AU761737B2

AU761737B2 - N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses

Info

Publication number: AU761737B2
Application number: AU77168/98A
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: 2003-06-12
Anticipated expiration: 2018-06-03
Also published as: AU7716898A; CA2334032A1; JP2002516842A; EP1082095A1; WO1999062486A1

Description

WO 99/62486 PCT/US98/11245 N-OXIDE OF HETEROCYCLIC ESTER, AMIDE, THIOESTER, OR KETONE 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 low molecular weight, small molecule N-oxides of heterocyclic esters, amides, thioesters, or ketones.

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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 2 The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific 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 of 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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 3 5,284,840; Organ et al., U.S. Patent No. 5,284,877).

These patents claim FK506 related compounds. Although 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 SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 4 nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and nonimmunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.

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 an N-oxide of a heterocyclic ester, amide, thioester, or ketone.

The present invention further relates to a pharmaceutical composition which comprises: an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

The N-oxides of heterocyclic esters, amides, thioesters, or ketones used in the inventive methods and pharmaceutical compositions have an affinity for FKBP-type immunophilins and do not exert any significant immunosuppressive activity.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a photograph of C57 Black 6 mice before being shaved for the hair regeneration experiment.

FIG. 2 is a photograph of mice treated with a vehicle after six weeks. FIG. 2 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.

FIG. 3 is a photograph of mice treated with 10 AM of GPI 1046, a related non-immunosuppressive neuroimmunophilin FKBP ligand, after six weeks. FIG. 3 shows the remarkable effects of neuro-immunophilin FKBP ligands, wherein 90% of the shaved area is covered with new hair growth.

FIG. 4 is a photograph of mice treated with 30 iM of GPI 1046, a related non-immunosuppressive neuroimmunophilin FKBP ligand, after six weeks. FIG. 4 shows the remarkable ability of these compounds to achieve, essentially, complete hair regrowth in the shaved area.

FIG. 5 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, and various non-immunosuppressive neuroimmunophilin FKBP ligands 14 days after treatment with each identified compound. Figure 5 demonstrates the remarkable early hair growth promoted by a wide variety of non-immunosuppressive neuroimmunophilin FKBP ligands.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 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 1605" refers to a compound of formula

S

0 GPI 1605 "GPI 1046" refers to 3-(3-pyridyl)-1-propyl (2s)- 1- (3,3-dimethyl-l, 2-dioxopentyl) -2pyrrolidinecarboxylate, a compound of formula SUBSTITUTE SHEET (RULE 26) WO 99/62486 WO 9962486PCTIUS98/1 1245 7

N

0 Ny 0 0 0 01 GPI1046 tIGPI 1312" refers to a compound of formula

N

0=300 0-1 GPI 1312 "GPI 1572"1 refers to a compound of formula GPI 1572 "GPI 1389"1 refers to a compound of formula GPI 1389 "GPI 1511"1 refers to a compound of formula GPI 1511 SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 8 "GPI 1234" refers to a compound of formula N oS GPI 1234 "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 such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/IS98/11245 9 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. Examples 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.

"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; SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 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 (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 SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 11 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 an N-oxide of a heterocyclic ester, amide, thioester, or ketone.

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: an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone for treating alopecia or promoting hair growth in an animal; and SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 12 (ii) a pharmaceutically acceptable carrier.

N-OXIDES OF HETEROCYCLIC ESTERS, AMIDES, THIOESTERS, AND KETONES The N-oxides of heterocyclic esters, amides, thioesters, and ketones used in the methods and pharmaceutical compositions of the present invention are low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins, such as FKBP12. When an N-oxide of a heterocyclic ester, amide, thioester, or ketone binds to an FKBP-type immunophilin, it has been found to inhibit the prolylpeptidyl cis-trans isomerase, or rotamase, activity of the binding protein. Unexpectedly, these compounds have also been found to stimulate hair growth. The compounds are devoid of any significant immunosuppressive activity.

FORMULA I The N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula I

B

A X-Y-Z

I

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 13 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH,

CH

2 O, S, SO, SO 2 N, NH and NR,; W is O, S, CH 2 or H 2 R is Ci-C, straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl,

C-C

7 cycloalkenyl, or Ar, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 1 C, alkyl, C 2

-C

4 alkenyl, hydroxy, C 3

-C

8 cycloalkyl, C 5

-C,

cycloalkenyl, and Ar 2 Ar and Ar 2 are independently selected from the group consisting of l-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 2

-C,

alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRI, S, CH, CR 1 or CRR 3 Y is a direct bond, C 1

-C

6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 14 substituted with one or more substituent(s) independently selected from the group consisting of C 1

C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3 cycloalkyl, Cs-C 7 .cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with alkyl, C 2

-C

4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH,

NR

2 S, SO, or SO,;

R

2 is selected from the group consisting of hydrogen, Cl-C, straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, and C,- C, bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Ci-C, straight or branched chain alkyl, C 2

-C

6 straight or branched SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCTIUS98/11245 chain alkenyl, Ci-C, alkoxy, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4

R

5 sR, wherein R 4 Rs, and

R

6 are independently selected from the group consisting of CI-C 6 straight or branched chain alkyl or C,-C, straight or branched chain alkenyl optionally substituted with one or more substituenc(s) independently selected from the group consisting of Ci-

C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, C 5

-C

7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C, alkyl, C 2

-C

4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NRI, S, SO, or SO 2 Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and RI and R 3 are independently hydrogen, CI-C 4 straight or branched chain alkyl, C 3 straight or branched chain alkenyl or alkynyl, or Y-Z.

