CA2333679A1

CA2333679A1 - Small molecule carbamate or urea hair growth compositions and uses

Info

Publication number: CA2333679A1
Application number: CA002333679A
Authority: CA
Inventors: Gregory S. Hamilton; Joseph P. Steiner
Original assignee: Individual
Current assignee: GPI Nil Holdings Inc
Priority date: 1998-06-03
Filing date: 1998-06-03
Publication date: 1999-12-09
Also published as: JP2002516840A; WO1999062484A1; EP1083875A1; AU7807798A; AU764032B2

Abstract

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

Description

SMALL MOLECULE CARBAMATE OR UREA
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 Invention This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, small molecule carbamates and ureas.

2. Description of Related Art Hair loss occurs in a variety of situations.
These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systematic disarders such as nutritional disorders and internal secretion disorders. The mechanisms causing hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.
The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific 2 . _ immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J.
Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner. One form of hair loss, alopecia areata, is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds are expected to demonstrate efficacy for treating that type of hair loss.. The hair growth stimulating effects of FK506 have been the subject of an international patent filing covering FK506 and structures related thereto for hair growth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al. discloses the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.
The hair growth and revitalization effects of FK506 and related agents are disclosed in many U.B.
patents (Goulet et al., U.S. Patent No. 5,258,389;
Luly et al., U.S. Patent No. 5,457,111; Goulet et al., U.S. Patent No. 5,532,248; Goulet et al., U.S. Patent No. 5,189,042; and Ok et al., U.S. Patent No.
5,208,241; Rupprecht et al., U.S. Patent No.
5,284,840; Organ et al., U.S. Patent No. 5,284,877).
These patents claim FK506 related compounds. Although 3 ._ they do not claim methods of hair revitalization, they disclose the known use of FK506 for effecting hair growth. Similar to FK506 (and the claimed variations in the Honbo et al. patent), the compounds claimed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which FK506's efficacy is well known.
Other U.S. patents disclose the use ~f l0 cyclosporin and related compounds for hair revitalization (Hauer et al., U.S. Patent No.
5,342,625; Eberle, U.S. Patent No. 5,284,826; Hewitt et al., U.S. Patent No. 4,996,193). These patents also relate to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth.
However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant, small molecule compounds which are useful as hair revitalizing compounds.
Hamilton and Steiner disclose in U.S. Patent No.
5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that .. _ these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and non-immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.
SUMMARY OF THE INVENTION
The present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a small molecule carbamate or urea.
The present invention further relates to a pharmaceutical composition which comprises:
(i) an effective amount of a small molecule carbamate or urea for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
The small molecule carbamates and ureas used in the inventive methods and aharm.aceutlcc.~. ccr..:positi~~s 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 99162484 PCTlUS98/11243 . _ BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a photograph of mice treated with a vehicle after six weeks. FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth 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 a 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 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 i~ a bar graph plotting the hair arowt'_u scores of unshaven animals and shaven animals treated with a vehicle, GPI 1044 ( 1 ~.M, 3 ~,M and 10 ~.M) , GPI
1116 ( 1 uM and 10 ~.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, related neuroimmunophilin FKBP ligand GPI 1116, and GPI 1206 14 days after treatment with 6 . _ 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, alopecia pelada and trichotillomania.
Alopecia results when the pilar cycle is disturbed.
The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out. A:Lopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mer_tal stresses, hormonal problems, and secondary effects of drugs.
"GPI 1044" refers to the compound ~ /o s N
O~O O D
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 - d i m a t h y 1 - 2 - o x o p a n t a n o y 1 ) - 2 -piperidinecarboxylate.
"GPI 1206" refers to a compound of formula N
O
N-~ O
HNI '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. "Diatcrec__~orrers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal parts of individual enantiomers or stereoisomers.
"Pharmaceutically acceptable salt, ester, or solvate" refers to a salt, ester, or solvate of a subject compound which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. A salt, ester, or solvate can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,naphthylate,2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts;
salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as argi_nine, lysir_e, and so forth. Alsc, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl WO 99/62484 PCTlUS98/11243 9 , _ halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.
"Pilar cycle" refers to the life cycle of hair follicles, and includes three phases:
(1) the anagen phase, the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years;
(2) the catagen phase, the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks; and (3 ) the telogen phase, the rest period when hair progressively separates and finally falls out which, insofar as scalp hair is concerned, lasts about three to four months .
Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase . In the telogen phase, hair is uniform in diameter with a slightly bulbous, non-pigmente~a rcot. 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) preventing alopecia in an animal which may be predisposed to alopecia; and/or (ii) inhibiting, retarding or reducing alopecia;
and/or (iii) promoting hair growth; and/or 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.
Methods of the Present Invention The present invention relates to a methad for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a small molecule carbamate or urea.
The inventive method is particularly useful for treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systematic disorders such as nutritional disorders and internal secretion disorders.

