MXPA00011937A - N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses - Google Patents

Abstract

This invention relates to pharmaceutical compositions and methods fortreating alopecia and promoting hair growth using N-linked ureas or carbamates of heterocyclic thioesters.

Description

COMPOSITIONS FOR HAIR GROWTH CONTAINING U N-VI NCU LADA OR CARBAMATE OF HETEROCICLIC TIOESTERS.

BACKGROUND OF THE I NVENTION 1. Field of the Invention This invention relates to pharmaceutical compositions and methods for treating alopecia and stimulating hair growth using low molecular weight, N-linked heterocyclic thioesters or carbamates. 2. Description of Related Art Hair loss occurs in a variety of situations. These situations include male alopecia, alopecia senilis, alopecia areata, diseases accompanied by injuries or basic skin 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, the activation of male hormones, the loss of blood supply to the hair follicles, and abnormalities of the skin. scalp The immunosuppressive drugs FK506, rapamycin and cyclosporine are well known as T-cell specific immunosuppressants, and are effective against graft rejection after organ transplantation. The application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol., 1995, has been reported as topical, but not oral. 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; since, immunomodulatory compounds administered topically are expected to demonstrate efficacy in treating that type of hair loss. The effects that stimulate hair growth of FK506 have been the subject of an investigation covering the international patent FK506 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 hair revitalizing agents. Hair growth and revitalizing agents of FK506 and related agents are described in many North American patents (Goulet et al., US Patent No. 5,258,389, Luly et al., US Patent 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., U.S. Patent No. 5,284,877). These patents claim the compounds related to FK506. Although they do not claim methods of hair revitalization, they describe the known use of FK506 for hair growth. Similar to FK506 (and the variations claimed in the Honbo et al. Patent), the compounds claimed in these patents are relatively large. In addition, the patents cited relate to immunomodulatory compounds for use in autoimmune related diseases, for which 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 5,284,826, Hewitt et al., US Patent No. 4,996,193). These patents also relate to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressant compounds for hair growth. * - ~ * > * However, the immunosuppressant compounds to suppress the definition of the immune system and also exhibit other toxic side effects. Accordingly, there is a need for small molecule, non-immunosuppressive compounds, which are useful as hair revitalizing compounds. Hamilton and Steiner disclose in US Pat. No. 5,614,547 novel pyrrolidine carboxylate compounds that bind to the FKBP12 immunophilin and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that these immunosuppressive compounds cause hair growth with an efficiency similar to FK506. Even its structure of novel molecule and non-immunosuppressive properties differ from FK506 and immunosuppressive compounds related found in the prior art.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a method for treating alopecia or stimulating hair growth in an animal, which comprises administering to the animal an effective amount of a N-linked heterocyclic thioester urea or carbamate. The present invention further relates to a pharmaceutical composition comprising: (i) an effective amount of a urea or carbamate of an N-linked heterocyclic thioester to treat alopecia or stimulate hair growth in an animal; and (ii) a pharmaceutically acceptable carrier. The ureas or carbamates of N-linked heterocyclic thioesters used in the inventive methods and pharmaceutical compositions have an affinity for immunofinilines of the FKBP type, such as FKBP12, and do not exert any significant immunosuppressive activity.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a photograph of 6 black C57 mice before being shaved for the hair regeneration experiment. Figure 2 is a photograph of a mouse treated with a vehicle after six weeks. Figure 2 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered. Figure 3 is a photograph of a mouse treated with GPI 1046, a non-immunosuppressive linked FKBP neuroinmunophilin ligand, after six weeks. Figure 3 shows the extraordinary effects of non-immunosuppressive neuroimmunophilin FKBP ligands, where 90% of the shaved area is covered with new hair growth. Figure 4 is a photograph of a mouse treated with 30 μM of GPI 1046, a non-immunosuppressive FKBP neuroimmunophilin ligand, after six weeks. Figure 4 shows the extraordinary ability of non-immunosuppressive neuroimmunophilin FKBP ligands to achieve, essentially, complete regrowth of the hair in the shaved area. Figure 5 is a bar graph depicting the relative hair growth rates for 6 C57 black mice treated with one vehicle, FK506, and several non-immunosuppressive FKBP neuroimmunophilin ligands, including GPI 1605, 14 days after treatment with each compound identified. Figure 5 demonstrates the extraordinary growth of hair early caused by a wide variety of non-immunosuppressive FKBP neuroimmunophilin ligands. Figure 5: A-Promotion of Hair Growth by Neuroimmunophilin Ligands; B-0 = no growth, 1 = start of growth on small crests; 2 = hair growth cover on < 25% of the shaved area; 3 = hair growth cover over > 25% but less than 50% of the shaved area; 4 = hair growth cover over > 50% but less than 75% of the shaved area; 5 = full hair growth of the shaved area; C-Control; D-Hair growth (Relative index).

