AU761083B2

AU761083B2 - Pipecolic acid derivative hair growth compositions and uses

Info

Publication number: AU761083B2
Application number: AU77167/98A
Authority: AU
Inventors: Gregory S. Hamilton; Joseph P. Steiner
Original assignee: Guilford Pharmaceuticals Inc; GPI Nil Holdings Inc
Current assignee: GPI Nil Holdings Inc
Priority date: 1998-06-03
Filing date: 1998-06-03
Publication date: 2003-05-29
Anticipated expiration: 2018-06-03
Also published as: JP2002516839A; AU7716798A; CA2333698A1; EP1083872A1; WO1999062483A1

Description

WO 99/62483 PCT/US98/11242 PIPECOLIC ACID DERIVATIVE HAIR GROWTH COMPOSITIONS AND USES This application is a continuation-in-part of U.S. Patent Application No. 08/869,426, filed on June 4, 1997, the entire contents of which are herein incorporated by reference.

BACKGROUND OF THE INVENTION 1. Field of Invention This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using pipecolic acid derivatives.

2. Description of Related Art Hair loss occurs in a variety of situations.

These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systematic disorders such as nutritional disorders and internal secretion disorders. The mechanisms causing hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.

The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific WO 99/62483 PCT/US98/11242 2 immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J.

Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner. One form of hair loss, alopecia areata, is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds are expected to demonstrate efficacy for treating that type of hair loss. The hair growth stimulating effects of FK506 have been the subject of an international patent filing covering FK506 and structures related thereto for hair growth stimulation (Honbo et al., EP 0 423 714 A2) Honbo et al. discloses the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.

The hair growth and revitalization effects cf FK506 and related agents are disclosed in many U.S.

patents (Goulet et al., U.S. Patent No. 5,258,389; Luly et al., U.S. Patent No. 5,457,111; Goulet et al., U.S. Patent No. 5,532,248; Goulet et al., U.S. Patent No. 5,189,042; and Ok et al., U.S. Patent No.

5,208,241; Rupprecht et al., U.S. Patent No.

5,284,840; Organ et al., U.S. Patent No. 5,284,877).

These patents claim FK506 related compounds. Although WO 99/62483 PCT/US98/11242 3 they do not claim methods of hair revitalization, they disclose the known use of FK506 for effecting hair growth. Similar to FK506 (and the claimed variations in the Honbo et al. patent), the compounds claimed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which FK506's efficacy is well known.

Other U.S. patents disclose the use of cyclosporin and related compounds for hair revitalization (Hauer et al., U.S. Patent No.

5,342,625; Eberle, U.S. Patent No. 5,284,826; Hewitt et al., U.S. Patent No. 4,996,193). These patents also relate to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth.

However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant, small molecule compounds which are useful as hair revitalizing compounds.

Hamilton and Steiner disclose in U.S. Patent No.

5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that 4 these non-immunosupressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and non-immuno-suppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

SUMMARY OF THE INVENTION The present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative.

The present invention further relates to a pharmaceutical composition which comprises: an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

The pipecolic acid derivative used in the inventive methods and pharmaceutical compositions include immunosuppressive and non-immunosuppressive compounds having "an affinity for FKBP-type immunophilins, particularly FKBP12. Non-immunosuppressive compounds, as their name suggests, do not exert any significant immunosuppressive activity.

In a first aspect, the present invention provides a method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of a non-immunosuppressive six-membered heterocyclic 25 compound having a single nitrogen heteroatom which has an N-linked ketone, diketo, or thioketo substituent, and which is additionally substituted with an ester or amide :i substituent attached to the heterocyclic ring, provided that said ester or amide substituent is not an N-oxide of an ester or amide, wherein said compound has an affinity for an FKBPtype immunophilin.

In a second aspect, the present invention provides a method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of SLB-506.

In a third aspect, the present invention provides a method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of Way-124,466.

In a fourth aspect, the present invention provides a method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of rapamycin.

In a fifth aspect, the present invention provides a method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of Rap-Pa.

In a sixth aspect, the present invention provides a method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of a compound selected from: 4-(4-methoxyphenyl)butyl(2S)-l1-[2-(3 ,4,5-trimethoxyphenyl)acetyI]hexahydro-2pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)- ,4,5 -trimethoxyphenyl)acryloyllhexahydro-2pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)- 1 ,4,5 -trimethoxyphenyl)propanoyl]hexahydro-2pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)- I-[2-oxo-2-(3 ,4,5-trimethoxyphenyl)acetyl]hexahydro-2pyridinecarboxylate; 3-cyclohexylpropyl(2S)- 1-(3 ,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 3 -phenylpropyl(2S)- 1-(3,3 -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 3-(3 ,4,5-trimethoxyphenyl)propyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate; (1 R)-2,2-dimethyl- I -phenethyl-3 -butenyl(2S)- 1 -(3,3-dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate; (1 1,3 -diphenylpropyl(2S)- 1-(3,3 -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; (1 R)-l1-cyclohexyl-3 -phenylpropyl(2S)- 1-(3,3 -dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate; (1 1,3 -diphenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; (1 1 -cyclohexyl-3 -phenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate; (22aS)- 15,15 -dimethylperhydropyrido[2,1 1,9,4]dioxazacyclononadecine- 1, 1,2,16,1 7-tetraone; (24aS)- 1 7,1 7-dimethylperhydropyrido[2, I1-c] 1,9,4]dioxazacyclohenicosine- 1, 1,4,18,1 9-tetraone; ethyl 1 -(2-oxo-3-phenylpropanoyl)-2-piperidinecarboxylate; ethyl 1 -pyruvoyl-2-piperidinecarboxylate; ethyl 1 -(2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -(3-methyl-2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -(4-methyl-2-oxopentanoyl)-2-piperidinecarboxylate; ethyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-[2-(ethyloxycarbonyl)piperidino]-2,2-dimethyl-3 ,4-dioxobutylacetate; ethyl 1 -[2-(2-hydroxytetrahydro-2H-2-pyranyl)-2-oxoacetyl] -2-piperidinecarboxylate; ethyl 1 -[2-(2-methoxytetrahydro-2H-2-pyranyl)-2-oxoacetyl] -2-piperidinecarboxylate; ethyl 1 -hydroxycyclohexyl)-2-oxoacetyl]-2-piperidinecarboxylate; ethyl 1 -methoxycyclohexyl)-2-oxoacetyl] -2-piperidinecarboxylate; *.ethyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; ethyl 1 -(2-oxo-2-piperidinoacetyl)-2-piperidinecarboxylate; :eooooethyl 1 ,4-dihydro-2H-6-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate; ethyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; ethyl 1 -(4-methyl-2-oxo- 1 -thioxopentyl)-2-piperidinecarboxylate; 3-phenylpropyl 1 -(2-hydroxy-3 ,3 -dimethylpentanoyl)-2-piperidinecarboxylate; o *(1R)-l1-phenyl-3-(3 ,4,5 -trimethoxyphenyl)propyl 1 -dimethylbutanoyl)-2piperidinecarboxyl ate; o 50. (1 1,3 -diphenyipropyl 1 -(benzylsulfonyl)-2-piperidinecarboxylate; 3 ,4,5-trimethoxyphenyl)propyl 1 -(benzylsulfonyl)-2-piperidinecarboxylate; o: 3R, 3E, 5E, 7E, 9S, 11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7tridecatrienyl]2-hydroxy -3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylic acid; methyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl-12-oxo- 3 ,5,7-tridecatrienyl] -2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; isopropyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl-12oxo-3 ,5 ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; benzyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl-12-oxo- ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; 1-phenylethyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl- 1 2-oxo-3 ,5 ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; (Z)-3-phenyl-2-propenyl 3R, 3E, 5E, 7E, 9S, I11R)-2,13-dimethoxy-3,9,1 1trimethyl- 12-oxo-3 ,5 ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)- 2-piperidinecarboxylate; 3-(3,4-dimethoxyphenyl)propyl 3R, 6S)-6-Ii(2S, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy- 3,9,1 1-trimethyl- 12-oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-211-2-pyranyl)-2oxoacetyl)-2-piperidinecarboxylate; N2-benzyl-1-(2-[(2R, 3R, 3E, 5E, 7E, 9S, 11IR)-2,13-dimethoxy-3,9,1 1-trimethyl-12oxo-3 ,S,7-tridecatrienyl] -2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; N2-(3-phenylpropyl)-1-(2-[(2R, 3R, 3E, 5E, 7E, 9S, I IR)-2,13-dimethoxy-3,9,1 1trimethyl- 12-oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)- 2-piperidinecarboxylate; ,4-dichlorophenyl)-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; -trimethoxyphenyl)-2-propenyl 1 -(3,3-dimethyl-2-oxopentanoyl)-2piperidinecarboxylate; -phenyl-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; -dimethoxy)-phenylpropyl)phenyl)-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2piperidinecarboxylate; -benzodioxol-S-yl)-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2piperidinecarboxylate; 4-4mtoypey*uy 2oo2peyaey)2pprdncroyae 4-4mexphenylbutyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; 3-3-peyidpropyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; 3-(3 -pyridyl)propyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-phenyl-l1-(3 -phenylpropyl)butyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4d 4-(4-methoxyphenyl)butyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1 -(4-methoxyphenethyl)-4-phenylbutyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 3 -dimethoxyphenyl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 3 -benzodioxol-5 -yl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1 -phenethyl-3-phenylpropyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -cyclohexyipropyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -phenyipropyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -cyclohexylpropyl 1 ,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; 3 -phenyipropyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; and 4-phenyl-l1-(3-phenylpropyl)butyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; pharmaceutically acceptable salts, esters, and solvates thereof.

