AU760663B2 - Small molecule sulfonamide hair growth compositions and uses - Google Patents

Description

004258486 1 SMALL MOLECULAR SULFONAMIDE HAIR GROWTH COMPOSITIONS AND USES BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, small molecule sulfonamides.

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

The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific g*co *oooo WO 99/62490 PCT/US98/11253 2 immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J.

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

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

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

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

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

These patents claim FK506 related compounds. Although WO 99/62490 PCT/US98/11253 3 they do not claim methods of hair revitalization, they disclose the known use of FK506 for effecting hair growth. Similar to FK506 (and the claimed variations in the Honbo et al. patent), the compounds claimed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which FK506's efficacy is well known.

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

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

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

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

5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that WO 99/62490 PCT/US98/11253 4 these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and non-immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.

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

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

The small molecule sulfonamides used in the inventive methods and pharmaceutical compositions may be immunosuppressive, but are preferably nonimmunosuppressive compounds having an affinity for FKBP-type immunophilins, particularly FKBP12. Nonimmunosuppressive compounds, as their name suggests, do not exert any significant immunosuppressive activity.

WO 99/62490 PCT/US98/11253 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a photograph of mice treated with a vehicle after six weeks. FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.

FIG. 2 is a photograph of mice treated with 10 AM of a related neuroimmunophilin FKBP ligand, GPI 1044, after six weeks. FIG. 2 shows that 90% of the shaved area is covered with new hair growth when GPI 1044 is administered.

FIG. 3 is a photograph of mice treated with 10 IM of another related neuroimmunophilin FKBP ligand, GPI 1116, after six weeks. FIG. 3 shows that 90% of the shaved area is covered with new hair growth when GPI 1116 is administered.

FIG. 4 is a photograph of mice treated with 3 [M of a third related neuroimmunophilin FKBP ligand, GPI 1102, after six weeks. FIG. 3 shows that 90% of the shaved area is covered with new hair growth when GPI 1102 is administered.

FIG. 5 is a bar graph plotting the hair growth scores of unshaven animals and shaven animals treated with a vehicle, GPI 1044 (1 AM, 3 jM and 10 AM), GPI 1116 (1 AM and 10 iM), and GPI 1102 (1 AM and 3 AM).

FIG. 6 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, and related neuroimmunophilin FKBP ligands 14 days after treatment with each identified WO 99/62490 PCT/US98/11253 6 compound. Figure 6 demonstrates the remarkable early hair growth promoted by neuroimmunophilin FKBP ligands.

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

Alopecia results when the pilar cycle is disturbed.

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

"GPI 1044" refers to the compound WO 99/62490 PCT/US98/11253 7 wherein B is 3-Phenylpropyl, D is 3-Phenylpropyl, and L is Phenyl.

"GPI 1102" refers to 4-phenyl-l-(3-phenylpropyl) butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2piperidinecarboxylate.

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

"GPI 1206" refers to a compound of formula

NN

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

"Pharmaceutically acceptable salt, ester, or solvate" refers to a salt, ester, or solvate of a WO 99/62490 PCT/US98/11253 8 subject compound which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. A salt, ester, or solvate can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl WO 99/62490 PCT/US98/1 1253 9 halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.

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

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

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

"Treating alopecia" refers to: preventing alopecia in an animal which may be WO 99/62490 PCT/US98/11253 predisposed to alopecia; and/or (ii) inhibiting, retarding or reducing alopecia; and/or (iii) promoting hair growth; and/or (iv) prolonging the anagen phase of the hair cycle; and/or converting vellus hair to growth as terminal hair. Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis. Vellus hair, on the other hand, is fine, thin, non-pigmented short hair in which the hair bulb is located superficially in the dermis. As alopecia progresses, the hairs change from the terminal to the vellus type.

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

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

WO 99/62490 PCT/US98/11253 11 Pharmaceutical Compositions of the Present Invention The present invention also relates to a pharmaceutical composition comprising: an effective amount of a small molecule sulfonamide; and (ii) a pharmaceutically acceptable carrier.

SMALL MOLECULE SULFONAMIDES The sulfonamides used in the methods and pharmaceutical compositions of the present invention are low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins, such as FKBP12. When a sulfonamide binds to an FKBP-type immunophilin, it has been found to inhibit the prolylpeptidyl cis-trans isomerase, or rotamase, activity of the binding protein. Unexpectedly, the compounds have also been found to stimulate hair growth. These rotamase inhibiting compounds are non-immunosuppressive. Examples of useful compounds are set forth below.