FORMULA II Additionally, the N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula II SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 16

F/G

X-Y-Z

w

R

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH 2 O, S, SO,

SO

2 NH or NR,; W is O, S, CH 2 or H,; R is CI-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3 cycloalkyl,

C

5

-C

7 cycloalkenyl, or Ar, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ci- C, alkyl, C 2

-C

4 alkenyl, hydroxy, C 3 cycloalkyl, C 5

-C

cycloalkenyl, and Ar,; Ar 1 is selected from the group consisting of 1napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4pyridyl, and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C.-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, and amino; SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 17 X is O, NH, NRi, S, CH, CRi, or CRR 3 Y is a direct bond, Ci-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C,-

C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, C 5

-C

7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C alkyl, C 2

-C

4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH,

NR

2 S, SO, or SO 2

R

2 is selected from the group consisting of hydrogen, C,-C 4 straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, and Ci-

C

4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, and isoquinolinyl, which is either unsubstituted or substituted with one or more SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 18 substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl,

C-C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 1 alkoxy, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4

R

5 wherein R 4 Rs, and

R

6 are independently selected from the group consisting of CI-C 6 straight or branched chain alkyl and C 2

-C

6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 1

-C

6 straight or branched chain alkyl,

C

2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, C 5

-C

7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C 4 alkyl, C 2

-C

4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR,, S, SO, or SO 2 Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, Ci-C 4 straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, or Y-Z.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 19 FORMULA III The N-oxide of a heterocyclic ester, amide, thioester, or ketone may further be a compound of formula III

F-G

E X-Y--Z.

III

O O

R

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH 2 O, S, SO, SO,, NH or NR,; W is 0, S, CH 2 or H 2 R is Ci-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C3-C, cycloalkyl, Cs-C, cycloalkenyl, or Ar 1 which is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cj- C, alkyl, C 2

-C

4 alkenyl, hydroxy, C 3

-C

8 cycloalkyl, Cs-C, cycloalkenyl, and Ar,; Ar is selected from the group consisting of 1napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NR,, S, CH, CR 1 or CRiR 3 Y is a direct bond, CI-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cj-

C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, Cs-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with CI-C, alkyl, C 2

-C

NR

2 S, SO, or SO 2

R

2 is selected from the group consisting of hydrogen, straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, and C,- C, bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 21 Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl,

C,-C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 1

-C

4 alkoxy, C,-C, alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4 RsR, wherein R 4 Rg, and R, are independently selected from the group consisting of C 1

-C

6 straight or branched chain alkyl and C 2

-C

6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C,-C straight or branched chain alkyl,

C

2 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, Cs-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C 4 alkyl, C 2

-C

4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR,, S, SO, or SO 2 Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 22 R, and R 3 are independently hydrogen, C--C 4 straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, or Y-Z.

FORMULA IV Moreover, the N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula IV CH2)n

X-Y-Z

N

IV

0 0

R

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2, or 3, forming a 5-7 member heterocyclic ring; W is O, S, CH 2 or H 2 R is Ci-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, cycloalkenyl, or Ar 1 which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 1

C

4 alkyl, C 2

-C

4 alkenyl, hydroxy, C 3 cycloalkyl, Cs-C, cycloalkenyl, and Ar,; SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 23 Ar, is selected from the group consisting of 1-, napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRi, S, CH, CR 1 or CRjR 3 Y is a direct bond, C,-C 6 straight or branched chain alkyl, or C 2 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C,-

C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, C 5

-C,

cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with alkyl, C 2

-C

4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR,, S, SO, or SO 2

R

2 is selected from the group consisting of hydrogen, Ci-C, straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, and C,- C, bridging alkyl wherein a bridge is formed between SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 24 the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, straight or branched chain alkenyl, Cl-C, alkoxy, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4 RsR 6 wherein R 4

R

5 and

R

6 are independently selected from the group consisting of C,-C straight or branched chain alkyl and C 2

-C

6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl,

C

2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, C 5 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C-C, alkyl, C 2

-C

4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is SUBSTITUTE SHEET (RULE 26) WO 99/62486 WO 9962486PCTIUS98/1 1245 optionally replaced with 0, NH, NR,, S, SO, or SO 2 Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R

1 and R 3 hydrogen, Cl-C, straight or branched chain alkyl, C 3 straight or branched chain alkenyl or alkynyl, or Y-Z.

Examples of the compounds of formula IV when W is O are presented in TABLE I.

TABLE I

(CH

2 n 0 0 0

R

No. nX Y Z R 1 1 2 1 3 1 4 1 1 6 1 o 3 o (CH 2 3 o (CH 2 3 o (CH 2 3 o (CH 2 3 o (CH 2 3 3-Pyridyl N-oxide 2-Pyridyl N-oxide 4-Pyridyl N-oxide 2-Quinolyl N-oxide 3-Quinolyl N-oxide 4-Quinolyl N-oxide 1, 1 -dimethyipropyl 1,1 -dimethyipropyl 1, 1-dimethyipropyl 1, 1-dimethylpropyl 1, 1-dimethyipropyl 1, 1 -dimethyipropyl SUBSTITUTE SHEET (RULE 26) WO 99/62486 WO 9962486PCTIUS98/1 1245 26 Preferred compounds of formula IV may be selected from the group consisting of: 3- (2-Pyridyl) -1-propyl (2S) 1-Dimethyl-1,2dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-Pyridyl) -1-propyl (2S) (l,-Dimethyl-l,2dioxopentyl) -2 -pyrrolidinecarboxylate, N-oxide; 3- (4-Pyridyl) -1-propyl (2S) (1,l1-Dimethyl-1,2dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (2-Quinolyl) -1-propyl (2S) (1,l1-Dimethyl-l,2dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-Quinolyl) -1-propyl (2S) 1-Dimethyl-l, 2dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (4-Quinolyl) -1-propyl (2S) (1,l1-Dimethyl-1,2dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; and pharmaceutically acceptable salts, esters, and solvates thereof.