In a seventh aspect, the present invention provides use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in :0 30 need thereof, wherein said compound is a six-membered heterocyclic compound having a single nitrogen heteroatom, wherein said compound is of a non-immunosuppressive six-membered heterocyclic compound having a single nitrogen heteroatom which has an N-linked ketone, diketo, or thioketo sub stituent, and which is additionally substituted with an ester or amide substituent attached to the heterocyclic ring, provided that said ester or amide substituent is not an N-oxide of an ester or amide, wherein said compound has an affinity for an FKiBPtype immunophilin.

In an eighth aspect, the present invention provides use of a compound for the ~.preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is Way-124,466.

:In a ninth aspect, the present invention provides use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is rapamycin.

In a tenth aspect, the present invention provides the use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is Rap-Pa.

In an eleventh aspect, the present invention provides use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is SLB-5 06.

In a twelfth aspect, the present invention provides use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is selected from: 4-(4-mnethoxyphenyl)butyl(2S)- 1 ,4,5-trimethoxyphenyl)acetyl]hexahydro-2pyridinecarboxylate; 4-(4-mnethoxyphenyl)butyl(2S)- 1 ,4,5 -trimethoxyphenyl)acryloyllhexahydro-2pyridinecarboxylate; 4-(4-mnethoxyphenyl)butyl(2S)- 1 ,4,5 -trimethoxyphenyl)propanoyl]hexahydro-2pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)- 1-[2-oxo-2-(3 ,4,5 -trimethoxyphenyl)acetyl]hexahydro-2pyridinecarboxylate; 3 -cyclohexylpropyl(2S)- 1 ,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 3 -phenylpropyl(2S)- 1-(3 ,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 3-(3,4,5 -trimethoxyphenyl)propyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate; (1 R)-2,2-dimethyl- 1 -phenethyl-3 -butenyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate; (1 1,3 -diphenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; (1 1 -cyclohexyl-3 -phenylpropyl(2S)-1 ,3-dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate; 1,3 -diphenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; (I1S)- I -cyclohexyl-3 -phenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate; (22aS)- 15,15 -dimethylperhydropyrido[2, 1 1,9,4]dioxazacyclononadecine- 1, 1,2,16,1 7-tetraone; (24aS)- 17,1 7-dimethylperhydropyrido[2, 1-c] [1 ,9,4]dioxazacyclohenicosine- 1,1,4,18,1 9-tetraone; ethyl 1 -(2-oxo-3 -phenylpropanoyl)-2-piperidinecarboxylate; ethyl 1 -pyruvoyl-2-piperidinecarboxylate; ethyl 1 -(2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -(3-methyl-2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -(4-methyl-2-oxopentanoyl)-2-piperidinecarboxylate; ethyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-[2-(ethyloxycarbonyl)piperidino]-2,2-dimethyl-3 ,4-dioxobutylacetate; ethyl I -[2-(2-hydroxytetrahydro-2H-2-pyranyl)-2-oxoacetyl] -2-piperidinecarboxylate; ethyl I -[2-(2-methoxytetrahydro-2H-2-pyranyl)-2-oxoacetyl]-2-piperidinecarboxylate; ethyl 1 -hydroxycyclohexyl)-2-oxoacetyllj-2-piperidinecarboxylate; ethyl 1 -methoxycyclohexyl)-2-oxoacetyl] -2-piperidinecarboxylate; ethyl I -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; ethyl 1 -(2-oxo-2-piperidinoacetyl)-2-piperidinecarboxylate; ethyl 1 ,4-dihydro-2H-6-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate; ethyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; ethyl I -(4-methyl-2-oxo-l1-thioxopentyl)-2-piperidinecarboxylate; 3-phenylpropyl 1 -(2-hydroxy-3 ,3 -dimethylpentanoyl)-2-piperidinecarboxylate; 35(1R)-l1-phenyl-3 -trimethoxyphenyl)propyl 1 ,3-dimethylbutanoyl)-2piperidinecarboxylate; 1,3 -diphenylpropyl 1 -(benzylsulfonyl)-2-piperidinecarboxylate; 3 -trimethoxyphenyl)propyl 1 -(benzylsulfonyl)-2-piperidinecarboxylate; 3R, 3E, 5E, 7E, 9S, 1 1R)-2,l3-dimethoxy-3,9,1 1-trimethyl-12-oxo-3,5,7tridecatrienyl]2-hydroxy -3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylic acid; S. 5 methyl 3R, 3E, 5E, 7E, 9S, I1lR)-2,13-dimethoxy-3,9,1 1-trimethyl-12-oxo- 3,5 ,7-tridecatrienyl]-2-hydrox y-3-methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; isopropyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 I1-trimethyl-12- :oxo-3,5,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2benzyl 3R, 6S)-6-II(2S, 3E, 5E, 7E, 9S, I11R)-2,13-dimethoxy-3,9,11I-trimethyl-12-oxo- 3,5 ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; 4g 1-phenylethyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl- 1 2-oxo-3 ,5 ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; (Z)-3-phenyl-2-propenyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1 trimethyl- 12-oxo-3 ,5 ,7-tridecatrienyl] -2-hydrox y-3-methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)- 2-piperidinecarboxylate; 3-(3,4-dimethoxyphenyl)propyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy- 3,9,1 1-trimethyl- 12-oxo-3 ,5 ,7-tridecatrienyl]-2-hydrox y-3-methyltetrahydro-2H-2-pyranyl)-2oxoacetyl)-2-piperidinecarboxylate; N2-benzyl-1-(2-[(2R, 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl-12oxo-3 ,5 ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2piperidinecarboxylate; N2-(3-phenylpropyl)-1 3R, 3E, 5E, 7E, 9S, 11IR)-2,13-dimethoxy-3,9,11Itrimethyl- 12-oxo-3 ,5 ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)- 2-piperidinecarboxylate; ,4-dichlorophenyl)-2-propenyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; -trimethoxyphenyl)-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2piperidinecarboxylate; -phenyl-2-propenyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; -dimethoxy)-phenylpropyl)phenyl)-2-propeny 1 -dimethyl-2-oxopentanoyl)-2piperidinecarboxylate; -benzodioxol-5 -yl)-2-propenyl 1 -dimethyl-2-oxopentanoyl)-2piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; 3 -phenyipropyl I -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; 3-(3 -pyridyl)propyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; 3 -pyridyl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-phenyl-l1-(3 -phenylpropyl)butyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1 -(4-methoxyphenethyl)-4-phenylbutyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 3 -dimethoxyphenyl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1,3-benzodioxol-5 -yl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1 -phenethyl-3 -phenyipropyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -cyclohexylpropyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -phenylpropyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -cyclohexyipropyl 1 -(3,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; 3 -phenylpropyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; and 4-phenyl-l1-(3 -phenylpropyl)butyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; pharmaceutically acceptable salts, esters, and solvates thereof.

Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

0..

S* WO 99/62483 PCT/US98/11242 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a photograph of mice treated with a vehicle after six weeks. FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.

FIG. 2 is a photograph of mice treated with 10 iM of a pipecolic acid derivative, GPI 1116, after six weeks. FIG. 2 shows that 90% of the shaved area is covered with new hair growth when GPI 1116 is administered.

FIG. 3 is a photograph of mice treated with 3 AM of a pipecolic acid derivative, GPI 1102, after six weeks. FIG. 3 shows that 90% of the shaved area is covered with new hair growth when GPI 1102 is administered.

FIG. 4 is a bar graph plotting the hair growth scores of unshaven animals and shaven animals treated with a vehicle, GPI 1116 (1 AM and 10 GPI 1102 (1 AM and 3 and a related pipecolic acid derivative neuroimmunophilin FKBP ligand, GPI 1044 (1 AM, 3 AM and 10 MM).

FIG. 5 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, related neuroimmunophilin FKBP ligand GPI 1206, and GPI 1116, 14 days after treatment with each identified compound. Figure 5 demonstrates the remarkable early hair growth promoted by neuroimmunophilin FKBP ligands.

WO 99/62483 PCT/US98/11242 6 DETAILED DESCRIPTION OF THE INVENTION Definitions "Alopecia" refers to deficient hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness), toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania.

Alopecia results when the pilar cycle is disturbed.

The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs.

"GPI 1044" refers to a compound of formula 0 B O.y OO

D

L

wherein B is 3-Phenylpropyl, D is 3-Phenylpropyl, and L is Phenyl.

"GPI 1102" refers to Compound 98, 4-phenyl-1-(3phenylpropyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2- WO 99/62483 PCT/US98/11242 7 piperidinecarboxylate.

"GPI 1116" refers to Compound 103, l-phenethyl-3phenylpropyl 1-(3, 3 -dimethyl-2-oxopentanoyl)-2piperidinecarboxylate.

"GPI 1206" refers to a compound of formula

N

S 0 SGPI 1206 "Isomers" refer to different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. "Diastereoisomers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal parts of individual enantiomers or stereoisomers.

"Pharmaceutically acceptable salt, ester, or solvate" refers to a salt, ester, or solvate of a subject compound which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. A salt, ester, or solvate can be formed with inorganic acids WO 99/62483 PCT/US98/11242 8 such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Eamples of base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.

WO 99/62483 PCT/US98/11242 9 "Pilar cycle" refers to the life cycle of hair follicles, and includes three phases: the anagen phase, the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years; the catagen phase, the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks; and the telogen phase, the rest period when hair progressively separates and finally falls out which, insofar as scalp hair is concerned, lasts about three to four months.

Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase. In the telogen phase, hair is uniform in diameter with a slightly bulbous, non-pigmented root. By contrast, in the anagen phase, hair has a large colored bulb at its root.

"Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair.

"Treating alopecia" refers to: preventing alopecia in an animal which may be predisposed to alopecia; and/or (ii) inhibiting, retarding or reducing alopecia; and/or WO 99/62483 PCT/US98/11242 (iii) promoting hair growth; and/or (iv) prolonging the anagen phase of the hair cycle; and/or converting vellus hair to growth as terminal hair. Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis. Vellus hair, on the other hand, is fine, thin, non-pigmented short hair in which the hair bulb is located superficially in the dermis. As alopecia progresses, the hairs change from the terminal to the vellus type.

Methods of the Present Invention The present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative.

The inventive method is particularly useful for treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systematic disorders such as nutritional disorders and internal secretion disorders.

Pharmaceutical Compositions of the Present Invention The present invention also relates to a pharmaceutical composition comprising: WO 99/62483 PCT/US98/11242 11 an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

PIPECOLIC ACID DERIVATIVES The pipecolic acid derivatives used in the methods and pharmaceutical compositions of the present invention have an affinity for FKBP-type immunophilins, such as FKBP12. When a pipecolic acid derivative binds to an FKBP-type immunophilin, it has been found to inhibit the prolyl-peptidyl cis-trans isomerase, or rotamase, activity of the binding protein. Unexpectedly, the compounds have also been found to stimulate hair growth. These rotamase inhibiting compounds may be immunosuppressive or nonimmunosuppressive. Examples of useful compounds are set forth below.

COMPOUND 1 Ocain et al., Biochemical and Biophysicai Research Communications, Vol. 192, No. 3, 1993, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula I. The compound was synthesized at Wyeth- Ayerst by Dr. Phil Hughes by reaction of 4-phenyl- 1,2,4-triazoline-3,5-dione with rapamycin.

WO 99/62483 PCT/US98/11242 12 FORMULA I Way-124,466 COMPOUND 2 rhakraborty et al., Chemistry and Biology, Vol.

2, pp. 157-161, March 1995, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula II.

WO 99/62483 PCT/US98/11242 13 FORMULA II RAP Pa COMPOUNDS Ikeda et al., J. Am. Chem. Soc., Vol. 116, pp.

4143-4144, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula III and Table I.

WO 99/62483 WO 9962483PCT[US98111242 14 FORMULA III

III

TABLE I Compound Structure n= 1 n=2 n 3 COMPOThDO 6- 9 Wang et al., Bic'organic and Medicinal Chemistry Letters, Vol. 4, No. 9, pp. 1161-1166, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula IV and Table II.

WO 99/62483 WO 9962483PCTJUS98/1 1242 FORMULA IV

CH

3 0- TABLE II Compound Structure X H X =CH 2 X

CH

3 x 0 COMPOUND Birkenshaw et al., Bioorganic Medicinal Chemistry Letters, Vol. 4, No. 21, pp. 2501-2506, 1994, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula V.

WO 99/62483 PCT/US98/11242 FORMULA V COMPOUNDS 11-21 Holt et al., J. Am. Chem. Soc., Vol. 115, pp.

9925-9938, 1993, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula VI and Tables III and TV.

WO 99/62483 WO 9962483PCTIUS98/1 1242 FORMULA VI TABLE III Compound 13 WO 99/62483 PCT/US98/I 1242 TABLE III (continued) Compound WO 99/62483 PCT/US98/1 1242 TABLE III (continued) Compound WO 99/62483 PCTJIJS98/1 1242 TABLE IV Compound Structure WO 99/62483 WO 9962483PCT/US98/1 1242 TABLE IV (continued) Structure Compound COMPOUNDS 22-30 Caffery et al., Bioorgalnic Medicinal Chenistry Letters, Vol. 4, No. 21, pp. 2507-2510, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas VII-IX and Tables V-VII.

WO 99/62483PCJS8124 PCTIUS98/11242 22 FORMULA VII vii TABLE V Compound Structure y 1 y 2 y= 3 WO 99/62483 WO 9962483PCTIUS98/1 1242 FORMULA VIII viii 0 TABLE VI Compound Structure n= 1 n 2 n 3 WO 99/62483 WO 9962483PCTIUS98/1 1242 24 FORMULA IX TABLE VII Compound Structure n I n =2 n =3 COMPOUND 31 Teague et al., Bioorganic Medicinal Chemistr-y Le tters, Vol. 3, No. 10, pp. 1947-1950, 1993, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula X.

WO 99/62483 PCT/US98/11242 FORMULA X COMPOUNDS 32-34 Yamashita et al., Bioorganic Medicinal Chemistry Letters, Vol. No. 2, pp. 325-328, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XI and Table VIII.

WO 99/62483 WO 9962483PCT/US98/1 1242 FORMULA XI TABLE VIII Compound Structure R phenyl 33 R N(allyl) 2 WO 99/62483 WO 9962483PCT[US98/1 1242 TABLE VIII (continued) Compound Structure COMPOUND 35-55 Holt et al., Bicorganic Medicinal Chemistry Letters, Vol. 4, No. 2, pp. 315-320, 1994, incorporated herein by reference, discloses exemp ry pipecolic acid derivatives represented by Formula XII and Tables IX-XI.

