AU7716898A

AU7716898A - N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses

Info

Publication number: AU7716898A
Application number: AU77168/98A
Authority: AU
Inventors: Gregory S. Hamilton; Joseph P. Steiner
Original assignee: Guilford Pharmaceuticals Inc
Current assignee: GPI Nil Holdings Inc
Priority date: 1998-06-03
Filing date: 1998-06-03
Publication date: 1999-12-20
Anticipated expiration: 2018-06-03
Also published as: CA2334032A1; JP2002516842A; EP1082095A1; AU761737B2; WO1999062486A1

Description

WO99/62486 PCTIUS98/11245 N-OXIDE OF HETEROCYCLIC ESTER, AMIDE, THIOESTER, OR KETONE HAIR GROWTH COMPOSITIONS AND USES This application is a continuation-in-part of 5 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 10 1. Field of Invention This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, 15 small molecule N-oxides of heterocyclic esters, amides, thioesters, or ketones. 2. Description of Related Art Hair loss occurs in a variety of situations. 20 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 25 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 PCTIUS98/11245 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.

WO 99/62486 PCTIUS98/11245 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 5 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 10 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 15 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. 20 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 25 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 PCTIUS98/11245 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 5 novel small molecule structure and non immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art. 10 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 15 ester, amide, thioester, or ketone. The present invention further relates to a pharmaceutical composition which comprises: (i) an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone for 20 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 25 and pharmaceutical compositions have an affinity for FKBP-type immunophilins and do not exert any significant immunosuppressive activity.

WO 99/62486 PCT/US98/11245 5 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 5 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 neuro 10 immunophilin 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 AM 15 of GPI 1046, a related non-immunosuppressive neuro immunophilin FKBP ligand, after six weeks. FIG. 4 shows the remarkable ability of these compounds to achieve, essentially, complete hair regrowth in the shaved area. 20 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 25 the remarkable early hair growth promoted by a wide variety of non-immunosuppressive neuroimmunophilin FKBP ligands.

WO99/62486 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 5 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 10 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 15 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 20 S N O 2 GPI 1605 25 "GPI 1046" refers to 3-(3-pyridyl)-l-propyl (2s) 1- (3,3 -dimethyl- 1,2 -dioxopentyl) -2 pyrrolidinecarboxylate, a compound of formula WO 99/62486 PCT/US98/11245 7 N 0 0 0 5 o GPI1046 5 "GPI 1312" refers to a compound of formula S 'N' O=S=O 0 10 GPI 1312 "GPI 1572" refers to a compound of formula SN 15 O r O 0 0 GPI 1572 "GPI 1389" refers to a compound of formula N 20 N 0 °t GPI 1389 "GPI 1511" refers to a compound of formula 25 O N s 0 0 GPI 1511 WO 99/62486 PCT/US98/11245 8 "GPI 1234" refers to a compound of formula SI Ny 0 0 5 0 GPI 1234 "Isomers" refer to different compounds that have the same molecular formula. "Stereoisomers" are 10 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 15 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 20 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 25 such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, WO 99/62486 PCT/US98/11245 9 ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, 5 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 10 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 15 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 20 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 25 follicles, and includes three phases: (1) the anagen phase, the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years; WO99/62486 PCT/US98/11245 10 (2) 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 5 (3) 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 10 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 15 root. "Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair. "Treating alopecia" refers to: 20 (i) 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 25 (iv) prolonging the anagen phase of the hair cycle; and/or (v) converting vellus hair to growth as terminal hair. Terminal hair is coarse, pigmented, long hair WO99/62486 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 5 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 10 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 15 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 20 disorders and internal secretion disorders. Pharmaceutical Compositions of the Present Invention The present invention also relates to a pharma ceutical composition comprising: 25 (i) 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 WO99/62486 PCT/US98/11245 12 (ii) a pharmaceutically acceptable carrier. N-OXIDES OF HETEROCYCLIC ESTERS, AMIDES, THIOESTERS, AND KETONES 5 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 10 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 prolyl peptidyl cis-trans isomerase, or rotamase, activity of the binding protein. Unexpectedly, these compounds 15 have also been found to stimulate hair growth. The compounds are devoid of any significant immunosuppressive activity. FORMULA I 20 The N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula I B A X-Y-Z 1 N 25 I 0 0 W

R

WO99/62486 PCTIUS98/11245 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, 5 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 NRj; W is O, S, CH 2 , or H 2 ; R is Cz-C 6 straight or branched chain alkyl, C 2

