MXPA00011877A - Small molecule carbamate or urea hair growth compositions and uses - Google Patents

Abstract

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

Description

COMPOSITIONS AND USES OF SMALL CARBAMATE OR UREA MOLECULE FOR HAIR GROWTH DESCRIPTION OF THE INVENTION This application is a continuation in part of US Patent Application No. 08 / 869,426, filed on June 4, 1997, the entire contents of which are incorporated herein by reference. This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight small molecule carbamates and ureas. Hair loss occurs in a variety of situations. These situations include male alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systemic disorders such as nutritional disorders and internal secretion disorders. The mechanisms that cause hair loss are very complicated, but in some cases they can be attributed to aging, genetic application, activation of male hormones, loss of blood supply to the hair follicles, and abnormalities of the scalp. 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 non-oral application of FK506 (Yammamoto 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. A form of hair loss, alopecia areata, is known to be associated with autoimmune activities; either, topically administered immunomodulatory compounds are expected to demonstrate efficacy in treating that type of hair loss. The effects of hair growth stimulation of FK506 have been the subject of an international patent file covering KF506 and structures related thereto for the stimulation of hair growth (Honbo et al., EP 0 423 714 A2). Honbo et al., Describes the use of relatively large tricyclic compounds, known for their immunosuppressive effects as agents that revitalize hair. Hair growth and the revitalizing effects of FK506 and related agents are described in many North American Patents (Goulet et al., US Patent No. 5,258,389; Luly et al., Patent North American No. 5,457,111 Goulet et al., US 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., US Patent No. 5,284,877). These patents claim the related compounds of FK506. Although they do not claim hair revitalization methods, they describe the known use of FK506 for effective hair growth. Compounds similar to FK506 (and the variations in the Honbo et al. Patent) claimed in these patents are relatively large. In addition, the patents cited relate to immunomodulatory compounds for use in autoimmune related diseases, whereby the efficacy of FK506 is well known. Other North American Patents describe the use of cyclosporin and related compounds for hair revitalization (Hauer et al., US Patent No. 5,342,625, Eberle, US Patent No. 5,284,826, Hewitt et al., US Patent No. 4,996,193). These patents also relate to compounds useful for the treatment of diseases and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth. However, the immunosuppressant compounds for the application suppress the immune system and also exhibit other toxic side effects. Therefore, there is a need for small non-immunosuppressive molecule compounds that are useful as hair revitalizing compounds. Hamilton and Steiner describe in US Pat. No. 5,614,547 novel pyrrolidine carboxylate compounds that bind to FKBP12 immunophilin and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressive compounds cause hair growth with an efficacy similar to FK506. Even its novel small molecule structure and non-immunosuppressive properties differ from FK506 and the related immunosuppressive compounds are found in the prior art. The present invention relates to a method for treating alopecia or causing hair growth in an animal, which comprises administering to the animal an effective amount of a small molecule of carbamate or urea. The present invention further relates to a pharmaceutical composition comprising: (i) an effective amount of a small molecule of carbamate or urea to treat alopecia or to cause hair growth in an animal; and (ii) a pharmaceutically acceptable carrier. The small molecules of carbamates or ureas used in the inventive methods and pharmaceutical compositions may be immunosuppressive, but are preferably non-suppressive compounds, which have an affinity for immunophilins of the FKBP type, particularly FKBP12. The non-immunosuppressive compounds, as the name suggests, do not exert any significant immunosuppressive activity. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a photograph of a mouse treated with a vehicle after six weeks. Figure 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered. Figure 2 is a photograph of a mouse treated with μM of a related FKBP neuroimmunophilin ligand, GPI 1044, after six weeks. Figure 2 shows that the 90% of the shaved area is covered with new hair growth when GPI 1044 is administered. Figure 3 is a photograph of a mouse treated with μM of a related FKBP neuroimmunophilin ligand, GPI 1116, after six weeks. Figure 3 shows that the 90% of the shaved area is covered with new hair growth when GPI 1116 is administered. Figure 4 is a photograph of a mouse treated with 3 μM of a related FKBP neuroimmunophilin ligand, GPI 1102, after six weeks. Figure 3 shows that 90% of the shaved area is covered with new hair growth when GPI 1102 is administered.

