AU7807998A

AU7807998A - N-linked sulfonamide of heterocyclic thioester hair growth compounds and uses

Info

Publication number: AU7807998A
Application number: AU78079/98A
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: 1999-12-20
Anticipated expiration: 2018-06-03
Also published as: WO1999062489A1; AU759286B2; EP1085854A1; JP2002516845A; CA2334008A1

Description

WO 99/62489 PCT/US98/11252 N-LINKED SULFONAMIDE OF HETEROCYCLIC THIOESTER HAIR GROWTH COMPOUNDS AND USES This application is a continuation-in-part of U.S. Patent Application No. 08/869,426, filed on June 5 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, small molecule N-linked sulfonamides of heterocyclic 15 thioesters. 2. Description of Related Art Hair loss occurs in a variety of situations. These situations include male pattern alopecia, 20 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 25 can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities. The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific WO 99/62489 PCTIUS98/11252 2 immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 5 102, 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 10 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 15 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. 20 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 25 No. 5,189,042; and Ok et al., U.S. Patent No. 5,208,241; Rupprecht et al., U.S. Patent No. 5,284,840; Organ et al., U.S. Patent No. 5,284,877). These patents claim FK506 related compounds. Although WO 99/62489 PCT/US98/11252 3 they do not claim methods of hair revitalization, they disclose the known use of FK506 for effecting hair growth. Similar to FK506 (and the claimed variations in the Honbo et al. patent), the compounds claimed in 5 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 10 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 15 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 20 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. 25 5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that WO 99/62489 PCTIUS98/11252 4 these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and non-immuno suppressive properties differentiate them from FK506 5 and related immunosuppressive compounds found in the prior art. SUMMARY OF THE 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-linked sulfonamide of a heterocyclic thioester. The present invention further relates to a 15 pharmaceutical composition which comprises: (i) an effective amount of an N-linked sulfonamide of a heterocyclic thioester for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier. 20 The N-linked sulfonamides of heterocyclic thioesters used in the inventive methods and pharmaceutical compositions have an affinity for FKBP type immunophilins and do not exert any significant immunosuppressive activity. 25 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a photograph of C57 Black 6 mice before being shaved for the hair regeneration experiment.

WO 99/62489 PCTIUS98/11252 5 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. 5 FIG. 3 is a photograph of mice treated with 10 pM of GPI 1046, a related non-immunosuppressive neuro immunophillin FKBP ligand, after six weeks. FIG. 3 shows the remarkable effects of non-immunosuppressive neuro-immunophillin FKBP ligands, wherein 90% of the 10 shaved area is covered with new hair growth. FIG. 4 is a photograph of mice treated with 30 pM of GPI 1046, a related non-immunosuppressive neuro immunophillin FKBP ligand, after six weeks. FIG. 4 shows the remarkable ability of non-immunosuppressive 15 neuro-immunophillin FKBP ligands 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 20 vehicle, FK506, and various non-immunosuppressive neuroimmunophilin FKBP ligands, including GPI 1312, 14 days after treatment with each identified compound. Figure 5 demonstrates the remarkable early hair growth promoted by a wide variety of non-immunosuppressive 25 neuroimmunophilin FKBP ligands.

WO 99/62489 PCTIUS98/11252 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 HN O GPI 1605 25 "GPI 1046" refers to 3- (3-pyridyl) -1-propyl (2s) 1-(3,3-dimethyl-1,2-dioxopentyl)-2 pyrrolidinecarboxylate, a compound of formula WO 99/62489 PCTIUS98/11252 7 N 0 0 0 0 GPI1046 5 "GPI 1312" refers to a compound of formula N 0=s=0 0 100 10 0GPI 1312 "GPI 1572" refers to a compound of formula N 15 N 0 GPI 1572 "GPI 1389" refers to a compound of formula N N 0 00 200 GPI 1389 "GPI 1511" refers to a compound of formula 25 S GPI 1511 01t WO 99/62489 PCTIUS98/11252 8 "GPI 1234" refers to a compound of formula S 0 0 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 10 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 15 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 20 subject compound which possess 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, 25 benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, WO 99/62489 PCT/US98/11252 9 glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, 5 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; 10 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, 15 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 20 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: 25 (1) the anagen phase, the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years; (2) the catagen phase, the period when growth WO 99/62489 PCT/US98/11252 10 stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks; and (3) the telogen phase, the rest period when hair 5 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 10 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. 15 "Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair. "Treating alopecia" refers to: (i) preventing alopecia in an animal which may be 20 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 25 cycle; and/or (v) converting vellus hair to growth as terminal hair. Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep WO 99/62489 PCTIUS98/11252 11 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 5 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 10 animal, which comprises administering to said animal an effective amount of an N-linked sulfonamide of a heterocyclic thioester. The inventive method is particularly useful for treating male pattern alopecia, alopecia senilis, 15 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. 20 Pharmaceutical Compositions of the Present Invention The present invention also relates to a pharma ceutical composition comprising: (i) an effective amount of an N-linked 25 sulfonamide of a heterocyclic thioester for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

WO 99/62489 PCTIUS98/11252 12 N-LINKED SULFONAMIDES OF HETEROCYCLIC THIOESTERS The N-linked sulfonamides of heterocyclic thioesters used in the methods and pharmaceutical compositions of the present invention are low 5 molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins, such as FKBP12. When an N-linked sulfonamide of a heterocyclic thioester binds to an FKBP-type immunophilin, it has been found to inhibit the prolyl-peptidyl cis-trans 10 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. 15 FORMULA I The N-linked sulfonamide of a heterocyclic thioester may be a compound of formula I A S-Y-Z 2 0 N~. N D I-I R1 or a pharmaceutically acceptable salt, ester, or 25 solvate thereof, wherein: A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated WO 99/62489 PCT/US98/11252 13 heterocyclic ring containing, in addition to the nitrogen atom, one or more additional 0, S, SO, SO2, N, NH, or NR 2 heteroatom(s); X is either 0 or S; 5 Y is a direct bond, Cl-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, 10 ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or SO 2 ; 15 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 the nitrogen and a carbon atom of said alkyl or 20 alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the 25 ring is either unsubstituted or substituted with one or more substituent (s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from WO 99/62489 PCTIUS98/11252 14 the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, Cl-C 6 straight or branched 5 chain alkyl, or C 2 -C, straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, 10 imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; C and D are independently hydrogen, Ar, C 1