-C

6 10 straight or branched chain alkenyl, C 3 -C, 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 C 1 C 4 alkyl, C 2

-C

4 alkenyl, hydroxy, C 3 -C, cycloalkyl, Cs-C 7 15 cycloalkenyl, and Ar 2 ; Arl 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, 2 pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one 20 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; 25 X is O, NH, NRj, 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 WO99/62486 PCT/US98/11245 14 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, Cs-C 7 5 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, 10 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, C,-C 4 straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, and C, 15 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; 20 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 25 substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C, straight or branched chain alkyl, C 2

-C

6 straight or branched WO99/62486 PCT/US98/11245 15 chain alkenyl, C 1

-C

4 alkoxy, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR4RR6, wherein R4, Rs, and R, are independently selected from the group consisting 5 of C 1

-C

6 straight or branched chain alkyl or C2-C 6 straight or branched chain alkenyl 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 10 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 C,-C 4 alkyl, C 2

-C

4 alkenyl, hydroxy, or carbonyl oxygen; wherein any 15 carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NRj, S, SO, or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, 20 quinolinyl, and isoquinolinyl; and

R

1 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. 25 FORMULA II Additionally, the N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula II WO 99/62486 PCT/US98/11245 16 F Gj N X-Y-Z 0 II 5 R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 10 E, F, G and J are independently CH 2 , O, S, SO,

SO

2 , NH or NRj; W is O, S, CH 2 , or H 2 ; R is C,-C, straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C cycloalkyl, 15 Cs-C7 cycloalkenyl, or Arl, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C C, alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, Cs-C, cycloalkenyl, and Arl; 20 Ar 1 is selected from the group consisting of 1 napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, and phenyl, having one or more substituent(s) independently selected from the group consisting of 25 hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cl-C6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; WO99/62486 PCT/US98/11245 17 X is O, NH, NR, 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 5 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; 10 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, 15 NR 2 , S, SO, or SO2;

R

-C

4 straight or branched chain alkenyl or alkynyl, and C,

C

4 bridging alkyl wherein a bridge is formed between 20 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 25 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 WO99/62486 PCTIUS98/11245 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

-C

4 alkoxy, C 2

-C

4 5 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4

R

5

R

6 , wherein R 4 , Rs, and

R

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

-C

6 straight or branched chain alkenyl; wherein said alkyl 10 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

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, C 5

-C

7 cycloalkenyl, hydroxy, carbonyl 15 oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C 1

-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 20 optionally replaced with O, NH, NRj, S, SO, or SO 2 ; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R

i and R 3 are independently hydrogen, C 1

-C

4 25 straight or branched chain alkyl, C 3

-C

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

WO99/62486 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 5 F-G E 1 N X-Y-Z , N III 0 0 w W 10 R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH 2 , O, S, SO, SO 2 , 15 NH or NR 1 ; 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, cycloalkyl,

C

5 -C, cycloalkenyl, or Arl, which is optionally 20 substituted with one or more substituent(s) independently selected from the group consisting of Cj

C

4 alkyl, C 2

-C

4 alkenyl, hydroxy, C 3

-C

8 cycloalkyl, Cs-C 7 cycloalkenyl, and Ar 1 ; Ar 1 is selected from the group consisting of 1 25 napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of WO99/62486 PCT/US98/11245 20 hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; 5 X is O, NH, NR

I

, S, CH, CR, or CRR 3 ; Y is a direct bond, Ci-C6 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) 10 independently selected from the group consisting of Cj C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, 15 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, cycloalkenyl, or Ar is optionally replaced with O, NH,

NR

2 , S, SO, or SO 2 ; 20 R 2 is selected from the group consisting of hydrogen, C,-C4 straight or branched chain alkyl, C3-C,4 straight or branched chain alkenyl or alkynyl, and Cj C, bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or 25 alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; WO99/62486 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 5 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 2

-C

4 10 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4 RR., wherein R 4 , R,, and R. 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 15 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, straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, Cs-C 7 cycloalkenyl, hydroxy, carbonyl 20 oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C 1

-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 25 optionally replaced with O, NH, NRj, S, SO, or SO 2 ; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and WO99/62486 PCTIUS98/11245 22 R, and R 3 are independently hydrogen, C 1