Figure 5 is a bar graph representation of hair growth results from unshaven animals and shaved 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). Figure 6 is a bar graph representation of hair relative growth rates for 6 C57 Black mice treated with a vehicle, FK506, FKBP neurokinmunity ligand related GPI 1116, and GPI 1206, 14 days after treatment with each identified compound . Figure 6 demonstrates the extraordinary hair growth early elicited by the neuroimmunophilin ligands FKBP. "Alopecia" refers to deficient hair growth and partial or complete hair loss, including without limitation androgenic alopecia (male baldness), toxic alopecia, alopecia senilis, alopecia areata, peeled alopecia and trichotillomania. Alopecia results when the pillar cycle is disrupted. The most frequent phenomenon is a shortening of 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 released from the dermal papilla, and the hairs fall off. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental tensions, hormonal problems and drug side effects. "GPI 1044" refers to the compound wherein B is 3-Phenylpropyl, D is 3-Phenylpropyl, and L is Phenyl. "GPI 1102" refers to 4-phenyl-1- (3-phenylpropyl) utilo 1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate. "GPI 1116" refers to 1-phenethyl-3-phenylpropyl-1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate. "GPI 1206" refers to a compound of the formula "Isomers" refers to different compounds that have the same molecular formula. "Stereoisomers are isomers that differ only in the way atoms are placed in space." Enantiomers "are a pair of 5 stereoisomers that are non-superimposed reflections of one another." Diastereoisomers "are stereoisomers that are not reflections of one another. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing parts Unequal amounts of individual enantiomers or stereoisomers. "Pharmaceutically acceptable salt, ester or solvate" refers to a salt, ester or solvate of an object compound that possesses the pharmacologically desired 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, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodhydrate, 2- hydroxyethane sulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of base salts, esters or solvates include ammonium salts; metal salts - * "-" ** - - > «* - > .._ «» »» -.- alkaline, 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, powerhouse and so on. Also, the basic groups containing nitrogen can be quaternized 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 chlorides, lauryl, myristyl, and stearyl, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Products soluble or dispersible in water or oil are therefore obtained. "Pillar cycle" refers to the life cycle of the hair follicles, and includes three phases: (1) the anagen phase, the period of active growth of the hair which, as far as possible, as a scalp is worrisome, at least approximately three to five years; (2) the catagen phase, the period when the growth stops and the atrophies of the follicle that, if possible as a scalp is disturbing, at least approximately one to two weeks; and (3) the telogen phase, the remaining period when the hair is progressively separated and finally the fall, which as far as possible as the scalp is worrisome, at least approximately three to four months. Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent are in the catagen phase, and the rest are in the telogen phase. In the telogen phase, the hair is uniform in diameter with a slightly bulbous non-pigmented root. In contrast, in the anagen phase, the hair has a large colored bulb at its root. "Hair growth promotion" refers to maintaining, inducing, stimulating, accelerating, or revitalizing hair germination. "Treating alopecia" refers to: (i) preventing alopecia in an animal that may be predisposed to alopecia; and / or (ii) inhibiting, retarding or reducing alopecia; and / or (iii) causing hair growth; and / or (iv) prolonging the anagen phase of the hair cycle; and / or (v) convert the hair to grow as terminal hair. The terminal hair is rough, pigmented, long hair in which the bulb of the hair follicle is lodged in the dermis. The hair, on the other side, is thin, thin, short, non-pigmented hair in which the capillary bulb is located superficially in the dermis. As well as the evolution of alopecia, the hair change from the terminal to the hair type.

