CA2334395A1 - Small molecule sulfonamide hair growth compositions and uses - Google Patents

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using small molecule sulfonamides.

Description

SMALL MOLECULE SULFONAMIDE
HAIR GROWTH COMPOSITIONS AND USES
This application is a continuation-in-part of U.S. Patent Application No. 08/869,426, filed on June 4, 1997, the entire contents of which are herein incorporated by reference.
BACKGROUND OF THE INVENTION
1. Field of In.veation This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, small molecule ~;ulfonamides.

2. Descriptior.~ 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 folliclE~s, and scalp abnormalities.
The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific _ immunosuppressan.ts, 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., :L994, 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 struci~ures 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 effer_ts, as hair revitalizing agents.
The hair growth and revitalization effects of FK506 and related agents are disclosed in many 11. S.
patents (Goulet et al., U.S. Patent No. 5,258,:389;
Luly et al . , U. f.. Patent No. 5, 457, 111; Goulet et <~1 . , 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 _ 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 re:Late 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 t.o 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 i.s 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 ha.s been discovered that _ these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and non-immuno-suppressive pro~rerties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.
S'(TMMARY 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:
(i) 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 non immunosuppressive compounds having an affinity for FKBP-type immunophilins, particularly FKBP12. Non immunosuppressive compounds, as their name suggests, do not exert any significant immunosuppressive activity.

WO 99/62490 PC'f/US98/11253 BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is .a photograph of mice treated with a vehicle after si:x weeks. FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth 5 when the vehicle (control) is administered.
FIG. 2 is a photograph of mice treated with 10 ~M
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 ~M
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 ~.M, 3 ~,M and 10 ~.M) , GPI
1116 ( 1 ~M and 1~_0 ~.M) , and GPI 1102 ( 1 ~M and 3 ~,M) .
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 1~KBP
ligands 14 days after treatment with each identified 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, alopec;ia pelada and trichotillomania.
Alopecia result; 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 te7_ogen 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 N~O~ ~B
O~ O D
O
L

wherein B is 3-Phenylpropyl, D is 3-Phenylpropyl, and L is Phenyl.
"GPI 1102" refers to 4-phenyl-1-(3-phenylpropyl) butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2 piperidinecarboxylate.
"GPI 1116" refers to 1-phenethyl-3-phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-~2-piperidinecarboxylate.
"GPI 1206" refers to a compound of formula N
O ~ /
N
~ O
HN' ' S

"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 part: of individual enantiomers or stereoisomers.
"Pharmaceutically acceptable salt, ester, or solvate" refer: to a salt, ester, or solvate of a _ subject compound which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. A salt, ester, or solvate can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benz~enesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate~, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate~,naphthylate,2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosyl.ate and undecanoate" Examples of base salts, esters, or solvates includes 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 arnino acids, such as arginine, lysine, and so forth. Also, the basic n~_trogen-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, dieth~Tl, dibutyl, and diamyl sulfates; .Long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; ara:lkyl _ halides, such a;~ benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
"Pilar cyc3_e" refers to the life cycle of hair follicles, and includes three phases:
(1) the anagen phase, the period of active hair growtr~ which, insofar as scalp hair is concerned, lasts about three to five years;
(2 ) the catagen phase, the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks; and (3) the te:logen phase, the rest period when hair progrEasively separates and finally falls out ~nrhich, 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 pha;3e, hair is uniform in diameter wii~h 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:
(i) preveni~ing alopecia in an animal which may be predisposed to a~lopecia; and/or (ii) inhibiting, retarding or reducing alopecia;
and/or (iii) promoting hair growth; and/or 5 (iv) prolonging the anagen phase of the hair cycle; and/or (v) converting vellus hair to growth as terminal hair. Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep 10 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.
Metho~3s of the Present Invention The present invention relates to a method for treating alopecia or promoting hair growth i.n 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 seni:Lis, alopecia areata,, alopecia resulting from skin lesions or tumors, alope:cia 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/IJS98/t1253 Pharmaceutical Compositions of the Present Invention The present: invention also relates to a pharma-ceutical composition comprising:
(i) an effective amount of a small molecule sul forsamide ; and (ii) a phax-maceutically acceptable carrier.
SMALL MOLECULE SULFONAMIDES
The sulfonamides used in the methods and pharmaceutical compositions of the present invent: ion 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 prolyl-peptidyl cis-t.r~ins 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-immuno-suppressive. Examples of useful compounds are set forth below.
FORMULA I
An exemplary small molecule sulfonamide is a compound of Formula I
B
J

