JP2002516846A - Small molecule sulfonamide hair growth compositions and uses - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] This application is related to US patent application Ser. No. 08/869, filed Jun. 4, 1997.
No. 426, which is a continuation-in-part application, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present 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 various situations. These situations include androgenetic alopecia, senile alopecia, alopecia areata, diseases associated with underlying skin lesions or tumors, and systemic disorders such as nutritional disorders and endocrine disorders. The mechanisms that cause hair loss are very complex, but can sometimes be attributed to aging, genetic predisposition, androgen activation, reduced blood supply to hair follicles, and scalp abnormalities.

[0004] The immunosuppressants FK506, rapamycin and cyclosporin are known as potent T-cell specific immunosuppressants and are effective in rejecting transplants after organ transplantation. FK506 (Yamamoto et al., J. Invest. Dermatol.,
1994, 102, 160-164; Jiang et al. Invest. Der
matol. 1995, 104, 523-525) and cyclosporine (Iw
Abuchi et al. Dermatol. Sci. 1995, 9, 64-69
) Is reported to stimulate hair growth in a dose-dependent manner, rather than orally.
One form of hair loss, alopecia areata, is known to be associated with autoimmune activity; therefore, topically administered immunomodulatory compounds are expected to show efficacy in treating that type of hair loss You. The hair growth stimulating effect of FK506 is the subject of an international patent application covering FK506 and its related structures for hair growth stimulation (Honbo et al., E.
P0 423 714 A2). Honbo et al. Disclose the use of relatively large tricyclic compounds known for their immunosuppressive effects as hair reactivating agents.

[0005] The hair growth and reactivation effects of FK506 and related drugs have been described in a number of US patents (G
Oulet et al., US Pat. No. 5,258,389; Luly et al., US Pat.
No. 457,111; Goulet et al., US Pat. No. 5,532,248; Gou.
Let et al., US Pat. No. 5,189,042; and Ok et al., US Pat.
No. 08,241; Rupprecht et al., US Pat. No. 5,284,840;
rgan et al., US Pat. No. 5,284,877). These patents claim FK506 related compounds. These do not claim a hair reactivation method, but disclose the known use of FK506 to effect hair growth. Like FK506 (and the claimed variants of 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 where the efficacy of FK506 is known.

Other US patents disclose the use of cyclosporins and related compounds for hair reactivation (Hauer et al., US Pat. No. 5,342,625; Eberle,
U.S. Patent No. 5,284,826; Hewitt et al., U.S. Patent No. 4,996,1.
No. 93). These patents also relate to compounds useful in the treatment of autoimmune diseases and cite the known use of cyclosporine and related immunosuppressive compounds for hair growth.

[0007] However, immunosuppressive compounds, by definition, suppress the immune system and exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressive small molecule compounds useful as hair reactivating compounds.

[0008] Hamilton and Steiner in US Pat. No. 5,614,547 disclose novel pyrrolidine carboxylate compounds that bind to immunophilin FKBP12 and stimulate nerve growth but have no immunosuppressive effects. Surprisingly, it has been discovered that these non-immunosuppressive compounds promote hair growth with an efficacy similar to FK506. However, its novel small molecule structure and non-immunosuppressive properties differ from FK506 and related immunosuppressive compounds found in the prior art.

SUMMARY OF THE INVENTION The present invention is directed to a method of treating alopecia or promoting hair growth in an animal, comprising administering to the animal an effective amount of a small molecule sulfonamide.

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

[0011] The small molecule sulfonamides used in the methods and pharmaceutical compositions of the present invention can be immunosuppressive, but are preferably non-immunosuppressive compounds having affinity for FKBP-type immunophilins, especially FKBP12. Non-immunosuppressive compounds, as the name implies, do not cause significant immunosuppressive activity.

DETAILED DESCRIPTION OF THE INVENTION The definition "alopecia" includes but is not limited to androgenic alopecia (male baldness), toxic alopecia, senile alopecia, alopecia areata and hair loss habit No hair loss and partial or complete hair loss. Alopecia occurs when the hair cycle is disrupted. The most frequent phenomenon is the shortening of the hair growth or anagen phase due to the cessation of cell proliferation. This leads to an earlier onset of the catagen phase, resulting in more hair in the telogen phase, during which the follicles detach from the dermal papilla and fall off.
Alopecia has many etiologies, including genetic factors, aging, local and systemic diseases, fever, mental stress, hormonal problems, and secondary effects of drugs.

“GPI 1044” is a compound

Embedded image Wherein B is 3-phenylpropyl, D is 3-phenylpropyl, and L is phenyl.

“GPI 1102” means 4-phenyl-1- (3-phenylpropyl) butyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate.

“GPI 1116” is 1-phenethyl-3-phenylpropyl 1- (3,
3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate.

“GPI 1206” is an expression

Embedded image Means the compound of

“Isomers” refer to different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the spatial arrangement of the atoms. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of one another. "Distereoisomers" are stereoisomers that are not mirror images of one another. "Racemic mixture" means a mixture containing equal proportions of the individual enantiomers. A “non-racemic mixture” is a mixture that contains the individual enantiomers or stereoisomers in unequal proportions.

A “pharmaceutically acceptable salt, ester, or solvate” is a salt, ester, or solvate of a subject compound that has the desired pharmacological activity and is biologically or otherwise desirable. Means things. Acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycero Phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
Salts, esters or solvates such as methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate can be formed with inorganic acids.
Examples of basic salts, esters or solvates are 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 and lysine.
Also, basic nitrogen-containing groups are lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromide, and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamylsulfate; decyl, lauryl , Myristyl, and long-chain halides such as stearyl chloride, bromide, and iodide; aralkyl halides such as benzyl and phenethyl bromide; and others. A water-soluble or oil-soluble or dispersible product is thereby obtained.

“Hair cycle” means the life cycle of a hair follicle and includes three phases: (1) the anagen phase, an active period of hair growth that lasts about 3-5 years as far as scalp hair is concerned (2) as long as the hair on the scalp lasts about 1-2 weeks, growth stops and the hair follicles atrophy;
Catagogen phase; and (3) resting phase, which is a quiescent period in which the hair progressively separates and eventually falls off, lasting about 3-4 months as far as scalp hair is concerned.

Typically, 80-90% of the hair follicles are in the anagen phase, less than 1% are in the catagen phase, and the rest are in the telogen phase. In the telogen phase, hair diameters are non-uniform and hair roots are slightly spherical and uncolored. In contrast, in the anagen phase, hair has large colored hair bulbs at its roots.

“Promoting hair growth” means maintaining, inducing, stimulating, promoting, or reactivating hair development.

