Phosphodiesterase 4 inhibitors, including N-substituted aniline and diphenylamine analogs
PDE4 inhibition is achieved by novel compounds, e.g., N-substituted aniline and diphenylamine analogs. The compounds of the present invention are of Formula I: wherein R 1 , R 2 , R 3 and R 4 are as defined herein.
1. A compound according to Formula I:
wherein
R 1 is H or alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen;
R 2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C 1-4 -alkoxy, oxo or combinations thereof, and wherein optionally one or more —CH 2 CH 2 — groups is replaced in each case by —CH═CH— or —C≡C—,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C 1-4 -alkyl, C 1-4 -alkoxy or combinations thereof,
aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF 3, OCF 3, alkyl having 1 to 12 carbon atoms, hydroxy, alkoxy having 1 to 12 carbon atoms, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof,
arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF 3 OCF 3, alkyl having 1 to 12 carbon atoms, hydroxy, alkoxy having 1 to 12 carbon atoms, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more —CH 2 CH 2 — groups are each optionally replaced by —CH═CH— or —C≡C—, and one or more —CH 2 — groups are each optionally replaced by -0— or -NH— and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof; or
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, hydroxy, nitro, cyano, oxo, or combinations thereof;
R 3 is heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, cyano, trifluoromethyl, CF 3 O, nitro, oxo, amino, alkylamino wherein the alkyl group has 1 to 12 carbon atoms, dialkylamino wherein each alkyl group has 1 to 12 carbon atoms, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
R 4 is aryl having 6 to 14 carbon atoms and which is substituted one or more times by halogen, alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, alkynyl having 2 to 12 carbon atoms, hydroxy, alkoxy having 1 to 12 carbon atoms, alkoxyalkoxy wherein each alkoxy group has 1 to 12 carbon atoms, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF 3, amino, aminoalkyl having 1 to 12 carbon atoms, aminoalkoxy having 1 to 12 carbon atoms, dialkylamino wherein each alkyl group has 1 to 12 carbon atoms, hydroxyalkyl having 1 to 12 carbon atoms, hydroxamic acid, pyrrolyl, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy having 1 to 12 carbon atoms, carboxy, alkyl —O—CO— wherein the alkyl portion has 1 to 12 carbon atoms, cyano, alkanoyl having 1 to 13 carbon atoms, aroyl having 7 to 15 carbon atoms, alkylthio having 1 to 12 carbon atoms, alkylsulfinyl having 1 to 12 carbon atoms, alkylsulfonyl having 1 to 12 carbon atoms, phenoxy, trialkylsilyloxy wherein each alkyl group has 1 to 12 carbon atoms, R 5 -L-, or combinations thereof;
R 5 is H,
alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C 1-4 -alkyl, C 1-4 -alkoxy, oxo, or combinations thereof,
alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms,
a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, nitro, cyano, oxo, or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy having 1 to 12 carbon atoms, alkyl having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms or combinations thereof,
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 12 carbon atoms, hydroxy, alkoxy having 1 to 12 carbon atoms, alkoxyalkoxy wherein each alkoxy group has 1 to 12 carbon atoms, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl having 1 to 12 carbon atoms, aminoalkoxy having 1 to 12 carbon atoms, dialkylamino wherein each alkyl group has 1 to 12 carbon atoms, hydroxyalkyl having 1 to 12 carbon atoms, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy having 1 to 12 carbon atoms, carboxy, alkyl —O—CO— wherein the alkyl portion has 1 to 12 carbon atoms, cyano, alkanoyl having 1 to 13 carbon atoms, aroyl having 7 to 15 carbon atoms, alkylthio having 1 to 12 carbon atoms, alkylsulfinyl having 1 to 12 carbon atoms, alkylsulfonyl having 1 to 12 carbon atoms, phenoxy, cycloalkyl having 3 to 10 carbon atoms, aryl having 6 to 14 carbon atoms which is substituted unsubstituted, heteroaryl having one or two rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is a heteroatom and which is substituted unsubstituted, or combinations thereof, or
arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF 3 O, nitro, amino, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, amino, alkylamino having 1 to 12 carbon atoms, dialkylamino wherein each alkyl group has 1 to 12 carbon atoms and/or substituted in the alkyl portion by halogen, cyano, or methyl
L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more —CH 2 — groups are each optionally replaced by —O—, —S—, —NR 6 —, —SO 2 NH—, —NHSO 2 —, —SO 2 NR 6 —, —NR 6 SO 2 —, —CO—, —NR 6 CO—, —CONR 6 —, —NHCONH—, -OCONH, —NHCOO—, —SCONH—, —SCSNH—, or —NHCSNH—; and
R 6 is H,
alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, C 1-4 -alkyl, C 1-4 -alkoxy, oxo, or combinations thereof;
arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF 3 O, nitro, amino, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, alkylamino having 1 to 12 carbon atoms, dialkylamino wherein each alkyl group has 1 to 12 carbon atoms, and/or substituted in the alkyl portion by halogen, cyano, or methyl;
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 12 carbon atoms, hydroxy, alkoxy having 1 to 12 carbon atoms, alkoxyalkoxy wherein each alkoxy group has 1 to 12 carbon atoms, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl having 1 to 12 carbon atoms, aminoalkoxy having 1 to 12 carbon atoms, dialkylamino wherein each alkyl group has 1 to 12 carbon atoms, hydroxyalkyl having 1 to 12 carbon atoms, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy having 1 to 12 carbon atoms, carboxy, alkyl —O—CO— wherein the alkyl portion has 1 to 12 carbon atoms, cyano, alkanoyl having 1 to 13 carbon atoms, aroyl having 7 to 15 carbon atoms, alkylthio having 1 to 12 carbon atoms, alkylsulfinyl having 1 to 12 carbon atoms, or alkylsulfonyl having 1 to 12 carbon atoms;
or a pharmaceutically acceptable salt thereof; with the provisos that:
(a) R 4 is at least monosubstituted by R 5 -L in which L is a divalent aliphatic radical having 1 to 8 carbon atoms wherein at least one —CH 2 — group is replaced by —SO 2 NR 6 — or —NR 6 SO 2 — in which R 6 is aryl or arylalkyl which in each case is substituted or unsubstituted;
(b) R 4 is at least monosubstituted by R 5 -L in which L is a divalent aliphatic radical having 1 to 8 carbon atoms wherein at least one —CH 2 — group is replaced by —NR 6 —, —SO 2 NR 6 —, —NR 6 SO 2 —, —NR 6 CO—, or —CONR 6 —and R 6 is aryl or arylalkyl which in each case is substituted or unsubstituted;
(c) R 4 is at least monosubstituted by R 5 -L in which R 5 is aryl or a heterocyclic group each being substituted by cycloalkyl, aryl or heteroaryl;
(d) R 4 is at least monosubstituted by R 5 -L in which L is —SO—, —SO 2 —, —CONR 6 SO 2 —, —SO 2 NR 6 CO—, or —SO 2 NR 6 —, with the further proviso that when R 4 is at least monosubstituted by R 5 -L in which L is —SO 2 NR 6 —, then R 6 is other than H; or
(e) said compound is selected from
3-Cyclopentyloxy-4-methoxy-N-(3-tert-butyloxycarbonylphenyl)-N-(3-pyridylmethyl))-aniline,
N-(3,4-Bis-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,
N-(3-Cyclobutyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,
N-(3,4-Dimethoxyphenyl)-N-(3 -pyridylmethyl)-4-aminobenzoic acid,
N-(3-Ethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,
N-(3-Isopropoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,
N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,
N-(3,4-Dimethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid,
and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 , wherein R 4 is at least monosubstituted by R 5 -L in which L is a divalent aliphatic radical having 1 to 8 carbon atoms wherein at least one —CH 2 — group is replaced by —SO 2 NR 6 — or —NR 6 SO 2 — in which R 6 is aryl or arylalkyl which in each case is substituted or unsubstituted.
3. A compound according to claim 1 , wherein R 4 is at least monosubstituted by R 5 -L in which L is a divalent aliphatic radical having 1 to 8 carbon atoms wherein at least one —CH 2 — group is replaced by —NR 6 —, —SO 2 NR 6 —, —NR 6 SO 2 —, —NR 6 CO—, or —CONR 6 — and R 6 is aryl or arylalkyl which in each case is substituted or unsubstituted.
4. A compound according to claim 1 , wherein R 4 is at least monosubstituted by R 5 -L in which R 5 is aryl substituted by cycloalkyl, aryl or heteroaryl.