-C

4 straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, or Y-Z. 5 FORMULA IV Moreover, the N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula IV 10 (CH 2 ) n 0 X-Y-Z N IV 0 0 W R 15 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2, or 3, forming a 5-7 member heterocyclic ring; 20 W is O, S, CH 2 , or H 2 ; R is C-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 3

-C

8 cycloalkyl, Cs-C 7 cycloalkenyl, or Ar, which is optionally substituted with one or more substituent(s) 25 independently selected from the group consisting of C 1 C 4 alkyl, C 2

-C

4 alkenyl, hydroxy, C 3

-C

8 cycloalkyl, Cs-C 7 cycloalkenyl, and Arl; WO 99/62486 PCTIUS98/11245 23 Ar 1 is selected from the group consisting of 1-, napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl and phenyl, having one or more substituent(s) 5 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; 10 X is O, NH, NR,, S, CH, CR, or CR:R 3 ; Y is a direct bond, Cl-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) 15 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, 20 or Ar is optionally substituted with Cl-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

2 , S, SO, or S0 2 ; 25 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 C 1 C 4 bridging alkyl wherein a bridge is formed between WO99/62486 PCT/US98/I11245 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; 5 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 10 substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C 1

-C

4 alkoxy, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, and amino; 15 said tertiary amine is NR 4

RR

6 , wherein R 4 , R,, 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 20 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

-C

7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, 25 cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C 1

-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 WO 99/62486 PCT/US98/11245 25 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 5 R, and R 3 hydrogen, C 1

-C

4 straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, or Y-Z. Examples of the compounds of formula IV when W is 0 are presented in TABLE I. 10 TABLE I

(CH

2 ) n X-Y-Z N 15 O O 0 R 0 No. n X Y Z R 20 1 1 O (CH2) 3 3-Pyridyl N-oxide 1,1-dimethylpropyl 2 1 O (CH2) 3 2-Pyridyl N-oxide 1,1-dimethylpropyl 3 1 O (CH2) 3 4-Pyridyl N-oxide 1,1-dimethylpropyl 25 4 1 O (CH2) 3 2-Quinolyl N-oxide 1,1-dimethylpropyl 5 1 O (CH2) 3 3-Quinolyl N-oxide 1,1-dimethylpropyl 6 1 O (CH2) 3 4-Quinolyl N-oxide 1,1-dimethylpropyl WO 99/62486 PCT/US98/11245 26 Preferred compounds of formula IV may be selected from the group consisting of: 3- (2-Pyridyl) -1-propyl (2S) -1- (1, l-Dimethyl-l,2 dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide; 5 3-(3-Pyridyl) -1-propyl(2S)-- -(l, l-Dimethyl-l,2 dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(4-Pyridyl)-l-propyl(2S)-l-(l, l-Dimethyl-l,2 dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide; 3- (2-Quinolyl)-1-propyl (2S) -1- (1, 1-Dimethyl-l,2 10 dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(3-Quinolyl)-1-propyl(2S) -1- (1, l-Dimethyl-l,2 dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(4-Quinolyl)-1-propyl (2S) -1- (1, l-Dimethyl-l,2 dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide; and 15 pharmaceutically acceptable salts, esters, and solvates thereof. FORMULA V The N-oxide of a heterocyclic ester, amide, 20 thioester, or ketone may further be a compound of formula V B AV X-Y-Z 25 0 V R

R

WO99/62486 PCTIUS98/11245 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 5 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,; 10 R 7 is either Cj-C 9 straight or branched chain alkyl, C 2 -C. straight or branched chain alkenyl, C 3

-C

9 cycloalkyl, Cs-C 7 cycloalkenyl, or Ar 3 , wherein R 7 is either unsubstituted or substituted with one or more substituent(s) independently selected from the group 15 consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, C -C 4 alkoxy, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, 20 alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 ; 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; wherein said heterocyclic ring contains 25 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.

WO99/62486 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 S stereoisomers. The individual stereoisomers may be 5 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 10 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. 15 Affinity for FKBP12 The compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. The 20 inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP may be measured as an indicator of this affinity. Ki Test Procedure 25 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 WO99/62486 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. 5 The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para nitroanilide from the trans form of the substrate. 10 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. 15 In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml in 1 mM HCl) and 10 mL of test compound at various 20 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 LiCl in trifluoroethanol). The absorbance at 390 nm versus time is monitored 25 for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.