“Treatment of alopecia” includes: (i) preventing alopecia in an animal that may be predisposed to alopecia; and / or (ii) inhibiting, delaying, or reducing alopecia; and / or Or (iii) promoting hair growth; and / or (iv) prolonging the anagen phase of the hair cycle; and / or (v) converting vellus to growth as hard hair. Hard hair is coarse, colored, long hair, and the follicle bulb is deep in the dermis. On the other hand, vellus hair is fine, thin, uncolored short hair, and the hair bulb is located on the surface of the dermis. As alopecia progresses,
The hair changes from a hard hair type to a soft hair type.

The present invention relates to a method for treating alopecia or promoting hair growth in an animal, the method comprising:
Administering an effective amount of a small molecule sulfonamide.

The method of the present invention is useful for treating androgenetic alopecia, senile alopecia, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapies such as chemotherapy or radiation therapy, and nutritional disorders and It is particularly useful for alopecia arising from systemic disorders such as endocrine disorders.

Pharmaceutical Compositions of the Invention The present invention also relates to pharmaceutical compositions comprising (i) an effective amount of a small molecule sulfonamide; and (ii) a pharmaceutically acceptable carrier.

Small molecule sulfonamide The sulfonamide used in the method and the pharmaceutical composition of the present invention is a low molecular weight small molecule compound having an affinity for FKBP-type immunophilin such as FKBP12. It was found that when sulfonamide binds to FKBP-type immunophilin, it inhibits prolyl-peptidyl cis-trans isomerase activity or rotamase activity of the binding protein. Surprisingly, the compound has been found to stimulate hair growth. These rotamase inhibitory compounds are non-immunosuppressive. Examples of useful compounds are shown below.

Formula I Exemplary small molecule sulfonamides have the formula I

Embedded image Wherein A is CH ₂ , O, NH, or N- (C ₁ -C ₄ alkyl); B and D are independently Ar, hydrogen, C ₁ -C ₆ linear or Branched alkyl,
Or a _C 2 -C ₆ straight or branched chain alkenyl, wherein said alkyl or alkenyl in is unsubstituted or _C 5 -C _{7 cycloalkyl,} optionally substituted with C 5 -C ₇ cycloalkenyl, or Ar is, where one or two carbon atoms of said alkyl or alkenyl (s), chemical O, S, by independently selected one or two heteroatoms from the group consisting of sO and sO ₂ (s) With a replacement pattern that is valid for

Embedded image[Wherein Q is hydrogen, C₁-C₆Linear or branched alkyl, or C₂-C₆Straight chain or
Is a branched alkenyl; and T is hydrogen, hydroxy, O- (C₁-C₄Alkyl), O-
(C₂-C₄Alkenyl), and carbonyl
Ar or C substituted with one or more substituent (s)₅-C₇A cycloalkyl
Wherein both B and D are not hydrogen; Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, individual
Has a ring size of 5 or 6, and one or both rings are composed of O, N and S.
Monocyclic or bicyclic groups containing a total of 1-4 heteroatoms independently selected from the group
Selected from the group consisting of terrorist ring systems; where Ar is hydrogen, halo, hydroxy,
Toro, trifluoromethyl, trifluoromethoxy, C₁-C₆Straight or branched
Chain alkyl, C₂-C₆Linear or branched alkenyl, O- (C₁-C₄Straight chain
Or branched-chain alkyl), O- (C₂-C₄Linear or branched alkenyl), O-
Benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl,
And E comprises a C-substituent (s) independently selected from the group consisting of₁-C₆Linear or branched alkyl, C₂-C₆Straight or branched chain
Kenil, C₅-C₇Cycloalkyl, C₁-C₄Linear or branched alkyl or
Is C₂-C₄C substituted with straight or branched chain alkenyl₅-C₇Cycloalkenyl
Le, (C₂-C₄Alkyl or C₂-C₄Alkenyl) -Ar, or Ar
Yes; J is hydrogen, C₁Or C₂Alkyl or benzyl; K is C₁-C ₄ Is a straight or branched alkyl, benzyl, or cyclohexylmethyl
Or both J and K are O, S, SO or SO₂To 5-7 members replaced by
N is 0-3; and the stereochemistry at carbon 1 and 2 is R or S] or a pharmaceutically acceptable salt thereof.

Formula II In a preferred embodiment of Formula I, I, J and K are taken together and the small molecule sulfonamide is represented by Formula II

Embedded image Wherein n is 1 or 2; and m is 0 or 1. or a pharmaceutically acceptable salt thereof.

In a more preferred embodiment, B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; D is phenyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxy Selected from the group consisting of phenyl; and E is 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.

Formula III Another exemplary small molecule sulfonamide is of the formula III

Embedded image Wherein B and D are independently Ar, hydrogen, C ₁ -C ₆ straight or branched alkyl,
Or a _C 2 -C ₆ straight or branched chain alkenyl, wherein said alkyl or alkenyl in is unsubstituted or _C 5 -C _{7 cycloalkyl,} optionally substituted with C 5 -C ₇ cycloalkenyl, or Ar is, where one or two carbon atoms of said alkyl or alkenyl (s), chemical O, S, by independently selected one or two heteroatoms from the group consisting of sO and sO ₂ (s) With a replacement pattern that is valid for

Embedded image Wherein Q is hydrogen, C ₁ -C ₆ straight or branched alkyl, or C ₂ -C ₆ straight or branched alkenyl; and T is hydrogen at positions 3 and 4; hydroxy, O- _(C 1 -C ₄ alkyl), O-
(C ₂ -C ₄ alkenyl), and Ar or C ₅ -C ₇ cycloalkyl substituted with one or more substituent (s) independently selected from the group consisting of carbonyl. With the proviso that both B and D are not hydrogen; Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, each having a ring size of 5 or 6, with one or both rings independently selected from the group consisting of O, N and S Selected from the group consisting of monocyclic or bicyclic heterocyclic systems containing all 1-4 heteroatoms; wherein Ar is hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ straight or branched chain _alkyl, C 2 -C ₆ straight or branched alkenyl, O- _(C 1 -C ₄ straight or branched chain alkyl), O- _(C 2 -C ₄ Linear or branched alkenyl), O-
Benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl,
And include independently selected 1-3 substituents from the group consisting of phenyl (the group); E _is, C 1 -C ₆ straight or branched chain _alkyl, C 2 -C ₆ straight or branched alkenyl , _C 5 -C _{7 cycloalkyl, C} 5 -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,; m is the compound of 0-3], or a pharmaceutically acceptable salt thereof.