The present invention relates to a method for treating alopecia or causing hair growth in an animal, which comprises administering to the animal an effective amount of a small molecule of carbamate or urea. Methods of the Present Invention The inventive method is particularly useful for treating male alopecia, alopecia senilis, alopecia areata, alopecia resulting from lesions or skin tumors, alopecia resulting from cancer therapy such as chemotherapy or radiation, and alopecia that It results from systemic disorders such as nutritional disorders and internal secretion disorders. Pharmaceutical Compositions of the Present Invention The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a small molecule of carbamate or urea to treat alopecia or to cause hair growth in an animal; and (ii) a pharmaceutically acceptable carrier. SMALL MOLECULES OF 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 that have an affinity for FKBP type immunophilins, such as FKBP12. When a carbamate or urea binds to an immunophilin of the FKBP type, has been found to inhibit propyl-peptidyl cis-trans isomerase, or rotamase, activity for protein binding. Unexpectedly, the compounds have also been found to stimulate hair growth. These compounds that inhibit rotamase can be immunosuppressive, but preferably are not immunosuppressive. Examples of useful compounds are set forth below. FORMULA I A small molecule of carbamate or urea is a compound of Formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A is CH 2, O, NH or N- (C 1 -C 4 alkyl); B and D are independently Ar, hydrogen, straight or branched chain Ci-Css, alkenyl or alkynyl of straight chain or branched C2-C6, C5-C7 substituted alkyl straight or branched chain Ci-SCs or alkenyl or alkynyl of straight or branched chain C3-C6, cycloalkenyl of C5-C7 alkyl substituted straight or branched Ci-SCs or alkenyl chain or alkynyl of straight or branched C3-Ce chain, Ar substituted alkyl linear or branched chain of Ci-Cß or Ar substituted by alkenyl or alkynyl of straight or branched chain of C3-C6; wherein any carbon atom of the alkyl is optionally replaced by a heteroatom selected from the group consisting of O, S, SO, S02 and NR, wherein R is selected from the group consisting of hydrogen, straight or branched chain alkyl of C1 -C4, alkenyl or alkynyl of straight or branched chain of C3-C4 and alkyl in connection of C? ~ C wherein a bridge is formed between the nitrogen and a carbon atom of the heteroatom-containing chain to form a ring, and wherein the ring is optionally fused to an Ar group; J is selected from the group consisting of hydrogen, straight or branched chain alkyl of Ci-Ce, straight or branched chain alkenyl of C3-C6, and -CH2Ar; K is selected from the group consisting of straight or branched chain alkyl of C 1 -C 4, -CH 2 Ar, 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 S02; Z is O or S; ^^ t Y is O or N, with the proviso that when Y is 0, then Ri is a single pair of electrons and R2 is selected from the group consisting of Ar, straight or branched chain alkyl of Ci-Cß and alkenyl or straight or branched chain alkynyl of C3-C6; and when Y is N, then Ri and R2 are independently selected from the group consisting of Ar, straight or branched chain alkyl of C? -C6, and straight or branched chain alkenyl or alkynyl of C3-C6; or Ri and R2 are taken together to form a 5-6 membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, 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 an aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-t? enyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, piraxolilo, 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-triatianilo, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thio-phenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naftidinilo, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and; wherein Ar is substituted or unsubstituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, nitro, -S03H, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of Ci-Ce, straight chain alkenyl or branched C2-C6, O- (straight or branched chain alkyl of C? -C6), O- (straight or branched chain alkenyl of C3-C4), O-benzyl, O-phenyl, 1,2-methylenedioxy , -NR3R4, carboxyl, N- (straight or branched chain alkyl of C1-C5 or straight or branched chain alkenyl of C1-C5) carboxamides, N, N-di- (straight or branched chain alkyl of C1-C5 or straight or branched chain alkenyl of C3-C5) carboxamides, morpholinyl, piperidinyl, OX, CH2- (CH2) qX, 0- (CH2) qX, (CH2) q-0-X, and CH = CH-X; R3 and R4 are independently selected from the group consisting of straight or branched chain C de-C6 alkyl, straight or branched chain alkenyl of C3-Cd, 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-dimethylisoxazolyl, isoxazolyl, 2-methylthiazolyl, thiazolyl, 2-thienyl, 3-thienyl and pyrimidyl; q is 0-2; and 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 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; Ar is as previously defined in Formula I; and each X is independently selected from the group consisting of CH2, O, S, SO, S02, and NR, wherein R is selected from the group consisting of hydrogen, straight or branched chain alkyl of C1-C4, alkenyl or alkynyl straight or branched chain of C3-C4, and alkyl in C1-C4 connection 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, 1,2,4,4-tetrahydroisoquinolinyl, and , 2,3,4-tetrahydroquinolinyl, wherein Ar is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of Ci-Ce, 0- (straight or branched chain alkyl of C? -C6), halogen, S03H, and NR3R4; and R3 and R4 are independently selected from the group consisting of straight or branched chain alkyl of Ci- C6, straight or branched chain alkenyl of C3-C6, 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 the formula I, the small carbamate or urea molecule is the compound GPI 1206, of the formula FORMULAS II AND III Another small molecule of carbamate or exemplary urea is a compound of Formula II or III "III" or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: Y, Ri and R2 are as defined above in Formula I. Ar is as defined above in Formula I. J is hydrogen, chain alkyl linear or branched C? -C6, or straight or branched chain alkenyl of C3-C6, and is 1 or 2. FORMULAS IV YV A small molecule of carbamate or urea and additionally emplarmente is a compound of Formula IV or V or a pharmaceutically acceptable salt, ester or solvate IV acceptable V thereof, wherein: Y, Ri and R2 are as previously defined in Formula I; Ar is as previously defined in Formula I; J is hydrogen, straight or branched chain alkyl of C? -C6, or straight or branched chain alkenyl of C3-C6; and is 1 or 2. FORMULA VI An exemplary additional 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, from a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatoms selected from the group consisting of O, S, SO, S02, N, NH, and NR; R is either straight or branched chain alkyl of Ci-Cg, straight or branched chain alkenyl of C2-Cg, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, or Ari, wherein R is either substituted or unsubstituted substituting with one or more substituents independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of C? -C6, straight or branched chain alkenyl of C2-C6, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl and Ar 2; Ari and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the size of the individual ring is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; A, B, D, Ri, 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 Ri R2 1 1 0 2 3-pyridyl H 2 -methylbutyl H 2 1 0 2 3-pyridyl H 1, 1-dimethylpropyl H 3 1 S 2 3-pyridyl H cyclohexyl H 4 1 0 2 3-pyridyl H cyclohexyl H 5 1 S 2 3-pyridyl H 1-adamantyl H All compounds of formulas I-VI possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R and S stereoisomers. The individual stereoisomers can be obtained using an optically active starting material, resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or solving the compounds of Formulas I-VI. It will be understood that the compounds of Formulas I-VI encompass - "* •" • "• * '-' • a0>: - '- individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers Preferably, the S-stereoisomers are used in the compositions and pharmaceutical methods of The present invention Synthesis of the Small Molecule of Carbamates and Ureas The compounds of the Formulas I-VI can be easily prepared by standard techniques of organic chemistry, using the general synthetic path represented in the following, as described in the Scheme. I, the cyclic amino acids 1 protected by suitable blocking groups P at the amino acid nitrogen can be reactive with alcohols ROH to generate esters 2. After removing the protecting group, the free amine 3 can be reactive with a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively Alternatively the reaction of 1 with amines provides the corresponding amide compounds tes.

SCHEME I Deprotective: 2 Isocyanates (R2NCO) or isothiocyanates (R1NCS) 4 can be conveniently prepared from the corresponding readily available amines by reaction with phosgene or thiophosgene, as depicted in Scheme II.