WO99/62486 PCT/US98/11245 30 Data is presented in Table II for 3-(3-Pyridyl) l-propyl(2S)-l-(l,l-Dimethyl-l,2-dioxopentyl)-2 pyrrolidine-carboxylate, N-oxide (compound 1) and its parent (unoxidized) compound. 5 Table II In Vitro Test Results - Formulas I to V Compound K (nM) Parent 7.5 10 1 225 Route of Administration To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods 15 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 20 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. 25 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, WO99/62486 PCT/US98/11245 31 sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Other routes of administration known in the 5 pharmaceutical art are also contemplated by this invention. Dosage Dosage levels on the order of about 0.1 mg to 10 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, 15 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 20 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. 25 The compounds can be administered with other hair revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the WO99/62486 PCTIUS98/11245 32 factors previously stated and the effectiveness of the drug combination. EXAMPLES 5 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. 10 Example 1 Synthesis of 3-(3-pyridyl)-l-propyl (2S)-1-(3,3 Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide (1) 15 Methyl (2S)-l- (l,2-dioxo-2-methoxyethyl)-2 pyrrolidinecarboxylate A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in dry methylene chloride was cooled to 0 0 C and treated with 20 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 25 0 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 WO 99/62486 PCT/US98/11245 33 in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. 1 H NMR (CDC1 3 ): 5 1.93 (din, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 5 3.79, 3.84 (s, 3H total); 4.86 (dd, 1H, J = 8.4, 3.3) Methyl (2S) -1- (1,2-dioxo-3,3-dimethylpentvyl)-2 pyrrol idinecarboxylate A solution of methyl (2S)-1-(1,2-dioxo-2 methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g; 10.90 10 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78 0 C and treated with 14.2 mL of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 0 C for three hours, the mixture was poured into saturated 15 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 20 hexane, to obtain 2.10 g (75%) of the oxamate as a colorless oil. 1 H NMR (CDC1 3 ) : 5 0.88 (t, 3H); 1.22, 1.26 (s, 3H each); 1.75 (din, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (din, 1H, J = 8.4, 3.4). 25 (2S) -1- (1,2-dioxo- 3 , 3-dimethylpentyl) -2 pyrrolidinecarboxylic acid A mixture of methyl (2S)-1-(1,2-dioxo-3,3 dimethylpentyl-2-pyrrolidine-carboxylate (2.10 g; 8.23 WO99/62486 PCT/US98/11245 34 mmol), 1 N LiOH (15 mL), and methanol (50 mL) was stirred at 0 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 5 of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. 'H NMR (CDCl 3 ) : d 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 10 (m, 1H); 2.25 (m, 1H); 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, 1H, j = 8.6, 4.1). 3 - (3-PYridv1)1propyl (2S)-1- (3 , 3-dimethyl-1, 2 dioxopentyl)-2-pyrrolidinecarboxylate A mixture of (2S)-1- (1,2-dioxo-3,3 15 dimethylpentyl)-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 4 dimethyl aminopyridine (773 mg; 6.33 mmol) in 20 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 25 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 WO 99/62486 PCT/US98/11245 35 acetate) to obtain 5.47 g (80%) of GPI 1046 as a colorless oil (partial hydrate). 'H NMR (CDC1 3 , 300 MHz): 6 0.85 (t, 3H); 1.23, 1.26 (s, 3H each); 1.63 1.89 (m, 2H); 1.90-2.30 (m, 4H); 2.30-2.50 (m, 1H); 5 2.72 (t, 2H); 3.53 (m, 2H) ; 4.19 (m, 2H) ; 4.53 (m, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45. Analysis calculated for C 20

H

28

NO

4 - 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-DropVl (2S)-1-(3,3-dimethyl-1,2 10 dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide (1) Asolutionof 3-(3-pyridyl)-1-propyl (2S)-1-(3,3 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 15 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 20 10% methanol in ethyl acetate, to obtain 130 mg of the Compound 1 of Example 1. 1H NMR (CDC1 3 , 300 MHz) : 5 0.83 (t, 3H); 1.21 (s, 3H); 1.25 (s, 3H); 1.75-2.23 (m, 8H); 2.69 (t, 2H, J = 7.5); 3.52 (t, 2H, J = 6.3); 4.17 (dd, 2H, J = 6.3); 4.51 (m, 1H); 7.16-7.22 (m, 25 2H) ; 8.06-8.11 (m, 2H). Analysis calculated for

C

20

H

28

N

2 0 s - 0.75 H 2 0: C, 61.60; H, 7.63; N, 7.18. Found: C, 61.79; H, 7.58; N, 7.23.

