US20020037924A1

US20020037924A1 - Small molecule carbamate or urea hair growth compositions and uses

Info

Publication number: US20020037924A1
Application number: US09/791,661
Authority: US
Inventors: Joseph Steiner; Gregory Hamilton
Original assignee: GPI Nil Holdings Inc
Current assignee: GPI Nil Holdings Inc
Priority date: 1997-06-04
Filing date: 2001-02-26
Publication date: 2002-03-28
Also published as: DE69826267D1; TW501931B; EP0983054A1; US6194440B1; JP2002510301A; MXPA99010886A; US6239164B1; US5945441A; US20010036952A1; EP1479373A1; AU7716998A; EP0983054B1; US6177455B1; ZA984621B; ATE275930T1; JP2002510302A; CA2292910C; WO1998055090A1; TW518220B; ZA984783B

Abstract

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

Description

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

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 disorders such as nutritional disorders and internal secretion disorders. The mechanisms causing hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.

The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J. Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner. One form of hair loss, alopecia areata, is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds are expected to demonstrate efficacy for treating that type of hair loss. The hair growth stimulating effects of FK506 have been the subject of an international patent filing covering FK506 and structures related thereto for hair growth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al. discloses the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.

The hair growth and revitalization effects of FK506 and related agents are disclosed in many U.S. patents (Goulet et al., U.S. Pat. No. 5,258,389; Luly et al., U.S. Pat. No. 5,457,111; Goulet et al., U.S. Pat. No. 5,532,248; Goulet et al., U.S. Pat. No. 5,189,042; and Ok et al., U.S. Pat. No. 5,208,241; Rupprecht et al., U.S. Pat. No. 5,284,840; Organ et al., U.S. Pat. No. 5,284,877). These patents claim FKS06 related compounds. Although they do not claim methods of hair revitalization, they disclose the known use of FK506 for effecting hair growth. Similar to FK506 (and the claimed variations in the Honbo et al. patent), the compounds claimed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which FK506's efficacy is well known.

Other U.S. patents disclose the use of cyclosporin and related compounds for hair revitalization (Hauer et al., U.S. Pat. No. 5,342,625; Eberle, U.S. Pat. No. 5,284,826; Hewitt et al., U.S. Pat. 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. Pat. 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 pharmaceutical compositions may be immunosuppressive, but are preferably non-immunosuppressive compounds having an affinity for FKBP-type immunophilins, particularly FKBP12. Non-immunosuppressive compounds, as their name suggests, do not exert any significant immunosuppressive activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of mice treated with a vehicle after six weeks. FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered. [0016]
FIG. 2 is a photograph of mice treated with 10 μM of a related neuroimmunophilin FKBP ligand, [0017] 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 μM of a related neuroimmunophilin FKBP ligand, [0018] 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 μM of a related neuroimmunophilin FKBP ligand, [0019] GPI 1102, after six weeks. FIG. 3 shows that 90% of the shaved area is covered with new hair growth when GPI 1102 is administered.
FIG. 5 is a bar graph plotting the hair growth scores of unshaven animals and shaven animals treated with a vehicle, GPI 1044 (1 μM, 3 μM and 10 μM), GPI 1116 (1 μM and 10 μM), and GPI 1102 (1 μM and 3 μM). [0020]
FIG. 6 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, related neuroimmunophilin [0021] FKBP ligand GPI 1116, and GPI 1206 14 days after treatment with each identified compound. FIG. 6 demonstrates the remarkable early hair growth promoted by neuroimmunophilin FKBP ligands.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Alopecia” refers to deficient hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness), toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania. Alopecia results when the pilar cycle is disturbed. The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs. “[0022] GPI 1044” refers to the compound
wherein B is 3-Phenylpropyl, D is 3-Phenylpropyl, and L is Phenyl. [0023]
“GPI 11021” refers to 4-phenyl-1-(3-phenylpropyl) butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate. [0024]
“[0025] GPI 1116” refers to 1-phenethyl-3-phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate.
“GPI 12061” refers to a compound of formula [0026]
“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. “Diasterecisomers” aere 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. [0027]
“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 arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained. [0028]
“Pilar cycle” refers to the life cycle of hair follicles, and includes three phases: [0029]
(1) the anagen phase, the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years; [0030]
(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 [0031]
(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. [0032]
Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase. In the telogen phase, hair is uniform in diameter with a slightly bulbous, non-pigmented root. By conzrast, in the anagen phase, hair has a large colored bulb at its root. [0033]
“Promoting hair growth” refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair. [0034]
“Treating alopecia” refers to: [0035]
(i) preventing alopecia in an animal which may be predisposed to alopecia; and/or [0036]
(ii) inhibiting, retarding or reducing alopecia; and/or [0037]
(iii) promoting hair growth; and/or [0038]
(iv) prolonging the anagen phase of the hair cycle; and/or [0039]
(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 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. [0040]