I

_ or a pharmaceutically acceptable salt thereof, wherein:
A is CH2, 0, NH, or N- (C1-C4 alkyl) ;
B and D are independently Ar, hydrogen, C1-C6 straight or branched chain alkyl, or Cz-C6 straight or branched chain alkenyl, wherein said alkyl or alke~nyl is unsubstituted or substituted with CS-C., cycloalkyl, CS-C., cycloalken~,rl or Ar, and wherein one or two carbon atoms) 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;, in chemically reasonable substitution patterns, or Q
wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or Cz-C6 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- (C1-C4 alkyl) , O- (C2-C4 alkenyl) , and carbonyl;
provided that both B and D are not hydrogen;

Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thi enyl , 3 - thienyl , 2 -pyridyl , 3 -pyridyl , 4 -pyri<iyl , 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 o:E O, N, and S; wherein Ar contains 1-3 substituent:(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethox~r, C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, O- (C1-C4 straight or branched chain alkyl) , O- (C2-C~ straight or branched chain alkenyl), O-benzyl, O-phenyl, :L,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C Z-C6 straight or branched chain alkenyl, CS-C, cycloalkyl, cycloalken.yl substituted with C1-C4 straight. or branched chain alkyl or Cz-C4 straight or branched chain alkenyl, (,Cz-C4 alkyl or Cz-C4 alkenyl) -Ar, or Ar;
J is hydrogen, C1 or CZ alkyl, or benzyl; K is C1 CQ 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 SOZ;
n is 0 to 3; and the stereochemistry at carbon positions 1 a:nd 2 is R or S.

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 wD
n O II
~ , . ~ O
H
~2 E
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2; and m is 0 or 7_.
In a more preferred embodiment, B is seler_ted from the group consisting of hydrogen, benzyl, 2-phenylethyl, anti 3-phenylpropyl;
D 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-trimethox;rphenyl, methyl, 1-naphthyl, 8 quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4 iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4 nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and E
5 styrenyl.
FORMLThA III
Another exemplary small molecule sulfonamides is a compound of Formula III
B
IIz C;
E
or a pharmaceutically acceptable salt thereof, wherein:
B and D a.re independently Ar, hydrogen, C1-C6 straight or branched chain alkyl, or Cz-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with CS-C, cycloalkyl, CS-C., cycloalkenyl or Ar, and wherein one or two carbon atoms) 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 T
s Q
wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or CZ-C6 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- (C1-C4 alkyl) , O- (CZ-C4 alkenyl) , and carbonyl;
provided that both B and D are not hydrogen;
Ar is selected from the group consisting of phenyl, Z-napth.yl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 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 ~~elected from the group consistinc3 of hydrogen, halo, hydroxy, n:itro, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, O-~(C1-C4 straight or branched chain alkyl) , O- (Cz-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, L,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C'2-C6 straight or branched chain alkenyl, CS-C~ cycloalkyl, CS-C, cycloalken.yl substituted with C1-C4 straight. or branched chain alkyl or CZ-C4 straight or branched chain alkenyl, (Cz-C4 alkyl or Cz-C4 alkenyl) -Ar, or Ar;
and m is 0 to FORMULA IV
A further exemplary small molecule sulfonamidE~ is a compound of Formula IV
B
m O IV
G ~ O O
E
or a pharmaceutically acceptable salt thereof, wherein:
B and D are independently Ar, hydrogen, C1-C6 straight or branched chain alkyl, or Cz-C6 straight or branched chain ~ilkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with CS-C, cycloalkyl, cycloalkenyl, or Ar, and wherein one or two carbon atoms) 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 S02 in chemically reasonable substitution patterns, or T
to Q
wherein Q is hydrogen, C1-C6 straight or branched chain alkyl , or CZ-C6 straight or branched chain alkenyl; and T is Ar or CS-C, cycloalkyl substituted at positic>ns 3 and 4 with one or more substitueni~(s) independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C4 alkyl) , O- (CZ-C4 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, 2 thienyl, 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, C1-C6 straight or branched cYaain alkyl, Cz-C6 straight or branched chain alkenyl, O- (C1-C4 straight or branched chain alkyl) , O- (C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1.,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, Cz-C6 straight or branched chain alkenyl, CS-C~ cycloalkyl, CS-C~ cycloalkenyl substituted with C,-C9 straight or branched chain alkyl or CZ-C4 straight or branched chain alkenyl, (CZ-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar;
and m is 0 to 3.
FORMULA V
A further exemplary small molecule sulfonamide' is a compound of Fc>rmula V
B
t'~ ' D
V