WO99/62486 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 5 molecular weight, small molecule, non-immuno suppressive 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, 10 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 15 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. 2), 10 pJM GPI 1046 (FIG. 3) or 30 pM GPI 1046 (FIG. 4) dissolved in the vehicle. The animals 20 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 25 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 WO99/62486 PCT/US98/11245 37 covered with new growth. In contrast, FIG. 3 shows that animals treated with 10 AM GPI 1046 exhibited dramatic hair growth, covering greater than 90% of the shaved area in all animals. Further, FIG. 4 shows 5 that mice treated with 30 AM 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 10 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 15 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 20 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 25 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 WO99/62486 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 5 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. 10 Example 3 A lotion comprising the following composition may be prepared. 15 (%) 95% Ethanol 80.0 an N-oxide of a heterocylic ester, amide, 10.0 thioester, or ketone as defined above a-Tocopherol acetate 0.01 20 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil purified water 9.0 perfume and dye q.s. 25 Into 95% ethanol are added an N-oxide of a heterocylic ester, amide, thioester, or ketone, a tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a dye. The 30 resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion.

WO99/62486 PCT/US98/11245 39 5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia. Example 4 5 A lotion comprising the following composition may be prepared. (%) 10 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 0.5 15 castor oil Purified water 19.0 Perfume and dye q.s. Into 95% ethanol are added an N-oxide of a 20 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 25 lotion. The lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia. 30 WO99/62486 PCT/US98/11245 40 Example 5 An emulsion may be prepared from A phase and B phase having the following compositions. 5 (A phase) (%) Whale wax 0.5 Cetanol 2.0 Petrolatum 5.0 Squalane 10.0 10 Polyoxyethylene (10 mole) monostearate 2.0 Sorbitan monooleate 1.0 an N-oxide of a heterocylic ester, amide, 0.01 thioester, or ketone as defined above (B phase) (%) 15 Glycerine 10.0 Purified water 69.0 Perfume, dye, and preservative q.s. 20 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 25 four times per day to a site having marked baldness or alopecia.

WO99/62486 PCT/US98/11245 41 Example 6 A cream may be prepared from A phase and B phase having the following compositions. 5 (A Phase) (%) Fluid paraffin 5.0 Cetostearyl alcohol 5.5 Petrolatum 5.5 Glycerine monostearate 33.0 10 Polyoxyethylene (20 mole) 2-octyldodecyl 3.0 ether Propylparaben 0.3 (B Phase) (%) an N-oxide of a heterocylic ester, amide, 0.8 15 thioester, or ketone as defined above Glycerine 7.0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium Hexametaphosphate 0.005 20 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 25 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.

WO99/62486 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 10 Propylene glycol 5.0 Polyoxyethylene hardened castor oil 0.4 derivative (ethylene oxide 80 mole adducts) Perfume q.s. Purified water q.s. 15 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 20 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. 25 WO99/62486 PCTIUS98/11245 43 Example 8 A shampoo comprising the following composition may be prepared. 5 (%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betaine lauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0 10 Polyethylene glycol 5.0 an N-oxide of a heterocylic ester, amide, 5.0 thioester, or ketone as defined above Ethanol 2.0 Perfume 0.3 15 Purified water 69.7 Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0 g of triethanolamine 20 laurylsulfate, 6.0 g of betaine lauryldimethyl aminoacetate. Then a mixture obtained by adding 5.0 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 25 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.

WO99/62486 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 5 composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. Example 10 10 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 15 expected to occur following treatment. Example 11 A patient is suffering from alopecia areata. An N-oxide of a heterocylic ester, amide, thioester, or 20 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. 25 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 WO99/62486 PCTIUS98/11245 45 pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. 5 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 10 administered to the patient. Increased hair growth is expected to occur following treatment. Example 14 A patient is suffering from hair loss caused by 15 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 20 patient. Increased hair growth is expected to occur following treatment. Example 15 A patient is suffering from hair loss caused by 25 chemotherapy. An N-oxide of a heterocylic ester, amide, thioester, or ketone as identified above, or a pharmaceutical composition comprising the same, may be WO 99/62486 PCT/US98/11245 46 administered to the patient. Increased hair growth is expected to occur following treatment. Example 16 5 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 10 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 15 from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

1. A method for treating alopecia or promoting hair growth in an animal, which comprises 5 administering to said animal an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone.