Formula IV Further exemplary small molecule sulfonamides have the formula IV

Embedded image Wherein B and D are independently Ar, hydrogen, C ₁ -C ₆ straight or branched alkyl,
Or a _C 2 -C ₆ straight or branched chain alkenyl, wherein said alkyl or alkenyl in is unsubstituted or _C 5 -C _{7 cycloalkyl,} optionally substituted with C 5 -C ₇ cycloalkenyl, or Ar is, where one or two carbon atoms of said alkyl or alkenyl (s), chemical O, S, by independently selected one or two heteroatoms from the group consisting of sO and sO ₂ (s) With a replacement pattern that is valid for

Embedded image Wherein Q is hydrogen, C ₁ -C ₆ straight or branched alkyl, or C ₂ -C ₆ straight or branched alkenyl; and T is hydrogen at positions 3 and 4; hydroxy, O- _(C 1 -C ₄ alkyl), O-
(C ₂ -C ₄ alkenyl), and Ar or C ₅ -C ₇ cycloalkyl substituted with one or more substituent (s) independently selected from the group consisting of carbonyl. With the proviso that both B and D are not hydrogen; Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, each having a ring size of 5 or 6, with one or both rings independently selected from the group consisting of O, N and S Selected from the group consisting of monocyclic or bicyclic heterocyclic systems containing all 1-4 heteroatoms; wherein Ar is hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ straight or branched chain _alkyl, C 2 -C ₆ straight or branched alkenyl, O- _(C 1 -C ₄ straight or branched chain alkyl), O- _(C 2 -C ₄ Linear or branched alkenyl), O-
Benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl,
And include independently selected 1-3 substituents from the group consisting of phenyl (the group); E _is, C 1 -C ₆ straight or branched chain _alkyl, C 2 -C ₆ straight or branched alkenyl , _C 5 -C _{7 cycloalkyl, C} 5 -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,; m is the compound of 0-3], or a pharmaceutically acceptable salt thereof.

Formula V Further exemplary small molecule sulfonamides have the formula V

Embedded imageWherein V is C, N, or S; J and K together with V and the carbon atom to which they are each attached, in addition to V
, O, S, SO, SO₂, N, NH, and NR
Forming a 5-7 membered saturated or unsaturated heterocycle, including the above heteroatom (s);₁-C₉Linear or branched alkyl, C₂-C₉Straight or branched chain
Kenil, C₃-C₉Cycloalkyl, C₅-C₇Cycloalkenyl, or Ar ₁ Wherein R is unsubstituted or halo, haloalkyl,
Carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C₁-C ₆ Linear or branched alkyl, C₂-C₆Linear or branched alkenyl, C₁−
C₄Alkoxy, C₂-C₄Alkenyloxy, phenoxy, benzyloxy,
Thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, amino
Noalkyl, aminocarboxyl, and Ar₂Independently selected from the group consisting of
Ar is substituted by one or more substituent (s); Ar₁And Ar₂Is independently aliphatic or aromatic, mono-, bi- or tricyclic, charcoal
Individual ring sizes are 5-8 members; wherein
Is a heterocyclic ring of 1-6, independently selected from the group consisting of O, N, and S.
A, B, D, E, and n are as defined in Formula I above, or a pharmaceutically acceptable salt, ester, or solvate thereof. Is
.

Representative Formula IV species are shown in Table I.

[0034]

[Table 1] All compounds of formula IV have asymmetric centers and can therefore be prepared as a mixture of stereoisomers or as individual R and S stereoisomers. Individual stereoisomers may be obtained by the use of optically active starting materials, by the resolution of racemic or non-racemic mixtures of intermediates at the appropriate time in the synthesis, or by the resolution of compounds of the formula IV. . Compounds of formula IV are understood to include the individual stereoisomers as well as mixtures of stereoisomers (racemic and non-racemic). Preferably, the S stereoisomer is used in the pharmaceutical compositions and methods of the present invention.

Synthesis of Small Molecule Sulfonamides Compounds of formula IV can be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic route set forth below. As described in Scheme I, amino acid 1 in which the amino acid nitrogen is protected by a suitable blocking group P can be reacted with an alcohol ROH to produce ester 2. After removal of the protecting groups, the free amine 3 is reacted with various sulfonyl chlorides 4 to give the final products 5 in good yields.

[0036]

Embedded image Affinity for FKBP12 The compounds used in the methods and pharmaceutical compositions of the present invention have affinity for FK506 binding proteins, particularly FKBP12. FKBP prolyl peptidyl cis-
Inhibition of transisomerase activity can be measured as an indicator of this affinity.

The peptidyl K _i of the test procedure the compounds used in the methods and pharmaceutical compositions of the present invention - Inhibition of prolyl isomerase (rotamase) activity can be evaluated by known methods described in the literature (Harding, etc., Nature, 1989 341: 758-760; H
olt et al. Am. Chem. Soc. 115: 9923-9938). These ratings were obtained as apparent K _i and are presented for representative compounds in Table II.

The cis-trans isomerization of the alanine-proline bond of the model substrate N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide results in a chymotrypsin bond releasing paranitroanilide from the trans form of the substrate. Monitor spectrophotometrically in the assay. 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, yielding an apparent K _i value.

In a plastic cuvette, 950 mL of ice-cold assay buffer (25 mM H
EPES, pH 7.8, 100 mM NaCl), 10 mL FKBP (10 m
M Tris-Cl pH 7.5, 100 mM NaCl, 2.5 mM in 1 mM dithiothreitol, 25 mL chymotrypsin (50 mg / ml in 1 mM HCl)
And 10 mL of test compound at various concentrations in dimethyl sulfoxide. Reaction was performed with 5 mL substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 2.35 mM in trifluoroethanol, 5 mg / mL in LiCl.
).

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

[0041]

[Table 2] Routes of Administration In order to effectively treat alopecia and promote hair growth, the compounds used in the methods and pharmaceutical compositions of the present invention must readily affect the target area. For these purposes, the compounds are preferably administered topically to the skin.

For topical application to the skin, the compound may be formulated, for example, in a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, a polyoxyethylene polyoxypropylene compound, an emulsified wax and water. It can be formulated in a suitable ointment containing the suspended or dissolved compound. Alternatively, the compound may be suspended in a mixture of, for example, one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Or they can be formulated in a suitable lotion or cream containing the dissolved active compound.

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

Dosage levels of the active ingredient compound on the order of about 0.1 mg to about 10,000 mg are useful in treating the above conditions, with preferred levels being from about 0.1 mg to about 1,1 mg.
000 mg. Specific dosage levels for any particular patient will depend on the activity of the particular compound used; age, weight, general health, sex and diet of the patient; time of administration;
It depends on a variety of factors including the rate of excretion; drug combination; the severity of the particular disease being treated; and the dosage form. Typically, in vitro dosage effect results provide useful guidance on the proper dosage to administer to a patient. Testing in animal models is also helpful. Considerations for determining the appropriate dosage level are known in the art.

The compounds can be administered with other hair reactivating agents. Specific dosage levels of other hair reactivating agents will depend on the factors described above and the efficacy of the drug combination.

The following examples [0046] Examples are intended to illustrate the invention without limiting it. Unless stated otherwise, all percentages are based on 100% by weight of the final composition.