FORMULA I An exemplary small molecule sulfonamide is a compound of Formula I K B A A 2 S0 2 0

E

WO 99/62490 PCT/US98/11253 12 or a pharmaceutically acceptable salt thereof, wherein: A is CH 2 O, NH, or N-(Ci-C 4 alkyl); B and D are independently Ar, hydrogen, CI-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C 5

-C

7 cycloalkyl, Cs-C 7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO2 in chemically reasonable substitution patterns, or

Q

wherein Q is hydrogen, C,-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl; and T is Ar or Cs-C 7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, alkyl), O-(C 2

-C

4 alkenyl), and carbonyl; provided that both B and D are not hydrogen; WO 99/62490 PCT/US98/ 11253 13 Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, Cl-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, 0-

C

4 straight or branched chain alkyl), O- (C 2

-C

4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2methylenedioxy, amino, carboxyl, and phenyl; E is Ci-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, cycloalkyl, Cs-C, cycloalkenyl substituted with C 1

-C

4 straight or branched chain alkyl or C 2

-C

4 straight or branched chain alkenyl, (C 2

-C

4 alkyl or C 2

-C

4 alkenyl)-Ar, or Ar; J is hydrogen, C 1 or C 2 alkyl, or benzyl; K is Ci-

C

4 straight or branched chain alkyl, benzyl, or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with O, S, SO, or S2,; n is 0 to 3; and the stereochemistry at carbon positions 1 and 2 is R or S.

WO 99/62490 PCT/US98/11253 14 FORMULA II In a preferred embodiment of Formula I, J and K are taken together and the small molecule sulfonamide is a compound of Formula II

B

(m D n 0

II

N

V

H o S02

E

or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; and m is 0 or 1.

In a more preferred embodiment, B is selected from the group consisting of hydrogen, benzyl, 2phenylethyl, and 3-phenylpropyl; D is selected from the group consisting of phenyl, 3-phenylpropyl, 3-phenoxyphenyl, and 4phenoxyphenyl; and E is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3methoxyphenyl, 2-methoxyphenyl, WO 99/62490 PCT/US98/11253 3,4,5-trimethoxyphenyl, methyl, l-naphthyl, 8quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and Estyrenyl.

FORMULA III Another exemplary small molecule sulfonamide is a compound of Formula III

B

(m D

IIII

O=S O

E

or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, C 1

-C

6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with Cs-C, cycloalkyl, cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of 0, S, SO, and SO 2 in WO 99/62490 PCT/US98/11253 16 chemically reasonable substitution patterns, or

T

wherein Q is hydrogen, Cl-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl; and T is Ar or C 5 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O-(Ci-C 4 alkyl), O-(C 2 alkenyl), and carbonyl; provided that both B and D are not hydrogen; Ar is selected from the group consisting of phenyl, l-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, CI-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, WO 99/62490 PCT/US98/11253 17

C

4 straight or branched chain alkyl), 0-(C 2

-C

4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2methylenedioxy, amino, carboxyl, and phenyl; E is Ci-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, Cs-C 7 cycloalkyl, Cs-C, cycloalkenyl substituted with Ci-C 4 straight or branched chain alkyl or C 2

-C

4 straight or branched chain alkenyl, (C 2

-C

4 alkyl or C 2

-C

4 alkenyl)-Ar, or Ar; and m is 0 to 3.

FORMULA IV A further exemplary small molecule sulfonamide is a compound of Formula IV

B

I

IV

N Yo o

E

or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, C 1

-C

6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain alkenyl, wherein said alkyl or alkenyl WO 99/62490 PCT/US98/11253 18 is unsubstituted or substituted with Cs-C, cycloalkyl,

C

5

-C

7 cycloalkenyl, or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2 in chemically reasonable substitution patterns, or

T

wherein Q is hydrogen, C,-C 6 straight or branched chain alkyl, or C 2 -CG straight or branched chain alkenyl; and T is Ar or Cs-C, cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy,

O-(C,-C

4 alkyl), O-(C 2

-C

4 alkenyl), and carbonyl; provided that both B and D are not hydrogen; Ar is selected from the group consisting of phenyl, l-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in WO 99/62490 PCT/US98/11253 19 either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C 1

-C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, 0-

C

4 straight or branched chain alkyl), 0-(C 2

-C

4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2methylenedioxy, amino, carboxyl, and phenyl; E is C 1

-C

6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, cycloalkyl,

C

5

-C

7 cycloalkenyl substituted with straight or branched chain alkyl or C 2

-C

4 straight or branched chain alkenyl, (C 2

-C

4 alkyl or C 2

-C

4 alkenyl)-Ar, or Ar; and m is 0 to 3.

FORMULA V A further exemplary small molecule sulfonamide is a compound of Formula V K B V 1 A

D

1 V

/SO

2 O

E

WO 99/62490 PCT/US98/ 1253 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is C, N, or S; J and K, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 N, NH, and NR; R is either Ci-C 9 straight or branched chain alkyl, C 2

-C

9 straight or branched chain alkenyl, C,-C 9 cycloakyl, C 5

-C

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

-C

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

-C

4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2 Ar, and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; A, B, D, E, and n are as defined in Formula I above.

WO 99/62490 WO 9962490PCTIUS98/1 1253 21 Representative species of Formulas presented in Table I.

