WO1999062486A1

WO1999062486A1 - N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses

Info

Publication number: WO1999062486A1
Application number: PCT/US1998/011245
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: AU761737B2; AU7716898A; CA2334032A1; JP2002516842A; EP1082095A1

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using N-oxides of heterocyclic esters, amides, thioesters, or ketones.

Description

N-OXIDE OF HETEROCYCLIC ESTER, AMIDE, THIOESTER, OR

KETONE 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

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, small molecule N-oxides of heterocyclic esters, amides, thioesters, or ketones .

2. Description of Related Art

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

The hair growth and revitalization effects of FK506 and related agents are disclosed in many U.S. patents (Goulet et al . , U.S. 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 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 an N-oxide of a heterocyclic ester, amide, thioester, or ketone .

The present invention further relates to a pharmaceutical composition which comprises:

(i) an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone for treating alopecia or promoting hair growth in an animal ; and

(ii) a pharmaceutically acceptable carrier. The N-oxides of heterocyclic esters, amides, thioesters, or ketones used in the inventive methods and pharmaceutical compositions have an affinity for FKBP-type immunophilins and do not exert any significant immunosuppressive activity. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of C57 Black 6 mice before being shaved for the hair regeneration experiment.

FIG. 2 is a photograph of mice treated with a vehicle after six weeks. FIG. 2 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.

FIG. 3 is a photograph of mice treated with 10 μM of GPI 1046, a related non-immunosuppressive neuro- immunophilin FKBP ligand, after six weeks. FIG. 3 shows the remarkable effects of neuro-immunophilin FKBP ligands, wherein 90% of the shaved area is covered with new hair growth.

FIG. 4 is a photograph of mice treated with 30 μM of GPI 1046, a related non- immunosuppressive neuroimmunophilin FKBP ligand, after six weeks. FIG. 4 shows the remarkable ability of these compounds to achieve, essentially, complete hair regrowth in the shaved are . FIG. 5 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, and various non-immunosuppressive neuroimmunophilin FKBP ligands 14 days after treatment with each identified compound. Figure 5 demonstrates the remarkable early hair growth promoted by a wide variety of non-immunosuppressive 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 prolifera ion. This results m 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 1605" refers to a compound of formula

"GPI 1046" refers to 3- (3 -pyridyl) -1-propyl (2s) 1- (3 , 3 -dimethyl -l , 2 -dioxopentyl) -2 pyrrolidinecarboxylate, a compound of formula

"GPI 1312" refers to a compound of formula

"GPI 1572" refers to a compound of formula

'GPI 1389" refers to a compound of formula

"GPI 1511" refers to a compound of formula

'GPI 1234" 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 su 1 f ona t e , cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide , hydroiodide, 2- hydroxye thanesul fonate , lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine ; and salts with amino acids, such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.

"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 m which tne 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 present invention relates to a method for treating alopecia or promoting hair growth m an animal, which comprises administering to said animal an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone.

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: d) an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone for treating alopecia or promoting hair growth in an animal ; and (ii) a pharmaceutically acceptable carrier.

N-OXIDES OF HETEROCYCLIC ESTERS, AMIDES, THIOESTERS, AND KETONES The N-oxides of heterocyclic esters, amides, thioesters, and ketones used in the methods and pharmaceutical compositions of the present invention are low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins , such as FKBP12. When an N-oxide of a heterocyclic ester, amide, thioester, or ketone 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, these compounds have also been found to stimulate hair growth. The compounds are devoid of any significant immunosuppressive activity.

FORMULA I The N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH, CH₂, 0, S, SO, S0₂, N, NH and R_lf- W is 0, S, CH₂, or H₂;

R is

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar_x, which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_x - C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar₂;

Ax_λ and Ar₂ are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , C-_L-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is 0, NH, NR_1; S, CH, CR^ or CR^;

Y is a direct bond,

straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C^ C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂;

R₂ is selected from the group consisting of hydrogen, C₁-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, and C__ - C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is selected from the group consisting of pyridyl , pyrimidyl , quinolinyl, or isoquinolinyl , which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , C^C_g straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄, R₅, and R_s are independently selected from the group consisting of C_j-Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl optionally substituted with one or more substituent (s) independently selected from the group consisting of C₁- C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl , alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with 0-, -C^ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR_X, S, SO, or S0₂;

Ar is selected from the group consisting of pyrrolidinyl, pyridyl , pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl ; and

R_τ and R₃ are independently hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, or Y-Z.

