

Novel CB 1 Receptor Inverse Agonists
The present invention is concerned with novel pyrrole and imidazole derivatives, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The active compounds of the present invention are useful in treating obesity and other disorders.
In particular, the present invention relates to compounds of formula (I):

wherein
X is C or N ;
R1 is hydrogen or lower alkyl;
R2 is lower alkyl or -(CH2)n-R2a;
R2a is cycloalkyl, optionally mono-, di-> tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy; a 5-or 6-membered monovalent saturated heterocyclic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, oxo, fluorinated lower alkyl or fluorinated lower alkoxy; a 5- or 6-membered monovalent heteroaromatic ring containing one to four

heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino or cycloalkyl; or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
R3 is cycloalkyl, optionally mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy; or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
R4 is a 5- or 6-membered monovalent heteroaromatic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino; naphthyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro; or phenyl which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, nitro, halogenated lower alkyl, halogenated lower alkoxy, cyano, lower alkylsulfonyl or -NR7R8; or two adjacent substituents of the said phenyl residue together are -0-(CH2)P-0 or -(CH2)2-C(0)NH-;
R5 and R6 are each independently hydrogen, lower alkyl, halogen or fluorinated methyl;
R7 and R8 are each independently hydrogen or lower alkyl; or R7 and R8 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or aromatic heterocyclic ring optionally containing one or two further heteroatoms independently selected from nitrogen, oxygen and sulfur, said saturated or aromatic heterocyclic ring being optionally substituted by hydroxy, lower alkyl, lower alkoxy, halogen, amino or lower alkylamino;
m is 1 or 2;
nisOor 1;
p is 1, 2 or 3;

and pharmaceutical^ acceptable salts thereof.
Two different subtypes of cannabinoid receptors (CBi amd CB2) have been isolated and both belong to G protein coupled receptor superfamily. An alternative spliced form of CBi, CBIA, has also been described, but it did not exhibit different properties in terms of ligand binding and receptor activation than CBi (D.Shire, C. Carrillon, M. Kaghad, B. Calandra, M. Rinaldi-Carmona, G. Le Fur, D. Caput, P. Ferrara, J. Biol. Chem. 270 (8) (1995) 3726-31). The CBi receptor is mainly located in the brain, whereas the CB2 receptor is predominately distributed in the peripheric primarily localized in spleen and cells of the immune system (S. Munro, K.L. Thomas, M. Abu-Shaar, Nature 365 (1993) 61-61). Therefore in order to avoid side effects a CBi-selective compound is desirable.
A9-tetrahydrocannabinol (A9-THC) is the principal psychoactive compound in the Indian hemp (Y. Gaoni, R. Mechoulam, J. Am. Chem. Soc, 86 (1964) 1646), canabis savita (marijuanan), which is used in medicine since ages (R. Mechoulam (Ed.) in "Cannabinoids
as therapeutic Agents"y 1986, pp. 1-20, CRC Press). A9-THC is a non-selective CBi/2
receptor agonist and is available in the USA as dronabinol (marinol®) for the alleviation of cancer chemotherapy-induced emesis (CIE) and the reversal of body weight loss experienced by AIDS patients through appetite stimulation. In the UK Nabolinone (LY-
109514, Cesamet®), a synthetic analogue of A9-THC, is used for CIE (R. G. Pertwee, Pharmaceut. Sci. 3 (11) (1997) 539-545, E. M. Williamson, F. J. Evans, Drugs 60 (6) (2000) 1303-1314).
Anandamide (arachidonylethanolamide) was identified as the endogenous ligand (agonist) for CBi (R.G. Pertwee, Curr. Med. Chem., 6 (8) (1999) 635-664;W,A. Devane, L. Hanus, A. Breuer, R.G. Pertwee, L.A. Stevenson, G. Griffin, D. Gibson, A. Mandelbaum, A. Etinger, R. Mechoulam, Science 258 (1992) 1946-9). Anandamide and 2-arachidonoylglycerol (2-AG) modulate at the presynaptic nerve teminal negatively adenylate cyclase and voltage-sensitive Ca channels and activates the inwardly rectifying K+ channel (V. Di Marzo, D. Melck, T. Bisogno, L. De Petrocellis, Trends in Neuroscience 21 (12) (1998) 521-8), thereby affecting neurotransmitter release and/or action, which decreases the release of neurotransmitter (A. C. Porter, C.C. Felder, Pharmacol. Ther., 90 (1) (2001) 45-60).

Anandamide as A9-THC also increases feeding through CBi receptor-mediated mechanism, CBi selective antagonists block the increase in feeding associated with administration of anandamide (CM. Williams, T.C. Kirkham, Psychopharmacology 143 (3) (1999) 315-317; C. C. Felder, E. M. Briley, J. Axelrod, J. T. Simpson, K. Mackie, W. A. Devane, Proc. Natl. Acad. ScL U. S. A. 90 (16) (1993) 7656-60) and caused appetite suppression and weight loss (G. Colombo, R. Agabio, G. Diaz, C. Lobina, R. Reali, G. L. Gessa, Life Sci. 63 (8) (1998) L113-PL117).
Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance. Following temporary food restriction, CBI receptor knockout mice eat less than their wild-type littermates, and the CBI antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signaling is associatedd with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CBI receptors to maintain food intake and form part of the neural circuitry regulated by leptin (V. Di Marzo, S. K. Goparaju, L. Wang, J. Liu, S. Bitkai, Z. Jarai, F. Fezza, G. I. Miura, R. D. Palmiter, T. Sugiura, G. Kunos, Nature 410 (6830) 822-825).
SR-141716A, a CBI selective antagonist / inverse agonist is undergoing currently phase III clinical trials for the treatment of obesity. In a double blind placebo-controlled study, at the doses of 5,10 and 20 mg daily, SR 141716 significantly reduced body weight when compared to placebo (F. Barth, M. Rinaldi-Carmona, M. Arnone, H. Heshmati, G. Le Fur, "Cannabinoid antagonists: From research tools to potential new drugs" Abstracts of Papers, 222nd ACS National Meeting, Chicago, IL, United States, August 26-30,2001).
Other compounds which have been proposed as CBI receptor antagonists respectively inverse agonists are aminoalkylindols (AAI; M. Pacheco, S. R. Childers, R. Arnold, F. Casiano, S. J. Ward, J. Pharmacol. Exp. Ther. 257 (1) (1991) 170-183), like 6-bromo- (WIN54661; F. M. Casiano, R. Arnold, D, Haycock, J. Kuster, S. J. Ward, NIDA Res. Monogr. 105 (1991) 295-6) or 6-iodopravadoline (AM630, K. Hosohata, R. M. Quock, R.M; Hosohata, T. H. Burkey, A. Makriyannis, P. Consroe, W. R. Roeske, H. I. Yamamura, Life Sci. 61 (1997) 115 -118; R. Pertwee, G. Griffin, S. Fernando, X. Li, A. Hill, A. Makriyannis, Life Sci. 56 (23-24) (1995) 1949-55). Arylbenzo[b]thiophene and benzo[b]furan (LY320135, C. C. Felder, K. E. Joyce, E. M. Briley, M. Glass, K. P. Mackie,

K. J. Fahey, G. J. Cullinan, D. G Hunden, D. W. Johnson, M. O. Chaney, G. A. Koppel, M. Brownstein, J. Pharmacol. Exp. Ther. 284 (1) (1998) 291-7) disclosed in WO9602248, US5596106, 3-aIkyl-(5,5-diphenyl)imidazolidinediones (M. Kanyonyo, S. J. Govaerts, E. Hermans, J. H, Poupaert, D. M. Lambert, Bioorg. Med. Chem. Lett. 9 (15) (1999) 2233 -2236.) as well as 3-alkyl-5-arylimidazolidinediones (F. Ooms, J. Wouters, O. Oscaro. T. Happaerts, G. Bouchard, P.-A. Carrupt, B. Testa, D. M. Lambert, J. Med. Chem. 45 (9) (2002) 1748-1756) are known to antagonize the CBi receptor respectively act as an inverse agonist on the hCBj receptor. WO0015609 (FR2783246-A1), WO0164634 (FR2805817-Al), WO0228346, WO0164632 (FR2805818-A1), WO0164633 (FR2805810-A1) disclosed substituted l-bis(aryl)methyl-azetidines derivatives as antagonists of CBi. In WO0170700 4,5-dihydro-lH-pyrazole derivatives are described as CBi antagonists. In several patents bridged and non-bridgedl,5-diphenyl-3-pyrazolecarboxamide derivatives are disclosed as CBi antagonists/inverse agonists (WO0132663, WO0046209, WO9719063, EP658546, EP656354, US5624941, EP576357, US3940418).
It is an object of this invention to provide selective, directly acting CBI receptor antagonists respectively inverse agonists. Such antagonists / inverse antagonists are useful in medical therapy, particularly in the treatment and/or prevention of diseases which are associated with the modulation of CBI receptors.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term "lower" is used to mean a group consisting of one to eight, preferably of one to four carbon atom(s).
The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably to chlorine and fluorine.
The term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.