FORMULA V The N-oxide of a heterocyclic ester, amide, thioester, or ketone may further be a compound of formula V

B

1 A yXYZV SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 27 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is C, N, or S; A and B, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO 2 N, NH, and NR,; R, is either Cl-C 9 straight or branched chain alkyl, C 2

-C

9 straight or branched chain alkenyl, C 3

-C,

cycloalkyl, C 5

-C

7 cycloalkenyl, or Ar 3 wherein R, is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, alkoxy, C 2 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar,; Ar 3 and Ar, are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and R, W, X, Y, and Z are as defined in Formula I above.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 28 All the compounds of Formulas I-V 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-V. It is understood that the compounds of Formulas I-V 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.

K, 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 SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 29 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 II.

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 LiCI 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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 Data is presented in Table II for 3-(3-Pyridyl)- 1-propyl(2S)-- (1,1-Dimethyl-1,2-dioxopentyl)-2pyrrolidine-carboxylate, N-oxide (compound 1) and its parent (unoxidized) compound.

Table II In Vitro Test Results Formulas I to V Compound Ki (nM) Parent 1 225 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 compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT[US98/1 1245 31 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.

Dosace 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 other hair revitalizing agents will depend upon the SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 32 factors 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 Synthesis of 3-(3-pyridvl)-1-propyl Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide (1) Methyl (1,2-dioxo-2-methoxvethvl)-2pyrrolidinecarboxylate A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in dry methylene chloride was cooled to 0°C and treated with triethylamine (3.92 g; 38.74 mmol; 2.1 eq) After stirring the formed slurry under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hour. After filtering to remove solids, the organic phase was washed with water, dried over MgSO, and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCTIUS98/11r245 33 in hexane, to obtain 3.52 g of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. 'H NMR (CDC1 3 6 1.93 (dm, 2H); 2.17 2H) 3.62 2H) 3.71 3H) 3.79, 3.84 3H total); 4.86 (dd, 1H, J 8.4, 3.3).

Methyl(2S)-l-(1,2-dioxo-3,3-dimethylpentyl)-2pyrrolidinecarboxylate A solution of methyl (2S)-1-(1,2-dioxo-2methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -780C and treated with 14.2 mL of a 1.0 M solution of 1,l-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -780C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g of the oxamate as a colorless oil. 'H NMR (CDC3) 6 0.88 3H); 1.22, 1.26 3H each); 1.75 (dm, 2H); 1.87-2.10 3H) 2.23 1H) 3.54 2H) 3.76 3H) 4.52 (dm, 1H, J 8.4, 3.4).

(2S) (1,2-dioxo-3,3-dimethylpentvl) -2 pyrrolidinecarboxylic acid A mixture of methyl (2S)-1-(1,2-dioxo-3,3dimethylpentyl-2-pyrrolidine-carboxylate (2.10 g; 8.23 SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 34 mmol), 1 N LiOH (15 mL), and methanol (50 mL) was stirred at 0°C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HC1, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g of snow-white solid which did not require further purification. 'H NMR (CDC3) d 0.87 3H) 1.22, 1.25 3H each); 1.77 (dm, 2H); 2.02 2H); 2.17 1H) 2.25 1H) 3.53 (dd, 2H, J 10.4, 7.3); 4.55 (dd, 1H, J 8.6, 4.1).

3- (3-Pvridyl) -1-proVyl (2S) (3,3-dimethyl-1,2dioxopentvl)-2-pyrrolidinecarboxylate A mixture of (2S)-1-(1,2-dioxo-3,3dimethylpentyl)-2-pyrrolidinecarboxylic acid (4.58 g; 19 mmol), 3-pyridinepropanol (3.91 g; 28.5 mmol), dicyclohexylcarbodiimide (6.27 g; 30.4 mmol), camphorsulfonic acid (1.47 g; 6.33 mmol) and 4dimethyl aminopyridine (773 mg; 6.33 mmol) in methylene chloride (100 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo. The crude material was triturated with several portions of ether, and the ether portions were filtered through Celite to remove solids and concentrated in vacuo. The concentrated filtrate was purified on a flash column (gradient elution, 25% ethyl acetate in hexane to pure ethyl SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 acetate) to obtain 5.47 g of GPI 1046 as a colorless oil (partial hydrate). 'H NMR (CDC1 3 300 MHz): 6 0.85 3H); 1.23, 1.26 3H each); 1.63- 1.89 2H); 1.90-2.30 4H) 2.30-2.50 1H) 2.72 2H) 3.53 2H) 4.19 2H) 4.53 (m, 1H) 7.22 1H) 7.53 (dd, 1H); 8.45. Analysis calculated for C 20

H

28 NO, 0.25 H 2 0: C, 65.82; H, 7.87; N, 7.68. Found: C, 66.01; H, 7.85; N, 7.64.

3-(3-Pyridvl)-1-propyl (2S)-1-(3,3-dimethyl-1,2dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide (1) A solutionof 3-(3-pyridyl)-1-propyl dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate (190 mg; 0.52 mmol) and m-chloroperbenzoic acid (160 mg of 57%-86% material, 0.53 mmol) was stirred in methylene chloride (20 mL) at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride and washed twice with 1 N NaOH.

The organic extract was dried and concentrated, and the crude material was chromatographed, eluting with 10% methanol in ethyl acetate, to obtain 130 mg of the Compound 1 of Example 1. 'H NMR (CDCl 3 300 MHz) 6 0.83 3H) 1.21 3H) 1.25 3H) 1.75-2.23 8H); 2.69 2H, J 3.52 2H, J 6.3); 4.17 (dd, 2H, J 4.51 1H); 7.16-7.22 (m, 2H) 8.06-8.11 2H) Analysis calculated for

C

20

H

2 8

N

2 0 5 0.75 H 2 0: C, 61.60; H, 7.63; N, 7.18.