FORMULA II

Additionally, the N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula II

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH₂, O, S, SO,

S0₂, NH or NR_X;

W is O, S, CH₂, or H₂ ;

R is Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁₍ which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C₁- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ax_λ ; Ar_x is selected from the group consisting of 1- napthyl, 2-napthyl, 1- indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl, and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl ,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is 0, NH, NRj, S, CH, CR_X , or CR^, ; Y is a direct bond,

straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_x- C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl , alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,_.-^ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂;

R₂ is selected from the group consisting of hydrogen, C^d straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyi, and C-, - C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ;

Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl , quinolinyl, and isoquinolinyl , which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , C_j-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄, R₅, and R₆ are independently selected from the group consisting of Ci-Cg straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_j-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR_1; S, SO, or S0₂;

Ar is selected from the group consisting of pyrrolidinyl , pyridyl, pyrimidyl, pyrazyl, pyridazyl , quinolinyl, and isoquinolinyl ; and

Ri and R₃ are independently hydrogen, C₁-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , or Y-Z. FORMULA III

The N-oxide of a heterocyclic ester, amide, thioester, or ketone may further be a compound of formula III

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

E, F, and G are independently CH₂, O, S, SO, S0₂, NH or NR_1;-

W is O, S, CH₂, or H₂;

R is

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar_lf which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C₁- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar_l-

Ax_λ is selected from the group consisting of 1- napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl ,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is O, NH, NR_X, S, CH, CR_lf or CR^;

Y is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_x- C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂; R₂ is selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , and C_x- C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl , quinolinyl, or isoquinolinyl , which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , Cn-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C^d alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄ , R_ς, and

R₆ are independently selected from the group consisting of Ci-Cg straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of -Cg straight or branched chain alkyl,

C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Cj-C, alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR_lf S, SO, or S0₂;

Ar is selected from the group consisting of pyrrolidinyl , pyridyl, pyrimidyl, pyrazyl, pyridazyl , quinolinyl, and isoquinolinyl; and R_x and R₃ are independently hydrogen, C₁-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, or Y-Z.

FORMULA IV

Moreover, the N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula IV

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2, or 3, forming a 5-7 member heterocyclic ring; W is 0, S, CH₂, or H₂;

R is C_j-C₈ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl,

C₅-C₇ cycloalkenyl, or Ar₁₍ which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C__ -

C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar_1#- Ax_λ is selected from the group consisting of 1- # napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl ,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is 0, NH. NR₁₍ S, CH, CR_X , or CR₁R₃ ;

Y is a direct bond,

straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_X- C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂; R₂ is selected from the group consisting of hydrogen, C₁-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , and C_x- C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused co an Ar group ; Z is an aromatic amine or a tertiary araine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, crifluoromechyl , C-_L-C₈ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_ι~C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄, R₅, and

R_s are independently selected from the group consisting of -C₈ straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl ; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C₃,-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR_lf S, SO, or S0₂;

Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R-_L and R₃ hydrogen, C₁-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , or Y-Z.

Examples of the compounds of formula IV when W is 0 are presented in TABLE I .

TABLE I

No. n X Y R

1 1 O (CH₂)₃ 3-Pyridyl N-oxide 1 , 1-dimethylpropyl

2 1 O (CH₂)₃ 2-Pyridyl N-oxide 1 , 1-dimethylpropyl

3 1 O (CH₂)₃ 4-Pyridyl N-oxide 1, 1-dimethylpropyl

4 1 O (CH₂)₃ 2-Quinolyl N-oxide 1 , 1-dimethylpropyl

5 1 O (CH₂)₃ 3-Quinolyl N-oxide 1, 1-dimethylpropyl

6 1 O (CH₂)₃ 4-Quinolyl N-oxide 1, 1-dimethylpropyl Preferred compounds of formula IV may be selected from the group consisting of:

3- (2-Pyridyl) -1 -propyl (2S) -1- (1 , 1-Dimethyl-l , 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (3 -Pyridyl) -1 -propyl (2S) -1- (1 , 1-Dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (4-Pyridyl) -1 -propyl (2S) -1- (1, 1-Dimethyl-l , 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (2-Quinolyl) -1-propyl (2 S) -1- (1, 1-Dimethyl-l , 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (3-Quinolyl) -1 -propyl (2S) -1- (1, 1-Dimethyl-l , 2 - dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (4-Quinolyl) -1-propyl ( 2 S) -1- (1, 1-Dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; and pharmaceutically acceptable salts, esters, and solvates thereof .

FORMULA V

The N-oxide of a heterocyclic ester, amide, thioester, or ketone may further be a compound of formula V

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is C, N, or S;

A and B, taken together with V and the carbon atom to which they are respectively attached, form a

5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom (s) independently selected from the group consisting of 0, S, SO, S0₂, N, NH, and NR₇; R₇ is either

straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₃, wherein R₇ is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl ,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C,-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl , and Ar₄;

Ar₃ and Ar₄ 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 ; and

R, W, X, Y, and Z are as defined in Formula I above . All the compounds of Formulas I-V 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-V. It is understood that the compounds of Formulas I-V 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.

K₁ 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 ec al . , Nature, 1989, 341:758-760; Holt et al . J. Am . Chem . Soc . , 115:9923-9938). These values are obtained as apparent K s and are presented for representative compounds in TABLE II. The cis- trans isomerization of an alanme-prolme bond m a model substrate, N-succmyl-Ala-Ala-Pro-Phe- p-nicroanilide, is monitored speccrophotometrically 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 firs -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 Duffer (25 mM HEPES, pH 7.8, 100 mM NaCl) , 10 mL of FKBP (2.5 mM m 10 mM Tπs-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml m 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 (succmyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL m 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 t me data files. Data is presented in Table II for 3- (3-Pyridyl) - 1 -propyl ( 2 S) -1- (1 , 1-Dimethyl-l , 2 -dioxopentyl ) -2- pyrrolidine-carboxylate, N-oxide (compound 1) and its parent (unoxidized) compound.

Table II In Vi tro Test Results - Formulas I to V Compound K. (nM)

Parent 7.5 1 225

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 Synthesis of 3- (3-pyridyl) -1-propyl (2S) -1- (3, 3- Dimethyl- 1 , 2-dioxopentyl) -2 -pyrrolidinecarboxylate,

N-oxide (1) Methyl ( 2 S ) - 1- (1,2 -dioxo-2 -me thoxyethyl ) -2 - pyrrolidinecarboxylate

A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in dry methylene chloride was cooled to 0°C and treated with triethylamine (3.92 g; 38.74 mmol; 2.1 eq) . After stirring the formed slurry under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride

(3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hour. After filtering to remove solids, the organic phase was washed with water, dried over

MgS0₄ and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis - trans amide rotamers; data for trans rotamer given. *H NMR (CDC1₃) : δ 1.93 (dm, 2H) ; 2.17 (m, 2H) ; 3.62 (m, 2H) ; 3.71 (s, 3H) ; 3.79, 3.84 (s, 3H total) ; 4.86 (dd, 1H, J = 8.4, 3.3) . Methyl (2S)-1- (1,2 -dioxo-3 , 3 -dimethylpentyl ) -2- pyrrolidinecarboxylate

A solution of methyl ( 2S) -1- (1 , 2-dioxo-2- methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78°C and treated with 14.2 mL of a 1.0 M solution of 1 , 1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78°C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%) of the oxamate as a colorless oil. ^lH NMR (CDC1₃) : δ 0.88 (t, 3H) ; 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H) ; 1.87-2.10 (m, 3H) ; 2.23 (m, 1H) ; 3.54 (m, 2H) ; 3.76 (s, 3H) ; 4.52 (dm, 1H, J = 8.4, 3.4) . ( 2 S ) -1- (1, 2-dioxo-3 , 3 -dimethylpentyl) - 2 - pyrrolidinecarboxylic acid