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 carbamate or urea for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
SMALL MOLECULE CARHAMATES AND UREAS
The carbamates and ureas used in the methods and pharmaceutical compositions of the present invention are low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins, such as FKBP12. When a carbamate or urea binds to an FKBP-type immunophil.in, it has been found to inhibit the prolyl-peptidyl cis-trans isomerase, or rotamase, activity of the binding protein. Unexpectedly, the compounds have also been found to stimulate hair growth. These rotamase inhibiting compounds may be immunosuppressive, but preferably are non-immunosuppressive. uxample~ of useful compounds ~.~=a set forth below.
FORMULA I
An exemplary small molecule carbamate or urea is a compound of Formula I

K D
J' A
n B I
Z~ wY R1 or a pharmaceutically acceptable salt, ester, or solvate 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, CZ-C6 straight or branched chain alkenyl or alkynyl, CS-C~ cycloalkyl substituted C1-C6 straight or branched chain alkyl or C3-C6 straight ar branched chain alkenyl or alkynyl, CS-C, cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C3-C6 straight or branched chain alkenyl or' alkynyl, Ar substituted C1-C6 straight or branched chain alkyl, or Ar substituted C,-C
straight or branched chain alkemy or ~l'cynyl; vahereir_ any carbon atom of said alkyl is optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SOz, and NR, wherein R is selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C1-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group;
J is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl, and -CHzAr; K is selected from the group consisting of Cl-C4 straight or branched chain alkyl, -CHzAr, and 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;
Z is O or S;
Y is O or N, provided that when Y is O, then R~ is a lone pair of electrons and Rz is selected from the group consisting of Ar, C1-C6 straight or branched chain alkyl, and C3-C6 straight or branched chain alkenyl or alkynyl; and when Vii.' is N, then R1 and R2 are independently selected from the group consisting of Ar, C1-C6 straight or branched chain alkyl, and C3-C6 straight or rranched chain alkenyl or alkynyi.; or F~i arc: ~.~e taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;
Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, c~arbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; wherein Ar is unsubstituted or substituted with one or more substituent(s) :independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, -S03H, trifluoromethyl., trifluoromethoxi~, C1-C6 st=aight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, O- (C1-C5 straight or branched chain alkyl) , O-(C3-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1, 2-methylenedioxy, -NR3R9, carboxyl, N- (Cl-CS
straight or branched chain alkyl or C3-CS straight or branched chain alkenyl) carboxamides, N,N-di-(C1-CS
straight or branched chain alkyl or C3-CS straight or branched chain. alkenyl) carboxamides, morpholinyl, piperidinyl, O~-X, CHZ- (CH2) q-X, O- (CHZ) Q-X, (CHz) q-O-X, and CH=CH-X;
R3 and R4 are independently selected from the 5 group consisting of Cl-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl, hydrogen, and benzyl; or R, and R4 are taken together to form a 5-6 membered heterocyclic ring;
X is selected from the group consisting of 4-10 methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl;
q is 0-2; and 15 n is 0 or 1.
In a preferred embodiment of Formula I, J and K
are taken together to form a 5-7 membered ring.
In a more preferred embodiment of Formula I, at least one of said B and D is/are independently represented by the formula - (CHZ) r- (X) - (CHI,) e-Ar, wherein:
r is 1-4;
s is 0-1;
Ar is as defined above in Formula I; and each X is independently selected from the group consisting of CH2, O, S, SO, 502, and NR, wherein R is selected from t:he group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen atom and Ar.
In another preferred embodiment of Formula T, Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, i.soquinolinyl, 1,2,3,4-tetrahydroiso-quinolinyl, and 1,2,3,4-tetrahydroquinolinyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, vitro, trifluoromethyl., C1-C6 straight or branched chain alkyl, O-(C,-C6 straight or branched chain alkyl), halogen, S03H, and NR3R4; and ~ R3 and R9 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl, hydrogen, and benzyl; or R3 and R4 are taken together to form a 5-6 membered heterocyclic ring.
In another preferred embodiment of the compounds of formula I, the small molecule carbamate or ureG is the compound GF~I 1206, of the formula N
~ ~ /
N