The term "lower alkyP, alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to eight carbon atoms, preferably one to four carbon atoms. This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like.
The term "alkoxy" refers to the group R'-O-, wherein R' is alkyl. The term "lower alkoxy" refers to the group R'-O-, wherein R5 is lower alkyl. Examples of lower alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy being especially preferred.
The term "lower alkylamino" refers to the group R'-NH-, wherein R' is lower alkyl.
The term "lower alkylsulfonyl" refers to the group R'-S(0)2-, wherein R' is lower alkyl.
The term "halogenated lower alkyl" refers to a lower alkyl group wherein at least one of the hydrogens of the lower alkyl group is replaced by a halogen atom, preferably fluoro or chloro. Among the preferred halogenated lower alkyl groups are trifluoromethyl, difluoromethyl, fluoromethyl and chloromethyl, with trifluoromethyl being especially preferred. The term "fluorinated lower alkyl" refers to a lower alkyl group wherein at least one of the hydrogens of the lower alkyl group is replaced by fluoro. Among the preferred fluorinated lower alkyl groups are trifluoromethyl, difluoromethyl and fluoromethyl, with trifluoromethyl being especially preferred.
The term "halogenated lower alkoxy" refers to a lower alkoxy group wherein at least one of the hydrogens of the lower alkoxy group is replaced by halogen, preferably by fluorine or chlorine. Among the preferred halogenated lower alkoxy groups are fluorinated lower alkoxy groups such as trifluoromethoxy, difluoromethoxy and fluoromethoxy, with trifluoromethoxy being especially preferred. The term "fluorinated lower alkoxy" refers to a lower alkoxy group wherein at least one of the hydrogens of the lower alkoxy group is replaced by fluoro. Among the preferred fluorinated lower alkoxy groups are trifluoromethoxy, difluoromethoxy and fluoromethoxy, with trifluoromethoxy being especially preferred.
The term "cycloalkyl" refers to a monovalent carbocyclic radical of three to six, preferably three to five carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "pharmaceutical^ acceptable salts" embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, salicylic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. Preferred salts with acids are formates, maleates, citrates, hydrochlorides, hydrobromides and methanesulfonic acid salts, with hydrochlorides being especially preferred.
In one embodiment, the present invention relates to a compound of formula (I) as defined above, wherein Rl is hydrogen or lower alkyl.
Preferable lower alkyl residues R1 are methyl and ethyl, with methyl being especially preferred. Most preferably, R1 is hydrogen.
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R2 is lower alkyl or -(CH2)n-R2a.
Preferable lower alkyl residues R are branched or straight chain alkyl residues with one to eight, preferably three to five carbon atoms, such as n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, n-pentyl and 2-ethylhexyl. Most preferred lower alkyl residues R2 are n-propyl, n-butyl, s-butyl, isobutyl and n-pentyl, with n-butyl being especially preferred. Preferable residues -(CH2)n-R2a are those wherein n is 0 and R2a is as defined below.
In one embodiment, R2a is cycloalkyl, optionally mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy; a 5- or 6-membered monovalent saturated heterocyclic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally mono-, di- or tri-substituted, independendy, by hydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, oxo, fluorinated lower alkyl or fluorinated lower alkoxy; a 5-or 6-membered monovalent heteroaromatic ring containing one to four heteroatoms independendy selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino or cycloalkyl; or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro.

Preferable cycloalkyl residues R2a are cycloalkyl residues with three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, which may optionally be mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy, preferably by lower alkyl, such as methyl, and/or hydroxy. Most preferable unsubstituted cycloalkyl residues R2a are unsubstituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with cyclohexyl being especially preferred. Most preferable substituted cycloalkyl residues R2* are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with 2-hydroxy-cyclohexyl being especially preferred. Preferable heterocyclic rings R2a are 5- or 6-memberd, with 5-membered being especially preferred, and contain one to three, preferably one or two, heteroatoms independently selected from nitrogen, oxygen and sulfur, preferably selected form nitrogen and oxygen, said heterocyclic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, oxo, fluorinated lower alkyl or fluorinated lower alkoxy. Examples of heterocyclic rings R2* are tetrahydrofuranyl, piperidinyl and isoxazolyl, optionally substituted as defined above. Preferably, heterocyclic rings R2* are unsubstituted or substituted by lower alkyl, such as methyl, or by oxo. Most preferred heterocyclic rings R2* are tetrahydrofuranyl, 2,2-dimethyl-tetrahydrofuranyl, piperidinyl and isoxazolidinone. Preferable heteroaromatic rings R2a are 5- or 6-membered and contain one to four, preferably one, two or four, heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino or cycloalkyl. Examples of heteroaromatic rings R2a are thienyl, furyl, tetrazolyl, imidazolyl and pyrazolyl, optionally substituted as defined above. Preferably, heteroaromatic rings R2a are unsubstituted or mono-substituted by lower alkyl, such as methyl, or by cycloalkyl, such as cyclopropyl. Most preferable heteroaromatic rings R2a are thienyl, furyl, 2-methyl-fiiryl, tetrazolyl, imidazolyl and 3-cyclopropyl-pyrazolyl. Preferable phenyl residues R2a are optionally mono-, di- or tri-substituted, preferably mono- or di-substituted, independently, by lower alkoxy, such as methoxy, halogen, such as chloro, halogenated lower alkyl, such as trifluoromethyl, halogenated lower alkoxy, such as trifluoromethoxy, or nitro. Most preferable phenyl residues R2a are unsubstituted phenyl, 4-trifluoromethyl-phenyl, 4-chloro-phenyl,. 3,4-dichloro-phenyl, 3,4-dimethoxy-phenyl, 2-nitro-phenyl and 4-trifluoromethoxy-phenyl.
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R is cycloalkyl, optionally mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or

fluorinated lower alkoxy; or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro.
Preferable cycloalkyl residues R3 are cycloalkyl residues with three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, which may optionally be mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy, preferably by lower alkyl, such as methyl, and/or hydroxyl. Most preferable unsubstituted cycloalkyl residues R3 are unsubstituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with cyclohexyl being especially preferred. Most preferable substituted cycloalkyl residues R3 are substituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with substituted cyclohexyl being especially preferred. Preferable phenyl residues R3 are optionally mono-, di- or tri-substituted, preferably mono- or di-substituted, independently, by lower alkoxy, such as methoxy, halogen, such as chloro, halogenated lower alkyl, such as trifluoromethyl, halogenated lower alkoxy, such as trifluoromethoxy, or nitro. Most preferable phenyl residues R23 are unsubstituted phenyl, 4-trifluoromethyl-phenyl, 4-chloro-phenyl, 3,4-dichloro-phenyl, 3,4-dimethoxy-phenyl, 2-nitro-phenyl and 4-trifluoromethoxy-phenyl.
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R4 is a 5- or 6-membered monovalent heteroaromatic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino; naphthyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro; or phenyl which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, nitro, halogenated lower alkyl, halogenated lower alkoxy, cyano, lower alkylsulfonyl or -NR7R8; or two adjacent substituents of the said phenyl residue together are -0-(CH2)p-0- or -(CH2)2-C(0)NH-. Preferable heteroaromatic rings R4 are 5- or 6-membered, preferably 6-membered, and contain one to three, preferably one or two, heteroatoms independently selected from nitrogen, oxygen and sulfur, preferably nitrogen, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino or lower alkylamino. Examples of heteroaromatic rings R4 are pyridinyl, pyrimidinyl and pyrazinyl, preferably pyridinyl and pyrazinyl, optionally substituted as defined above. Preferably, heteroaromatic rings R4 are unsubstituted or

mono-substituted by lower alkyl, such as methyl and ethyl. Most preferable heteroaromatic rings R are pyridinyl, pyrazinyl, 4-methyl-pyridinyl, 3-methyl-pyrazinyl, 3-ethyl-pyrazinyl and 3,5-dimethyl-pyrazinyl. Preferably, naphthyl residues R4 are unsubstituted. Preferable phenyl residues R4 are optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, such as methyl and t-butyl, lower alkoxy, such as methoxy, halogen, such as chloro, fluoro and bromo, nitro, halogenated lower alkyl, such as trifluoromethyl, halogenated lower alkoxy, such as di- and trifluoromethoxy, cyano, lower alkylsulfonyl, such as methylsulfonyl, or by -NR7R8, wherein R7 and R8 are as defined below; or two adjacent substituents of the said phenyl residue together are -0-(CH2)p-0-or -(CH2)2-C(0)NH-, and p is 1,2 or 3, preferably 2 or 3.
Preferable -NR7R8 substituents of a phenyl residue R4 are those wherein R7 and R8 are each independently hydrogen or lower alkyl, such as methyl and ethyl. Preferably, both R7 and R8 are methyl or both R7 and R8 are ethyl. Further preferable -NR7R8 substituents of a phenyl residue R4 are those wherein R7 and R8 together with the nitrogen atom to which they are attached form a 5- or 6-membered, preferably 5-membered, saturated or aromatic, preferably saturated, heterocyclic ring optionally containing one or two, preferably one, further heteroatom(s) independently selected from nitrogen, oxygen and sulfur, preferably selected from nitrogen and oxygen, said saturated or aromatic heterocyclic ring being optionally mono- or di-substituted, preferably mono-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino or lower alkylamino, preferably by lower alkyl, such as methyl. Preferably, the said saturated or aromatic heterocyclic ring formed by R7 and R8 together with the nitrogen atom to which they are attached is unsubstituted and does not contain any fixrter heteroatom. Most preferable
"7 11
saturated or aromatic heterocyclic ring formed by R and R together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, imidazolyl, and morpholino, with pyrrolidinyl being especially preferred. Preferably, -NR7R8 substituents of a phenyl residue R4 are at the para-position. Most preferable phenyl residues R4 are mono- or di-substituted, independently, by halogen, such as chloro and fluoro, halogenated lower alkyl, such as trifluoromethyl, lower alkoxy, such as methoxy, or mono-substituted at the para-position by a residue -NR7R8, preferably by pyrrolidinyl.
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R5 and R6 are each independently hydrogen, lower alkyl, halogen or fluorinated methyl.