Found: C, 61.79; H, 7.58; N, 7.23.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 36 Example 2 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 a low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligand, GPI 1046, which is related to N-oxides of heterocylic esters, amides, thioesters, and ketones. Referring now to FIGS. 1 and 2 of the drawings, 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. 2, 3 and 4, four animals per group were treated by topical administration with 20% propylene glycol vehicle (FIG. 10 pM GPI 1046 (FIG. 3) or 30 yM GPI 1046 (FIG. 4) dissolved in the vehicle. The animals were treated with vehicle or GPI 1046 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. 2 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 SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 37 covered with new growth. In contrast, FIG. 3 shows that animals treated with 10 pM GPI 1046 exhibited dramatic hair growth, covering greater than 90% of the shaved area in all animals. Further, FIG. 4 shows that mice treated with 30 IpM GPI 1046 exhibited essentially complete hair regrowth and their shaved areas were indistinguishable from unshaven C57 black 6 mice.

Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of various low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligands.

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 topical administration with a vehicle, FK506, or one of the low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligands (GPI 1605, 1046, 1312, 1572, 1389, 1511, and 1234) 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 observer, on a scale of SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 38 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 any one of the low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligands exhibited dramatic hair growth.

Example 3 A lotion comprising the following composition may be prepared.

Ethanol 180.0 an N-oxide of a heterocylic ester, amide, 10.0 thioester, or ketone as defined above 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 an N-oxide of a heterocylic ester, amide, thioester, or ketone, utocopherol acetate, ethylene oxide (40 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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 39 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia.

Example 4 A lotion comprising the following composition may be prepared.

95% Ethanol 80.0 an N-oxide of a heterocylic ester, amide, 0.005 thioester, or ketone as defined above 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 an N-oxide of a heterocylic ester, amide, thioester, or ketone, 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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 Example 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 an N-oxide of a heterocylic ester, amide, 0.01 thioester, or ketone as defined above (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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 41 Example 6 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) an N-oxide of a heterocylic ester, amide, 0.8 thioester, or ketone as defined above 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 0 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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT[US98/11245 42 Example 7 A liquid comprising the following composition may be prepared.

Polyoxyethylene butyl ether 20.0 Ethanol 50.0 an N-oxide of a heterocylic ester, amide, 0.001 thioester, or ketone as defined above 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, an N-oxide of a heterocylic ester, amide, thioester, or ketone, 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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCTIUS98/11r245 43 Example 8 A shampoo comprising the following composition may be prepared.

Sodium laurylsulfate Triethanolamine laurylsulfate Betaine lauryldimethylaminoacetate Ethylene glycol distearate Polyethylene glycol an N-oxide of a heterocylic ester, amide, thioester, or ketone 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 an N-oxide of a heterocylic ester, amide, thioester, or ketone, 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.

SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 44 Example 9 A patient is suffering from alopecia senilis. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 male pattern alopecia. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 alopecia areata. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 12 A patient is suffering from hair loss caused by skin lesions. An N-oxide of a heterocylic ester, amide, thioester, or ketone as identified above, or a SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 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 tumors. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 a systematic disorder, such as a nutritional disorder or an internal secretion disorder. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 chemotherapy. An N-oxide of a heterocylic ester, amide, thioester, or ketone as identified above, or a pharmaceutical composition comprising the same, may be SUBSTITUTE SHEET (RULE 26) WO 99/62486 PCT/US98/11245 46 administered to the patient. Increased hair growth is .lexpected to occur following treatment.

Example 16 A patient is suffering from hair loss caused by radiation. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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.

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 o000 the scope of the following claims.

000* Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, o. component or group thereof t..rtrW V.V.V. C. YVfl n.r ~fl 'V fl

Claims

1. A method for treating alopecia or promoting hair growth in an animal in need thereof, comprising administering an effective amount of a nitrogen- containing heterocyclic compound which has an N-linked ketone, diketo, or thioketo substituent, and which compound is additionally substituted with an N-oxide of an ester, amide, thioester, or ketone substituent attached to the heterocyclic ring.

2. The method of claim 1, wherein the compound is of formula I B A *II 0 0 R 20 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring which has any combination of CH, CH2, O, S, SO, SO 2 N, NH and NRj; W is O, S, CH2, or two hydrogen atoms; 48 R is Cl-C6 straight or branched chain alkyl, C2-Cg straight or branched chain alkenyl, C3-C8 cycloalkyl, C, cycloalkenyl, or Ar,, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of CI-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C 8 cycloalkyl, C5-C7 cycloalkenyl, and Ar 2 Ari and Ar 2 are independently selected from the group consisting of l-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar 1 and Ar 2 independently have one or more substituent(s) independently 15 selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Ci-C6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl,. C2-C4 alkenyloxy, phenoxy, benzyloxy, 20 and amino; X is 0, NH, NRj, S, CH 2 CHR, or CRR 3 Y is a direct bond, C,-C6 straight or branched chain alkyl, or C2-C, straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group 49 consisting of Ci-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C, cycloalkyl, C5-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally i replaced with O, NH, NR,, S, SO, or SO2; R2 is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C-C4 bridging alkyl, wherein a bridge is formed between the 20 nitrogen and a carbon atom of said alkyl or g alkenyl to form a ring, C wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Cl-Cg straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, CI-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 RsR 6 wherein R 4 Rs, and R 6 are independently selected from the group consisting of Ci-C 6 straight or branched chain alkyl and C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is 9 15 optionally substituted with one or more substituent independently selected from the group consisting of C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched 20 chain alkenyl, C 3 -C 8 cycloalkyl, 99 C cycloalkenyl, hydroxy, carbonyl 9 oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C4 alkyl, C2-C4 51 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, c y cloal k y cycloalkenyl, or Ar is optionally replaced with O, NH, NRI, S, SO, or SO 2 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, Ci-C 4 straight e* 0 or branched chain alkyl, C3-C4 straight or branched 15 chain alkenyl or alkynyl, or Y-Z. *0A