Example 1 3- (3-pyridyl) -1-propyl (2S) -N- (α-toluenesulfo
Synthesis of (nyl) pyrrolidine-2-carboxylate (4) 3- (3-pyridyl) -1-propyl N- (tert-butyloxy-carbo
Nyl) pyrrolidine-2-carboxylate 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 m)
mol), camphorsulfonic acid (21.60 g; 9.26 mmol) and 4
A solution of a mixture of -dimethylaminopyridine (1.12 g; 9.26 mmol) in dry methylene chloride (200 mL) was stirred overnight. The reaction mixture was filtered through celite,
Concentrate and purify on a silica gel column, eluting with 40% ethyl acetate in hexane to give 5.0 g (53%) of the product as a clear oil. ¹ H NMR (30
0 MHz, CDCl ₃ ): δ 1.42 (s, 9H); 1.43-1.95 (m,
6H); 2.68 (m, 2H); 3.46-3.52 (m, 2H); 4.11-
4.22 (m, 2H); 4.33 (m, 1H); 7.17-7.24 (m, 1H)
); 7.47 (m, 1H); 8.43 (s, 2H).

3- (3-pyridyl) -1-propylpyrrolidine-2-carboxylate 3- (3-pyridyl) -1-propylN- (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 3 hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3 times). The combined organic extracts were dried and concentrated to 1.60 g (
77%) of the free amine was obtained as a thick oil. ¹ H NMR (300 MHz,
_{CDCl 3): δ1.71-2.09 (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,
2H).

3- (3-pyridyl) -1-propyl (2S) -N- (α-toluene-sulfoni
B) pyrrolidine-2-carboxylate (4) 3- (3-pyridyl) -1-propylpyrrolidine-2-carboxylate (2
00 mg; 0.9 mmol) and α-toluenesulfonyl chloride (160 m
g; 0.9 mmol) in methylene chloride (20 mL).
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 and eluted with 50% ethyl acetate in hexane to give 150 mg (43%) of compound 4 (Table I) as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.81-1.85 (m
1.95-2.02 (m, 3H); 2.10-2.25 (m, 1H)
2.69-2.74 (t, 2H); 2.85-2.97 (m, 1H); 3.2
4-3.27 (m, 1H); 4.16-4.20 (m, 2H); 4.29 (d,
1H); 4.34 (m, 1H); 4.45 (d, 1H); 7.20-7.25 (
m, 1H); 7.35 (m, 3H); 7.49-7.52 (m, 3H); 8.4
6 (s, 2H). C ₂₀ Analysis calculated for _{H 24 N 2 O 3 S:} C, 61.83; H,
6.23; N, 7.21. Found: C, 61.59; H, 6.24; N, 7.1.
7.

Example 2 4-Phenyl-1-butyl 1- (α-tolylsulfonyl) -2-pipecolineate
Synthesis of (7) Methyl 1- (α-tolylsulfonyl) -2-pipecolinate A solution of methyl pipecolinate hydrochloride (1.79 g; 10 mmol) and triethylamine (1.01 g; 10 mmol) in dry methylene chloride (20 mL)
α-Toluenesulfonyl chloride (1.9 g; 10 mmol) was added. The resulting mixture was stirred at room temperature overnight and then dried in vacuo. The crude residue was purified on a silica gel column, eluting with ethyl acetate to give 2.20 g (74%) of the product as an oil, which solidified on standing. ¹ H NMR (CDCl ₃ , 300 MH
z): δ 1.26-1.71 (m, 5H); 2.15 (d, 1H, J = 14.4)
); 3.17 (dt, 1H); 3.45 (d, 1H, J = 12.6); 3.78
(S, 3H); 4.28 (s, 2H); 4.58 (m, 2H); 7.26-7.
48 (m, 5H).

Methyl N- (α-tolylsulfonyl) -2-pipecolate 1- (α-tolylsulfonyl) -2-pipecolinate (2.0 g;
72 mmol) was dissolved in ethanol (25 mL) and treated with 20 mL of 1N lithium hydroxide. The mixture was stirred at room temperature for 2 hours, then ethyl acetate (200 mL
) And acidified (pH 2) with 1N HCl. Wash the organic layer with saline,
Dry over magnesium sulfate and concentrate to give 1.90 g (100%) of the acid as a white solid.

4-Phenyl-1-butyl 1- (α-tolylsulfonyl) -2-pipecolinate
(7) N- (α-tolylsulfonyl) -2-pipecolic acid (400 mg; 1.41 m)
mol), dicyclohexylcarbodiimide (312 mg; 1.5 mmol),
Dimethylaminopyridine (7 mg) and 4-phenyl-1-butanol (24
(0 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 give 380 mg (48%) of compound 7 (Table I) as a clear oil. ¹ H NMR (CDCl ₃ , 300 MHz): δ1.1
0-1.69 (m, 5H); 1.70 (tt, 4H, J = 6.1, 6.6); 2
. 15 (m, 1H); 2.66 (t, 2H, J = 6.6); 3.16 (m, 1H)
); 3.45 (m, 1H); 4.19 (t, 2H, J = 6.1); 4.28 (s)
4.5H (m, 1H); 7.18-7.47 (m, 10H). Analysis calculated for _{C 23 H 29 NO 4 S:} C, 66.48; H, 7.03; N, 3.37.
Found: C, 66.34; H, 7.06; N, 3.41.

Example 3 1,5-diphenyl-3-pentyl (N- (α-toluenesulfonyl) pipecole
Synthesis of salt (2) 3- Fyl -1-propanol-A solution of oxalyl chloride (2.90 g; 2.29 mmol) in methylene chloride (50 mL) cooled to 78 ° C was added to 10 mL of dimethyl sulfoxide (3.4 mL).
Treated with methylene chloride solution. After stirring for 5 minutes, a solution of 3-phenyl-1-propanol (2.72 g; 20 mmol) in 20 mL of methylene chloride was added and the resulting mixture was stirred at -78 ° C for 15 minutes, treated with 14 mL of triethylamine, and further treated with Stir for minutes and pour into 100 mL water. The layers were separated, the organic layer was dried and concentrated, and the crude residue was purified on a silica gel column eluting with 10% ethyl acetate in hexane to give 1.27 g (47%) of the aldehyde as a clear oil. ¹ H
NMR (300 MHz, CDCl ₃ ): δ 2.80 (m, 2H); 2.98 (
m, 2H); 7.27 (m, 5H); 9.81 (s, 1H).

A solution of 1,5-diphenyl-3-pentanol 2- (bromoethyl) benzene (1.73 g; 9.33 g mmol) in diethyl ether (10 mL) was treated with magnesium chips (250 mL) in 5 mL ether.
mg; 10.18 mmol). The reaction starts with a hot-wire gun,
After the addition was complete, the mixture was heated in an oil bath for 30 minutes. 3-Phenyl-1-propanol (1.25 g; 9.33 mmol) was added to 10 mL ether and reflux was continued for 1 hour. The reaction was cooled, quenched with saturated ammonium chloride, extracted with 2x ethyl acetate, and the combined organic portions were dried and concentrated. Chromatographic purification on a silica gel column (10% ethyl acetate in hexane) gave diphenyl alcohol 1
. 42 g (63%) were obtained. ¹ H NMR (300 MHz, CDCl ₃ ):
δ 1.84 (m, 4H); 2.61-2.76 (m, 4H); 3.65 (m, 1
H); 7.19-7.29 (m, 10H).

