MXPA00011850A - Small molecule pipecolic acid derivative hair growth compositions and uses - Google Patents

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using pipecolic acid derivatives.

Description

COMPOSITIONS FOR HAIR GROWTH OF SMALL MOLECULE PIPECOLIC ACID DERIVATIVES AND USE OF MOLECULES SAME RELATED REQUESTS This application is a continuation in part of the patent application of E.U.A. No. 08 / 869,426, filed June 4, 1997, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to pharmaceutical compositions and methods for treating alopecia and to promote hair growth using pipecolic acid derivatives.

DESCRIPTION OF THE RELATED TECHNIQUE Hair loss occurs in a variety of situations. These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systemic disorders such as nutrition disorders and internal secretion disorders. The mechanisms that cause hair loss are very complicated, but in some cases it can be attributed to aging, genetic disposition, activation of male hormones, loss of blood supply to hair follicles, and abnormalities of the scalp. The immunosuppressive drugs FK506, rapamycin and cyclosporin are well known as potent T cell-specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al, J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al, J. Invest. Dermatol., 1995, 104, 523- 525) and cyclosporin (Iwabuchi et al, J. Dermatol, Sci. 1995, 9, 64-69) stimulate hair growth in a dose-dependent manner. It is known that a form of hair loss, alopecia aereata, is associated with autoimmune activities; Therefore, it is expected that topically administered immunomodulatory compounds demonstrate efficacy in treating that type of hair loss. The hair growth stimulating effects of FK506 have been the subject of an international patent application covering FK506 and structures related thereto for stimulation of hair growth (Honbo et al, EP 0 423 714 A2). Honbo et al. describe the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.

The effects of hair growth and revitalization of FK506 and related agents are described in many US patents. (Goulet et al, U.S. Patent No. 5,258,389, Luly et al, U.S. Patent No. 5,457,111, Goulet et al, U.S. Patent No. 5,532,248, Goulet et al, U.S. Patent No. 5,189,042, and Ok et al, U.S. Patent No. 5,208,241, Rupprecht et al, U.S. Patent No. 5,284,840, Organ et al, U.S. Patent No. 5,284,877). These patents claim compounds related to FK506. Although they do not claim hair revitalization methods, they describe the known use of FK506 for effective hair growth. Similar to FK506 (and the variations claimed in the Honbo et al patent), the compounds claimed in those patents are relatively large. In addition, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which the efficacy of FK506 is well known. Other patents of E.U.A. describe the use of cyclosporin and related compounds for hair revitalization (Hauer et al, U.S. Patent No. 5,342,625, Eberle, U.S. Patent No. 5,284,826, Hewitt et al, U.S. Patent No. 4,996,193). These patents also refer to compounds useful for treating autoimmune diseases, and cite the known use of cyclosporin and related immunosuppressant compounds for hair growth.

However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects.

Accordingly, there is a need for non-immunosuppressive, small molecule compounds that are useful as hair revitalizing compounds. Hamilton and Steiner describe in U.S. Patent No. 5,614,547 novel pyrrolidine carboxylate compounds that bind to immunofilin FKB12 and stimulate nerve growth, but lack immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressive compounds promote hair growth with an efficiency similar to FK506. However, their new small molecule structure and their non-immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a method for treating alopecia or to promote hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative. The present invention further relates to a pharmaceutical composition comprising: (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier. The piccoleic acid derivatives that are used in the methods and pharmaceutical compositions of the invention, include immunosuppressive and non-immunosuppressive compounds that have an affinity for FKBP type immunophilins, particularly FKBP12. The non-immunosuppressive compounds, as their name suggests, do not exert any important immunosuppressive activity BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a photograph of mice treated with a vehicle after six weeks. Figure 1 shows that less than 3% of the shaved area is covered with new hair that grew when the vehicle was administered (control). Figure 2 is a photograph of mice treated with 10 μM of GPl 1044, after six weeks. Figure 2 shows that 90% of the shaved area is covered with new hair that grew when GPl 1044 was administered. Figure 3 is a bar graph describing hair growth evaluations of non-shaved animals and shaved animals treated with a vehicle. , GPl 1144 (1 μM, 3 μM and 10 μM), and ligands of neurokinmunophilin FKBP of related pipecolic acid derivative, GPl 1116 (1 μM and 10 μM) and GPl 1102 (1 μM and 3 μM). Figure 4 is a bar graph describing the relative hair growth rates for C57 Black 6 mice treated with a vehicle, FK506, and related FKBP neuroimmunophilin ligands, 14 days after treatment with each identified compound. Figure 4 demonstrates the remarkable initial hair growth promoted by FKBP neuroimmunophilin ligands.