-C

6 15 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 3

-C

8 cycloalkyl, C 5

-C

7 cycloalkenyl, 20 hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cl-C 6 alkyl, C 2

-C

6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, 25 alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein WO 99/62489 PCT/US98/11252 15 any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR,, S, SO, or S02; and

R

1 is selected from the group consisting of Ar, C,-C. cycloalkyl, CI-C 6 straight or branched chain 5 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 Ar, C 3

-C

8 cycloalkyl, amino, halo, haloalkyl, hydroxy, 10 trifluoromethyl, Cl-C6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any 15 carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR,, S, SO, or S02. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, 20 indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, 25 furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, WO 99/62489 PCT/US98/11252 16 pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, 5 phenothiazinyl, and phenoxazinyl. In a preferred embodiment of formula I, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, 10 isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. In another preferred embodiment of formula I, A and B are taken together, with the nitrogen and carbon 15 atoms to which they are respectively attached, to form a 6 membered saturated or unsaturated heterocyclic ring; and R 2 is C 4 -C, branched chain alkyl, C 4 -C, cycloalkyl, phenyl, or 3,4,5-trimethoxyphenyl. In another preferred embodiment of formula I, the 20 N-linked sulfonamide of a hetero-cyclic thioester is the compound GPI 1312, of the formula S N 0=S=0 0 25 GPI 1312 WO 99/62489 PCT/US98/11252 17 In the most preferred embodiment of formula I, the compound is selected from the group consisting of: 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (benzenesulfonyl)pyrrolidine-2-carboxylate; 5 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (a-toluenesulfonyl) pyrrolidine-2-carboxylate; 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (a-toluenesulfonyl)pyrrolidine-2-carboxylate; 1,5-Diphenyl-3-pentylmercaptyl N- (para 10 toluenesulfonyl)pipecolate; and pharmaceutically acceptable salts, esters, and solvates thereof. FORMULA II 15 The N-linked sulfonamide of a heterocyclic thioester may also be a compound of formula II F J C Es S-Y-Z 20 I D II Ri or a pharmaceutically acceptable salt, ester, or 25 solvate thereof, wherein: E, F, G and J are independently CH 2 , 0, S, SO,

SO

2 , NH or NR 2 ; X is either 0 or S; WO 99/62489 PCT/US98/11252 18 Y is a direct bond, Cl-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more 5 position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally 10 replaced with 0, NH, NR,, S, SO, or S02;

R

2 is selected from the group consisting of hydrogen, C1-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 15 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 a direct bond, CI-C 6 straight or branched 20 chain alkyl, or C 2 -C, straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, 25 imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2

;

WO 99/62489 PCT/US98/11252 19 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring 5 size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; 10 C and D are independently hydrogen, Ar, C 1

-C

6 straight or branched chain alkyl, or C 2 -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 15 consisting of C 3

-C

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

-C

6 alkyl, C 2

-C

6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, 20 thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein 25 any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2; and

R

1 is selected from the group consisting of Ar,

C

3

-C

8 cycloalkyl, Ci-C 6 straight or branched chain WO 99/62489 PCT/US98/11252 20 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 5 Ar, C 3 -C3 cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C 1

-C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, 10 sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or SO 2 Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, 15 azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, 20 isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, 25 pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, WO 99/62489 PCT/US98/11252 21 phenothiazinyl, and phenoxazinyl. In a preferred embodiment of formula II, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, 5 pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. FORMULA III 10 The N-linked sulfonamide of a heterocyclic thioester may further be a compound of formula III F-G C E S-Y-Z D III o==s X 15 R1 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH 2 , 0, S, SO, SO 2 , 20 NH or NR 2 ; X is either 0 or S; Y is a direct bond, Cl-C6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or 25 alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, WO 99/62489 PCTIUS98/11252 22 sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ;

R

2 is selected from the group consisting of 5 hydrogen, Cl-C 4 straight or branched chain alkyl, C3-04 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 chain containing said heteroatom to form a 10 ring, wherein said ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one 15 or more substituent (s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally 20 oxidized to a corresponding N-oxide; Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more 25 position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any WO 99/62489 PCT/US98/11252 23 atom of said alkyl or alkenyl is optionally replaced with 0, 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 5 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 10 group; C and D are independently hydrogen, Ar, 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 15 substituent(s) independently selected from the group consisting of C 3

-C

8 cycloalkyl, C 5 -C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 1

-C

4 alkyl, C 2

-C

4 alkenyl, or hydroxy; 20 wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; and 25 Ri is selected from the group consisting of Ar,

C

3

-C

8 cycloalkyl, C1-C 6 straight or branched chain alkyl, and C 2

-C

6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally WO 99/62489 PCTIUS98/11252 24 substituted with one or more substituent(s) independently selected from the group consisting of Ar, C 3

-C

8 cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C 1

-C

6 straight or branched chain 5 alkyl, C 2

-C

6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally 10 replaced with 0, NH, NR 3 , S, SO, or S02 Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, 15 benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, 20 thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, 25 quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

WO 99/62489 PCT/US98/11252 25 In a preferred embodiment of formula III, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, 5 isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. In another preferred embodiment of formula III, the N-linked sulfonamide of a heterocyclic thioester 10 is the compound GPI 1312, of the formula s N o=s=o o GPI 1312 15 FORMULA IV Additionally, the N-linked sulfonamide of a 20 heterocyclic thioester may be a compound of formula IV

(CH

2 )n S-Y-C ND IV o=s~ 0 25 a R, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: WO 99/62489 PCT/US98/11252 26 n is 1, 2 or 3; X is either 0 or S; Y is a direct bond, CI-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain 5 alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, 10 sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ;

R

2 is selected from the group consisting of hydrogen, C 1

-C

4 straight or branched chain alkyl, C 3

-C

4 15 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 20 group; Z is a direct bond, CI-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more 25 position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any WO 99/62489 PCTIUS98/11252 27 atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ;

R

2 is selected from the group consisting of hydrogen, C 1

-C

4 straight or branched chain alkyl, C 3

-C

4 5 straight or branched chain alkenyl or alkynyl, and C 1 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 10 group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring 15 size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; 20 C and D are independently hydrogen, Ar, Ci -C6 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 25 consisting of C 3

