WO1999062483A1

WO1999062483A1 - Pipecolic acid derivative hair growth compositions and uses

Info

Publication number: WO1999062483A1
Application number: PCT/US1998/011242
Authority: WO
Inventors: Gregory S. Hamilton; Joseph P. Steiner
Original assignee: Gpi Nil Holdings, Inc.
Priority date: 1998-06-03
Filing date: 1998-06-03
Publication date: 1999-12-09
Also published as: JP2002516839A; CA2333698A1; AU7716798A; AU761083B2; EP1083872A1

Abstract

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

Description

PIPECOLIC ACID DERIVATIVE HAIR GROWTH COMPOSITIONS AND USES

This application is a continuation-in-part of U.S. Patent Application No. 08/869,426, filed on June 4, 1997, the entire contents of which are herein incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of Invention

2. Description of Related Art

Hair loss occurs in a variety of situations. These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systematic disorders such as nutritional disorders and internal secretion disorders. The mechanisms causing hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.

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

FK50 and related agents are disclosed in many U.S. patents (Goulet et al . , U.S. Patent No. 5,258,389; uly et al . , U.S. Patent No. 5,457,111; Goulet et al . , U.S. Patent No. 5,532,248; Goulet et al . , U.S. Patent No. 5,189,042; and Ok et al . , U.S. Patent No. 5,208,241; Rupprecht et al . , U.S. Patent No. 5,284,840; Organ et al . , U.S. Patent No. 5,284,877). These patents claim FK506 related compounds. Although they do not claim methods of hair revitalization, they disclose the known use of FK506 for effecting hair growth. Similar to FK506 (and the claimed variations in the Honbo et al . patent), the compounds claimed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which FK506's efficacy is well known.

Other U.S. patents disclose the use of cyclosporin and related compounds for hair revitalization (Hauer et al . , U.S. Patent No. 5,342,625; Eberle, U.S. Patent No. 5,284,826; Hewitt et al., U.S. Patent No. 4,996,193). These patents also relate to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth.

However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant , small molecule compounds which are useful as hair revitalizing compounds .

Hamilton and Steiner disclose in U.S. Patent No. 5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and non-immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art .

SUMMARY OF THE INVENTION

The present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative.

The present invention further relates to a pharmaceutical composition which comprises : (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 pipecolic acid derivatives used in the inventive methods and pharmaceutical compositions include immunosuppressive and non-immunosuppressive compounds having an affinity for FKBP-type immunophilins, particularly FKBP12. Non- immunosuppressive compounds, as their name suggests, do not exert any significant immunosuppressive activity. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of mice treated with a vehicle after six weeks. FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.

FIG. 2 is a photograph of mice treated with 10 μM of a pipecolic acid derivative, GPI 1116, after six weeks. FIG. 2 shows that 90% of the shaved area is covered with new hair growth when GPI 1116 is administered.

FIG. 3 is a photograph of mice treated with 3 μM of a pipecolic acid derivative, GPI 1102, after six weeks. FIG. 3 shows that 90% of the shaved area is covered with new hair growth when GPI 1102 is administered.

FIG. 4 is a bar graph plotting the hair growth scores of unshaven animals and shaven animals treated with a vehicle, GPI 1116 (1 μM and 10 μM) , GPI 1102 (1 μM and 3 μM) , and a related pipecolic acid derivative neuroimmunophilin FKBP ligand, GPI 1044 (1 μM, 3 μM and 10 μM) .

FIG. 5 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, related neuroimmunophilin FKBP ligand GPI 1206, and GPI 1116, 14 days after treatment with each identified compound. Figure 5 demonstrates the remarkable early hair growth promoted by neuroimmunophilin FKBP ligands. DETAILED DESCRIPTION OF THE INVENTION Definitions

"Alopecia" refers to deficient hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness) , toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania . Alopecia results when the pilar cycle is disturbed. The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs.

"GPI 1044" refers to a compound of formula

wherein B is 3 -Phenylpropyl , D is 3 -Phenylpropyl , and L is Phenyl .

"GPI 1102" refers to Compound 98, 4 -phenyl -1- (3 - phenylpropyl) butyl 1- (3 , 3 -dimethyl - 2 -oxopentanoyl) -2- piperidinecarboxylate .

"GPI 1116" refers to Compound 103, l-phenethyl-3- phenylpropyl 1- (3 , 3 -dimethyl-2 -oxopentanoyl) -2- piperidinecarboxylate . "GPI 1206" refers to a compound of formula

"Isomers" refer to different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. "Diastereoisomers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal parts of individual enantiomers or stereoisomers.

"Pharmaceutically acceptable salt, ester, or solvate" refers to a salt, ester, or solvate of a subject compound which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. A salt, ester, or solvate can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, c amphor sul f ona t e , cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulf onate , lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate . Eamples of base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl , and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained. "Pilar cycle" refers to the life cycle of hair follicles, and includes three phases:

(1) the anagen phase, the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years;

(2) the catagen phase, the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks ; and (3) the telogen phase, the rest period when hair progressively separates and finally falls out which, insofar as scalp hair is concerned, lasts about three to four months.

Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase. In the telogen phase, hair is uniform in diameter with a slightly bulbous, non-pigmented root. By contrast, in the anagen phase, hair has a large colored bulb at its root.

"Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair.

"Treating alopecia" refers to: (i) preventing alopecia in an animal which may be predisposed to alopecia; and/or

(ii) inhibiting, retarding or reducing alopecia; and/or (iii) promoting hair growth; and/or (iv) prolonging the anagen phase of the hair cycle; and/or

(v) converting vellus hair to growth as terminal hair. Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis . Vellus hair, on the other hand, is fine, thin, non-pigmented short hair in which the hair bulb is located superficially in the dermis. As alopecia progresses, the hairs change from the terminal to the vellus type.

Methods of the Present Invention

The inventive method is particularly useful for treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systematic disorders such as nutritional disorders and internal secretion disorders.

Pharmaceutical Compositions of the Present Invention

The present invention also relates to a 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.

PIPECOLIC ACID DERIVATIVES

The pipecolic acid derivatives used in the methods and pharmaceutical compositions of the present invention have an affinity for FKBP-type immunophilins, such as FKBP12. When a pipecolic acid derivative binds to an FKBP-type immunophilin, it has been found to inhibit the prolyl-peptidyl cis- trans isomerase, or rotamase, activity of the binding protein. Unexpectedly, the compounds have also been found to stimulate hair growth. These rotamase inhibiting compounds may be immunosuppressive or non- immunosuppressive . Examples of useful compounds are set forth below.

COMPOUND 1

Ocain et al . , Biochemical and Biophysical Research Communica tions , Vol. 192, No. 3, 1993, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula I. The compound was synthesized at Wyeth- Ayerst by Dr. Phil Hughes by reaction of 4 -phenyl - 1, 2 , 4-triazoline-3 , 5-dione with rapamycin. FORMULA I

Way-124,466

COMPOUND 2 ^rhakraborty et al . , Chemistry and Biology, Vol. 2, pp. 157-161, March 1995, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula II. FORMULA II

RAP-Pa

COMPOUNDS 3-5

Ikeda et al . , J^". Am. Chem . Soc , Vol. 116, pp. 4143-4144, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula III and Table I.

