Phosphodiesterase 4 inhibitors, including N-substituted aniline and diphenylamine analogs

A compound according to Formula I:

• wherein
• R1 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;
• R2 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, C1-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more —CH2CH2— 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, C1-4-alkyl, C1-4-alkoxy or combinations thereof,
• aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, 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, CF3 OCF3, 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 —CH2CH2— groups are each optionally replaced by —CH═CH— or —C≡C—, and one or more —CH2— 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;
• R3 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, CF3O, 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;
• R4 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, OCF3, 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, R5-L-, or combinations thereof;
• R5 is H,
• alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-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, CF3O, 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 —CH2— groups are each optionally replaced by —O—, —S—, —NR6—, —SO2NH—, —NHSO2—, —SO2NR6—, —NR6SO2—, —CO—, —NR6CO—, —CONR6—, —NHCONH—, -OCONH, —NHCOO—, —SCONH—, —SCSNH—, or —NHCSNH—;
• and
• R6is 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, C1-4-alkyl, C1-4-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, CF3O, 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) R4 is at least monosubstituted by R5-L in which L is a divalent aliphatic radical having 1 to 8 carbon atoms wherein at least one —CH2— group is replaced by —SO2NR6— or —NR6SO2— in which R6 is aryl or arylalkyl which in each case is substituted or unsubstituted;
• (b) R4 is at least monosubstituted by R5-L in which L is a divalent aliphatic radical having 1 to 8 carbon atoms wherein at least one —CH2— group is replaced by —NR6—, —SO2NR6—, —NR6SO2—, —NR6CO—, or —CONR6—and R6 is aryl or arylalkyl which in each case is substituted or unsubstituted;
• (c) R4 is at least monosubstituted by R5-L in which R5 is aryl or a heterocyclic group each being substituted by cycloalkyl, aryl or heteroaryl;
• (d) R4 is at least monosubstituted by R5-L in which L is —SO—, —SO2—, —CONR6SO2—, —SO2NR6CO—, or —SO2NR6—, with the further proviso that when R4 is at least monosubstituted by R5-L in which L is —SO2NR6—, then R6is 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.