1,5-diphenyl-3-pentyl N- (α-toluenesulfonyl) pipecole
G (2) N- (α-tolylsulfonyl) -2-pipecolic acid (380 mg; 1.34 m)
mol), 1,5-diphenyl-3-pentanol (485 mg; 2.01 mm
ol), dicyclohexylcarbodiimide (445 mg; 2.15 mmol),
A 20 mL methylene chloride solution of a mixture of camphorsulfonic acid (105 mg; 0.45 mmol) and dimethylaminopyridine (55 mg; 0.45 mmol) 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 give 270 mg (40%) of compound 2 (Table I) as a clear oil. ¹ H NMR (CDCl ₃ , 300
MHz): δ 0.80 (m, 4H); 1.23-1.97 (m, 5H); 2.1
5 (d, 1H); 2.61-2.69 (m, 4H); 3.23 (m, 1H);
. 44 (dm, 1H); 4.27 (s, 2H); 4.53 (d, 1H, J = 4.
5); 5.06 (m, 1H); 7.16-7.34 (m, 15H). Analysis calculated for _{C 30 H 3 5 NO 4 S} : C, 71.26; H, 6.98; N, 2.77. Found: C, 72.82; H, 7.17; N, 2.53.

Example 4 In Vivo Hair Development Test Experiments Using C57 Black 6 Mice Experiment A: Using C57 Black 6 mice, the related neuronal nofilin FKBP ligands GPI 1044, GPI 1116 and GPI 1102 were used.
Demonstrated hair reactivation properties. An approximately 7-week-old C57 Black 6 mouse, about a 2 inch by about 2 inch area of the quadrant was then shaved to remove any existing hair. Care was taken to avoid damaging or abrading the underlying skin layer. Animals
It was in a anagen phase, as indicated by the pinkish color of the skin. here
FIG. 1, 2, 3 and 4, four animals were treated by topical administration of 20% propylene glycol (FIG. 1), and for each compound, seven animals were each treated with 10 μM GPI 1044 (FIG. 2) 10 μM GPI
Treatment was by topical administration of 1116 (FIG. 3) or 3 μM GPI 1102 (FIG. 4). Animals were treated with vehicle, GPI 1044, GPI 111
6, or treatment with GPI 1102 every 48 hours (3 applications in 5 days) and hair growth was allowed to progress for 6 weeks. Hair growth was quantified by the percentage of shaved area covered by new hair growth during this period.

FIG. 1 shows that animals treated with vehicle show only minimal hair growth in plaques or tresses and less than 3% of the shaved area was covered with new growth. On the other hand, FIG. 2, 3 and 4 are related neuronal nofilin FKBP ligands,
10 μM GPI 1044, 10 μM GPI 1116, and 3 μM G
Animals treated with PI 1102 showed dramatic hair growth, indicating that as much as 50% of the shaved area of some animals was covered. FIG. 5 shows the hair growth score of non-sheared animals and the GPI 1044 of the vehicle and the related neuronal nofilin FKBP ligand
(1 μM, 3 μM and 10 μM), GPI 1116 (1 μM and 10 μM
) And GPI 1102 (1 μM and 3 μM) are compared for hair growth scores.

Experiment B: Neuromnofilin FK was performed using C57 Black 6 mice
The hair reactivation properties of the BP ligand were demonstrated. 55-75 day old C57 Black 6
An area of approximately 2 inches × 2 inches of the quadrant was then shaved from the strain mice to remove any existing hair. Care was taken not to damage the underlying skin layer or cause abrasions. Animals were in the anagen phase at the time of shaving. Five animals per group were treated with vehicle, FK506, or neuron nofilin FKBP ligand (
GPI 1116 or 1206) was treated topically at a concentration of 1 μmol / ml in the shaved area. Animals were treated three times per week and hair growth was assessed 14 days after the start of treatment. Hair growth is quantified by the percentage of shaved area covered by new hair growth and
Scores were given by unknown observers on a scale from 5 (no growth) to 5 (full hair growth in the shaved area).

FIG. 6 shows that after 14 days, animals treated with vehicle showed onset of growth with small hair bundles. In contrast, animals treated with the neuronophilin FKBP ligand exhibited dramatic hair growth.

Example 5 A lotion containing the following composition can be prepared.

[0061]

[Table 3] To 95% ethanol was added small molecule sulfonamide, α-tocopherol acetate, ethylene oxide (40 mol) adduct of hydrogenated castor oil, fragrance and dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a clear liquid lotion.

[0062] 5 ml of lotion may be applied once or twice daily to sites with significant baldness or alopecia.

A lotion containing the following composition shown in Example 6 can be prepared.

[0064]

[Table 4] To 95% ethanol was added small molecule sulfonamide, hinokitol, ethylene oxide (40 mol) adduct of hydrogenated castor oil, fragrance and dye. Stir the resulting mixture and add purified water to the mixture to obtain a clear liquid lotion.

The lotion may be applied by spraying 1-4 times a day to sites with significant baldness or alopecia.

Example 7 An emulsion can be prepared from Phases A and B having the following composition:

[0067]

[Table 5] Phases A and B were each heated, melted and maintained at 80 ° C. The two phases are then mixed and cooled to normal temperature under stirring to obtain an emulsion.

The emulsion may be applied by spraying 1-4 times a day to sites with significant baldness or alopecia.

Example 8 A cream can be prepared from phases A and B having the following composition:

[0070]

[Table 6] Heat phase A to melt and maintain at 70 ° C. Add phase B to phase A and stir the mixture to obtain an emulsion. Then, the emulsion is cooled to obtain a cream.

The cream may be applied 1-4 times a day to sites with significant baldness or alopecia.

Example 9 A liquid containing the following composition can be prepared.

[0073]

[Table 7] To the ethanol is added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hydrogenated castor oil, small molecule sulfonamide, and fragrance. Stir the resulting mixture and add purified water to the mixture to obtain a liquid.

The fluid may be applied 1-4 times a day to sites with significant baldness or alopecia.

Example 10 A shampoo containing the following composition can be prepared.

[0076]

[Table 8] To 69.7 g of purified water, 5.0 g of sodium lauryl sulfate, 5.0 g of triethanolamine lauryl sulfate, and 6.0 g of lauryl dimethylamino acetate betaine are added. Then 5.0 g of small molecule sulfonamide, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate in 2.0 g
Of ethanol and 3.0 g of perfume and then the mixture obtained with stirring is added continuously. The resulting mixture is heated and subsequently cooled to obtain a shampoo.