FORMULA III

TABLE I Compound Structure

3 n = 1 4 n = 2

5 n = 3

COMPOUNDS 6-9

Wang et al . , Bioorgani c and Medicinal Chemistry Letters , Vol. 4, No. 9, pp. 1161-1166, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula IV and Table II . FORMULA IV

TABLE II

Compound Structure

6 = H , H 7 = CH₂ 8 = H , CH₃ 9 ₌ 0

COMPOUND 10

Birkenshaw et al . , Bioorganic & Medi cinal Chemistry Letters , Vol. 4, No. 21, pp. 2501-2506, 1994, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula V. FORMULA V

COMPOUNDS 11-21

Holt et al . , J^". Am. Chem . Soc , Vol. 115, pp. 9925-9938, 1993, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula VI and Tables III and IV.

FORMULA VI

TABLE III

Compound

TABLE III (continued) Compound R₂

TABLE III (continued) Compound R₂

TABLE IV

Compound Structure

TABLE IV (continued)

Compound Structure

COMPOUNDS 22-30

Caffery et al . , Bioorgani c & Medicinal Chemistry Let ters , Vol. 4, No. 21, pp. 2507-2510, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas VII -IX and Tables V-VII.

FORMULA VII

15 TABLE V

Compound Structure

22 y = 1

20 23 y = 2 24 y = 3

FORMULA VIII

15 TABLE VI

Compound Structure

25 n = 1

20 26 n = 2 27 n = 3

FORMULA IX

TABLE VII Compound Structure

28 n = 1 29 n = 2 30 n = 3

COMPOUND 31

Teague et al . , Bioorganic & Medicinal Chemis try Letters, Vol. 3, No. 10, pp. 1947-1950, 1993, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula X. FORMULA X

COMPOUNDS 32-34

Yamashita et al . , Bioorganic & Medicinal Chemistry Let ters, Vol. 4., No. 2, pp. 325-328, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XI and Table VIII. FORMULA XI

TABLE VIII

15 Compound Structure

32 R = phenyl

20 33 R = N(allyl)

TABLE VIII (continued) Compound Structure

COMPOUND 35-55

Holt et al . , Bioorganic & Medicinal Chemistry Letters , Vol. 4, No. 2, pp. 315-320, 1994, incorporated herein by reference, discloses exemp^" -jry pipecolic acid derivatives represented by Formula XII and Tables IX-XI . FORMULA XII

TABLE IX

Compound Structure

36 R

~Me

TABLE IX (continued) Compound Structure

TABLE IX (continued) Compound Structure

TABLE IX (continued) Compound Structure

TABLE X

Compound Structure

51

TABLE XI

Compound Structure

COMPOUNDS 56-68 Holt et al . , Bioorganic & Medicinal Chemistry

Letters , Vol. 3, No. 10, pp. 1977-1980, 1993, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas XIII and XIV and Tables XII-XIV. FORMULA XIII

TABLE XII

Compound Structure

15

56 X = OH 57 X = OMe 58 X = Oi Pr 59 X = OBn

20 60 X = OCH MePh 61 X = OCH₂CHCHPh 62 X = OCH₂CH₂CH₂ (3 , 4-OMe₂) Ph 63 X = NHBn 64 X = NHCH₂CH₂CH₂Ph

25 FORMULA XIV

15

TABLE XIII Compound Structure

20

65 R = Me

66 R = Bn

TABLE XIV

Compound Structure

COMPOUNDS 69-83

Hauske et al . , J^". Med. Chem., Vol. 35, pp. 4284- 4296, 1992, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas XV-XVIII and Tables XV-XVIII.

FORMULA XV

TABLE XV

Compound Structure

R₂ = Phe-o- tert-butyl

70 n = 2

R₂ = Phe-o- ert-butyl FORMULA XVI

TABLE XVI

Compound Structure

71 R, = m-OCH₃Ph

R₃ = Val-O- ert-butyl

R₃ = Leu-O- tert-butyl

73 R_ = m-OCH₃Ph R₃ = Ileu-O- ert-butyl

74 R_λ = m-OCH₃Ph

R₃ = hexahydro-Phe-O- ert- butyl

75 R_ = iΩ-OCH₃Ph

R₃ = allylalanine-O- tert- butyl

76 R_x = B-naphthyl R₃ = Val-O- ert-butyl FORMULA XVII

TABLE XVII

Compound Structure

77 Ri CH₂(CO) ^•ϋ?-OCH₃Ph

R₄ = CH₂Ph

R₅ = OCH₃

78 R_ = CH₂ (CO) -jg-naphthyl

R, = CH₂Ph

R, OCH, FORMULA XVIII

XVIII

TABLE XVIII Compound Structure

15

X = : trans- CH=CH

R₄ = H

20 Y = : OC(O) Ph

X = = trans- CH=CH

R₄ = H

25 Y = = OC(0)CF₃ TABLE XVIII (continued) Compound Structure

81 R_x = ϋi-0CH₃Ph

X = trans-CH=CHI R₄ = - Y = -

82 R₁ = i?7-0CH₃Ph

X = trans-CH=CH

R₄ = H

Y = OCH₂CH=CH₂

X = C=0

R₄ = H

Y — Ph

COMPOUND 84

Teague et al . , Bioorganic & Med . Chem . Letters, Vol. 4, No. 13, pp. 1581-1584, 1994, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XIX. FORMULA XIX

15

SLB506

COMPOUNDS 85-88

Stocks et al., Bioorganic & Med . Chem . Letters, Vol. 4, No. 12, pp. 1457-1460, 1994, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XX and Tables XIX and XX.

TABLE XIX

Compound Structure

FORMULA XX

TABLE XX

Compound Structure

R = OMe

R₃ = CH₂OMe

87 R_λ = H

R₂ = H

R₃ = H TABLE XX (continued)

Compound Structure

R, = H

H

COMPOUNDS 89-110 Additional exemplary pipecolic acid derivatives are represented by Formulas XXI -XXV and Tables XXI- XXV.

FORMULA XXI

TABLE XXI

Compound Structure

89 R = 3,4-dichloro

90 R = 3 , 4 , 5-trimethoxy TABLE XXI (continued) Compound Structure

91 R = H

92 R = 3- (2, 5 -Dimethoxy) phenylpropyl

93 R = 3- (3 , 4 -Methylenedioxy) phenylpropyl

FORMULA XXII

TABLE XXII

Compound Structure

94 R = 4- (p-Methoxy) butyl 95 R = 3 -Phenylpropyl 96 R = 3- (3-Pyridyl) propyl FORMULA XXIII

XXIII

TABLE XXIII

Compound Structure

97 R = 3- (3-Pyridyl) propyl

98 R = 1, 7-Diphenyl-4-heptyl

99 R = 4- (4-Methoxy) butyl

100 R = l-Phenyl-6- (4-methoxyphenyl) -4- hexyl

101 R = 3 - (2 , 5 -Dimethoxy) phenylpropyl

102 R = 3- (3 , 4 -Methylenedioxy) phenylpropyl

103 R = 1, 5-Diphenylpentyl FORMULA XXIV

TABLE XXIV

Compound Structure

104 R = 4- (4-Methoxy) butyl

105 R = 3 -Cyclohexylpropyl

106 R = 3 -Phenylpropyl

FORMULA XXV

TABLE XXV

Compound Structure

107 R = 3 -Cyclohexylpropyl

108 R = 3 -Phenylpropyl

109 R = 4- (4-Methoxy) butyl

110 R = 1, 7-Dιphenyl-4 -heptyl

The names of some of the compounds identified above are provided below in Table XXVI . TABLE XXVI Compound Name of Species

6 4- (4-methoxyphenyl) butyl (25) -1- [2- (3 , 4 , 5- trimethoxyphenyl ) acetyl] hexahydro-2- pyridinecarboxylate