-C

8 cycloalkyl, C 5

-C

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

-C

4 alkyl, C 2

-C

4 alkenyl, or hydroxy; WO 99/62489 PCT/US98/11252 28 wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 5 0, NH, NR 2 , S, SO, or SO 2 ; and

R

1 is selected from the group consisting of Ar,

C

3

-C

8 cycloalkyl, C 1 -C6 straight or branched chain alkyl, and 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 Ar, C 3

-C

8 cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, CI-C6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, 15 carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or SO2. 20 Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, 25 tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, WO 99/62489 PCT/US98/11252 29 thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, 5 tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. In a preferred embodiment of formula IV, Ar is 10 selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and 15 thienyl. Exemplary compounds of formula IV are presented in TABLE I. TABLE I

(CH

2 )n -C CN S-Y-Z C ND 10

R,

WO 99/62489 PCT/US98/11252 30 TABLE I (continued) No. n Y Z C D R1 1 1 CH 2 CH Phenyl H Phenyl 2 1 CH 2 CH Phenyl H a-Methylphenyl 3 1 CH 2 CH Phenyl H 4-Methylphenyl 4 1 (CH 2

)

2 CH p-Methoxy H Phenyl phenyl 5 1 (CH 2

)

2 CH p-Methoxy H a-Methylphenyl phenyl 6 1 (CH 2

)

2 CH p-Methoxy H 4-Methylphenyl phenyl 7 1 (CH 2

)

2 CH Phenyl Phenyl Phenyl 8 1 (CH 2

)

2 CH Phenyl Phenyl a-Methylphenyl 9 1 (CH 2

)

2 CH Phenyl Phenyl 4-Methylphenyl 10 2 (CH 2

)

3 CH Phenyl H Phenyl 11 2 (CH 2

)

3 CH Phenyl H a-Methylphenyl 12 2 (CH 2

)

3 CH Phenyl H 4-Methylphenyl 13 2 (CH 2

)

3 CH Phenyl H 3,4,5-trimethoxyphenyl 14 2 (CH 2

)

3 CH Phenyl H Cyclohexyl 15 2 Direct CH 3-Phenylpropyl 3-Phenylpropyl Phenyl bond 16 2 Direct CH 3-Phenylpropyl 3-Phenylpropyl a-Methylphenyl bond 17 2 Direct CH 3-Phenylpropyl 3-Phenylpropyl 4-Methylphenyl bond 18 2 Direct CH 3-Phenylethyl 3-Phenylethyl 4-Methylphenyl bond WO 99/62489 PCTIUS98/11252 31 TABLE I (continued) No. n Y Z C D R1 19 2 Direct CH 3-(4-Methoxy- 3-Phenylpropyl 4-Methylphenyl bond phenyl)-propyl 20 2 Direct CH 3-(2-Pyridyl)- 3-Phenylpropyl 4-Methylphenyl bond propyl In another preferred embodiment of formula I, the N-linked sulfonamide of a heterocyclic thioester is the compound GPI 1312, of the formula 5 S 0S00 GPI 1312 10 The most preferred compounds of formula IV are selected from the group consisting of: 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (benzenesulfonyl) pyrrolidine-2 -carboxylate; 15 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (a-toluenesulfonyl) pyrrolidine-2 -carboxylate; 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (a-toluenesulfonyl)pyrrolidine-2-carboxylate; 1,5-Diphenyl-3-pentylmercaptyl N- (para 20 toluenesulfonyl)pipecolate; and pharmaceutically acceptable salts, esters, and solvates thereof.

WO 99/62489 PCT/US98/11252 32 FORMULA V Additionally, the N-linked sulfonamide of a heterocyclic thioester may be a compound of formula V 5 B C A S-Y-Z V 1 )y ~D O=S X Ri 10 10 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is C, N, or S; A, B, C, D, R 1 , X, Y, and Z are as defined in formula I above. 15 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 20 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 25 Formulas I-V encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, S-stereoisomers are used WO 99/62489 PCT/US98/11252 33 in the pharmaceutical compositions and methods of the present invention. Synthesis of N-linked Sulfonamides 5 of Heterocyclic Thioesters The compounds of formulas I to V may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathway depicted below. As described by Scheme I, cyclic amino acids 10 1 protected by suitable blocking groups P on the amino acid nitrogen may be reacted with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine 3 may be reacted with various sulfonyl chlorides 4 to provide final products 15 5 in good to excellent yield. SCHEME I

(CH

2 )n (CH 2 )n OH R-SH S-R Deprotect 20N - N 20 Coupling Method P O P 0 1. 2 Cl O=S=0 (C9 ~I .(CH 2 ) n S-R 4 S-R N -~N 25 H o Et 3 N, CH 2 C1 2 O=1== O 3 5 WO 99/62489 PCTIUS98/11252 34 Thiols R-SH may be conveniently prepared from the corresponding readily available alcohols or halides via a two step replacement of halogen by sulfur, as described in Scheme II. Halides may be reacted with 5 thiourea, and the corresponding alkyl thiouronium salts hydrolyzed to provide thiols RSH. If alcohols are used as the starting materials, they may be first converted to the corresponding halides by standard methods. 10 SCHEME II 1) PBr 3 H 2 N NH 2 or 15 R-OH R-Br R-SH CBr 4 /Ph 3 P 2) OH~ Affinity for FKBP12 The compounds used in the inventive methods and pharmaceutical compositions have an affinity for the 20 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. 25 K. Test Procedure Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can WO 99/62489 PCT/US98/11252 35 be evaluated by known methods described in the 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 K's and are presented 5 for representative compounds in TABLE I. 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 10 nitroanilide 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 15 concentration to yield the apparent Ki values. 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 20 in 1 mM HCl) 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-nitroanil ide, 5 mg/mL in 2.35 mM LiCl in trifluoroethanol). 25 The absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.

WO 99/62489 PCTIUS98/11252 36 TABLE I In Vitro Test Results - Formulas I to V Compound Ki (nM) 1 +++ 5 2 ++ 3 ++ 4 ++ 5 ++ 6 + 10 7 ++ 8 +++ 9 +++ 10 +++ 11 ++ 15 12 +++ 13 +++ 14 +++ 15 +++ 16 ++ 20 Relative potencies of compounds are ranked according to the following scale: ++++ denotes Ki or ED50 < 1 nM; +++ denotes Ki or ED50 of 1-50 nM; ++ denotes Ki or ED 50 of 51-200 nM; + denotes Ki or ED of 201-500 25 nM.