DETAILED DESCRIPTION OF THE INVENTION Definitions "Alopecia" refers to deficient hair growth and complete or partial loss of hair, including without limitation androgenic alopecia (male hereditary baldness), toxic alopecia, alopecia senilis, alopecia aereata, peeled alopecia and tricitilomania. 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 fact that the proliferation of cells ceases. This results in an early emergence of the catagen phase, and consequently a large number of hair in the telogen phase, during which the follicles detach from the dermal papillae, and the hair falls out. Alopecia has a number of etiologies, including genetic factors, aging, local and systematic diseases, febrile conditions, mental tensions, hormonal problems and drug side effects. "GPl 1044" refers to compound 4. "GPl 1102" refers to 4-phenyl-1- (3-phenylpropyl) butyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate. "GPi 1116" refers to 1-phenethyl-3-phenylpropyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate. "GP1206" refers to a compound of 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 stereosisomers that are mirror images that are not overlapping with each other. "Diastereoisomers" are stereoisomers that are not images identical to one another. "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 that possesses the desired pharmacological activity, and which is not biologically or otherwise undesirable. A salt, ester or solvate can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, alcamforate, camphorsulfonate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphtylate, 2-naphthalenesulfonate, 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, metalalcalinoterne 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, usina, and so on. Also, basic groups containing nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfate, long chain halides, such as decyl chloride, lauryl, myristyl and stearyl, bromides and iodides; aralkyl halides, such as benzyl bromide and phenethyl; and others. Soluble or dispersible products are obtained in this way in water or in oil. "Hair cycle" refers to the life cycle of hair follicles, and includes three phases: (1) the anagen phase, the period of active hair growth which, in regards to hair of the scalp, lasts for three to five years; (2) the catagen phase, the period when the growth stops and the follicle atrophies, which, in regard to the hair of the scalp, lasts from one to two weeks; and (3) the telogen phase, the resting period when the hair separates progressively and finally falls, which, in regard to the hair of the scalp, lasts three to four months. Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent is in the catagen phase, and the rest is in the telogen phase. In the telogen phase, the hair has a uniform diameter and a slightly bulbous, non-pigmented root. In contrast, in the anagen phase, the hair has a large bulb of color at its root. "Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating, or revitalizing hair germination. Alopecia treatment "refers to: (i) avoiding alopecia in an animal, which may be predisposed to alopecia, and / or (ii) inhibiting, retarding or reducing alopecia, and / or (iii) promoting growth of the hair. hair, and / or (v) prolonging the anagen phase of the hair cycle, and / or (v) converting hair from hair to growth as terminal hair.The terminal hair is coarse, pigmented, long hair, in which the bulb The hair follicle is deeply seated in the dermis, hair on the other hand, is thin, thin, non-pigmented short hair, in which the bulb is located superficially in the dermis. Hair changes from the terminal type to the hair type.

METHODS OF THE PRESENT INVENTION The present invention relates to a method for treating alopecia or promoting hair growth in an animal, comprising administering to said animal an effective amount of a pipecolic acid derivative. The method of the invention is particularly useful for the treatment of male pattern alopecia, alopecia senilis, alopecia aereata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia which It results from systemic disorders such as nutrition 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 pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and (i) a pharmaceutically acceptable carrier.

Pipecolic Acid Derivatives The pipecolic acid derivatives which are used in the methods and pharmaceutical compositions of the present invention are low molecular weight small molecule compounds, which have an affinity for FKBP type immunophilins, such as FKBP12. It has been found that when a pipecolic acid derivative binds to an FKBP-type immunophilin, it inhibits the prolyl-peptidyl cis-trans isomerase activity, or rotamase of the binding protein. Unexpectedly, it has also been discovered that the compounds stimulate hair growth. These rotamase inhibitor compounds can be immunosuppressants or non-immunosuppressants. Next, examples of useful compounds are described.