7 4- (4-methoxyphenyl) butyl (2S) -1- [2- (3 , 4 , 5- trimethoxyphenyl ) acryloyl] hexahydro-2- pyridinecarboxylate

8 4- (4-methoxyphenyl) butyl (2S)-l-[2-(3,4,5- trimethoxyphenyl) propanoyl] hexahydro-2 - pyridinecarboxylate

9 4- (4-methoxyphenyl) butyl (2S) -1- [2-oxo-2- (3,4, 5 -trimethoxyphenyl) acetyl] hexahydro-2- pyridinecarboxylate

11 3 -cyclohexylpropyl (2S) -1- (3 , 3 -dimethy] -2- oxopentanoyl) hexahydro-2 -pyridinecarboxy ate

12 3 -phenylpropyl (2S) -1- (3 , 3 -dimethyl-2 - oxopentanoyl) hexahydro-2 -pyridinecarboxylate

13 3- (3 , 4, 5 -trimethoxyphenyl) propyl (25) -1- (3,3 -dimethyl -2 -oxopentanoyl) hexahydro-2 - pyridine -carboxylate TABLE XXVI (continued) Compound Name of Species

14 (IR) -2, 2-dimethyl-l-phenethyl-3-butenyl

{ 2 S ) - 1 - ( 3 , 3 - d i m e t h y l - 2 - oxopentanoyl) hexahydro-2 -pyridinecarboxylate

15 {IR) -1, 3-diphenylpropyl (25) -1- (3,3- dimethyl -2-oxopentanoyl) hexahydro - 2 - pyridinecarboxylate

16 (IR) -1-cyclohexyl- 3 -phenylpropyl (25) -1- (3,3 -dimethyl -2 -oxopentanoyl) hexahydro-2 - pyridine -carboxylate

17 (15) -1, 3-diphenylpropyl (25) -l- (3,3- di methyl -2-oxopentanoyl) hexahydro - 2 - pyridinecarboxylate

18 (15) -l-cyclohexyl-3-phenylpropyl (25) -1- (3,3 -dimethyl -2 -oxopentanoyl ) hexahydro-2 - pyridine-carboxylate

19 (22a5) -15 , 15 -dimethylperhydropyrido [2 , 1- c] [1,9,4] dioxazacyclononadecine-1, 12 , 16 , 17- tetraone TABLE XXVI (continued) Compound Name of Species

20 (24a5) -17, 17-dimethylperhydropyrido [2, 1- c] [1,9,4] dioxazacyclohenicosine-1, 14 , 18 , 19- tetraone

35 ethyl 1 - ( 2 -oxo- 3 -phenylpropanoyl ) -2 - piperidinecarboxylate

36 ethyl 1 -pyruvoyl -2 -piperidinecarboxylate

37 ethyl 1 - ( 2 -oxobutanoyl ) -2 -piperidine- carboxylate

38 ethyl 1 - ( 3 -methyl - 2 -oxobutanoyl ) - 2 - piperidine- carboxylate

39 ethyl 1 - ( 4 -methyl - 2 -oxopentanoyl ) - 2 - piperidinecarboxylate

40 ethyl 1- (3 , 3 -dimethyl-2-oxobutanoyl) -2 - piperidinecarboxylate

41 ethyl 1- (3 , 3 -dimethyl-2-oxopentanoyl) -2- piperidinecarboxylate TABLE XXVI (continued) Compound Name of Species

42 4- [2- (ethyloxycarbonyl) piperidino] -2 , 2- dimethyl-3 , 4-dioxobutyl acetate

43 ethyl 1- [2 - (2 -hydroxytetrahydro-2H-2 - p y r a n y l ) - 2 - o x o a c e t y l ] - 2 - piperidinecarboxylate

44 ethyl 1- [2 - (2 -methoxytetrahydro-2H-2 - p y r a n y l ) - 2 - o x o a c e t y l ] - 2 - piperidinecarboxylate

45 ethyl 1 - [2 - ( 1 - hydroxycyclohexyl ) - 2 - oxoacetyl] -2 -piperidinecarboxylate

46 ethyl 1 - [ 2 - ( 1 -methoxycyclohexyl ) - 2 - oxoacetyl] -2 -piperidinecarboxylate

47 ethyl 1 - ( 2 -cyclohexyl - 2 -oxoacetyl ) -2 - piperidinecarboxylate

48 ethyl 1 - ( 2 -oxo- 2 -piperidinoacetyl ) -2 - piperidinecarboxylate

49 ethyl 1- [2- (3 , 4-dihydro-2H-6-pyranyl) -2- oxoacetyl ) - 2 -piperidinecarboxylate TABLE XXVI (continued) Compound Name of Species

50 ethyl 1 - ( 2 - oxo - 2 - pheny 1 ac e t y1 ) - 2 - piperidinecarboxylate

51 ethyl 1- (4-methyl-2-oxo-l-thioxopentyl) -2- piperidinecarboxylate

52 3 - pheny lpropyl 1 - ( 2 - hydr oxy - 3 , 3 - dimethylpentanoyl) -2 -piperidinecarboxylate

53 ( l i? ) - l - p h e n y l - 3 - ( 3 , 4 , 5 - t r ime t hoxypheny 1 ) pr opy 1 l- (3,3- dimethylbutanoyl) -2 -piperidine-carboxylate

54 (li?) -1, 3-diphenylpropyl 1- (benzylsulfonyl) - 2 -piperidinecarboxylate

55 3 - ( 3 , 4 , 5 - trimethoxyphenyl ) propyl 1- ( benzylsulf onyl) -2 -piperidinecarboxylate

56 1- (2- [ (2i?, 3i?, 65) -6- [ (25,3E,5E, 7£, 95, Hi?) - 2,13 -dimethoxy- 3 , 9, 11-trime hy 1-12 -oxo-

3 , 5, 7-tridecatrienyl] -2-hydroxy-3- methyltetrahydro-2H- 2 -pyranyl) -2-oxoacetyl) - 2-piperidine-carboxylic acid TABLE XXVI (continued) Compound Name of Species

57 methyl 1- (2- [ (2i?, 3i?, 6S) -6- [(25, 3E, SE, 7E, 95,

Hi?) -2, 13 -dimethoxy- 3, 9, ll-trimethyl-12-oxo- 3,5, 7-tridecatrienyl] - 2 -hydroxy- 3 -methyl - tetrahydro-2H-2 -pyranyl) -2-oxoacetyl) -2- piperidinecarboxylate

58 isopropyl 1- (2- [ (22?, 3i?, 65) -6- [ (25, 3E, SE, 7E, 95, Hi?) -2, 13-dimethoxy-3 , 9, ll-trimethyl-12- oxo- 3,5,7- ridecatrienyl ] - 2 -hydroxy- 3 - methyl -tetrahydro- 2 H- 2 -pyranyl ) -2 - oxoacetyl) -2 -piperidinecarboxylate

59 benzyl 1- (2- [ (22?, 322, 65) -6- [ (25, 3E, SE, IE, 95, Hi?) -2, 13 -dimethoxy- 3, 9, ll-trimethyl-12-oxo- 3,5, 7-tridecatrienyl] -2 -hydroxy- 3 -methyl - tetrahydro- 22ϊ- 2 -pyranyl) -2-oxoacetyl) -2- piperidinecarboxylate