Methods of the Present Invention

The present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a small molecule carbamate or urea. [0041]
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. [0042]

Pharmaceutical Compositions of the Present Invention

The present invention also relates to a pharmaceutical composition comprising: [0043]
(i) an effective amount of a small molecule carbamate or urea for treating alopecia or promoting hair growth in an animal; and [0044]
(ii) a pharmaceutically acceptable carrier. [0045]

SMALL MOLECULE CARBAMATES 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 immunophilin, 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. Examples of useful compounds are set forth below. [0046]

FORMULA I

An exemplary small molecule carbamate or urea is a compound of Formula I [0047]
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: [0048]
A is CH[0049] ₂, O, NH or N—(C₁-C₄alkyl);
B and D are independently Ar, hydrogen, C[0050] ₁-C₆straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl or alkynyl, C₅-C₇cycloalkyl substituted C₁-C₆straight or branched chain alkyl or C₃-C₆straight or branched chain alkenyl or alkynyl, C₅-C₇cycloalkenyl substituted C₁-C₆straight or branched chain alkyl or C₃-C₆straight or branched chain alkenyl or alkynyl, Ar substituted C₁-C₆straight or branched chain alkyl, or Ar substituted C₃-C₆straight 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-C₄straight or branched chain alkyl, C₃-C₄straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging 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, C[0051] ₁-C₆straight or branched chain alkyl, C₃-C₆straight or branched chain alkenyl, and —CH₂Ar; K is selected from the group consisting of C₁-C₄straight 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; [0052]
Y is O or N, provided that [0053]
when Y is O, then R[0054] ₁is a lone pair of electrons and R₂is selected from the group consisting of Ar, C₁-C₆straight or branched chain alkyl, and C₃-C₆straight or branched chain alkenyl or alkynyl; and
when Y is N, then R[0055] ₁and R₂are independently selected from the group consisting of Ar, C₁-C₆straight or branched chain alkyl, and C₃-C₆straight or branched chain alkenyl or alkynyl; or R₁and R₂are 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, —SO[0056] ₃H, trifluoromethyl, trifluoromethoxy, C₁-C₆straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, O-(C₁-C₆straight or branched chain alkyl), O-(C₃-C₄straight or branched chain alkenyl), 0-benzyl, O-phenyl, 1,2-methylenedioxy, —NR₃R₄, carboxyl, N-(C₁-C₅straight or branched chain alkyl or C₃-C₆straight or branched chain alkenyl) carboxamides, N,N-di-(C₁-C₅straight or branched chain alkyl or C₃-C₅straight 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;
R[0057] ₃and R₄are independently selected from the group consisting of C₁-C₆straight or branched chain alkyl, C₃-C₆straight or branched chain alkenyl, hydrogen, and benzyl; or R₃and R₄are 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; [0058]
q is 0-2; and [0059]
n is 0 or 1. [0060]
In a preferred embodiment of Formula I, J and K are taken together to form a 5-7 membered ring. [0061]
In a more preferred embodiment of Formula I, at least one of said B and D is/are independently represented by the formula —(CH[0062] ₂)_r—(X)—(CH₂)_s—Ar, wherein:
r is 1-4; [0063]
s is 0-1; [0064]
Ar is as defined above in Formula I; and [0065]
each X is independently selected from the group consisting of CH[0066] ₂, O, S, SO, SO₂, and NR, wherein R is selected from the group consisting of hydrogen, C₁-C₄straight or branched chain alkyl, C₃-C₄straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging alkyl wherein a bridge is formed between the nitrogen atom and Ar.
In another preferred embodiment of Formula I, 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, C[0067] ₁-C₆straight or branched chain alkyl, O-(C₁-C₆straight or branched chain alkyl), halogen, SO₃H, and NR₃R₄; and
R[0068] ₃and R₄are independently selected from the group consisting of C₁-C₆straight or branched chain alkyl, C₃-C₆straight or branched chain alkenyl, hydrogen, and benzyl; or R₃and R₄are 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 urea is the [0069] compound GPI 1206, of the formula