WO 99/62483PCUS8124 PCTIUS98/11242 FORMULA XII xii TABLE IX Compound Suture A'Me WO 99/62483 WO 9962483PCT/US98/1 1242 29 TABLE IX (continued) Structure Compound OAc WO 99/62483 PCTIUS98/1 1242 TABLE IX (continued) Structure Compound WO 99/62483 PCT/US98/1 1242 TABLE IX (continued) Structure Compound

NU

WO 99/62483 WO 9962483PCTUS98/1 1242 TABLE X Compound Structure OMe WO 99/62483 PCT/US98/11242 33 TABLE XI Compound Structure

Q

COMPOUNDS 56-68 Holt et al., Bioorganic Medicinal Chemistry Letters, Vol. 3, No. 10, pp. 1977-1980, 1993, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas XIII and XIV and Tables XII-XIV.

WO 99/62483 WO 9962483PCTIUS98/1 1242 34 FORMULA XIII xiii TABLE XII Structure Compound

OH

OMe Oi Pr OBn OCH MePh

OCH

2 CHCHPh

-OCH

2

CH

2

CH

2 4 OMe 2 Ph =NHI3n

=NHCH

2

CH

2

CH

2 Ph WO 99/62483 WO 9962483PCTIUS98/1 1242 FORMULA XIV xiv TABLE XIII Compound Structure R =Me R En WO 99/62483 PCTIUS98/1 1242 36 TABLE XIV Structure Compound WO 99/62483 WO 9962483PCTIUS98/1 1242 COMPOUNDS 69-83 Hauske et al., J. Med. Chem., Vol. 35, pp. 4284- 4296, 1992, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas XV-XVIII and Tables XV-XVIII.

FORM4ULA XV 0 N XV TABLE XV Compound Structure n 2

CH

3

R

2 =Phe-o-tert-butyl n= 2 0

R

2 =Phe-o-tert-butyl WO 99/62483PC/S/124 PCT[US98/11242 38 FORMULA XVI xv' TABLE XVI Structure Compound R, mOCII 3 Ph

R

3 Val-O-tert-butyl R= m-OCH 3 Ph

R

3 Leu-O-tert-butyl R= m-OCH 3 Ph R3=Ileu-O-tert-buty R= m-OCH 3 Ph

R

3 =hexahydro-Phebutyl R= m-OCHi 3 Ph R3 allylalaninebutyl R= B-naphthyl

R

3 Val-O-tert-butyl 1 0- tert- 0- tert- WO 99/62483PCUS/124 PCTIUS98/11242 39 FORMULA XVII -K4 xv I TABLE XVII Structure Compound

R

1 L CH 2 (CC) -M-OCH- 3 Ph CH.lPh

OCH

3

CH

2 (CO) -ig-naphthyl

CH

2 Ph

OCH

3

R,

WO 99/62483 WO 9962483PCT/US98/1 1242 FORMULA XVIII xviii TABLE XVIII Compound Structure R= m-OCH 3 Ph X trans-CH=CH R4 H Y =OC (0)Ph R, m-OCH-j'h X= trans-CH=CH R4 H Y =OC(O) CF 3 WO 99/62483 PCT/IJS98/11242 41 TABLE XVIII (continued) Compound Structure 81 R, M-OCH 3 Ph X trans-CH=CHI 82 R, m-OCH 3 Ph X trans-CH=CH

R

4

=H

Y =OCH 2

CH=CH

2 83 R, m-OCH 3 Ph x o R4 H Y =Ph COMPOUND B4 Teague et al., Bioorganic Med. Chem. Letr-nrs, Vol. 4, No. 13, pp. 1581-1584, 1994, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XIX.

WO 99/62483 PCTIUS98/11242 42 FORMULA XIX

HO,,

MeO 00 100 0 OH 0- H OMe SLB506 WO 99/62483 PCT/US98/11242 43 COMPOUNDS 85-88 Stocks et al., Bioorganic Med. Chem. Letters, Vol. 4, No. 12, pp. 1457-1460, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XX and Tables XIX and XX.

TABLE XIX Compound Structure

HO,,,

MeO" 2N 1 -\\OMe WO 99/62483 WO 9962483PCTIUS98/1 1242 44 FORMULA XX TABLE XX Structure Compound R, H-

R

2 W~e R3CH 2 OMe R, H R2 H

R

3

H

WO 99/62483PCIS/124 PCTIUS98/11242 TABLE XX (continued) Structure Compound R= Me

R

2

H

R

3

H

COMPOUNDS 89-110 Additional exemplary pipecolic acid derivatives are represented by Formulas XXI-XXV and Tables XXI-

XXV.

FORMULA XXI

XXI

TABLE XXI Structure Compound R =3,4-dichloro R 3,4,5-trimethoxy WO 99/62483 WO 9962483PCTIUS98/1 1242 TABLE XXI (continued) Stuture Compound R H R 3 R 3 -(3,4-Methylenedioxy)phenylpropyl FORMULA XXII xxi I TABLE XXII Structure Compound R 4-(p-Methoxy)butyl R 3-Phenylpropyl R 3-(3-Pyridyl)propyl WO 99/62483 WO 9962483PCTIUS98/1 1242 47 FORMULA XXIII xxiii TABLE XXIII Compound Structure R =3-(3-Pyridyl)propyl R 1. 7-Diphenyl-4-heptyl R 4-(4-Methoxy)butyl 100 R hexyl 1-Phenyl-6- (4-methoxyphenyl) -4- 101 102 R 3-(2,5-Dirnethoxy)phenylpropyl R 3- (3,4-Methylenedioxy)phenylpropyl 103 103 R 1, WO 99/62483 WO 9962483PCTIUS98/1 1242 FORMULA XXIV

XXIV

TABLE XXIV Compound Structure 104 105 R 4 -Methoxy) butyl R 3-Cyclohexyipropyl R 3-Phenylpropyl 106 WO 99/62483PCUS/124 PCTIUS98/11242 49 FORMULA XXV Xxv TABLE XXV Structure Compound 107 108 109 R 3-Cyclohexyipropyl R 3-Phenylpropyl R 4-(4-Methoxy)butyl 110 R 1,7-Diphenyl-4-heptyl The names of some of the compounds identif ied above are provided below in Table XXVI.

WO 99/62483 PCTfUS98/11242 TABLE XXVI Compound Name of Species 6 4-(4-methoxyphenyl)butyl t rime thoxypherlyl) acetyll hexahydro-2pyridinecarboxylate 7 4-(4-methoxyphenyl)butyl t rime thoxyphenyl) acryloyll hexahydro-2pyridinecarboxylate 8 4-(4-methoxyphenyl)butyl t rime thoxyphenyl) prop anoyl]I hexahydro -2 pyridinecarboxylate 9 4-(4-rethoxyphenyl)butyl (2S) [2-oxo-2- 5 -t rime thoxyphenyl) acetyl] hexahydro-2pyridinecarboxylate 11 3-cyclohexyipropyl (3,3-dimethy2 -2oxopentanoyl) hexahydro-2-pyrid;'necaboxy.atc' 12 3-phenylpropyl (2S)-l-(3,3-dimethyl-2oxopentanoyl) hexahydro-2-pyridinecarboxylate 13 3-(3,4,5-trimethoxyphenyl)propyl (2S)-l- 3 -dimethyl-2-oxopentanoyl) hexahydro-2 pyridine -carboxyl ate WO 99/62483 WO 9962483PCTIUS98/1 1242 TABLE XXVI (continued) Name of Species Compound 14 (iR) -2,2-dimethy1--1-phenethyl-3-butenyl 2 S 1- 3 ,3 d im e thy 1 -2 oxopentanoyl) hexahydro -2 -pyridinecarboxylate (1R)-1,3-diphenylpropyl dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxylate (iR) -1-cyclohexyl-3-phenylpropy. (2S) -1- 3- dime thyl-2-oxopentanoyl) hexahydro-2pyridine -carboxylate (1S)-1,3-diphenylpropyl dimethyl-2-oxopentanoyl)hexahydro-2pyridinecarboxyl ate (iS) -1-cyclohexyl-3-phenylpropyl (2S) -1- 3 -dime thyl-2 -oxopentanoyl) hexahydrao-2pyridine -carboxylate 19 (22aS) -15,15-dimethylperhydropyrido[2,1c] [1,9,4]dioxazacyciononadecine-1,12,16,17tetraone WO 99/62483 WO 9962483PCT/US98/I 1242 TABLE XXVI (continued) Name of Species Compound 20 (24aS) -17,17-dimethylperhydropyrido[2,1.