~t~s 1~ ,.
FORMULAS II AND III
Another exemplary small molecule carbamate or urea is a compound of Formula iI or III
Ar S
i i''~ O
Ar J\N O~~AI
/~ Rl ~\
O-"Y-Rl ) w ~Y~O O/\~Ar Rz ~r Rz II III
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Y, R1 and R2 are as defined above in Formula I;
Ar is as defined above in Formula I;
J is hydrogen, C1-C6 straight or branched chain alkyl , or C3-C6 straight or branched chain alkenyl ; and w is 1 or 2.
FORMULAS IV AND V
A further exemplary small molecule carbamate or urea is a compound of Formula IV or V
n ,- r _ Ar Ar IV V

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Y, R1 and Rz are as defined above in Formula I;
Ar is as defined above in Formula I;
J is hydrogen, C1-C6 straight or branched chain alkyl, or C,-C6 straight or branched chain alkenyl; and w is 1 or 2.
FORMULA VI
A further exemplary small molecule carbamate or urea is a compound of Formula VI
K D
JwV 1 A n 2 B
O VI
Y Z

or a pharmaceutically acceptable salt, ester, or solvate theree:f, 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 heteracyclic ring containing, in addition to V, one oz. more heteroatom(s) selected from the group consisting of O, S, SO, 502, N, NH, and NR;

19 . _ _ R is either Cl-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, CS-C~ cycloalkenyl, or Arl, wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, C1-C~ alkoxy, Cz-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Arl 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, R1, R2, Y, Z, and n are as defined in Formula I above.
Representative compounds of Formulas I-VI are presented in Table I.

TABLE I
(CH2)m D
O
\N n B

O

1 o Compound m Z n D B R1 R2 1 1 O 2 3-pyridylH 2-methylbutyl H

2 1 O 2 3-pyridylH 1,1-dimethylpropyl H

15 3 1 S 2 3-pyridylH cyclohexyl H

4 1 O 2 3-pyridylH cyclohexyl H

5 1 S 2 3-pyridylH 1-adamantyl H

All the compounds of Formulas I-VI possess 20 asymmetric centers 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-VI. It is understood that the compounds of Formulas I-VI encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, S-stereoisomers are used in the pharmaceutical compositions and methods of the present invention.
Synthesis of Small Molecule Carbainates and Ureas The compounds of Formulas I-VI may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathway depicted below. As described by Scheme I, cyclic amino acids 1 protected by suitable blocking groups P on the amino acid nitrogen may be reacted with alcohols ROH to generate esters 2. After removal of the protecting group, the free amine 3 may be reacted with a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively. Alternatively, reaction of 1 with amines provides the corresponding amide compounds.

SCHEME I
( CHa ) m -( CHZ ) ~
OH , R-OH ~ O-R nepzotect Coupliag Method ~N
P O ~ O

~( CHZ ) ~
Ri - 4 C=Z
O-R

O

Isocyanates (R1NC0) or isothiocyanates (R1NCS) 4 may be conveniently prepared from the corresponding readily available amines by reaction with phosgene or thiophosgene, as depicted in Scheme II.
SCHEME II
Z
--,. Rm_~TC;