WO 99/62489 PCT/US98/11252 37 Route of Administration To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions must readily affect 5 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, 10 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 15 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, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl 20 alcohol and water. Other routes of administration known in the pharmaceutical art are also contemplated by this invention. 25 Dosage 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 WO 99/62489 PCT/US98/11252 38 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 5 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 10 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 15 revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the factors previously stated and the effectiveness of the drug combination. 20 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 25 composition.

WO 99/62489 PCT/US98/11252 39 Example 1 Synthesis of 3-(para-Methoxyphenyl)-1 propylmercaptyl(28)-N-(benzenesulfonyl)pyrrolidine 2-carboxylate (4) 5 3-(p-Methoxvphenyl)-1-propylbromide To a solution of 3-(p-methoxyphenyl)-l-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0 0 C, was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the 10 addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3x) 15 and brine (3x). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluting with 10% EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1 propylbromide. 20 3-(P-Methoxyphenyl)-1-propylmercaptan A mixture of 3-(p-methoxyphenyl)-1 propylbromide (14 g; 61 mmol) and thiourea (5.1 g; 67 mmol) in ethanol (150 mL) was refluxed for 48 hours. Evaporation of the solvent provided a clear 25 glassy compound, which was dissolved in 50 mL of water and treated with 100 mL of 40% aqueous sodium hydroxide. After stirring the resulting mixture for two hours, the product was extracted into ether WO 99/62489 PCT/US98/11252 40 (3x), and the combined organic extracts were washed with sodium bicarbonate and brine, dried, and concentrated. Chromatographic purification of the crude thiol on a silica gel column eluting with 2% 5 either in hexane delivered 10.2 g of 3-(p methoxyphenyl)- 1-propylmercaptan as a clear liquid. 'H NMR (300 MHz, CDCl 3 ) 6 1.34 (t, 1H); 1.88-1.92 (m, 2H); 2.49-2.53 (m, 2H); 2.64-2.69 (m, 2H); 3.77 (s, 3H); 6.80-6.84 (m, 2H); 7.06-7.24 (m, 2H). 10 3-(p-Methoxyphenyl)-1-mercaptyl N-(tert butyloxycarbonyl)pvrrolidine-2-carboxylate A mixture of N-(tert-butyloxycarbonyl)-(S) proline (2.0 g; 9.29 mmol), 3-(p-methoxyphenyl)-1 propylmercaptan (1.86 g; 10.22 mmol), 1-(3 15 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.96 g; 10.22 mmol), and 4 dimethylaminopyridine (catalytic) in dry methylene chloride (50 mL) was stirred overnight. The reaction mixture was diluted with methylene chloride 20 (50 mL) and water 100 (mL), and the layers were separated. The organic phase was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated to provide 3.05 g of the product (100%) as a thick oil. 'H NMR (300 MHz, CDCl 3 ): 6 1.15 (s, 25 9H); 1.84-2.31 (m, 6H); 2.61 (m, 2H); 2.83 (m, 2H); 3.51 (m, 2H); 3.75 (s, 3H); 6.79 (d, 2H, j = 8.04); 7.05 (m, 2H).