DETAILED DESCRIPTION OF THE INVENTION Definitions "Alopecia" refers to the growth of deficient hair 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 the hair growth or anagen phase due to the 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 separate from the dermal papilla, and the hair falls out. 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 1605" refers to compounds of formula "GPI 1046" refers to (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl, a compound of the formula "GPI 1312" refers to a compound of the formula "GPI 1572" refers to a compound of the formula "GPI 1389" refers to a compound of the formula "GPI 1511" refers to a compound of the formula "GPI 1234" 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 that atoms are arranged in space." Enantiomers "are a pair of stereo? Somers that are not superimposed on mirror images of each other." Diastereoisomers "are stereoisomers that are not images mirror "each other." "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal portions of individual enantiomers or stereoisomers. "Pharmaceutically acceptable salt, ester, or solvate" refers to a salt, ester or solvate of an object compound, which possesses the desired pharmacological activity and which is also not biologically undesirable in any way.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, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthanesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of salts, esters or base 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 on. Also, basic nitrogen containing groups 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, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. The soluble or dispersible products in water or oil are therefore obtained. "Pillar cycle" refers to the life cycle of hair follicles, and includes three phases: (1) the anagen phase, the active hair growth period, which, to the extent that the scalp is affected, less approximately three to five years; (2) the catagen phase, the period when the hair stops and the follicular atrophies that, to the extent that the scalp is affected, at least approximately one to two weeks; and (3) the telogen phase, the remaining period when the hair progressively separates and eventually falls which, to the extent that the scalp is affected, 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 bulb colored at its root. "Stimulating hair growth" refers to maintaining, inducing, stimulating, accelerating or revitalizing hair germination. "Treating alopecia" refers to: (i) preventing alopecia in an animal which may be predisposed to alopecia; and / or (ii) inhibit, slow or reduce alopecia; and / or (iii) stimulating 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 deep in the dermis. The hair, on the other hand, is thin, thin, short, non-pigmented hair in which the hair bulb is located superficially in the dermis. As the alopecia progresses, the hairs change from the terminal to the hair type.

Methods of the Present Invention The present invention relates to a method for treating alopecia or stimulating hair growth in an animal, which comprises administering to the animal an effective amount of an N-linked heterocyclic thioester urea or carbamate. The inventive method is particularly useful for treating male alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy or radiation, and alopecia resulting 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 urea or carbamate of an N-linked heterocyclic thioester to treat alopecia or stimulate hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

UREAS AND CARBAMATES OF N-LINKED HETEROCICLIC THYESTERS The ureas and carbamates of N-linked heterocyclic thioesters used in the methods and pharmaceutical compositions of the present invention are low molecular weight small molecule compounds, which have an affinity for an immunophilin of the FKBP type. , such as FKBP12. When a urea or carbamate of an N-linked heterocyclic thioester binds to an immunophilin of the FKBP type, it has been found to inhibit the activity of the proli-peptide i I cis-trans isomerase binding protein, or rotamase. Unexpectedly, these compounds have also been found to stimulate hair growth. These compounds are devoid of any significant immunosuppressive activity.

FORMULA I The urea or carbamate of an N-linked thioester may be a compound of Formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, taken together with the nitrogen and carbon atoms to which they respectively bind, form a 5-7 membered, saturated or unsaturated heterocyclic ring which contains, in addition to the nitrogen atom, one or more additional heteroatoms O, S, SO, SO2, N, NH or NR3; X is either O or S; Y is a direct bond, straight or branched chain alkyl of or a straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl , thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O , NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C ^ Ce, straight or branched alkenyl or alkynyl of C3-C6, and C, -C4 connecting alkyl wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents selected independently from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C9, C, -C9 alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9l cycloalkyl C3-C8, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring containing 1-6 heteroatoms is independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7-cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl are optionally substituted with C2-C6 alkenyl alkyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO, or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R ,, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, alkyl straight or branched chain of C, -C8 and straight or branched chain alkenyl of C2-Cß, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and cycloalkyl of C3 -C8; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, straight or branched chain alkenyl of C2 -C6, wherein the alkyl or alkenyl is substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R., and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquininoinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolium, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl, pyrazoloinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naftidinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of Formula I, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolium, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl. In a more preferred embodiment of the compounds of the formula I, the urea or carbamate of an N-linked heterocyclic thioester is the compound GPI 1605, of the formula FORMULA II The urea or carbamate of an N-linked heterocyclic thioester may also be a compound of formula II or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, SO2, NH or NR3; X is either O or S; Y is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-Cß, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C4, alkenyl or alkynyl of straight or branched chain of C3-C4, and C, -C4, connecting alkyl wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents selected independently from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C2-C9 alkenyloxy alkoxy, straight or branched chain alkenyl of C2-C9, cycloalkyl of C3-C8, cycloalkenyl of C5- C7, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; 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; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, axynoxy, cyano, nitro, amino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or where any carbon atom "s, 22 of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then Rn is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, alkyl linear or branched chain and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R1 and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -5C6, and straight or branched chain alkenyl of C2 -C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, 5-benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl. , pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinilinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl , pyrazoloinyl, pi-razolidyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of formula II, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl. , and thienyl.