FORMULAS II AND III

Another exemplary small molecule carbamate or urea is a compound of Formula II or III [0070]
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: [0071]
Y, R[0072] ₁and R₂are as defined above in Formula I;
Ar is as defined above in Formula I; [0073]
J is hydrogen, C[0074] ₁-C₆straight or branched chain alkyl, or C₃-C₆straight or branched chain alkenyl; and
w is 1 or 2. [0075]

FORMULAS IV AND V

A further exemplary small molecule carbamate or urea is a compound of Formula IV or V [0076]
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: [0077]
Y, R[0078] ₁and R₂are as defined above in Formula I;
Ar is as defined above in Formula I; [0079]
J is hydrogen, C[0080] ₁-C₆straight or branched chain alkyl, or C₃-C₆straight or branched chain alkenyl; and
w is 1 or 2. [0081]

FORMULA VI

A further exemplary small molecule carbamate or urea is a compound of Formula VI [0082]
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: [0083]
V is C, N, or S; [0084]
J and K, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO[0085] ₂N, NH, and NR;
R is either C[0086] ₁-C₉straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl, C₃-C₉cycloalkyl, C₅-C₇cycloalkenyl, 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-C₆straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄alkoxy, C₂-C₄alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar₂;
Ar[0087] ₁and Ar₂are 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, R[0088] ₁, 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

Compound	m	Z	n	D	B	R₁	R₂

1	1	O	2	3-pyridyl	H	2-methylbutyl	H
2	1	O	2	3-pyridyl	H		1,1-dimethylpropyl	H
3	1	S	2	3-pyridyl	H	cyclohexyl	H
4	1	O	2	3-pyridyl	H	cyclohexyl	H
5	1	S	2	3-pyridyl	H	1-adamantyl	H

All the compounds of Formulas I-VI possess asymmetric centers and thus can be produced as mixtures of stereolsomers or as individual R- and S-stereoisomers. The individual stereoisomers may be obtained by using an optically active starting mnaterial, 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. [0090]

Synthesis of Small Molecule Carbamates 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, [0091] 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.
Isocyanates (R[0092] ¹NCO) 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.

Affinity for FKBP12

The compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. The inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP may be measured as an indicator of this affinity. [0093]

K_iTest 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., [0094] Nature, 1989, 341:758-760; Holt et al. J. Am. Chem. Soc., 115:9923-9938). These values are obtained as apparent K_i's and are presented for representative compounds in TABLE II.
The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para- nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent K[0095] _ivalues.
In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml 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). [0096]
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. [0097]

TABLE II

In Vitro Test Results - Formulas I-V

Compound K_i(nM)

1 70

2 742

3 131

4 1482

5 116

Route of Administration

To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions must readily affect the targeted areas. For these purposes, the compounds are preferably administered topically to the skin. [0098]
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 suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [0099]
Other routes of administration known in the pharmaceutical art are also contemplated by this invention. [0100]

Dosafe

Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art. [0101]
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. [0102]

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. [0103]

Example 1

Synthesis of 3-(3-pyridyl)-1-propyl(2S)-1-[(2-methylbutyl)carbamoyl]pyrrolidine-2-carboxylate(1)3-(3-pyridyl)-1-propyl(2S) -N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate [0104]
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 (3×100 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. [0105] ¹H NMR (300 MHz, CDCl₃): δ 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, H); 8.48 (m, 2H).
3-(3-pridyl)-1-propyl pyrrolidine-2-carboxylate [0106]
A solution 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 (3×). The combined organic extracts were dried and concentrated to yield 2.00 g (95%) of the free amine as a thick oil. [0107] ¹H NMR (300 MHz, CDCl₃): δ 1.87-2.20 (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).
3-(3-pyridvl)-1-propyl(2S)-1-[(2-methybutyl)carbamoyl]-pyrrolidine-2-carboxylate(1) [0108]
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 (55w) of the compound of Example 1 ([0109] Compound 1, Table I) as an oil. ¹H NMR (CDCl₃, 300 MHz): δ 0.89-0.93 (m, 6H); 1.10-1.20 (m, 1H); 1.27 (s, 1H); 1.36-1.60 (m, 2H)I 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 C₁₉H₂₉N₃O₃-0.5 H₂O: C, 64.02; H, 8.48; N, 11.79. Found: C, 63.72; H, 8.42; N, 11.83.