A mixture of methyl (2S) -1- (1, 2-dioxo-3 , 3- dimethylpentyl-2-pyrrolidine-carboxylate (2.10 g; 8.23 mmol) , 1 N LiOH (15 mL) , and methanol (50 mL) was stirred at 0°C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. *H NMR (CDC1₃) : d 0.87 (t, 3H) ; 1.22, 1.25 (ε, 3H each); 1.77 (dm, 2H) ; 2.02 (m, 2H) ; 2.17 ( , 1H) ; 2.25 (m, 1H) ; 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, 1H, j = 8.6, 4.1) .

3- (3-Pyridyl) -1 -propyl ( 2 S ) -1- (3,3-dime hyl-l,2- dioxopentyl) -2 -pyrrolidinecarboxylate

A mixture of ( 2 S ) - 1 - ( 1 , 2 - dioxo- 3 , 3 - dimethylpentyi) -2-pyrrolidinecarboxylic acid (4.58 g; 19 mmol), 3 -pyridinepropanol (3.91 g; 28.5 mmol), dicyclohexylcarbodiimide (6.27 g; 30.4 mmol), camphorsuifonic acid (1.47 g; 6.33 mmol) and 4- dimethyl aminopyridine (773 mg; 6.33 mmol) in methylene chloride (100 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo . The crude material was triturated with several portions of ether, and the ether portions were filtered through Celite to remove solids and concentrated in vacuo. The concentrated filtrate was purified on a flash column (gradient elution, 25% ethyl acetate in hexane to pure ethyl acetate) to obtain 5.47 g (80%) of GPI 1046 as a colorless oil (partial hydrate) . ^lH NMR (CDC1₃, 300 MHz): δ 0.85 (t, 3H) ; 1.23, 1.26 (s, 3H each) ; 1.63- 1.89 (m, 2H) ; 1.90-2.30 (m, 4H) ; 2.30-2.50 (m, 1H) ; 2.72 (t, 2H) ; 3.53 (m, 2H) ; 4.19 (m, 2H) ; 4.53 (m, 1H) ; 7.22 (m, 1H) ; 7.53 (dd, 1H) ; 8.45. Analysis calculated for C₂₀H₂₈NO₄ - 0.25 H₂0 : C, 65.82; H, 7.87; N, 7.68. Found: C, 66.01; H, 7.85; N, 7.64. 3- (3 -Pyridyl) -1-propyl ( 2 S) -1- (3 , 3 -dimethyl -1 , 2 - dioxopentyl) -2-pyrrolidinecarboxylate , N-oxide (1)

A solution of 3- (3-pyridyl) -1 -propyl (2S) -1- (3,3- dimethyl-1 , 2 -dioxopentyl) -2 -pyrrolidinecarboxylate

(190 mg; 0.52 mmol) and m-chloroperbenzoic acid (160 mg of 57%-86% material, 0.53 mmol) was stirred in methylene chloride (20 mL) at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride and washed twice with 1 N NaOH. The organic extract was dried and concentrated, and the crude material was chromatographed, eluting with 10% methanol in ethyl acetate, to obtain 130 mg of the Compound 1 of Example 1. ^XH NMR (CDC1₃, 300 MHz): δ 0.83 (t, 3H) ; 1.21 (s, 3H) ; 1.25 (s, 3H) ; 1.75-2.23 (m, 8H) ; 2.69 (t, 2H, J = 7.5); 3.52 (t, 2H, J = 6.3); 4.17 (dd, 2H, J = 6.3); 4.51 (m, 1H) ; 7.16-7.22 (m, 2H) ; 8.06-8.11 (m, 2H) . Analysis calculated for C₂₀H₂₈N₂O₅ - 0.75 H₂0: C, 61.60; H, 7.63; N, 7.18. Found: C, 61.79; H, 7.58; N, 7.23. Example 2