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 propyl peptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of this affinity. K-Test Procedure The inhibition of the peptidyl-propyl 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., Na ture, 1989, 341: 758-760; Holt et al., J. Am. Chem. Soc, 115: 9923-9938). These values are obtained as K? apparent and are presented by 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 verified spectrophotometrically in an assay chemotrypsin coupling, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of the inhibitor is determined, and the data is analyzed as a change in the first order rate constant as a concentration function to produce the apparent Kx values.

In a plastic cuvette, 950 ml of cold assay regulator (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 the Test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 ml of the substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg / ml in 2.35 mM LiCl in trifluoroethanol). The absorbance at 390 nm is checked against time for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance against time of the data files. TABLE II In Vitro Test Results - Formulas IV Compound Ki (nM) 1 70 2 742 3 131 4 1482 5 116 Route of Administration To effectively treat alopecia or cause hair growth, the compounds used in the inventive methods and pharmaceutical compositions they can easily affect the target 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 suspended or dissolved compounds 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 in 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, cetylester wax, alcohol cetearyl, 2-octyldodecanol, benzyl alcohol and water. Other routes of administration known in the pharmaceutical art are also contemplated by this invention. Dosage Dosage levels in the range of about 0.1 mg to about 10,000 mg of the compound of the active ingredient are useful in treating 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 on 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, the results of the in vitro dose effect provide useful guidance at the correct doses for administration to the patient. Animal studies are also useful. Considerations for determining the correct dose levels are well known in the art. The compounds can be administered with other hair revitalization agents. The specific dose levels for the other hair revitalization agents will depend on the previously established factors and the effectiveness of the combination of the drug. EXAMPLES The following examples are illustrative of the present invention and are not intended to be limitations thereof. Unless otherwise indicated, all percentages are based on up to 100% by weight of the final composition.