Affinity for FKBP12 The compounds used in the inventive methods and pharmaceutical compositions have an affinity fox the FK506 binding protein, particularly FKBP12. The inhibition of t:he prolyl peptidyl cis-traps isomerase activity of FKBP may be measured as an indicator of this affinity.
Ki Test Procedure Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can be evaluated by known methods described in the literature (Harding et al., Nature, 1989, 341:758-760;
Holt et al. J. Am. Chem. Soc., 115:9923-9938). These values are obtained as apparent Ki's and are presented for representative compounds in TABLE II.
The cis-traps isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para-nitroanilide from the traps 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 rage constant as a functior_ of inhib'tor concentration to yield the apparent Ki values.
In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL
of FKBP (2.5 mM in 10 mM Tris-C1 pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (SO mg/ml in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-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 ) Route of Administration To effectively treat alopecia or promote hair growth, the compounds used ir: the ~nv~ntive method and pharmaceutical compositions must readily affect the targeted areas. For these purposes, the compounds are preferably administered topically to the skin.
For topical application to the skin, the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
Alternatively, the compounds can be formulated into 5 suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl 10 alcohol and wager.
Other routes of administration known in the pharmaceutical art are also contemplated by this invention.
15 Do s acre 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 leve:Ls of about 0 . 1 mg to about 1, 000 mg.
20 The specific dose level for any particular patient will vary depending upon a variety of factc;~-s, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration;
25 the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses 26 ' for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art.
The compounds can be administered with other hair revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the factors previously stated and the effectiveness of the drug combination.
EXAMPLES
The following examples are illustrative of the present invention and are not intended to be limitations thereon. Unless otherwise indicated, all percentages are based upon 100% by weight of the final composition.
Examp 1 a 1 Synthesis of 3-(3-pvridvl)-1-propyl (2S)-1-[(2-methylbutyl) carbamoyl] pyrrolidine-2-carboxylate (1) 3 - ( 3 -pvridyl ) --1-propel ( 2 S) -N- ( tert-butyloxy-carbonyl)Qyrrolidine-2-carbaxylate A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (3.0 g;; 13.9 mmol), 3-(3-Pyridyl)-1-propanol (2.90 g; 20.9 mmol) , dicyclohexylcarbodiimide (4.59 g;
22.24 mmol), camphorsulfonic acid (1.08 g; 4.63 mmol), and 4-dimethylaminopyridine (0.60 g; 4.63 mmol) in dry methylene chloride (100 mL) was stirred overnight.
The reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting with ethyl acetate to obtain 4.60 g (95%) of the ester as a thick oil. 1H NMR (300 MHz, CDC13): b 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71 (t, 2H); 3.50 (m, 2H); 4.15 (m, 2H);
4.18 (m, 1H); 7.24 (m, 1H); 7.51 (m, 1H); 8.48 (m, 2H) .
3-(3-pyridyl)-1-taropyl pyrrolidine-2-carboxylate A solutian of 3- (3-pyridyl) -1-propyl (2S) -N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.00 g; 9 mmol) in methylene chloride (50 mL) and trifluoroacetic acid (5 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 2.00 g (95%) of the free amine as a thick oil. 1H NMR (30C MHz, CDC1-..) ~ S ' .8';-2.2~
(m, 6H); 2.79 (m, 2H); 3.03 (m, 2H total); 3.07 (m, 2H); 3.84 (m, 1H); 4.24 (m, 2H); 7.32 (m, 1H),; 7.60 (m, 1H) ; 8.57 (m, 2H) .
2S 3- (3 _pyridyl) --:L-propyl (2S) -1- [ (2-methybutyl) -carbamoyl)pyrralidine-2-carboxvlate (1) A solution of 2-methylbutylamine (113 mg; 1.3 mmol) and triethylamine (132 mg; 1.3 mmol) in methylene chloride (5 mL) was added to a solution of triphosgene (128 mg; 0.43 mmol) in methylene chloride (5 mL). The resulting mixture was refluxed for 1 hour and then cooled to room temperature . 3 - ( 3 -Pyridyl ) -1-propyl (2S)-pyrrolidine-2-carboxylate (300 mg; 1.3 mmol} in 5 mL of methylene chloride was added and the resulting mixture was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 250 mg (55%) of the compound of Example 1 (Compound 1, Table I) as an oil. 'H NMR (CDC13, 300 MHz) : 8 0.89-0.93 (m, 6H) ;
1.10-1.20 (m, 1H); 1.27 (s, 1H); 1.36-1.60 (m, 2H);
1.72 (s, 2H); :1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H);
2.92-3.54 (m, 4H); 4.16-4.20 (dt, 2H); 4.45-4.47 (m, 2H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd, 1H); 8.46-8.48 (s, 2H) . Analysis calculated for C19H29N3~3 - 0.5 H20:
C, 64.02; H, 8.48; N, 11.79. Found: C, 63.72; H, 8.42; N, 11.83.
Examine 2 Synthesis of 3-(3-pyridyl)-1-propel (2S)-1-[(1',1'-dimeth~rlpropyl)carbamoyl]pyrrolidine-2-carboxylate (2) Reaction of 3- (3-pyridyl) -1-propyl (2S) -pyrrolidine-2-carboxylate with the isocyanate generated from tert-amylamine and triphosgene, as described for Example 1, provided the compound of Example 2 (Compound 2, Table I) in 62% yield. 1H NMR
(CDC13, 300 MHz): b 0.83 (t, 3H); 1.27 (s, 6H); 1.64-1.71 (m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (t, 2H);
3.29-3.42 (m, 2H); 4.11-4.15 (t, 3H); 4.37-4.41 (m, 1H) . Analysis calculated for C19Hz9N3O3 - 0,.5 H20: C, 64.04; H, 8.48; N, 11.79. Found: C, 64.23; H, 8.31;
N, 11.30.
Example 3 Synthesis of 3-(3-pyridyl)-1-propel (2S)-1 f(cyclohexyl)thiocarbamoyll-pyrrolidine-2 carboxylate (3) A mixture of cyclohexylisothiocyanate (120 mg;
0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate {200 mg; 0.9 mmol) triethylamine (90 mg;
0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50°~ ethyl acetate/hexane) to obtain 160 mg (470) of the compound of Example 3 (Compound 3, Table I) . 1H NMR (CDC13, 300 MHz) : 81.16-1.40 (m, 6H) ; 1 .50-1.71 (m, 4H) ; 1. 95-2 . 08 (m, 7H) ; 2 .70-2 .75 (t, 2H); 3.40-3.60 (m, 2H); 4.17-4.26 (m, 2H); 4.95-4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m., 1H).
Analysis calculated for CZOHz9N30zS : C, 63 . 97 ; H, 7 . 78 ;
N, 11.19. Found: C, 63.25; H, 7.80; N, 11.07.