60 1-phenylethyl 1- (2- [ (22?, 32?, 65) -6- [ (25, 32?, SE, IE, 95, 112?) -2, 13-dimethoxy-3, 9, 11-trimethyl- 12 -oxo -3 , 5 , 7-tridecatrienyl] -2 -hydroxy- 3 - methyl- tetrahydro- 2H- 2 -pyranyl) - 2 - oxoacetyl) -2 -piperidinecarboxylate TABLE XXVI (continued) Compound Name of Species

61 (Z) -3 -phenyl -2 -propenyl 1- (2- [ (22?, 32?, 65) -6-

[ (25,325, SE,7E, 95, 112?) -2 , 13-dimethoxy-3 , 9 , 11- trimethyl-12-oxo-3 , 5, 7-tridecatrienyl] -2- hydroxy- 3 -methyl tetrahydro- 2H- 2 -pyranyl) -2- oxoacetyl) -2 -piperidinecarboxylate

62 3- (3, 4-dimethoxyphenyl) propyl 1- (2- [ (22?, 32?, 65) -6- [ (25, 3E, SE, 7E, 95, 112?) -2 , 13 -dimethoxy - 3 , 9 , ll - trimethyl - 12 - oxo - 3 , 5 , 7 - t r i de c a t r i enyl ] - 2 - hydroxy - 3 - methyltetrahydro-2H- 2 -pyranyl) -2-oxoacetyl) -

2 -piperidine-carboxylate

63 272 -benzyl - l - ( 2 - [ ( 22? , 32? , 65) - 6 -

[ (25, 32?, 5E, IE, 95, 112?) -2, 13 -dimethoxy - 3 , 9 , ll - trimethyl - 12 - oxo- 3 , 5 , 7 - tridecatrienyl] -2 -hydroxy-3 - methyl - tetrahydro- 2 H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate

64 N2- (3 -phenylpropyl) -1- (2- [ (22?, 32?, 6S) -6-

[ (25,32?, 52?, 72?, 95, 112?) -2 , 13 -dimethoxy-3 , 9 , 11- trimethyl-12-oxo-3 , 5 , 7-tridecatrienyl] -2- hydroxy- 3 -methyl tetrahydro-2H- 2 -pyranyl) -2- oxoacetyl) -2 -piperidinecarboxylate . TABLE XXVI (continued) Compound Name of Species

89 (2?) -3- (3 , 4-dichlorophenyl) -2 -propenyl 1-

(3 , 3 -dimethyl-2 -oxopentanoyl) -2 -piperidinecarboxylate

90 (2?) -3- (3, 4, 5-trimethoxyphenyl) -2 -propenyl 1- (3 , 3 -dimethyl -2 -oxopentanoyl) -2-piperidine- carboxylate

91 (E) - 3 -phenyl -2 -propenyl 1- (3 , 3 -dimethyl-2- oxo-pentanoyl) -2 -piperidinecarboxylate

92 (2?) -3- ((3- (2, 5 -dimethoxy) -phenylpropyl) - phenyl ) -2 -propenyl 1- (3,3 -dimethyl -2- oxopentanoyl ) -2 -piperidinecarboxylate

93 (E) - 3 - (1, 3-benzodioxol-5-yl) -2-propenyl 1-

(3 , 3-dimethyl-2 -oxopentanoyl) -2-piperidine- carbcxylate

94 4 - (4 -methoxyphenyl ) butyl l-(2-oxo-2- phenylacetyl) -2 -piperidinecarboxylate

95 3 -phenylpropyl 1- (2 -oxo- 2 -phenylacetyl) -2- piperidinecarboxylate TABLE XXVI (continued) Compound Name of Species

96 3 - ( 3 -pyr idyl ) propyl l- (2-oxo-2- phenylacetyl) -2 -piperidinecarboxylate

97 3- ( 3 -pyridyl) propyl 1- (3 , 3 -dimethyl-2- oxopentanoyl ) -2 -piperidinecarboxylate

98 4 -phenyl-1- (3 -phenylpropyl) butyl l-(3,3- dimethyl - 2 -oxopentanoyl ) -2 -piperidinecarboxylate

99 4- (4-methoxyphenyl) butyl 1- (3, 3 -dimethyl -2- oxopentanoyl ) - 2 -piperidinecarboxylate

100 1- (4-methoxyphenethyl) -4-phenylbutyl l-(3,3- di methyl- 2-oxopentanoyl) -2 -piperidine - carboxylate

101 3 - (2 , 5 -dimethoxyphenyl ) propyl 1 - (.3,3- d i me t hy l - 2 - oxop e n t a noy l ) - 2 - piperidinecarboxylate

102 3- (1 , 3-benzodioxol-5-yl) propyl l-(3,3 dimethyl - 2 -oxopentanoyl ) -2 -piperidinecarboxylate TABLE XXVI (continued) Compound Name of Species

103 1-phenethyl -3 -phenylpropyl 1- (3 , 3 -dimethyl- 2-oxopentanoyl ) -2 -piperidinecarboxylate

104 4- (4-methoxyphenyl) butyl 1- (2-cyclohexyl-2- oxoacetyl ) -2 -piperidinecarboxylate

105 3 -cyclohexylpropyl 1 - ( 2 -cyclohexyl -2 - oxoacetyl) -2 -piperidinecarboxylate

106 3 -phenylpropyl 1- (2-cyclohexyl-2-oxoacetyl) ■ 2 -piperidinecarboxylate

107 3 -cyclohexylpropyl 1- ( 3 , 3 -dimethyl -2 oxobutanoyl ) - 2 -piperidinecarboxylate

108 3 -phenylpropyl 1 - ( 3 , 3 - dime t hy 1 - 2 ■ oxobutanoyl ) -2 -piperidinecarboxylate

109 4- (4-methoxyphenyl) butyl 1- (3 , 3 -dimethyl-2- oxobutanoyl ) -2 -piperidinecarboxylate

110 4 -phenyl -1- (3 -phenylpropyl) butyl l-(3,3 dimethyl -2-oxobutanoyl) -2 -piperidinecarboxylate All the compounds of Formulas I-XXV possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R- and S- stereoisomers. The individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compounds of

Formulas I -XXV. It is understood that the compounds of Formulas I -XXV encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, S-stereoisomers are used in the pharmeceutical compositions and methods of the present invention.

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

K_i Test Procedure Inhibition of the peptidyl -prolyl isomerase

(rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can be evaluated by known methods described in the literature (Harding et al . , Na ture, 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 XXVII. The cis- trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe- p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para- nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent K_± values. In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCI) , 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCI, 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 files. TABLE XXVII In Vi tro Test Results - Formulas I-XXV

Compound K_t (μM)

6 140

9 13

11 170

12 250 13 25

15 17

19 12

36 >10,000

41 1300 50 >10,000

89 1800

90 28

91 39

92 75 93 70

94 165

95 740

96 725

97 130 98 30

99 60

100 15

101 12

102 120 TABLE XXVII (continued) In Vi tro Test Results - Formulas I-XXV Compound K_± (μM)

103 20

104 103

105 760

106 210 107 32

108 2

109 24

110 5

Route of Administration

To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions must readily affect the targeted areas. For these purposes, the compounds are preferably administered topically to the skin.

For topical application to the skin, the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Other routes of administration known in the pharmaceutical art are also contemplated by this invention.

Dosage

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

The compounds can be administered with other hair revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the factors previously stated and the effectiveness of the drug combination.

EXAMPLES

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

Example 1 In Vivo Hair Generation Tests With C57 Black 6 Mice

Experiment A: C57 black 6 mice were used to demonstrate the hair revitalizing properties of pipecolic acid derivatives GPI 1116 and GPI 1102, as well as related pipecolic acid derivative neuroimmunophilin FKBP ligand GPI 1044. C57 black 6 mice, approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers.

The animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGS. 1, 2, and 3, four animals were treated by topical administration with 20% propylene glycol vehicle (FIG. 1) , and seven animals per group were treated by topical administration with 10 μM GPI 1116 (FIG. 2) , or 3 μM GPI 1102 (FIG. 3) . The animals were treated with vehicle, GPI 1116, or GPI 1102 every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area covered by new hair growth during this time period.

FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. In contrast, FIGS. 2 and 3 show that animals treated with 10 μM GPI 1116 and 3 μM GPI 1102 exhibited dramatic hair growth, covering as much as 50% of the shaved area in some animals. FIG. 4 compares the hair growth score of unshaven animals with the hair growth scores of shaven animals treated with a vehicle, GPI 1116 (1 μM and 10 μM) , GPI 1102 (1 μM and 3 μM) , and related neuroimmunophilin FKBP ligand GPI 1044 (1 μM, 3 μM and 10 μM) . Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of neuroimmunophilin FKBP ligands, including GPI 1116. C57 Black 6 mice, 55 to 75 days old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlying dermal layers . The animals were in a anagen growth phase when shaved. Five animals per group were treated by topical administration with a vehicle, FK506, or a neuroimmunophilin FKBP ligand (GPI 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area. The animals were treated three times per week, and hair growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent of shaved area covered by new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area) .

Figure 5 shows that after 14 days, the animals treated with vehicle exhibited the beginning of growth in small tufts. In contrast, animals treated with one of the neuroimmunophilin FKBP ligands exhibited dramatic hair growth.

Example 2

A lotion comprising the following composition may be prepared.

Into 95% ethanol are added a pipecolic acid derivative, α-tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion. 5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia.

Example 3

A lotion comprising the following composition shown may be prepared.

Into 95% ethanol are added a pipecolic acid derivative, hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and a dye.

The resulting mixture is stirred, and purified water is added to the mixture to obtain a transparent liquid lotion. The lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia .

Example 4

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

The A phase and the B phase are respectively heated and melted and maintained at 80°c. Both phases are then mixed and cooled under stirring to normal temperature to obtain an emulsion.

The emulsion may be applied by spraying once to four times per day to a site having marked baldness or alopecia . Example 5

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

The A phase is heated and melted, and maintained at 70°c. The B phase is added into the A phase and the mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream.

The cream may be applied once to 4 times per day to a site having marked baldness or alopecia. Example 6

A liquid comprising the following composition may be prepared.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a pipecolic acid derivative, and perfume. The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid. The liquid may be applied once to 4 times per day to a site having marked baldness or alopecia.

Example 7

A shampoo comprising the following composition may be prepared .

Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betaine lauryldimethylaminoacetate . Then a mixture obtained by adding 5.0 g of a 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 successively added. The resulting mixture is heated and subsequently cooled to obtain a shampoo .

The shampoo may be used on the scalp once or twice per day. Example 8

A patient is suffering from alopecia senilis. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 9

A patient is suffering from male pattern alopecia. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 10

A patient is suffering from alopecia areata. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 11

A patient is suffering from hair loss caused by skin lesions. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. Example 12

A patient is suffering from hair loss caused by tumors. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 13

A patient is suffering from hair loss caused by a systematic disorder, such as a nutritional disorder or an internal secretion disorder. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 14

A patient is suffering from hair loss caused by chemotherapy. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient . Increased hair growth is expected to occur following treatment.

Example 15

A patient is suffering from hair loss caused by radiation. A pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

The invention being thus described, it will be obvious that the same may be varied in many ways . Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

WE CLAIM :

1. A method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative.

2. The method of claim 1, wherein the pipecolic acid derivative has an affinity for an FKBP-type immunophi1in .

3. The method of claim 2, wherein the FKBP-type immunophilin is FKBP-12.

4. The method of claim 1, wherein the pipecolic acid derivative is immunosuppressive.

5. The method of claim 1, wherein the pipecolic acid derivative is non- immunosuppressive .

6. The method of claim 1, wherein the pipecolic acid derivative is Way-124,666.

7. The method of claim 1, wherein the pipecolic acid derivative is rapamycin.

8. The method of claim 1, wherein the pipecolic acid derivative is Rap-Pa.

9. The method of claim 1, wherein the pipecolic acid derivative is SLB-506.

10. The method of claim 1, wherein the pipecolic acid derivative is selected from the group consisting of:

4- (4-methoxyphenyl) butyl (25) -l- [2- (3,4,5- t rimethoxyphenyl ) acetyl ] hexahydro - 2 - pyridinecarboxylate ; 4- (4-methoxyphenyl) butyl ( 25) - 1 - [2 - (3 , 4 , 5 - trimethoxyphenyl ) acryloyl ] hexahydro- 2 - pyridinecarboxylate ;

4- (4-methoxyphenyl) butyl (25) -l- [2- (3,4,5- trimethoxyphenyl ) propanoyl] hexahydro-2 - pyridinecarboxylate;

4- (4-methoxyphenyl) butyl (25) -1- [2 -oxo- 2- (3,4,5- t rimethoxyphenyl ) acetyl ] hexahydro - 2 - pyridinecarboxylate ;

3 -cyclohexylpropyl (25) -1- (3 , 3 -dimethyl -2 - oxopentanoyl) hexahydro- 2 -pyridinecarboxylate;

3-phenylpropyl (25) -1- (l , 3-╬¼irr.ethyl-2- oxopentanoyl) hexahydro- 2 -pyridinecarboxylate;

3- (3,4, 5 -trimethoxyphenyl) propyl (25) -1- (3, 3- dime thyl - 2 - oxopentanoyl ) hexahydro - 2 - pyridinecarboxylate;

(12?) -2, 2-dimethyl-l-phenethyl-3-butenyl (25) -1- (3 , 3-dimethyl-2-oxopentanoyl) hexahydro-2- pyridinecarboxylate ; (12?) -1, 3-diphenylpropyl (25) -1- (3 , 3 -dimethyl-2- oxopentanoyl) hexahydro-2 -pyridinecarboxylate;

(12?) -1-cyclohexyl- 3 -phenylpropyl (25) -1- (3,3- dimethyl - 2 - oxopentanoyl ) hexahydro- 2 - pyridinecarboxylate;

(15) -1, 3-diphenylpropyl (25) -1- (3 , 3 -dimethyl-2- oxopentanoyl) hexahydro-2 -pyridinecarboxylate;

(15) -1-cyclohexyl -3 -phenylpropyl (25) -1- (3, 3- dimet hyl - 2 - oxopent anoyl ) hexahydro - 2 - pyridinecarboxylate;

(22a5) -15, 15-dimethylperhydropyrido [2, 1 - c] [1,9,4] dioxazacyclononadecine-1, 12 , 16 , 17-tetraone;

(24a5) -17, 17-dimethylperhydropyrido [2, 1 - c] [1,9,4] dioxazacyclohenicosine-1 , 14 , 18 , 19-tetraone ; ethyl 1 - ( 2 - oxo - 3 - pheny 1 p r op anoy 1 ) - 2 - piperidinecarboxylate ; ethyl 1 -pyruvoyl - 2 -piperidinecarboxylate ; ethyl 1- (2 -oxobutanoyl) - 2 -piperidinecarboxylate ; ethyl 1- (3 -methyl-2-oxobutanoyl) - 2 - piperidinecarboxylate; ethyl 1- (4 -methyl -2 -oxopen anoyl) - 2 - piperidinecarboxylate ; ethyl 1 - ( 3 , 3 - dimethyl -2-oxobutanoyl) - 2 - piperidinecarboxylate ; ethyl 1 - ( 3 , 3 - dimethyl - 2 - oxopentanoyl ) - 2 - piperidinecarboxylate ;