FORMULA III Additionably, the N-linked heterocyclic thioester urea or carbamate can be a compound of formula III or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F and G are independently CH2, O, S, SO, SO2, NH, and NR3; X is either O or S; Y is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O , NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C4, alkenyl or alkynyl straight or branched chain of C3-C4, and C1-C4 connecting alkyl wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents, independently selected from the group included, but is not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C8 alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9, C3 cycloalkyl -C8, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the size of the individual ring is 5-8 members; where the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl , thioalkyl, sulfonyl, or oxygen to form a Carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-Cß; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO, or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, straight or branched chain of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and cycloalkyl of C3 -C8; and when U is N, then R ^ and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine, and piperazine. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl, pyrazoloinyl, pi, razolid ini lo, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naftridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of Formula III, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl. In a more preferred embodiment of the compounds of the formula III, the urea or carbamate of an N-linked heterocyclic thioester is the compound GPI 1605, of the formula FORMULA IV The urea or carbamate of an N-linked heterocyclic thioester may also be a compound of the formula IV or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3; X is either O or S; Y is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or anynyl is optionally replaced with O, NH, NR3, S, SO or S02; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C4, alkenyl or alkynyl straight or branched chain of C3-C4, and C, -C4 connecting alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents selected independently from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C2-C9 alkenyloxy alkoxy, straight or branched chain alkenyl of C2-C9, cycloalkyl of C3-C8, cycloalkenyl of C5- C7, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH , NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C C6, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 6 alkyl, C 2 -C 8 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino , aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or S02; W is O or S; and U is either O or N, with the proviso that: when U is O, then R, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, straight or branched chain of and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C3 cycloalkyl; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinylinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl.

In a preferred embodiment of formula IV, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl. , and thienyl. Exemplary compounds of formula IV are presented in Table I. TABLE I 1 1 O (CH2) 2 CH 3-Pyridyl H H 2-Methylbutyl 2 1 0 (CH 2) 2 CH 3 -Pyridyl H H 1, 1 -dimethylpropi lo 3 1 O (CH 2) 2 CH 4 -Metoxy H H 1, 1-dimethylpropi lo phenyl 4 1 O CH 2 CH Phenyl H H 1, 1-dimethylpropi lo 1 S (CH 2) 2 CH 4-Methoxy HH Cyclohexyl Phenyl 6 1 O (CH 2) 2 CH 3 -Pyridyl HH Cyclohexyl 7 1 s (CH 2) 2 CH 3 -Pyridyl HH Cyclohexyl 8 1 S (CH 2) 2 CH 3 Pyridyl HH 1 -Adamantyl 9 1 S (CH2) 2 CH 3-Pyridyl HH 1,1-dimethylpropyl 1 O (CH2) 2 CH Phenyl Phenyl 1, 1-dimethylpropyl 11 2 O (CH2) 2 CH Phenyl, H, 1,1-dimethylpropyl 12 2 O (CH2) 2 CH Phenyl, HH Phenyl, 13 2 O, CH 2 -Phenyl, 2-Phenyl, H, Phenyl, ethyl, ethyl, 14 2 O, CH 2 -phenyl, 2-phenyl, HC, I ohexyl, or ethyl, ethyl, 15 2 S bond. Link CH 2-Phenyl 2-Phenyl H Cyclohexyl Direct ethyl ethyl 6 2 O (CH 2) 2 CH 4 -Metoxy HH Cyclohexyl phenyl The most preferred compounds of Formula IV are selected from the group consisting of: 3- (3-Pyridyl) -1-propyl-2S-1 - [(2-methylbutyl) carbamoyl] pyrrolidine-2-carboxylate; 3- (3-P i ridyl) -1-prop i I-2S-1 - [(1 ', 1' -Dimethylpropyl) carbamoyl] pyrro lid i n-2-carboxylate; 3- (3-Pyridyl) -1-propyl-2S-1 - [(cyclohexyl) thiocarbamoyl] pyrrolidine-2-carboxylate; and pharmaceutically acceptable salts, esters and solvates thereof.