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 a low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligand, GPI 1046, which is related to N-oxides of heterocylic esters, amides, thioesters, and ketones. Referring now to FIGS. 1 and 2 of the drawings, 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. 2, 3 and 4, four animals per group were treated by topical administration with 20% propylene glycol vehicle (FIG. 2), 10 μM GPI 1046 (FIG. 3) or 30 μM GPI 1046 (FIG. 4) dissolved in the vehicle. The animals were treated with vehicle or GPI 1046 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. 2 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. In contrast, FIG. 3 shows that animals treated with 10 μM GPI 1046 exhibited dramatic hair growth, covering greater than 90% of the shaved area in all animals. Further, FIG. 4 shows that mice treated with 30 μM GPI 1046 exhibited essentially complete hair regrowth and their shaved areas were indistinguishable from unshaven C57 black 6 mice.

Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of various low molecular weight, small molecule, non- immunosuppressive neuroimmunophilin FKBP ligands. 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 one of the low molecular weight, small molecule, non- immunosuppressive neuroimmunophilin FKBP ligands (GPI 1605, 1046, 1312, 1572, 1389, 1511, and 1234) 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 any one of the low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligands exhibited dramatic hair growth.

Example 3

A lotion comprising the following composition may be prepared.

Into 95% ethanol are added an N-oxide of a heterocylic ester, amide, thioester, or ketone, 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 4

A lotion comprising the following composition may be prepared.

Into 95% ethanol are added an N-oxide of a heterocylic ester, amide, thioester, or ketone, 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 5

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 6

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 7

A liquid comprising the following composition may be prepared.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, an N-oxide of a heterocylic ester, amide, thioester, or kecone, and perfume. The resulcing 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 8

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 an N-oxide of a heterocylic ester, amide, thioester, or ketone, 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 9

A patient is suffering from alopecia senilis. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 male pattern alopecia. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 alopecia areata. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 skin lesions. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 tumors. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 a systematic disorder, such as a nutritional disorder or an internal secretion disorder. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 patienc is suffering from hair loss caused by chemotherapy. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 16 A patient is suffering from hair loss caused by radiation. An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 che 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 an N-oxide of a heterocyclic ester, amide, thioester, or ketone .

2. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is non-immunosuppressive .

3. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone has an affinity for an FKBP-type immunophilin.

4. The method of claim 3 , wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is FKBP-12.

5. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH, CH₂, 0, S, SO, S0₂, N, NH and NR_X; W is 0, S, CH₂, or H₂ ;

R is C-_L-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar_1; which is optionally substituced with one or more substituent (s) independently selected from the group consisting of C__- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₃-C₇ cycloalkenyl, and Ar₂ ;

Ar_x and Ar₂ are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyi, 2- pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl ,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is 0, NH, NR_X, S, CH, CR_1# or CR^ ;

Y is a direct bond, straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_:- C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl , alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR₂, S, SO, or S0₂;

R₂ is selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , and C_:- C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_:-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄, R₅, and R₆ are independently selected from the group consisting of C-_L-Cg straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl ; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_j-Cg straight or branched chain alkyl, C₂-C₃ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₃-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C_:-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR_1; S, SO, or S0₂ ;

Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R_j and R₃ are independently hydrogen, C^-^ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, or Y-Z.

6. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula II

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: ╬₧, F, G and J are independently CH₂ , 0, S, SO,

S0₂, NH or NR_╬╣;

W is O, S, CH₂, or H₂;

R is

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C_a cycloalkyl, C₅-C₇ cycloalkenyl, or Ar_lf which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C__ - C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar_x; Ar_x is selected from the group consisting of 1- napthyl , 2-napthyl, 1- indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl ,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is 0, NH, NR_X, S, CH, CR,, or CR_XR₃ ; Y is a direct bond,

straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C^ C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂ ;

R₂ is selected from the group consisting of hydrogen, 0,-0₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , and C-_- C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ;

Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , -Cg straight or branched chain alkyl, C₂-C_G straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino ; said tertiary amine is NR₄R₅R₆, wherein R₄ , R₅, and R₆ are independently selected from the group consisting of straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl ; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from che group consisting of

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C-_L-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR_l; S, SO, or S0₂;

R_x and R, are independently hydrogen, C_J-C_J straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , or Y-Z.

7. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula III

or a pharmaceutically accepcable salt, ester, or solvate thereof, wherein:

E, F, and G are independently CH₂ , O, S, SO, S0₂, NH or NR_1#- W is 0, S, CH₂, or H₂ ;

R is 0,-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₃-C₇ cycloalkenyl, or Ax_ , which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_x- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar_:;

Ax_╬╗ is selected from the group consiscing of 1- napthyl , 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , C^C_g straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NR_lf S _ CH, CR_X , or CR_XR₃ ; Y is a direct bond,

straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C-_- C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl , alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with

alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂;

R₂ is selected from the group consisting of hydrogen, C -C^ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , and C__- C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ;

Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino ; said tertiary amine is NRΓÇ₧R₅R₆, wherein R₄, R₅, and R₆ are independently selected from the group consisting of C.-Cg straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of

straight or branched chain alkyl,

C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR_X, S, SO, or S0₂;

R_x and R₃ are independently hydrogen, C_j-^ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyi, or Y-Z.

8. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula IV

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3 forming a 5-7 member heterocyclic ring ;

W is O, S, CH₂, or H₂ ;

R is C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar_x, which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C__- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar_x; Ar, is selected from the group consisting of 1- napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl ,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and ammo;

X is 0, NH, NR_X, S, CH, CR_X , or CR^, ; Y is a direct bond, 0,-Cg straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is opcionally substituted with one or more substituent (s) independently selected from the group consisting of C_╬╗- C_b straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂ ;

R₂ is selected from the group consisting of hydrogen, C^C,, straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, and C_╬╗- C₄ bridging alkyl where a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar grou ; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , C-_L-C_J straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄, R₅, and

R₆ are independently selected from che group consisting of Ci-Cg straight or branched chain alkyl and C₂-C₃ straight or branched chain alkenyl ; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C-_L-Cg straight or branched chain alkyl,

C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR_X, S, SO, or S0₂;

Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R₁ and R₃ are independently hydrogen, C^^ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyi, or Y-Z.

9. The method of claim 8, wherein the compound is selected from the group consisting of:

3- (2-Pyridyl) -1 -propyl (25) -1- (1 , 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (3-Pyridyl) -1 -propyl (2S) -1- (1 , 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide;

3 - (4 -Pyridyl ) - 1 -propyl (2 S) - 1- ( 1 , 1 -Dimethyl -1,2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (2-Quinolyl) -1-propyl (2S) -1- (1, 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-Quinolyl) -1 -propyl (2S) -1- (1, 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (4-Quinolyl) -1 -propyl ( 2S) -1- (1 , 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; and pharmaceutically acceptable salts, esters, and solvates thereof.

10. The method of claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula V

5-7 membered saturated or unsacuraCed heterocyclic ring containing, in addition to V, one or more heteroatom (s) selected from the group consisting of 0,

S, SO, S0₂, N, NH, and NR₇; R₇ is either

straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₃ , wherein R₇ is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl ,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0,-0₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, chioalkyl , alkylthio, sulfhydryl, ammo, alkylamino, aminoalkyl , aminocarboxyl , and Ar₄;

Ar₃ and Ar₄ are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; where said heterocyclic ring contains 1-6 heteroatom (s) independently selected from the group consisting of 0, N, and S; and

R, W, X, Y, and Z are as defined in claim 5 above .

11. A pharmaceutical composition which comprises :

(I) an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone for treating alopecia or promoting hair growth m an animal ; and

(ii) a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, wherem the N-oxide of a heterocyclic ester, amide, thioester, or ketone is non- immunosuppressive .

13. The pharmaceutical composition of claim 11, wherem the N-oxide of a heterocyclic ester, amide, thioester, or ketone has an affinity for an FKBP-type immunophilin.