WO 99/62489 PCT/US98/11252 41 3-(p-Methoxvphenyl)-1-mercaptyl pyrrolidine-2 carboxylate A solution of 3-(p-methoxyphenyl)-mercaptyl N (tert-butyloxycarbonyl)pyrrolidine-2-carboxylate 5 (3.0 g; 8.94 mmol) in methylene chloride (60 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene 10 chloride (3x). The combined organic extracts were dried and concentrated to yield 1.73 g (69%) of the free amine as a thick oil. 'H NMR (300 MHz, CDC1 3 ) 6 1.80-2.23 (m, 6H); 2.62 (m, 2H); 2.81 (m, 2H); 3.01 (m, 2H); 3.75 (s, 3H); 3.89(m, 1H); 6.81 (m, 15 2H); 7.06 (m, 2H). 3-(para-Methoxyphenyl)-1-propylmercaptyl (2S)-N (benzenesulfonyl)pyrrolidine-2-carboxylate (4) A solution of 3-(p-methoxyphenyl)-l-mercaptyl pyrrolidine-2-carboxylate (567 mg; 2.03 mmol) and 20 benzenesulfonyl chloride (358 mg; 2.03 mmol) in methylene chloride (5 mL) was treated with diisopropylethylamine (290 mg; 2.23 mmol) and stirred overnight at room temperature. The reaction mixture was filtered to remove solids and applied 25 directly to a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 540 mg of Compound 4 (Table I) as a clear oil. 'H NMR (300 MHz, CDCl 3 ): 6 1.65-1.89 (m, 6H); 2.61 (t, 2H, j = WO 99/62489 PCT/US98/11252 42 7.3); 2.87 (t, 2H, j = 7.6); 3.26 (m, 1H); 3.54 (m, 1H); 3.76 (s, 3H); 4.34 (dd, 1H, j = 2.7, 8.6); 6.79 (d, 2H, j = 8.7); 7.06 (d, 2H, j = 8.6); 7.49-7.59 (n, 3H); 7.86 (dd, 2H, j = 1.5, 6.8). 5 Example 2 Synthesis of 3-(para-Methoxyphenyl)-1 propylmercaptyl(2S)-N-(a toluenesulfonyl)pvrrolidine-2-carboxylate (5) 10 A solution of 3-(p-Methoxyphenyl)-1-mercaptyl pyrrolidine-2-carboxylate (645 mg; 2.30 mmol) and a toluenesulfonyl chloride (440 mg; 2.30 mmol) in methylene chloride (5 mL) was treated with diisopropylethylamine (330 mg; 2.53 mmol) and 15 stirred overnight at room temperature. Purification as described for Example 1 provided the compound of Example 2 (Compound 5, Table I) as a clear oil. 'H NMR (300 MHz, CDCl 3 ): 5 1.65-2.25 (m, 8H); 2.65 (t, 2H); 2.89-2.96 (m, 2H); 3.55-3.73 (m, 2H); 3.80 (s, 20 3H); 4.32 (s, 2H); 4.70-4.81 (m, 1H); 6.83 (d, 2H); 7.09 (d, 2H); 7.14 (m, 3H); 7.26 (m, 2H). Example 3 Synthesis of 3-(para-Methoxyphenyl)-1 25 propylmercaptyl(2S)-N-(q toluenesulfonvl)pyrrolidine-2-carboxylate (6) A solution of 3-(p-methoxyphenyl)-l-mercaptyl pyrrolidine-2-carboxylate (567 mg; 2.30 mmol) and p- WO 99/62489 PCTIUS98/11252 43 toluenesulfonyl chloride (425 mg; 2.23 mmol) in methylene chloride (5 mL) was stirred overnight at room temperature. Purification as described for Example 1 provided the compound of Example 3 5 (Compound 6, Table I) as a clear oil. 'H NMR (300 MHz, CDCl 3 ): 6 1.67-1.94 (m, 6H); 2.40 (s, 3H); 2.61 (t, 2H, j = 7.3); 2.84 (m, 2H, j = 7.2); 3.22 (m, 1H); 3.52 (m, 1H); 3.76 (s, 3H); 4.32 (dd, 1H, J 2.9, 8.5); 6.79 (d, 2H, j = 6.5); 7.07 (d, 2H, j = 10 6.5); 7.29 (d, 2H, j = 6.5); 7.74 (d, 2H, j = 6.5). Example 4 Synthesis of 1,5-Diphenyl-3-pentylmercaptyl N-(para toluenesulfonyl)pipecolate (18) 15 3-Phenyl-1-propanal Oxalyl chloride (2.90 g; 2.29 mmol) in methylene chloride (50 mL), cooled to -78 0 C, was treated with dimethylsulfoxide (3.4 mL) in 10 mL of methylene chloride. After stirring for 5 min, 3 20 phenyl-1-propanol (2.72 g; 20 mmol) in 20 mL of methylene chloride was added, and the resulting mixture was stirred at -78 0 C for 15 min, treated with 14 mL of triethylamine, stirred an additional 15 min, and poured into 100 mL of water. The layers 25 were separated, the organic phase was dried and concentrated, and the crude residue was purified on a silica gel column, eluting with 10% ethyl acetate in hexane, to obtain 1.27 g (47%) of the aldehyde as WO 99/62489 PCTIUS98/11252 44 a clear oil. 'H NMR (300 MHz, CDCl 3 ) 6 2.80 (m, 2H); 2.98 (m, 2H); 7.27 (m, 5H); 9.81 (2, 1H). 1,5-Diphenyl-3-pentanol A solution of 2-(bromoethyl)benzene (1.73 g; 5 9.33 mmol) in diethylether (10 mL) was added to a stirred slurry of magnesium turnings (250 mg; 10.18 mmol) in 5 mL of ether. The reaction was initiated with a heat gun, and after the addition was complete the mixture was heated on an oil bath for 30 min. 3 10 Phenyl-1-propanal (1.25 g; 9.33 mmol) was added in 10 mL of ether, and reflux was continued for 1 hour. The reaction was cooled and quenched with saturated ammonium chloride, extracted into 2x ethyl acetate, and the combined organic portions were dried and 15 concentrated. Chromatographic purification on a silica gel column (10% ethyl acetate in hexane) delivered 1.42 g(63%) of the diphenyl alcohol. 'H NMR (300 MHz, CDC1 3 ): 6 1.84 (m, 4H); 2.61-2.76(m, 4H); 3.65 (m, 1H); 7.19-7.29 (m, 10H). 20 1,5-Diphenyl-3-bromopentane To a solution of 1,5-diphenyl-3-pentanol (1.20 g (5 mmol) and carbon tetrabromide (1.67 g; 5 mmol) in methylene chloride (20 mL) was added triphenylphosphine (1.31 g; 5 mmol) portionwise, at 25 0 0 C. After stirring at room temperature for 18 hours, the mixture was concentrated, triturated with ether, and the solids removed by filtration. The filtrate was passed through a plug of silica gel, WO 99/62489 PCTIUS98/11252 45 eluting with hexane:methylene chloride, 10:1, to give 1.35 g (90%) of the bromide as an oil which was used without further purification. 1H NMR (300 MHz, CDCl 3 ): 6 2.11-2.18 (m, 4H); 2.73 (m, 2H); 2.86 (m, 5 2H); 3.95 (m, 1H); 7.16-7.30 (m, 10H). 1,5-Diphenyl-3-pentvlmercaptan Using the procedure described in Example 10 for the conversion of bromides to thiols, 1,5-diphenyl 3-bromopentane was converted to 1,5-diphenyl-3 10 pentylmercaptan in 35% overall yield. 'H NMR (300 MHz, CDC1 3 ): 5 1.79 (m, 2H); 1.98 (m, 2H); 2.71 (m, 3H); 2.80 (m, 2H); 7.16-7.28 (m, 10H). 1,5-Diphenyl-3-pentylmercaptyl N-(tert butyloxycarbonyl) pvrrolidine-2-carboxylate 15 A mixture of N-(tert-butyloxycarbonyl)-(S) pipecolic acid (2.11 g; 9.29 mmol), 1,5-diphenyl-3 pentylmercaptan (2.58 g; 10.22 mmol), 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.96 g; 10.22 mmol) and 4 20 dimethylaminopyridine (catalytic) in dry methylene chloride (50 mL) was stirred overnight. the reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water 25 (3 x 100 mL), dried over magnesium sulfate, and concentrated to provide 870 mg (20%) of the product as a thick oil, which was used without further purification.

