Claims
- 1. A method for treating COPD, which method comprises administering to a mammal suffering from COPD an effective amount of a compound of Formula (I): wherein:R1 is —(CR4R5)nC(O)O(CR4R5)mR6, —(CR4R5)nC(O)NR4(CR4R5)mR6, —(CR4R5)nO(CR4R5)mR6, or —(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl moieties may be optionally substituted by OH, 1 to 3 methyl groups or one ethyl group; 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 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 and —CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; R3 is CN; 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, (5-tetrazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]), wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; the dotted line in formula (a) optionally 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, —F, —Br, —Cl, —NO2, —NR10R11, —C(O)R8, —C(O)OR8, —OR8, —CN, —C(O)NR10R11, —OC(O)NR10R11, —OC(O)R8, —NR10C(O)NR10R11, —NR10C(O)R11, —NR10C(O)OR9, —C(NR10)NR10R11, —C(NCN)NR10R11, —C(NCN)SR9, —NR10C(NCN)SR9, —NR10C(NCN)NR10R11, —NR10S(O)2R9, —S(O)m′R9, —NR10C(O)C(O)NR10R11, —NR10C(O)C(O)R10, or 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; q is 0, 1, or 2; R12 is C3-C7-cycloalkyl; R8 is independently selected from hydrogen or R9; R9 is C1-4 alkyl optionally substituted by one to three fluorines; R10 is OR8 or R11; 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 in a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/or S; R14 is hydrogen or R7; or the pharmaceutically acceptable salts thereof.
- 2. The method of claim 1 wherein in Formula (I) R1 is —CH2-cyclopropyl, cyclopentyl, methyl or CF2H; R3 is CN; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl.
- 3. The method of claim 2 wherein subject is a human and the compound is:methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate; 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylic acid; methyl cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]; methyl trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]; methyl cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate]; methyl trans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate]; cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate], tris(hydroxymethyl)ammonium methane salt; cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid]; trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl,cyclohexane-1-carboxylic acid]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]; methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl-cyclohexane-1-carboxylate]; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate]; methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate]; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy4-difluoromelhoxyphenyl)cyclohexane-1-carboxylate]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]; cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide]; trans-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide]; cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carbohydrazide]; cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-(2-cetylcarbohydrazide)]; cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane}; cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane}; cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane}; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methyleyclohexane]; methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide]; methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate]; cis-[4-cyano-4-(3-cyclopropyhnethoxy-4-methoxyphenyl)-1-metlhoxycyclohexane-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxanide]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxaldehyde]; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid]; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide]; cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamic acid]; N-methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamic acid]; cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoethyl)carboxamide]; cis-[1-(2-cyanoethyl)-5-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl}tetrazole]; or cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(tetrazol-5-yl)cyclohexane].
- 4. The method of claim 1 wherein the subject is a human and the compound is cis-[4-cyano-4(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
- 5. The method of claim 4 wherein the compound is administered at least twice daily.
- 6. The method of claim 5 wherein the compound is administered twice daily and at each time is administered in an amount between 1 mg and 20 mg.
- 7. The method of claim 6 wherein the amount of compound administered at each time is 15 mg, is in tablet form and is administered orally.
- 8. A method for the phrophylatic treatment of a mammal at risk for developing COPD, said method comprising administering a composition comprising a compound of Formula (I) in an amount between 1 and 60 mg admixed with a pharmaceutically acceptable excipient at least once daily, wherein Formula (I) comprises: wherein:R1 is —(CR4R5)nC(O)O(CR4R5)mR6, —(CR4R5)nC(O)NR4(CR4R5)mR6, —(CR4R5)mO(CR4R5)mR6, or —(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl moieties may be optionally substituted by OH, 1 to 3 methyl groups or one ethyl group; 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 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 and —CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; R3 is CN; 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, (5-tetrazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]), wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; the dotted line in formula (a) optionally 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 —F, —Br, —Cl, —NO2, —NR10R11, —C(O)R8, —C(O)OR8, —OR8, —CN, —C(O)NR10R11, —OC(O)NR10R11, —OC(O)R8, —NR10C(O)NR10R11, —NR10C(O)R11, —NR10C(O)OR9, —C(NR10)NR10R11, —C(NCN)NR10R11, —C(NCN)SR9, —NR10C(NCN)SR9, —NR10C(NCN)NR10R11, —NR10S(O)2R9, —S(O)m′R9, —NR10C(O)C(O)NR10R11, —NR10C(O)C(O)R10, or 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; q is 0, 1, or 2; R12 is C3-7 cycloalkyl,; R8 is independently selected from hydrogen or R9; R9 is C1-4 alkyl optionally substituted by one to three fluorines; R10 is OR8 or R11; 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; R14 is hydrogen or R7; or the pharmaceutically acceptable salts thereof.
- 9. The method of claim 8 wherein in Formula (I) R1 is —CH2-cyclopropyl, cyclopentyl, methyl or CF2H; R3 is CN; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl.
- 10. The method of claim 9 wherein the subject is a human and the compound ismethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate; 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylic acid; methyl cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]; methyl trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]; methyl cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate]; methyl trans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate]; cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate], tris(hydroxymethyl)ammonium methane salt; cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid]; trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]; methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate]; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate]; methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-ifluoromethoxyphenyl)cyclohexane-1-carboxylate]; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]; cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide]; trans-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide]; cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carbohydrazide]; cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-(2-cetylcarbohydrazide)]; cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane}; cis-{4-(3,4-bisdifluloromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane}; cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane}; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane]; methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid]; SB 208970 cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxanmide]; methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxaldehyde]; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid]; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid]; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide]; cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamic acid]; N-methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamic acid]; cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoetlhyl)carboxamide]; cis-[1-(2-cyanoethyl)-5-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl}tetrazole]; or cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(tetrazol-5-yl)cyclohexane].
- 11. The method of claim 9 wherein the subject is a human and the compound is cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
- 12. The method of claim 9 wherein the compound is administered at least twice daily and at each time is administered in an amount between 1 mg and 20 mg.
- 13. The method of claim 9 wherein the compound is administered twice daily and at each time is administered in an amount between 1 mg and 20 mg.
- 14. The method of claim 13 wherein the amount of compound administered at each time is 15 mg, is in tablet form, and is administered orally.
Parent Case Info
This application claims benefit of provisional application Ser. No. 60/070,718 filed Jan. 7, 1998 and Ser. No. 60/106,908 filed Oct. 28, 1998.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US99/00214 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO99/34798 |
7/15/1999 |
WO |
A |
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5552438 |
Christensen |
Sep 1996 |
A |
Non-Patent Literature Citations (1)
Entry |
Silvestre et al., Drugs Future, 23(6), 607-615 (1998) (abstract). |
Provisional Applications (2)
|
Number |
Date |
Country |
|
60/070718 |
Jan 1998 |
US |
|
60/106908 |
Oct 1998 |
US |