Patent EA-003673-B1 (EA)
Title: 4-phenylpyridine derivatives, use and medicament thereof
Inventor: BOES MICHAEL
IPC: A61P9/00
Filed: 2000-02-23
Abstract: 1. Compounds of the general formula I wherein R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; R<1> is hydrogen or halogen; or R and R<1> may be together -CH=CH-CH=CH-; R<2> and R<2>' are independently from each other hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; or R<2> and R<2>' may be together -CH=CH-CH=CH-, optionally substituted by one or two substituents selected from lower alkyl or lower alkoxy; R<3> is hydrogen, lower alkyl or form a C3-C6 cycloalkyl group; R<4> is hydrogen, -N(R<5>)2, -N(R<5>)(CH2)nOH, -N(R<5>)S(O)2-lower alkyl, -N(R<5>)S(O)2-phenyl, -N=CHN(R<5>)2, -N(R<5>)C(O)R<5> or a cyclic tertiary amine of the group optionally bound via a group -(CH2)nN(R<5>)- and represents pyrrol-1-yl, imodazol-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, oxothiomorpholine-4-yl or 1,1-dioxothiomorpholine-4-yl; R<5> is independently from each other, hydrogen, C3-C6-cydoalkyl, benzyl or lower alkyl; R<6> is hydrogen, hydroxy, lower alkyl, -(CH2)nCOO-lower alkyl, -N(R<5>) CO-lower alkyl, hydroxy-lower alkyl, cyano, -(CH2)nO(CH2)nOH, -CHO or a heterocyclic group, optionally bonded via an alkylene group and represent pyridine, pyrimidine, oxsadiazolyl, triazolyl, tetrazolyl, furyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl; X is -C(O)N(R<5>)-, -(CH2)mO-, -(CH2)m,N(R<5>)-, N(R<5>)C(O)-, or -N(R<5>)(CH2)m-; n is 0 - 4; and m is 1 or 2; wherein lower alkyl is straight or branched a C1-C7 alkyl group, and lower alkoxy contains a straight or branched a C1-C7 alkyl moiety and pharmaceutically acceptable acid addition salts thereof. 2. A compound according to claim 1, wherein X is -C(O)N(R<5>)- and R<5> is methyl, ethyl or cyclopropyl. 3. A compound according to claim 2, which is N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-chloro-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-trifluoromethyl-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-fluoro-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-methoxy-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-phenyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-ethyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-cyclopropyl-4-o-tolyl-nicotinamide, N-[1-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Di-fluorobenzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Di-chlorobenzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, 2'-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoro-methyl-benzyl)-methyl-amide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide, (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazin-1-yl)-acetic acid ethyl ester, 5'-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4'-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazm-1-yl)-4-o-tolyl-nicotinamide, (RS)-6-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-thiomorpholin-4-yl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(1-oxo-λ<4>-thiomorpholin-4-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(1,1-dioxo-λ<6>-thiomorpholin-4-yl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide, N-(3.5-Bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(5-oxo-4,5-dihydro-1H-[1,2,4] triazol-3-ylmethyl)-piperazin-1-yl]-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide and N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide. 4. A compound according to claim 1, wherein X is -N(R<5>)C(O)- and R<5> is hydrogen or methyl. 5. A compound according to claim 4, which is 2-(3,5-Bis-trifluoromdhyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-acetamide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-propionamide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-{6-(methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-dimethylamino-pyridin-3-yl]-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazm-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-hydroxy-4-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-{6-[(2-hydroxy-ethyl)-methyl-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide, (R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide or [2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazm-1-yl)-pyridin-3-yl]-methyl-amine. 6. A medicament containing one or more compounds as claimed in any one of claims 1-5 and pharmaceutically acceptable excipients. 7. A medicament according to claim 6 for the treatment of diseases related to NK-1 receptor antagonists. 8. The use of a compound in any one of claims 1-5 for the treatment of diseases related to NK-1 receptor antagonists. 9. The use of a compound in any one of claims 1-5 for the manufacture of medicaments containing one or more compounds of formula I for the treatment of diseases related to NK-1 receptor antagonists.