Small molecule inhibitors of rotamase enzyme activity

A non-immunosuppresive compound selected from the group consisting of:

• 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(2-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(4-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl (2S)-N-(›2-thienyl! glyoxyl)pyrrolidinecarboxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate, and
• 3,3-Diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate and pharmaceutically acceptable salt, hydrate, and mixture thereof.

A pharmaceutical composition comprising a neurotrophically effective amount of a compound of the formula:

• ##STR13## where R.sub.1 is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl group optionally substituted with C.sub.3 to C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkyl, or Ar.sub.1, where Ar.sub.1 is selected from the group consisting of 2-furyl, 2-thienyl, or phenyl;
• X is selected from the group consisting of oxygen and sulfur;
• Y is oxygen;
• and
• Z is a C.sub.2 -C.sub.6 straight chain alkyl or alkenyl, wherein the alkyl or alkenyl chain is substituted in one or more positions with 2-furyl, 2-thienyl, C.sub.3 -C.sub.6 cycloalkyl, pyridyl, or phenyl, each optionally having one to three C.sub.1 -C.sub.4 alkoxy substituents or pharmaceutically acceptable salt, hydrate, or mixture thereof,
• and a pharmaceutically acceptable carrier.

A method of stimulating growth of damaged nerves, which comprises:

• administering to damaged nerves a compound of the formula:
• ##STR14## where R.sub.1 is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl group optionally substituted with C.sub.3 to C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkyl, or Ar.sub.1, where Ar.sub.1 is selected from the group consisting of 2-furyl, 2-thienyl, or phenyl;
• X is selected from the group consisting of oxygen and sulfur;
• Y is oxygen;
• and
• Z is a C.sub.2 -C.sub.6 straight chain alkyl or alkenyl, wherein the alkyl or alkenyl chain is substituted in one or more positions with 2-furyl, 2-thienyl, C.sub.3 -C.sub.6 cycloalkyl, pyridyl, or phenyl, each optionally having one to three C.sub.1 -C.sub.4 alkoxy substituents or pharmaceutically acceptable salt, hydrate, or mixture thereof,
• in sufficient amounts to stimulate the growth of said nerves.

A method of treating a neurological disorder selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration in an animal which comprises administering a therapeutically effective amount of a compound of the formula:

• ##STR15## where R.sub.1 is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl group optionally substituted with C.sub.3 to C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkyl, or Ar.sub.1, where Ar.sub.1 is selected from the group consisting of 2-furyl, 2-thienyl, or phenyl;
• X is selected from the group consisting of oxygen and sulfur;
• Y is oxygen;
• and
• Z is a C.sub.2 -C.sub.6 straight chain alkyl or alkenyl, wherein the alkyl or alkenyl chain is substituted in one or more positions with 2-furyl, 2-thienyl, C.sub.3 -C.sub.6 cycloalkyl, pyridyl, or phenyl, each optionally having one to three C.sub.1 -C.sub.4 alkoxy substituents or pharmaceutically acceptable salt, hydrate, or mixture thereof,
• where said compound has an affinity for FKBP-type immunophilins wherein the immunophilin exhibits rotamase activity and the compound inhibits the rotamase activity of the immunophilin.

A compound selected from the group consisting of:

• 3-(3-Pyridyl)-1-propyl(2S)-1(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecar boxylate;
• 3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate;
• and,
• 3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate or a pharmaceutical salt or hydrate thereof.

A method of stimulating growth of damaged nerves, which comprises:

• administering to damaged nerves a compound in sufficient amounts to stimulate the growth of said nerves, wherein the compound is selected from the group consisting of:
• 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-(2-Pyridyl)-1-propyl(2S)-1(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecar boxylate,
• 3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl (2S)-N-(›2-thienyl! glyoxyl)pyrrolidinecarboxylate,
• 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarb oxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and
• a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

A method of treating a neurological disorder selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration in an animal which comprises administering a therapeutically effective amount of a compound selected from the group consisting of:

• 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl (2S)-N-(›2-thienyl! glyoxyl) pyrrolidinecarboxylate,
• 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarb oxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,
• 3. 3-Diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and
• a pharmaceutically acceptable salt, hydrate, or a mixture thereof, where said compound has an affinity for FKBP-type immunophilins wherein the immunophilin exhibits rotamase activity and the compound inhibits the rotamase activity of the immunophilin.

A pharmaceutical composition comprising:

• i) a neurotrophically effective amount of a compound selected from the group consisting of:
• 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl (2S)-N-(›2-thienyl! glyoxyl) pyrrolidinecarboxylate,
• 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarb oxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and a pharmaceutically acceptable salt, hydrate, or a mixture thereof;
• and
• ii) a pharmaceutically acceptable carrier.

A method of treating Parkinson's disease in an animal which comprises administering a therapeutically effective amount of a compound selected from the group consisting of:

• 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidineca rboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,
• 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,
• 3-(3-Pyridyl)-1-propyl (2S)-N-(›2-thienyl! glyoxyl) pyrrolidinecarboxylate,
• 3. 3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecar boxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,
• 3,3-Diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and
• a pharmaceutically acceptable salt, hydrate, or a mixture thereof,
• where said compound has an affinity for FKBP-type immunophilins wherein the immunophilin exhibits rotamase activity and the compound inhibits the rotamase activity of the immunophilin.