3. The method of claim 1, wherein the compound A is of formula II F/'J 0 0 2 :20 F E X-Y-Z .0 N 0 0 W 0 R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, SO2,, NH or NR,; 52 W is O, S, CH 2 or two hydrogen atoms; R is Ci-C, straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C3-C, cycloalkyl, C7 cycloalkenyl, or Ari, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ci-C4 alkyl, C2-C4 alkenyl, hydroxy,. C3-C, cycloalkyl, Cs-C, cycloalkenyl, and Arl; Ar is selected from the group consisting of 1- naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and phenyl, wherein said Ar has one or more t 15 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C2-C6 o *e straight or branched chain alkenyl, C2-C4 20 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRi, S, CH2, CHR 1 or CRR 3 Y is a direct bond, C-CG straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group 53 consisting of C1-CG straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, 10 wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally replaced with O, NH, NR 2 S, SO, or SO 2 15 R 2 is selected from the group consisting of hydrogen, Ci-C 4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, 54 which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Cl-C, straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 R 5 R 6 .1 0 wherein R 4 R 5 and R 6 are independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl and C 2 -C 6 straight or branched chain alkenyl, -wherein said alkyl or alkenyl is 15 optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C, cycloalkyl, C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with CI-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, c y cloal k y cycloalkenyl, or Ar is optionally replaced with O, NH, NRI, S, SO, or SO 9 .1 0 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, Ci-C 4 straight 9 or branched chain alkyl, C3-C4 straight or branched o 15 chain alkenyl or alkynyl, or Y-Z. is of formula III 9 G E YX-Y-Z R III or a pharmaceutically acceptable salt, ester, or solvate the method of claim of, wherein the compoundwherein: E, F, and G are independently CH2, O, S, SO, SO2 is of formula III W is S, CH r 20 hydrogen atoms; °F\v° R III or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH 2 0, S, SO, SO2, NH or NRi; W is 0, S, CH 2 or two hydrogen atoms; 56 R is C-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C7 cycloalkenyl, or Ar,, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of C,-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, and Ar 1 Ar 1 is selected from the group consisting of 1- naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and phenyl, wherein said Ar, has one or more a substituent(s) independently selected from S. .15 the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRi, S, CH 2 CHRi, or CR 1 R 3 Y is a direct bond, straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ci-C6 straight or branched chain 57 alkyl, C2-C6 straight or branched chain alkenyl, C3-C, cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said 10 alkyl, alkenyl, cycloalkyl, or 9 cycloalkenyl, is optionally replaced with O, NH, NR 2 S, SO, or SO,; R2 is selected from the group consisting of 15 hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 9** f 0 straight or branched chain alkenyl or alkynyl, and C1-C4