5. A compound according to claim 1 , wherein R 4 is at least monosubstituted by R 5 -L in which L is —SO—, —SO 2 —, —CONR 6 SO 2 —, SO 2 NR 6 CO—, or —SO 2 NR 6 —, with the further proviso that when R 4 is at least monosubstituted by R 5 -L in which L is —SO 2 NR 6 —, then R 6 is other than H.
6. A compound according to claim 1 , wherein said compound is selected from:
N-(3,4-Bis-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,
N-(3-Cyclobutyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,
and pharmaceutically acceptable salts thereof,
wherein compounds that are optically active can be in the form of their separate enantiomers or mixtures thereof, including racemic mixtures.
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
8. A composition according to claim 7 , wherein said composition contains 0.1-50 mg of said compound.
9. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.
10. A composition according to claim 9 , wherein said composition contains 0.1-50 mg of said compound.
11. A pharmaceutical composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier.
12. A composition according to claim 11 , wherein said composition contains 0.1-50 mg of said compound.
13. A pharmaceutical composition comprising a compound according to claim 4 and a pharmaceutically acceptable carrier.
14. A composition according to claim 13 , wherein said composition contains 0.1-50 mg of said compound.
15. A pharmaceutical composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier.
16. A composition according to claim 15 , wherein said composition contains 0.1-50 mg of said compound.
17. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier.
18. A composition according to claim 17 , wherein said composition contains 0.1-50 mg of said compound.
19. An intermediate compound which is N-(3-hydroxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid.
20. A compound according to claim 1 , wherein R 1 is methyl or difluoromethyl.
21. A compound according to claim 1 , wherein R 2 cycloalkyl.
22. A compound according to claim 21 , wherein R 2 is cyclopentyl.
23. A compound according to claim 1 , wherein R 2 is phenyl, methylphenyl, methoxyphenyl, chlorophenyl, phenethyl, phenpropyl, phenbutyl, phenylethenyl, phenoxyethyl, phenoxypropyl, phenoxybutyl, chlorophenylethyl, methoxyphenyl ethyl, chlorophenylethenyl, chlorophenoxyethyl, chlorophenypropyl, methoxyphenpropyl, methoxyphenbutyl, chlorophenbutyl, nitrophenbutyl, or chlorophenylaminoethyl.
24. A compound according to claim 1 , wherein R 2 is cyclohexenyl, or cyclohexadienyl, which in each case is unsubstituted or substituted.
25. A compound according to claim 1 , wherein R 2 is an alkyl group having 1 to 4 carbon atoms, which is substituted or unsubstituted.
26. A compound according to claim 1 , wherein R 2 is methyl, difluoromethyl, trifluoromethyl, or methoxyethyl.
27. A compound according to claim 1 , wherein R 2 cyclopentyl, CHF 2 , methoxyethyl, cyclopropylmethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, or phenylaminoethyl.
28. A compound according to claim 2 , wherein R 4 is phenyl which is at least monosubstituted by R 5 -L.
29. A compound according to claim 5 , wherein R 4 is phenyl which is at least monosubstituted by R 5 -L.
30. A compound according to claim 2 , wherein R 4 is phenyl, naphthyl, or biphenyl, which is at least monosubstituted by R 5 -L.
31. A compound according to claim 5 , wherein R 4 is phenyl, naphthyl, or biphenyl, which is at least monosubstituted by R 5 -L.
32. A compound according to claim 1 , wherein said compound is 3-Cyclopentyloxy-4-methoxy-N-(3-tert-butyloxycarbonylphenyl)-N-(3-pyridylmethyl))-aniline, or a pharmaceutically acceptable salt thereof.
33. A compound according to claim 1 , wherein said compound is N-(3,4-Bis-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, or a pharmaceutically acceptable salt thereof.
34. A compound according to claim 1 , wherein said compound is N-(3-Cyclobutyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, or a pharmaceutically acceptable salt thereof.
35. A compound according to claim 1 , wherein said compound is N-(3,4-Dimethoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, or a pharmaceutically acceptable salt thereof.
36. A compound according to claim 1 , wherein said compound is N-(3-Ethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, or a pharmaceutically acceptable salt thereof.
37. A compound according to claim 1 , wherein said compound is N-(3-Isopropoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, or a pharmaceutically acceptable salt thereof.
38. A compound according to claim 1 , wherein said compound is N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, or a pharmaceutically acceptable salt thereof.
39. A compound according to claim 1 , wherein said compound is N-(3,4-Dimethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, or a pharmaceutically acceptable salt thereof.