Preferable lower alkyl residues R5 and R6 are methyl and ethyl, with methyl being especially preferred. Preferable halogen residues R5 and R6 are fluoro and chloro, with chloro being especially preferred. Preferable residue R5 is lower alkyl, such as methyl. Preferable residues R6 are hydrogen and lower alkyl, such as methyl.
In one embodiment of the present invention X is C. In another embodiment of the present invention X is N.
The symbol m is 0 or 1; more preferably, m is 1.
The symbol n is 0 or 1; more preferably, n is 0.
The symbol p is 1, 2 or 3;more preferably, p is 2 or 3.
Preferred compounds of general formula (I) are the compounds of Examples 1 to 66 and 67 to 306 (see section Examples below) and pharmaceutically acceptable salts thereof. Especially preferred are the compounds selected from the group consisting of:
1 -Cyclohexylmethyl-5-(4-methoxy-phenyl)-2-methyl- lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5»(3-methoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-2-methyl-5-(4-trifluoromethyl-phenyl)-lH-pyrrole-3-carboxylic acid butylamide,
5-(4-Chloro-phenyl)-l-cyclohexylmethyI-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-2-methyl-5-p*tolyl-lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5-(2-methoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-5-(4-fluoro-phenyl)-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-5»(2,4-dimethoxy-phenyl)-2-methyl-lH"pyrrole-3--carboxylic acid butylamide,
5-(4-Bromo-phenyl)-l-cyclohexylmethyl-2-methyMH-pyrrole-3-carboxylicacid butylamide,

5-(3-Cyano-phenyl)-l-cyclohexylmet^^ butylamide,
l-Cydohexylmethyl-5-(2,4-dimethyl-pheny^ acid butylamide,
l-Cydohexylmethyl~5-(4-diflu^ carboxylic acid butylamide,
l-Cyclohexylmethyl-2"methyl-5-(4-pyrrolidin-l-yl-phenyl)-lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5»(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole«3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5«(3,4-difluoro-phenyl)-2«methyl-lH-pyrrole-3-carboxylicacid butylamide,
5-(3-Chloro-phenyl)-l-cyclohe^lmethyl-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-2-methyl-5-(4-trifluoromethoxy-phenyl)-lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5"(3,4-dimethoxy-phenyl)-2«methyl-lH-pyrrole«3-carboxylic acid butylamide,
5-(2-Chloro-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmetliyl-2-methyl-5-(4-nitro-phenyl)-lH-pyrrole-3-carboxylicacid butylamide,
l-Cydohexylmethyl-5-(2,5-dimethoxy"phenyl)-2--methyl-lH-pyrrole-3-carboxylic acid cyclohexylamide,
l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid cyclopentylamide,
l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid cyclobutylamide,
l-Cydohexylmethyl-5-(2,5-dime&^ acid cyclopropylamide,
l-Cyclohexylmethyl-5-(2,5-difluoro^ butylamide,

1-Cyclohexylmethyl-5^ carboxyiic acid butylamide,
l-Cyclohexjdmethyl-5-(3-fluoro-phenyl)-2-m butylamide,
5-Benzo[l»3]dioxol-5-yl-l-cyclohe^ butylamide,
l-Cyclohexylmethyl-5-(2,5-dicWoro-phenyl)^ acid butylamide,
5-(3,5-Bis-trifluoromethyl-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylic acid butylamide,
5-(3,5-Bis-1xifluoromethyl-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3^ carboxyiic acid cyclohexylamide,
l-Cyclohexylmethyl-2-methyl-5-(4-pyrrolidin-l-yl-phenyl)-'lH-pyrro]e-3-carboxyiic acid cyclohexylamide,
(R)-l-Cyclohexylmethyl"5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole»3-carboxylic acid sec-butylamide,
5-(3,5-Bis-trifluoromethyl-phenyl)-l-(4-methoxy-benzyl)-2-methyl-lH-pyrrole-3-carboxylic acid cyclohexylamide,
l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3--carboxylic acid piperidin-1-ylamide,
l-CyclohexylmethyI-2-methyl-5-pyridin-2-yl-lH-pyrrole-3-carboxyIicacid butylamide,
l-Cyclohexylmethyl-2-(2-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid butylamide,
l-Cyclohexylmethyl-2-(2-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid piperidin-1-ylamide,
and pharmaceutically acceptable salts thereof.
Additional particularly preferred compounds from examples 67 to 306 are
l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid cyclopropylmethyl-amide

1 -CyclohexyImethyl-5-(2,5-dimethoxy-phenyl)-2-methyl» lH-pyrrole-3-carboxylic acid (furan-2-ylmethyl)-amide
1-Cyclohexylmethyl-5-(2,^ acid(3-methyl~thiophen-2-ylmethyl)-amide
(S)-l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH"pyr^ carboxylic acid sec-butylamide
5-(5-Chloro-2-methoxy-4-methyl-phenyl)-l-cyclohexylmethyl-2-methyl-lH« pyrrole-3-carboxylic acid cyclohexylamide
5-(3,5-Bis-trifluoromethyl-phenyl)^ carboxylic acid piperidin-1-ylamide
l-Cyclohexylmethyl-5-(5-fluoro-2-methoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid piperidin-1-ylamide
5-(5-Chloro-2-methoxy-phenyl)-l"Cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylic acid piperidin-1-ylamide
5-(5-Chloro-2-methoxy-4-methyl-phenyl)-l-cyclohexylmethyl-2-methyl-l pyrrole-3-carboxylic acid piperidin-1-ylamide
5-(2-Chloro-5-trifluoromethyl-phenyl)-l-^ carboxylic acid ((lRS,2RS)-2-hydroxy-cyclohexyl)-amide
5-(2-Chloro-5-trifluoromethyl-phenylH^ carboxylic acid ((lR,2R)-2-hydroxy-cyclohexyl)-amide
5-(2,5-Bis-trifluoromethyl-phenyI)-l-^^ carboxylic acid piperidin-1-ylamide
5-(2-Chloro-5-txifluoromethyl-phenyl)-l^ carboxylic acid piperidin-1-ylamide
5-(2-Fluoro-5-trifluoromethyl-phenyl)-H^ 2-methyl-lH-pyrrole-3-carboxylic acid cyclohexylamide
5-(2-Fluoro-5-trifluoromethyl-phenyl)»l-((lRS,2RS)-2-hydroxy-cyclohexylmethyl)--2-methyl-lH-pyrrole-3-carboxylic acid cyclohexylamide
5-(2-Fluoro-5"trifluoromethyl»phenyl)"l-(lRS>2RS)-2-hydroxy»cyclohexylmethyl)-2-methyl-lH-pyrrole-3-carboxylic acid ((lR,2R)-2-hydroxy-cyclohexyl)-amide
5-(2>5-Bis-trifluoromethyl-phenyl)-l-(2-cyclopropyl-ethyl)-2-methyl-rH-pyrrole»3-carboxylic acid ((lR>2R)-2«hydroxy-cyclohexyl)-amide

5-(2-Chloro-5-trifluoromethyl-phenyl)-l-((lRS,2RS)-2»hydroxy-cyclohexylmethyl)-2-methyl-lH-pyrrole-3-carboxylic acid cyclohexylamide
l-CyclohexylmethyI-2-methyl-5-(2-methyI-5^^ 3-carboxylic acid ((lR,2R)-2-hydroxy-cyclohexyl)-amide
and pharmaceutically acceptable salts thereof.
The present invention also relates to a process for the manufacture of compounds of formula (I) as defined above. The compounds of formula (I) can be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below or in the Examples or by methods known in the art.
The compounds of formula (I) maybe prepared using the general methods described below:
Compounds of formula (I), wherein R1 to R6 and m are as previously defined and X = C, can be prepared by reaction of enamines of formula A with alfa-bromoketones of formula B according to methods known in the art (Scheme 1). For example, the reaction can be performed in an inert solvent, such as DMF, in the presence of a hindered base, such as 2,6-di-tert-butylpyridine or 2,6-lutidine.
Scheme 1

Enamines of formula A can be prepared from beta-ketoamides of formula C and amines of formula D by methods known in the art (Scheme 2). For example a beta-keto amide of formula C can be reacted with an amine of formula D in a suitable inert solvent (e.g. DMF) in the presence of a hindered base (e.g. 2,6-di-tert-butylpyridine) to yield enamine of formula A.
Scheme 2




Compounds of formula H can be obtained by hydrolysis of compounds of formula K by methods known in the art (Scheme 6). For example, the reaction can proceed in a polar solvent (e.g. ethanol) in the presence of a base (e.g. sodium hydroxide).







Scheme 12

The invention further relates to compounds of formula (I) as defined above, when manufactured according to a process as defined above.
Some compounds of formula (I) may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres as well as mixtures, including racemic mixtures, thereof. Such isomers maybe prepared by asymmetric synthesis, for example using chiral intermediate, or mixtures maybe resolved by conventional mehtods, eg., chromatography (chromatography with a chiral adsorbens or eluent), or use of a solving agent.
It will be appreciated, that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
As described above, the compounds of formula (I) or pharmaceutical^ acceptable salts thereof can be used as medicaments for the treatment and/or prophylaxis of diseases which are associated with the modulation of the CB1 receptors.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutical^ acceptable carrier and/or adjuvant.
Further, the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with the modulation of CBl receptors.