FORMULA V The urea or carbamate of an N-linked heterocyclic thioester can be a compound of the formula V or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N, or S; Y is a straight, straight or branched chain alkyl of C, -C6, straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is replaced optionally with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or C3-C6 alkynyl, and C, -C4 connecting alkyl wherein a bridge is formed between the nitrogen and an alkyl or alkenyl chain carbon atom containing a heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic carbo- or heterocyclic ring, wherein the ring is either substituted or substituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C, alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; and A, B, R1, R2, U, W and X are as defined otherwise in formula I above. All the compounds of the formulas I-V possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R and S stereoisomers. Individual stereoisomers can be obtained by using an optically active starting material, resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or resolving the compounds of Formulas I-V. It will be understood that the compounds of Formulas l-V encompass 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 Ureas and Carbamates of N-Linked Heterocyclic Thioesters The compounds of Formulas I to V can be easily prepared by standard techniques of organic chemistry, using the general synthetic pathway represented in the following. As described in Scheme I, the cyclic amino acids 1 protected by appropriate blocking groups P on the amino acid nitrogen can be reactive with thiols of RSH to generate thioesters 2. After removing the protecting group, the free amine 3 can be reactive with a variety of? socianates or isothiocyanates to provide the final ureas or thioureas, respectively.

• Check out Isocyanates (R'NCO) or isothiocyanates (R'NCS) 4 can be conveniently prepared from the corresponding readily available amines by reaction with phosgene or thiophosgene, as depicted in Scheme II.

SCHEME II The R-SH thiols can conveniently be prepared from the corresponding alcohols or halides readily available through two halide replacement steps by sulfur, as described in Scheme Ill. The halides can be reactive with thiourea, and the corresponding alkyl thiouronium salts hydrolyze to provide RSH thiols. If the alcohols are used as the starting materials, they can be first converted to corresponding halides by standard methods.

SCHEME lll R-OH R-Bx R-SH CBx4 / Ph3P OH "Affinity for FKBP12 Compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12.Inhibition of propyl peptidyl activity cis-trans isomerase 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., Nature, 1989, 341: 758-760; Holt et al., J. Am. Chem. Soc, 115: 9923-9938). These values are obtained as apparent K i and are presented by representative compounds in TABLE II The cis-trans isomerization of an alanine-proline linkage in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide , is verified spectrophotometrically in a coupled assay of chymotrypsin, 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 K i 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-CI pH 7.5, 100 mM NaCl are added. , 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 I to V Composite Ki (nM) 1 + + + 2 + + 3 + + 4 + + 5 + + 6 + 7 + + 8 + + + 9 +++ 10 + + + 11 + + 12 + + + 13 + + + 14 + + + 15 + + + 16 + + The relative powers of compounds are classified according to the following scale: + + + + means K¡ or DE50 < 1 nM; + + + means K, or DE50 of 1-50 nM; ++ means K, or DE50 of 51-200 nM; + means K or DE of 201-500 nM.