9. bridging alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted 58 with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Ci-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 R 5 R 6 wherein R 4 Rs, and R 6 are independently selected from the group consisting of C-C6 straight or branched chain alkyl and C2-6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting 4 of C,-C6 straight or branched chain alkyl, C2-C, straight or branched chain alkenyl, C3-C, cycloalkyl, Cs- C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C4 alkyl, C2-C4 alkenyl, hydroxy, or 59 carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, c y cloal ky 1 cycloalkenyl, or Ar is optionally replaced with O, NH, NRi, S, SO, or SO 2 Ar is independently selected from the group 10 consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and RI and R 3 are independently hydrogen, Ci-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z. 5. The method of claim 1, wherein the compound S* is of formula IV 2 X-Y--Z -0 0 w R IV or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3 forming a 5-7 member heterocyclic ring; W is O, S, CH 2 or two hydrogen atoms; R is Ci-C6 straight or branched chain alkyl, C2-C, straight or branched chain alkenyl, C3-C 8 cycloalkyl, C, cycloalkenyl, or Arl, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C, alkyl, C 2 -C 4 alkenyl, hydroxy, C3-C, cycloalkyl, C 5 -C 7 cycloalkenyl, and Ar 1 Ar 1 is selected from the group consisting of 1- naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- 10 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and phenyl, wherein said Ari has one or more substituent(s) independently selected from the group consisting of hydrogen, halo, 15 hydroxy, nitro, trifluoromethyl, Ci-C straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRi, S, CH 2 CHRi, or CRiR 3 Y is a direct bond, C-C, straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ci-C6 straight or branched chain alkyl, C2-C6 straight or branched chain 61 alkenyl, C3-C8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C 4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or 10 cycloalkenyl, is optionally replaced with O, NH, NR,, S, SO, or S* SO2; R 2 is selected from the group consisting of hydrogen, Ci-C4 straight or branched chain alkyl, C3-C4 15 straight or branched chain alkenyl or alkynyl, and Ci-C4 9 bridging alkyl, 9. wherein a bridge is formed between the 9 nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently 62 selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 R 5 R 6 wherein R 4 R 5 and R 6 are independently selected from the group consisting of C 1 -C 6 10 straight or branched chain alkyl and C 2 -C 6 0 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently 15 selected from the group consisting go of Cl-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 cycloalkyl, C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, 63 wherein any carbon atom of said alkyl, alkenyl, c y c.1 o a 1 k y 1 cycloalkenyl, or Ar is optionally replaced with 0, NH, NRj, S, SO, or SO 2 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, 01-C4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z. 6. The method of claim 5, wherein the compound is selected from the group consisting of: 3- (2-Pyridyl) -1-propyl (2S) l-Dimethyl-l, 2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3- (3-Pyridyl) -1-propyl (2S) l-Dimethyl-l, 2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3- (4-Pyriyl) -1-propyl (2S) l-Dimethyl-l, 2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3- (2-Quinolyl) -1-propyl (2S) 1-l, l-Dimethyl-l, 2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(3-Quinolyl)-l-propyl(2S)-l-(1,l-Dimethyl-1,2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; and 3- (4-Quinolyl) -1-propyl (2S) -1-Cl, 1-Dimethyl-1, 2- 64 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; or a pharmaceutically acceptable salt, ester, or solvate thereof. 7. A method for treating alopecia or promoting hair growth in an animal in need thereof, comprising administering an effective amount of a compound of formula V *1 *B 1e, A*-XY 0 0 :V is CH or N; to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which has one or more heteroatom(s) selected from the group consisting of S SO Septable salt, esteand NR, or; R, is either Ct-C, straight or branched chain alkyl, C2-C9 Straight or branched chain alkenyl, C3-C, cycloalkyl, C5-C, cycloalkenyl, or Ar3, grou c is CH or N; A and B, taken together with V and the carbon atom wherein R, is either unsubstituted or substituted with one or more substituent(s) independently selected from the group independently selected from the group S S S.. S. S *5 S consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, Ci- C 6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 Ar 3 and Ar 4 are independently an alicyclic or 10 aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the individual ring size is 5-8 members, and wherein said heterocyclic ring has 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; W is O, S, CH 2 or two hydrogen atoms; R is Ci-C 6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C3-Ce cycloalkyl, C7 cycloalkenyl, or Arl, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of CI-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C, cycloalkyl, C5-C7 cycloalkenyl, and Ar 2 Ar 1 and Ar 2 are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 66 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar 1 and Ar 2 independently have one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, 10 and amino; X is O, NH, NRI, S, CH,, CHR 1 or CRjR 3 Y is a direct bond, Ci-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, 4 15 wherein said alkyl or alkenyl is optionally 99 S0 substituted with one or more substituent(s) independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl, C2-C, straight or branched chain alkenyl, C3-C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C -C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said 67 alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally replaced with O, NH, NR 2 S, SO, or SO 2 R 2 is selected from the group consisting of hydrogen, Ci-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and Ci-C 4 bridging alkyl, wherein a bridge is formed between the 10 nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine too* 15 oxidized to a corresponding N-oxide, So wherein said aromatic amine is pyridyl, fo pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 R,R,, wherein R 4 R 5 and R 6 are independently 68 selected from the group consisting of C-C6 straight or branched chain alkyl and C2-Cg straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ci-C 6 straight or branched chain alkyl, C2-C6 straight or branched 10 chain alkenyl, C3-C, cycloalkyl, C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, 15 cycloalkenyl, or Ar is optionally substituted CS with Ci-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, c y cloal k y cycloalkenyl, or Ar is optionally replaced with 0, NH, NRi, S, SO, or SO,; 69 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, CI-C4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z. 8. The method of any one of claims 1-7, wherein the compound is non-immunosuppressive. 9. The method of any one of claims 1-7, wherein the compound has an affinity for an FKBP-type, immunophilin. 15 10. The method of claim 9, wherein the FKBP-type immunophilin is FKBP-12.

11. The method of any one of claims 1-7, wherein the compound is immunosuppressive.

12. A pharmaceutical composition which comprises: an effective amount of a compound for treating alopecia or promoting hair growth in an animal, wherein said compound is of formula V T w V R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is CH or N; A and B, taken together with V and the carbon atom 1. 0 to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which has one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 N, NH, and NR 7 R 7 is either Ci-C 9 straight or branched chain alkyl, 15 C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloalkyl, C 5 -C7 cycloalkenyl, or Ar 3 wherein R, is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, Cj- C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 71 Ar 3 and Ar 4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the individual ring size is 5-8 members, and wherein said heterocyclic ring has 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; SW is 0, S, CH 2 or two hydrogen atoms; 10 R is Ci-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C7 cycloalkenyl, or Arl, wherein said R is optionally substituted with one or more substituent(s) independently 15 selected from the group consisting of C--C alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, and Ar 2 Ari and Ar 2 are independently selected from the group consisting of l-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ari and Ar 2 independently have one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C-C, straight or branched chain alkyl, C2-C6 straight or branched chain 72 alkenyl, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRi, S, CH 2 CHRi, or CRiR 3 Y is a direct bond, Ci-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group 10 consisting of Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C3-C, cycloalkyl, CS-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally replaced with O, NH, NR 2 S, SO, or SO 2 R 2 is selected from the group consisting of hydrogen, Cl-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C,-C4 bridging alkyl, *Y C C C 73 wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, Cz-C 6 straight or branched chain alkenyl, Ci-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 R 5 R 6 wherein R 4 R 5 and R 6 are independently selected from the group consisting of C,-C 6 straight or branched chain alkyl and C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C,-C6 straight or branched chain 74 alkyl, C2-C6 straight or branched chain alkenyl, C 3 cycloalkyl, C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C4 alkyl, C2-C4 10 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, c y cloal k y cycloalkenyl, or Ar is ptionally replaced with O, NH, NRi, S, SO, or SO 2 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, Ci-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, or Y-Z; and (ii) a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein the compound is non-immunosuppressive.

14. The pharmaceutical composition of claim 12, wherein the compound has an affinity for an FKBP-type immunophilin. The pharmaceutical composition of claim 14, wherein the FKBP-type immunophilin is FKBP-12.