In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with the modulation of CB1 receptors, which method comprises administering a compound as defined above to a human being or animal.
The invention further relates to the use of compounds as defined above for the treatment and/or prophylaxis of diseases which are associated with the modulation of CB1 receptors.
In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are associated with the modulation of CB1 receptors. Such medicaments comprise a compound as defined above.
In this context, the expression 'diseases associated with modulation of CB1 receptors' means diseases which can be treated and/or prevented by modulation of CB1 receptors. Such diseases encompass, but are not limited to, psychic disorders, especially anxiety, psychosis, schizophrenia, depression, abuse of psychotropes, for example for the abuse and/or dependence of a substances, including alcohole dependency and nicotine dependency, neuropathies, migraine, stress, epilepsy, dyskinesias, Parkinson's disease, amnesia, cognitive disorders, senile dementia, Alzheimer's disease, eating disorders, obesity, diabetes type II or non insulin dependent diabetes (NIDD), gastrointestinal diseases, vomiting, diarrhea, urinary disorders, cardiovascular disorders, infertility disorders, inflammations, infections, cancer, neuroinflammation, in particular in atherosclerosis, or the Guillain-Barr^ syndrome, viral encephalitis, cerebral vascular incidents and cranial trauma.
In a preferable aspect, the expression 'diseases associated with modulation of CB1 receptors' relates to eating disorders, obesity, diabetes type II or non insulin dependent diabetes (NIDD), neuroinflammation, diarrhea, abuse and/or dependence of a substances, including alcohole dependency and nicotine dependency. In a more preferable aspect, the said term related to eating disorders, obesity, diabetes type II or non insulin dependent diabetes (NIDD), abuse and/or dependence of a substances, including alcohole dependency and nicotine dependency, with obesity being especially preferred.
It is a further preferred object to provide a method of treatment or prevention of Type II diabetes (non-insulin dependent diabetes mellitus (NIDDM) in a human which comprises administration of a therapeutically effective amount of a compound according

to formula (I) in combination or association with a therapeutically effective amount of a lipase inhibitor, particularly, wherein the lipase inhibitor is orlistat. Also an object of the invention is the method as described above for the simultaneous, separate or sequential administration of a compound according to formula (I) and a lipase inhibitor, particularly tetrahydrolipstatin.
It is a further preferred object to provide a method for the treatment or prevention of obesity and obesity related disorders which comprises administration of a therapeutically effective amount of a compound according to formula (I) in combination or association with a therapeutically effective amount of other drugs for the treatment of obesity or eating disorders so that together they give effective relief. Suitable other drugs include but are not limited to anorectic agents, lipase inhibitors and selective serotonin reuptake inhibitors (SSRI). Combinations or associations of the above agents may be encompassing separate, sequential or simultaneous administration.
Preferable lipase inhibitor is tetrahydrolipstatin.
Suitable anorectic agents of use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine, and pharmaceutical^ acceptable salts thereof.
Most preferable anorectic agents are sibutramine and phentermine.
Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutical^ acceptable salts thereof.
Demonstration of additional biological activities of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of obesity-related disorders such as diabetes, Syndrome X, or atherosclerotic disease and related disorders such as hypertriglyceridemia and hypercholesteremia, the following assays may be used.

Method for Measuring Blood Glucose Levels
db/db mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (by either eye or tail vein) and grouped according to equivalent mean blood glucose levels. They are dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test compound once daily for 7 to 14 days. At this point, the animals are bled again by eye or tail vein and blood glucose levels are determined.

Method for Measuring Triglyceride Levels
hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (by either eye or tail vein) and grouped according to equivalent mean serum triglyceride levels. They are dosed orally (by gavage in a pharmaceutical^ acceptable vehicle) with the test compound once daily for 7 to 14 days. The animals are then bled again by eye or tail vein, and serum triglyceride levels are determined.
Method for Measuring HDL-Cholesterol Levels
To determine plasma HDL-cholesterol levels, hApoAl mice are bled and grouped with equivalent mean plasma HDL-cholesterol levels. The mice are orally dosed once daily with vehicle or test compound for 7 to 14 days, and then bled on the following day. Plasma is analyzed for HDL-cholesterol.
In addition, to demonstrate CNS activities of the compounds of the present invention, the following in vivo assays maybe used.
Method for Testing Task Learning and Spatial Memory
The Morris Water Maze is routinely used to assess task learning and spatial memory (Jaspers et aL, Neurosci. Lett 117:149-153,1990; Morris, J. Neurosci. Methods 11:47-60, 1984). In this assay, animals are placed in a water pool which is divided into quadrants. One platform is hidden in one of the quadrants. The animal is placed in the water pool and is expected to locate the hidden platform within a predetermined time. During a number of training trials, the animal learns the location of the platform and escape from the pool. The animal receives multiple trials in this task. Total distance traveled, number of trials to locate platform, latency to find platform, and the swimming path is recorded for each animal. The animal's learning ability is measured by the length of time or number of trials required to find the hidden platform. Memory deficit or improvement is determined by the number of trials or the latency to find the platform at predetermined delay time after acquisition. Leaning and memory may be measured by the number of times that the animal crosses the quadrant where the platform was located during the acquisition phase.
Method for Testing Drug Dependence
Self-administration in animals is a predictor of a compound's abuse potential in humans. Modifications to this procedure may also be used to identify compounds that prevent or block the reinforcing properties of drugs that have abuse potential. A compound that

extinguishes the self-administration of a drug may prevent that drug's abuse or its dependence. (Ranaldi et aL, Psychopharmacol. 161:442-448,2002; Campbell et al., Exp. Clin. Psychopharmacol. 8:312-25,2000). In a self-administration test, animals are placed in the operant chambers containing both an active and inactive lever. Each response on the active lever produces an infusion of either the test compound or a drug known to be self-administered. Presses on the inactive lever have no effect, but are also recorded. Animals are then trained to self-administer compound/drug over a set period of time by having drug access during each daily session. Illumination of the chamber house light signals the beginning of the session and the availability of the compound/drug. When the session ends, the house light is turned off. Initially, a drug infusion occurs with every press of the active lever. Once lever-pressing behavior has been established, the number of presses to produce a drug infusion is increased. After stable compound/drug self-administration is obtained, the effect of a second compound on the drug-reinforced behavior maybe evaluated. Administration of this second compound prior to the session can either potentiate, extinguish, or produce no change to the self-administrating behavior.
The following tests were carried out in order to determine the activity of the compounds of formula (I).
The affinity of the compounds of the invention for cannabinoid CB1 receptors was determined using membrane preparations of human embryonic kidney (HEK) cells in which the human cannabis CB1 receptor is transiently transfected using the Semliki Forest Virus system in conjunction with [3H]-CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.
The affinity of the compounds of the invention for cannabinoid CB2 receptors was determined using membrane preparations of human embryonic kidney (HEK) cells in which the human cannabis CB2 receptor is transiently transfected using the Semliki Forest virus system in conjunction with [3H]-CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.

The cannabinoid CB1 antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB1 receptors are stably expressed (see M. Rinaldi-Carmona et. aL, J. Pharmacol Exp. Ther. 278 (1996) 871). The stable expression of the human cannabinoid receptor in cell systems was first described in Nature 1990,346,561-564 (CBl) and Nature 1993,365,61-65 (CB2) respectively. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CBl receptors by CBl receptor agonists (e.g. CP-55>940 or (R)-WIN-55212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration dependent manner. This CBl receptor mediated response can be antagonised by CBl receptor antagonists such as the compounds of the invention.
The compounds of formula (I) show an excellent affinity for the CBl receptor, determined with the experimental conditions described in Devane etal. Mol. Pharmacol. 34 (1988) 605-613. The compounds of the present invention or their pharmaceutical^ acceptable salts are antagonists and selective for the CBl receptor with affinites below IC50
= 2 nM, preferably 1 nM to 100 nM. They exhibit at least a 10 fold selectivity against the CB2 receptor.



All measurements were made between 12:00 am and 5:00 pm. Mice were brought in this environment and habituated for at least two hours before the start of the experiment. They had always free access to food and water. For each dose, 8 mice were used. Rectal body temperature measurements were recorded by mean of a rectal probe (RET2 of Physitemp) and digital thermometer (Digi-sense n°8528-20 of Cole Parmer, Chicago USA). The probe was inserted about 3.5 cm in each mouse.
The body temperature was taken 15 min before administration of either Vehicle or CB1 receptor antagonist/inverse agonist. 30 or 90 min after Lp. or p.o. administration of this compound, respectively, rectal body temperature was recorded in order to evaluate any influence of the compound itself. The CB receptor agonist CP 55,940 (0.3 mg/kg) was immediately administered intravenously, then 20 min after i.v. administration of CP 55940, body temperature was again measured.
The in vivo activity of compounds of formula (1) was assessed for their ability to regulate feeding behaviour by recording food consumption in food deprived animals.
Rats were trained to have access to food for 2h per day and were food deprived for 22h. When they were trained under this schedule, the amount of food taken every day during these 2h food intake session Avas consistent day after day.
To test the ability of compounds of formula (1) to decrease food intake, 8 animals were used in a cross-over study. Rats were individually housed in Plexiglas boxes with a grid on the floor and a paper was placed below the cage floor to collect any spillage. A food dispenser (becher) filled with a pre-weighed amount of food was presented to them for 2h. At the end of the food intake session, rats returned to their home cage. Each rat was weighed before the start of the experiment and the amount of food consumed during this 2h food intake session was recorded. Either various doses of test compound or vehicle was administered orally 60 min before the 2h food intake session. A positive control Rimonabant (SR141716) was included in the experiment. An Anova analysis with repeated measures was used followed by a posthoc test Student Neumann-Keuls. * P Furthermore the utility of compounds of formula (1) in diseases or disorders maybe demonstrated in animal disease models that have been reported in the literature. The following are examples of such animal disease models: a) reduction of sweet food intake in marmosets (Behavioural Pharm, 1998, 9,179-181); b) reduction of sucrose and ethanol intake in mice (Psychopharm. 1997, 132, 104-106); c) increased motor activity and place conditioning in rats (Psychopharm. 1998, 135, 324-332; Psychopharmacol 2000, 151: 25-