Example 4 Synthesis of 3-(3-pvridyl)-1-propyl (2S)-1 L(cvclohexyl)carbamovl7-pyrrolidine-2-carboxylate (4) 5 A mixture of cyclohexylisocyanate (100 mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water 10 and a 1 :1 mixture of ethyl acetate and hexane . The organic phase was dried, concentrated and purified by column chromatography (50°s ethyl acetate/hexane) to obtain 120 mg (36°s) of the compound of Example 4 ( Compound 4 , Tabl a I ) . 1H NMR ( CDC13 , 3 0 0 MHz ) : b 15 1.20-1.27 (m, 6H); 1.69-1.75 (m, 4H); 1.94-2.03 (m, 4H); 2.67-2.73 (t, 2H); 3.31-3.44 (m, 3H); 4.12-4.16 (m, 2H); 4.39-4.42 (m, 1H); 7.25-7.34 (m, 1H); 7.25-7.55 (dd, 1H); 8.45 (s, 2H). Analysis calculated for CzoH29N3O3 - 0 . 6 Hz0 : C, 64 . 88 ; H, 8 . 22 ; N, 11 . 3 5 .
20 Found: C, 64.6'0; H, 8.18; N, 11.21.
Example 5 Synthesis of 3-(3-pyridyl)-1-propyl S2S)-1-[(1-adamantyl)thiocarbamoyl7-pyrrolidine-2-carboxylate 25 (5) A mixture of 1-adamantylisocyanate (250 mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane . The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 150 mg (38%) of the compound of Example 5 (Compound 5, Table I), 1H NMR (CDC13, 300 MHz): b 1.39-1.44 (d, 2H); 1.65 (s, 4H); 1.95-2.07 (m, 8H);
2.07-2.20 (m, 5H); 2.71-2.76 (m, 2H); 3.37-3.45 (m, 1H); 3.50-3.60 (m, 1H); 4.09-4.18 (m, 2H); 4.99-5.21 (d, 1H); 7.21-7.25 (m, 1H). Analysis calculated for CZQH33N3OZS - 0 . 4 HzO: C, 66 . 30 ; H, 7 . 84 ; N, 9 . 66 .
Found: C, 66.41; H, 7.79; N, 9.50.
Example 6 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 neuro-i.mmunophilin FKBP ligands GPI 1044, GPI
1116 and GPI 1102. C57 black 6 mice, approximately 7 weeks old, had an area of about ?. ~.r~ches by ~ irL:WE~
on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers. The animals were in anagen growth phase, as indicated by the pinkish color of the skin . Ref erring now to FIGS . 1, 2 , 3 and 4 , four animals were treated by topical administration with 20% propylene glycol vehicle (FIG. 1), and, for 32 w each compound, seven animals were treated by topical administration with 10 ACM GPI 1044 (FIG. 2) , 10 ACM GPI
1116 (FIG. 3) , or 3 ACM GPI 1102 (FIG. 4) . The animals were treated with vehicle, GPI 1044, GPI 1116, or GPI
1102 every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area covered by new hair growth during this time period.
FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. In contrast, FIGS. 2, 3 and 4 show that animals treated with the related neuroimmunophilin ligands, 10 ~M GPI 1044, 10 ACM 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 of unshaven animals with the hair growth scores of shaven animals treated with a vehicle, GPI 1044 (1 ACM, 3 :cM ~a.nd 1 0 yM) , GPI 1116 ( 1 uM and 1 C ~M) , and CFI
1102 ( 1 ~.M and 3 ACM) .
Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of neuroimmunophilin FKBP ligands, including GPI 1206.
C57 Black 6 mire, 55 to 75 days old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlying dermal layers. The animals were in a anagen growth phase when shaved. Five animals per group were treated by topical administration with a vehicle, FK506, or a neuroimmunophilin FKHP ligand (GPI 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area. The animals were treated three times per week, and hair. growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent. of shaved area covered by new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area).
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 one of the neuroimmunophilin FKBP ligands, GPI 1206, exhibited dramatic hair growth.