The shampoo may be used on the scalp 1-2 times daily.

Example 11 A patient is suffering from senile alopecia. A pharmaceutical composition comprising a small molecule sulfonamide or the like can be administered to a patient. It is expected that an increase in hair growth will occur after the treatment.

Example 12 A patient suffers from male pattern baldness. A pharmaceutical composition comprising a small molecule sulfonamide or the like can be administered to a patient. It is expected that an increase in hair growth will occur after the treatment.

Example 13 A patient is suffering from alopecia areata. A pharmaceutical composition comprising a small molecule sulfonamide or the like can be administered to a patient. It is expected that an increase in hair growth will occur after the treatment.

Example 14 A patient is suffering from hair loss caused by skin lesions. A pharmaceutical composition comprising a small molecule sulfonamide or the like can be administered to a patient. It is expected that an increase in hair growth will occur after the treatment.

Example 15 A patient is suffering from hair loss caused by a tumor. A pharmaceutical composition comprising a small molecule sulfonamide or the like can be administered to a patient. It is expected that an increase in hair growth will occur after the treatment.

Example 16 A patient suffers from hair loss caused by a systemic disorder such as a nutritional or endocrine disorder. A pharmaceutical composition comprising a small molecule sulfonamide or the like can be administered to a patient. It is expected that an increase in hair growth will occur after the treatment.

Example 17 A patient is suffering from hair loss caused by chemotherapy. A pharmaceutical composition comprising a small molecule sulfonamide or the like can be administered to a patient. It is expected that an increase in hair growth will occur after the treatment.

Example 18 A patient is suffering from hair loss caused by radiation therapy. A pharmaceutical composition comprising a small molecule sulfonamide or the like can be administered to a patient. It is expected that an increase in hair growth will occur after the treatment.

[0086] Although the invention has thus been described, it is clear that the same can be varied in many ways. Such changes are not to be considered as departures from the spirit and scope of the invention, and all such modifications are intended to be included within the scope of the following claims.

[Brief description of the drawings]

FIG. 1 FIG. 1 is a photograph of the mice treated with vehicle after 6 weeks. FIG. 1 shows that when the vehicle (control) is administered, less than 3% of the shaved area is covered by new hair growth.

FIG. 2 shows the GP of 10 μM of the related neuronal nofilin FKBP ligand
6 is a photograph of a mouse treated with I 1044 after 6 weeks. FIG. 2 is GPI
1044 shows that 90% of the shaved area is covered with new hair growth.

FIG. 3 is a photograph of a mouse after 6 weeks of treatment with 10 μM of another related neuronal nofilin FKBP ligand, GPI 1116. FIG. 3 is GP
Shows that 90% of the shaved area is covered with new hair growth when I 1116 is administered.

FIG. 4 is a photograph of a mouse after 6 weeks of treatment with 3 μM of the third related neuronal nofilin FKBP ligand, GPI 1102. FIG. 3 is GP
I 1102 shows that 90% of the shaved area is covered with new hair growth when administered.

FIG. 5 were unsheared animals, as well as vehicle, GPI 1044 (1 μM, 3 μM
M and 10 μM), GPI 1116 (1 μM and 10 μM), and GP
FIG. 4 is a bar graph plotting the hair growth score of sheared animals treated with I 1102 (1 μM and 3 μM).

FIG. 6 is a vehicle, FK506, and related neuronal nofilin FK
FIG. 7 is a bar graph showing the relative hair growth index of C57 black 6 mice treated with BP ligand 14 days after treatment with each of the identified compounds. FIG. 6 demonstrates significantly faster hair growth promoted by the neuromnofilin FKBP ligand.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 107 A61P 43/00 107 // C07D 207/16 C07D 207/16 211/96 211/96 ( 81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM) , AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventors Steiner, Joseph P. United States 21074 Maryland Hampstead Sugar Maple Street 988 F-term (Reference) 4C054 AA02 BB03 CC08 DD04 DD33 EE01 FF01 4C069 AA23 4C083 AA082 AB282 AC012 AC022 AC072 AC102 AC122 AC392 AC402 AC432 AC442 AC482 AC712 AC782 AD8538 AD042 EE22 4C086 AA01 AA02 BC07 BC21 MA01 MA04 ZA92 4C206 AA01 AA02 JA11 MA01 MA04 ZA92

Claims (22)