16. 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 nitrogen-containing heterocyclic compound 15 which has an N-linked ketone, diketo, or thioketo substituent, and which compound is additionally substituted with an N-oxide of an ester, amide, thioester, or ketone substituent attached to the heterocyclic ring.

17. The use of claim 16, wherein the compound is of formula I SII I 00 W R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, 10 to form a 5-7 membered saturated or unsaturated heterocyclic ring which has any combination of CH, CH,, O, S, SO, SO, N, NH and NRI; W is O, S, CH2, or two hydrogen atoms; R is Ci-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C-C cycloalkyl, C, cycloalkenyl, or Arl, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of C,-C alkyl, C2-C4 alkenyl, hydroxy, C3-C 8 cycloalkyl, C5-C, cycloalkenyl, and Ar 2 Ari and Ar 2 are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ari and Ar 2 independently have one or more substituent(s) independently 77 selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Ci-C6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Cz-C4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRI, S, CH2, CHR 1 or CRjR 3 Y is a direct bond, C 1 -C 6 straight or branched :chain alkyl, or C 2 -C 6 straight or branched chain 10 alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group 1consisting of Ci-C6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C3-C, cycloalkyl, Cs-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally replaced with O, NH, NR 2 S, SO, or SO 2 78 R2. is selected from the group consisting of hydrogen, Cl-C 4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and Ci-C4 bridging alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally fused to an Ar group; 0 10 Z is an aromatic amine or a tertiary amine 0 oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, 0 which is either unsubstituted or substituted 15 with one or more substituent(s) independently 0 selected from the group consisting of halo, 0 0 hydroxy, nitro, trifluoromethyl, C1-C6 0 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, Ci-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 RsR 6 wherein R 4 Rs, and R 6 are independently selected from the group consisting of CI-C, straight or branched chain alkyl and C2-C6 straight or branched chain alkenyl, 79 wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C-CG straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C3-C, cycloalkyl, C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, 10 wherein said alkyl, S alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted S with Ci-C4. alkyl, C,-C4 15 alkenyl, hydroxy, or 0S carbonyl oxygen, 0o 5 wherein any carbon atom of said alkyl, alkenyl, c y cl o a l ky cycloalkenyl, or Ar is optionally replaced with O, NH, NRi, S, SO, or SO 2 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, C1-C4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z.

18. The use of claim 16, wherein the compound is of formula II F/Gj F J E N X-Y-Z N 0 II R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, SO2, 15 NH or NR; W is O, S, CH,, or two hydrogen atoms; 00 R is Cl-C 6 straight or branched chain alkyl, C 2 -C 6 *000 straight or branched chain alkenyl, C3-C 8 cycloalkyl, C,- C7 cycloalkenyl, or Ar,, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of C-C 4 alkyl, C2-C4 alkenyl, hydroxy, C3-C, cycloalkyl, Cs-C7 cycloalkenyl, and Arl; Ar 1 is selected from the group consisting of 1- naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- 81 pyridyl, and phenyl, wherein said Ar has one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, CI-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRI, S, CH 2 CHRi, or CRiR 3 1. Y is a direct bond, Ci-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C 3 cycloalkyl, C 5 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally 82 replaced with O, NH, NR 2 S, SO, or SO2; R 2 is selected from the group consisting of hydrogen, Cl-C 4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and Ci-C4 bridging alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, 10 wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, 0 wherein said aromatic amine is pyridyl, 15 pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, Ci-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 RR 6 wherein R 4 R 5 and R 6 are independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl and C2-CG 83 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C7 cycloalkenyl, hydroxy, carbonyl 10 oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is .optionally substituted with C-C4 alkyl, C2-C 4 g alkenyl, hydroxy, or B carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, c y cloa l ky cycloalkenyl, or Ar is optionally replaced with O, NH, NRi, S, SO, or SO 2 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and 84 R, and R 3 are independently hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, or Y-Z.

19. The use of claim 16, wherein the compound is of formula III F-G E\ X-Y-Z N 0 0w 10 R III o or a pharmaceutically acceptable salt, ester, or C.. solvate thereof, wherein: E, F, and G are independently CH 2 O, S, SO, SO 2 NH or NRi; 15 W is 0, S, CH 2 or two hydrogen atoms; R is Ci-C, straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C, cycloalkyl, C, cycloa.lkenyl, or Arl, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C4 alkyl, Cz-C4 alkenyl, hydroxy, C3-C, cycloalkyl, C5-C, cycloalkenyl, and Ar 1 Ari is selected from the group consisting of 1- naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and phenyl, wherein said Ari has one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Ci-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRI, S, CH 2 CHR 1 or CRjR 3 Y is a direct bond, Ci-C, straight or branched 10 chain alkyl, or C2-C6 straight or branched chain 0 alkenyl, **6 wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group 15 consisting of C1-C6 straight or branched chain S@ alkyl, C2-C 6 straight or branched chain *0 0 alkenyl, C3-C8 cycloalkyl, C5-C, cycloalkenyl, 0 hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally replaced with O, NH, NR 2 S, SO, or 86 SO 2 R 2 is selected from the group consisting of hydrogen, CI-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and Ci-C4 bridging alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally 1. 0 fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, 15 which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Ci-CE straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 RsR 6 wherein R 4 R 5 and R 6 are independently selected from the group consisting of Ci-Cg straight or branched chain alkyl and C2-C 6 straight or branched chain alkenyl, 87 wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C,- C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, 10 wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 15 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, c y c l oal k y cycloalkenyl, or Ar is optionally replaced with O, NH, NRi, S, SO, or SO 2 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and 88 R, and R 3 are independently hydrogen, Ci-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, or Y-Z.