I-V are TABLE I Structure Compound 4 -p he nyl1 1 bu tyl1 -1 (benzylsulfonyl)-(2R,S)-2pipecolimate 1,5-diphenyl-3-pentyl-N-(ytoluene-sulfonyl) pipecolate WO 99/62490 WO 9962490PCT/US98/1 1253 TABLE I (continued) Structure Compound 1,7-diphenyl-4-heptyl-N- (paratoluene-sulfonyl) pipecolate 3 (3 -pyridyl) 1-propyl (2 S) (aetoluenesulfonyl) pyrrolidine-2carboxyl ate WO 99/62490 WO 9962490PCTIUS98/1 1253 TABLE I (continued) Structure Compound 4-phenyl-l-butyl-N- (para-toluenesulfonyl) pipecolate 4 -phenyl-l1-butyl-N- (benzenesulfonyl) pipecolate WO 99/62490 PCT/US98/11253 24 TABLE I (continued) Compound Structure 7 N 0 O=S=0 0 4-phenyl-l-butyl-N-(a-toluenesulfonyl)pipecolate All the compounds of Formulas I-V possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R- and Sstereoisomers. The individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compounds of Formulas I-V. It is understood that the compounds of Formulas I-V encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, S-stereoisomers are used in the pharmeceutical compositions and methods of the present invention.

WO 99/62490 PCT/US98/ 1253 Synthesis of Small Molecule Sulfonamides The compounds of Formulas I-V may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathway depicted below. As described by Scheme I, amino acids 1 protected by suitable blocking groups P on the amino acid nitrogen may be reacted with alcohols ROH to generate esters 2. After removal of the protecting group, the free amine 3 may be reacted with various sulfonyl chlorides 4 to provide final products 5 in good to excellent yield.

SCHEME I

CH

2 r(CH 2 )n OH R OH OR Deprotect N Coupling Method N P 0 0 1 2

C

(CH

2 )n o=S= (CH 2 o-R 4 E O-R H O EtN,CH2C12 O S 0

E

3 Affinity for FKBP12 The compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. The WO 99/62490 PCT/US98/11253 26 inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP may be measured as an indicator of this affinity.

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

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

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

In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaC) 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaC1, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml in 1 mM HC1) and 10 mL of test compound at various WO 99/62490 PCT/US98/11253 27 concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35 mM LiCI in trifluoroethanol).

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

WO 99/62490 WO 9962490PCT/US98/1 1253 28 TABLE I I In Vitro Test Results Formulas I-V Compound Ki (nM1) 4-phenyl--1-butyl-1- (benzylsulfonyl) (2R,S) -2-pipecolinate (1) 1, 5-diph-enyl-3-pentyl-N- (u-toluenesulfony1) pipecolate (2) WO 99/62490 WO 9962490PCTIUS98/1 1253 29 TABLE 11 (continued) In Vitro Test Results Formulas I-V Compound K. (rim) 107 1, 7-diphenyl-4-heptyl-N- (para-toluenesulfonyl) pipecolate (3) 332 3- (3-pyridyl) -1-propyl- (2S) (c-toluenesulfonyl) pyrrolidine-2-carboxylate (4) WO 99/62490 WO 9962490PCTIUS98/1 1253 TABLE II (continued) In Vitro Test Results Formulas I-V Compound Ki (nM) 504

CH

3 4-phenyl-1--butyl-N- (para-toluenesulfonyl) pipecolate 470 4-phenyl-l-butyl-N- (benzenesulfonyl)pipecolate (6) WO 99/62490 PCT/US98/11253 31 TABLE II (continued) In Vitro Test Results Formulas I-V Compound

K

i (nM) 127 N 0 O=S=0 0 4-phenyl-l-butyl-N- (a-toluenesulfonyl) pipecolate (7) Route of Administration To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions must readily affect the targeted areas. For these purposes, the compounds are preferably administered topically to the skin.

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

Alternatively, the compounds can be formulated into WO 99/62490 PCT/US98/1 1253 32 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 alcohol and water.

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

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 preferred levels of about 0.1 mg to about 1,000 mg.

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

WO 99/62490 PCT/US98/11253 33 The compounds can be administered with other hair 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.

EXAMPLES

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

Example 1 Synthesis of 3-(3-Pvridvl)-l-propyl toluenesulfonyl)pyrrolidine-2-carboxylate (4) 3-(3-Pyridyl)-1-propyl N-(tert-butyloxycarbonvl)pyrrolidine-2-carboxylate A mixture of N-(tert-butyloxycarbonyl)-(S)proline (6.0 g; 28 mmol), 3-(3-pyridyl)-l-propanol (5.80 g; 41.8 mmol), dicyclohexylcarbodiimide (9.20 g; 44.48 mmol), camphorsulfonic acid (21.60 g; 9.26 mmol), and 4-dimethylaminopyridine (1.12 g; 9.26 mmol) in dry methylene chloride (200 mL) was stirred overnight. The reaction mixture was filtered through Celite, concentrated, and purified on a silica gel column eluting with 40% ethyl acetate in hexane to obtain 5.0 g of the product as a clear oil H WO 99/62490 PCT/US98/11253 34 NMR (300 MHz, CDC1 3 6 1.42 9H); 1.43-1.95 (m, 6H); 2.68 2H) 3.46-3.52 2H); 4.11-4.22 (m, 2H) 4.33 1H) 7.17-7.24 1H) 7.47 1H); 8.43 2H).