WO 99/62489 PCT/US98/11252 46 1,5-Dichenyl-3-pentylmercaptvl pyrrolidine-2 carboxylate A solution of 1,5-diphenyl-3-pentylmercaptyl N (tert-butyloxycarbonyl)pyrrolidine-2-carboxylate 5 (850 mg; 1.8 mmol) in methylene chloride (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene 10 chloride. The combined organic extracts were dried and concentrated to yield 480 mg (72%) of the free amine as a thick oil, which was used without further purification. 1,5-Diphenyl-3-pentylmercaptyl N-(para 15 toluenesulfonyl)pipecolate (18) 1,5-Diphenyl-3-pentylmercaptyl N-(para toluenesulfonyl)pipecolate (18) was prepared from 1,5-diphenyl-3-pentylmercaptyl pyrrolidine-2 carboxylate and para-toluenesulfonyl chloride as 20 described for Example 3, in 65% yield. 'H NMR (CDCl 3 , 300 MHz): 6 0.80 (m, 4H); 1.23-1.97 (m, 5H); 2.15 (d, 1H); 2.61-2.69 (m, 4H); 3.23 (m, 1H); 3.44 (dm, 1H); 4.27 (s, 2H); 4.53 (d, 1H, j = 4.5); 5.06 (m, 1H); 7.16-7.34 (m, 15H). 25 WO 99/62489 PCT/US98/11252 47 Example 5 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 5 low molecular weight, small molecule, neuro immunophilin FKBP ligand, GPI 1046, which is related to N-linked sulfonamides of heterocyclic thioesters. Referring now to FIGS. 1 and 2 of the drawings, C57 black 6 mice, approximately 7 weeks old, had an area 10 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 15 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 ptM GPI 1046 (FIG. 3) or 30 pIM GPI 1046 (FIG. 4) dissolved in the vehicle. The animals were 20 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 WO 99/62489 PCT/US98/11252 48 area 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. 5 Further, FIG. 4 shows that mice treated with 30 yM 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, including GPI 1312. C57 Black 6 mice, 55 to 75 days old, had an area of about 2 inches by 2 15 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 anagen growth phase when shaved. Five animals per group were treated by topical 20 administration with a vehicle, FK506, or one of the low molecular weight, small molecule, non-immuno suppressive neuroimmunophilin FKBP ligands (GPI 1605, 1046, 1312, 1572, 1389, 1511, and 1234) at a concentration of one micromole per milliliter to the 25 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 WO 99/62489 PCT/US98/11252 49 new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area). Figure 5 shows that after 14 days, the animals 5 treated with vehicle exhibited the beginning of growth in small tufts. In contrast, animals treated with one of the low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligands, including GPI 1312, exhibited dramatic 10 hair growth. Example 6 A lotion comprising the following composition may be prepared. 15 (%) 95% Ethanol 80.0 an N-linked sulfonamide of a heterocyclic 10.0 20 thioester as defined above a-Tocopherol acetate 0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil purified water 9.0 25 perfume and dye q.s. Into 95% ethanol are added an N-linked sulfonamide of a heterocyclic thioester, a 30 tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a dye. The resulting mixture is stirred and dissolved, and WO 99/62489 PCTIUS98/11252 50 purified water is added to the mixture to obtain a transparent liquid lotion. 5 ml of the lotion may be applied once or twice per day to a site having marked baldness or 5 alopecia. Example 7 A lotion comprising the following composition shown may be prepared. 10 (%) 95% Ethanol 80.0 an N-linked sulfonamide of a heterocyclic 0.005 thioester as defined above 15 Hinokitol 0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil Purified water 19.0 Perfume and dye q.s. 20 Into 95% ethanol are added an N-linked sulfonamide of a heterocyclic thioester, hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and a dye. The resulting mixture is 25 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. 30 WO 99/62489 PCT/US98/11252 51 Example 8 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 Squalene 10.0 10 Polyoxyethylene (10 mole) monostearate 2.0 Sorbitan monooleate 1.0 an N-linked sulfonamide of a heterocyclic 0.01 thioester 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'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.

WO 99/62489 PCT/US98/11252 52 Example 9 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-linked sulfonamide of a heterocyclic 0.8 15 thioester 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'c. The B phase is added into the A phase and the mixture is stirred to obtain an 25 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. 30 WO 99/62489 PCTIUS98/11252 53 Example 10 A liquid comprising the following composition may be prepared. 5 (%) Polyoxyethylene butyl ether 20.0 Ethanol 50.0 an N-linked sulfonamide of a heterocyclic 0.001 thioester 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-linked sulfonamide of a heterocyclic thioester, 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 WO 99/62489 PCT/US98/11252 54 Example 11 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-linked sulfonamide of a heterocyclic 5.0 thioester 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 laurylsulfate, 6.0 g of betaine lauryldimethyl 20 aminoacetate. Then a mixture obtained by adding 5.0 g of an N-linked sulfonamide of a heterocyclic thioester, 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 25 successively added. The resulting mixture is heated and subsequently cooled to obtain a shampoo. The shampoo may be used on the scalp once or twice per day.

WO 99/62489 PCTIUS98/11252 55 Example 12 A patient is suffering from alopecia senilis. An N-linked sulfonamide of a heterocyclic thioester as identified above, or a pharmaceutical composition 5 comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. Example 13 10 A patient is suffering from male pattern alopecia. An N-linked sulfonamide of a heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to 15 occur following treatment. Example 14 A patient is suffering from alopecia areata. An N-linked sulfonamide of a heterocyclic thioester as 20 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 15 A patient is suffering from hair loss caused by skin lesions. An N-linked sulfonamide of a heterocyclic thioester as identified above, or a WO 99/62489 PCT/US98/11252 56 pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. 5 Example 16 A patient is suffering from hair loss caused by tumors. An N-linked sulfonamide of a heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered 10 to the patient. Increased hair growth is expected to occur following treatment. Example 17 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-linked sulfonamide of a heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased 20 hair growth is expected to occur following treatment. Example 18 A patient is suffering from hair loss caused by chemotherapy. An N-linked sulfonamide of a 25 heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

WO 99/62489 PCT/US98/11252 57 Example 19 A patient is suffering from hair loss caused by radiation. An N-linked sulfonamide of a heterocyclic thioester 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. The invention being thus described, it will be 10 obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