FORMULA I An exemplary pipecolic acid derivative is a compound of formula or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: m is 0-3; A is CH2, O, NH or N- (C4 alkyl); B and D are independently C5-C substituted cycloalkyl Ar, straight or branched chain C-Cß alkyl or straight or branched chain C 2 -C β alkenyl, substituted Cs-C 7 cycloalkenyl, straight or branched chain Ci-Cß alkyl, alkenyl Direct or branched chain C2-C6, straight or branched chain substituted Ci-Cß Ar alkyl, or straight or branched chain C 2 -C 6 alkenyl, wherein in each case, one or two carbon atoms of said alkyl or alkenyl may be replaced by one or two heteroatoms independently selected from the group consisting of oxygen, sulfur, SO and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, straight or branched chain alkyl, or straight or branched chain C2-C6 alkenyl; and T is C5-C7 cycloalkyl Ar substituted at positions 3 and 4, with substituents independently selected from the group consisting of hydrogen, hydroxy, 0- (C 1 -C 4 alkyl), 0- (C 2 -C 4 alkenyl), and carbonyl; Ar is selected from the group consisting of 1 -naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, heterocyclic ring systems , monocyclic and bicyclic, with individual ring sizes of 5 or 6 containing in one or both rings a total of 1-4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar contains 1-3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, straight or branched chain Ci-Cs alkyl, straight or branched chain C2-CT alkenyl, - (straight or branched chain C -? - C4 alkyl), O- (straight or branched chain C2-C4 alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl and phenyl; L is hydrogen or U; M is either oxygen or CH-U, provided that if L is hydrogen, then M is CH-U, or if M is oxygen then L is U; U is hydrogen, 0- (straight or branched chain C 1 -C 4 alkyl), O- (straight or branched chain C1-C4 alkenyl), straight or branched chain Ci-C3 alkyl, straight or branched chain C2-C6 alkenyl, C5-C cycloalkyl, C5-C7 cycloalkenyl substituted with C? -C4 alkyl direct or branched chain or C2-C4 alkenyl straight or branched chain, (C? -C4 alkyl or C2-C4 alkenyl) -Ar, or Ar; J is hydrogen, C1 or C2 alkyl or benzyl; K is straight or branched chain C? -C alkyl, benzyl or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring, which is substituted with oxygen, sulfur, SO, or SO2; and said pipecolic acid derivative has an affinity for FKBP type immunophilins. Table 1 shows representative species of formula I.

TABLE 1 Compound n m B D L 1 2 0 3-phenyl-3- (3-pyridyl) - Phenyl propyl propyl 2 2 0 3-phenyI- 3- (2-pyridyl) - Phenyl propyl propyl 3 2 0 3-phenyl- 2- (4- Phenyl propyl methoxyphenyl) ethyl 4 2 0 3-phenyl-3-phenylepropyl Phenyl propyl 5 2 0 3-phenyl-3-phenylpropyl 3,4,5-propyl trimethoxy phenyl 6 2 0 3-phenyl-2- (3-pyridyl) -3,4,5-propyltrimethoxy-phenyl 7 2 0 3-phenyl-3- (2-pyridyl) -3,4,5-propyl propyl trimethoxy phenyl TABLE 1 (CONTINUED) Compound n m B D 8 2 0 3-phenyl-3- (4-methoxy-3,4,5-propyl phenyl) propyl trimethoxyphenyl 9 2 0 3-phenyl-3- (3-pyridyl) -3-propyl propyl isopropoxyphenyl FORMULA II The patent of E.U.A. No. 5,330,993, incorporated herein by reference, discards an exemplary pipecolic acid derivative of formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A is O, NH, or N- (C2-C4 alkyl); B is hydrogen, CHL-Ar, straight or branched chain C1-C6 alkyl, straight or branched chain C2-C2 alkenyl, Cs-C cycloalkyl, C5-C cycloalkenyl, substituted C1-C1 Ar alkyl, C2-C6 alkenyl, or Where L and Q are independently hydrogen, straight or branched chain C 1 -C 6 alkyl or straight or branched chain C 2 -C 6 alkenyl; and T is Ar or C5-C7 cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O- (C-? -C alkyl), 0- (C2-C4 alkenyl) , and carbonyl; Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having 1-3 substituents selected from independently of the group consisting of hydrogen, halogen, hydroxy, nitro, CF3, straight or branched chain C6-6 alkyl, straight or branched chain C2-C6 alkenyl, O- (straight or branched chain C2-C alkyl) ), O- (straight or branched chain C2-C4 alkenyl), O-benzyl, O-phenyl, amino and phenyl. D is hydrogen or U; E is oxygen or CH-U, provided that if D is hydrogen, then E is CH-U, or if E is oxygen, then D is U; U is hydrogen, O- (straight or branched chain CrC alkyl), 0- (straight or branched chain C2-C4 alkenyl), straight or branched chain C-? -C6 alkyl, straight or branched chain C2-C2 alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C-alkyl? Direct or branched chain C4 or straight or branched chain C2-C4 alkenyl, 2-indolyl, 3-indolyl, (C? -C alkyl or C2-C4 alkenyl) -Ar, or Ar; J is hydrogen, alkyl, CrC2, or benzyl; K is straight or branched chain C 1 -C 4 alkyl, benzyl or cyclohexylethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or S02.