c] 9,41dioxazacyclohenicosine-1, 14,18, 19t e traone ethyl 1- (2-oxo-3-phenylprpaioyl) -2piperidinecarboxylate ethyl 1 -pyruvoy..-2 -piperidiriecarboxylate ethyl 1- (2-oxobutanoyl) -2-piperidinecarboxylate 38 39 ethyl 1-(3-rethyl-2-oxobutanoyl)-2piperidine -carboxylate ethyl 1-(4-methyl-2-oxopentanoyl)-2piperidinecarboxylate ethyl 1- (3,3-dimethyl-2-oxobutanoyl) -2piperidinecarboxylate ethyl 1- (3,3-dimethyl-2-oxopentanoyl) -2piperidinecarboxylate WO 99/62483 WO 9962483PCT/US98/1 1242 TABLE XXVI (continued) Name of Species Compound 42 43 4- (ethyloxycarbonyl)piperidino] -2,2dimethyl-3 ,4-dioxobutyl acetate ethyl (2-hydroxytetrahydro-2H-2p yr a ny 1) -2 -o x oa ce ty 1 2 piperidinecarboxylate 46 47 48 ethyl 1- [2-(2-methoxytetrahydro-2H-2p y ra ny 2- ox ca ce ty 1 2 piperidinecarboxylate ethyl 1-[2-(1-hydroxycyclohexyl)-2oxoacetyl] -2-piperidinecarboxylate ethyl 1-[2-(1-methoxycyclohexylV2oxoacetyl] -2 -piperidinecarboxylate ethyl 1-( 2 -cyclohexyl--2-oxoacetyl)-2piperidinecarboxylate ethyl 1- 2 -oxo-2-piperidinoacetyl) -2piperidinecarboxyl ate ethyl l-[2-(3,4-dihydro-2H-6-pyranyl)-2oxoacetyl) -2-piperidinecarboxylate WO 99/62483 WO 9962483PCTIUS98/1 1242 TABLE XXVI (continued) Name of Species Compound 50 51 ethyl 1-(2-oxo-2-phenylacetyl)-2piperidinecarboxylate ethyl 1- (4-methyl-2-oxo-1-thioxopentyl) -2piperidinecarboxyl ate 3-phenyipropyl 1-(2-hydroxy-3,3dimethylpentanoyl) -2-piperidinecarboxylate (1 R 1 p h e fly 1- 3 4 trimethoxyphenyl)propyl 1-(3,3dimethylbutanoyl) -2-piperidine-carboxylate (1R) 1, 3 -diphenylpropyl 1 (benzyl sul fonyl) 2 -piperidinecarboxylate 3-(3,4,5-trirnethoxyphenyl)propyl 1- (benzylsulfonyl) -2 -piperidinecarboxylate 1- 3R, 6S) 3E, SE, 7E, 9S, 11R) 2, 13- d ime thoxy 9,11 tr ime thy 1- 12 -cxo- 3,5,7-tridecatrienyl]-2-hydroxy-3methyltetrahydro-2H-2-pyranyl) -2-oxoacetyl) 2 -piperidine-carboxylic acid WO 99/62483 WO 9962483PCTJUS98/1 1242 TABLE XXVI (continued) Name of Species Compound 57 0 58 methyl 1- 3R, 6S) 3E, SE, 7E, 9S, 11R) 13-dimethoxy-3, 9, 11-trimethyl-12-oxo- 3, 5, 7-tridecatrienyl] -2-hydroxy-3-methyltetrahydro-2H-2-pyranyl) -2-oxoacetyl) -2piperidinecarboxylate isopropyl 1-(2 3R,6S) -6 3E, 5E,7E, 9S, liR) 13-dimethoxy-3, 9, 11-trimethyl-12oxo-3,5,7-tridecatrienyl]-2-hydroxy-3methyl-tetrahydro-2H-2-pyranyl)-2oxoacetyl) -2-piperidinecarboxylate benzyl 1- 3R, 6S) 3E, 5E, 7E, 9S, 1iR) -2,13-dimethoxy-3, 9,11-trimethyl-12-oxo- 3, 5, 7-tridecatrienyl] -2-hydroxy-3-methyltetrahydro-2H-2-pyranyl) -2-oxoacetyl) -2piperidinecarboxylate 1-phenylethyl 1-(2-[C2R,3R,6S)-6-[(2S,3E,5E, 7E,9S,11R) -2,13-dimethoxy-3, 9,11-trimethyl- 12-oxo-3, 5, 7-tridecatrienyl] -2-hydroxy-3methyl-tetrahydro-2H-2-pyranyl)-2oxoacetyl) -2-piperidinecarboxylate WO 99/62483 WO 9962483PCTIUS98/1 1242 TABLE XXVI (continued) Name of Species Compound 61 .0 62 WZ)-3-phenyl-2-propenyl 1- 2R, 3R,6S) -6- (2S, 3E, 5E, 7E, 9S, 11R) -2,13-dimethoxy-3, 9, 1 trimethyl-12-oxo-3,5,7-tridecatrienyl] -2hydroxy-3-methyltetrahydro-2H-2-pyranyl) -2oxoacetyl) -2-piperidinecarboxy late 3-(3,4-dimethoxy-_henyl)propy1 E(2R,3R, 6S) (2S, 3E, 5E, 7E, 9S, 11R) 13 -dimethoxy- 3,9, 11-trimethyl-12-oxo-3 ,5,7tridecatrienyl] -2-hydroxy-3 methyltetrahydro-2H-2-pyranyl) -2-oxoacetyl) 2 -piperidine-carboxylate N2 ben zyl1 1- 2- 2 R 3 R 6 S) -6- (2S, 3E, 5E, 7E, 9S, 11R)-2,13-dimethoxy- 3,9,11-trimethyl-12-oxo-3,5,7tridecatrienyl]-2-hydroxy-3-methyltetrahydro-2H--2-pyranyl) -2-oxoacetyl) -2piperidinecarboxyl ate N2- (3-phenyipropyl) (2R, 3R, 6S) -6- (2S, 3E, 5E, 7E, 9S, 11R) 13-dimethoxy-3, 9, 11trimethyl-12-oxo-3, 5, 7-tridecatrienyl] -2hydroxy-3-methyltetrahydro-2H-2-pyranyl) -2oxoacetyl)- 2-piperidinecarboxylate.