Example 1 Synthesis of 3- (3-pyridyl) -1-propyl (25) -l- [(2-methylbutyl) carbamoyl] pyrrolidine-2-carboxylate (1) 3- (3-pyridyl) -l-propyl (25 ) -N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylate A mixture of N- (tert-butyloxycarbonyl) - (S) -proline (3.0 g, 13.9 mmol), 3- (3-) was stirred overnight. 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). The reaction mixture was diluted with methylene chloride (50 ml) and water (100 ml), and the layers separated. The organic phase was washed with water (3 x 100 ml), dried over magnesium sulfate, and concentrated, and the residue was purified on a column of silica gel eluting with ethyl acetate to obtain 4.60 g (95%). %) of the ester as a thick oil. 1 H NMR (300 MHz, CDC13): d 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, 1 HOUR); 8.48 (m, 2H). 3- (3-pyridyl) -1-propyl pyrrolidine-2-carboxylate A solution of 3- (3- (3- (3- (3- (3- (3- (3- (3- (3-tert-butyloxycarbonyl) pyrrolidine-2-carboxylate) was stirred at room temperature for three hours. pyridyl) -1-propyl (3.00 g, 9 mmol) in methylene chloride (50 ml) and trifluoroacetic acid (5 ml). 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 the concentrate produced 2.00 g (95%) of the free amine as a thick oil. 1ti NMR (300 MHz, CDC13) d 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). (25) -1- [(2-Methylbutyl) -carbamoyl] pyrrolidin-2-carboxylate 3- (3-pyridyl) -1-propyl (1) A solution of 2-methylbutylamine (113 mg, 1.3 mmol) was added. and triethylamine (132 mg, 1.3 mmol) and methylene chloride (5 ml) were 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-Pyrrolidin-2-carboxylic acid 3- (3-pyridyl) -1-propyl (300 mg, 1.3 mmoles) was added in 5 ml of methylene chloride and the resulting mixture was stirred for 1 hour and then divided. 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. . 1R NMR (CDC13, 300 MHz): d 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 C? 9H29N3O3-0.5 H20: 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 (2) (2S) (2) (25) -l- [(! ',!' -dimethylpropyl) -carbamoyl] -pyrrolidine-2-carboxylate 3- (3-pyridyl) -1-propylpyrrolidine-2-carboxylate with the isocyanate generated from ter-amylamine and triphosgene, as described by Example 1, provided the compound of Example 2 (Compound 2, Table I) in a 62% yield. XH NMR (CDC13, 300 MHz): d 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 Ci9H29N3? 3-0.5 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-propyl (3) (25) -1- [(cyclohexyl) thiocarbamoyljpyrrolidin-2-carboxylate (3) A mixture of cyclohexylisothiocyanate (120 mg, 0.9 mmol) was stirred for 1 hour. , (2S) -pyrrolidine-2-carboxylate of 3- (3-pyridyl) -1-propyl (200 mg; 0.9 mmole) triethylamine (90 mg, 0.9 mmol) in 20 ml of methylene chloride and then divided 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 (Compound 3, Table I). 1 H NMR (CDC13, 300 MHz): d 1.16-1.40 (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 C 20 H 29 N 3 O 2 S: 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 () (25) -1- [(cyclohexyl) carbamoyl] pyrrolidin-2-carboxylate () A mixture of cyclohexyl isocyanate (100 mg, 0.9 mmol) was stirred for 1 hour. ), (25) -pyrrole? 3- (3-pyridyl) -1-propyl din-2-carboxylate (200 mg, 0.9 mmol) and triethylamine (90 mg, 0.9 mmol) in 20 ml of methylene chloride and then it was 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 120 mg (36%) of the compound of Example 4 (Compound 4, Table I). 1 H NMR (CDC13, 300 MHz): d 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 C2oH29N3? 3 - 0.6 H20: 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 (25) -1- [(1-adamantyl) thiocarbamoyl] pyrrolidin-2-carboxylate (5) A mixture of 1-adamantyl isocyanate ( 250 mg, 0.9 mmol), (2S) -pyrrolidine-2-carboxylic acid 3- (3-pyridyl) -1-propyl (200 mg, 0.9 mmol) and triethylamine (90 mg, 0.9 mmol) in 20 ml of sodium chloride. methylene 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), XH NMR (CDC13 , 300 MHz): d 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 C 24 H 3 N 302 S-0.4 H 20: 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 6 C57 Black Mice Experiment A: 6 C57 black mice were used to demonstrate the hair revitalization properties of FKBP neuro-immunophilin ligands related to GPI 1044, GPI 1116 and GPI 1102. C57 black mice, approximately 7 weeks old, had an area of approximately 2 inches by 2 inches on their shaved bottoms to remove all existing hair. Care was not taken to cut or cause abrasion to the underlying dermal layers. The animals were in an anagen growth phase, as indicated by the pinkish color of the skin. Referring now to Figures 1, 2, 3 and 4, four animals were treated by topical administration with 20% propylene glycol vehicle (Figure 1), and, for each compound, seven animals were treated by topical administration with 10 μM GPI. 1044 (Figure 2), 10 μM of GPI 1116 (Figure 3) or 3 μM of GPI 1102 (Figure 4). Animals were treated with vehicle, GPI 1044, GPI 1116, or GPI 1102 for 48 hours (3 total applications during the course of 5 days) and hair growth was allowed to proceed for 6 weeks. The hair growth was quantified by the percent of the shaved area covered by the growth of new hair during this period of time. Figure 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, Figures 2, 3 and 4 show that animals treated with the related immunophilin ligands, 10 μM GPI 1044, 10 μM GPI 1116, and 3 μM GPI 1102, exhibited dramatic hair growth, covering much more than 50% of the shaved area in some animals. Figure 5 compares the hair growth result of unshaven, vehicle treated, GPI 1044 (1 μM, 3 μM and 10 μM), GPI 1116 (1 μM and 10 μM), and GPI 1102 (1 μM and 3 μM). Experiment B: 6 C57 black mice were used to demonstrate the hair revitalization properties of FKBP neuroimmunophilin ligands, including GPI 1206. 6 C57 black mice, 55 to 75 days old, had an area of approximately 2 inches by 2 inches in your shaved bottoms to remove all existing hair. No care was taken to cut or cause abrasion to the underlying dermal layers. The animals were in an anagen growth phase when they shaved. Five animals per group were treated by topical administration with a vehicle, FK506, or a neuroimmunophilin ligand FKBP (GPI 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area. The animals were treated three times a week, and the hair growth was evaluated 14 days after starting the treatment. Hair growth was quantified by the percent of the shaved area covered by new hair growth, as classified by an observer, on a scale of 0 (no growth) to five (full hair regrowth in the shaved area). Figure 6 shows that after 14 days, animals treated with vehicle exhibited the origin of growth in small tufts. In contrast, animals treated with one of the FKBP neuroinmunophilin ligands, GPI 1206, exhibited dramatic hair growth. Example 7 A lotion comprising the following composition can be prepared.

A small molecule of carbamate or urea, α-tocopherol acetate, ethylene oxide (40 moles), customary castor oil adducts, perfume and a dye was added in 95% ethanol. The resulting mixture was stirred and dissolved, and the purified water was added to the mixture to obtain a clear liquid lotion. 5 ml of the lotion can be applied once or twice a day to a site marked by baldness or alopecia. Example 8 A lotion comprising the following composition shown can be prepared. 95% ethanol was added to a small molecule of carbamate or urea, hinokitol, ethylene oxide (40 moles), hardened castor oil adducts, perfume and a dye. The resulting mixture is stirred, and the purified water is added to the mixture to obtain a clear liquid lotion. The lotion can be applied by spraying once to 4 times a day to a site marked by baldness or alopecia.

Example 9 An emulsion can be prepared starting from phase A and phase B having the following compositions.

Phase A and phase B were respectively heated and melted and maintained at 80 ° C. Both phases were then mixed and cooled under stirring at normal temperature to obtain an emulsion. The emulsion can be applied by spraying once to four times a day to a site marked by baldness or alopecia.

Example 10 A cream can be prepared from phase A and phase B having the following compositions.

Phase A was heated and melted, and maintained at 70 ° C. Phase B was added in phase A and the mixture was stirred to obtain an emulsion. The emulsion was then cooled to obtain a cream. The cream can be applied once to 4 times a day to a site marked by baldness or alopecia.

Example 11 A liquid comprising the following composition can be prepared.