30); d) spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996,277,586-594); e) reduction in opiate self-administration in mice (Sci. 1999,283,401-404).
The compounds of formula (I) and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, drag^es, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula (I) and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeuticaUy compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer

substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 1-100 mg, of a compound of formula (I).
The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.
Examples
MS = mass spectrometry; ISP = ion spray (positive ion), corresponds to ESI (electrospray, positive ion); mp = melting point; TBTU = O-CBenzotriazol-l-y^-N^'jN'-tetramethyl-uronium-tetrafluoroborate; DMF = dimethylformamide.
Example 1 l-Cyclohexylmethyl"5-phenyl-2-methyl-lH-pyrrole-3-carboxylicacidbutylamide


To a solution of 4.2 g of diketene in dichloromethane (70 ml) cooled at 0°C was added over 1 hour a solution of 3.7 g of butylamine in 50 ml of dichloromethane. The reaction mixture was then stirred for one hour at 0°C and was then allowed to stir at room temperature for another hour. The reaction mixture was concentrated in vacuo and the crude residue was partitioned in batches which were directly used in the next step.
To 2.0 g of the previous crude material in 55 ml of dimethylformamide was added 1.65 ml of cyclohexylmethylamine together with 1.4 ml of trimethyl orthoformate and the reaction mixture was stirred for 24 hours at room temperature.
3.4 ml of the previous solution was then transferred into another reaction vessel and 120 mg of 2-bromo-phenyl-ethanone was added together with 0.092 ml of 2,6-lutidine and the reaction mixture was stirred for another 24 hours at room temperature. After such time the reaction mixture was concentrated in vacuo and purified by column chromatography (50 g of SiC>2» n-Heptane - Ethyl acetate 0-80%) to yield 112 mg of the title compound as a light brown gum, MS (ISP) 353.4 (M-hH)+.
Examples 2-48 were synthesized in analogy to Example 1, using the indicated educts.
Example 2
l-Cyclohexylmethyl-5-(3,4-dichloro-phenyl)»2-methyl-lH-pyrrole-3-carboxylicacid
butylamide

The title compound was obtained using butylamine as R R NH, aminoethylcyclohexane as R3-(CH2)m-NH2 and 2-bromo-3',4'-dichloroacetophenone> MS (ISP) 421.4(M+H)+.
Example 3
l-Cyclohexylmethyl-5-(4-methoxy-phenyl)-2-methyl-lH-pyrrole-3--carboxylicacid
butylamide



































1-Cyclohexylmethyl^

The title compound was obtained using butylamine as RlR2NH, aminomethylcyclohexane as R3-(CH2)m-NH2 and 2-(bromoacetyl)pyridine, MS (ISP) 354.3(M+H)+.
Example 49
l-Cyclohexylmethyl-2-(2-chloro-phenyl)-5-methyl-lH-imidazole-4-carboxylicacid
butylamide
Preparation of 2-(2-ChIoro-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid ethyl ester:
To a solution of 8.5 g of ethyl 2-oximinoacetoacetate in acetonitrile (100 ml) was added 7.5 ml of 2-chlorobenzylamine. The reaction mixture was then refluxed for 4 hours under argon atmosphere. After such time the reaction mixture was then concentrated in vacuo and the residue was triturated with warm ethylacetate for 10 minutes. After allowing to cool down to room temperature the solid was filtered and dried in vacuo to yield 11.3 g of a white powder, MS (ISP) 265.1 (M+H)+.
Preparation of 2-(2-Chloro-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid:
To 11.2 g of 2-(2-chloro-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid ethyl ester in 150 ml of ethanol was added 80 ml of a 2N-NaOH solution and the reaction mixture was stirred at 95° C for 17 hours. After such time ethanol was removed in vacuo and the remaining aqueous solution was treated with a 2N HC1 solution until obtaining pH=3. The precipitate was filtered and dried under high vacuum to yield 9.0 g of a pale yellow powder.
Preparation of 2-(2-Chloro-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid piperidin-1-ylamide:
To 1 g of 2-(2-chloro-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid in 10 ml of DMF was added 1.36 g of TBTU and 3.6 ml of Hiinigs5 base and the reaction mixture was stirred for 1 minute. Then 0.46 ml of 1-aminopiperidin was added and the reaction mixture was stirred for 1.5 hour at room temperature. After such time the reaction mixture was poured

onto 200 ml of water and extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were then washed with water (2 x 100 ml) and brine (50 ml), dried (MgS04) and concentrated in vacuo to yield an oil which crystallized on standing. The residue was then triturated with heptane, the solid was filtered and dried to yield 1.12 g of the title compound, MS (ISP) 319.0 (M+H)+.
Preparation of l-Cyclohexylmethyl-2-(2-chloro-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid butylamide
To a suspension of 90 mg of 2-(2-chloro«phenyl)-5-methyl-lH-imidazole-4-carboxylic acid piperidin-1-ylamide in 4 ml of acetonitrile was added 35 mg of potassium tert-butylate and the reaction mixture was stirred at room temperature for 2 minutes. After such time, 0.04 ml of (bromomethyl)cyclohexane was added and the reaction mixture was stirred at 80°C for 28 hours under argon atmosphere. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiC>2> Heptane/EtOAC: 1/1) to give 64 mg of the title compound as a pale yellow solid, MS (ISP) 415.3 (M+H)+.
Examples 50-66 were synthesized in analogy to example 49, using the indicated educts.
Example 50
l"(4-Chloro-benzyl)-2-(4-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylicacid
butylamide

The title compound was obtained using 4-Methoxy benzylamine as R4-CH2-NH2, Butylamine as RlR2NH and 4-Chlorobenzyl chloride as R3-(CH2)m-Br, MS (ISP) 412.3(M+H)+.
Example 51

l-Cyclohexylmethyl-2-^
butylamide

The title compound was obtained using 4-Methoxy benzylamine as R4-CH2-NH2> Butylamine as RXR2NH and (Bromomethyl) cyclohexane as R3-(CH2)m-Br, MS (ISP) 384.3(M+H)+.
Example 52
l-Cyclohexylmetiiyl-2-(2-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylicacid
butylamide

The title compound was obtained using 2-Methoxy benzylamine as R4-CH2-NH2, Butylamine as R*R2NH and (Bromomethyl) cyclohexane as R3-(CH2)m-Br, MS (ISP) 384.3(M+H)+.
Example 53
l-(4-Chloro-benzyl)-2-(2-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylicacid
butylamide


The title compound was obtained using 2-Methoxy benzylamine as R4-CH2-NH2, Butylamine as R*R2NH and 4-Chlorobenzyl chloride as R3-(CH2)m-Br, MS (ISP) 412.3(M+H)+.
Example 54
l-Cyclohexylmethyl-2-(2-methoxy-phenyl)-5^methyl-lH-imidazole-4-carboxylicacid
piperidin-1 -ylamide

The title compound was obtained using 2-Methoxy benzylamine as R4-CH2-NH2>1-Aminopiperidine as RJR2NH and (Bromomethyl) cyclohexane as R3-(CH2)m-Br, MS (ISP) 411.4(M+H)+.
Example 55
l-Cyclopropylmethyl-2-(2-methoxy-phenyl)-5-methyl-lH-imidazole"4-carboxylicacid
butylamide

The title compound was obtained using 2-Methoxy benzylamine as R4-CH2-NH2, Butylamine as R1R2NH and Bromomethyl cyclopropane as R3-(CH2)m-Br, MS (ISP) 342.2(M+H)+.
Example 56
l-(3-Chloro-benzyl)-2-(2-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylicacid
piperidin-1 -ylamide


The title compound was obtained using 2-Methoxy benzylamine as R4-CH2-NH2> 1-Aminopiperidine as R!R2NH and 3-Chlorobenzylchloride as R3-(CH2)m-Br, MS (ISP) 439.2(M+H)+.
Example 57
l-(2-Cyclohexyl-ethyl)-2-(2-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylicacid
piperidin-1 -ylamide

The title compound was obtained using 2-Methoxy benzylamine as R4-CH2-NH2, 1-Aminopiperidine as R!R2NH and (Bromoethyl) cyclohexane as R3"(CH2)m-Br> MS (ISP) 425.3(M+H)+.
Example 58
l-(2-Cyclohexyl-ethyl)"2-(2-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylicacid
butylamide

The title compound was obtained using 2-Methoxy benzylamine as R4-CH2-NH2> Butylamine as RlR2NH and (Bromoethyl) cyclohexane as R3-(CH2)m-Br, MS (ISP) 398.3(M+H)+.