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

2. The method of claim 1, wherein the N-linked sulfonamide is non-immunosuppressive. 10

3. The method of claim 1, wherein the N-linked sulfonamide has an affinity for an FKBP-type immunophilin. 15

4. The method of claim 3, wherein the FKBP-type immunophilin is FKBP-12.

5. The method of claim 1, wherein the N-linked sulfonamide is a compound of formula I 20 B A S-Y-Z N D o~s~ x R, 25 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: WO 99/62489 PCT/US98/11252 59 A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the 5 nitrogen atom, one or more additional 0, S, SO, SO 2 , N, NH, or NR 2 heteroatom(s); X is either 0 or S; 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 any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, 15 sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or SO 2 ; R 2 is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, C 3 -C 4 20 straight or branched chain alkenyl or alkynyl, and C 1 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; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one WO 99/62489 PCT/US98/11252 60 or more substituent (s) ; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an 5 aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or 10 alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any 15 atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; C and D are independently hydrogen, Ar, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl; wherein said alkyl or alkenyl 20 is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8 cycloalkyl, C 5 -C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally 25 substituted with Cl-C 6 alkyl, C 2 -C 6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or WO 99/62489 PCT/US98/11252 61 sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position (s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally 5 replaced with 0, NH, NR 3 , S, SO, or SO 2 ; and Ri is selected from the group consisting of Ar, C 3 -C, cycloalkyl, C 1 -C6 straight or branched chain alkyl, and 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 Ar, C 3 -C 8 cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, 15 carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or SO 2 20

6. The method of claim 5, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, 25 pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. WO 99/62489 PCT/US98/11252 62

7. The method of claim 5, wherein: A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 6 membered saturated or unsaturated 5 heterocyclic ring; and R 2 is C 4 -C 7 branched chain alkyl, C 4 -C, cycloalkyl, phenyl, or 3,4,5-trimethoxyphenyl.

8. The method of claim 5, wherein the compound 10 is selected from the group consisting of: 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (benzenesulfonyl) pyrrolidine-2-carboxylate; 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (a-toluenesulfonyl)pyrrolidine-2-carboxylate; 15 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N (a-toluenesulfonyl)pyrrolidine-2-carboxylate; 1,5-Diphenyl-3-pentylmercaptyl N-(para toluenesulfonyl)pipecolate; and pharmaceutically acceptable salts, esters, and 20 solvates thereof.

9. The method of claim 1, wherein the N-linked sulfonamide is a compound of formula II 25 /G F J C S-Y-Z _ID IT 0 S X R0 WO 99/62489 PCT/US98/11252 63 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH 2 , 0, S, SO, SO 2 , NH or NR 2 ; 5 X is either 0 or S; Y is a direct bond, Cl-C6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more 10 position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally 15 replaced with 0, NH, NR 3 , 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 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 a direct bond, Cl-C 6 straight or branched 25 chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, WO 99/62489 PCT/US98/11252 64 ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced 5 with 0, NH, NR 2 , S, SO, or SO 2 ; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring 10 size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; 15 C and D are independently hydrogen, Ar, C 1 -C 6 straight or branched chain alkyl, or C 2 -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 20 consisting of C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C,-C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is 25 optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; and WO 99/62489 PCT/US98/11252 65 R, is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, 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 5 substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8 cycloalkyl.

10. The method of claim 9, wherein the mono- or 10 bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, 15 thiazolyl, pyrazolyl, and thienyl.

11. The method of claim 1, wherein the N-linked sulfonamide is a compound of formula III 20 F-G C E 1NS-Y-ZD N D III o==s X R, 25 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: WO 99/62489 PCTIUS98/11252 66 E, F, and G are independently CH 2 , 0, S, SO, SO 2 , NH or NR 2 ; X is either 0 or S; Y is a direct bond, C 1 -C 6 straight or branched 5 chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, 10 imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or S02; R 2 is selected from the group consisting of 15 hydrogen, C-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 the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a 20 ring, wherein said ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one 25 or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an WO 99/62489 PCTIUS98/11252 67 aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, C 1 -C 6 straight or branched chain alkyl, or C 2 -C, straight or branched chain 5 alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, 10 sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; R 2 is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, C 3 -C 4 15 straight or branched chain alkenyl or alkynyl, and C 1 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 20 group; C and D are independently hydrogen, Ar, CI-C6 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 25 substituent(s) independently selected from the group consisting of C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally WO 99/62489 PCTIUS98/11252 68 substituted with Ci-C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom 5 of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; and R 1 is selected from the group consisting of Ar, C 3 -C, cycloalkyl, Cl-C 6 straight or branched chain alkyl, and C 2 -C 6 straight or branched chain alkenyl, 10 wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8 cycloalkyl. 15

12. The method of claim 11, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, 20 furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

13. The method of claim 1, wherein the N-linked sulfonamide is a compound of formula IV WO 99/62489 PCTIUS98/11252 69 (CH 2 ) n -C CN S-Y- C ND IV o o0 5 10 R, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3; 10 X is either O or S; Y is a direct bond, Ci-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more 15 position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally 20 replaced with 0, NH, NR 3 , 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 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; WO 99/62489 PCTIUS98/11252 70 Z is a direct bond, Cl-C. straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more 5 position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced 10 with 0, NH, NR 2 , S, SO, or SO 2 ; R 2 is selected from the group consisting of hydrogen, C 1 -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 15 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; Ar is an alicyclic or aromatic, mono-, bi- or 20 tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent (s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from 25 the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; C and D are independently hydrogen, Ar, CI-C 6 WO 99/62489 PCTIUS98/11252 71 straight or branched chain alkyl, or C 2 -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 5 consisting of C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is 10 optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; and R 1 is selected from the group consisting of Ar, 15 C 3 -C 8 cycloalkyl, 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 Ar 20 and C 3 -C 8 cycloalkyl.

14. The method of claim 13, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, benzyl, naphthyl, 25 indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. WO 99/62489 PCT/US98/11252 72

15. The method of claim 1, wherein the N-linked sulfonamide is a compound of formula V B c 5 A s-Y-z D x Ri 10 or a pharmaceutically acceptable salt, ester, or 10 solvate thereof, wherein: V is C, N, or S; A, B, C, D, R 1 , X, Y, and Z are as defined in claim 5 above. 15

16. A pharmaceutical composition which comprises: (i) an effective amount of an N-linked sulfonamide of a heterocyclic thioester for treating alopecia or promoting hair growth 20 in an animal; and (ii) a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16, wherein the N-linked sulfonamide is non 25 immunosuppressive. WO 99/62489 PCT/US98/11252 73

18. The pharmaceutical composition of claim 16, wherein the N-linked sulfonamide has an affinity for an FKBP-type immunophilin. 5