FORMULA III A preferred pipecolic acid derivative is a compound of formula or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 2; D is phenyl, methoxy, 2-furyl, or 3,4,5-trimethoxyphenyl; and B is benzyl, 3-phenylpropyl, 4- (4-methoxyphenyl) butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3- (3-indolyl) ) propyl or 4- (4-methoxyphenyl) butyl; Whenever: when D is phenyl, then B is benzyl, 3-phenylpropyl, 4- (4-methoxyphenyl) butyl, 4-phenylbutyl, phenethyl or 4-cyclohexyl butyl; when D is methoxy, B is benzyl, 4-cyclohexyl butyl, 3-cyclohexylpropyl or 3-cyclopentylpropyl; when D is 2-furyl, then B is benzyl; and when D is 3,4,5-trimethoxyphenyl, then B is 4-cyclohexyl butyl, 3-phenoxybenzyl, 4-phenylbutyl, 3- (3-indolyl) propyl or 4- (4-methoxyphenyl) butyl. Table II shows representative species of formula TABLE II TABLE II (CONTINUED) FORMULA IV The pipecolic acid derivative can also be a compound of formula IV or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; J and K, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatoms selected from the group consisting of O, S, SO, SO2, N, NH and NR; R is straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C9 cycloalkyl, Cd-C7 cycloalkenyl, or Ar-i, wherein R is unsubstituted or substituted with one or more selected substituents independently of the group consisting of halogen, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain C 1 -C 6 alkyl, straight or branched chain C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, alkenyloxy C2-C4, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2; Ar-i and Ar 2 are independently an alicyclic or aromatic, mono-, bi-, or tricyclic, carbo-, or heterocyclic ring; wherein the size of the individual ring is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N, and S; A, B, D, L, M, and m are as defined in formula I above; and said pipecolic acid derivative has an affinity for FKBP type immunophilins. All compounds of formulas I-IV possess asymmetric centers and therefore 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 suitable stage of the synthesis, or solving the compounds of formulas I-IV. It is understood that the compounds of formulas I-IV encompass individual stereoisomers, as well as mixtures (racemic or non-racemic) of stereoisomers. Preferably, S- stereoisomers are used in the pharmaceutical compositions and methods of the present invention.

Affinity for FKBP12 The compounds that are used in the methods and pharmaceutical compositions of the invention have an affinity for the binding protein FKBP06, particularly FKBP12. The inhibition of prolylpeptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of this affinity.

Test procedure K1 The inhibition of the peptidylprolyl activity of the compounds used in the methods and pharmaceutical compositions of the invention can be evaluated by known methods described in the literature (Harding et al., 1989). , 341: 758-760; Holt et al, J. Am. Chem. Soc, 115: 9923-9938). These values are obtained as apparent Ki's and are presented for representative compounds in Table III. The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a coupled chymotrypsin assay, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in the first order rate constant, as a function of concentration of the inhibitor to produce the apparent K i values. 950 ml of ice-cold assay pH buffer (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 to a plastic tube. , 1 mM dithiothreitol), 25 ml of chymotrypsin (50 mg / ml in 1 mM HCl)) and 10 ml of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 ml of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg / ml in 2.35 mM LiCl in trifluoroethanol). The absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer, and the rate constants are determined from the absorbance versus time data records.

TABLE III In vitro test results - Formulas I -111 Compound K? (μM) 10 1.5 13 0.35 14 1.1 15 0.4 16 80 17 6 18 20 19 35 20 3 21 0.04 22 0.018 23 0.019 24 0.017 25 0.013 Route of administration To effectively treat alopecia or promote hair growth, the compounds which are used in the methods and pharmaceutical compositions of the invention should rapidly 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 in suitable ointments containing the suspended or dissolved compounds in, for example, mixtures with one or more of the following substances: 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 substances: mineral oil, sorbitan monostearate, polysorbate 60, wax cetyl ester, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Other routes of administration known in the pharmaceutical arts are also contemplated for this invention.