3-(3-Pvridyl)-1-propyl pyrrolidine-2-carboxylate A solution of 3-(3-pyridyl)-l-propyl N-(tertbutyloxycarbonyl) pyrrolidine-2-carboxylate (3.0 g; 8.9 mmol) in methylene chloride (40 mL) and trifluoroacetic acid (8 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 chloride The combined organic extracts were dried and concentrated to yield 1.60 g of the free amine as a thick oil. 1H NMR (300 MHz, CDC13) 6 1.71-2.09 6H) 2.63 2H) 2.86 1H) 2.94 1H) 3.71 1H) 4.11 2H) 7.18 1H) 7.45 (m, 1H) 8.41 2H).

3-(3-Pyridvl)-1-propyl (2S)-N-(u-toluenesulfonyl)pyrrolidine-2-carboxylate (4) A solution of 3- (3-Pyridyl)-1-propyl pyrrolidine- 2-carboxylate (200 mg; 0.9 mmol) and c-toluenesulfonyl chloride (160 mg; 0.9 mmol) in methylene chloride mL) was treated with triethylamine (90 mg; 0.9 mmol) and stirred for 2 hours at room temperature. The reaction mixture was filtered to remove solids and applied directly to a silica gel column, eluting with ethyl acetate in hexane, to obtain 150 mg of WO 99/62490 PCT/US98/11253 Compound 4 (Table I) as a clear oil. 'H NMR (300 MHz, CDC1 3 6 1.81-1.85 2H) 1.95-2.02 3H) 2.10- 2.25 1H); 2.69-2.74 2H) 2.85-2.97 1H); 3.24-3.27 1H); 4.16-4.20 2H) 4.29 1H); 4.34 1H); 4.45 1H); 7.20-7.25 1H) 7.35 3H) 7.49-7.52 3H) 8.46 2H) Analysis calculated for C 20

H

24

N

2 0 3 S: C, 61.83; H, 6.23; N, 7.21.

Found: C, 61.59; H, 6.24; N, 7.17.

Example 2 Synthesis of 4-Phenyl-l-butyl 1-(a-tolylsulfony1)- 2-pipecolinate (7) Methyl 1- (a-tolylsulfonl)-2-pipecolinate To a solution of methyl pipecolinate hydrochloride (1.79 g; 10 mmol) and triethylamine (1.01 g; 10 mmol) in dry methylene chloride (20 mL) was added e-toluenesulfonyl chloride (1.9 g; 10 mmol).

The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The crude residue was purified on a silica gel column, eluting with ethyl acetate, to provide 2.20 g of the product was an oil which solidified upon standing. 1H NMR (CDC13, 300 MHz): 6 1.26-1.71 5H); 2.15 (d, 1H, J 14.4); 3.17 (dt, 1H); 3.45 1H, J 12.6); 3.78 3H); 4.28 2H); 4.58 1H); 7.26-7.48 N- (-tolylsulfonyl)-2-pipecolic acid Methyl 1-(a-tolylsulfonyl)-2-pipecolinate (2.0 g; WO 99/62490 PCT/US98/11253 36 6.72 mmol) was dissolved in ethanol (25 mL) and treated with 20 mL of 1 N lithium hydroxide. The mixture was stirred for 2 hours at room temperature, and then diluted with ethyl acetate (200 mL) and made acidic (pH 2) with 1 N HCL. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to obtain 1.90 g (100%) of the acid as a white solid.

4-Phenvl-l-butvl 1-(c-tolylsulfonvl)-2-pipecolinate (7) A solution of N-(a-tolylsulfonyl)-2-pipecolic acid (400 mg; 1.41 mmol), dicyclohexylcarbodiimide (312 mg; 1.5 mmol), dimethylaminopyridine (7 mg) and 4-phenyl-l-butanol (240 mg; 1.60 mmol) in 100 mL of methylene chloride was stirred overnight at room temperature. The mixture was filtered through Celite, concentrated, and purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 380 mg of Compound 7 (Table I) as a clear oil.

1H NMR (CDC13, 300 MHz): 6 1.10-1.69 5H); 1.70 (tt, 4H, J 6.1, 2.15 1H); 2.66 2H, J 3.16 1H); 3.45 1H); 4.19 2H, J 4.28 2H) 4.58 1H) 7.18-7.47 Analysis calculated for C 2 3

H

29

NO

4 S: C, 66.48; H, 7.03; N, 3.37. Found: C, 66.34; H, 7.06; N, 3.41.

WO 99/62490 PCT/US98/11253 37 Example 3 Synthesis of 1,5-Diphenyl-3-pentyl toluenesulfonyl)pipecolate (2) 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 minutes, 3-phenyl-lpropanol (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 minutes, treated with 14 mL of triethylamine, stirred an additional 15 minutes, and poured into 100 mL of water. The layers 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 of the aldehyde as a clear oil. 'H NMR (300 MHz, CDC1) 6 2.80 2H); 2.98 2H); 7.27 5H); 9.81 1H).