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 5 atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO2, N, NfH, and NR;
10 R is either Cl-C9 straight or branched chain alkyl, Cz-C9 straight or branched chain alkenyl, C 3-C9 cycloakyl, CS-C;, cycloalkenyl, or Arl, wherein R: is either unsubstil~uted.of substituted with one or more substituent(s) independently selected from the group 15 consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, C1-C4 alkoxy, CZ-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, 20 alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Arl and Ar~z 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 heteroatoml;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.

Representative species of Formulas I-V are presented in Table I.
TABLE I
Compound Structure ~Ni~~O
O
f/ t 4 - p h a n y 1 - 1 - b a t y 1 - 1 -(benzylsulfonyl) - (2R, S) -2-pipecolinate O /
N
i O=S=O O
1,5-diphenyl-3-pentyl-N-(a-toluene-sulfonyl)pipecolate TABLE I (continued) Compound Structure N
0=S=O O

1,7-diphenyl-4-heptyl-N-(para-toluene-sulfonyl)pipecolate N

O
N
I
O=S=O O
3- (3-pyridyl) -1-propyl- (2S) -N~- (a-toluenesulfonyl)pyrrolidine-2-carboxylate _ TABLE I (continued) Compound Structure 0=S=O O \
to ( /

4-phenyl-1-butyl-N-(para-toluene-sulfonyl) p:ipecolate N ~ /
0=S=O O \
4-phenyl-1-butyl-N-(benzene-sulfonyl)pipecolate TAHLE I (continued) Compound Structure O
N

to 4-phenyl-1-butyl-N-(a-toluene-sulfonyl)pipecolate All the compounds of Formulas I-V possess asymmetric ceni~ers and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers. 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.

_ 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 depicaed 5 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 protect:inq group, the free amine 3 may be reacted with various 10 sulfonyl chlorides 4 to provide final products 5 in good to excellent yield.
SCHEME I
( CHZ ) n ( CHZ ) n 15 OH - R-OH~ O-R Deprotect;
Coupling Method C
(CHZ) n O=S=0 2 0 O-R. 4 Et3N,CHzClz H O

25 Affini~ for FKHP12 The compounds used in the inventive methods and pharmaceutical compositions have an affinity fox the FK506 binding protein, particularly FKBP12. The inhibition of the prolyl peptidyl cis-trans isomerase _.
activity of FKBP may be measured as an indicatox- of this affinity.
Ki Test Procedure Inhibition of the peptidyl-prolyl isomer_ase (rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can be evaluated by known methods described in the literature (Hard.ing et al., Nature, 1989, 341:758-760;
Holt et al . J. porn. Chem. Soc. , 115:9923-9938) . These values are obtained as apparent K;'s and are presented for representative compounds in TABLE II.
The cis-tra.ns isomerization of an alanine-proline bond in a model ~~ubstrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometricall:y in a chymotrypsin-coupled assay, which releases para-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 concentration to yield the apparent K; 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-C1 pH 7.5, 100 mM NaCl, 1 mM dithiothrei.tol), 25 mL of chymotrypsin (50 mg/ml in 1 mM HC1) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL
in 2.35 mM LiCl 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.