Dosage Dosage levels in the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The specific dosage level for any particular patient will vary depending on a variety of factors, including the activity of the specific compound used; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide a useful guide to suitable dosages for administration to the patient. Studies in animal models are also useful. Considerations for determining appropriate dose levels are well known in the art. The compounds can be administered with other hair revitalizing agents. The specific dose levels for the other hair revitalizing agents will depend on the previously established factors and the effectiveness of the drug combination.

EXAMPLES The following examples are illustrative of the present invention and are not intended to be limitations thereof. Unless indicated otherwise, all percentages are based on 100% by weight of the final composition.

EXAMPLE 1 In vivo hair generation tests with C57 Black 6 mice Experiment A: C57 Black 6 mice were used to demonstrate the hair revitalization properties of pipecolic acid derivative GPl 1044 (compound 4) as well as FKBP neuroinmunophilin ligands of related pipecolic acid derivative, GPl 1102 and GPl 1116. To C57 mice Black 6, approximately 7 weeks old, was shaved an area of approximately 5.08 by 5.08 cm from its hind legs to remove all existing hair. Care was taken not to cut or cause abrasion to the underlying dermal layers. The animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to Figures 1 and 2, four animals were treated by topical administration with 20% propylene glycol vehicle (Figure 1), and seven animals were treated by topical administration with 10 pM of GPl 1044 (Figure 2). The animals were treated with vehicle or GPl 1044 every 48 hours (3 applications in total over the course of 5 days) and the hair growth was allowed to continue for 6 weeks. Hair growth was quantified by the percentage of shaved area covered by new hair growth during this period. Figure 1 shows that animals treated with vehicle presented only a small amount of hair growth in parts or tufts, with less than 3% shaved area covered with new growth. In contrast, Figure 2 shows that animals treated with 10 pM of 1044 GPl showed dramatic hair growth, covering as much as 50% of the shaved area in some animals. Figure 3 compares the hair growth score of shaved animals with the hair growth scores of shaved animals treated with a vehicle and GPl 1044 (1 pM, 3 pM and 10 pM), as well as FKBP ligands of neuroinmunophilin GPl 1116 (1 pM and 10 pM) and GPl 1102 (1 pM and 3 pM).

Experiment B Six C57 black mice were used to demonstrate the hair revitalizing properties of the FKBP ligands of neuroimmunofilin. Six C57 black mice, 55 to 75 days old, were shaved an area of approximately 5.08 cm x 5.08 cm in the back quarters of their body to remove all existing hair. Care was taken not to cut lightly 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 a vehicle, FK506, or a neurokinmunophilin FKBP ligand (GPl 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area. The animals were treated three times a week, and hair growth was evaluated 14 days after the start of treatment. Hair growth was quantified by the percentage of shaved area covered by new hair growth, as recorded by the blind method by an observer, on a scale of 0 (no growth) to five (new growth of full hair in shaved area). ). Figure 4 shows that after 14 days, the animals treated with vehicle showed the start of growth in small tufts. In contrast, animals treated with one of the small molecule, low molecular weight neuroimmunophilin FKBP ligands showed dramatic hair growth.

EXAMPLE 2 A lotion comprising the following composition can be prepared.

In 95% ethanol there is added a pipecolic acid derivative, α-tocopherol acetate, ethylene oxide (40 mol) adducts of hardened castor oil, perfume and a dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a clear liquid lotion.

You can apply 5 ml of the lotion once or twice a day to a place that has marked baldness or alopecia.

EXAMPLE 3 A lotion comprising the following composition can be prepared.

In 95% ethanol there is added a pipecolic acid derivative, hinochitol, ethylene oxide (40 mol) adducts of hardened castor oil, perfume, and a colorant. The resulting mixture is stirred, and purified water is added to the mixture to obtain a clear liquid lotion. The lotion can be applied by spraying one to four times a day to a place that has marked baldness or alopecia.

EXAMPLE 4 An emulsion can be prepared from phase A and phase B having the following compositions.

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

EXAMPLE 5 A cream can be prepared from phase A and phase B having the following compositions.

Phase A is heated and melted, and maintained at 70 ° C. Phase B is added in phase A and the mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream. The cream can be applied one to four times a day to a place that has baldness or marked alopecia.

EXAMPLE 6 A liquid comprising the following composition can be prepared.