34 ' Exam~~le 7 A lotion comprising the following composition may be prepared.
(%) 95% Ethanol 80.0 a small molecule carbamate or urea as defined 10.0 above 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 carbamate or urea, a-tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion.
5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia.

Example 8 A lotion comprising the following composition shown may be prepared.
5 (%) 95% Ethanol 80.0 a small molecule carbamate or urea as defined 0.005 above Hinokitol 0.01 10 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil Purified water 19.0 Perfume arid dye q,s, 15 Into 95% ethanol are added a small molecule carbamate or urea, hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and a dye.
The resulting mixture is stirred, and purified water is added to the mixture to obtain a transparent liquid 20 lotion.
The lotion. may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia.

36 . .
Example 9 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 carbamate or urea as defined 0.01 above (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 k:-a app'.ied by spraying once to four times per day to a site having marked baldness or alopecia.

WO 99/b2484 PCT/US98/Z 1243 Example 10 A cream may 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 carbamate or urea as 0.8 defined 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 mixr_ure 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.

3g Examine I1 A liquid comprising the following composition may be prepared.

Polyoxyethylene butyl ether 20.0 Ethanol 50.0 a small molecule carbamate or urea as defined 0.001 above Propylene glycol 5.0 Polyoxyethylene hardened castor oil 0.4 derivative (ethylene oxide 80 mole adducts) Perfume q,s, Purified water q,s, Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a small molecule carbamate or urea, and perfume. The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid.
The liquid may be applied once to 4 times per day to a site having marked baldr_ess or alopecia.

39 . _ Example 12 A shampoo comprising the following composition may be prepared.
(%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betaine lauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0 Polyethylene glycol 5.0 a small molecule carbamate or urea as defined 5.0 above Ethanol 2.0 Perfume 0.3 Purified water' Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betaine lauryldimethyl-aminoacetate. Then a mixture obtained by adding 5.0 g of a small molecule carbamate or urea, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, followed by stirr~_:g, 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.

