Patent NZ-505521-A (NZ)
Title: Method for treating chronic obstructive pulmonary disease (COPD) using a cis-substituted-cyclohexane-1- carboxylic acid
Inventor: CHRISTENSEN SIEGFRIED B
IPC: C07D285/12
Filed: 1999-01-06
Abstract: Use of a compound of Formula (I) for treating COPD where: - R1 is -(CR4R5)nC(O)O(CR4R5)mR6,- (CR4R5)nC(O)NR4(CR4R5)mR6, - (CR4R5)nO(CR4R5)mR6, or - (CR4R5)rR6, where the alkyl moieties may be optionally substituted with one or more halogens; - m is 0 to 2; - n is 1 to 4; - r is O to 6; - R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; - R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxyCl-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by OH, 1 to 3 methyl groups or one ethyl group; - provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in - (CR4R5)nO(CR4R5)mR6; - X is YR2, halogen, nitro,NR4R5, or formyl amine; Y is O or S (O)m'; m' is 0, 1, or 2; X2 is O or NR8; X3 is hydrogen or X; X4 is of formulae (a) or (b); X5 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8; R2 is independently selected from the group consisting of -CH3 an CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo substituted C1-4 alkyl, -CH=CR8'R8', cyclopropyl optionally substituted by R8', CN, OR8,CH2OR8, NR8R10, CH2NR8R10, C(Z')H, C(O)OR8, C(O) NR8R10, or C=CR8'; Z' is O, NR9, NOR8, NCN, C(-CN)2, CR8CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(- CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8; Z is C(Y')R14, C(O)OR14, C(Y')NR10R14, C(NR10)NR10R14, CN, C(NOR8)R14, C(O)NR8NR8C(O)R8, C(O)NR8NR10R14, C(NOR14)R8, C(NR8)NR10R14, C(NR14) NR8R8, C(NCN)NR10R14, C(NCN)SR9, (2-, 4-or 5-imidazolyl), (3-, 4-or 5-pyrazolyl), (4-or 5- triazolyl [1,2,3]), (3-or 5-triazolyl [1,2,4]), (5- tetrazolyl), (2-, 4-or 5-oxazolyl), (3-, 4-or 5-isoxazolyl), (3or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2- thiadiazolyl[1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R 14; the dotted line in formula (a) represents a single or double bond; Y' is O or S; R7 is -(CR4R5)qR12 or C1-6 alkyl wherein the R12 or C1-6 alkyl group is optionally substituted one or more times by C1-2 alkyl optionally substituted by one to three fluorines,-F, -Br, -Cl, -NO2, - NR10R11, -C(O)R8, -C(O)OR8, -OR8, -CN, -OC(O)R8, - NR10C(O)NR10R11, -C(O)NR10R11, -OC(O)NR10R11, -NR10C(O)R13, -C(NR10)NR10R11, -NR10C(O)R11,-NR10C(O)OR9, -NR10C(NCN)SR9,- NR10C(NCN)NR10R11,-C(NCN)NR10R11,-C(NCN)SR9, -NR10S(O)2R9, - S(O)m'R9, -NR10C(O)C(O)NR10R11, -NR10C(O)C(O)R10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2; R12 is C3-7 cycloalkyl, (2-, 3-or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3- thienyl), (4- or 5- thiazolyl), quinolinyl, naphthyl, or phenyl; R8 is independently selected from hydrogen or R9; R8' is R8 or fluorine; R9 is C1-4 alkyl optionally substituted by one to three fluorines; R10 is OR8 or R1; R11 is hydrogen, or C1-4 alkyl optionally substituted by one to three fluorines; or when R10 and R11 are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S; R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C1-2 alkyl groups; R14 is hydrogen or R7; or when R10 and R14 are as NR10R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S; provided that: f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, Npiperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or g) when X2R1 is OCF2H or OCF3, X is F, OCF2H or OCF3, X3 is H, s is zero, X5 is H, Z is C(O)OR14 and R14 is C1-7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof. The compound as described above may be used in treating chronic obstructive pulmonary disease (COPD).