Example 59
2-(2-CMoro-phenyl)-l-cyclohexylmethyl-5-meth^
butylamide

The title compound was obtained using 2-Chloro benzylamine as R4-CH2-NH2, Butylamine as RlR2NH and (Bromomethyl) cyclohexane as R3-(CH2)„rBr, MS (ISP) 388.2(M+H)+.
Example 60
2- (2-Chloro-phenyl)- l-cydopropylmethyl-5-methyl- lH-imidazole-4-carboxylic acid
butylamide

The title compound was obtained using 2-Chloro benzylamine as R4-CH2-NH2, Butylamine as R*R2NH and Bromomethyl cyclopropane as R3-(CH2)m-Br, MS (ISP) 346.1(M+H)+.
Example 61
2-(2-Chloro-phenyl)-l-cyclopropylmethyl-5-methyl-lH-imidazole-4-carboxylicacid
piperidin-1 -ylamide
A







Example 68
l-Cyclohexylmethyl-5-(2,5^
(3-hydroxy-propyl)-amide

Preparation of 2-[2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid methyl ester:
To a solution of 3 g of 3-oxo-butyric acid methyl ester in THF (60 ml) and 5.2 ml of a solution of sodium methoxide (5.4 M in methanol) was added over 15 minutes a solution of 7 g of 2-bromo-l-(2,5-dimethoxy-phenyl)-ethanone in 30 ml of THF. The reaction mixture was allowed to stir at room temperature for 16 hours, during which time a precipitation occurred. The reaction mixture was then diluted in diethyl ether and washed several times with water. The organic phase was then dried with sodium sulfate and concentrated in vacuo. The residue was then triturated with isopropyl ether and filtered to give 6.3 g of the title compound. MS (ISP) 295.1 (M+H)+.
Preparation of l-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2"methyI-lH-pyrroie-3-
carboxylic acid methyl ester
To a solution of 2 g of-[2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl]-3«oxo-butyric acid methyl ester in methanol was added 0.88 ml of cyclohexanemethylamine and 40 mg of p-toluene sulfonic acid. The reaction mixture was then heated at reflux for 2 days. After such time the reaction mixture was allowed to cool to room temperature before being concentrated in vacuo and purified by column chromatography to give 2.3 g of the title compound; MS (ISP) 372.2 (M+H)+.

Preparation of l-cyclohexylmethyl-5-(2,5^
carboxylic acid
To a solution of 2.3 g of l-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)--2-"methyl-lH-pyrrole-3-carboxylic acid methyl ester in dioxane (50 ml) and water (50 ml) was added 18.8 ml of a IN solution of sodium hydroxide. The reaction mixture was heated at reflux for 16 hours. After such time the reaction mixture was allowed to cool down to room temperature before being neutralized with 18.8 ml of a IN solution of hydrochloride acid. Dioxane was distilled off and the precipitate was then filtered and washed with water to give 2.1 g of the title compound; MS (ISP) 356.3 (M-H).
Preparation of l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2*methyl-lH-pyrrole-3-
carboxylic acid (3-hydroxy-propyl)-amide
The coupling reaction between l-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid and 3-amino-propan-l-ol was similar to the reaction exemplified in the synthesis of Example 49 to give l-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid (3-hydroxy-propyl)-amide; MS (ISP) 415.3 (M+H)+.
Example 69
l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-metiiyl-lH-pyrrole-3-carboxylicacid
cyclopropylmethyl-amide
25

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2,5-dimethoxy-phenyl)~ethanone as compound of formula S, c-cyclohexyl-methylamine as R3-(CH2)m-NH2 and c-cyclopropyl-methylamine as RlR2NH, MS (ISP) 411.4 (M+H)+.
Example 70
l-Cyclohexylmethyl-5-(2,5-dimethoxy"phenyl)-2-methyl-lH-pyrrole-3-carboxylicacid
morpholin-4-ylamide

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2,5-dimethoxy-phenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R3-(CH2)m-NH2 and morpholin-4-ylamine as RlR2NH, MS (ISP) 442.4 (M+H)+.
Example 71
l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylicacid
(furan-2-ylmethyl)-amide

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2,5-dimethoxy-phenyl)-ethanone as

compound of formula S, c-cyclohexyl-methylamine as R3-(CH2)m-NH2 and furan-2-yl-methylamine as RlR2NH, MS (ISP) 437.4 (M+H)+.
Example 72
l-Cyclohexylmethyl-5-(2,5-dimethoxy-pheny^
(3-methyl-thiophen-2-ylmethyl)-amide

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-Bromo-l-(2,5-dimethoxy-phenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R -(CH2)m-NH2 and C-(3-Methyl-thiophen-2-yl)-methylamine as RlR2NH, MS (ISP) 467.3 (M+H)+.
Example 73
l-Cyclohexylmethyl-5-(2,5-dimetiiox^
(1 -ethyl-pyrrolidin-2-ylmethyl)-amide

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2,5-dimethoxy-phenyl)-ethanone as

compound of formula S, c-cyclohexyl-methylarnine as R3-(CH2)m-NH2 and C-(l-ethyl-pyrrolidin-2-yl)-methylamine as R!R2NH, MS (ISP) 468.2 (M+H)+.
Example 74
l-Cyclohexylmeliiyl-5-(2,5-dimethoxy-phe
(3,3,3-trifluoro-propyl)-amide

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2,5-dimethoxy-phenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R3-(CH2)m-NH2 and 3,3,3-trifluoro-propylamine as R!R2NH, MS (ISP) 453.1 (M+H)+.
Example 75
(S)-l-Cyclohexylmethyl-5-(2,5-dimedioxy-phenyl)«2-methyl-lH-pyrrole-3-carboxylic
acid sec-butylamide


The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2,5-dimethoxy-phenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R3-(CH2)m-NH2 and (S)-sec-butylamine as R!R2NH, MS (ISP) 413.3 (M+H)+.
Example 76
2-(5-Chloro-2-methoxy-phenyl)-l-cyclohexylmethyl-5-methyl-lH-imidazole«4-
carboxylic acid butylamide

The title compound was synthesized in analogy to Example 49, using 2-methoxy-5-ch!oro benzylamine as R -CH2-NH2, butylamine as R R NH and (bromomethyl) cyclohexane as R3-(CH2)m-Br, MS (ISP) 418.2 (M+H)+.
Example 77
2-(5-Chloro-2-methoxy-phenyl)-l-(2-cyclohexyl«ethyl)-5-methyl-lH-imidazole-4-carboxylic acid butylamide
The title compound was synthesized in analogy to Example 49, using 2-methoxy-5-chloro benzylamine as R4-CH2-NH2, butylamine as R2R2NH and (bromoethyl) cyclohexane as R3-20 (CH2)m-Br, MS (ISP) 432.3 (M+H)+.























ExampIelQO
1-Cyclohexylmet^
(piperidin-4-ylmethyl)-amide, trifluoro-acetic acid salt

Preparation of 4-({[l-Cyclohexylmethyl-5-(2>5-dimethoxy-phenyl)-2-metJiyl-lH-pyrrole-3-carbonyl]-amino}-methyl)-piperidine-l-carboxylic acid tert-butyl ester.
4-({ [ l-Cyclohexylmethyl-5-(2,5-dim
amino}-methyl)-piperidine-l-carboxylic acid tert-butyl ester was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2,5-dimethoxy-phenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R -(CH2)m-NH2 and 4-Aminomethyl-piperidine-l-carboxylic acid tert-butyl ester as RlR2NH, MS (ISP) 554.5 (M+H)+.
Preparation of l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid (piperidin-4-ylmethyl)-amide) trifluoro-acetic acid salt
To 147 mg of 4-({[l-Cyclohexylmethyl-5-(2>5-dimethoxy-phenyl)-2«methyl-lH-pyrrole-3«carbonyl]-amino}-methyl)-piperidine«l-carboxylic acid tert-butyl ester in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml) and the reaction mixture was stirred for 45 minutes at room temperature. After such time, the reaction mixture was concentrated in vacuo to yield the title compound; MS (ISP) 454.3 (M+H)+.

Example 101
l-Cyclohexylmethyl-5-(2^
(2-methoxy-ethyl)-amide

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2,5-dimethoxy-phenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R3-(CH2)m-NH2 and 2-methoxy-ethylamine as R1R2NH> MS (ISP) 415.2 (M+H)+.
Example 102
2-(5-Chloro-2«methoxy-phenyl)-l-cyclohexylmethyl-5-methyl-lH-imidazole-4-carboxylic acid cyclohexylamide

The title compound was synthesized in analogy to Example 49, using 5-chloro-2-methoxy-
M I *7
benzylamine as R -CH2-NH2, cyclohexylamine as R R NH and (bromomethyl)cyclohexane as R3-(CH2)m-Br, MS (ISP) 445.5 (M+H)+.









































































Preparation of 5-(3,5-Bis-trifluoromethyl-phenyl)-l^
pyrrole-3-carboxylic acid cyclohexylamide
A solution of 59.5 |il (0.52 mmol) of cyclohexylamine in toluene (2 ml) was treated at RT dropwise with 0.26 |il of a 2 M solution of trimethylaluminum in toluene (0.52 mmol). The reaction solution was stirred 1 h at RT, 200 mg ( 0.43 mmol) of 5-(3,5-bis-trifluorometiiyl-phenyl)-l-cyclohexylmethyl-2,4-dimethyl-lH-pyrrole-3-carboxylicacid methyl ester in toluene (2 ml) were added and reaction mixture was heated at 110°C for 3 h. The mixture was then partitioned between water and ethyl acetate, the organic layer was isolated, dried over sodium sulfate and concentrated in vacuo and purified by column chromatography to give 114 mg of the title compound, MS (ISP) 529.3 (M+H)+.
Example 176
l-(2-Cyclohexyl-ethyl)-5-methyl-2-(2-trifluoromethoxy-phenyl)-lH-imidazole-4-
carboxylic acid piperidin-1-ylamide

The title compound was synthesized in analogy to Example 49, using 2-trifluoromethoxy-benzylamine as R4»CH2-NH2,1-amino-piperidine as R!R2NH and (bromoethyl)-cyclohexane as R3-(CH2)m-Br, MS (ISP) 479.2 (M+H)+.



