40 .
Example 13 A patient is suffering from alopecia senilis. A
small molecule carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 14 A patient is suffering from male pattern alopecia. A small molecule carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 15 A.patient is suffering from alopecia areata. A
small molecule carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following trea~me~a.
Example 16 A patient is suffering from hair loss caused by skin lesions. A small molecule carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 17 A patient is suffering from hair loss caused by tumors. A small molecule carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 18 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 carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example i3 A patient is suffering from hair loss caused by chemotherapy. A small molecule carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 20 A patient is suffering from hair loss caused by radiation. A small molecule carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
The invention being thus described, it will be obvious that the same may be varied in many ways.
Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

WE CLAIM:
1. 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 carbamate or urea.
2. The method of claim 1, wherein the small molecule carbamate or urea 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 carbamate or urea is immunosuppressive.
5. The method of claim 1, wherein the small molecule carbamate or urea is non-immunosuppressive.
5. The method of claim 1, wherein the small molecule carbamate or urea is a compound of formula I
or a pharmaceutically acceptable salt, ester, ar solvate 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, C2-C6 straight or branched chain alkenyl or alkynyl, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C3-C6 straight ar branched chain alkenyl or alkynyl, C5-C7 cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C3-C6 straight or branched chain alkenyl or alkynyl, Ar substituted C1-C6 straight or branched chain alkyl, or Ar substituted C3-C6 straight or branched chain alkenyl or alkynyl ; wherein any carbon atom of said alkyl is optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO2 and NR, wherein R is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group;
J is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl , and -CH2Ar; K is selected from the group consisting of C1-C4 straight or branched chain alkyl, -CH2Ar, and 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 ;
Z is O or S;
Y is O or N, provided that when Y is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C1-C6 straight or branched chain alkyl, and C3-C6 straight or branched chain alkenyl or alkynyl; and when Y is N, then R1 and R2 are independently selected from the group consisting of Ar, C1-C6 straight or branched chain alkyl, and C3-C6 straight or branched chain alkenyl or alkynyl; or R1 and R2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;
Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; wherein Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O- (C1-C6 straight or branched chain alkyl), O-(C3-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1, 2-methylenedioxy, -NR3R4, carboxyl, N-(C1-C5 straight or branched chain alkyl or C3-C5 straight or branched chain alkenyl) carboxamides, N,N-di-(C1-C5 straight or branched chain alkyl or C3-C5 straight or branched chain alkenyl) carboxamides, morpholinyl, piperidinyl, O-X, CH2- (CH2) q-X, O- (CH2) q-X, (CH2) q-O-X, and CH=CH-X;
R3 and R4 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl, hydrogen, and benzyl; or R3 and R4 are taken together to form a 5-6 membered heterocyclic ring;

X is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl;
q is 0-2; and n is 0 or 1.
7. The method of claim 6, wherein J and K are taken together to form a 5-7 membered ring.
8. The method of claim 7, wherein at least one of said B and D is/are independently represented by the formula - (CH2) r- (X) - (CH2) s-Ar, wherein:
r is 1-4;
s is 0-1; and each X is independently selected from the group consisting of CH2, O, S, SO, SO2, and NR, wherein R is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl , and C1-C4, bridging alkyl wherein a bridge is formed between the nitrogen atom and Ar.
9. The method of claim 6, wherein:
Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroiso-quinolinyl, and 1,2,3,4-tetrahydroquinolinyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, O-(C1-C6 straight or branched chain alkyl) , halogen, SO3H, and NR3R4; and R3 and R4 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl, hydrogen, and benzyl; or R3 and R4 are taken together to form a 5-6 membered heterocyclic ring.
10. The method of claim 1, wherein the small molecule carbamate or urea is a compound of formula II
or III
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Y, R1 and R2 are as defined in claim 6;
Ar is as defined in claim 6;
J is hydrogen, C1-C6 straight or branched chain alkyl , or C3-C6 straight or branched chain alkenyl ; and w is 1 or 2.
11. The method of claim 1, wherein the small molecule carbamate or urea is a compound of formula IV
or V
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Y, R1 and R2 are as defined in claim 6;
Ar is as defined in claim 6;
J is hydrogen, C1-C6 straight or branched chain alkyl, or C3-C6 straight or branched chain alkenyl; and w is 1 or 2.
12. The method of claim 1, wherein the small molecule carbamate or urea is a compound of formula VI
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 cycloalkyl, 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, R1, R2, Y, Z, and n are as defined in claim 6 above.