In ethanol, polyoxyethylene butyl ether, propylene glycol, castor oil hardened with polyoxyethylene, a pipecolic acid derivative, and perfume are added. The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid. The liquid can be applied one to four times a day to a place that has baldness or marked alopecia.

EXAMPLE 7 A shampoo comprising the following composition can be prepared.

In 69.7 of purified water are added 5.0 g of sodium lauryl sulfate, 5.0 g of triethanolamine lauryl sulfate, 6.0 g of betaine lauryldimethylaminoacetate. Then a mixture is obtained by adding 5.0 g of a pipecolic acid derivative, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, followed by stirring, and 0.3 g of perfume are added consecutively. The resulting mixture is heated and subsequently cooled to obtain a shampoo. The shampoo can be used on the scalp once or twice a day.

EXAMPLE 8 A patient is suffering from senile alopecia. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.

EXAMPLE 9 A patient is suffering from male hereditary alopecia. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.

EXAMPLE 10 A patient is suffering from alopecia areata. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.

EXAMPLE 11 A patient is suffering from hair loss caused by skin lesions. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.

EXAMPLE 12 A patient is suffering from hair loss caused by tumors. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, can be administered to the patient. It is expected that increased hair growth occurs after treatment.

EXAMPLE 13 A patient is suffering from hair loss caused by a systemic disorder, such as a nutritional disorder or an internal secretion disorder. A pipecolic acid derivative or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.

EXAMPLE 14 A patient is suffering from hair loss caused by chemotherapy. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.

EXAMPLE 15 A patient is suffering from hair loss caused by radiation. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment. It will be obvious that the invention thus described may vary in many ways. Said variations should not be considered as a deviation from the spirit and scope of the invention and it is intended that said modifications be included within the scope of the following claims.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - A method for treating alopecia or promoting hair growth in an animal, comprising administering to said animal an effective amount of a piccoleic acid derivative of formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A is CH2, O, NH, or N- (CrC alkyl); B and D are independently Ar, straight or branched chain alkyl of C Cß or straight or branched chain alkenyl of C 2 -C 6 substituted with C 5 -C 7 cycloalkyl, straight or branched chain alkyl of C-pCβ or straight chain alkenyl or branched C2-Cd substituted with C5-C7 cycloalkenyl, or straight or branched chain alkyl of Ci-Cβ or straight or branched chain alkenyl of C2-Cβ substituted with Ar, wherein in each case, one or two atom (s) carbon of said alkyl or alkenyl can be substituted with one or two heteroatom (s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution standards, or wherein Q is hydrogen, straight or branched chain alkyl of Ci-Cß or straight or branched chain alkenyl of C2-Cß; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, 0- (Cr C alkyl), O- (C2-C alkenyl), and carbonyl; Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, heterocyclic ring systems monocyclic and bicyclic with individual ring sizes of 5 or 6 containing in either or both rings a total of 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein Ar contains 1-3 substituent (s) independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, straight or branched chain alkyl of C? -C6, straight or branched chain alkenyl of C2-C6, 0- (straight or branched chain alkyl of C? -C4), 0- (straight or branched chain alkenyl of C2-C4), O-benzyl, O-phenyl, amine, 1, 2- methylenediox, carbonyl, and phenyl; L is either hydrogen or U; M is either oxygen or CH-U, provided that if L is hydrogen, then M is CH-U, or if M is oxygen then L is U; U is hydrogen, O- (straight or branched chain alkyl of CrC4), 0- (straight or branched chain alkenyl of C2-C), straight or branched chain alkyl of CI-CT, straight or branched chain alkenyl of C2-C6, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with straight or branched chain alkyl of C -? - C4 or straight or branched chain alkenyl of C2-C4, (C -? - C alkyl or C2-C alkenyl) -Ar, or Ar; J is hydrogen, C1 or C2 alkyl, or benzyl; K is straight or branched chain alkyl of C? -C4, benzyl or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or S02; n is 0-3; and said pipecolic acid derivative has an affinity with FKBP type immunophilins.