20. The use of claim 16, wherein the compound is of formula IV YX-Y-Z N O R IV or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3 forming a 5-7 member heterocyclic .ring; 15 W is O, S, CH 2 or two hydrogen atoms; R is Ci-CG straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C 8 cycloalkyl, C7 cycloalkenyl, or Ar,, wherein said R is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C 8 cycloalkyl, C5-C7 cycloalkenyl, and Ar,; Ar 1 is selected from the group consisting of 1- naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and phenyl, 89 wherein said Ar 1 has one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cj-C 6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRI, S, CH 2 CHRI, or CRR 3 Y is a direct bond, Ci-C 6 straight or branched .4 10 chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, -wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s). independently selected from the group 15 consisting of Ci-C 6 straight or branched chain e Salkyl, C 2 -C 6 straight or branched chain alkenyl, C3-C, cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C4 alkyl, C 2 -C 4 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally replaced with O, NH, NR 2 S, SO, or SO 2 R 2 is selected from the group consisting of hydrogen, Ci-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C-C4 bridging alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally 10 fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, 15 which is either unsubstituted or substituted with one or more substituent independently ~selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, CI-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 R 5 R,, wherein R 4 Rs, and R 6 are independently selected from the group consisting of C-Cg straight or branched chain alkyl and C2-C6 straight or branched chain alkenyl, 91 wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C,- C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, 10 wherein said alkyl, *e* alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C-C4 alkyl, C2-C4 15 alkenyl, hydroxy, or *9 carbonyl oxygen, 9 wherein any carbon atom of said alkyl, alkenyl, c y cloa l ky cycloalkenyl, or Ar is optionally replaced with O, NH, NRI, S, SO, or SO 2 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, CI-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z.

21. The use of claim 20, wherein the compound is selected from the group consisting of: 3- (2-Pyridyl)-l-propyl(2S)-l-(1,1-Dimethyl-l,2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(3-Pyridyl)-1-propyl(2S)--(1, 1-Dimethyl-,2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(4-Pyridyl)-l-propyl(2S)-l-(1,1-Dimethyl-l,2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3-(2-Quinolyl)-l-propyl(2S)-l-(1,1-Dimethyl-1,2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(3-Quinolyl)-1-propyl(2S)-l-(l,l-Dimethyl-l,2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; and 3-(4-Quinolyl)-l-propyl(2S)-l-(1,1-Dimethyl-l,2- dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; or a pharmaceutically acceptable salt, ester, or solvate thereof.

22. 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 of formula V X-Y-Z W v R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is CH or N; A and B, taken together with V and the carbon atom 1 0 to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which has one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 N, NH, and NR,; R, is either C 1 -C 9 straight or branched chain alkyl, 15 C 2 -C 9 straight or branched chain alkenyl, C3-C, cycloalkyl, Cs-C, cycloalkenyl, or Ar 3 wherein R 7 is either unsubstituted or *D substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C,- CG straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, Ci-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 94 Ar 3 and Ar 4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the individual ring size is 5-8 members, and wherein said heterocyclic ring has 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; W is O, S, CH,, or two hydrogen atoms; 10 R is C 1 -C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C, cycloalkyl, Cs- C7 cycloalkenyl, or Arl, wherein said R is optionally substituted with one or more substituent(s) independently 15 selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C, cycloalkyl, Cs-C7 cycloalkenyl, and Ar 2 o: Ar 1 and Ar 2 are independently selected from the group consisting of l-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar 1 and Ar 2 independently have one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRi, S, CH 2 CHRi, or CRiR 3 Y is a direct bond, Cl-C 6 straight or branched chain alkyl, or C 2 -Cg straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C3-C, cycloalkyl, C5-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, 15 cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Cl-C4 alkyl, C2-C4 alkenyl, hydroxy, or o S: carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, or cycloalkenyl, is optionally replaced with O, NH, NR 2 S, SO, or SO2; R 2 is selected from the group consisting of hydrogen, Cl-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C,-C4 bridging alkyl, 9. 9 9*9 *999 .9 9 9 99 9 9* 9 9 96 wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl to form a ring, wherein said ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide, wherein said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, Ci-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, wherein said tertiary amine is NR 4 R 5 R 6 wherein R 4 R 5 and R 6 are independently selected from the group consisting of Cl-C6 straight or branched chain alkyl and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C-C6 straight or branched chain 97 alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Ci-C4 alkyl, C2-C4 10 alkenyl, hydroxy, or carbonyl oxygen, wherein any carbon atom o of said alkyl, alkenyl, c y c 1 o a 1 k y 1 15 cycloalkenyl, or Ar is optionally replaced with C Co O, NH, NRi, S, SO, or S02; SO 2 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, Ci-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, or Y-Z.

23. The use of any one of claims 16-22, wherein the compound is non-immunosuppressive.

24. The use of any one of claims 16-22, wherein the compound has an affinity for an FKBP-type immunophilin.

25. The use of claim 24, wherein the FKBP-type immunophilin is FKBP-12.

26. The use of any.one of claims 16-22, wherein the compound is immunosuppressive. *505 •27. The pharmaceutical composition of claim 12, wherein the compound is immunosuppressive. S

28. The method of any one of claims 1 to 11, substantially as hereindescribed with reference to any one of the Examples.

29. The pharmaceutical composition of any one of claims 12 to or 27, substantially as hereindescribed with reference to any one of the Examples. The use of the compounds of any one of claims 16 to 26, substantially as hereindescribed with reference to any one of the Examples. Dated this 8 th day of August, 2001. GPI NIL HOLDINGS, INC. By their Patent Attorneys: CALLINAN LAWRIE I Kk^ 07/08/01,gc11703.spe,2