2. The method of claim 1, wherein the N-oxide 10 of a heterocyclic ester, amide, thioester, or ketone is non-immunosuppressive.

3. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone 15 has an affinity for an FKBP-type immunophilin.

4. The method of claim 3, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is FKBP-12. 20

5. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula I 25 B A X-Y-Z N I 0 0 W R WO99/62486 PCT/US98/I11245 48 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, 5 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 i ; W is O, S, CH 2 , or H 2 ; R is C 1 -C, straight or branched chain alkyl, C 2 -C 6 10 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C.-C, cycloalkenyl, or Arl, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C, C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, Cs-C 7 15 cycloalkenyl, and Ar 2 ; Ar 1 and Ar 2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2 pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one 20 or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C -C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; 25 X is O, NH, NRj, S, CH, CR 1 , or CR:R 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 WO99/62486 PCTIUS98/11245 49 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, 5 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, 10 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 Cj 15 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; 20 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 25 substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, CI-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C -C, alkoxy, C 2 -C 4 WO99/62486 PCT/US98/11245 50 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR4RR 6 , wherein R , R. , and R 6 are independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl and C 2 -C 6 5 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 -C 6 straight or branched chain alkenyl, C 3 -C 8 10 cycloalkyl, C,-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 15 alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NRj, S, SO, or SO 2 ; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and 20 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.

6. The method of claim 1, wherein the N-oxide 25 of a heterocyclic ester, amide, thioester, or ketone is a compound of formula II WO99/62486 PCTIUS98/11245 51 FG 'I X-Y-Z 0 0I W 5 R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 10 E, F, G and J are independently CH 2 , 0, S, SO, SO 2 , NH or NR,; W is O, S, CH 2 , or H 2 ; R is Cl-C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, 15 Cs-C 7 cycloalkenyl, or Ar, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C, C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and Ar; 20 Ar 1 is selected from the group consisting of 1 napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of 25 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; WO99/62486 PCT/US98/11245 52 X is O, NH, NRJ, S, CH, CR I , or CRjR 3 ; Y is a direct bond, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally 5 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, Cs-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; 10 wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Cl-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, 15 NR 2 , S, SO, or SO 2 ; R 2 is selected from the group consisting of hydrogen, Cl-C 4 straight or branched chain alkyl, C,-C 4 straight or branched chain alkenyl or alkynyl, and Cj C 4 bridging alkyl wherein a bridge is formed between 20 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 25 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 WO99/62486 PCTIUS98/11245 53 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, Cz-C 4 alkoxy, C 2 -C 4 5 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4 RsR 6 , wherein R 4, R. , 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 10 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, C0 3 -C 8 cycloalkyl, C,-C, cycloalkenyl, hydroxy, carbonyl 15 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 20 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 1 and R 3 are independently hydrogen, C 1 -C 4 25 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z. WO 99/62486 PCT/US98/11245 54

7. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula III 5 F-G E NX-Y-Z E\ N ~III 0 0 W R 10 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH 2 , 0, S, SO, SO 2 , NH or NR,; 15 W is O, S, CH 2 , or H 2 ; R is C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, Cs-C 7 cycloalkenyl, or Ar, which is optionally substituted with one or more substituent(s) 20 independently selected from the group consisting of Cj C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, Cs-C 7 cycloalkenyl, and Arl; Ar 1 is selected from the group consisting of 1 napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 25 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 WO99/62486 PCT/US98/11245 55 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, NRj, S, CH, CR,, or CRR 3 ; 5 Y is a direct bond, Cz-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 10 C. straight or branched chain alkyl, C2-6 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 Cl-C 4 alkyl, C 2 -C 4 15 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 20 hydrogen, C-C4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and Cl 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 25 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; WO99/62486 PCTIUS98/11245 56 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 5 consisting of halo, hydroxy, nitro, trifluoromethyl, C,-C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Cl-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4 RR 6 , wherein R 4 , Rs, and 10 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 15 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 20 substituted with C 1 -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, NRj, S, SO, or S0 2 ; Ar is selected from the group consisting of 25 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 WO 99/62486 PCTIUS98/11245 57 branched chain alkenyl or alkynyl, or Y-Z.

8. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone 5 is a compound of formula IV (CH2) n C X-Y-Z N IV 0 0 10 W R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 15 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, 20 C5-C 7 cycloalkenyl, or Ar, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of Cj C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and Ar 1 ; 25 Ar 1 is selected from the group consisting of 1 napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl and phenyl, having one or more substituent(s) WO99/62486 PCTIUS98/11245 58 independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cl-C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 2 -C 4 alkenyloxy, phenoxy, 5 benzyloxy, and amino; X is O, NH, NR, S, CH, CR, or CR 1 R 3 ; Y is a direct bond, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally 10 substituted with one or more substituent(s) independently selected from the group consisting of C, C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C5-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; 15 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, 20 NR 2 , S, SO, or SO2; R 2 is selected from the group consisting of hydrogen, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and Cj C 4 bridging alkyl wherein a bridge is formed between 25 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; WO99/62486 PCT/US98/11245 59 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 5 unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 10 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR4RsR 6 , wherein R 4, R, , 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 15 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 -C6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, Cs-C 7 cycloalkenyl, hydroxy, carbonyl 20 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 25 optionally replaced with O, NH, NR, S, SO, or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and WO99/62486 PCT/US98/11245 60 R, and R 3 are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z. 5

9. The method of claim 8, wherein the compound is selected from the group consisting of: 3-(2-Pyridyl)-l-propyl(2S)-l-(l,1-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(3-Pyridyl)-1-propyl(2S)-1-(1,1l-Dimethyl-l,2 10 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(4-Pyridyl)-1-propyl(2S)-l-(1,l-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(2-Quinolyl)-1-propyl(2S)-1-(1,1l-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 15 3-(3-Quinolyl)-1-propyl(2S)-1-(1,1l-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(4-Quinolyl)-1-propyl(2S)-l-(1,1-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; and pharmaceutically acceptable salts, esters, and 20 solvates thereof.

10. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula V 25 B AV X-Y-Z 0 W0 ~wv WO99/62486 PCTIUS98/11245 61 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 5 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) selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR,; 10 R7, is either C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloalkyl, Cs-C 7 cycloalkenyl, or Ar 3 , wherein R, is either unsubstituted or substituted with one or more substituent(s) independently selected from the group 15 consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Cl-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, 20 alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 ; 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; wherein said heterocyclic ring contains 25 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 claim 5 above. WO99/62486 PCT/US98/11245 62

11. A pharmaceutical composition which comprises: (i) an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or 5 ketone for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, 10 wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is non-immunosuppressive.

13. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, 15 thioester, or ketone has an affinity for an FKBP-type immunophilin.

14. The pharmaceutical composition of claim 13, wherein the FKBP-type immunophilin is FKBP-12. 20

15. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula I 25 B A X-Y-Z 0 W0 R WO 99/62486 PCT/US98/11245 63 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, 5 to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH, CH 2 , O, S, SO, SO2, N, NH and NRj; W is O, S, CH 2 , or H 2 ; R is C.-C. straight or branched chain alkyl, C 2 -C 6 10 straight or branched chain alkenyl, C 3 -C 8 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 C 1 C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, Cs-C 7 15 cycloalkenyl, and Ar 2 ; Ar 1 and Ar 2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2 pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one 20 or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C l -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; 25 X is O, NH, NR,, 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 WO99/62486 PCTIUS98/11245 64 substituted with one or more substituent(s) independently selected from the group consisting of Cj C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 5 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C 1 -C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, 10 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, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and Cj 15 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; 20 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 25 substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 WO99/62486 PCT/US98/11245 65 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4 RR 6 , wherein R 4 , R s, and R, are independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl and C 2 -C 6 5 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 -C 6 straight or branched chain alkenyl, C 3 -C 8 10 cycloalkyl, C,-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Cz-C 4 alkyl, C2-C 4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said 15 alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR, S, SO, or S02; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and 20 R, and R 3 are independently hydrogen, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z.

16. The pharmaceutical composition of claim 11, 25 wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula II WO99/62486 PCT/US98/11245 66 FGJ EN X-Y-Z 0 0 W 5 I R or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 10 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 2 ; R is C,-C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, 15 Cs-C, cycloalkenyl, or Ar, 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 -C 8 cycloalkyl, C,-C 7 cycloalkenyl, and Arl; 20 Ar 1 is selected from the group consisting of 1 napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of 25 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; WO99/62486 PCTIUS98/11245 67 X is O, NH, NR,, S, CH, CR,, 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 5 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; 10 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, 15 NR 2 , S, SO, or SO2; R 2 is selected from the group consisting of hydrogen, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and C 1 C 4 bridging alkyl wherein a bridge is formed between 20 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 25 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 WO99/62486 PCT/US98/11245 68 substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 5 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4 RR 6 , wherein R 4 , R s , and R 6 are independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl and C 2 -C6 straight or branched chain alkenyl; wherein said alkyl 10 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 -C 7 cycloalkenyl, hydroxy, carbonyl 15 oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C 1 -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 20 optionally replaced with O, NH, NRj, 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 25 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z. WO 99/62486 PCT/US98/11245 69

17. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula III F-G 5/ E N X-Y-Z 0 III 0 0 w W R 10 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH 2 , O, S, SO, SO2, NH or NR,; W is O, S, CH 2 , or H 2 ; 15 R is C,-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 Arl, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 20 C4 alkyl, C.-C 4 alkenyl, hydroxy, C3-C,8 cycloalkyl, Cs-C 7 cycloalkenyl, and Ar,; Ar 1 is selected from the group consisting of 1 napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 25 pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cl-C6 straight or branched chain alkyl, C2-C6 straight or WO99/62486 PCTIUS98/11245 70 branched chain alkenyl, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NRj, S, CH, CR1, or CRjR 3 ; Y is a direct bond, Cl-C 6 straight or branched 5 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 10 branched chain alkenyl, C 3 -C cycloalkyl, C 5 -C, 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 15 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, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 20 straight or branched chain alkenyl or alkynyl, and Cj 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 25 group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, WO99/62486 PCT/US98/11245 71 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, 5 Cl-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 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 10 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 optionally substituted with one or more substituent(s) independently selected from the group consisting of Cl-C 6 straight or branched chain alkyl, 15 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 Cl-C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, or 20 carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NRj, S, SO, or SO 2 ; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, 25 quinolinyl, and isoquinolinyl; and R, and R 3 are independently hydrogen, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z. WO 99/62486 PCT/US98/11245 72

18. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula IV 5 (CH 2 ) n X-Y-Z N IV O 0 W R 10 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 H 2 ; R is CI-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C, cycloalkyl, Cs-C 7 cycloalkenyl, or Ar, which is optionally substituted with one or more substituent(s) 20 independently selected from the group consisting of C 1 C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, C,-C 7 cycloalkenyl, and Arl; Ar 1 is selected from the group consisting of 1 napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3 25 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C,-C 6 SUBSTITUTE SHEET (RULE 26) WO99/62486 PCTIUS98/11245 73 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, NRl, S, CH, CRl, or CRR 3 ; 5 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 substituted with one or more substituent(s) independently selected from the group consisting of Cl 10 C 6 straight or branched chain alkyl, C2-C6 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 Cl-C 4 alkyl, C 2 -C 4 15 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 20 hydrogen, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and C, 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 25 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; WO99/62486 PCTIUS98/11245 74 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 5 consisting of halo, hydroxy, nitro, trifluoromethyl, Cl-C 6 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; said tertiary amine is NR 4 RR 6 , wherein R 4 , R s , and 10 R 6 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 15 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, Cs-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally 20 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, NRj, S, SO, or S0 2 ; Ar is selected from the group consisting of 25 pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R i and R 3 are independently hydrogen, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 straight or WO99/62486 PCT/US98/11245 75 branched chain alkenyl or alkynyl, or Y-Z.

19. The pharmaceutical composition of claim 18, wherein the compound is selected from the group 5 consisting of: 3-(2-Pyridyl)-1-propyl(2S)-1-(l,l-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(3-Pyridyl)-l-propyl(2S)-l-(1,l-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 10 3-(4-Pyridyl)-l-propyl(2S)-l-(1,1-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(2-Quinolyl)-1-propyl(2S)-1-(1,1-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(3-Quinolyl)-1-propyl (2S)-1-(1,l-Dimethyl-l,2 15 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; 3-(4-Quinolyl)-1-propyl(2S)-1-(1, l-Dimethyl-l,2 dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; and pharmaceutically acceptable salts, esters, and solvates thereof. 20

20. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula V 25 B A X-Y-Z V 0 0 w R WO99/62486 PCT/US98/11245 76 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 5 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) selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR 7 ; 10 R7, is either Cl-C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloalkyl, Cs-C 7 cycloalkenyl, or Ar 3 , wherein R 7 is either unsubstituted or substituted with one or more substituent(s) independently selected from the group 15 consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, Cl-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C,-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, 20 alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 ; 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; wherein said heterocyclic ring contains 25 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 claim 15 above.