2. A method for treating alopecia or promoting hair growth in an animal, comprising administering to said animal an effective amount of a pipecolic acid derivative of formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A is O, NH, or N- (C? -C4 alkyl); B is hydrogen, CHL-Ar, straight or branched chain alkyl of Ci-Cß, straight or branched chain alkenyl of C2-C6, C?-C7 cycloalkyl, C5-C7 cycloalkenyl) Ci-Cß alkyl or C2-C6 alkenyl substituted with Ar, or wherein L and Q are independently hydrogen, straight or branched chain alkyl of C? -C6, or straight or branched chain alkenyl of C2-C6; and T is C5-C7-ary-cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O- (C-? -C alkyl), O- (C2-C alkenyl) ), and carbonyl; Ar is selected from the group consisting of 1 -naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent (s) independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, CF3, straight or branched chain alkyl of Ci-Cβ, straight or branched chain alkenyl of C2-C6, O- (straight or branched chain alkyl of CrC), O- (straight or branched chain alkenyl of C2-C), O-benzyl, O-phenyl, amino, and phenyl. D is hydrogen or U; E is oxygen or CH-U, provided that if D is hydrogen, then E is CH-U, or if E is oxygen, then D is U; U is hydrogen, 0- (straight or branched chain alkyl of C 1 -C 4), O- (straight or branched chain alkenyl of C 2 -C 4), straight or branched chain alkyl of Ci-Ce, straight or branched chain alkenyl of C2-C6, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with straight or branched chain alkyl of C1-C4 or straight or branched chain alkenyl of C2-C4, 2-indolyl, 3-indolyl, (alkyl) of C -? - C4o C2-C4 alkenyl) -Ar, or Ar; J is hydrogen, Ci or C2 alkyl, or benzyl; K is straight or branched chain alkyl of benzyl or cyclohexylethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2.

3. A method for treating alopecia or promoting hair growth in an animal, comprising administering to said animal an effective amount of a pipecolic acid derivative of formula III or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 2; D is phenyl, methoxy, 2-furyl, or 3,4,5-trimethoxyphenyl; and B is benzyl, 3-phenylpropyl, 4- (4-methoxyphenyl) butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3- (3-indoI) I) propyl, or 4- (4-methoxyphenyl) butyl; provided that when D is phenyl, then B is benzyl, 3-phenylpropyl, 4- (4-methoxyphenyl) butyl, 4-phenylbutyl, phenethyl, or 4-cyclohexylbutyl; when D is methoxy, then B is benzyl, 4-cyclohexyl butyl, 3-cyclohexylpropyl, or 3-cyclopentylpropyl; when D is 2-furyl, then B is benzyl; and when D is 3,4,5-trimethoxyphenyl, then B is 4-cyclohexyl butyl, 3-phenoxybenzyl, 4-phenylbutyl, 3- (3-indole) propyl, or 4- (4-methoxyphenyl) butyl.

4. A method for treating alopecia or promoting hair growth in an animal comprising administering to said animal an effective amount of a pipecolic acid derivative of formula IV or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is C, N, or S; J and K, taken together with V and the carbon atom to which they are attached respectively, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom (s) selected from the group consisting of of O, S, SO, SO2, N, NH, and NR; R is either straight or branched chain alkyl of C1-C9, straight or branched chain alkenyl of C2-C9, cycloalkyl of C3-C9, cycloalkenyl of C5-C7, or Ar-i, wherein R is either not substituted or substituted with one or more substituent (s) independently selected from the group consisting of halogen, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of C Cß, straight or branched chain alkenyl of C2 -C6, C? -C alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2; An and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom (s) independently selected from the group consisting of O, N, and S; A, B, D, L, M, and m are as defined in claim 1 above; and said pipecolic acid derivative has an affinity with FKBP type immunophilins.