19. The pharmaceutical composition of claim 18, wherein the FKBP-type immunophilin is FKBP-12.

20. The pharmaceutical composition of claim 16, wherein the N-linked sulfonamide is a compound of 10 formula I B A S-Y-Z N D 15 0 R, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 20 A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more additional 0, S, SO, SO2, N, 25 NH, or NR 2 heteroatom(s); X is either 0 or S; Y is a direct bond, Ci-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain WO 99/62489 PCTIUS98/11252 74 alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, 5 imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or SO 2 ; R 2 is selected from the group consisting of 10 hydrogen, C 1 -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 the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a 15 ring, wherein said ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one 20 or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally 25 oxidized to a corresponding N-oxide; Z is a direct bond, C 1 -C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or WO 99/62489 PCT/US98/11252 75 alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, 5 sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; C and D are independently hydrogen, Ar, CI-C 6 straight or branched chain alkyl, or C 2 -C6 straight or 10 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 3 -C, cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, 15 alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or 20 sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR,, S, SO, or SO 2 ; and 25 R, is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, 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 WO 99/62489 PCT/US98/11252 76 substituted with one or more substituent(s) independently selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C 1 i-C6 straight or branched chain 5 alkyl, C 2 -C 6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally 10 replaced with 0, NH, NR 3 , S, SO, or SO 2

21. The pharmaceutical composition of claim 20, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, 15 benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. 20

22. The pharmaceutical composition of claim 21, wherein: A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, 25 to form a 6 membered saturated or unsaturated heterocyclic ring; and R 2 is C 4 -C, branched chain alkyl, C 4 -C, cycloalkyl, phenyl, or 3,4,5-trimethoxyphenyl. WO 99/62489 PCT/US98/11252 77

23. The pharmaceutical composition of claim 20, wherein the compound is selected from the group consisting of: 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N 5 (benzenesulfonyl) pyrrolidine-2-carboxylate; 3- (para-Methoxyphenyl) -1-propylmercaptyl (2S) -N (a-toluenesulfonyl) pyrrolidine-2-carboxylate; 3- (para-Methoxyphenyl) -1-propylmercaptyl (2S) -N (a-toluenesulfonyl) pyrrolidine-2-carboxylate; 10 1,5-Diphenyl-3-pentylmercaptyl N-(para toluenesulfonyl)pipecolate; and pharmaceutically acceptable salts, esters, and solvates thereof. 15

24. The pharmaceutical composition of claim 16, wherein the N-linked sulfonamide is a compound of formula II F J C 20 E SYZ N D 0=s~x R0 25 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH 2 , 0, S, SO, SO2, NH or NR 2 ; WO 99/62489 PCT/US98/11252 78 X is either 0 or S; Y is a direct bond, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or 5 alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any 10 carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or SO 2 ; R 2 is selected from the group consisting of hydrogen, C 1 -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 a direct bond, Cl-C. straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, 25 ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced WO 99/62489 PCTIUS98/11252 79 with 0, NH, NR 2 , S, SO, or S02; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one 5 or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally 10 oxidized to a corresponding N-oxide; C and D are independently hydrogen, Ar, C 1 -C 6 straight or branched chain alkyl, or C 2 -C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more 15 substituent(s) independently selected from the group consisting of C 3 -C 8 cycloalkyl, Cs-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; 20 wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; and

25 R 1 is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, 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 WO 99/62489 PCTIUS98/11252 80 substituted with one or more substituent(s) independently selected from the group consisting of Ar and C,-C 8 cycloalkyl. 5 25. The pharmaceutical composition of claim 24, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, 10 quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

26. The pharmaceutical composition of claim 16, 15 wherein the N-linked sulfonamide is a compound of formula III F-G C E S-Y-Z KN D 20 -- X III O- O R1 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 25 E, F, and G are independently CH 2 , 0, S, SO, SO 2 , NH or NR 2 ; X is either 0 or S; Y is a direct bond, C 1 -C 6 straight or branched WO 99/62489 PCT/US98/11252 81 chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, 5 ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or SO 2 ; 10 R 2 is selected from the group consisting of hydrogen, C 1 -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 the nitrogen and a carbon atom of said alkyl or 15 alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the 20 ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an 25 aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, C 1 -C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain WO 99/62489 PCTIUS98/11252 82 alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, 5 imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; R 2 is selected from the group consisting of 10 hydrogen, C,-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 the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a 15 ring, wherein said ring is optionally fused to an Ar group; C and D are independently hydrogen, Ar, Cl-C6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl 20 is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally 25 substituted with Cl-C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom WO 99/62489 PCT/US98/11252 83 of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or S02; and R 1 is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, C 1 -C 6 straight or branched chain 5 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 Ar and C 3 -C, cycloalkyl. 10

27. The pharmaceutical composition of claim 26, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, 15 pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. 20

28. The pharmaceutical composition of claim 16, wherein the N-linked sulfonamide is a compound of formula IV (CH 2 )n 25 S-Y-Z N D IV O=S O R0 WO 99/62489 PCTIUS98/11252 84 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3; X is either 0 or S; 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 any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, 10 ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 3 , S, SO, or S02; 15 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 the nitrogen and a carbon atom of said alkyl or 20 alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; Z is a direct bond, C 1 -C. straight or branched chain alkyl, or C 2 -C 6 straight or branched chain 25 alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, WO 99/62489 PCT/US98/11252 85 imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; 5 R 2 is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C 3 -04 straight or branched chain alkenyl or alkynyl, and C1 C 4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or 10 alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the 15 ring is either unsubstituted or substituted with one or more substituent (s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an 20 aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-CE straight or branched chain alkenyl, wherein said alkyl or alkenyl 25 is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-Cs cycloalkyl, C-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, WO 99/62489 PCTIUS98/11252 86 alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cl-C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with 5 oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR 2 , S, SO, or SO 2 ; and R 1 is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, C 1 -C 6 straight or branched chain 10 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 Ar and C 3 -C 8 cycloalkyl. 15

29. The pharmaceutical composition of claim 28, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, 20 pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. 25

30. The pharmaceutical composition of claim 16, wherein the N-linked sulfonamide is a compound of formula V WO 99/62489 PCTIUS98/11252 87 B C A S-Y-Z V 1 s x 5~1 0 Ri or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 10 V is C, N, or S; A, B, C, D, R 1 , X, Y, and Z are as defined in claim 20 above.