Polyoxypropylene butyl ether, propylene glycol, castor oil hardened with polyoxyethylene, a small carbamate or urea molecule, and perfume were added in ethanol. The resulting mixture was stirred, and water was added to the mixture to obtain a liquid. The liquid can be applied one to four times a day to a site marked by baldness or alopecia. Example 12 A shampoo comprising the following composition can be prepared. I In 69.7 of purified water, 5.0 g of sodium lauryl sulfate, 5.0 g of triethanolamine lauryl sulfate, 6.0 g of betaine lauryldimethylaminoacetate were added. Then, a mixture was obtained by adding 5.0 g of a small molecule of 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 agitation, and 0.3 g of perfume were added successively. The resulting mixture was heated and subsequently cooled to obtain a shampoo. The shampoo can be used on the scalp once or twice a day. Example 13 A patient suffering from alopecia senilis. A small carbamate or urea molecule as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected to occur following the treatment. Example 14 A patient suffering from male alopecia. A small carbamate or urea molecule as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected to occur following the treatment. Example 15 A patient suffering from alopecia areata. A small carbamate or urea molecule as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected to occur following the treatment. Example 16 A patient suffering from hair loss caused by skin lesions. A small carbamate or urea molecule as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected to occur following the treatment.

Example 17 A patient suffering from hair loss caused by tumors. A carbamate or small molecule urea as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected to occur following the treatment. Example 18 A patient suffering from hair loss caused by a systemic disorder, such as nutritional disorder or an internal secretion disorder. A small carbamate or urea molecule as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected to occur following the treatment. Example 19 A patient suffering from hair loss caused by chemotherapy. A small carbamate or urea molecule as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected to occur following the treatment. Example 20 A patient suffering from hair loss caused by radiation. A small carbamate or urea molecule as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected to occur following treatment. The invention, which is described in this way, will be obvious, since it can be varied in many ways. Such variations are not contemplated as a deviation 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 (24)