.. TABLE II
In Vitro Test Results - Formulas I-V
Compound Ki (nM) \N~ ~1~~ ~ ~ 2 o=s=o 0 i 4-phenyl-1-butyl.-1-(benzylsulfonyl)-(2R, S) -2-pipecol.inate (1) N
I
O =S=O O
I
I
\
1,5-diphenyl-3-pentyl-N-(a-toluenesulfonyl)-pipecolate (2) TABLE II (continued) _.
In Vitro Test Results - Formulas I-V
Compound Ki (nM) 1,7-diphenyl-4-heptyl-N-(para-toluene-sulfonyl)pipecolate (3) N

O /
N
2o O=S=O O
3- (3-pyridyl) -1--propyl- (2S) -N- (a-toluene-sulfonyl)pyrrolidine-2-carboxyl.ate (4) WO 99/62490 PC'f/US98/11253 .. TABLE II (continued) In Vitro Test Results - Formulas I-V
Compound Ki (nM) (] 504 N
o=s=o o \ I
10 \
/
CHI
15 4-phenyl-1-butyl.-N-(para-toluenesulfonyl)-pipecolate (5) 2 0 (' N ~ ~ /
O=S=O O I
I
4-phenyl-1-butyl-N-(benzenesulfonyl)pipecolate (6) TABLE II (continued) Ia Vitro Test Results - Formulas I-V
Compound Ki (nM) 12 ;~
~1V/\ v /
O=S=O O
io /
I
4-phenyl-1-buty:L-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 b~e formulated into suitable ointments containing the compounds suspended or dissolved in, for example, nnixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethy:Lene polyoxypropylene compound, emulsifying wax and water.
Alternatively, the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral ail, 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.
Dosaae 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 level, 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 healthy 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 loses for patient administration. Studies in animal models axe also helpful.. The considerations for determining the proper dose levels are well known in the art.

The compounds can be administered with other hair revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the 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 :fi.nal composition.
Example I
Synthesis of 3-(3-Pyridyl)-1-propyl (2S)-N-(a-toluenesulfonyl)pyrrolidine-2-carboxylate (4) 3 - ( 3 - P~rid~l ) - 1 =propyl N- ( tert-butylo:xy-carbonyl)pyrroli.dine-2-carboxylate A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (6.0 g; 28 mmol), 3-(3-pyridyl)-1-propanol (5.80 g; 41.8 mmol), dicyclohexylcarbodiimide (9.20 g;
44.48 mmol), camphorsulfonic acid (21.60 g; ~~.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 (53%). 1H

NMR (300 MHz,CI7C13) : b 1.42(s, 9H) 1.43-1.95 (m, ;

6H); 2.68 (m, 2:H); 3.46-3.52 (m, 2H); 4.11-4.22 (m, 2H) ; 4.33 (m, l:Ei) ; 7. 17-7.24{m, 1H) 7.47 (m, 1H) ;
;

8.43 (s, 2H) .
3-(3-PVridyl)-1-propel pyrrolidine-2-carboxvlate A solution of 3-(3-pyridyl)-1-propyl N-(tert-butyloxycarbonyl)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 (3x). The combined organic extracts were dried and concentrated to yield 1.60 g (77%) of the free amine as a thick oil. 1H NMR (300 MHz, CDC13): b 1.71-2.09 (m, 6H); 2.63 (m, 2H); 2.86 (m, 1H); 2.94 (m, 1H);
3.71 (m, 1H); 4.11 (m, 2H); 7.18 {m, 1H); 7.45 (m, 1H) ; 8 .41 (m, 2Hf) .
3-(3-Pyridvl)-1-propyl (2S)-N-(a-toluene-sulfonvl)pyrrolidine-2-carboxylate (4) A solution of 3-(3-Pyridyl)-1-propyl pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and a-toluenesulfonyl chloride (160 mg~; 0.9 mmol) in methylene chloride (20 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 50% ethyl acetate in hexane, to obtain 150 mg (43%) of Compound 4 (Table I) as a clear oil. 1H NMR (300 MHz, CDC13) : b 1.81-1..85 (m, 2H) ; 1.95-2.02 (m, 3H) ; 2.10-2.25 (m, 1H); 2.69-2.74 (t, 2H); 2.85-2.97 (m, LH);
3.24-3.27 (m, 1H); 4.16-4.20 (m, 2H); 4.29 (d, :LH);
5 4.34 (m, 1H); 4.45 (d, 1H); 7.20-7.25 (m, 1H); '7.35 (m, 3H); 7.49-7.52 (m, 3H); 8.46 (s, 2H). Analysis calculated for C ZoH24NzO3S : C, 61 . 83 ; H, 6 . 23 ; N, 7 . 21 .
Found: C, 61.5.'3; H, 6.24; N, 7.17.
10 Example 2 Synthesis of 4-Phenyl-1-butyl 1-(a-tolvlsulfonvl) 2-uipecolinate (7) Methyl 1-(a-tolvlsulfonvl)-2-pipecolinate To a solution of methyl pipecolinate 15 hydrochloride (1.79 g; 10 mmol) and triethylamine (1.01 g; 10 mmol) in dry methylene chloride (20 mL) was added a-toluenesulfonyl chloride (1.9 g; 10 mmol).
The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The crude 20 residue was purified on a silica gel column, eluting with ethyl acetate, to provide 2.20 g (74~) of the product was an oil which solidified upon standing. 1H
NMR {CDC13, 300 MHz) : b 1.26-1.71 (m, 5H) ; 2.15 (d, 1H, ~ - 14.4); 3.17 (dt, 1H); 3.45 (d, 1H, ~ - 12.6);
25 3.78 (s, 3H); 9:.28 (s, 2H); 4.58 (m, 1H); 7.26-'7.48 (m, 5H) .
N-(a-tolylsulfo~~l)-2-pipecolic acid Methyl 1- (cr-tolylsulfonyl) -2-pipecolinate (2.0 g;