63 64 WO 99/62483 WO 9962483PCT[US98/1 1242 TABLE XXVI (continued) Name of Species Compound 89 (3,4-dichiorophenyl) -2-propenyl 1- 3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate (E)-3-(3,4,5-trimethoxyphenyl)-2-propenyl 1- 3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate 93 94 -3-phenyl-2-propenyl 1-(3,3-dimethyl-2oxo-pentanoyl) -2 -piperidinecarboxylate 3- (3 5 -dimethoxy) -phenyipropyl) phenyl)-2-propenyl 1-(3,3-dimethyl-2oxopentanoyl) -2 -piperidinecarboxylate (E)-3-i1,3-benzodioxol-5-yl)-2-propenyl 1- 3-dimethyl-2-oxopentanoyl) -2-piperidinecarbcxylate 4-(4-methoxyphenyl)butyl 1-(2-oxo-2phenylacetyl) 2 -pipe ri dinec arboxyl ate 3-phenyipropyl 1- (2-oxo-2-phenylacetyl) -2piperidinecarboxylate WO 99/62483 WO 9962483PCTJUS98/1 1242 TABLE XXVI (continued) Name of Species Compound 96 97 3-(3-pyridyl)propyl -2o phenylacetyl) -2-piperidinecarboxylate 3-(3-pyridyl)propyl 1-C3,3-dimethyl-2oxopentanoyl) -2-piperidinecarboxylate 4-phenyl-1- (3-phenylpropyl)butyl 1- (3,3dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate 4 (4 -methoxyphenyl) butyl 1- 3 -dimethyl -2 oxopentanoyl) -2 -piperidinecarboxylate 1- (4-methoxyphenethyl) -4-phenylbutyl 1- (3,3dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate 3-(2,5-dimethoxyphenyl)propyl dimethyl-2-oxopentanoyl)-2piperidinecarboxylate 3-(1,3-benzodioxol-5-yl)propyl 1-(3,3dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate 100 101 102 WO 99/62483 WO 9962483PCT/US98/1 1242 TABLE XXVI (continued) Name of Species Compound 103 104 105 106 107 108 1-phenethyl-3-phenylpropyl 1- 3-dimethyl- 2 -oxopentanoyl) -2 -piperidinecarboxylate 4- (4-methoxyphenyl)butyl 1- (2-cyclohexyl-2oxoacetyl) -2-piperidinecarboxy late 3-cyclohexyipropyl 1- (2-cyclohexyl-2oxoacetyl) -2-piperidiriecarboxylate 3-phenyipropyl 1- 2 -cyclohexyl-2-oxoacetyl) 2 -piperidinecarboxylate 3-cyclohexyipropyl 1- (3,3-dirnethyl-2oxobutanoyl) -2 -piperidinecarboxylate 3-phenylpropyl 1-(3,3-dimethyl-2oxobutanoyl) -2 -piperidinecarboxylate 4- (4-methoxyphenyl)butyl 1- 3-dimethyl-2oxobutanoyl) -2 -piperidinecarboxylate 4-phenyl-1- (3-phenylpropyl)butyl 1- (3,3dimethyl oxobutanoyl) -2 -piperidine carboxyl ate 109 110 WO 99/62483 PCT/US98/11242 All the compounds of Formulas I-XXV possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R- and Sstereoisomers. The individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compounds of Formulas I-XXV. It is understood that the compounds of Formulas I-XXV encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, S-stereoisomers are used in the pharmeceutical compositions and methods of the present invention.

Affinity for FKBP12 The compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. The inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP may be measured as an indicator of this affinity.

Ki Test Procedure Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can be evaluated by known methods described in the WO 99/62483 PCT/US98/11242 61 literature (Harding et al., Nature, 1989, 341:758-760; Holt et al. J. Am. Chem. Soc., 115:9923-9938). These values are obtained as apparent Ki's and are presented for representative compounds in TABLE XXVII.

The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phep-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases paranitroanilide from the trans form of the substrate.

The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent K i values.

In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaC1), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaC1, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml in 1 mM HC1) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35 mM LiC1 in trifluoroethanol).

The absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.

WO 99/62483 WO 9962483PCT/US98/I 1242 TABLE XXVII In Vitro Test Results Formulas I-XXV Compound Ki (AM) 6 9 11 12 13 19 36 41 89 91 92 93 94 96 97 98 99 100 101 102 140 13 170 250 17 12 >10, 000 1300 >10, 000 1800 28 39 165 740 725 130 12 120 WO 99/62483 PCT/US98/11242 63 TABLE XXVII (continued) In Vitro Test Results Formulas I-XXV Compound K, (1M) 103 104 103 105 760 106 210 107 32 108 2 109 24 110 Route of Administration To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions must readily affect the targeted areas. For these purposes, the compounds are preferably administered topically to the skin.

For topical application to the skin, the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.

Alternatively, the compounds can be formulated into suitable lotions or creams containing the active WO 99/62483 PCT/US98/11242 64 compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Other routes of administration known in the pharmaceutical art are also contemplated by this invention.

DosaQe Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg.

The specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art.

The compounds can be administered with other hair revitalizing agents. Specific dose levels for the WO 99/62483 PCT/US98/11242 other hair revitalizing agents will depend upon thefactors previously stated and the effectiveness of the drug combination.

EXAMPLES

The following examples are illustrative of the present invention and are not intended to be limitations thereon. Unless otherwise indicated, all percentages are based upon 100% by weight of the final composition.

Example 1 In Vivo Hair Generation Tests With C57 Black 6 Mice Experiment A: C57 black 6 mice were used to demonstrate the hair revitalizing properties of pipecolic acid derivatives GPI 1116 and GPI 1102, as well as related pipecolic acid derivative neuroimmunophilin FKBP ligand GPI 1044. C57 black 6 mice, approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers.

The animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGS. 1, 2, and 3, four animals were treated by topical administration with 20% propylene glycol vehicle (FIG. and seven animals per group were treated by topical administration with 10 AM GPI 1116 WO 99/62483 PCT/US98/11242 66 (FIG. or 3 AM GPI 1102 (FIG. The animals were treated with vehicle, GPI 1116, or GPI 1102 every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area covered by new hair growth during this time period.

FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. In contrast, FIGS. 2 and 3 show that animals treated with 10 iM GPI 1116 and 3 iM GPI 1102 exhibited dramatic hair growth, covering as much as 50% of the shaved area in some animals. FIG.

4 compares the hair growth score of unshaven animals with the hair growth scores of shaven animals treated with a vehicle, GPI 1116 (1 iM and 10 AM), GPI 1102 (1 AM and 3 IM), and related neuroimmunophilin FKBP ligand GPI 1044 (1 iM, 3 AM and 10 iM).

Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of neuroimmunophilin FKBP ligands, including GPI 1116.

C57 Black 6 mice, 55 to 75 days old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlying dermal layers. The animals were in a anagen growth phase when shaved. Five animals per group were treated by WO 99/62483 PCT/US98/11242 67 topical administration with a vehicle, FK506, or a neuroimmunophilin FKBP ligand (GPI 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area. The animals were treated three times per week, and hair growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent of shaved area covered by new hair growth, as scored by a blinded cbserver, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area).

Figure 5 shows that after 14 days, the animals treated with vehicle exhibited the beginning of growth in small tufts. In contrast, animals treated with one of the neuroimmunophilin FKBP ligands exhibited dramatic hair growth.

WO 99/62483 PCT/US98/11242 68 Example 2 A lotion comprising the following composition may be prepared.

Ethanol 80.0 a pipecolic acid derivative as defined above 10.0 a-Tocopherol acetate 0.01 Ethylene oxide (40 mole) adducts of hardened castor oil purified water perfume and dye q.s.

Into 95% ethanol are added a pipecolic acid derivative, a-tocopherol acetate, ethylene oxide mole) adducts of hardened castor oil, perfume and a dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion.

5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia.

WO 99/62483 PCT/US98/11242 69 Example 3 A lotion comprising the following composition shown may be prepared.

Ethanol 80.0 a pipecolic acid derivative as defined above 0.005 Hinokitol 0.01 Ethylene oxide (40 mole) adducts of hardened castor oil Purified water 19.0 Perfume and dye q.s.

Into 95% ethanol are added a pipecolic acid derivative, hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and a dye.

The resulting mixture is stirred, and purified water is added to the mixture to obtain a transparent liquid lotion.

The lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia.

WO 99/62483 PCT/US98/11242 Example 4 An emulsion may be prepared from A phase and B phase having the following compositions.

(A phase) Whale wax Cetanol Petrolatum Squalane 10.0 Polyoxyethylene (10 mole) monostearate Sorbitan monooleate a pipecolic acid derivative as defined above 0.01 (B phase) Glycerine 10.0 Purified water 69.0 Perfume, dye, and preservative q.s.

The A phase and the B phase are respectively heated and melted and maintained at 80 0 c. Both phases are then mixed and cooled under stirring to normal temperature to obtain an emulsion.

The emulsion may be applied by spraying once to four times per day to a site having marked baldness or alopecia.

WO 99/62483 PCT/US98/11242 71 Example A cream may be prepared from A phase and B phase having the following compositions.

(A Phase) Fluid paraffin Cetostearyl alcohol Petrolatum Glycerine monostearate 33.0 Polyoxyethylene (20 mole) 2-octyldodecyl ether Propylparaben 0.3 (B Phase) a pipecolic acid derivative as defined above 0.8 Glycerine Dipropylene glycol 20.0 Polyethylene glycol 4000 Sodium Hexametaphosphate 0.005 Purified water 44.895 The A phase is heated and melted, and maintained at 70°c. The B phase is added into the A phase and the mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream.

The cream may be applied once to 4 times per day to a site having marked baldness or alopecia.