4- [2- (ethyloxycarbonyl) piperidino] -2 , 2-dimethyl- 3 , 4-dioxobutyl acetate; ethyl 1- [2- (2-hydroxytetrahydro-2H-2-pyranyl) -2- oxoace tyl ] - 2 -piperidinecarboxylate ; ethyl 1- [2- (2-methoxytetrahydro-2H-2-pyranyl) -2- oxoace tyl ] - 2 -piperidinecarboxylate ; ethyl 1- [2- (1-hydroxycyclohexyl) -2-oxoacetyl] -2- piperidinecarboxylate ; ethyl 1- [2- (1-methoxycyclohexyl) -2-oxoacetyl] -2- piperidinecarboxylate ; ethyl 1- (2-cyclohexyl-2-oxoacetyl) - 2 - piperidinecarboxylate; ethyl 1- (2-oxo-2-piperidinoacetyl) - 2 - piperidinecarboxylate ; ethyl 1- [2- (3 , 4 - di hydro - 2H- 6 -pyranyl ) -2- oxoacetyl ) - 2 -piperidinecarboxylate ; ethyl 1- ( 2 -oxo- 2 -phenylacetyl ) - 2 - piperidinecarboxylate ; ethyl 1- (4 -methyl -2 -oxo- 1- thioxopentyl ) -2- piperidinecarboxylate ;

3 -phenylpropyl 1 - ( 2 - hydroxy- 3 , 3 - dimethylpentanoyl) -2 -piperidinecarboxylate ;

(12?) -1 -phenyl -3- (3,4, 5 -trimethoxyphenyl) propyl 1- (3 , 3-dimethylbutanoyl) -2 -piperidinecarboxylate;

(12?) -1, 3-diphenylpropyl 1- (benzylsulf onyl) -2- piperidinecarboxylate ; 3 - (3 , 4 , 5-trimethoxyphenyl) propyl 1-

( benzylsulf onyl) -2 -piperidinecarboxylate ; l- (2- [(2i?,32?,65) -6- [(25,3E, SE,7E, 95, 112?) -2 , 13 - dimethoxy-3 , 9 , ll -trimethyl - 12 -oxo-3 , 5 , 7 - tridecatrienyl] -2 -hydroxy- 3 -methyl tetrahydro -2H- 2 - pyranyl) -2-oxoacetyl) -2-piperidinecarboxylic acid; methyl 1- (2- [ (22?, 32?, 65) -6- [ (25, 32?, 52?, IE, 95, 112?) - 2 , 13-dimethoxy-3, 9, ll-trimethyl-12-oxo-3, 5, 7 - tridecatrienyl] -2-hydroxy-3 -methyltetrahydro-2H-2 - pyranyl) -2-oxoacetyl) -2 -piperidinecarboxylate; i s op r op y l 1 - ( 2 - [ ( 22? , 32? , 65 ) - 6 -

[ (25, 32?, 52?, 72?, 95, Hi?) -2 , 13 - dimethoxy-3 , 9 , 11- trimethyl-

12-OXO-3 , 5 , 7-tridecatrienyl] -2-hydroxy-3 - methyl tetrahydro- 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate ; benzyl 1- (2- [ (22?, 32?, 65) -6- [ (25, 32?, 52?, 72?, 95, 112?) - 2, 13-dimethoxy-3, 9, ll-trimethyl-12-oxo-3,5, 7- tridecatrienyl] -2 -hydroxy- 3 -methyltetrahydro- 2H- 2 - pyranyl) -2-oxoacetyl) -2 -piperidinecarboxylate;

1 -phenylethyl 1 - ( 2 - [ ( 22?, 32?, 65) - 6 -

[ (25, 32?, 52?, 72?, 95, 112?) -2 , 13 -dimethoxy-3 , 9 , 11-trimethyl-

12-oxo-3 , 5 , 7-tridecatrienyl] -2 -hydroxy-3 - methyltetrahydro- 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate;

(Z) -3 -phenyl -2 -propenyl l- (2- [(22?,32?,65) -6-

[ (25, 32?, 52?, 72?, 95,112?) -2 , 13 -dimethoxy-3 , 9 , 11-trimethyl-

12-OXO-3 , 5 , 7-tridecatrienyl] -2-hydroxy-3 - methyl tetrahydro- 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate;

3- (3 , 4-dimethoxyphenyl) propyl 1- (2- [ (22?, 32?, 65) -6- [ (25,32?, 52?, IE, 95,112?) -2, 13 -dimethoxy-3 , 9, 11-trimethyl- 12-OXO-3 , 5 , 7-tridecatrienyl] -2 -hydroxy-3 - methyltetrahydro- 2H-2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate ;

W2 - b e n z y l - l - ( 2 - [ ( 22? , 3 2? , 65 ) - 6 -

[ (25, 3E, SE, 72?, 95, 112?) -2 , 13 -dimethoxy-3 , 9 , 11-trimethyl- 12-OXO-3 , 5 , 7-tridecatrienyl] -2-hydroxy-3 - methyl tetrahydro- 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate ;

N2- (3-phenylpropyl) -1- (2- [ (22?, 32?, 65) - 6 -

[ (25,32?, SE, 7E, 9S, Hi?) -2 , 13 -dimethoxy-3 , 9 , 11-trimethyl- 12-OXO-3 , 5 , 7-tridecatrienyl] - 2 -hydroxy- 3 - methyltetrahydro- 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate ;

(i?) -3- (3,4-dichlorophenyl) -2 -propenyl 1- (3, 3- dimethyl - 2-oxopentanoyl ) - 2 -piperidinecarboxylate ; (2?) -3- (3,4, 5 -trimethoxyphenyl) -2 -propenyl l-(3,3- dimethyl - 2-oxopentanoyl ) - 2 -piperidinecarboxylate ;

(E) -3 -phenyl -2 -propenyl 1- (3,3 -dimethyl-2- oxopent anoyl ) - 2 -piper idinecarboxylat e ;

(E) -3- ( (3- (2, 5 -dimethoxy) -phenylpropyl) phenyl) -2- propenyl 1 - ( 3 , 3 - dime thy 1 - 2 - oxopentanoyl ) - 2 - piperidinecarboxylate ;

(2?) -3- (1, 3-benzodioxol-5-yl) -2 -propenyl 1- (3,3- dimethyl - 2 - oxopentanoyl ) - 2 -piperidinecarboxylate ;

4 - (4-methoxyphenyl) butyl 1- (2-oxo-2- phenylacetyl) -2 -piperidinecarboxylate ;

3-phenylpropyl 1- ( 2 -oxo-2 -phenylacetyl ) -2- piperidinecarboxylate ;

3- ( 3 -pyr idyl) propyl 1- (2 -oxo- 2 -phenylacetyl) -2- piperidinecarboxylate ;

3- (3-pyridyl)propyl 1- (3,3-dimethyl-2- oxopentanoyl) -2 -piperidinecarboxylate ;

4-phenyl-1- (3-phenylpropyl) butyl 1- (3 , 3 -dimethyl- 2-oxopentanoyl) -2 -piperidinecarboxylate;