WO 99/62490 PC'T/US98/11253 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-Phenyl-1-butyl 1- (a-toivlsulfon~rl) -2-pipecolinate ~7 ,_ A solution of N-(a-tolylsulfonyl)-2-pipecolic acid (400 mg; 1.41 mmol), dicyclohexylcarbodiirnide (312 mg; 1.5 mmol) , dimethylaminopyridine (7 mg) and 4-phenyl-1-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, a:nd purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 380 mg (48%) of Compound 7 (Table I) as a clear oil.
1H NMR (CDC13, 300 MHz) : b 1.10-1 . 69 (m, 5H) ; .l .70 (tt, 4H, ~ - 6.:1, 6.6) ; 2.15 (m, 1H) ; 2.66 (t, 2Fi, - 6.6); 3.16 (m, 1H); 3.45 (m, 1H); 4.19 (t, 2H, 6.1); 4.28 (s, ~:H); 4.58 (m, 1H); 7.18-7.47 (m, 1UH).
Analysis calculated for Cz3H29NO4S : C, 66 . 48 ; H, 7 ,. 03 ;
N, 3.37. Found.. C, 66.34; H, 7.06; N, 3.41.

_ Exaau~le 3 Synthesis of 1,5-biphenyl-3-pentyl (N-(a-toluenesulfonvl)pipecolate (2) 3-Phenyl-1-pro~~nal Oxalyl chloride (2.90 g; 2.29 mmol) in methylene chloride (50 mL), cooled to -78°C, was treated with dimethylsulfoxide (3.4 mL) in 10 mL of methy:Lene chloride. After stirring for 5 minutes, 3-pheny:L-1-propanol (2.72 g; 20 mmol) in 20 mL of methy:Lene chloride was added, and the resulting mixture was stirred at -78°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 (47%) of the aldehyde as a clear oil. 'H TfMR (300 MHz, CDC13) : b 2.80 (m, 2H) ;
2.98 (m, 2H) ; 7.,27 (m, 5H) ; 9.81 (s, 1H} .
1,5-biphenyl-3-x~entanol A solution of 2-(bromoethyl)benzene (1.73 g; 9.33 mmol) in diethy:lether (10 mL) was added to a stirred slurry of magne:aium turnings (250 mg; 10. Z8 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 minutes. 3-Phenyl-1-propanal (1.25 g; 9.33 mmol) was added in 10 mL of ether, and refT~ux 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 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, CDC13) : b I . 84 (m, 4H) ; 2 . 61-2 . 76 (m, 4H) ;
3.65 (m, 1H); 7.19-7.29 (m, 10H).
1, 5-Diyhenyl-3-t~entyl N- (a-toluenesulfonyl)pipeco:L ate 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; ;Z.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 Cel:ite, concentrated, and purified on a silica gel column, eluting with 155 ethyl acetate in hexane, to obtain 270 mg (40~) of Compound 2 (Table I) as a clear oil.
'H NMR (CDC13, 300 MHz) : b 0.80 (m, 4H) ; 1.23-1.97 (m, 5H) ; 2.15 (d, 1.H) ; 2 .61-2.69 (m, 4H) ; 3 .23 (m, 1H) ;
3.44 (dm, IH); 4.27 (s, 2H); 4.53 (d, 1H, , - 4.5);
5.06 (m, 1H); 7.16-7.34 (m, 15H). Analysis calculated for C3oH35NO4S: C, 71.26; H, 6.98; N, 2.77. Found: C, 72.82; H, 7.17; N, 2.53.