Route of Administration To effectively treat alopecia or stimulate hair growth, the compounds used in the inventive methods and pharmaceutical compositions 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 may 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 2- (3-pyridyl) -1-propyl (1) 3- (3-pyridip-1-pro-pylidene) 2S-1-f (2-methylbutipcarbamoyl) pyrrolidin-2-carboxylate is added in drops to a solution of 3- (3-pyridyl) -1-propanol (10 g, 72.4 mmol) in chloroform (100 mL) to a solution of thionyl chloride (12.9 g, 108.6 mmol) in chloroform (50 mL) The resulting mixture was refluxed for 1 hour, then emptied into 50% cold aqueous potassium hydroxide (150 mL) .The layers were separated, and the organic phase was dried, concentrated and purified on a silica gel, eluting with 40% ethyl acetate in hexane, to obtain 10 g (65%) of chloride as a clear oil.1H NMR (300 MHz, CDCl 3): d 2.02-2.11 (m, 2H); 2.77 (m , 2H), 3.51 (m, 2H), 7.20 (m, 1H), 7.49 (m, 1H), 8.45 (m, 2H), 3- (3-Pi ridyl) -1 -prop i I mercaptan The mixture was refluxed for 24 hours with a mixture of 3- (3-pyridyl) -1-propylchloride (3 g, 19.4 mmol) and thiourea (1.48 g, 19.4 mmol) in ethanol (10 mL). aqueous sodium hydroxide, 15 mL of a 0.75 N solution, and the mixture was refluxed for an additional 2 hours. After cooling to room temperature, the solvent was removed in vacuo. Chromatographic purification of the unpurified thiol on a silica gel column eluted with 50% ethyl acetate in hexane supplying 1.2 g of 3- (3-pyridyl) -1-propyl mercaptan as a clear liquid. H NMR (300 MHz, CDCl 3): d 1.34 (m, 1H); 1.90 (m, 2H); 2.52 (m, 2H); 2.71 (m, 2H); 7.81 (m, 1H); 7.47 (m, 1H); 8.42 (m, 2H). N- (fer-butyloxycarbonyl) pyrrolidine-2-carboxylic acid 3- (3-pyridyl) -1-propylmercaptyl A mixture of N- (fer-butyloxycarbonyl) - (S) -proline (3.0 g) was stirred overnight. 13.9 mmoles); 3- (3-Pyridyl) -1-propylmercaptan (3.20 g, 20.9 mmol), dicyclohexylcarbodiimide (4.59 g, 22.24 mmol), camphorsulfonic acid (1.08 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 were separated. The organic phase was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated, and the unpurified residue was purified on a column of silica gel, eluting with ethyl acetate to obtain 4.60 g ( 95%) of the thioester as a thick oil. 1 H NMR (300 MHz, CDCl 3): d 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71 (t, 2H); 2.85 (m, 2H); 3.50 (m, 2H); 4.18 (m, 1H); 7.24 (m, 1H); 7.51 (m, 1H); 8.48 (m, 2H). 3- (3-Pyridi-1-propyl mercaptyl) pyrrolidine-2-carboxylate A solution of 3- (3-pyridyl) -1-mercaptyl-N- (fe-butyloxycarbonyl) -pyrrolidin- was stirred at room temperature for three hours. 2-carboxylate (4.60 g, 13.1 mmol) in methylene chloride (60 mL) and trifluoroacetic acid (6 mL) Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with sodium chloride. methylene (3x) The combined organic extracts were dried and concentrated to yield 2.36 g (75%) of the free amine as a thick oil.1H NMR (300 MHz, CDCl 3): d 1.87-2.20 (m, 6H); 2.79 (m, 2H), 3.03-3.15 (m, total 4H), 3.84 (m, 1H), 7.32 (m, 1H), 7.60 (m, 1H), 8.57 (m, 2H), 2S-1-r (2-methylbutyl) carbamoyl pyrrolidin-2-carboxylate 3- (3-pyridyl-1-propylmercaptyl) (1) A solution of 2-methylbutylamine (113 mg, 1.3 mmol) and triethylamine (132 mg, 1.3 mmol) was added Methylene chloride (5 mL) to a solution of triphosgene (128 mg, 0.43 mmol) in chlorine methylene oxide (5 mL). The resulting mixture was refluxed for 1 hour and then cooled to room temperature. 3- (3-Pyridyl) -1-propyl mercaptyl 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 divided between water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (ethyl acetate 50% / hexane) to obtain 250 mg (55%) of the compound of Example 1 (Compound 1, Table II) as an oil. 1 H NMR (300 MHz, CDCl 3): d 1 H NMR (CDCl 3, 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, 6H); 4.45-4.47 (m, 1H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd, 1H); 8.46-8.48 (s, 2H).

Example 2 Synthesis of 2- (3-pyridyl) -1-propyl 2S-1-f (1 '. 1' -Dimethylpropyl) carbamoylpyrrolidin-2-carboxylate (2) The reaction of 3- (3-pyridyl) -1 -propylmercaptyl pyrrolidin-2-carboxylate with the isocyanate generated from re-amylamine and triphosgene, as described by Example 1, provides the compound of Example 2 (Compound 2, Table II in 62% yield. 1H NMR ( CDCI3, 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), 2.85 ( m, 2H), 3.29-3.42 (m, 2H), 4.11 (br, 1H), 4.37-4.41 (m, 1H).

EXAMPLE 3 Synthesis of 2S-1-r (cyclohexyl) thiocarbamoin-pyrrolidine-2-carboxylate of 3- (3-pyridyl) -1-pro-pil-p rea reayl (7) A mixture of cyclohexylisothiocyanate (120 mg) was stirred for 1 hour. 0.9 mmol), 3- (3-pyridyl) -1-propylmercaptyl pyrrolidine-2-carboxylate (200 mg, 0.9 mmol) and triethylamine (90 mg, 0.9 mmol) in 20 mL of methylene chloride and then divided into water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (ethyl acetate 50% / hexane) to obtain 160 mg (47%) of the compound of Example 3 (Compound 7, Table II). H NMR (CDCl 3, 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); 3.03 (m, 2H); 3.40-3.60 (m, 2H); 4.95-4.98 (d, 1H); . 26-5.29 (d, 1H); 7.17-7.25 (m, 1H).