The title compound was synthesized in analogy to Example 1, using cyclohexylamine as R*R2NH, c-cyclohexyl-methylamine as R3-(CH2)m-NH2 and 2-bromo-l-(3-methyl-pyridin-2-yl)-ethanone [220270-42-8], MS (ISP) 394.3 (M+H)+.
Example 201
l-Cyclohexylmethyl-2-meliiyl-5-(2-methyl-pyridin-3-yl)-lH-pyrrole-3-carboxylicacid
cyclohexylamide

The title compound was synthesized in analogy to Example 1, using cyclohexylamine as R*R2NH, c-cyclohexyl-methylamine as R3-(CH2)m"NH2 and 2-bromo-l-(2-methyl-pyridin-3-yl)-ethanone [67279-27-0], MS (ISP) 394.3 (M+H)+.
Example 202
l-Cydohexylmethyl-2-methiyl-5-(3-methyl-pyrazin-2-yl)-lH-pyrrole-3-carboxylicacid
cyclohexylamide

















































The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, l-(2,4-bis-trifluoromethyl-phenyl)-2-bromo-ethanone as compound of formula S, c-cyclohexyl-methylamine as R3-(CH2)m-NH2 and cyclohexylamine as R1R2NH1 MS (ISP) 515.3 (M+H)+.
Example 250
l-Cyclohexylmethyl-5-(2-fluoro-5-trifluoromethyl-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid ((lSR,2RS)-2«hydroxy-cyclohexyl)-amide

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2-fluoro-5-trifluoromethylphenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R ~(CH2)m-NH2 and cis-2-aminocyclohexanole as RlR2NH, MS (ISP) 481.5 (M+H)+.
Example 251
5-(2-Chloro-5-trifluoromethyl-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-
carboxylic acid ((lS,2S)-2-hydroxy-cyclohexyl)-amide
























The title compound was synthesized in analogy to Example 49, using 2,3-dichloro-
1 "5 '
benzylamine as R4-CH2-NH2,1-aminopiperidine as R R NH and (bromomethyl)cyclohexane as R3-(CH2)m-Br, MS (ISP) 449 (M+H)+.

































Example307
5-(2-CUoro-5-trifluorometh^^
pyrrole-3-carboxylic acid ((lR,2R)-2-hydroxy-cyclohexyl)-amide

The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-l-(2-chloro-5-trifluoromethyl-phenyl)-ethanone as compound of formula S, ci5-2-aminomethyl-l-cyclohexanol as R3-(CH2)m-NH2 and (lR,2R)-2-amino-cydohexanol as R*R2NH, MS (ISP) 513.5 (M+H)+

Galenical Examples Example A
Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
Ingredients Per tablet
Kernel:
Compound of formula (I) 10,0 mg 200.0 mg
Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
Povidone K30 12.5 mg 15.0 mg
Sodium starch glycolate 12.5 mg 17.0 mg
Magnesium stearate 1.5 mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg
Film Coat:
Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glycol 6000 0.8 mg 1.6 mg
Talc 1.3 mg 2.6 mg
Iron oxyde (yellow) 0.8 mg 1.6 mg
Titan dioxide 0.8 mg 1.6 mg
The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.

Example B
Capsules containing the following ingredients can be manufactured in a conventional manner:
Ingredients Per capsule
Compound of formula (I) 25.0 mg
Lactose 150.0 mg
Maize starch 20.0 mg
Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition:
Compound of formula (I) 3.0 mg
Polyethylene glycol 400 150.0 mg
Acetic acid q.s. ad pH 5.0
Water for injection solutions ad 1.0 ml
The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

WO 2004/060870 PCT/EP2003/014720
Claims 1. Compounds of formula (I)
a)
wherein
XisCorN;
R1 is hydrogen or lower alkyl;
R2 is lower alkyl or -(CH2)n-R2a;
R2a is cycloalkyl, optionally mono-, di-> tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy; a 5-or 6-membered monovalent saturated heterocyclic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, cycloalkyl, oxo, fluorinated lower alkyl or fluorinated lower alkoxy; a 5- or 6-membered monovalent heteroaromatic ring containing one to four heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino or cycloalkyl; or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;
R3 is cycloalkyl, optionally mono-, di-, tri- or tetra-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, fluorinated lower alkyl or fluorinated lower alkoxy; or phenyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro;

R4 is a 5- or 6-membered monovalent heteroaromatic ring containing one to three heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino; naphthyl, which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, lower alkylamino, halogenated lower alkyl, halogenated lower alkoxy or nitro; or phenyl which may optionally be mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, nitro, halogenated lower alkyl, halogenated lower alkoxy, cyano, lower alkylsulfonyl or -NR7R8; or two adjacent substituents of the said phenyl residue together are -0-(CH2)p-0- or -(CH2)2-C(0)NH-;
R5 and R6 are each independently hydrogen, lower alkyl, halogen or fluorinated methyl;
R7 and R8 are each independently hydrogen or lower alkyl; or R7 and R8 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or aromatic heterocyclic ring optionally containing one or two further heteroatoms independently selected from nitrogen, oxygen and sulfur, said saturated or aromatic heterocyclic ring being optionally substituted by hydroxy, lower alkyl, lower alkoxy, halogen, amino or lower alkylamino;
m is 0,1 or 2;
n is 0 or 1;
pis 1,2 or3;
and pharmaceutical^ acceptable salts thereof.
2. Compounds according to claim 1, wherein R1 is hydrogen.
3. Compounds according to any of claims 1 or 2, wherein R2 is lower alkyl or -(CH2)n-R2a.
4. Compounds according to claim 3, wherein R2a is a cycloalkyl residues with three to six carbon atoms which may optionally be mono-, di-, tri- or tetra-substituted, independently, by lower alkyl and/or hydroxy.
5. Compounds according to claim 3, wherein R2a is a 5-membered heterocyclic
i ring containing one or two heteroatoms independently selected from nitrogen and oxygen,

said heterocyclic ring being optionally mono-, di- or tri-substituted, independently, by lower alkyl or by oxo.
6. Compounds according to claim 3, wherein R23 is a 5- or 6-membered heteroaromatic ring containing one, two or four heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally mono-substituted by lower alkyl or by cycloalkyl.
7. Compounds according to claim 3, wherein R2a is a phenyl residue which is optionally mono- or di-substituted, independently, by lower alkoxy, halogen, halogenated lower alkyl, halogenated lower alkoxy or nitro.
8. Compounds according to any of claims 1 to 7, wherein R3 is an unsubstituted cycloalkyl residue with five or six carbon atoms.
9. Compounds according to any of claims 1 to 7, wherein R3 is a phenyl residue which is optionally mono- or di-substituted, independently, by lower alkoxy, halogen, halogenated lower alkyl, halogenated lower alkoxy or nitro.
10. Compounds according to any of claims 1 to 9, wherein R4 is a 6-membered heteroaromatic ring containing one or two nitrogen atoms, said heteroaromatic ring being optionally mono-substituted by lower alkyl.
1L Compounds according to any of claims 1 to 9, wherein R4 is phenyl optionally mono-, di- or tri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy, halogen, nitro, halogenated lower alkyl, halogenated lower alkoxy, cyano, lower alkylsulfonyl, or by a residue -NR7R8.
12. Compounds according to any of claims 1 to 9, wherein two adjacent substituents of a phenyl residue R4 together are -0-(CH2)p-0- or -(CH2)2-C(0)NH-, and p is 2 or 3.
13. Compounds according to claim 12, wherein both R7 and R8 are methyl or both R7 and R8 are ethyl.
14. Compounds according to claim 12, wherein R7 and R8 together with the nitrogen atom to which they are attached form a 5-membered, saturated heterocyclic ring optionally containing one further heteroatom independently selected from nitrogen and oxygen, said saturated or aromatic heterocyclic ring being optionally mono-substituted by lower alkyl.
15. Compounds according to any of claims 1 to 14, wherein X is C.