1. CLAIMS 1. A method for treating alopecia or causing hair growth in an animal, characterized in that it comprises administering to the animal an effective amount of a small molecule of carbamate or urea.
2. 2. The method according to claim 1, characterized in that the small carbamate or urea molecule has an affinity for an immunophilin of the FKBP type.
3. 3. The method according to claim 2, characterized in that the immunophilin of the FKBP type is FKBP-12.
4. 4. The method of compliance with the claim 1, characterized in that the small molecule of carbamate or urea is immunosuppressive.
5. 5. The method of compliance with the claim 1, characterized in that the small molecule of carbamate or urea is non-immunosuppressive.
6. 6. The method of compliance with the claim 1, characterized in that the small carbamate or urea molecule is a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A is CH 2, O, NH or N- (C 1 -C 4 alkyl); B and D are independently Ar, hydrogen, straight or branched chain alkyl of Ci-Ce, alkenyl or alkynyl straight or branched chain of C2-C6, cycloalkyl of C5-C7 substituted straight or branched chain alkyl of Ci- C3-C6 straight or branched chain or alkenyl or alkenyl, C5-C6 cycloalkenyl substituted with straight or branched chain alkyl of Ci-Ce or alkenyl or alkynyl of straight or branched chain of C3-C6, alkyl substituted Ar straight or branched chain of C? -C6 or substituted alkenyl or alkynyl straight or branched chain of C3-C6; wherein any carbon atom of the alkyl is optionally replaced by a heteroatom selected from the group consisting of O, S, SO, S02 and NR, wherein R is selected from the group consisting of hydrogen, straight or branched chain alkyl of C1 -C4, alkenyl or alkynyl of straight or branched chain of C3-C4 and alkyl in connection of C? -C wherein a bridge is formed between the nitrogen and a carbon atom of the heteroatom-containing chain to form a 1-ring, and wherein the ring is optionally fused to an Ar group; J is selected from the group consisting of hydrogen, straight or branched chain alkyl of Ci-Cβ, straight or branched chain alkenyl of C3-C6, and -CH2Ar; K is selected from the group consisting of straight or branched chain alkyl of C 1 -C 4, -CH 2 Ar, 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 S02; Z is 0 or S; Y is 0 or N, with the proviso that when Y is 0, then Ri is a single pair of electrons and R2 is selected from the group consisting of Ar, straight or branched chain alkyl of Ci-Cβ and alkenyl or alkynyl of linear or branched chain of C3-C6, 'and when Y is N, then Ri and R2 are independently selected from the group consisting of Ar, straight or branched chain alkyl of Ci-Cß, and straight or branched chain alkenyl or alkynyl of C3-C6; or Ri and R2 are taken together to form a 5-6 membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, 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 an 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, pyrazolyl, 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-triatianyl, indolizinyl, iridolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thio-phenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, , 2, 3, 4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naftidinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; wherein Ar is substituted or unsubstituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, l-chain, ineal or branched Ci-Ce, chain alkenyl linear or branched C2-C6, O- (straight or branched chain alkyl of Ci-Ce), O- (straight or branched chain alkenyl of C3-C4), 0-benzyl, O-phenyl, 1, 2- methylenedioxy, -NR3R4, carboxyl, N- (straight or branched chain alkyl of C1-C5 or straight or branched chain alkenyl of C1-C5) carboxamides, N, N-di- (straight or branched chain alkyl of C1- C5 or straight or branched chain alkenyl of C3-Cs) carboxamides, morpholinyl, piperidinyl, OX, CH2- (CH2) qX, 0- (CH2) qX, (CH2) q-0-X, and CH = CH-X; R3 and R4 are independently selected from the group consisting of straight or branched chain alkyl of Cj.-CQ, straight or branched chain alkenyl of C3-Cd, 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-dimethylisoxazolyl, isoxazolyl, 2-methylthiazolyl, thiazolyl, 2-thienyl, 3-thienyl and pyrimidyl; q is 0-2; and n is 0 or 1.
7. 7. The method according to claim 6, characterized in that J and K are taken together to form a ring of 5-7 members. The method according to claim 7, characterized in that at least one of B and D is / are independently represented by the formula - (CH2) r_ (X) _ (CH2) S-Ar, where: r is 1 -4; s is 0-1; and each X is independently selected from the group consisting of CH2, O,
8. S, SO, S02 and NR, wherein R is selected from the group consisting of hydrogen, straight or branched chain alkyl of C? -C4, alkenyl or straight or branched chain alkynyl of C3-C4, and C1-C4 connecting alkyl wherein a bridge is formed between the nitrogen atom and Ar.
9. 9. The method according to claim 6, characterized in that: Ar is selected from the group consisting of ifenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydroiso-quinolinyl, and 1, 2, 3, 4-tetrahydroquinolinyl wherein Ar is substituted or unsubstituted with one or more substituents independently selected from the group consisting of hydrogen, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of C? -C6, O- (straight or branched chain alkyl of C? -C6), halogen, S03H, and NR3R4; and R3 and R4 are independently selected from the group consisting of straight or branched chain alkyl of Ci-, straight or branched chain alkenyl of C3-C6, hydrogen, and benzyl; or R3 and R4 are taken together to form a 5-6 membered heterocyclic ring.
10. The method according to claim 1, characterized in that the small carbamate or urea molecule is a compound of the formula II or III or a pharmaceutically acceptable salt, ester or solvate
11. II III acceptable thereof, wherein: Y, Ri and R2 are as defined in the claim Ar is as defined in claim 6; J is hydrogen, straight or branched chain alkyl of Ci-Cß, or straight or branched chain alkenyl of C3-C6; and w is 1 or 2. The method according to claim 1, characterized in that the small carbamate or urea molecule is a compound of formula IV or V IV V or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: Y, Ri and R2 are as defined in claim 6; Ar is as defined in claim 6; J is hydrogen, straight or branched chain alkyl of Ci-Cß, or straight or branched chain alkenyl of C3-C6; and w is 1 or 2.
12. 12. The method according to claim 1, characterized in that the small carbamate or urea molecule is a compound of the 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, from a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatoms selected from group consisting of O, S, SO, S02, N, NH, and NR; R is either straight or branched chain alkyl of Ci-Cg, straight or branched chain alkenyl of C2-C9, cycloalkyl of C3-C9, cycloalkenyl of C5-C7, or Ari, wherein R is either substituted or unsubstituted substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of Ci-Cß, straight or branched chain alkenyl of C2-C6 , C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, carbonyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl and Ar 2; Ari and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the size of the individual ring is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; A, B, D, Ri, R2, Y, Z and n are as defined in claim 6 above.
13. 13. A pharmaceutical composition which comprises: (i) an effective amount of a small molecule of carbamate or urea to treat alopecia or cause hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