Example 2

Synthesis of 3-(3-pyridyl)-1-propyl(2S)-1-[(1′,1′-dimethylpropyl)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 ([0110] Compound 2, Table I) in 62% yield. ¹H NMR (CDCl₃, 300 MHz): δ 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 C₁₉H₂₉N₃O₃-0.5 H₂O: 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-propyl(2S)-1-[(cyclohexyl)thiocarbamoyl]-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 (47%) of the compound of Example 3 ([0111] Compound 3, Table I). ¹H NMR (CDCl₃, 300 MHz): δ1.16-1.40 (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 C₂₀H₂₉N₃O₂S: 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-pyridyl)-1-propyl (2S)-1-[(cyclohexyl)carbamoyl]-pyrrolidine-2-carboxylate (4)

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 and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50s ethyl acetate/hexane) to obtain 120 mg (36%) of the compound of Example 4 ([0112] Compound 4, Table I). ¹H NMR (CDCl₃, 300 MHz) δ 1.10-1.27 (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 C₂₀H₂₉N₃O₃-0.6 H₂O: C, 64.88; H, 8.22; N, 11.35. Found: C, 64.60; H, 8.18; N, 11.21.

Example 5

Synthesis of 3-(3-pyridyl)-1-Propyl (2S)-1-[(1-adamantyl)thiocarbamoyyl]-pyrrolidine-2-carboxylate (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 (38s) of the compound of Example 5 ([0113] Compound 5, Table I), ¹H NMR (CDCl₃, 300 MHz): δ 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 C₂₄H₃₃N₃O₂S-0.4 H₂O: 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 [0114]
Experiment A: C57 black 6 mice were used to demonstrate the hair revitalizing properties of related neuro-immunophilin [0115] FKBP ligands GPI 1044, GPI 1116 and GPI 1102. C57 black 6 mice, approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers. The animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGS. 1, 2, 3 and 4, four animals were treated by topical administration with 20% propylene glycol vehicle (FIG. 1), and, for each compound, seven animals were treated by topical administration with 10 μM GPI 1044 (FIG. 2), 10 μM GPI 1116 (FIG. 3), or 3 μM 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 [0116] μM GPI 1044, 10 μM GPI 1116, and 3 μM 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 μM, 3 μM and 10 μM), GPI 1116 (1 μM and 10 μM), and SP 1102 (1 μM and 3 μM).
Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of neuroimmunophilin FKBP ligands, including [0117] GPI 1206. C57 Black 6 mice, 55 to 75 days old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlying dermal layers. The animals were in a anagen growth phase when shaved. Five animals per group were treated by topical administration with a vehicle, FK506, or a neuroimmunophilin FKBP ligand (GPI 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area. The animals were treated three times per week, and hair growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent of shaved area covered by new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area).
FIG. 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, [0118] GPI 1206, exhibited dramatic hair growth.

Example 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
	α-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, α-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. [0120]
5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia. [0121]

Example 8

A lotion comprising the following composition shown may be prepared.



	(%)

	95% Ethanol	80.0
	a small molecule carbamate or urea as defined	0.005
	above
	Hinokitol	0.01
	Ethylene oxide (40 mole) adducts of hardened	0.5
	castor oil
	Purified water	19.0
	Perfume and dye	q.s.

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 lotion. [0123]
The lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia. [0124]

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. [0126]
The emulsion may be applied by spraying once to four times per day to a site having marked baldness or alopecia. [0127]

Example 10

A cream may be prepared from A phase and B phase having the following compositions.



	(%)

(A Phase)

	Fluid paraffin	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 mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream. [0129]
The cream may be applied once to 4 times per day to a site having marked baldness or alopecia. [0130]

Example 11

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. [0132]
The liquid may be applied once to 4 times per day to a site having marked baldness or alopecia. [0133]

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	69.7

Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betaine lauryldimethylaminoacetate. Then a mixture obtained by adding 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 stirring, and 0.3 g of perfume are successively added. The resulting mixture is heated and subsequently cooled to obtain a shampoo. [0135]
The shampoo may be used on the scalp once or twice per day. [0136]

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. [0137]

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. [0138]

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 treatment. [0139]

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. [0140]

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. [0141]

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. [0142]

Example 19

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. [0143]

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. [0144]
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. [0145]

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.