WO 99/62483 PCT/US98/11242 72 Example 6 A liquid comprising the following composition may be prepared.

Polyoxyethylene butyl ether 20.0 Ethanol 50.0 a pipecolic acid derivative as defined above 0.001 Propylene glycol Polyoxyethylene hardened castor oil 0.4 derivative (ethylene oxide 80 mole adducts) Perfume q.s.

Purified water q.s.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a pipecolic acid derivative, and perfume.

The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid.

The liquid may be applied once to 4 times per day to a site having marked baldness or alopecia.

WO 99/62483 PCT/US98/ 1242 73 Example 7 A shampoo comprising the following composition may be prepared.

Sodium laurylsulfate Triethanolamine laurylsulfate Betaine lauryldimethylaminoacetate Ethylene glycol distearate Polyethylene glycol a pipecolic acid derivative as defined above Ethanol Perfume 0.3 Purified water 69.7 Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betaine lauryldimethylaminoacetate. Then a mixture obtained by adding g of a pipecolic acid derivative, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, followed by stirring, and 0.3 g of perfume are successively added. The resulting mixture is heated and subsequently cooled to obtain a shampoo.

The shampoo may be used on the scalp once or twice per day.

WO 99/62483 PCT/US98/11242 74 Example 8 A patient is suffering from alopecia senilis. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 9 A patient is suffering from male pattern alopecia. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example A patient is suffering from alopecia areata. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 11 A patient is suffering from hair loss caused by skin lesions. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

WO 99/62483 PCTIUS98/11242 Example 12 A patient is suffering from hair loss caused by tumors. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 13 A patient is suffering from hair loss caused by a systematic disorder, such as a nutritional disorder or an internal secretion disorder. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 14 A patient is suffering from hair loss caused by chemotherapy. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example A patient is suffering from hair loss caused by radiation. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the WO 99/62483 PCT[US98/11242 76 same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

The invention being thus described, it will be obvious that the same may be varied in many ways.

Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

1. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of a non- immunosuppressive six-membered heterocyclic compound having a single nitrogen heteroatom which has an N-linked ketone, diketo, or thioketo substituent, and which is additionally substituted with an ester or amide substituent attached to the heterocyclic ring, provided that said ester or amide substituent is not an N-oxide of an ester or amide, wherein said compound has an affinity for an FKBP-type immunophilin.

2. The method of claim 1, wherein the FKBP-type immunophilin is FKBP-12.

3. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of SLB-506.

4. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of Way-124,466. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of rapamycin.

6. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of Rap-Pa.

7. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of a compound selected from: 4-(4-methoxyphenyl)butyl(2S)- -[2-(3,4,5-trimethoxyphenyl)acetyl]hexahydro-2- pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)-1-[2-(3,4,5-trimethoxyphenyl)acryloyl]hexahydro-2- pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)-1-[2-(3,4,5-trimethoxyphenyl)propanoyl]hexahydro-2- S* pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)-l-[2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl]hexahydro-2- pyridinecarboxylate; 3-cyclohexylpropyl(2S)-l-(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 3-phenylpropyl(2S)- -(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 3-(3 ,4,5 -trimethoxyphenyl)propyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2- pyridinecarboxylate; (1 R)-2,2-dimethyl- 1 -phenethyl-3-butenyl(2S)- 1 ,3-dimethyl-2-oxopentanoyl)hexahydro-2- pyridinecarboxylate; (1 1,3 -diphenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; (1 1 -cyclohexyl-3 -phenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2- pyridinecarboxylate; (1 1,3 -diphenylpropyl(2S)- I -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; (1 1 -cyclohexyl-3 -phenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2- pyridinecarboxylate; (22aS)- 15,15 -dimethylperhydropyrido[2, I1-c] 1,9,4]dioxazacyclononadecine- 1, 1,2,16,1 7-tetraone; (24aS)- 17,1 7-dimethylperhydropyrido[2, I1-c] 1,9,4]dioxazacyclohenicosine- 1, 1,4,18,1 9-tetraone; ethyl 1 -(2-oxo-3 -phenylpropanoyl)-2-piperidinecarboxylate; ethyl 1 -pyruvoyl-2-piperidinecarboxylate; ethyl 1 -(2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -(3-methyl-2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -(4-methyl-2-oxopentanoyl)-2-piperidinecarboxylate; V6000ethyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-[2-(ethyloxycarbonyl)piperidino] -2,2-dimethyl-3 ,4-dioxobutylacetate; ety :00900rxttrhdo2-2prnl--ooctl ieiiecroyae ethyl 1 -[2-(2-methoxytetrahydro-2H-2-pyranyl)-2-oxoacetyl] -2-piperidinecarboxylate; 1 -[2-(21-mtoerhydroohexnyl)-2-oxoacetyl]-2-piperidinecarboxylate; ethyl 1 -methoxycyclohexyl)-2-oxoacetyl]-2-piperidinecarboxylate; V. 45 ethyl 1 -[2-(l-excyclohexyl)-2-oxoacetyl-2-piperidinecarboxylate; ethyl 1 -(2-oxo-2-piperidinoacetyl)-2-piperidinecarboxylate; ethyl 1 ,4-dihydro-2H-6-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate; ethyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; ethyl 1 -(4-methyl-2-oxo-l1-thioxopentyl)-2-piperidinecarboxylate; 3-phenylpropyl 1 -(2-hydroxy-3 ,3 -dimethylpentanoyl)-2-piperidinecarboxylate; 79 (1 R)-l1-phenyl-3 -trimethoxyphenyl)propyl 1 -dimethylbutanoyl)-2- piperidinecarboxylate; (1 1,3 -diphenyipropyl 1 -(benzylsulfonyl)-2-piperidinecarboxylate; 3-(3 ,4,S -trimethoxyphenyl)propyl 1 -(benzylsulfonyl)-2-piperidinecarboxylate; 1 3R, 3E, 5E, 7E, 9S, 1 1R)-2, 13-dimethoxy-3,9, 11 -trimethyl-1 2-oxo-3,5,7- tridecatrienyl]2-hydroxy -3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylic acid; methyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13 -dimethoxy-3,9,11I-trimethyl- 12-oxo- ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; isopropyl 3R, 3E, 5E, 7E, 9S, 11IR)-2,13-dimethoxy-3,9,1 1-trimethyl-12- oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; benzyl 3R, 3E, 5E, 7E, 9S, I11R)-2,13-dimethoxy-3,9,1 1-trimethyl-12-oxo- ,7-tridecatrienyl] -2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; 1 -phenylethyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1 -trimethyl- 1 2-oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; (Z)-3-phenyl-2-propenyl 3R, 3E, 5E, 7E, 9S, 11IR)-2,13-dimethoxy-3,9,1 1- trimethyl- 12-oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)- 2-piperidinecarboxylate; 3-34dmtoyhny:rpl1(-(R 3R, 6S)-6-II(2S, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy- 3,91 1trietyl-2-oo-35,-trdectriny]-2hydoxy-3 -methyltetrahydro-2H-2-pyranyl)-2- oxoacetyl)-2-piperidinecarboxylate; N2-benzyl-1-(2-[(2R, 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl-12- oxo-3,S ,7-tridecatrienyl] -2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; N2-(3-phenylpropyl)-1-(2-[(2R, 3R, 3E, 5E, 7E, 9S, I11R)-2,13-dimethoxy-3,9,11I- trimethyl- 12-oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)- 2-piperidinecarboxylate; ,4-dichlorophenyl)-2-propenyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; -trimethoxyphenyl)-2-propenyl 1 -dimethyl-2-oxopentanoyl)-2- piperidinecarboxylate; (E)-3-phenyl-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; -dimethoxy)-phenylpropyl)phenyl)-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2- piperidinecarboxylate; -benzodioxol-S -yl)-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2- piperidinecarboxylate; 4-(4-methoxyphenyl)butylI 1-(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; 3-phenyipropyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; 3 -pyridyl)propyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; 3 -pyridyl)propyl 1 -(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-phenyl-l1-(3 -phenylpropyl)butyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1 -(4-methoxyphenethyl)-4-phenylbutyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 3 -dimethoxyphenyl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 3 -benzodioxol-5 -yl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1 -phenethyl-3 -phenyipropyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -cyclohexylpropyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -phenyipropyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3 -cyclohexylpropyl 1 ,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; 3 -phenyipropyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; and 4-phenyl-l1-(3 -phenylpropyl)butyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; pharmaceutically acceptable salts, esters, and solvates thereof.

8. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is a six- membered heterocyclic compound having a single nitrogen heteroatom, wherein said compound is of a non-immuno suppressive six-membered heterocyclic compound having a single nitrogen hetero atom which has an N-linked ketone, diketo, or thioketo sub stituent, and which is additionally substituted with an ester or amide sub stituent attached to the heterocyclic ring, provided that said ester or amide sub stituent is not an N-oxide of an ester or amide, wherein said compound 45 has an affinity for an FKBP-type immunophilin.

9. The use of claim 8, wherein the FKBP-type immunophilin is FKBP-12. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is Way- 124,466.

11. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is rapamycin.

12. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is Rap-Pa.

13. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is SLB-

506. 14. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is selected from: 4-(4-methoxyphenyl)butyl(2S)- ,4,5-trimethoxyphenyl)acetyl]hexahydro-2- pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)- ,4,5 -trimethoxyphenyl)acryloyl]hexahydro-2- pyridinecarboxyl ate; 4-(4-methoxyphenyl)butyl(2S)- 1 ,4,5 -trimethoxyphenyl)propanoyl]hexahydro-2- pyridinecarboxylate; 4-(4-methoxyphenyl)butyl(2S)- 1 -[2-oxo-2-(3 ,4,5 -trimethoxyphenyl)acetyl]hexahydro-2- pyridinecarboxylate; 3 -cyclohexylpropyl(2S)- 1 ,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 3 -phenylpropyl(2S)- 1 ,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 3 -trimethoxyphenyl)propyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2- ~:pyridinecarboxylate; (I R)-2,2-dimethyl- 1 -phenethyl-3-butenyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2- 35 pyridinecarboxylate; (1 1,3 -diphenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; (1 R)-l1-cyclohexyl-3-phenylpropyl(2S)-l1-(3,3 -dimethyl-2-oxopentanoyl)hexahydro-2- pyridinecarboxylate; (1 1,3 -diphenylpropyl(2S)- 1-(3,3 -dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate; 82 (1 1 -cyclohexyl-3 -phenylpropyl(2S)- 1 -dimethyl-2-oxopentanoyl)hexahydro-2- pyridinecarboxylate; (22aS)- 1 5,15 -dimethylperhydropyrido[2, 1 1,9,4]dioxazacyclononadecine- 1, 1,2,16,1 7-tetraone; (24aS)- 1 7,1 7-dimethylperhydropyrido[2, I1-c] [1 ,9,4]dioxazacyclohenicosine- 1, 1,4,18,1 9-tetraone; ethyl 1 -(2-oxo-3 -phenylpropanoyl)-2-piperidinecarboxylate; ethyl 1 -pyruvoyl-2-piperidinecarboxylate; ethyl 1 -(2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -(3-methyl-2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -(4-methyl-2-oxopentanoyl)-2-piperidinecarboxylate; ethyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; ethyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-[2-(ethyloxycarbonyl)piperidino]-2,2-dimethyl-3 ,4-dioxobutylacetate; ethyl 1 -[2-(2-hydroxytetrahydro-2H-2-pyranyl)-2-oxoacetyl]-2-piperidinecarboxylate; ethyl 1 -[2-(2-methoxytetrahydro-2H-2-pyranyl)-2-oxoacetyl]-2-piperidinecarboxylate; ethyl 1 1-hydroxycyclohexyl)-2-oxoacetyl]-2-piperidinecarboxylate; ethyl 1 -methoxycyclohexyl)-2-oxoacetyl]-2-piperidinecarboxylate; ethyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; ethyl 1 -(2-oxo-2-piperidinoacetyl)-2-piperidinecarboxylate; ethyl I ,4-dihydro-2H-6-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate; ethyl 1 -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; ethyl 1 -(4-methyl-2-oxo-l1-thioxopentyl)-2-piperidinecarboxylate; 3-phenyipropyl 1 -(2-hydroxy-3 ,3 -dimethylpentanoyl)-2-piperidinecarboxylate; (1 R)-l1-phenyl-3 -trimethoxyphenyl)propyl 1 ,3-dimethylbutanoyl)-2- piperidinecarboxylate; (1 1,3 -diphenylpropyl 1 -(benzylsulfonyl)-2-piperidinecarboxylate; 3 -trimethoxyphenyl)propyl 1 -(benzylsulfonyl)-2-piperidinecarboxylate; 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl-12-oxo-3,5,7- tridecatrienyl]2-hydroxy -3-methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylic acid; methyl 3R, 3E, 5E, 7E, 9S, I1IR)-2,13-dimethoxy-3,9,1 1-trimethyl-12-oxo- ,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- 83 piperidinecarboxylate; isopropyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl-12- oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; benzyl 3R, 3E, 5E, 7E, 9S, I11R)-2,13-dimethoxy-3,9,11I-trimethyl-12-oxo- ,7-tridecatrienyl] -2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; I1-phenylethyl 3R, 3E, 5E, 7E, 9S, I1IR)-2,13-dimethoxy-3,9,11I-trimethyl- 1 2-oxo-3,5,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; (Z)-3-phenyl-2-propenyl 3R, 3E, 5E, 7E, 9S, I11R)-2,13-dimethoxy-3,9,1 1- trimethyl- 12-oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)- 2-piperidinecarboxylate; 3-(3,4-dimethoxyphenyl)propyl 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy- 3,9,1 1-trimethyl- 12-oxo-3 ,S,7-tridecatrienyl] -2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2- oxoacetyl)-2-piperidinecarboxylate; N2-benzyl-1-(2-[(2R, 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1-trimethyl-12- oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3 -methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2- piperidinecarboxylate; N2-(3-phenylpropyl)-1-(2-[(2R, 3R, 3E, 5E, 7E, 9S, 1 1R)-2,13-dimethoxy-3,9,1 1- trimethyl- 12-oxo-3 ,S,7-tridecatrienyl]-2-hydrox y-3-methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)- 2-piperidinecarboxylate; ,4-dichlorophenyl)-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; -(3,4,S-trimethoxyphenyl)-2-propenyl 1 ,3-dimethyl-2-oxopentanoyl)-2- piperidinecarboxylate; -phenyl-2-propenyl 1 -(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; -dimethoxy)-phenylpropyl)phenyl)-2-propenyl 1 -(3,3-dimethyl-2-oxopentanoyl)-2- piperidinecarboxylate; -benzodioxol-S -yl)-2-propenyl 1 -dimethyl-2-oxopentanoyl)-2- piperidinecarboxylate; 4-(4-methoxyphenyl)butyl I -(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate; -heypopl1-2-x--peyactl--ppr45eaboyae 3. 3 -penylpropyl I -(2-oxo-2-phenylacetyl)-2-piperdinecarboxylate; 50 3 -pyridyl)propyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; ~4-phenyl-l1-(3 -phenylpropyl)butyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 ,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1 -(4-methoxyphenethyl)-4-phenylbutyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 84 3-(2,5 -dimethoxyphenyl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1,3 -benzodioxol-5 -yl)propyl 1 -dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 1 -phenethyl-3 -phenyipropyl 1 -(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3-cyclohexyipropyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3-phenyipropyl 1 -(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate; 3-cyclohexyipropyl 1 ,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; 3-phenyipropyl 1 ,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; 4-(4-methoxyphenyl)butyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; and 4-phenyl-l1-(3 -phenylpropyl)butyl 1 -dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate; pharmaceutically acceptable salts, esters, and solvates thereof A method for treating alopecia or promoting hair growth, substantially as herein described with reference to any one of the embodiments of the invention as illustrated in the accompanying drawings and/or examples but excluding comparative examples. 16. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth, substantially as herein described with reference to any one of the of the invention as illustrated in the accompanying drawings and/or examples but excluding comparative examples. *DATED this 2 4 1h Day of March 2003 BALDWIN SHELSTON WATERS Attorneys for: GPI NIL Holdings, Inc