Example 4 In vivo Hair Generation Tests with 6 C57 Black Mice Experiment A: Six C57 black mice were used to demonstrate the revitalization properties of a non-immunosuppressive low molecular weight small molecular molecule FKBP ligand, GPI 1046, which it is related to ureas and carbamates of N-linked heterocyclic thioesters.

Referring now to Figures 1 and 2 of the drawings, 6 black C57 mice, approximately 7 weeks old, had an area of approximately 2 inches by 2 inches in their 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 the anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGURES 2, 3 and 4, four animals per group were treated by topical administration with 20% of the propylene glycol vehicle (FIGURE 2), 10 μM GPI 1046 (FIGURE 3) or 30 μM GPI 1046 (FIGURE 4) dissolved in the vehicle. The animals were treated with vehicle or GPI 1046 every 48 hours (3 total applications during the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantified by the percent of the shaved area covered by new hair growth during this period of time. FIGURE 2 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, FIGURE 3 shows that animals treated with 10 μM of GPI 1046 exhibited dramatic hair growth, which covers more than 90% of the shaved area in all animals. In addition, FIGURE 4 shows that mice treated with 30 μM of GPI 1046 exhibited essentially regrowth of the complete hair and their shaved areas were indistinguishable from the 6 unshaven C57 mice. Experiment B: Six C57 black mice were used to demonstrate the hair revitalization properties of a variety of low molecular weight, small molecule, non-immunosuppressive FKBP neuroinmunophilin ligands, including GPI 1605. 6 C57 black mice, 55 to 75 days old, had an area of approximately 2 inches by 2 inches on their shaved backs to remove all existing hair. No care was taken to cut or cause abrasion to the underlying dermal layers. The animals were in the anagen growth phase when they were shaved. Five animals per group were treated by topical administration with one vehicle, FK506, in one of the small molecule, low molecular weight FKBP non-immunosuppressive neuroinmunophilin ligands (GPI 1605, 1046, 1312, 1572, 1389, 1511 and 1234) a 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 the initiation of 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 5 shows that after 14 days, the animals treated with vehicle exhibited the start of growth in small tufts. In contrast, animals treated with one of the small molecule, low molecular weight, nonimmunosuppressive FKBP neuroinmunophilin ligands, including GPI 1605, exhibited dramatic hair growth.

Example 5 A lotion comprising the following composition can be prepared. 95% ethanol was added to a urea or carbamate of an N-linked heterocyclic thioester, α-tocopherol acetate, ethylene oxide (40 moles) hardened castor oil adducts, perfume and a dye. 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 6 A lotion comprising the following composition shown can be prepared. 95% ethanol was added to a urea or carbamate of an N-linked heterocyclic thioester, 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 7 An emulsion can be prepared 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 8 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 9 A liquid comprising the following composition can be prepared.

Polyoxypropylene butyl ether, propylene glycol, castor oil hardened with polyoxyethylene, a urea or carbamate of an N-linked heterocyclic thioester, 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 once to 4 times a day to a site marked by baldness or alopecia.

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

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 N-linked heterocyclic thioester urea or carbamate, 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 successively added. . 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 11 A patient suffering from alopecia senilis. A N-linked heterocyclic thiol ester urea or carbamate as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following the treatment.

Example 12 A patient suffering from male alopecia. A urea or carbamate of an N-linked heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following the treatment.

Example 13 A patient suffering from alopecia areata. A N-linked heterocyclic thiol ester urea or carbamate as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following the treatment.

Example 14 A patient suffering from hair loss caused by skin lesions. A urea or carbamate of an N-linked heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following the treatment.

Example 15 A patient suffering from hair loss caused by tumors. A urea or carbamate of an N-linked heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may 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 a systemic disorder, such as nutritional disorder or an internal secretion disorder. A urea or carbamate of an N-linked heterocyclic t-oester 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 chemotherapy. A urea or carbamate of an N-linked heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may 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 radiation. A urea or carbamate of an N-linked heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following the treatment. The invention being thus described, will be obvious, since it can be varied in many ways. Such variations are not to be considered as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims (30)