[Claims] 1. A method of treating alopecia in an animal or promoting hair growth, comprising administering to the animal an effective amount of a small molecule sulfonamide. 2. The method of claim 1, wherein the small molecule sulfonamide has an affinity for FKBP-type immunophilin. 3. The method of claim 2, wherein said FKRP-type immunophilin is FKBP-12. 4. The method of claim 1, wherein said small molecule sulfonamide is immunosuppressive. 5. The small molecule sulfonamide is non-immunosuppressive.
the method of. 6. The small molecule sulfonamide of formula IWherein A is CH₂, O, NH, or N- (C₁-C₄B) and D are independently Ar, hydrogen, C₁-C₆Straight or branched chain alkyl,
Or C₂-C₆Straight or branched chain alkenyl, wherein the alkyl or
Or alkenyl is unsubstituted or C₅-C₇Cycloalkyl, C₅ -C₇Substituted with cycloalkenyl or Ar, wherein said alkyl or
One or two carbon atoms of the alkenyl are O, S, SO and SO₂A group consisting of
Chemically relevant substitution patterns by one or two heteroatoms independently selected from
Or[Wherein Q is hydrogen, C₁-C₆Linear or branched alkyl, or C₂-C₆Straight chain or
Is a branched alkenyl; and T is hydrogen, hydroxy, O- (C₁-C₄Alkyl), O-
(C₂-C₄1 independently selected from the group consisting of alkenyl) and carbonyl
Ar or C substituted with one or more substituents₅-C₇Wherein both B and D are not hydrogen; Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, individual
Has a ring size of 5 or 6, and one or both rings are composed of O, N and S.
Monocyclic or bicyclic groups containing a total of 1-4 heteroatoms independently selected from the group
Selected from the group consisting of terrorist ring systems; where Ar is hydrogen, halo, hydroxy,
Toro, trifluoromethyl, trifluoromethoxy, C₁-C₆Straight or branched
Chain alkyl, C₂-C₆Linear or branched alkenyl, O- (C₁-C₄Straight chain
Or branched-chain alkyl), O- (C₂-C₄Linear or branched alkenyl), O-
Benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl,
E comprises C 1-3 and 1-3 substituents independently selected from the group consisting of phenyl;₁-C₆Linear or branched alkyl, C₂-C₆Straight or branched chain
Kenil, C₅-C₇Cycloalkyl, C₁-C₄Linear or branched alkyl or
Is C₂-C₄C substituted with straight or branched chain alkenyl₅-C₇Cycloalkenyl
Le, (C₂-C₄Alkyl or C₂-C₄Alkenyl) -Ar, or Ar
Yes; J is hydrogen, C₁Or C₂Alkyl or benzyl; K is C₁-C ₄ Is a straight or branched alkyl, benzyl, or cyclohexylmethyl
Or both J and K are O, S, SO or SO₂To 5-7 members replaced by
N is 0-3; and the stereochemistry at carbon 1 and 2 is R or S]. 7. J and K are taken together and the compound has the formula II Or wherein n is 1 or 2; and m is 0 or 1. or a pharmaceutically acceptable salt thereof. 8. B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; D is phenyl, 3-phenylpropyl,
Selected from the group consisting of 3-phenoxyphenyl and 4-phenoxyphenyl;
And E are phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxy Phenyl, 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-
7. The method of claim 6, wherein the method is selected from the group consisting of chlorophenyl, and E-styrenyl. 9. The small molecule sulfonamide has the formula III Wherein B and D are independently Ar, hydrogen, C ₁ -C ₆ straight or branched alkyl,
Or a _C 2 -C ₆ straight or branched chain alkenyl, wherein said alkyl or alkenyl in is unsubstituted or _C 5 -C _{7 cycloalkyl,} optionally substituted with C 5 -C ₇ cycloalkenyl, or Ar Wherein one or two carbon atoms of the alkyl or alkenyl are replaced by one or two heteroatoms independently selected from the group consisting of O, S, SO and SO ₂ in a chemically relevant substitution pattern. Or Wherein Q is hydrogen, C ₁ -C ₆ straight or branched alkyl, or C ₂ -C ₆ straight or branched alkenyl; and T is hydrogen at positions 3 and 4; hydroxy, O- _(C 1 -C ₄ alkyl), O-
(C ₂ -C ₄ alkenyl), and Ar or C ₅ -C ₇ cycloalkyl substituted with one or more substituents independently selected from the group consisting of carbonyl; Ar is not phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, wherein one or both rings have an individual ring size independently selected from the group consisting of O, N and S of 5 or 6; Selected from monocyclic or bicyclic heterocyclic ring systems containing a total of 1-4 heteroatoms; Ar is hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, O- (C ₁ -C ₄ straight or branched alkyl), O- (C ₂ -C ₄ straight or E is a branched alkenyl), containing 1-3 substituents independently selected from the group consisting of O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl; C ₁ -C ₆ straight chain Or branched chain _alkyl, C 2 -C ₆ straight or branched chain _alkenyl, C 5 -C _{7 cycloalkyl,} C 1 -C ₄ straight or branched chain alkyl or _C 2 -C ₄ linear or branched _C 5 -C ₇ cycloalkenyl substituted with _{alkenyl, (C} 2 -C ₄ alkyl or _C 2 -C ₄ alkenyl) -Ar Yes or Ar,; m compounds of 0-3] or a pharmaceutically, 2. The method of claim 1, wherein the salt is a chemically acceptable salt. 10. The small molecule sulfonamide has the formula IV Wherein B and D are independently Ar, hydrogen, C ₁ -C ₆ straight or branched alkyl,
Or a _C 2 -C ₆ straight or branched chain alkenyl, wherein said alkyl or alkenyl in is unsubstituted or _C 5 -C _{7 cycloalkyl,} optionally substituted with C 5 -C ₇ cycloalkenyl, or Ar Wherein one or two carbon atoms of the alkyl or alkenyl are replaced by one or two heteroatoms independently selected from the group consisting of O, S, SO and SO ₂ in a chemically relevant substitution pattern. Or Wherein Q is hydrogen, C ₁ -C ₆ straight or branched alkyl, or C ₂ -C ₆ straight or branched alkenyl; and T is hydrogen at positions 3 and 4; hydroxy, O- _(C 1 -C ₄ alkyl), O-
(C ₂ -C ₄ alkenyl), and Ar or C ₅ -C ₇ cycloalkyl substituted with one or more substituents independently selected from the group consisting of carbonyl; And D are not hydrogen; Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and the individual ring size is 5 or 6, and one or both rings have O, N and S
Selected from the group consisting of monocyclic or bicyclic heterocyclic systems containing a total of 1-4 heteroatoms independently selected from the group consisting of: wherein Ar is hydrogen, halo, hydroxy, nitro , Trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched 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 It includes independently selected 1-3 substituents from the group consisting of; E _is, C 1 -C ₆ straight or branched chain _alkyl, C 2 -C ₆ straight or branched chain _alkenyl, C 5 -C _{7 cycloalkyl, C} 5 -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) There -Ar or Ar,; m is a compound or a pharmaceutically acceptable salt, of 0-3] the method of claim 1. 11. The small molecule sulfonamide has the formula VWherein V is C, N, or S; J and K together with V and the carbon atom to which they are each attached, in addition to V
, O, S, SO, SO₂, N, NH, and NR
Forming a 5-7 membered saturated or unsaturated heterocycle containing the above heteroatoms;₁-C₉Linear or branched alkyl, C₂-C₉Straight or branched chain
Kenil, C₃-C₉Cycloalkyl, C₅-C₇Cycloalkenyl, or Ar ₁ Wherein R is unsubstituted or halo, haloalkyl,
Carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C₁-C ₆ Linear or branched alkyl, C₂-C₆Linear or branched alkenyl, C₁−
C₄Alkoxy, C₂-C₄Alkenyloxy, phenoxy, benzyloxy,
Thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, amino
Noalkyl, aminocarboxyl, and Ar₂Independently selected from the group consisting of
Ar substituted by one or more substituents; Ar₁And Ar₂Is independently aliphatic or aromatic, mono-, bi- or tricyclic, charcoal
Individual ring sizes are 5-8 members; wherein
Is a heterocyclic ring of 1-6, independently selected from the group consisting of O, N, and S.