13. A pharmaceutical composition which comprises:
(i) an effective amount of a small molecule carbamate or urea for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13, wherein the small molecule carbamate or urea has an affinity for an FKBP-type immunophilin.
15. The pharmaceutical composition of claim 14, wherein the FKBP-type immunophilin is FKBP-12.
16. The pharmaceutical composition of claim 13, wherein the small molecule carbamate or urea is immunosuppressive.
17. The pharmaceutical composition of claim 13, wherein the small molecule carbamate or urea is non-immunosuppressive.
18. The pharmaceutical composition of claim 13, wherein the small molecule carbamate or urea is a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate 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, C2-C6 straight or branched chain alkenyl or alkynyl, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C3-C6 straight or branched chain alkenyl or alkynyl, C5-C7, cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C3-C6 straight or branched chain alkenyl or alkynyl, Ar substituted C1-C6 straight or branched chain alkyl, or Ar substituted C3-C6 straight or branched chain alkenyl or alkynyl ; wherein any carbon atom of said alkyl is optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO2 and NR, wherein R is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group;
J is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl, and -CH2Ar; K is selected from the group consisting of C1-C4 straight or branched chain alkyl, -CH2Ar, and 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;
Z is O or S;
Y is O or N, provided that when Y is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C1-C6 straight or branched chain alkyl, and C3-C6 straight or branched chain alkenyl or alkynyl; and when Y is N, then R1 and R2 are independently selected from the group consisting of Ar, C1-C6 straight or branched chain alkyl, and C3-C6 straight or branched chain alkenyl or alkynyl; or R1 and R2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;
Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3, 4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; wherein Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain;
alkenyl , O- (C1-C6; straight or branched chain alkyl ) , O-(C3-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl , 1,2 -methylenedioxy, -NR3R4, carboxyl , N- (C1-C5 straight or branched chain alkyl or C3-C5 straight or branched chain alkenyl) carboxamides, N,N-di-(C1-C5 straight or branched chain alkyl or C3-C5 straight or branched chain alkenyl) carboxamides, morpholinyl, piperidinyl , O-X, CH2- (CH2) q-X, O- (CH2) q-X, (CH2) q-O-X, and CH=CH-X;
R3 and R4 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl, hydrogen, and benzyl; or R3 and R4 are taken together to form a 5-6 membered heterocyclic ring;
X is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl;
q is 0-2; and n is 0 or 1.
19. The pharmaceutical composition of claim 18, wherein J and K are taken together to form a 5-7 membered ring.
20. The pharmaceutical composition of claim 19, wherein at least one of said B and D is/are independently represented by the formula -(CH2)r-(X)-(CH2) s-Ar, wherein:
r is 1-4;
s is 0-1; and each X is independently selected from the group consisting of CH2, O, S, SO, SO2, and NR, wherein R is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen atom and Ar.

21. The pharmaceutical composition of claim 18, wherein:
Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroiso-quinolinyl, and 1,2,3,4-tetrahydroquinolinyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, O-(C1-C6 straight or branched chain alkyl), halogen, SO3H, and NR3R4; and R3 and R4 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl, hydrogen, and benzyl; or R1 and R4 are taken together to form a 5-6 membered heterocyclic ring.

22. The pharmaceutical composition of claim 13, wherein the small molecule carbamate or urea is a compound of formula II or III

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Y, R1 and R2 are as defined in claim 18;
Ar is as defined in claim 18;
J is hydrogen, C1-C6 straight or branched chain alkyl, or C3-C6 straight or branched chain alkenyl; and w is 1 or 2.

23. The pharmaceutical composition of claim 13, wherein the small molecule carbamate or urea is a compound of formula IV or V

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Y, R1 and R2 are as defined in claim 18;

Ar is as defined in claim 18;
J is hydrogen, C1-C6 straight or branched chain alkyl, or C3-C6 straight or branched chain alkenyl; and w is 1 or 2.

24. The pharmaceutical composition of claim 13, wherein the small molecule carbamate or urea is a compound of formula VI

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is C, N, or S;
J and K, taken together with V and 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 ar branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, 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, R1, R2, Y, Z, and n are as defined in claim 18 above.