1. CLAIMS 1. A method for treating alopecia or stimulating hair growth in an animal, characterized in that it comprises administering to the animal an effective amount of a N-linked heterocyclic thioester urea or carbamate.
2. 2. The method according to claim 1, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is not immunosuppressant.
3. 3. The method according to claim 1, characterized in that the urea or carbamate of an N-linked heterocyclic thioester has an affinity for an immunophilin of the FKBP type.
4. 4. The method according to claim 3, characterized in that the immunophilin of the FKBP type is FKBP-12.
5. The method according to claim 1, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B are taken together with the atoms of nitro-carbon and the atoms, respectively, to form a heterocyclic, saturated or Nsaturad (';'; \, contains, in the case of the nitrogen atom, one or more heteroatory atoms, S, SO, SO2, N, NH or NR3; X is either O or S, Y is a direct bond, straight or branched chain alkyl of 0, -Cg or a straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or where any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or S02; R3 is selected from the group consisting of hydrogen, straight-chain alkyl or C, -C6, straight or branched chain C3-C6 alkynyl, and C-C4 connecting alkyl wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring containing 1-6 heteroatoms is independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, suifhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl are optionally substituted with C2-C6 alkenyl alkyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO, or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R. ,, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, straight or branched chain alkyl and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C, straight or branched chain alkenyl of C2- Cβ, wherein the alkyl or alkenyl is substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R1 and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine.
6. The method according to claim 5, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.
7. The method according to claim 1, characterized in that the urea or carbamate of a N-linked heterocyclic thioester is a compound of the formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently selected from the group consisting of CH 2, O, S, SO, SO 2, NH or NR 3; X is either O or S; Y is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C4, alkenyl or alkynyl straight or branched chain of C3-C4, and connecting alkyl of 0, -04, wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or ahenynyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of Cj-Cg, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to forming a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalicynyl is optionally substituted with C, -C4 alkyl, C2-C4 alkenyl, or hydroxy; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3,
8. S, SO or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then Rt is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, chain alkyl straight or branched chain and straight-chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R, and Rz are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2 -C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine. The method according to claim 7, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl and phenyl.
9. 9. The method according to claim 1, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula III or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F and G are independently selected from the group consisting of CH 2, O, S, SO, SO 2, NH, and NR 3; X is either O or S; Y is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkeniion is optionally substituted at one or more positions with oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C1-C4, alkenyl or alkynyl of C3-C4, and connecting alkyl of 0, -0, where a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents, wherein the size of the single ring is 5-8. members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkenyl straight or branched chain alkyl of C2-C6, wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C4 alkyl, C2-C4 alkenyl, or hydroxy; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with the oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO, or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, straight or branched chain of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then Rt and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl and straight or branched chain alkenyl of C2-C6, in wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine, and piperazine.
10. The method according to claim 9, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.
11. The method according to claim 1, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula IV or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3; X is either O or S; Y is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 0, -04, alkenyl or alkynyl straight or branched chain of C3-C4, and connecting alkyl of 0, -04, wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 0, -Cg, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C4 alkyl, C2-C4 alkenyl, or hydroxy; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, alkyl straight or branched chain of C, -C6 and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3 cycloalkyl C8; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2 -C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine.
12. The method according to claim 11, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl and phenyl.
13. The method according to claim 11, characterized in that: n is 1 or 2; And it is (CH2) 2 or a direct link; Z is CH; C is 3-pyridyl, 4-methoxyphenyl, phenyl or 2-phenylethyl; D is hydrogen, phenyl or 2-phenylethyl; R, is hydrogen; and R 2 is 2-methylbutyl, 1,1-dimethylpropyl, cyclohexyl, 1-adamantyl, or phenyl.
14. The method according to claim 13, characterized in that the compound is selected from the group consisting of: 3- (3-pyridyl) -1-propyl-2S-1 - [(2-methylbutyl) carbamoyl ] -pyrrolidin-2-carboxylate; 3- (3-P i rid il) -1-prop il-2S-1 - [(1 ', 1'-D imeti Ipropyl) carbamatoyl] pyrrolidine-2-carboxylate; 3- (3-Pyridyl) -1-propyl-2S-1 - [(cyclohexyl) thiocarbamoyl] -pyrrolidine-2-carboxylate; and pharmaceutically acceptable salts, esters and solvates thereof.
15. The method according to claim 1, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula V Ri or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N, or S; Y is a straight, straight or branched chain alkyl of C, -C6, straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of alkyl or aikenyl is replaced optionally with O, NH, NR3, S, SO or SO 2 'R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or C3-C6 alkynyl, and C, -C4 connecting alkyl wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing a heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic carbo- or heterocyclic ring, wherein the ring is either substituted or substituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-Cß; wherein alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino , alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; and A, B, R1, R2, U, W and X are as defined otherwise in claim 5 above.
16. 16. A pharmaceutical composition characterized in that it comprises: (i) an effective amount of a urea or carbamate of an N-linked heterocyclic thioester to treat alopecia or stimulate hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
17. 17. The pharmaceutical composition according to claim 16, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is non-immunosuppressant.
18. 18. The pharmaceutical composition according to claim 16, characterized in that the urea or carbamate of an N-linked heterocyclic thioester has an affinity for an immunophilin of the FKBP type.
19. 19. The pharmaceutical composition according to claim 18, characterized in that the immunophilin of the FKBP type is FKBP-12.
20. 20. The pharmaceutical composition according to claim 16, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B , taken together with the nitrogen and carbon atoms to which they are attached respectively, form a 5-7 membered, saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more additional heteroatoms O, S, SO, SO2, N, NH or NR3; X is either O or S; Y is a direct bond, straight or branched chain alkyl of C, -C6 or a straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkeniion is optionally substituted at one or more positions with amino halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl straight or branched chain of C3-C6, and C, -C4 connecting alkyl wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring containing 1-6 heteroatoms is independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl are optionally substituted with C, -C, alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino , alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R ,, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, alkyl straight or branched chain of 0, -Cg and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and cycloalkyl of C3 -C8; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, straight or branched chain alkenyl of C2- C6, wherein the alkyl or alkenyl is substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine.
21. 21. The pharmaceutical composition according to claim 20, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.
22. 22. The pharmaceutical composition according to claim 16, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, SO2, NH or NR3; X is either O or S; Y is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C4, alkenyl or alkynyl straight or branched chain of C3-C4, and C, -C4 connecting alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with oxygen to form a carbonyl, or where any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C4 alkyl, C2-C4 alkenyl, or hydroxy; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, straight or branched chain of C, -Cg and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and cycloalkyl of C3- C8; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2 -C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine.
23. 23. The pharmaceutical composition according to claim 22, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl and phenyl.
24. 24. The pharmaceutical composition according to claim 16, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F and G are independently CH2, O, S, SO, SO2, NH, and NR3; X is either O or S; Y is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-Cß, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C4, alkenyl or C3-C4 alkynyl, and C, -C4 connecting alkyl wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents, wherein the size of the single ring is 5-8. members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, straight or branched chain alkenyl of C2-Cß, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to forming a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C2 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R, is a single pair of electrons and R2 is selected from the group consisting of Ar, cycloalkium of C3-C8, alkyl of straight or branched chain of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and cycloalkyl of C3 -C8; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine, and piperazine.
25. 25. The pharmaceutical composition according to claim 24, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.
26. 26. The pharmaceutical composition according to claim 16, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula IV or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3; X is either O or S; Y is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C4, alkenyl or alkynyl straight or branched chain of C3-C4, and C, -C4 connecting alkyl, wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-Cß; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkion, C5-C7 cycloalkenyl, hydroxy, carbonyloxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C4 alkyl, C2-C4 alkenyl, or hydroxy; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or where any carbon atom of! alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S; and U is either O or N, with the proviso that: when U is O, then R, is a single pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, straight or branched chain of C, -C6 and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and cycloalkyl of C3- C8; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2 -C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine.
27. 27. The pharmaceutical composition according to claim 26, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl and phenyl.
28. 28. The pharmaceutical composition according to claim 26, characterized in that: n is 1 or 2; And it is (CH2) 2 or a direct link; Z is CH; C is 3-pyridyl, 4-methoxyphenyl, phenyl or 2-phenylethyl; D is hydrogen, phenyl or 2-phenylethyl; R, is hydrogen; and R 2 is 2-methylbutyl, 1,1-dimethylpropyl, cyclohexyl, 1-adamantyl, or phenyl.
29. 29. The pharmaceutical composition according to claim 28, characterized in that the compound is selected from the group consisting of: 3- (3-pyridyl) -1-propyl-2S-1 - [(2-methylbutyl) carbamoyl] -pyrididine-2-carboxylate; 3- (3-Pyridyl) -1-propyl-2S-1 - [(1 ', 1'-Dimethylpropyl) carbamaoyl] pyrrolidine-2-carboxylate; 3- (3-Pyridyl) -1-propyl-2S-1 - [(cyclohexyl) thiocarbamoyl] -pyrrolidine-2-carboxylate; and pharmaceutically acceptable salts, esters and solvates thereof.
30. 30. The pharmaceutical composition according to claim 16, characterized in that the urea or carbamate of an N-linked heterocyclic thioester is a compound of the formula V or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N, or S; Y is a straight, straight or branched chain alkyl of C, -C6, straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, amino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or S02; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkeniion is optionally substituted at one or more positions with amino halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or S02; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 ayenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, mino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either substituted or unsubstituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamino is optionally oxidized to a corresponding N-oxide; and A, B, R1, R2, U, W and X are as defined otherwise in claim 20 above.