16. Compounds according to any of claims 1 to 14, wherein X is N.
17. Compounds according to any of claims 1 to 16, selected from the group consisting of:
1 -Cyclohexylmethyl-5-(4-methoxy-phenyl)-2-methyl- lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5«(3-methoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-2«methyl-5-(4-trifluoromethyl-phenyl)»lH-pyrrole-3-carboxylic acid butylamide,
5-(4-Chloro-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
1 -Cydohexylmethyl-2-methyl-5-p-tolyl-lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5«(2-methoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-5-(4-fluoro-phenyl)-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-5-(2,4-dimellioxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid butylamide,
5-(4-Bromo-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
5-(3-Cyano-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohexylmethyl-5-(2,4-dimethyl-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5-(4-difluoromethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-2-methyl-5-(4-pyrrolidin-l-yl-phenyl)-lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5»(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3"Carboxylic acid butylamide,

l-Cyclohexylmethyl-5-(3,4-difluoro-p^ butylamide,
5-(3-Chloro-phenyl)-l-cydohexylmethy^^ butylamide,
l-Cyclohexylmethyl»2-methyl-5-(4-trifluoromethoxy-phenyl)«lH-pyrrole-3-carboxylic acid butylamide,
l-Cydohexylmeiliyl-5-(3,4-dimethoxy-phe^ acid butylamide,
5-(2-Chloro-phenyl)--l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylicacid butylamide,
l-CyclohexyImethyl-2-methyI-5-(4-nitro-phenyl)-lH"pyrrole-3-carboxylicacid butylamide,
1-Cyclohexylmethyl-5-(2,5-dimetho acid cyclohexylamide,
l-Cyclohexylmethyl«5«(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid cyclopentylamide,
l-Cyclohexylmethyl"5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxy]ic acid cyclobutylamide,
l-Cyclohexylmethyl»5"(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid cyclopropylamide,
l-Cyc!ohexylmetiiyl"5-(2,5-difluoro-phenyl)-2-melJiyI-lH-pyrroIe-3-carboxyIicacid butylamide,
l-Cyclohexylmetiiyl-5'(4-hydroxy«3-methoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5-(3«fluoro-phenyl)-2--methyl--lH-pyrrole-3-carboxylicacid butylamide,
5-Benzo [1,3 ]dioxol-5-yl-l-cyc!ohexylmethyl-2- methyl- lH-pyrrole-3-carboxylic acid butylamide,
l-Cyclohexylmethyl-5-(2,5-dichloro-phenyl)-2-methyl»lH-pyrrole-3-carboxylic acid butylamide,
5-(3,5-Bis-trifluoromethyl-phenyl)-l-cyclohexylmethyl-2»methyl-lH-pyrrole-3-carboxylic acid butylamide,

5-(3,5-Bis-trifluoromethyI-p^ carboxyiic acid cyclohexylamide,
l-Cyclohexylmethyl-2-methyl-5-(4-pyrrolidin-l-yl-phenyl)-lH-pyrrole-3 carboxyiic acid cyclohexylamide,
(R)-l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid sec-butylamide,
5-(3,5-Bis»trifluoromethyl-phenyl)-l»(4«methoxy-benzyl)-2-methyl-lH-pyrrole-3" carboxyiic acid cyclohexylamide,
l-Cyclohexylmethyl~5-(2>5-dimethoxy-phenyO^ acid piperidin-1-ylamide,
l-CyclohexylmethyI-2«methyl-5-pyridin-2-yl-lH-pyrrole-3-carboxylicacid butylamide,
l-Cyclohe;tylmethy]-2-(2-methoxy-phenyl)-5-me acid butylamide,
l-CycIohexylmethyl"2-(2-methoxy-phenyl)-5-methyl-lH-imidazole-4-carboxylic acid piperidin-1-ylamide,
and pharmaceutically acceptable salts thereof.
18. Compounds according to any one of claims 1-16 selected from the group consisting of:
l-Cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid cyclopropylmethyl-amide
!-CyclohexylmethyI-5-(2,5-dimethoxy--phenyl)-2-methyl«lH-pyrrole--3--carboxyIic acid (furan-2-ylmethyl)-amide
l-Cyclohexylmethyl-5-(2,5"dimethoxy-phenyl)-2-methyl-lH-pyrrole-3-carboxylic acid (3-methyl-thiophen-2-ylmethyl)~amide
(S)-l-Cyclohexylmethyl-5-(2>5-dimethoxy»phenyl)-2-methyl-lH"pyrrole-3-carboxylic acid sec-butylamide
5-(5-Chloro-2-methoxy-4-methyl-phenyl)"l-cyclohexylmethyl-2*methyl-lH-pyrrole-3-carboxylic acid cyclohexylamide
5-(3,5-Bis-trifluoromethyl-phenyI)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylic acid piperidin-1-ylamide

l-uycionexyimemyi-^-p-fluoro«2-memoxy-pnenyi;-2-metnyi-iii-pyrroieo-carboxylic acid piperidin-l-ylamide
5-(5-Chloro-2-methoxy-phenyI)-l-cyclohexylmethyl-2-methyI-lH-pyrrole-3-carboxylic acid piperidin-l-ylamide
5-(5»Chloro-2-methoxy-4-methyl-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylic acid piperidin-1-ylarnide
5-(2-Chloro-5-trifluoromethyl-phenyl)-l-cyclohexylmethyl-2-methyl-lH-^ carboxylic acid ((lRS,2RS)-2-hydroxy-cyclohexyl)-amide
5-(2«Chloro-5-trifluoromethyl-phenyl)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylic acid ((lR,2R)-2-hydroxy-cycIohexyI)-amide
5-(2,5-Bis-trifluoromethyI-phenyI)-l-cyclohexylmethyl-2-methyl-lH-pyrrole-3-carboxylic acid piperidin-l-ylamide
5-(2-Chloro-5-trifluoromethyl-phenyl)-l-cycloh^ carboxylic acid piperidin-l-ylamide
5-(2-Fluoro-5-trifluoromethyl-phenyl)-l-((lSR^ 2-methyI-lH-pyrrole-3-carboxylic acid cyclohexylamide
5-(2-Fluoro-5-trifluoromethyl-phenyl)-l-((lRS^ 2-methyl-lH-pyrrole-3-carboxyIic acid cyclohexylamide
5-(2-Fluoro-5-trifluoromethyl-phenyl)-l-(lRS,2RS)-2-hydroxy-cyclohexylmethyl)-2-methyl-lH-pyrrole-3-carboxylicacid((lR,2R)-2-hydroxy-cyclohexyl)--amide
5-(2,5-Bis-trifluoromethyl-phenyl)-l-(2-(^clopropyl-ethyI)-2-methyI-lH-pyrroI^ carboxylic acid ((lR,2R)-2-hydroxy-cyclohexyl)-amide
5-(2-Chloro-5-trifluoromethyl-phenyl)-l-((lRS,2RS)-2-hydroxy-cyclohexylmethyI)-2-methyl-lH-pyrrole-3-carboxylic acid cyclohexylamide
l-Cyclohexylmethyl-2-methyl-5-(2"methyl-5-trifluoromethyl-phenyl)-lH-pyrrole-3-carboxylic acid ((lR,2R)-2-hydroxy-cyclohexyl)-amide
and pharmaceutical^ acceptable salts thereof.
19. A process for the manufacture of compounds of formula (I) as defined in any of claims 1 to 18, which process comprises:




wherein R and R are as defined claim 1;
and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof.
20. Compounds according to any of claims 1 to 19 when manufactured by a process
according to claiml9
21. Pharmaceutical compositions comprising a compound according to any of
claims 1 to 18 and a pharmaceutically acceptable carrier and/or adjuvant.
22. Compounds according to any of claims 1 to 18 for use as therapeutic active
substances.
23. Compounds according to any of claims 1 to 18 for use as therapeutic active
substances for the treatment and/or prophylaxis of diseases which are associated with
modulation of the CBl receptor.
24. A method for the treatment and/or prophylaxis of diseases which are associated
with the modulation of the CBl receptors which method comprises administering a
compound according to any of claims 1 tol8 to a human being or animal.
25. The use of compounds according to any of claims 1 to 18 for the treatment
and/or prophylaxis of diseases which are associated with the modulation of CBl receptors.
26. The use of compounds according to any of claims 1 to 18 for the preparation of
medicaments for the treatment and/or prophylaxis of diseases which are associated with
the modulation of CBl receptors.

Documents:

1469-chenp-2005 abstract granted.pdf

1469-chenp-2005 claims granted.pdf

1469-chenp-2005 description (complete) granted-1.pdf

1469-chenp-2005 description (complete) granted-2.pdf

1469-chenp-2005 description (complete) granted-3.pdf

1469-chenp-2005 description (complete) granted.pdf

1469-chenp-2005-abstract.pdf

1469-chenp-2005-claims.pdf

1469-chenp-2005-correspondnece-others.pdf

1469-chenp-2005-correspondnece-po.pdf

1469-chenp-2005-description(complete).pdf

1469-chenp-2005-form 1.pdf

1469-chenp-2005-form 18.pdf

1469-chenp-2005-form 3.pdf

1469-chenp-2005-form 5.pdf

1469-chenp-2005-pct.pdf


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Patent Number 225883
Indian Patent Application Number 1469/CHENP/2005
PG Journal Number 02/2009
Publication Date 09-Jan-2009
Grant Date 01-Dec-2008
Date of Filing 01-Jul-2005
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address 124 GRENZACHERSTRASSE, CH-4070 BASEL,
Inventors:
# Inventor's Name Inventor's Address
1 MAYWEG, ALEXANDER HANGSTRASSE 34, D-79539 LOERRACH,
2 MARTY, HANS, PETER MARKIRCHERSTRASSE 25, CH-4055 BASE,
3 MUELLER, WERNER IM AUGARTEN 10, CH-4147 AESECH,
4 NARQUIZIAN, ROBERT 4 RUE DE MONTREUX, F-68300 ST LOUIS,
5 NEIDHART, WERNER 9 RUE DU STEINLER, F-68220 HAGENTHAL LE BAS,
6 PFLEIGER, PHILIPPE 1 RUE DU VIGNOBLE, F-68130 SCHWOBEN, FRANCE
7 ROEVER, STEPHAN SCHLOSSTRASSE 15, D-79594 INZLINGEN,
PCT International Classification Number C07D207/34
PCT International Application Number PCT/EP03/14720
PCT International Filing date 2003-12-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03000003.8 2003-01-02 EUROPEAN UNION