4- (4-methoxyphenyl) butyl 1- (3 , 3 -dimethyl -2- oxopentanoyl) -2 -piperidinecarboxylate;

1- (4-methoxyphenethyl) -4-phenylbutyl 1- (3,3- dimethyl -2-oxopentanoyl ) -2 -piperidinecarboxylate ; 3- (2, 5 -dimethoxyphenyl) propyl 1- (3, 3 -dimethyl-2- oxopentanoyl ) -2 -piperidinecarboxylate ;

3- (1, 3-benzodioxol-5-yl)propyl 1- (3 , 3-dimethyl-2- oxopentanoyl) -2 -piperidinecarboxylate ;

1-phenethyl -3 -phenylpropyl 1- (3 , 3 -dimethyl -2- oxopentanoyl) -2 -piperidinecarboxylate ;

4- (4-methoxyphenyl) butyl 1- (2 -cyclohexyl-2- oxoacetyl ) -2 -piperidinecarboxylate ;

3 -cyclohexylpropyl 1- ( 2 -cyclohexyl -2 -oxoacetyl) - 2 -piperidinecarboxylate ; 3-phenylpropyl 1- (2-cyclohexyl-2-oxoacetyl) -2- piperidinecarboxylate ;

3-cyclohexylpropyl 1- (3, 3-dimethyl-2- oxobutanoyl ) -2 -piperidinecarboxylate ;

3 -phenylpropyl 1- (3,3 -dimethyl -2 -oxobutanoyl) -2- piperidinecarboxylate;

4- (4-methoxyphenyl) butyl 1- (3,3 -dimethyl -2- oxobutanoyl ) -2 -piperidinecarboxylate ;

4 -phenyl-1- (3-phenylpropyl) butyl 1- (3 , 3 -dimethyl- 2 -oxobutanoyl) -2 -piperidinecarboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof .

11. A pharmaceutical composition which comprises :

(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.

12. The pharmaceutical composition of claim 11, wherein the pipecolic acid derivative has an affinity for an FKBP-type immunophilin .

13. The pharmaceutical composition of claim 12, wherein the FKBP-type immunophilin is FKBP-12.

14. The pharmaceutical composition of claim 11, wherein the pipecolic acid derivative is immunosuppressive .

15. The pharmaceutical composition of claim 11, wherein the pipecolic acid derivative is non- immunosuppressive.

16. The pharmaceutical composition of claim 11, wherein the pipecolic acid derivative is Way-124,666.

17. The pharmaceutical composition of claim 11, wherein the pipecolic acid derivative is rapamycin.

18. The pharmaceutical composition of claim 11, wherein the pipecolic acid derivative is Rap-Pa.

19. The pharmaceutical composition of claim 11, wherein the pipecolic acid derivative is SLB-506.

20. The pharmaceutical composition of claim 11, wherein the pipecolic acid derivative is selected from the group consisting of:

4- (4-methoxyphenyl) butyl (25) -1- [2- (3, 4, 5- t rimethoxyphenyl ) acetyl ] hexahydro - 2 - pyridinecarboxylate;

4- (4-methoxyphenyl) butyl (25) -l- [2-(3,4,5- trimethoxyphenyl ) acryloyl ] hexahydro-2 - pyridinecarboxylate ;

4- (4-methoxyphenyl) butyl (25) -1- [2- (3,4,5- trimethoxyphenyl ) propanoyl] hexahydro-2 - pyridinecarboxylate ;

4- (4-methoxyphenyl) butyl (25) -1- [2 -oxo- 2- (3,4,5- t rime thoxyphenyl ) acetyl ] hexahydro - 2 - pyridinecarboxylate ; 3 -cyclohexylpropyl (25) -1 - ( 3 , 3 -dimethyl -2 - oxopentanoyl ) hexahydro-2 -pyridinecarboxylate ;

3-phenylpropyl (25) -1- (3 , 3-dimethyl-2- oxopentanoyl) hexahydro-2 -pyridinecarboxylate; 3- (3,4, 5 -trimethoxyphenyl) propyl (25) -1- (3,3- dime thyl - 2 - oxopent anoyl ) hexahydro - 2 - pyridinecarboxylate ;

(12?) -2, 2- dimethyl -1 -phenethyl- 3 -butenyl (25) -1- (3 , 3-dimethyl-2 -oxopentanoyl ) hexahydro- 2- pyridinecarboxylate ;

(12?) -1, 3-diphenylpropyl (25) -1- (3, 3 -dimethyl -2- oxopentanoyl) hexahydro-2 -pyridinecarboxylate;

(12?) -1-cyclohexyl -3 -phenylpropyl (25) -1- (3,3- dimet hyl - 2 - oxopent anoyl ) hexahydro - 2 - pyridinecarboxylate ;

(15) -1, 3-diphenylpropyl (25) -1- (3 , 3 -dimethyl -2- oxopentanoyl) hexahydro- 2 -pyridinecarboxylate ;

(15) -1-cyclohexyl -3 -phenylpropyl (25) -1- (3,3- dime t hyl - 2 - oxopent anoyl ) hexahydro - 2 - pyridinecarboxylate ;

(22a5) -15, 15- dime t hy lperhydropyr ido [2, 1- c] [1,9,4] dioxazacyclononadecine-1, 12 , 16, 17-tetraone; (24a5) -17, 17-dimethylperhydropyrido [2, 1- c] [1, 9, 4] dioxazacyclohenicosine-1, 14 , 18 , 19-tetraone; ethyl 1- (2-oxo-3 -phenylpropanoyl) -2- piperidinecarboxylate ; ethyl 1 -pyruvoyl - 2 -piperidinecarboxylate ; ethyl 1- (2 -oxobutanoyl) -2 -piperidinecarboxylate; ethyl l- (3 -methyl-2 -oxobutanoyl ) -2- piperidinecarboxylate ; ethyl 1- (4-methyl-2-oxopentanoyl) -2- piperidinecarboxylate ; ethyl l- (3, 3-dimethyl-2 -oxobutanoyl) -2- piperidinecarboxylate ; ethyl 1- (3,3 -dime thyl - 2 -oxopentanoyl ) -2- piperidinecarboxylate ; 4- [2- (ethyloxycarbonyl) piper idino] -2 , 2 -dimethyl -

3 , 4-dioxobutyl acetate; ethyl 1- [2- (2-hydroxytetrahydro-2H-2-pyranyl) -2- oxoacetyl] -2 -piperidinecarboxylate; ethyl 1- [2- (2-methoxytetrahydro-2H-2-pyranyl) -2- oxoacetyl] -2 -piperidinecarboxylate; ethyl 1- [2- (1-hydroxycyclohexyl) -2-oxoacetyl] -2- piperidinecarboxylate ; ethyl 1- [2- (1-methoxycyclohexyl) -2-oxoacetyl] -2- piperidinecarboxylate ; ethyl 1 - ( 2 - cy c 1 ohexy 1 - 2 - oxoace t y 1 ) - 2 - piperidinecarboxylate ; ethyl 1- (2-oxo-2-piperidinoacetyl) -2- piperidinecarboxylate ; ethyl 1- [2- (3 , 4 - di hydro- 2H- 6 -pyranyl ) -2- oxoacetyl) -2 -piperidinecarboxylate ; ethyl 1 - ( 2 -oxo- 2 -phe y acetyl ) - 2 - piperidinecarboxylate ; ethyl 1- (4 -methyl-2 -oxo- 1 - thioxopentyl ) -2- piperidinecarboxylate ; 3 -phenylpropyl l - ( 2 - hydroxy- 3 , 3 - dimethylpentanoyl ) - 2 -piperidinecarboxylate ;