6. The method of claim 1, 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-C₄alkyl);

B and D are independently Ar, hydrogen, C₁-C₆straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl or alkynyl, C₅-C₇cycloalkyl substituted C₁-C₆straight or branched chain alkyl or C₃-C₆straight or branched chain alkenyl or alkynyl, C₅-C₇cycloalkenyl substituted C₁-C₆straight or branched chain alkyl or C₃-C₆straight or branched chain alkenyl or alkynyl, Ar substituted C₁-C₆straight or branched chain alkyl, or Ar substituted C₃-C₆straight 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, SO₂and NR, wherein R is selected from the group consisting of hydrogen, C₁-C₄straight or branched chain alkyl, C₃-C₄straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging 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-C₆straight or branched chain alkyl, C₃-C₆straight or branched chain alkenyl, and —CH₂Ar; K is selected from the group consisting of C₁-C₄straight 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 C or S;

Y is O or N, provided that

when Y is O, then R₁is a lone pair of electrons and R₂is selected from the group consisting of Ar, C₃-C₆straight or branched chain alkyl, and C₃-C₆straight or branched chain alkenyl or alkynyl; and

when Y is N, then R₁and R₂are independently selected from the group consisting of Ar, C₁-C₆straight or branched chain alkyl, and C₃-C₆straight or branched chain alkenyl or alkynyl; or R₁and R₂are 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 blfuranyl, 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-C₆straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, O-(C₁-C₆straight or branched chain alkyl), O-(C₃-C₄straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, —NR₃R₄, carboxyl, N-(C₁-C₅straight or branched chain alkyl or C₃-C₅straight or branched chain alkenyl) carboxamides, N,N-di-(C₁-C₅straight or branched chain alkyl or C₃-C₅straight 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;

R₃and R₄are independently selected from the group consisting of C₁-C₆straight or branched chain alkyl, C₃-C₆straight or branched chain alkenyl, hydrogen, and benzyl; or R₃and R₄are 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-C₄straight or branched chain alkyl, C₃-C₄straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging 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-C₆straight or branched chain alkyl, O-(C₁-C₆straight or branched chain alkyl), halogen, SO₃H, and NR₃R₄; and

R₃and R₄are independently selected from the group consisting of C₁-C₆straight or branched chain alkyl, C₃-C₆straight or branched chain alkenyl, hydrogen, and benzyl; or R₃and R₄are 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, R₁and R₂are as defined in claim 6;

Ar is as defined in claim 6;

J is hydrogen, C₁-C₆straight or branched chain alkyl, or C₃-C₆straight 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 R₂are as defined in claim 6;

Ar is as defined in claim 6;

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-C₉straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl, C₃-C₉cycloalkyl, C₅-C₇cycloalkenyl, 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-C₆straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄alkoxy, C₂-C₄alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar₂;

Ar₁and Ar-₂are 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:

(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-C₄alkyl);

B and D are independently Ar, hydrogen, C₁-C₆straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl or alkynyl, C₅-C₇cycloalkyl substituted C₁-C₆straight or branched chain alkyl or is C₃-C₆straight or branched chain alkenyl or alkynyl, C₅-C₇cycloalkenyl substituted C₁-C₆straight or branched chain alkyl or C₃-C₆straight or branched chain alkenyl or alkynyl, Ar substituted C₁-C₄straight or branched chain alkyl, or Ar substituted C₃-C₆straight or branched chain alkenyl or alkynyl; wherein any carbon atom of said alkyl is optionally replaces by a heteroatom selected from the group consisting of O, S, SO, SO₂and NR, wherein R is selected from the group consisting of hydrogen, C₁-C₄straight or branched chain alkyl, C₃-C₄straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging 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;

Z is O or S;

Y is O or N, provided that

when Y is O, then R₁is a lone pair of electrons and R₂is selected from the group consisting of Ar, C₁-C₆straight or branched chain alkyl, and C₃-C₆straight or branched chain alkenyl or alkynyl; and

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-C₆straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, O-(C₁-C₆straight or branched chain alkyl), O-(C₃-C₄straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, —NR₃R₄, carboxyl, N-(C₁-C₅straight or branched chain alkyl or C₃-C₅straight or branched chain alkenyl) carboxamides, N,N-di-(C₁-C₅straight or branched chain alkyl or C₃-C₅straight 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;

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

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-C₆straight or branched chain alkyl, O-(C₁-C₆straight or branched chain alkyl), halogen, SO₃H, and NR₃R₄; and

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, R₁and R₂are as defined in claim 18;

Ar is as defined in claim 18;

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, R₁and R₂are as defined in claim 18;

Ar is as defined in claim 18;

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, 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 a, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO₂, N, NH, and NR;

Ar₁and Ar₂are 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.