14. 14. The pharmaceutical composition according to claim 13, characterized in that the small molecule of carbamate or urea has an affinity for an immunophilin type FKBP.
15. 15. The pharmaceutical composition according to claim 14, characterized in that the immunophilin of the FKBP type is FKBP-12.
16. 16. The pharmaceutical composition according to claim 13, characterized in that the small molecule of carbamate or urea is immunosuppressive.
17. 17. The pharmaceutical composition according to claim 13, characterized in that the small carbamate or urea molecule is not immunosuppressive.
18. 18. The pharmaceutical composition according to claim 13, characterized in that the small carbamate or urea molecule is a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A is CH 2, O, NH or N- (C 1 -C 4 alkyl); B and D are independently Ar, hydrogen, straight or branched chain alkyl of Ci-Ce, alkenyl or alkynyl straight or branched chain of C2-C6, cycloalkyl of C5-C7 substituted straight or branched chain alkyl of C? - C6 or straight or branched chain alkenyl or alkynyl of die C3-C6, C5-C7 cycloalkenyl substituted with straight or branched chain alkyl of Ci-Cß or alkenyl or alkynyl of straight or branched chain of C3-C6, substituted alkyl of alkyl of > linear or branched chain of Ci-Cβ or Ar substituted by alkenyl or alkynyl of straight or branched chain of C3-C6, "wherein any carbon atom of the alkyl is optionally replaced by a heteroatom selected from the group consisting of O, S, SO, S02 and NR, wherein R is selected from the group consisting of hydrogen, straight or branched chain alkyl of C 1 -C 4, alkenyl or alkynyl straight or branched chain of C 3 -C 4 and alkyl in connection of C 1 -C 4 in where a bridge is formed between the nitrogen and a carbon atom of the heteroatom-containing chain to form a ring, and wherein the ring is optionally fused to an Ar group; J is selected from the group consisting of hydrogen, chain alkyl linear or branched Ci-Cβ, straight or branched chain alkenyl of C3-C6, and -CH2Ar; K is selected from the group consisting of straight or branched chain alkyl of C1-C4, -CH2Ar, and cyclohexylmethyl; and K are taken together to fo rm a 5-7 membered heterocyclic ring, which is substituted with O, S, SO, or S02; Z is O or S; Y is O or N, with the proviso that when Y is 0, then Ri is a single pair of electrons and R2 is selected from the group consisting of Ar, straight or branched chain alkyl of C? ~ C6 and alkenyl or alkynyl straight or branched chain of C3-C6; and when Y is N, then Ri and R2 are independently selected from the group consisting of Ar, straight or branched chain alkyl of C? -C6, and straight or branched chain alkenyl or alkynyl of C3-C6; or Ri and R2 are taken together to form a 5-6 membered heterocyclic ring selected from the group consisting of pyridine, imidazolidine, pyrazolidin, 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 an 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, pyrazolyl, 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-triatianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thio-phenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1, 2, 3,4-tetrahydroquinolinyl, isoquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthidinyl, pyridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; wherein Ar is substituted or unsubstituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, nitro, '-S03H, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of C? -C6, straight or branched chain alkenyl of C2-C6, O- (straight or branched chain alkyl of C-? Cβ), O- (straight or branched chain alkenyl of C 3 -C 4), O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR 3 R 4, carboxyl, N- (straight or branched chain alkyl of C 1 -C 5 or straight or branched chain alkenyl of C 1 -C 5) carboxamides, N, N-di- (straight or branched chain alkyl of C 1 -C 5 or straight or branched chain alkenyl of C 3 -C 5) carboxamides, morpholinyl, piperidinyl, OX , CH2- (CH2) qX, 0- (CH2) qX, (CH2) q-0-X, and CH = CH-X; R3 and R are independently selected from the group consisting of straight chain or branched chain C de ~C ?, alkyl, straight or branched chain alkenyl of 1 C3-Cβ, 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-dimethylisoxazolyl, isoxazolyl, 2-methylthiazolyl, thiazolyl, 2-thienyl, 3-thienyl and pyrimidyl; q is 0-2; and n is 0 or 1.
19. 19. The pharmaceutical composition according to claim 18, characterized in that J and K are taken together to form a 5-7 membered ring.
20. 20. The pharmaceutical composition according to claim 19, characterized in that at least one of B and D is / are independently represented by the formula - (CH2) r- (X) - (CH2) S-Ar, wherein: is 1-4; s is 0-1; and each X is independently selected from the group consisting of CH2, O, S, SO, S02, and NR, wherein R is selected from the group consisting of hydrogen, straight or branched chain alkyl of C1-C4, alkenyl or alkynyl straight or branched chain of C3-C4 and C alquilo-C4 connecting alkyl, wherein a bridge is formed between the nitrogen atom and Ar.
21. The composition according to claim 18, characterized in that: Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, and 1, 2, 3, -tetrahydroquinolinyl wherein Ar is substituted or unsubstituted with one or more substituents independently selected from the group consisting of hydrogen, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of Ci-Cß, O- (straight or branched chain alkyl of Ci-Cß), halogen, S03H, and NR3R4; and R3 and R4 are independently selected from the group consisting of straight or branched chain alkyl of C? -C.sub.4, straight or branched chain alkenyl of C3-C6, hydrogen, and benzyl; or R3 and R4 are taken together to form a 5-6 membered heterocyclic ring.
22. 22. The pharmaceutical composition according to claim 13, characterized in that the small carbamate or urea molecule is a compound of formula II or III III or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: Y, Ri and R2 are as defined in claim 18, Ar is as defined in claim 18, J is hydrogen, straight chain alkyl or branched chain of Ci-Cß, or straight or branched chain alkenyl of C3-C6, and w is 1 or 2.
23. 23. The pharmaceutical composition according to claim 13, characterized in that the small molecule of carbamate or urea is a compound of the Formula IV or V IV V or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: Y, Ri and R2 are as defined in claim 18; Ar is as defined in claim 18; J is hydrogen, straight or branched chain alkyl of C? -C6, or straight or branched chain alkenyl of C3-C6; and w is 1 or 2.
24. 24. The pharmaceutical composition according to claim 13, characterized in that the small carbamate or urea molecule is a compound of the 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 parone atom to which they are respectively attached, from a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteratoms selected from the group consisting of O, S, SO, S02, N, NH, and NR; R is either straight or branched chain alkyl of C1-C9, straight or branched chain alkenyl of C2-C9, cycloalkyl of C3-C9, cycloalkenyl of C5-C7, or Ari, wherein R is either substituted or unsubstituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of Ci-Cß, straight chain alkenyl or branched C 2 -Cd, C 1 -C 4 alkoxy, C 2 -C alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl and Ar 2; Ari and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the size of the individual ring is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; A, B, D, Ri, R2, Y, Z and n are as defined in claim 18 above.