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 weres in anagen growth phase, as indicated by the pinkish color of the skin . F;eferring now to FIGS . 1, 2 , 3 and 4 , four animals were treated by topical administration with 20% propylene glycol vehicle (FTG. 1), and, for each compound, seven animals were treated by topical administration with, respectively, 10 ~,M GPI 1044 (FIG. 2) , 10 ~N! GPI 1116 (FIG. 3) , or 3 ACM GPI 1102 (FIG. 4). The animals were treated with vehicle, GPI
1044, GPI 111E>, 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. Flair 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 ne~N growth. In contrast, FIGS. 2, 3 and 4 show that animals treated with the related . neuroimmunophilin FKBP ligands, 10 ~M GPI 1044, 10 ~.M
GPI 1116, and 3 ~M 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 5 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 ~M, 3 ACM and 10 ACM) , GPI 1116 (1 ~M and 10 ACM) , and GPI
1102 (1 ~.M and 3 ~M).
10 Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of neuroimmunophilin FKBP ligands. C57 Black 6 mice, 55 to 75 days old,, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all 15 existing hair. Care was taken not to nick or cause abrasion to the underlying dermal layers. The animals were in a anac~en growth phase when shaved. Five animals per group were treated by topical administration with a vehicle, FK506, or a 20 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 25 by the percent of shaved area covered by new hair growth, as scorE_d by a blinded observer, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area) .

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 5 A lotion comprising the following composition may be prepared.
(%) 95% Ethanol X30.0 a small molecule sulfonamide as defined above :L0.0 a-Tocopherol acetate 0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil purified water 9.0 perfume and dye q.s.

Into 95% ethanol are added a small molecule sulfonamide, a-tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a dye. The resuli~ing mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion.
5 ml of th.e lotion may be applied once or twice per day to a site having marked baldness or alopecia.

Examt~le 6 A lotion comprising the following composition shown may be prepared.
{%) 95% Ethanol 80.0 a small molecule sulfonamide as defined above 0.005 Hinokitol 0.01 Ethylene oxides (40 mole) adducts of hardened 0.5 castor oil Purif ied water 19 , Perfume and d;te 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 rnixture 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.

Example 7 An emulsion may be prepared from A phase and B
phase having the following compositions.
(A phase) (%) Whale wax 0.5 Cetanol 2.0 Petrolatum 5.0 Squalane 10.0 Polyoxyethylene (10 mole) monostearate 2.0 Sorbitan monooleate 1.0 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°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.

- Example 8 _.
A cream ma.y be prepared from A phase and B phase having the following compositions.
(A Phase) Fluid paraf f in 5 . 0 Cetostearyl alcohol 5.5 Petrolatum 5.5 Glycerine monostearate 33.0 Polyoxyethylene (20 mole) 2-octyldodecyl 3.0 ether Propylparaben 0.3 (B Phase) a small molecule sulfonamide as defined 0.8 above Glycerine 7.0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium Hexametaphosphate 0.005 Purified water' 44.895 The A phase is heated and melted, and maintained at 70°c . The B phase is added into the A phase and. the mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream.
The cream may be applied once to 4 times per day to a site having marked baldness or alopecia.

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 5.0 10 Polyoxyethylene hardened castor oil 0.4 derivative (et:hylene 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, a small molecule sulfonamide, and perfume.
The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid.
20 The liquid may be applied once to 4 times per. day to a site having marked baldness or alopecia.