5. A pharmaceutical composition comprising: (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal, wherein the pipecolic acid derivative is a compound of formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A is CH2, O, NH, or N- (CrC alkyl); B and D are independently Ar, straight or branched chain alkyl of C Cß or straight or branched chain alkenyl of C2-Cβ substituted by C5-C7 cycloalkyl, straight or branched chain alkyl of C Cß or straight chain alkenyl or branched C2-Cβ substituted with C5-C7 cycloalkenyl, or straight or branched chain alkyl of Ci-Cβ or straight or branched chain C2-C6 alkenyl substituted with Ar, wherein in each case, one or two atom ( s) of carbon of said alkyl or alkenyl can be substituted with one or two heteroatom (s), independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O- (Cr C4 alkyl), 0- (C2-C4 alkenyl) , and carbonyl; Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic rings with individual ring sizes of 5 or 6 containing in either or both rings a total of 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein Ar contains 1-3 substituent (s) independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxymethyl, nitro, CF 3, tr? fluoromethoxy, straight or branched chain alkyl of Ci-Cß, straight chain alkenyl or branched C2-C6, O- (straight or branched chain alkyl of C? -C), 0- (straight or branched chain alkenyl of C2-C4), O-benzyl, O-phenyl, amino, , 2-methylenedioxy, carbonyl, and phenyl; L is either hydrogen or U; M is either oxygen or CH-U, provided that if L is hydrogen, then M is CH-U, or if M is oxygen then L is U; U is hydrogen, O- (straight or branched chain alkyl of C? -C), 0- (straight or branched chain alkenyl of C2-C4), straight or branched chain alkyl of C1-C6, straight chain alkenyl or branched of C2-C6, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with straight or branched chain alkyl of C? -C or straight or branched chain alkenyl of C2-C, (C1-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar; J is hydrogen, C1 or C2 alkyl, or benzyl; K is straight or branched chain alkyl of C? -C, benzyl or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2; n is 0-3; and said pipecolic acid derivative has an affinity with FKBP type immunophilins; and (ii) a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising: (1) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal, wherein the pipecolic acid derivative is a compound of formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A is O, NH, or N- (C 1 -C 4 alkyl); B is hydrogen, CHL-Ar, straight or branched chain alkyl of C? -C6, straight or branched chain alkenyl of C2-C6, cycloalkyl of C5-C7, cycloalkenyl of C5-C7, alkyl of C? -C6 or C -C6 alkenyl substituted with Ar, or wherein L and Q are independently hydrogen, branched straight chain alkyl of CrC6, or straight or branched chain alkenyl of C2-C6; and T is C5-C7-ary-cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, 0- (C? -C alkyl), 0- (C2-C4 alkenyl) , and carbonyl; Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent (s) independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, CF3, straight or branched chain alkyl of C -? - C6, straight or branched chain alkenyl of C2-C6, O- (branched straight chain alkyl of C? -C4), O- (straight or branched chain alkenyl of C2-C4), O-benzyl, O-phenyl, amino, and phenyl. D is hydrogen or U; E is oxygen or CH-U, provided that if D is hydrogen, then E is CH-U, or if E is oxygen, then D is U; U is hydrogen, O- (straight or branched chain alkyl of C 1 -C 4), O- (straight or branched chain alkenyl of C 2 -C 4), straight or branched chain alkyl of Ci-Ce, straight chain alkenyl or C2-C6 branched chain, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with branched straight chain C4 alkyl or straight or branched chain alkenyl of C2-C4, 2-indolyl, 3-indolyl, C C4 or C2-C4 alkenyl) -Ar, or Ar; J is hydrogen, C1 or C2 alkyl, or benzyl; K is straight or branched chain alkyl of C 1 -C 4, benzyl or cyclohexylethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or S02; and (ii) a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising: (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal, wherein the pipecolic acid derivative is a compound of formula III or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 2; D is phenyl, methoxy, 2-furyl, or 3, 4, 5-trimethoxyphenyl; and B is benzyl, 3-phenylpropyl, 4- (4-methoxyphenyl) butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3- (3-phenyl); n-tolyl) propyl, or 4- (4-methoxyphenyl) butyl; provided that when D is phenyl, then B is benzyl, 3-phenylpropyl, 4- (4-methoxy-phenyl) butyl, 4-phenylbutyl, phenethyl, or 4-cyclohexyl butyl; when D is methoxy, then B is benzyl, 4-cyclohexyl butyl, 3-cyclohexylpropyl, or 3-cyclopentylpropyl; when D is 2-furyl, then B is benzyl; and when D is 3, 4, 5-trimethoxyphenyl, then B is 4-cyclohexybutyl, 3-phenoxybenzyl, 4-phenylbutyl, 3- (3-indolyl) propyl, or 4- (4-methoxyphenyl) butyl; and (i) a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising: (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal, wherein the pipecolic acid derivative is a compound of formula IV or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is C, N, or S; J and K, taken together with V and the carbon atom to which they are attached respectively, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom (s) selected from the group consisting of of O, S, SO, SO2 N, NH, and NR; R is either straight or branched chain alkyl of C1-C9, straight or branched chain alkenyl of C2-Cg, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, or An, wherein R is either unsubstituted or substituted with one or more substituents (s) independently selected from the group consisting of halogen, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of Ci-Cß, straight or branched chain alkenyl of C2- C6, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2; Ar? and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatoms (s) independently selected from the group consisting of O, N, and S; A, B, D, L, M, and m are as defined in claim 5 above; and (i) a pharmaceutically acceptable carrier.