1,5-Diphenyl-3-pentanol A solution of 2-(bromoethyl)benzene (1.73 g; 9.33 mmol) in diethylether (10 mL) was added to a stirred slurry of magnesium turnings (250 mg; 10.18 mmol) in 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 minutes. 3-Phenyl-1propanal (1.25 g; 9.33 mmol) was added in 10 mL of ether, and reflux was continued for 1 hour. The WO 99/62490 PCT/US98/11253 38 reaction was cooled and quenched with saturated ammonium chloride, extracted into 2x ethyl acetate, and the combined organic portions were dried and concentrated. Chromatographic purification on a silica gel column (10% ethyl acetate in hexane) delivered 1.42 g of the diphenyl alcohol. 1 H NMR (300 MHz, CDC1 3 6 1.84 4H); 2.61-2.76 (m,4H); 3.65 1H); 7.19-7.29 1, 5-Diphenyl-3 -entyl N- (a-toluenesulfonvl) pipecolate (2) A mixture of N- (a-tolylsulfonyl) -2-pipecolic acid (380 mg; 1.34 mmol), 1,5-diphenyl-3-pentanol (485 mg; 2.01 mmol), dicyclohexylcarbodiimide (445 mg; 2.15 mmol), camphorsulfonic acid (105 mg; 0.45 mmol) and dimethylaminopyridine (55 mg; 0.45 mmol) in 20 mL of methylene chloride was stirred overnight at room temperature. The mixture was filtered through Celite, concentrated, and purified on a silica gel column, eluting with 15% ethyl acetate in hexane, to obtain 270 mg of Compound 2 (Table I) as a clear oil.

'H NMR (CDC13, 300 MHz): 6 0.80 4H); 1.23-1.97 (m, 2.15 1H) 2.61-2.69 4H) 3.23 1H); 3.44 (dm, 1H); 4.27 2H); 4.53 1H, J 5.06 1H) 7.16-7.34 15H) Analysis calculated for C, 3

H

3 sN0 4 S: C, 71.26; H, 6.98; N, 2.77. Found: C, 72.82; H, 7.17; N, 2.53.

WO 99/62490 PCTIUS98/ 1253 39 Example 4 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 related neuroimmunophilin FKBP ligands, GPI 1044, GPI 1116, and GPI 1102. C57 black 6 mice, approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers. The animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGS. i, 2, 3 and 4, four animals were treated by topical administration with 20% propylene glycol vehicle (FIG. and, for each compound, seven animals were treated by topical administration with, respectively, 10 jIM GPI 1044 (FIG. 10 AM GPI 1116 (FIG. or 3 jiM GPI 1102 (FIG. The animals were treated with vehicle, GPI 1044, GPI 1116, or GPI 1102 every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area covered by new hair growth during this time period.

FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. In contrast, FIGS. 2, 3 and 4 show that animals treated with the related WO 99/62490 PCT/US98/11253 neuroimmunophilin FKBP ligands, 10 AM GPI 1044, 10 AM GPI 1116, and 3 iM GPI 1102, exhibited dramatic hair growth, covering as much as 50% of the shaved area in some animals. FIG. 5 compares the hair growth score of unshaven animals with the hair growth scores of shaven animals treated with a vehicle and with the related neuroimmunophilin FKBP ligands GPI 1044 (1 IM, 3 pM and 10 AM), GPI 1116 (1 iM and 10 pM), and GPI 1102 (1 iM and 3 iM).

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

WO 99/62490 PCTIUS98/11253 41 Figure 6 shows that after 14 days, the animals treated with vehicle exhibited the beginning of growth in small tufts. In contrast, animals treated with a neuroimmunophilin FKBP ligand exhibited dramatic hair growth.

Example A lotion comprising the following composition may be prepared.

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

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

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

WO 99/62490 PCT/US98/11253 42 Example 6 A lotion comprising the following composition shown may be prepared.

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

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

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

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

WO 99/62490 PCT/US98/11253 43 Example 7 An emulsion may be prepared from A phase and B phase having the following compositions.

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

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

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

WO 99/62490 PCT/US98/11253 44 Example 8 A cream may be prepared from A phase and B phase having the following compositions.

(A Phase) Fluid paraffin Cetostearyl alcohol Petrolatum Glycerine monostearate 33.0 Polyoxyethylene (20 mole) 2-octyldodecyl ether Propylparaben 0.3 (B Phase) a small molecule sulfonamide as defined 0.8 above Glycerine Dipropylene glycol 20.0 Polyethylene glycol 4000 Sodium Hexametaphosphate 0.005 Purified water 44.895 The A phase is heated and melted, and maintained at 70 0 c. The B phase is added into the A phase and the mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream.

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

WO 99/62490 PCT/US98/11253 Example 9 A liquid comprising the following composition may be prepared.

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

Purified water q.s.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a small molecule sulfonamide, and perfume.

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

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

WO 99/62490 PCT/US98/11253 46 Example A shampoo comprising the following composition may be prepared.

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

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

WO 99/62490 PCT/US98/1 1253 47 Example 11 A patient is suffering from alopecia senilis. A small molecule sulfonamide, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 12 A patient is suffering from male pattern alopecia. A small molecule sulfonamide, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 13 A patient is suffering from alopecia areata. A small molecule sulfonamide, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 14 A patient is suffering from hair loss caused by skin lesions. A small molecule sulfonamide, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

WO 99/62490 PCT/US98/11253 48 Example A patient is suffering from hair loss caused by tumors. A small molecule sulfonamide, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 16 A patient is suffering from hair loss caused by a systematic disorder, such as a nutritional disorder or an internal secretion disorder. A small molecule sulfonamide, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 17 A patient is suffering from hair loss caused by chemotherapy. A small molecule sulfonamide, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 18 A patient is suffering from hair loss caused by radiation. A small molecule sulfonamide, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is 004258486 49 expected to occur following treatment.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

It will be understood that the term "comprises" or its grammatical variants as used in this specification and claims is equivalent to the term "includes" and is not to be taken as excluding the presence of other elements or features.

Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other country.

ego• *Do* *oe **e

Claims (16)

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

2. The method of claim 1, wherein the compound is of formula I K B NA 02 02 or a pharmaceutically acceptable salt thereof, wherein: A is CH 2 O, NH, or N-(Cl-C4 alkyl); B and D are independently Ar, hydrogen, CI-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, 25 wherein said alkyl or alkenyl is 4s-T unsubstituted or substituted with 51 cycloalkyl, C 5 -C 7 cycloalkenyl, or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2 in chemically reasonable substitution patterns, or B and D are independently the fragment T 1 Q wherein Q is hydrogen, Cl-CE straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, and wherein T is Ar or C 5 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O- (Cl-C 4 alkyl), O- (C 2 -C 4 alkenyl), and carbonyl, provided that both B and D are not hydrogen; Ar is selected from the group consisting of phenyl, benzyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and monocyclic or bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 004258486 52 heteroatoms independently selected from the group consisting of 0, N, and S. wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, Ci-Cs straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, O-(C 1 -C 4 straight or branched chain alkyl), O-(C 2 -C 4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl; E is Ci-C6 straight or branched chain alkyl, C 2 C 6 straight or branched chain alkenyl, Cs-C 7 cycloalkyl, Cs-C 7 cycloalkenyl substituted with Ci-C 4 straight or branched chain alkyl or C 2 -C 4 straight or branched chain alkenyl, (C 2 C 4 alkyl or C 2 -C 4 alkenyl)-Ar, or Ar; J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with O, S, SO, or SO 2 n is 0 to 3; and Sthe stereochemistry at carbon positions 1 and 2 is R or S. o* o *9OO *ee *eo° *ooo 53

3. The method of claim 2, wherein J and K are taken together and the compound is represented by formula II D o\ IIo H 0 02 E or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; and m is 0 or 1.

4. The method of claim 2, wherein: B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; D is selected from the group consisting of phenyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl; I and E is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6- triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2- Smethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5- trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, N,N-dimethylamino)-naphthyl, 4-iodophenyl, 2,4,6- trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl, 54 4-chlorophenyl, and E-styrenyl. The method of claim 1, wherein the compound is of formula III D O SII 0===O E or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, C-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said **oo alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2 in chemically reasonable substitution :o patterns, 25 or B and D are independently the fragment T Q wherein Q is hydrogen, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, .and wherein T is Ar or Cs-C, cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O-(CI-C 4 alkyl), O-(C 2 -C 4 alkenyl),. and carbonyl, provided that both B and D are not hydrogen; Ar is selected from the group consisting of phenyl, benzyl, l-naphthyl, 2-naphthyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and monocyclic or bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 20 heteroatoms independently selected from the group consisting of O, N, and S, wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, Ci-C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, O-(Ci-C4 a a* 0 a 0 sea S S S S S 0 56 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), 0- benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl; E is Ci-C, straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C7 cycloalkenyl substituted with Cl-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C 2 -C 4 alkyl or C2-C4 alkenyl)-Ar, or Ar; and m is 0 to 3.

6. The method of claim 1, wherein the compound is of formula IV D I O= O E or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, Cl-C, straight or branched chain alkyl, or C2-C6 straight or gor branched chain alkenyl, *25 wherein said alkyl or alkenyl is unsubstituted or substituted with cycloalkyl, Cs-C, cycloalkenyl, or Ar, 57 and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2 in chemically reasonable substitution patterns, or B and D are independently the fragment T Q wherein Q is hydrogen, C1-C 6 straight or branched chain alkyl, or C2-C 6 straight or branched chain alkenyl, and wherein T is Ar or C 5 -C 7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O-(Cl-C 4 alkyl), 0-(C 2 -C 4 alkenyl), and carbonyl, provided that-both B and D are not hydrogen; Ar is selected from the group consisting of **phenyl, benzyl, l-naphthyl, 2-naphthyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and monocyclic or bicyclic heterocyclic ring f systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 S heteroatoms independently selected from the group consisting of O, N, and S, wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, 0-(Cl-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), 0- benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl; E is C-C6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, Cs-C, cycloalkyl, C7 cycloalkenyl substituted with Cl-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar; and *m is 0 to 3. S" 7. A method for treating alopecia or promoting hair growth in an animal in need thereof, comprising administering to said animal an effective amount a compound of formula V K V I n /SO2 O v E 59 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is CH or N; J and K, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which has one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 N, NH, and NR; R is either Ci-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl., or Arl, wherein R is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, Cj- straight r branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, 20 thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and ~Ar 2 g Ar 1 and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or 25 heterocyclic ring, wherein the individual ring size is 5-8 members, and wherein said heterocyclic ring has 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; A is CH 2 O, NH, or N-(Cl-C 4 alkyl); B and D are independently Ar, hydrogen, Cl-C 6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with cycloalkyl, Cs-C7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl are optionally substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2 S' or B and D are independently the fragment T *Q wherein Q is hydrogen, C,-C6 straight or branched chain alkyl, or C2-C6 straight or *branched chain alkenyl, and wherein T is Ar or Cs-C 7 cycloalkyl ooo substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, 61 hydroxy, 0- (Cl-C4 alkyl) (C 2 -C 4 alkenyl), and carbonyl, provided that both B and D are not hydrogen; E is C-C, straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C7 cycloalkenyl substituted with Ci-C4 straight or branched chain alkyl or C 2 -C 4 straight or branched chain alkenyl, (C 2 -C 4 alkyl or C2-C4 alkenyl)-Ar, or Ar; Ar is selected from the group consisting of phenyl, benzyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and monocyclic or bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently' selected from the group consisting of O, N, and S, wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C-CG *straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C0-C4 S'straight or branched chain alkyl), 0-(C2-C4 a. straight or branched chain alkenyl), 0- a benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl; and SR n is 0 to 3. -9o 62