_ Example 10 A shampoo comprising the following composition may be preparedl.
(%) Sodium lauryl:~ulfate 5.0 Triethanolamine laurylsulfate 5.0 Betaine laury7_dimethylaminoacetate 6.0 Ethylene glycol distearate 2.0 Polyethylene c;lycol 5.0 a small molecule sulfonamide as defined above 5.0 Ethanol 2.0 Perfume 0 . 3 Purified water 69.7 Into 69.7 of purified water are added 5.0 g of sodium lauryl:~ulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betaine lauryldimethyl-aminoacetate. Then a mixture obtained by adding 5.0 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.

.. Examvle 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 pataern 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.
Exam»le 13 A patient is suffering from alopecia areata. A
small molecules 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.

_ Example 15 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.
Examm~le 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 expected to occur following treatment.
The invent: ion 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 th.e following claims.

Claims (22)

WE CLAIM:

1. A method for treating alopecia or promating hair growth in an animal, which comprises administering to said animal an effective amount of a small molecule sulfonamide.

2. The method of claim 1, wherein the small molecule sulfonamide has an affinity for an FKBP-type immunophilin.

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

4. The method of claim 1, wherein the small molecule sulfonamide is immunosuppressive.

5. The method of claim 1, wherein the small molecule sulfonamide is non-immunosuppressive.

6. The method of claim 1, wherein the small molecule sulfonamide is a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:
A is CH2, O, NH, or N- (C1-C4 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 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 O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and 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- (C1-C4 alkyl) , O- (C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual rind 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl; K is C1-C4 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 SO2;
n is 0 to 3; and the stereochemistry at carbon positions 1 and 2 is R or S.

7. The method of claim 6, wherein J and K are taken together and the compound is represented by formula II
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2; and m is 0 or 1.

8. The method of claim 6, 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; and E is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6-triisoprapylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and E-styrenyl.

9. The method of claim 1, wherein the small molecule sulfonamide is a compound of formula III

~

or a pharmaceutically acceptable salt thereof, wherein:
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 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 O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and 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-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-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.

10. The method of claim 1, wherein the small molecule sulfonamide is a compound of formula IV

or a pharmaceutically acceptable salt thereof, wherein:
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 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 O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and 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-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O- (C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-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.

11. The method of claim 1, wherein the small molecule sulfonamide is a compound of formula V
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, SO2, N, NH, and NR;
R is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloakyl, C5-C7 cycloalkenyl, or Ar1, 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Ar1 and Ar2 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 claim 6 above.

12. A pharmaceutical composition which comprises:

(i) an effective amount of a small molecule sulfonamide for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein the small molecule sulfonamide has an affinity for an FKBP-type immunophilin.

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

15. The pharmaceutical composition of claim 12, wherein the small molecule sulfonamide is immunosuppressive.

16. The pharmaceutical composition of claim 12, wherein the small molecule sulfonamide is non-immunosuppressive.

17. The pharmaceutical composition of claim 12, wherein the small molecule sulfonamide is a compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
A is CH2, O, NH, or N- (C1-C4 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 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 O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and 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-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;

Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl) , O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl; K is C1-C4 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 SO2;
n is o to 3; and the stereochemistry at carbon positions 1 and 2 is R or S.

18. The pharmaceutical composition of claim 17, wherein J and K are taken together and the compound is represented by formula II
wherein:
n is 1 or 2; and m is 0 or 1.

19. The pharmaceutical composition of claim 16, 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; 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, 1-naphthyl, 8-quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and E-styrenyl.

20. The pharmaceutical composition of claim 12, wherein the small molecule sulfonamide is a compound of formula III
or a pharmaceutically acceptable salt thereof, wherein:
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 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 O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and 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-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl,O-(C1-C4 straight or :branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-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.

21. The pharmaceutical composition of claim 12, wherein the small molecule sulfonamide is a compound of formula IV
or a pharmaceutically acceptable salt thereof, wherein:
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 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 O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and 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-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7, cycloalkenyl substituted with C1-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.

22. The pharmaceutical composition of claim 12, wherein the small molecule sulfonamide is a compound of formula V

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, SO2, N, NH, and NR;
R is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloakyl, C5-C7 cycloalkenyl, or Ar1, 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Ar1 and Ar2 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 claim 17 above.