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

15. The pharmaceutical composition of claim 11, wherem the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherem:

A and B are taken together, with the nitrogen and carbon atoms to whicn they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH, CH₂, 0, S, SO, S0₂, N, NH and NR_X; W is 0, S, CH₂, or H₂;

R is 0,-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁₍ which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C__- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar₂;

Ar, and Ar₂ are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2 -indolyl, 2-furyl, 3-furyl, 2-th╬╣enyl, 3-th╬╣enyl, 2- pyndyl, 3 -pyridyl, 4 -pyridyl, and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , 0,-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and ammo; X is 0, NH, NR_1# S, CH, CR_1; or CR^ ;

Y is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherem said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C__ - C₆ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, C,-C₈ cycloalkyl, C₅ - C_╬╖ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl , alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂;

R₂ is selected from the group consisting of hydrogen, C₁-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, and C__ - C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherem said ring is optionally fused to an Ar group ; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , 0,-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅Rg, wherem R₄ , R₅, and R₆ are independently selected from the group consisting of C,-C₆ straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C,-C₆ straight or branched chain alkyl, C₂-C₃ straight or branched chain alkenyl, C₃-C_a cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with 0,-0₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR_lf S, SO, or S0₂;

Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R, and R₃ are independently hydrogen, 0,-0₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , or Y-Z.

16. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula II

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH₂ , O, S, SO,

S0₂, NH or NR,;

W is 0, S, CH₂, or H₂;

R is C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar,, which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C,- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar,; Ar, is selected from the group consisting of 1- napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is 0, NH, NR,, S, CH, CR,, or CR,R₃ ; Y is a direct bond, C,-C₆ straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C,- C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl , alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂ ;

R₂ is selected from the group consisting of hydrogen, C,-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , and C,- C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ;

Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C,-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄, R₅, and R₆ are independently selected from the group consisting of C,-C₆ straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₃-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR,, S, SO, or S0₂;

R, and R₃ are independently hydrogen, C,-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl , or Y-Z.

17. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula III

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

E, F, and G are independently CH₂, O, S, SO, S0₂, NH or NR,;

W is 0, S, CH₂, or H₂; R is C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar, , which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C,- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar, ;

Ar, is selected from the group consisting of 1- napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NR,, S, CH, CR,, or CR,R₃; Y is a direct bond, C,-C₆ straight or branched chain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C,- C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR₂, S, SO, or S0₂;

Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, ^ci^_C straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C,-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R_SR₆, wherein R₄, R₅, and R_╬▓ are independently selected from the group consisting of C,-C₆ straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of

straight or branched chain alkyl, ^C ₂ ^_C ₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR,, S, SO, or S0₂;

R, and R₃ are independently hydrogen, C,-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, or Y-Z.

18. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula IV

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3 forming a 5-7 member heterocyclic ring; W is O, S, CH₂, or H₂;

R is C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar,, which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C,- C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar,;

Ar, is selected from the group consisting of 1- napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , C,-C₈ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

R₂ is selected from the group consisting of hydrogen, C,-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, and C,- C₄ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ;

Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C,-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄, R₅, and R₆ are independently selected from the group consisting of C,-C₆ straight or branched chain alkyl and C₂-C₆ straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C,-C₆ straight or branched chain alkyl,

C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C,-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR,, S, SO, or S0₂;

19. The pharmaceutical composition of claim 18, wherein the compound is selected from the group consisting of:

3- (2-Pyridyl) -1-propyl (2S) -1- (1, 1-Dimethyl-l, 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (3-Pyridyl) -1 -propyl (2S) -1- (1, 1-Dimethyl-l, 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (4 -Pyridyl) -1 -propyl (2S) -1- (1, 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (2-Quinolyl) -1-propyl (2S) -1- (1 , 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (3-Quinolyl) -1-propyl (2S) -1- (1, 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (4-Quinolyl) -1-propyl ( 2 S) -1- (1, 1-Dimethyl-l , 2- dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; and pharmaceutically acceptable salts, esters, and solvates thereof .

20. The pharmaceutical composition of claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester, or ketone is a compound of formula V

5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom (s) selected from the group consisting of 0,

S, SO, S0₂, N, NH, and NR₇; R₇ is either C,-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₃, wherein R₇ is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C,-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C,-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl , aminocarboxyl , and Ar₄;

Ar₃ and Ar₄ 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 0, N, and S; and

R, W, X, Y, and Z are as defined in claim 15 above .