A, B, D, E, and n are as defined in claim 6 above, or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising: (i) an effective amount of a small molecule sulfonamide for treating alopecia in an animal or promoting hair growth; and (ii) a pharmaceutically acceptable carrier. 13. The pharmaceutical composition according to claim 12, wherein the small molecule sulfonamide has an affinity for FKBP-type immunophilin. 14. The pharmaceutical composition according to 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 small molecule sulfonamide is non-immunosuppressive.
Pharmaceutical composition. 17. A small molecule sulfonamide having the formula IWherein A is CH₂, O, NH, or N- (C₁-C₄B) and D are independently Ar, hydrogen, C₁-C₆Straight or branched chain alkyl,
Or C₂-C₆Straight or branched chain alkenyl, wherein the alkyl or
Or alkenyl is unsubstituted or C₅-C₇Cycloalkyl, C₅ -C₇Substituted with cycloalkenyl or Ar, wherein said alkyl or
One or two carbon atoms of the alkenyl are O, S, SO and SO₂A group consisting of
Chemically relevant substitution patterns by one or two heteroatoms independently selected from
Or[Wherein Q is hydrogen, C₁-C₆Linear or branched alkyl, or C₂-C₆Straight chain or
Is a branched alkenyl; and T is hydrogen, hydroxy, O- (C₁-C₄Alkyl), O-
(C₂-C₄Alkenyl), and carbonyl
Ar or C substituted with one or more substituents₅-C₇Wherein B and D are not both hydrogen; Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, individual
Has a ring size of 5 or 6, and one or both rings are composed of O, N and S.
Monocyclic or bicyclic groups containing a total of 1-4 heteroatoms independently selected from the group
Selected from the group consisting of terrorist ring systems; where Ar is hydrogen, halo, hydroxy,
Toro, trifluoromethyl, trifluoromethoxy, C₁-C₆Straight or branched
Chain alkyl, C₂-C₆Linear or branched alkenyl, O- (C₁-C₄Straight chain
Or branched-chain alkyl), O- (C₂-C₄Linear or branched alkenyl), O-
Benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl,
And E comprises a C-substituent (s) independently selected from the group consisting of₁-C₆Linear or branched alkyl, C₂-C₆Straight or branched chain
Kenil, C₅-C₇Cycloalkyl, C₁-C₄Linear or branched alkyl or
Is C₂-C₄C substituted with straight or branched chain alkenyl₅-C₇Cycloalkenyl
Le, (C₂-C₄Alkyl or C₂-C₄Alkenyl) -Ar, or Ar
Yes; J is hydrogen, C₁Or C₂Alkyl or benzyl; K is C₁-C ₄ Is a straight or branched alkyl, benzyl, or cyclohexylmethyl
Or both J and K are O, S, SO or SO₂To 5-7 members replaced by
N is 0-3; and the stereochemistry at carbon 1 and 2 is R or S] or a pharmaceutically acceptable salt thereof. Pharmaceutical composition. 18. J and K are taken together and the compound has the formula II 18. The pharmaceutical composition of claim 17, wherein n is 1 or 2; and m is 0 or 1. 19. B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; D is the group consisting of phenyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl And E is 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
17. selected from the group consisting of -chlorophenyl, and E-styrenyl.
Pharmaceutical composition. 20. A small molecule sulfonamide having the formula III Wherein B and D are independently Ar, hydrogen, C ₁ -C ₆ straight or branched alkyl,
Or a _C 2 -C ₆ straight or branched chain alkenyl, wherein said alkyl or alkenyl in is unsubstituted or _C 5 -C _{7 cycloalkyl,} optionally substituted with C 5 -C ₇ cycloalkenyl, or Ar Wherein one or two carbon atoms of the alkyl or alkenyl are replaced by one or two heteroatoms independently selected from the group consisting of O, S, SO and SO ₂ in a chemically relevant substitution pattern. Or Wherein Q is hydrogen, C ₁ -C ₆ straight or branched alkyl, or C ₂ -C ₆ straight or branched alkenyl; and T is hydrogen at positions 3 and 4; hydroxy, O- _(C 1 -C ₄ alkyl), O-
(C ₂ -C ₄ alkenyl), and Ar or C ₅ -C ₇ cycloalkyl substituted with one or more substituents independently selected from the group consisting of carbonyl; And D are not hydrogen; Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, each having a ring size of 5 or 6, with one or both rings independently selected from the group consisting of O, N and S Selected from the group consisting of monocyclic or bicyclic heterocyclic systems containing all 1-4 heteroatoms; wherein Ar is hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ straight or branched chain _alkyl, C 2 -C ₆ straight or branched alkenyl, O- _(C 1 -C ₄ straight or branched chain alkyl), O- _(C 2 -C ₄ Linear or branched alkenyl), O-
Benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl,
E comprises 1-3 substituents independently selected from the group consisting of: C ₁ -C ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, C ₅ -C ₇ cycloalkyl, C ₅ -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; m is 0-3], or a pharmaceutically acceptable salt thereof. 21. A small molecule sulfonamide having the formula IV Wherein B and D are independently Ar, hydrogen, C ₁ -C ₆ straight or branched alkyl,
Or a _C 2 -C ₆ straight or branched chain alkenyl, wherein said alkyl or alkenyl in is unsubstituted or _C 5 -C _{7 cycloalkyl,} optionally substituted with C 5 -C ₇ cycloalkenyl, or Ar Wherein one or two carbon atoms of the alkyl or alkenyl are replaced by one or two heteroatoms independently selected from the group consisting of O, S, SO and SO ₂ in a chemically relevant substitution pattern. Or Wherein Q is hydrogen, C ₁ -C ₆ straight or branched alkyl, or C ₂ -C ₆ straight or branched alkenyl; and T is hydrogen at positions 3 and 4; hydroxy, O- _(C 1 -C ₄ alkyl), O-
(C ₂ -C ₄ alkenyl), and Ar or C ₅ -C ₇ cycloalkyl substituted with one or more substituents independently selected from the group consisting of carbonyl; And D are not hydrogen; Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, each having a ring size of 5 or 6, with one or both rings independently selected from the group consisting of O, N and S Selected from the group consisting of monocyclic or bicyclic heterocyclic systems containing all 1-4 heteroatoms; wherein Ar is hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ straight or branched chain _alkyl, C 2 -C ₆ straight or branched alkenyl, O- _(C 1 -C ₄ straight or branched chain alkyl), O- _(C 2 -C ₄ Linear or branched alkenyl), O-
Benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl,
E comprises 1-3 substituents independently selected from the group consisting of: C ₁ -C ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, C ₅ -C ₇ cycloalkyl, C ₅ -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; m is 0-3], or a pharmaceutically acceptable salt thereof. 22. A small molecule sulfonamide having the formula VWherein V is C, N, or S; J and K together with V and the carbon atom to which they are each attached, in addition to V
, O, S, SO, SO₂, N, NH, and NR
Forming a 5-7 membered saturated or unsaturated heterocycle containing the above heteroatoms, wherein R is C₁-C₉Linear or branched alkyl, C₂-C₉Straight or branched chain
Kenil, C₃-C₉Cycloalkyl, C₅-C₇Cycloalkenyl, or Ar ₁ Wherein R is unsubstituted or halo, haloalkyl,
Carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C₁-C ₆ Linear or branched alkyl, C₂-C₆Linear or branched alkenyl, C₁−
C₄Alkoxy, C₂-C₄Alkenyloxy, phenoxy, benzyloxy,
Thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, amino
Noalkyl, aminocarboxyl, and Ar₂Independently selected from the group consisting of
Ar substituted by one or more substituents; Ar₁And Ar₂Is independently aliphatic or aromatic, mono-, bi- or tricyclic, charcoal
Individual ring sizes are 5-8 members; wherein
Is a heterocyclic ring of 1-6, independently selected from the group consisting of O, N, and S.
A, B, D, E, and n are as defined in claim 17 above, or a pharmaceutically acceptable salt, ester, or solvate thereof.
13. The pharmaceutical composition of claim 12.