8. The method of any one of claims 1-7, wherein the compound has an affinity for an FKBP-type immunophilin.

9. The method of claim 8, wherein the FKBP-type immunophilin is FKBP-12. The method of any one of claims 1-7, wherein the compound is immunosuppressive.

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

12. A pharmaceutical composition which comprises: an effective amount of a compound for treating alopecia or promoting hair growth in an animal, wherein said compound is of e formula V K S:: JS A 2 v E or a pharmaceutically acceptable salt, ester, or 25 solvate thereof, wherein: SV is CH or N; J and K, taken together with V and the carbon atom 63 to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which has one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 N, NH, and NR; R is either C-C, straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, or Ar,, wherein R is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, Ci- C 6 straight or branched chain alkyl, C,-C, straight or branched chain alkenyl, C1-C4 alkoxy, Cz-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2 Arl and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, .wherein the. individual ring size is 5-8 members, and wherein said heterocyclic ring has 1-6 25 heteroatom(s) independently selected from the group consisting of O, N, and S; A is CH 2 O, NH, or N-(C-C 4 alkyl); 64 B and D are independently Ar, hydrogen, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C 5 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl are optionally substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2 or B and D are independently the fragment T Q wherein Q is hydrogen, C 1 -C 6 straight or s branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, and wherein T is Ar or C 5 -C 7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O-(Ci-C 4 alkyl), O-(C 2 -C 4 alkenyl), and carbonyl, 25 provided that both B and D are not hydrogen; E is Ci-C 6 straight or branched chain alkyl, C2-C 6 P -Z 1 straight or branched chain alkenyl, C 5 cycloalkyl, Cs- C7 cycloalkenyl substituted with C 1 -C 4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar; Ar is selected from the group consisting of phenyl, benzyl, l-naphthyl, 2-naphthyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and monocyclic or bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, 15 trifluoromethyl, trifluoromethoxy, C-C6 straight or branched chain alkyl, C2-C6 0 00 straight or branched chain alkenyl, 0-(CI-C4 e straight or branched chain alkyl), 0- (C-C4 straight or branched chain alkenyl), 0- 20 benzyl, O-phenyl, 1,2-methylenedioxy, amino, 9 carboxyl, and phenyl; and n is 0 to 3; and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein the compound has an affinity for an FKBP-type immunophilin. 66

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

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

17. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said compound is a heterocyclic compound which has an N- linked sulfone substituent, 15 and which compound is additionally g substituted with a ketone, ester, or amide substituent attached to the heterocyclic ring. 20 18. The use of claim 17, wherein the compound is o of formula I K B N 1 A D 02 I E or a pharmaceutically acceptable salt thereof, wherein: 67 A is CH 2 O, NH, or N-(C-C 4 alkyl); B and D are independently Ar, hydrogen, C1-C, straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C5-C7 cycloalkyl, Cs-C, cycloalkenyl, or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2 in chemically reasonable substitution patterns, or B and D are independently the fragment 15 T wherein Q is hydrogen, C1-C, straight or branched chain alkyl, or Cz-C6 straight or 20 branched chain alkenyl, and wherein T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O-(C,-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl, provided that both B and D are not hydrogen; 004258486 68 Ar is selected from the group consisting of phenyl, benzyl, 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and monocyclic or bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein Ar has 1-3 substitutent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, 0- (Ci-C 4 straight or branched chain alkyl), O- (C 2 -C 4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2- methylenedioxy, amino, carboxyl, and phenyl; E is Ci-C6 straight or branched chain alkyl, C2 C 6 straight or branched chain alkenyl, Cs-C 7 cycloalkyl, Cs-C 7 cycloalkenyl substituted with C 1 -C 4 straight or branched chain alkyl or C 2 -C 4 straight or branched chain alkenyl, (C 2 -C 4 alkyl or C 2 -C 4 alkenyl)-Ar, or Ar; J and K are taken together to form a 5-7 *oo *oo *oo oooo o*o *ooo* 69 membered heterocyclic ring which is substituted with O, S, SO, or SO 2 n is 0 to 3; and the stereochemistry at carbon positions 1 and 2 is R or S.

19. The use of claim 18, wherein J and K are taken together and the compound is represented by formula II B D O II S 15 S0 2 E or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; and m is 0 or 1. or 20. The use of claim 18, wherein: B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; a SD is selected from the group consisting of phenyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl; and E is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6- triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2- methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5- trimethoxyphenyl, methyl, l-naphthyl, 8-quinolyl, N,N-dimethylamino)-naphthyl, 4-iodophenyl, 2,4,6- trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and E-styrenyl.

21. The use of claim 17, wherein the compound is of formula III D 0 15 N III I C or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, C-Cg 9*99** e 20 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with Cs-C7 cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one Ror two heteroatom(s) independently selected 71 from the group consisting of O, S, SO, and SO 2 in chemically reasonable substitution patterns, or B and D are independently the fragment T Q wherein Q is hydrogen, Ci-C, straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, and wherein T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, 15 hydroxy, O-(CI-C4 alkyl), O-(C2-C4 alkenyl), .y and carbonyl, provided that both B and D are not hydrogen; Ar is selected from the group consisting of phenyl, benzyl, l-naphthyl, 2-naphthyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and monocyclic or bicyclic heterocyclic ring c.. systems with individual ring sizes being 5 or 6 which C contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein Ar has 1-3 substituent(s) independently selected from the group 72 consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, Ci-C 6 straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, O-(Ci-C 4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), 0- benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl; E is Ci-CG straight or branched chain alkyl, C2-C 6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C7 cycloalkenyl substituted with C-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar; and m is 0 to 3. o 22. The use of claim 17, wherein/the compound is of formula IV I or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, Cl-C, straight or branched chain alkyl, or C2-C6 straight or

5555-- I ^S^RA^ straight or branched chain alkyl, or 02-06 straight or 73 branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl, or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of 0, S, SO, and SO 2 in chemically reasonable substitution patterns, or B and D are independently the fragment T Q 15 wherein Q is hydrogen, Cl-C 6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, and wherein T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or 20 more substituent(s) independently selected from the group consisting of hydrogen, a.. hydroxy, O-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl, Sprovided that both B and D are not hydrogen; Ar is selected from the group consisting of phenyl, benzyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3- SR furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- 74 pyridyl, and monocyclic or bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, CI-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(Cl-C, straight or branched chain alkyl), 0-(C 2 -C, straight or branched chain alkenyl), 0- benzyl, O-phenyl, 1,2-methylenedioxy, amino, 15 carboxyl, and phenyl; E is CI-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C s C7 cycloalkenyl substituted with C-C4 straight or branched chain alkyl or C2-C4 straight or branched chain 20 alkenyl, (C2-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar; and m is 0 to 3. 4oo 23. Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal in need thereof, wherein said Scompound is of formula V K B JA 2 D /SO2 0 v E or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is CH or N; J and K, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which has one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 N, NH, and NR; R is either Cj-C 9 straight or branched chain alkyl, 15 C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloalkyl, C 5 -C 7 cycloalkenyl, or Ar 1 wherein R is either unsubstituted or 4. substituted with.one or more substituent(s) independently selected from the group 20 consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C,- Sstraight or branched chain alkyl, C C 6 straight or branched chain alkenyl, C 2 -C4 straight or branched chain alkenyl, 01-04 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2 76 Ari and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the individual ring size is 5-8 members, and wherein said heterocyclic ring has 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; A is CH 2 O, NH, or N-(C-C 4 alkyl); B and D are independently Ar, hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein 'said alkyl or alkenyl is unsubstituted or substituted with Cs-C7 15 cycloalkyl, C5-C, cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl are optionally substituted a. with one or two heteroatom(s) independently selected from the group consisting of O, S, 20 SO, and SO or B and D are independently the fragment T a S* Q wherein Q is hydrogen, Ci-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, 77 and wherein T is Ar or C 5 -C 7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O-(Cl-C 4 alkyl), (C 2 -C 4 alkenyl), and carbonyl, provided that both B and D are not hydrogen; E is Cl-C6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C7 cycloalkenyl substituted with Ci-C 4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C alkenyl)-Ar, or Ar; Ar is selected from the group consisting of phenyl, benzyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3- furyl, 2-thienyl,. 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and monocyclic or bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, CI-C, straight or branched chain alkyl, C2-Cg straight or branched chain alkenyl, O-(Cl-C4 004258486 78 straight or branched chain alkyl), O-(C 2 -C 4 straight or branched chain alkenyl), 0- benzyl, O-phenyl, 1,2-methylenedixoy, amine carboxyl, and phenyl; and 24. The use of any one of claims 17-23, wherein the compound has an affinity for an FKBP- type immunophilin. The use of claim 24, wherein the FKBP- type immunophilin is FKBP-12. 26. The use of any one of claims 17-23, wherein the compound is immunosuppressive. 27. The use of any one of claims 17-23, wherein the compound is non-immunosuppressive. 0 0* 0 *0* 28. A method according substantially as hereinbefore reference to the examples. Freehills Carter Smith Beadle Patent Attorneys for the Applicant GPI Nil Holdings, Inc to cla: described im 1, with 12 March 2003 00 o 0 ooo 0000 0 0000 00 00 0 0 0 g 0 000000 o