(12?) -l-phenyl-3- (3 , 4 , 5 -trimethoxyphenyl) propyl 1- (3 , 3-dimethylbutanoyl) - 2 -piperidinecarboxylate ; (12?) -1, 3-diphenylpropyl 1- (benzylsulf onyl) -2- piperidinecarboxylate ;

3 - (3 , 4 , 5-trimethoxyphenyl) propyl 1 -

(benzylsulfonyl) -2 -piperidinecarboxylate; l- (2- [( 22?, 32?, 65) -6- [ (25, 32?, 52?, 72?, 95, 112?) -2,13- dimethoxy-3 , 9 , ll -trimethyl-12 -oxo-3 , 5 , 7 - tridecatrienyl] -2 -hydroxy- 3 -methyltetrahydro-2H-2 - pyranyl) -2-oxoacetyl) -2-piperidinecarboxylic acid; methyl 1- (2- [ (22?, 32?, 65) -6- [ (25, 32?, 52?, 72?, 95, 112?) - 2, 13-dimethoxy-3, 9, ll-trimethyl-12-oxo-3, 5, 7- tridecatrienyl] -2 -hydroxy- 3 -methyltetrahydro- 2H- 2 - pyranyl) -2-oxoacetyl) -2 -piperidinecarboxylate; i s op r opy l l - ( 2 - [ ( 22? , 32? , 6 S ) - 6 -

[ (25, 32?, 52?, 72?, 95,112?) -2, 13 -dimethoxy-3 , 9, 11-trimethyl- 12-oxo-3 , 5 , 7-tridecatrienyl] -2 -hydroxy-3 - methyltetrahydro- 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate ; benzyl 1- (2- [ (22?, 32?, 65) -6- [ (25, 32?, 52?, 72?, 95, 112?) - 2 , 13-dimethoxy-3, 9, ll-trimethyl-12-oxo-3, 5, 7- tridecatrienyl] -2-hydroxy-3 -methyltetrahydro-2H-2 - pyranyl) -2-oxoacetyl) -2 -piperidinecarboxylate;

1 -phenylethyl 1 - ( 2 - [ ( 22?, 32?, 65) - 6 -

[ (25, 32?, 52?, 72?, 95,112?) -2, 13 -dimethoxy-3 , 9, 11-trimethyl-

12-0X0-3 , 5 , 7-tridecatrienyl] -2 -hydroxy-3 - methyltetrahydro- 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate ;

(Z) -3 -phenyl -2 -propenyl l- (2- [( 22?, 32?, 65) -6-

[ (25,32?, SE,1E, 95,112?) -2 , 13 -dimethoxy-3 , 9 , 11- trimethyl- 12-0X0-3 , 5 , 7-tridecatrienyl] -2 -hydroxy-3- methyltetrahydro-2 ff- 2 -pyranyl) - 2 -oxoacetyl ) -2- piperidinecarboxylate ;

3- (3, 4-dimethoxyphenyl) propyl 1- (2- [ (2i?,3i?,65) -6- [ (25,32?, SE, 7E, 95, Hi?) -2 , 13 -dimethoxy-3 , 9 , 11- trimethyl-

12-OXO-3 , 5 , 7-tridecatrienyl] -2 -hydroxy-3 - methyltet rahydro - 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate ;

J╬¬2 - b e n z y l - l - ( 2 - [ ( 22? , 3 2? , 6 5 ) - 6 - [ (2S, 3E, SE, IE, 95, Hi?) -2 , 13 -dimethoxy-3 , 9 , 11-trimethyl-

12-oxo-3 , 5 , 7-tridecatrienyl] -2 -hydroxy-3 - methyl tetrahydro- 2H- 2 -pyranyl ) -2-oxoacetyl) -2- piperidinecarboxylate ;

N2- (3-phenylpropyl) -1- (2- [ (22?, 32?, 6 S) - 6 - [ (25, 32?, 5i?, 72?, 95, 112?) -2 , 13 -dimethoxy-3 , 9 , 11-trimethyl-

(i?) -3- (3 , 4-dichlorophenyl) -2 -propenyl 1- (3,3- dimethyl -2 -oxopentanoyl) -2 -piperidinecarboxylate;

(E) -3- (3,4, 5 -trimethoxyphenyl) -2 -propenyl 1- (3, 3- dimethyl - 2-oxopentanoyl ) - 2 -piperidinecarboxylate ;

(2?) -3 -phenyl -2 -propenyl 1- (3 , 3 -dimethyl -2 - oxopentanoyl ) - 2 -piperidinecarboxylate ; (2?)-3-((3- (2, 5 -dimethoxy) -phenylpropyl) phenyl) -2- propenyl 1- (3, 3-dimethyl-2-oxopentanoyl) -2- piperidinecarboxylate ;

(2?) -3- (1, 3-benzodioxol-5-yl) -2-propenyl 1- (3 , 3- dimethyl -2 -oxopentanoyl ) -2 -piperidinecarboxylate ;

4- (4-methoxyphenyl)butyl 1- (2-oxo-2- phenylacetyl ) -2 -piperidinecarboxylate ;

3-phenylpropyl 1- (2 -oxo-2 -phenylacetyl) -2- piperidinecarboxylate;

3- (3 -pyridyl) propyl 1- (2-oxo-2-phenylacetyl) -2- piperidinecarboxylate ;

3- (3-pyridyl)propyl 1- (3,3-dimethyl-2- oxopentanoyl ) -2 -piperidinecarboxylate ; 4-phenyl-1- (3-phenylpropyl) butyl 1- (3 , 3-dimethyl-

2 -oxopentanoyl) -2 -piperidinecarboxylate ;

4- (4-methoxyphenyl) butyl 1- (3 , 3 -dimethyl -2 - oxopentanoyl ) -2 -piperidinecarboxylate ;

1- (4-methoxyphenethyl) -4-phenylbutyl 1- (3,3- dimethyl-2 -oxopentanoyl) -2 -piperidinecarboxylate ;

3- (2, 5 -dimethoxyphenyl) propyl 1- (3 , 3 -dimethyl-2- oxopentanoyl) -2 -piperidinecarboxylate;

3- (l,3-benzodioxol-5-yl)propyl 1- (3 , 3-dimethyl-2- oxopentanoyl) -2 -piperidinecarboxylate; 1-phenethyl-3 -phenylpropyl 1- (3 , 3 -dimethyl-2- oxopentanoyl) -2 -piperidinecarboxylate ;

4- (4-methoxyphenyl) butyl 1- (2-cyclohexyl-2- oxoacetyl) -2 -piperidinecarboxylate ;

3 -cyclohexylpropyl 1- ( 2 -cyclohexyl -2 -oxoacetyl) - 2 -piperidinecarboxylate ;

3-phenylpropyl 1- (2-cyclohexyl-2-oxoacetyl) -2- piperidinecarboxylate ;

3-cyclohexylpropyl 1- (3 , 3-dimethyl-2- oxobutanoyl) -2-piperidinecarboxylate;

3-phenylpropyl 1- (3, 3 -dimethyl-2-oxobutanoyl) -2- piperidinecarboxylate ;

4- (4-methoxyphenyl) butyl 1- (3, 3 -dimethyl-2- oxobutanoyl) -2-piperidinecarboxylate ;

4-phenyl-1- (3-phenylpropyl) butyl 1- (3 , 3-dimethy1- 2-oxobutanoyl) -2-piperidinecarboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof.