CA2292910C - Hair growth compositions and uses - Google Patents

Hair growth compositions and uses Download PDF

Info

Publication number
CA2292910C
CA2292910C CA002292910A CA2292910A CA2292910C CA 2292910 C CA2292910 C CA 2292910C CA 002292910 A CA002292910 A CA 002292910A CA 2292910 A CA2292910 A CA 2292910A CA 2292910 C CA2292910 C CA 2292910C
Authority
CA
Canada
Prior art keywords
straight
branched chain
alkyl
alkenyl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA002292910A
Other languages
French (fr)
Other versions
CA2292910A1 (en
Inventor
Gregory S. Hamilton
Joseph P. Steiner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GPI Nil Holdings Inc
Original Assignee
GPI Nil Holdings Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GPI Nil Holdings Inc filed Critical GPI Nil Holdings Inc
Publication of CA2292910A1 publication Critical patent/CA2292910A1/en
Application granted granted Critical
Publication of CA2292910C publication Critical patent/CA2292910C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/70—Biological properties of the composition as a whole

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using non-immunosuppressive neuroimmunophilin FKBP ligands.

Description

HAIR GROWTH COMPOSITIONS AND USES

BACKGROUND OF THE INVENTION
1. Field of Invention This invention relates to pharmaceutical compositions methods for treating alopecia and promoting hair growth using non-immunosuppressive neuroimmunophilin FKBP ligands.
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 cau4ing 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 a non-immunosuppressive neuroimmunophilin FKBP ligand.

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

(i) an effective amount of a non-immunosuppressive neuroimmunophilin FKBP ligand for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

As its name suggests, the non-immunosuppressive neuroimmunophilin FKBP ligand used =n th:: =nvent.'-.ve method and pharmaceutical composition has an affinity for FKBP-type immunophilins and does not exert any significant immunosuppressive activity. In a preferred embodiment, the non-immunosuppressive neuroimmunophilin FKBP ligand is selected from the group consisting of: a heterocyclic thioester or ketone; a heterocyclic ester or amide; an N-oxide of a heterocyclic ester, amide, thioester, or ketone; an N-linked urea or carbamate of a heterocyclic thioester; an N-linked sulfonamide of a heterocyclic , thioester; and a pyrrolidine derivative.
BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of C57 Black 6 mice before being shaved for the experiment. FIG. 1 shows the condition of the mice prior to the 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 M
of GPI 1046 after six weeks. FIG. 3 shows the remarkable effects of non-immunosuppressive neuroimmunophilin FKBP ligands wherein 90% of the shaved area is covered with new hair growth.

FIG. 4 is a photograph of mice treated with 30 M
of GPI 1046 after six weeks. FIG. 4 shows the remarkable ability of non-immunosuppressive neuroimmunophilin FKBP ligands to achieve, essentially, complete hair regrowth in the shaved area.

FIG. 5 is a bar graph depicting the relative hair growth indices of mice treated with a vehicle, FK506, and various non-immunosuppressive neuroimmunophilin FKBP ligands 14 days after treatment with each identified compound. FIG. 5 demonstrates the remarkable early hair growth promoted by 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 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 1605" refers to a compound of formula S
N
O
HN O
"GPI 1046" refers to 3- (3-pyridyl) -1-propyl (2s) -1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, a compound of formula N
o O
O
O

"GPI 1312" refers to a compound of formula N
I
o=S=O O

"GPI 1572" refers to a compound of formula N
S
O
N/
r, O O
O

"GPI 1389" refers to a compound of formula N
N
O O

to "GPI 1511" refers to a compound of formula N
o 0 "GPI 1234" refers to a compound of formula s CN~'Y 0 o o "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;ixture con,~:aininq equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal parts of individual enantiomers or stereoisomers.

"Pharmaceutically acceptable salt" refers to a salt of the inventive compounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. The salt can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocya-nate, tosylate and undecanoate. Examples of a base salt 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 and lysine. Also, the basic nitrogen-containing groups can be quarternized with agents including: 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; and aralkyl halides such as benzyl and phenethyl bromides.

"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, 5 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 10 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 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 non-immunosuppressive neuroimmunophilin FKBP ligand.

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 pharma-ceutical composition comprising:

(i) an effective amount of a non-immunosuppressive neuroimmunophilin FKBP
ligand for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.

Non-Ixnmunosuppressive Neuroimmunophilin FKBP Ligands The non-immunosuppressive neuroimmunophilin FKBP
ligand used in the method and pharmaceutical composition of the present invention is a low molecular weight, small molecule compound having an affinity for an FKBP-type immunophilin, such as FKBP12. When the compound binds to an FKBP-type immunophilin, it has been found to inhibit the prolyl-peptidyl cis-trans isomerase activity, or rotamase, activity of the binding protein. Unexpectedly, the compound has also been found to stimulate hair growth.
As its name suggests, the compound is devoid of any significant immunosuppressive activity.

Examples of a non-immunosuppressive neuroimmunophilin FKBP ligand that may be used in the inventive method and pharmaceutical composition are set forth below.

I. HETEROCYCLIC THIOESTERS AND KETONES
FORMULA I

The non-immunosuppressive neuroimmunophilin FKBP
ligand may be a compound of formula I
fl N Rl I

T2, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of 0, S, SO, SO2, N, NH, and NR2;

X is either 0 or S;

Z is either S, CH2, CHRl or CR1R3;

W and Y are independently 0, S, CH2 or H2;

R1 and R. are independently C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Arl) n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl) n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, and Ar2;
n is 1 or 2;

R2 is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-CQ straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, and hydroxy;
and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein sa-id ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-Cq alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 hetercatom(s) independently selected from the group consisting of 0, N, and S.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, 5 thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, 10 quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

FORMTTLA II
15 The non-immunosuppressive neuroimmunophilin FKBP
ligand may also be a compound of formula II

[CH2] n ~ZR1 II
o x or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

n is 1 or 2;
X is 0 or S;

Z is selected from the group consisting of S, CH21 CHR1, and CR1R3;

R1 and R. are independently selected from the group consisting of C1-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, and Arl, wherein said alkyl, alkenyl or Arl is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, and Ar,;

R2 is selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS - C, cycloalkenyl, and Arl; and Arl is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said Arl is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, trifluoromethyl, hydroxy, nitro, C1-CE straight or branched chain alkyl, C2-Cl stra=qht or branched chain alkenyl, Cl-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino.

Preferred compounds of formula II are presented in TABLE I.
TABLE I

No. n X Z R, R2 1 1 0 CH2 3-Phenylpropyl 1,1-Dimethylpropyl 2 1 0 CH2 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 3 1 0 CH2 3-Phenylpropyl tert-Butyl 4 1 0 CH2 3-(3-Pyridyl)propyl tert-Butyl 5 1 0 CH2 3-(3-Pyridyl)propyl Cyclohexyl 6 1 0 CH2 3-(3-Pyridyl)propyl Cyclopentyl 7 1 0 CH2 3-(3-Pyridyl)propyl Cycloheptyl 8 1 0 CH2 2-(9-Fluorenyl)ethyl 1,1-Dimethylpropyl 9 1 0 S 2-Phenethyl 1,1-Dimethylpropyl 10 2 0 S 2-Phenethyl 1,1-Dimethylpropyi 11 1 0 S Methyl(2-thioindole) 1,1-Dimethylpropyl 12 1 0 S 2-Phenethyl Cyclohexyl 13 2 0 S 2-Phenethyl tert-Butyl 14 2 0 S 2-Phenethyl Phenyl 15 1 0 CH2 3-(4-Methoxyphenyl)propyl 1,1-Dimethylpropyl 16 2 0 CH2 4-(4-Methoxyphenyl)butyl 1,1-Dimethyipropyl 17 2 0 CH2 4-Phenylbutyl 1,1-Dimethylpropyl 18 2 0 CH2 4-Phenylbutyl Phenyl 19 2 0 CH2 4-Phenylbutyl Cyclohexyl 20 1 S CH2 3-Phenylpropyl 1,1-Dimethylpropyl 21 1 S S 2-Phenethyl 1,1-Dimethylpropyl 22 2 S CH2 3-Phenylpropyl 1,1-Dimethylpropyl TABLE I (continued) No. n X Z R, R2 23 2 S S 2-Phenethyl 1,1-Dimethylpropyl 24 2 0 CHR, 3-Phenylpropyl 1,1-Dimethylpropyl 25 2 0 CHR, 3-Phenylpropyl Cyclohexyl 26 2 0 CHR, 3-Phenylpropyl Phenyl 27 2 0 CHR, 3-Phenyipropyl 3,4,5-Trimethoxy-phenyl 28 1 0 S 2-Phenethyl Cyclopentyl 29 2 0 S 3-PhenyipropyI tert-Butyl 30 1 0 S 3-Phenylpropyl 1,1-Dimethylpropyl 31 1 0 S 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 32 1 0 S 3-Phenylpropyl Cyclohexyl 33 1 0 S 4-Phenylbutyl Cyclohexyl 34 1 0 S 4-Phenylbutyl 1,1-Dimethylpropyl 35 1 0 S 3-(3-Pyridyl)propyl Cyclohexyl 36 1 0 S 3,3-Diphenylpropyl 1,1-Dimethylpropyl 37 1 0 S 3,3-Diphenylpropyl Cyclohexyl 38 1 0 S 3-(4-Methoxyphenyl) 1, 1 -Dimethylpropyl propyl 39 2 0 S 4-Phenylbutyl tert-Butyl 40 2 0 S 1,5-Diphenylpentyl 1,1-Dimethylpropyl 41 2 0 S 1,5-Diphenylpentyl Phenyl 42 2 0 S 3-(4-Methoxyphenyl) 1,1-Dimethylpropyl propyl TABLE I (continued) No. n X Z R, R2 43 2 0 S 3-(4-IVlethoxyphenyl) Phenyl propyl 44 2 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 45 1 0 S 3,3-Di(4-fluoro)phenyl- 1,1-Dimethylpropyl propyl 46 1 0 S 4,4-Di(4-fluoro)phenyl- 1,1-Dimethylpropyl butyl 47 1 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 48 1 0 S 2,2-Diphenylethyl 1,1-Dimethylpropyl 49 2 0 S 2,2-Diphenylethyl 1,1-Dimethylpropyl 50 2 0 S 3,3-Diphenylpropyl 1,1-Dimethylpropyl 51 1 0 S 3-(4-{Trifluoromethyl}- 1,1-Dimethylpropyl phenyl)propyl 52 1 0 S 3-(2-Naphthyl)propyl 1,1-Dimethylpropyl 53 2 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 54 1 0 S 3-(3-Chloro)phenylpropyl 1,1-Dimethylpropyl 55 1 0 S 3-(3-{Trifluoromethyl}- 1,1-Dimethylrropyl phenyl)propyl 56 1 0 S 3-(2-Biphenyl)propyl 1, 1-Dimethylpropyl 57 1 0 S 3-(2-Fluorophenyl)propyl 1,1-Dimethyipropyl 58 1 0 S 3-(3-Fluorophenyl)propyl 1,1-Dimethylpropyl 59 2 0 S 4-Phenylbutyl 1,1-Dimethylpropyl 60 2 0 S 3-Phenylpropyl 1,1-Dimethylpropyl 61 1 0 S 3-(2-Chloro)phenylpropyl 1,1-Dimethylpropyl TABLE I (continued) No. n X Z R, R2 5 62 2 0 S 3-(3-Chloro)phenylpropyl 1,1-Dimethylpropyl 63 2 0 S 3-(2-Fluoro)phenylpropyl 1,1-Dimethylpropyl 64 2 0 S 3-(3-Fluoro)phenylpropyl 1,1-Dimethylpropyl 65 1 0 S 3-(2,5-Dimethoxyphenyl)- 1,1-Dimethylpropyl propyl 10 66 1 0 CH2 3-Phenylpropyl Cyclohexyl 67 1 0 CH2 3-Phenylethyl tert-Butyl 68 2 0 CH2 4-Phenylbutyl Cyclohexyl 69 2 0 CHR, 2-Phenylethyl tert-Butyl 70 1 0 CH2 3,3-Di(4-fluorophenyl)- l,l-Dimethylpropyl 15 propyl 71 2 0 CH2 3-Phenylpropyl 1,1-Dimethyipropyl Preferred compounds of TABLE I are named as follows:

20 1 (2S)-2-({1-Oxo-5-phenyl}-pentyl-l-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine 2 3,3-Dimethyl-l- [ (2S) -2- (5- (3-pyridyl)pentanoyl) -1-pyrrolidine]-1,2-pentanedione 3 (2S)-2-({l-Oxo-4-phenyl}-butyl-l-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine 9 2-Phenyl-l-ethyl (2S)-1-(3,3-dimethyl-l,2-dioxopentyl)-2-pyrrolidinecarbothioate 10 2-Phenyl-l-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate 11 (3-Thioindolyl)methyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 12 2-Phenyl-l-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 14 2-Phenyl-l-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate 28 2-Phenyl-l-ethyl (2S)-1-(1-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 29 3-Phenyl-l-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate 30 3-Phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 31 3- (3-Pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarbothioate 32 3-Phenyl-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 33 4-Phenyl-l-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 34 4-Phenyl-l-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbotr.i-oate 35 3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 36 3,3-Diphenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 37 3,3-Diphenyl-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 38 3- (para-Methoxyphenyl) -1-propyl (2S) -1- (3, 3-_....~

dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carbothioate 39 4-Phenyl-l-butyl 1- (1,2-dioxo-3,3-dimethylbutyl) -2-piperidinecarbothioate 40 1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate 41 1,5-Diphenyl-3-mercaptopentyl 1-(3-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate 42 3-(para-Methoxyphenyl)-i-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate 43 3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate 44 3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate 45 3,3-Di(para-fluoro)phenyl-i-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carbothioate 46 4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 47 3-(1-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 48 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)tetrahydro-lH-2-pyrrolidine-carbothioate 49 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 50 3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 51 3- [ 4-( Tri f luoromethyl ) phenyl ] propyl ( 2 S) -1- ( 3, 3-dimethyl-2-oxopentanoyl)-2-pyrrolidine-carbothioate 52 3- (2-Naphthyl)propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 53 3- (2-Naphthyl)propyl (2R, S) -1- (3, 3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 54 3- (3-Chlorophenyl)propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 55 3- [3- (Trifluoromethyl)phenyl]propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl)-2-pyrrolidine-carbothioate 56 3-(1-Biphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 57 3-(2-Fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 58 3-(3-Fluorophenyl)propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 59 4-Phenylbutyl 1 - (3, 3 - dimethyl - 2 - oxopentanoyl) - 2 -piperidinecarbothioate 60 3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 61 3-(2-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 62 3-(2-Chlorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 63 3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate WO 98/55090 PCT[US98/11237 64 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 65 3- ( 3 , 4-Dimethoxyphenyl ) propyl ( 2 S) - 1 - ( 3, 3-d i m e t h y 1- 2- o x o p e n t a n o y 1)- 2-pyrrolidinecarbothioate 66 (2S)-2-({1-Oxo-4-phenyl}-butyl-i-(2-Cyclohexyl-1,2-dioxoethyl)pyrrolidine 67 2-({1-Oxo-4-phenyl}-butyl-l-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine 68 2-({1-Oxo-6-phenyl}-hexyl-i-(2-Cyclohexyl-l,2-dioxoethyl)piperidine 69 2-({1-Oxo-[2-{2'-phenyl}ethylJ-4-phenyl}-butyl-l-(3,3-dimethyl-1,2-dioxobutyl)piperidine 70 1-{ (2S) -2- [5, 5-di (4-Fluorophenyl)pentanoyl] -2-pyrrolidine}-3,3-dimethyl-1,2-pentanedione 71 3,3-Dimethyl-l-[2-(4-phenylpentanoyl)piperidino]-1,2-pentanedione FORMULA III

Furthermore, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula III

B-C

~N
III
O x or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

A, B, and C are independently CH2, 0, S, SO, SOz, NH or NR2 ;

5 X is 0 or S;

Z is S, CH2 1 CHRl or CR1R3 ;

R1 and R3 are independently C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is 10 substituted with one or more substituent(s) independently selected from the group consisting of (Arl) n, C1-C6 straight or branched chain alkyl or CZ-C6 straight or branched chain alkenyl substituted with (Arl) ,,, C3-CB cycloalkyl, C1-C6 straight or branched 15 chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-Ce cycloalkyl, and Ar2;

n is 1 or 2;

R2 is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-CB
20 cycloalkyl, C5-C7 cycloalkenyl or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is eicher unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 straight or branched chain alkyl, 25 C2-C4 straight or branched chain alkenyl, and hydroxyl;
and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl;

C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.

Preferred compounds of formula III are presented in TABLE II.

TABLE II

No. A B C X Z R, RZ
72 CH2 S CH2 0 S 2-phenethyl 1,1-dimethyl-propyl 73 CH2 S CH2 0 CHZ 3-phenylpropyl 1,1-dimethyl-propyl 74 CH2 CH2 NH 0 S 2-phenethyl 1,1-dimethyl-propyl 75 CHZ S CH2 S S 2-phenethyl 1,1-dimethyl-propyl FORMULA IV

Alternatively, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula IV

BI-, cD

P' "IN Z R1 IV
O p X

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

A, B, C and D are independently CH2, 0, S, S0, SO2, NH or NR2;

X is 0 or S;

Z is S, CH2 1 CHRl or CR1R3 ;

R1 and R3 are independently C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Arl) n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, and Ar2;

n is 1 or 2;

R2 is either C1-C9 straight or branched chain alkyl, CZ-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain.

alkenyl, and hydroxyl; and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.

Preferred compounds of formula IV are presented in TABLE III.

TABLE III

No. A B C D X Z R, R2 76 CH2 CH2 0 CH2 0 CH2 3-phenylpropyl 1,1-dimethylpropyl 77 CH2 CH2 0 CH2 0 S 2-phenethyl 1,1-d'unethylpropyl 78 CHZ CH2 S CH2 0 CH2 3-phenylpropyl 1,l-dinethylpropyl 79 CHZ CH2 S CH2 0 S 2-phenethyl i,l-dimethylpropyl FORMULA V

The non-immunosuppressive neuroimmunophilin FKBP
ligand may further be a compound of formula V

flB
A'1~
V ~Rl V
Y, w x or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

V is C, N, or S;

A and B, 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, SO2, N, NH, and NR4;

R4 is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloakyl, CS-C7 cycloalkenyl, or Ar3, wherein R4 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-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 5 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 R1, R2, W, X, Y, and Z are as defined in Formula 10 I above.

II. HETEROCYCLIC ESTERS AND AMIDES
FORMULA VI

Additionally, the non-immunosuppressive 15 neuroimmunophilin FKBP ligand may be a compound of formula VI

B
20 Ri Y X
W
12, or a pharmaceutically acceptable salt, ester, or 25 solvate thereof, wherein:

A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more heteroatom(s) independently selected from the group consisting of 0, S, SO, SO2, N, NH, and NRl;

X is 0 or S;

Z is 0, NH or NRl;

W and Y are independently 0, S, CHZ or H2;

Rl is C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, which is substituted with one or more substituent(s) independently selected from the group consisting of (Arl) r,, C1-C6 straight or branched chain alkyl or C2-Cb straight or branched chain alkenyl substituted with (Arl) n, C,-Ce cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-Ce cycloalkyl, and ArZ;

n is 1 or 2; =

R2 is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain or alkenyl, C,-C8 cycloalkyl, CS-C, cycloalkenyl, or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or nicre substituent(s) independently selected from the group consisting of C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, and hydroxyl;
and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, Cz-C, alkoxy, CZ-C, alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.

Suitable carbo- and heterocyclic rings include without limitation naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.

FORMULA VII

The non-immunosuppressive neuroimmunophilin FKBP
ligand may also be a compound of formula VII

B C

A~ O-R1 VII

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

A, B and C are independently CH21 0, S, SO, SO21 NH or NRl ;

Rl is C1-C5 straight or branched chain alkyl or C2-CS straight or branched chain alkenyl, which is substituted with one or more substituent(s) independently selected from the group consisting of (Arl) n and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl) ni n is 1 or 2;

R2 is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-Cg cycloalkyl, CS-C7 cycloalkenyl, or Arl; and Arl is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual r_ny size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.

In a preferred embodiment of the compounds of formula VII, the heterocyclic ester or amide is the Compound GPI 1572, of the formula N
s \.., 0 N/
ir o a In a particularly preferred embodiment of formula VII compounds:

A is CH2;

B is CH2 or S;
C is CH2 or NH;

R1 is selected from the group consisting of 3-phenylpropyl and 3-(3-pyridyl)propyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, and tert-butyl.

Specific examples of this embodiment are presented in TABLE IV.

TABLE IV

No. A B C R, R2 80 CH2 S CH2 3-phenylpropyl 1,1-dimethylpropyl 81 CH2 S CH2 3-(3-pyridyl)propyl 1, 1 -dimethylpropyl 82 CH2 S CH2 3-phenylpropyl cyclohexyl 83 CH2 S CH2 3-phenylpropyl tert-butyl 84 CH, CH2 NH 3-phenylpropyl 1,1-dimethyipropyl 85 CH2 CH2 NH 3-phenylpropyl cyclohexyl 86 CH2 CH2 NH 3-phenylpropyl tert-butyl FORMULA VIII

In a further embodiment of this invention, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula VIII

B/C~D
( VIII

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

A, B, C and D are independently CH2, 0, S, SO, 15 SO2 , NH or NRl ;

Rl is C1-C5 straight or branched chain alkyl or C2-CS straight or branched chain alkenyl, which is substituted with one or more substituent(s) independently selected from the group consisting of 20 (Arl) n and C1-C6 straight or branched chain alkyl or CZ-C6 straight or branched chain alkenyl substituted with (Arl) n;

n is 1 or 2;

R2 is either C1-C9 straight or branched chain 25 alkyl, C2-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, or Arl; and Arl is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, Cz-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.

In a particularly preferred embodiment of formula VIII compounds:

A is CH2;
B is CH2;

C is S, 0 or NH;
D is CHz ;

R1 is selected from the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy)phenylpropyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and 3,4,5-trimethoxyphenyl.

Specific examples of this embodiment are presented in TABLE V.

TABLE V

No. A B C D Rl R2 87 CH2 CH2 S CH2 3-phenylpropyl 1,1-d'unethylpropyl 88 CH2 CH2 0 CH2 3-phenylpropyl 1,14nnethylpropyl 89 CH2 CH2 S CH2 3-phenylpropyl cyclohexyl 90 CH2 CH2 0 CH2 3-phenylpropyl cyclohexyl 91 CH2 CH2 S CH2 3-phenylpropyl phenyl 92 CH2 CH2 0 CH2 3-phenylpropyl phenyl 93 CH2 CH2 NH CH2 3-phenylpropyl 1,1-d'nnethylpropyl 94 CH2 CH2 NH CH2 3-phenylpropyl phenyl FORMULA IX

Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula IX

B
A
v Z
\ ~1 ix Y, wX

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

V is C, N, or S;

A and B, 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, SO2, N, NH, and NR;

R is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, Cj-C9 cycloakyl, C5-C7 cycloalkenyl, or Ar3, wherein R is either unsubstituted or substituted with one ox more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-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 R1, R2, W, X, Y, and Z are as defined in Formula VI above.

III. N-OXIDES OF HETEROCYCLIC ESTERS, AMIDES, THIOESTERS AND KETONES
FORMULA X

The non-immunosuppressive neuroimmunophilin FKBP
ligand may further be a compound of formula X

B

X
O O
W
R
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of CH, CH21 0, S, SO, SO2, N, NH, and NRl;

W is 0, S, CH2, or H2;

R is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ca cycloalkyl, CS-C7 cycloalkenyl, or Arl, 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-CB cycloalkyl, CS-C7 cycloalkenyl, and Ar2;

Arl 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 5 or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;

10 X is 0, NH, NRl, S, CH, CR1, or CR1R3;

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) 15 independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, 20 or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenvl, hydroxy, or carbonyl oxygen; wherein an_-carbon atom of said alkyl, alkenyl, cyc3.oalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NRZ, S, SO, or SOz;

25 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 C1-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, C1-C6 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 NR4RSR6, wherein Rq, R5, and R6 are independently selected from the group consisting of C1-C6 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 cf L;-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;

wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, Cz-C, alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR1, S, SO, or SO2;

Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 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 XI

Moreover, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XI

FiG~ J
I
E, N X-Y-Z

p\ W ~ X I
R

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

E, F, G and J are independently CH21 O, S, SO, SO2, NH or NRl;

W is 0, S, CH21 or H2;

R is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, or Arl, 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-Ce cycloalkyl, CS-C, cycloalkenyl, and Arl;

Arl 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, C1-C6 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, CR1, or CR1R3;

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 C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, C3-C8 cycloalky_, C--C'-cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C9 = 25 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 SO2;

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 C1-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, C1-C6 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 C1-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 C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ca cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with Cl-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is-5 optionally replaced with 0, NH, NR1, S, SO, or SO2;
Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3 are independently hydrogen, C1-C, 10 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, or Y-Z.

FORMULA XII

Furthermore, the non-immunosuppressive 15 neuroimmunophilin FKBP ligand may be a compound of formula XII

F-G
~
E~ X-Y-Z
N
20 xii W
R

or a pharmaceutically acceptable salt, ester, or = 25 solvate thereof, wherein:

E, F, and G are independently CH21 O, S, SO, SOZ, NH or NRl ;

W is 0, S, CH21 or H2;

R is C 1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, or Ar,, 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-Ce cycloalkyl, C5-C7 cycloalkenyl, and Arl;

Arl 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, C1-C6 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, CR1, or CR1R3;

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 substituer. :12~) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Cg cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-Cq 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 SO2;

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 C1-C, 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, Cl-C4 alkoxy, C2-Cq alkenyloxy, phenoxy, benzyioxy, and aminc;

said tertiary amine is NR4RSR6, wherein R4, R5, and R6are independently selected from the group consisting of Cl-Cb straight or branched chain alkyl and Cz-C6 = 25 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 C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-CB
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, NR1, S, SO, or SOZ;

Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 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 XIII

The non-immunosuppressive neuroimmunophilin FKBP
ligand may also be a compound of formula XIII

CH2) n X-Y-Z
N 1~
xiii o lz~:I~ w R

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 C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl,.
CS-C7 cycloalkenyl, or Arl, 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,;

Arl 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, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NRl, S, CH, CRõ or CR1R3;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chzir...
alkenyl; wherein said alkyl or alkenyl is 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, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, CZ-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, 5 NR2, S, SO, or SO2;

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 C1-C4 bridging alkyl wherein a bridge is formed between 10 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 15 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 20 consisting of halo, hydroxy, nitro, trifluoromethyl, Cl-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, Cl-C4 alkoxy, C2-Cq alkenyloxy, phenoxy, benzyloxy, and amino;

said tertiary amine is NR4R5R6, wherein R4, R5, and 25 R. are independently selected from the group consisting of C1-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 C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ce cycloalkyl, C5-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted -with C1-C4 alkyl, CZ-C, alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR1, S, SO, or SO2;
Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 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 XIII when W
is 0 are presented in TABLE VI.

TABLE VI
(CH2) n X-Y-Z
O O

)__~ O
R

No. n X Y Z R
95 1 O(CH2)3 3-Pyridyl N-oxide 1,1-dimethylpropyl 96 1 O(CHZ)3 2-Pyridyl N-oxide 1,1-dimethylpropyl 97 1 O(CH2)3 4-Pyridyl N-oxide 1,1-dimethylpropyl 98 1 O(CH2)3 2-Quinolyl N-oxide 1,1-dimethyipropyl 99 1 O(CH2)3 3-Quinolyl N-oxide 1,1-dimethylpropyl 100 1 O(CHZ)3 4-Quinolyl N-oxide 1,1-dimethylpropyl Preferred compounds of formula XIII may be selected from the group consisting of:

3- (2-Pyridyl) -1-propyl (2S) -1- (1, 1-Dimethyl-l,2-5 dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;

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

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

10 3 - (2 -Quinolyl) - 1 -propyl (2 S) - 1 - (1, 1 - Dimethyl - 1, 2 -dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;
3-(3-Quinolyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;

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

FORMULA XIV

Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XIV

B
A X-Y-Z

O xiv O
W
R

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

V is C, N, or S;

A and B, 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, SO2, N, NH, and NR7;

R7 is either C1-Cy strai ght or branched chair_ alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, CS-C7 cycloalkenyl, or Ar3, wherein R, 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, C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, C1-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 Formula X
above.

IV. N-LINKED UREAS AND CARBAMATES OF HETEROCYCLIC
THIOESTERS
The non-immunosuppressive neuroimmunophilin FKBP

ligand may further be a compound of formula XV
B C
/
P'~ 1 IY S-~'_Z\
N D
xv Ra 1__I LT W X
I

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

A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more additional heteroatom(s) independently selected from the group consisting of 0, S, SO, SOz, N, NH, and NR3;

5 X is either 0 or S;

Y is a direct bond, Cl-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more 10 position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally 15 replaced with 0, NH, NR3, S, SO, or SO2;

R3 is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a bridge is formed between 20 the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to Forn, a ring, wherein said ring is optionally fused to an Ar group;

Ar is an alicyclic or aromatic, mono-, bi- or 25 tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, Cz-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures;
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 wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positicn(s) with amino, halo, haloalkyl, thiocarbony-I , ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S. SO, or SO2;

C and D are independently hydrogen, Ar, 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 C3-C8 cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarboriyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SOz;

W is 0 or S; and U is either 0 or N, provided that:

when U is 0, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C3-Ce cycloalkyl, C1-C6 straight or branched chain alkyl, and C.-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 Ar and C3-CB cycloalkyl;
and when U is N, then R1 and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or Rl and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, t-riazolyl, thiadiazolyl, pyridazinyl, pyrimidinyi, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In a preferred embodiment of formula XV, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

FORMULA XVI

Moreover, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XVI

FG\ H
C
E~ -ly S-Y-Z/
N \ D xvI
R2*111U w X

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

E, F, G and J are independently CH2, O, S, SO, SO2 , NH, or NR3;

X is either 0 or S;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally 5 replaced with 0, NH, NR3, S, SO, or SOZ;

R. 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 C1-C4 bridging alkyl wherein a bridge is formed between 10 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;

Ar is an alicyclic or aromatic, mono-, bi- or 15 tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched 20 chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-CP cvcloalkyl, CS-C7 cycloalkenyl, carbonyl, carcoxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, 25 phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures;

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 wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SOz;

C and D are independently hydrogen, Ar, 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 g.,-oup ;.onsisting of C3-CB cycloalkyl, CS-C7 cycloalkeriyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S. SO, or SOZ;
W is 0 or S; and U is either 0 or N, provided that:

when U is 0, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C3-CB cycloalkyl, C1-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 Ar and C3-C8 cycloalkyl;
and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-CB cycloalkyl, C1-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 Ar and C3-CB cycloalkyl;

or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In a preferred embodiment of formula XVI, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrol ~.dinyi , nvridir_yl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

FORMULA XVII

The non-immunosuppressive neuroimmunophilin FKBP
ligand may also be a compound of formula XVII

F-G
C

N \D
XVII
R2", U W X

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

E, F, and G are independently CH21 O, S, SO, SO21 NH, and NR3;

X is either 0 or S;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is opti= :._--tepiaced with 0, NH, NR3, S, SO, or SO2;

R3 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 C1-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;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the 5 ring is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, Cl-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 10 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, 15 thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures;
wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 20 heteroatom(s) independently selected from the group consisting of 0, N, and S;.and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C1-C6 straight or branched 25 chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2;

C and D are independently hydrogen, Ar, 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 C3-Ce cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkvl or alke~~.yl is optionally replaced with 0, NH, NR3, S, S0, Cr SOz;

W is 0 or S; and U is either 0 or N, provided that:

when U is 0, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C3-Ce cycloalkyl, C1-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 Ar and C3-Ce cycloalkyl;
and when U is N, then R1 and R2 are independently selected from the group consisting of hydrogen, Ar, C3-Ca cycloalkyl, C1-C5 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 Ar and C3-Ca cycloalkyl;
or R1 and Rz are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azuler.yl, fluorenyl, anthracenyl, indolyl, isoindo'_-?, indoiinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In a preferred embodiment of formula XVII, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

FORMULA XVIII

The non-immunosuppressive neuroimmunophilin FKBP
ligand may further be a compound of formula XVIII
C (CH2) n C
SYZ\
N 1~ D
XVIII
R2~U~. w X

I

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1, 2 or 3;

X is either 0 or S;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or CZ-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2;

R3 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 C1-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;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent (s) independently se'Lected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic 5 moieties, including alicyclic and aromatic structures;
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 wherein said aromatic 10 or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or 15 alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any 20 carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2;

C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl 25 is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, CZ-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2;

W is 0 or S; and U is either 0 or N, provided that:

when U is 0, then R1 is a lone pair of electrons and RZ is selected from the group consisting of Ar, C3-CB cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl;
and when U is N, then R1 and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, and CZ-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 Ar and C3-CB cycloalkyl;
or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In a preferred embodiment of formula XVIII, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

Exemplary compounds of formula XVIII are presented in TABLE VII.

TABLE VII

(CH2 )n C
S-Y-Z\
N D
R2~ X
U W

No. n W Y Z C D R, R, 101 1 0(CHZ)2 CH 3-Pyridyl H H 2-Methylbutyl 102 1 0(CHZ)Z CH 3-Pyridyl H H 1,1-dimethylpropyl 103 1 O(CHZ)Z CH 4-Methoxy H H 1,1-dimethylpropyl phenyl 104 1 0 CH2 CH Phenyl H H 1,1-dimethylpropyl 105 1 S(CH2)Z CH 4-Methoxy H H Cyclohexyl phenyl 106 1 0(CH2)Z CH 3-Pyridyl H H Cyclohexyl 107 1 S (CH2)2 CH 3-Pyridyl H H Cyclohexyl 108 1 S (CH2)2 CH 3-Pyridyl H H 1-Adamantyl 109 1 S(CH2)Z CH 3-Pyridyl H H 1,1-dimethylpropyl 110 1 0(CH2)2 CH Phenyl Phenyl H 1,1-dimethylpropyl TABLE VII (continued) No. n W Y Z C D R, R2 111 2 O(CH2)2 CH Phenyl H H 1,1-dimethylpropyl 112 20 (CH2)2 CH Phenyl H H Phenyl 113 2 0 Direct CH 2-Phenyl 2-Phenyl H Phenyl bond ethyl ethyl 114 2 0 Direct CH 2-Phenyl 2-Phenyl H Cyclohexyl bond ethyl ethyl 115 2 S Direct CH 2-Phenyl 2-Phenyl H Cyclohexyl bond ethyl ethyl 116 2 O(CH2)2 CH 4-Methoxy H H Cyclohexyl phenyl The most preferred compounds of formula XVIII are selected from the group consisting of:
3-(3-Pyridyl)-1-propyl-2S-1-[(2-methylbutyl) carbamoyl]pyrrolidine-2-carboxylate;

3-(3-Pyridyl)-1-propyl-2S-1-[(1',1'-Dimethylpropyl) carbamoyl]pyrrolidine-2-carboxylate;
3-(3-Pyridyl)-1-propyl-2S-1-[(cyclohexyl) thiocarbamoyl]pyrrolidine-2-carboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof.

FORMULA XIX

Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XIX

B

A 1 S-y-Z
V D

5 ~u a, , I .

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

10 V is C, N, or S;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more 15 position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally 20 replaced with 0, NH, NR3, S, SO, or SO2;

R, is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a bridge is formed between 25 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;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); 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 wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SOz;

C and D are independently hydrogen, Ar, C1-C6 straight or branched chair. 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 C3-Ce cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NRõ S, SO, or SO2; and A, B, Rl, R2, U, W, and X are as otherwise defined in formula XV.

V. N-LINKED SULFONAMIDES OF HETEROCYCLIC THIOESTERS
FORMULA XX

The non-immunosuppressive neuroimmunophilin FKBP
ligand may further be a compound of formula XX

B C
A 1 S-Y-Z\
XX
O=S~ x 1 ~o Rl or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more heteroatom(s) independently selected from the group consisting of 0, S, SO, SO2, N, NH, and NR2;

X is either 0 or S;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarhonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2;

R2 is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-Cg straight or branched chain alkenyl or alkynyl, and Ci-C, 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;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C1-C6 straight or branched chain alkyl, or CZ-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or SO2;

C and D are independently hydrogen, Ar, 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 C3-CB cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-CE alkyl, C2-C,, alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SOz; and R1 is selected from the group consisting of Ar, C3-CB cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl,.

5 wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, C3-C8 cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain 10 alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, al-koxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally 15 replaced with 0, NH, NR3, S, SO, or SO2.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, 20 benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydrcpyranyl, pyridyl, pyrrolyl, pyrrolic:i:.yl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, 25 thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In a preferred embodiment of formula XX, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, t-hiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

In another preferred embodiment of formula XX, A
and B, together with the nitrogen and carbon atoms to which they are respectfully attached, form a 6 membered saturated or unsaturated heterocyclic ring;
and R2 is CQ-C, branched chain alkyl, C4-C, cycloalkyl, phenyl, or 3,4,5-trimethoxyphenyl.

In the most preferred embodiment of formula XX, the compound is selected from the group consisting of:
3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate;

3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(a-toluenesulfonyl)pyrrolidine-2-carboxylate;
3-(para-Methoxyphenyl)-i-propylmercaptyl(2S)-N-(u-toluenesulfonyl)pyrrolidine-2-carboxylate;
1,5-Diphenyl-3-pentylmercaptyl N-(para-toluenesulfonyl)pipecolate; and pharmaceutically acceptable salts, esters, and solvates thereof.

FORMULA XXI

Moreover, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XXI

FI-IGI--IJ
E~ --Jy S-Y-Z
i D XXI
x or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

E, F, G and J are independently CHz, O, S, SO, SO21 NH or NR2;

X is either 0 or S;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or CI-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2;

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 C1-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 a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or SOz;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the rincr is either unsubstituted or substituted wit:: :~ne or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

C and D are independently hydrogen, Ar, 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 C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SOz; and R1 is selected from the group consisting of Ar, C3-Ce cycloalkyl, C1-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 Ar, C3-CB cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, 5 azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, 10 isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, 15 pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

20 In a preferred embodiment of formula XXI, Ar is selected from the group consisting o'L phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, 25 imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

FORMULA XXII

The non-immunosuppressive neuroimmunophilin FKBP
ligand may also be a compound of formula XXII
F-G
C
E S-Y-Z
XXII
I D
o= i ~ x or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

E, F, and G are independently CHz, 0, S, SO, SO21 NH or NR2;

X is either 0 or S;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, :~_'fonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NRz, S, SO, or SO2;

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 C1-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;

Ar is an alicyclic or aromatic, mono-, bi- or.
tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent (s) ; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sul f onyl , or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NRZ, S, SO, or SO2;

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 C1-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;

C and D are independently hydrogen, Ar, 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 C3-Cg cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-CQ alkyl, C2-Cq alkenyl, or hydroxy;
wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or SO2; and R1 is selected from the group consisting of Ar, C3-Ca cycloalkyl, C1-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 Ar, C3-Ce cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SO2.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl,-azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In a preferred embodiment of formula XXII, Ar is selected from the group consisting of pheny'_, benz%=', naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

FORMULA XXIII

Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XXIII

( CH2 ) n C
S-YZ
N ~D
~ XXIII
o=l~0 0 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

n is 1, 2 or 3;

X is either 0 or S;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NRZ, S, SO, or SOZ;

R2 is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C,-C4 straight or branched chain alkenyl or alkynyl, and C1-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 a direct bond, C1-C6 straight or branched chain alkyl, or CZ-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or SOZ;

R2 is selected from the group consisting of hydrogen, C1-CQ straight or branched chain alkyl, C3-Cq straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroazom to form. a ring, wherein said ring is optionally fused to an Ar group;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein an aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

C and D are independently hydrogen, Ar, 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 C3-CB cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, or hydroxy;
wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or SO2; and R1 is selected from the group consisting of Ar, C3-C8 cycloalkyl, C1-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 Ar, C3-CB cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or SOZ.

Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In a preferred embodiment of formula XXIII, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

Exemplary compounds of formula XXIII are presented in TABLE VIII.

TABLE VIII

CH2)n C
S-Y-Z
N D
o=i~ o No. n Y Z C D R1 117 1 CH2 CH Phenyl H Phenyl 118 1 CH2 CH Phenyl H a-Methylphenyl 119 1 CH2 CH Phenyl H 4-Methylphenyl 120 1 (CH2)2 CH p-Methoxy H Phenyl phenyl 121 1 (CH2)2 CH p-Methoxy H a-Methylphenyl phenyl 122 1 (CH2)2 CH p-Methoxy H 4-Methylphenyl phenyl 123 1 (CH2)2 CH Phenyl Phenyl Phenyl 124 1 (CH2)2 CH Phenyl Phenyl a-Methylphenyl 125 1 (CH2)2 CH Phenyl Phenyl 4-Methylphenyl 126 2 (CHZ)3 CH Phenyl H Phenyl 127 2 (CH2)3 CH Phenyl H a-Methylphenyl 128 2 (CH2)3 CH Phenyl H 4-Methylphenyl TABLE VIII (continued) CH2) n C C
:sIY_z No. n R1 129 2 (CH2)3 CH Phenyl H 3,4,5-tri-methoxyphenyl 130 2 (CH2)3 CH Phenyl H Cyclohexyl 131 2 Direct CH 3-Phenyl- 3-Phenyl- Phenyl bond propyl propyl 132 2 Direct CH 3-Phenyl- 3-Phenyl- a-Methylphenyl bond propyl propyl 133 2 Direct CH 3-Phenyl- 3-Phenyl- 4-Methylphenyl bond propyl propyl 134 2 Direct CH 3-Phenylethyl 3-Phenyl- 4-Methylphenyl bond ethyl 135 2 Direct CH 3-(4-Methoxy- 3-Phenyl- 4-Methylphenyl bond phenyl)propyl propyl 136 2 Direct CH 3-(2-Pyridyl)- 3-Phenyl- 4-Methylphenyl bond propyl propyl The most preferred compounds of formula XXIII are selected from the group consisting of:

5 3-(para-Methoxyphenyl)-i-propylmercaptyl(2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate;

3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(a-toluenesulfonyl)pyrrolidine-2-carboxylate;
3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(cx-toluenesulfonyl)pyrrolidine-2-carboxylate;

1,5-Diphenyl-3-pentylmercaptyl N-(para-toluenesulfonyl)pipecolate; and pharmaceutically acceptable salts, esters, and solvates thereof.

FORMULA XXIV

Moreover, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XXIV

B C
A S_Y_Z~

0 S x D XXIV

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

V is C, N, or S;

A, B, C, D, Rl, X, Y, and Z are as defined in formula XX above.

VI. PYRROLIDINE DERIVATIVES

FORMULA XXV

The non-immunosuppressive neuroimmunophilin FKBP
ligand may also be a compound of formula XXV

N Y-Z

p 0 XXV
X

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

R1 is C1-C9 straight or branched chain alkyl, Cz-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl or Arl, wherein said Rl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cl-C6 alkyl, CZ-C6 alkenyl, C3-Ca cycloalkyl, C5-C, cycloalkenyl, hydroxy, and Ar2;

Arl and Ar2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Arl is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-Cq alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, S, CH2 or H2;

Y is 0 or NR2, wherein R2 is hydrogen or C1-C6 alkyl; and Z is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of Arl, C3-C8 cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is fragment wherein:

R3 is C1-C9 straight or branched chair. alkyi which is unsubstituted or substituted with C3-Cg cycloalkyl or Arl ;

X2 is 0 or NRS, wherein R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C1-CS straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-CS straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl.

In a preferred embodiment of formula XXV, Z and R1 are lipophilic.

In a more preferred embodiment of formula XXV, the compound is selected from the group consisting of:
3-phenyl-i-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

3-phenyl-l-prop-2- (E) -enyl (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (3,4,5-trimethoxyphenyl) -1-propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

3-(4,5-dichlorophenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (4,5-dichlorophenyl) -1-prop-2- (E) -enyl (2S) -1-( 3, 3- d i m e t h y l- 1, 2- d i o x o p e n t y l)- 2-pyrrolidinecarboxylate;

3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-2 5 ( 3, 3- d i m e t h y 1- 1, 2- d i o x o p e n t y 1)- 2-pyrrolidinecarboxylate;

3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

3-cyclohexyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-cyclohexyl-l-prop-2-(E)-enyl (2S)-1-(3,3-.

dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R) -1, 3-diphenyl-l-propyl (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

(1R) -1, 3-diphenyl-i-prop-2- (E) -enyl (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R) -i-cyclohexyl-3-phenyl-l-propyl (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-i-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

(1R)-1-(4,5-dichlorophenyl)-3-phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate;

3-phenyl-l-propyl (2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate;
3-phenyl-l-propyl (2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidir_ecarboxylate;
3-phenyl-l-propyl (2S) -1- (1, 2-dioxo-2- [2-furanyl])ethyl-2-pyrrolidinecarboxylate;

3-phenyl-l-propyl (2S) -1- (1, 2-dioxo-2- [2-thienyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-l-propyl (2S)-l-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-l-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate;

1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate;
3-phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxamide;

1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester;

1-[1-(3,3-dimethyl-l,2-dioxopentyl)-L-proline]-L-leucine ethyl ester;

1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-prolinel-L-phenylglycine ethyl ester;

1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine phenyl ester;

1-[1-(3,3-dimethyl-l,2-dioxopentyl)-L-proline]-L-phenylalanine benzyl ester;

1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester; and pharmaceutically acceptable salts, esters, and solvates thereof.

FORMULA XXVI

Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XXVI

O-Z
N

O I XXVI
O

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

R1 is C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Arl, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, hydroxy, and Ar2;

Ari and Ar2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Arl is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;

Z is C1-C6 straight or branched chain alkyl, or Cz-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of Arl, C3-C8 cycloalkyl, and C1-C6 straight or branched.

chain alkyl or CZ-C6 straight or branched chain alkenyl substituted with C3-Ce cycloalkyl; or Z is fragment wherein:

R3 is C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl or Arl ;

X2 is 0 or NRS, wherein R. is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group con sisting of phenyl, benzyl, Cl-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, Cl-CS straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl.

In a preferred embodiment of formula XXVI, R1 is selected from the group consisting of Cl-C9 straight or branched chain alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl.

In another preferred embodiment of formula XXVI, Z and R1 are lipophilic.

FORMULA XXVII

Furthermore, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XXVII

H

CN
XXVII
O p or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

Z' is fragment O

wherein:
R3 is C1-C9 straight or branched chain alkyl or unsubstituted Arl, wherein said alkyl is unsubstituted or substituted with C3-CB cycloalkyl or Arl;

XZ is 0 or NRS, wherein RS is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;

R4 is selected from the group consisting of phenyl, benzyl, C1-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, C1-CS straight or branched chain alkyl substituted with phenyl, and C2-CS straight or branched chain alkenyl substituted with phenyl; and Arl is as defined in formula XXVI.

In a preferred embodiment of formula XXVII, Z' is lipophilic.

FORMU'LA XXVIII

The non-immunosuppressive neuroimmunophilin FKBP
ligand may also be a compound of formula XXVIII

N Y-Z

X

wherein:
R, is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C6 cycloalkyl or Ari, wherein said alkyl or alkenyl is unsubstituted or substituted with C3-C6 cycloalkyl or ArZ;

Arl and Ar2 are independently selected from the group consisting of 2-furyl, 2-thienyl, and phenyl;

X is selected from the group consisting of oxygen and sulfur;

Y is oxygen;

Z is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of 2-furyl, 2-thienyl, C3-C6 cycloalkyl, pyridyl, and phenyl, each having one or more substituent(s) independently selected from the group consisting of hydrogen and C1-Cq alkoxy.

In a preferred embodiment of formula XXVIII, Z
and R1 are lipophilic.

In another preferred embodiment of formula XXVIII, the compound is selected from the group consisting of:

3- ( 2 , 5 - dimethoxypher.yl ) -1-propyl ( 2 S) -1- ( 3 , 3 -dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (2, 5-dimethoxyphenyl) -1-prop-2- (E) -enyl (2S) -1-(3,3-dimethyl-l,2-dioxopentyl)-2-pyrrolidine-carboxylate;

2 - (3, 4, 5 -trimethoxyphenyl) - 1 -ethyl (2S)-1-(3,3-dimethyl-l,2-dioxopentyl)-2-pyyrrolidinecarboxylate;
3- (3-pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarboxylate;

3-(2-pyridyl)-i-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-.

dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-i-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;

3-phenyl-l-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3- (3-pyridyl) -1-propyl (2S) -1- (2-tert-butyl-1, 2-dioxoethyl)-2-pyrrolidinecarboxylate;

3,3-diphenyl-l-propyl (2S)-1-(3,3-dimethyl-l,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3- (3-pyridyl) -1-propyl (2S) -N- ( [2-thienyl]
glyoxyl)pyrrolidinecarboxylate;

3,3-diphenyl-l-propyl (2S)-1-(3,3-dimethyl-l,2-dioxobutyl)-2-pyrrolidinecarboxylate;
3,3-diphenyl-l-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate;
3,3-diphenyl-l-propyl (2S)-1-(2-thienyl)glyoxyl-. 25 2-pyrrolidinecarboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof.

In a more preferred embodiment of formula XXVIII, the compound is selected from the group consisting of:

3-(3-pyridyl)-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(2-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-l,2-.

dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-i-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof.

In the most preferred embodiment of formula XXVI I I, the compound is 3-( 3-pyridyl )-1-propyl (2S) -1-(3,3-dimethyl-l,2-dioxopentyl)-2-pyrrolidine-carboxylate, and pharmaceutically acceptable salts, esters, and solvates thereof.

FORMULA XXIX

Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XXIX

A\ yY-Z

XXIX
O\ X 0 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

V is C, N, or S;

A and B, 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 O, S, SO, SO2, N, NH, and NR;

R is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-Cg cycloakyl, C5-C7 cycloalkenyl, or Arl, wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2;

Rl is C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C, cycloalkenyl or Arl, wherein said Rl ~.s unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, and Ar2;

Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent (s) ; 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;
X is 0, S, CH2 or H2;

Y is 0 or NRz, wherein R2 is hydrogen or C1-C6 alkyl; and Z is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of Arl, C3-CB cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is fragment 11 x2 ~
-C

wherein:

R3 is C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-Ca cycloalkyl or Arl;

Xz is 0 or NRS, wherein R. is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C1-CS straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, Cl-C5 straight-or branched chain alkyl substituted with phenyl, and C2-CS straight or branched chain alkenyl substituted with phenyl.

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

Synthesis of Non-Ixtanunosuppressive NeuroimmunoQhilin FKBP liaands The compounds of formulas XV to XIX may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathway depicted below. As described by Scheme I, cyclic amino acids 1 protected by suitable blocking groups P
on the amino acid nitrogen may be reacted with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine 3 may be reacted with a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively.

SCHEME I
C(CHZ) n (CHZ) n OH R-SH Deprotect C. S-R
N --~ N
I Coupling Method I
p 0 p O

(Z)n R -N=C=W (CHZ) n I CH2ClZ

HN W

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

SCHEME II
W

R'-NH2 + C1 )1-" C1 30 R'-NCW

Thiols R-SH may be conveniently prepared from the corresponding readily available alcohols or halides via a two step replacement of halide by sulfur, as described in Scheme III. Halides may be reacted with_ thiourea, and the corresponding alkyl thiouronium salts hydrolyzed to provide thiols RSH. If alcohols are used as. the starting materials, they may be first converted to the corresponding halides by standard methods.

SCHEME III

1) S
PBr3 H2N ',' NH2 or R-OH R-Br R-SH
CBr4/Ph3P 2) OH

The compounds of formulas XX to XXIV may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathway depicted below. As described by Scheme IV, cyclic amino acids 1 protected by suitable blocking groups P
on the amino acid nitrogen may be reacted with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine 3 may be reacted with various sulfonyl chlorides 4 to provide final products 5 in good to excellent yield.

SCHEME IV

(CHZ)n (CHZ)n OH R-SH S-R Deprotect N No. N
Coupling Method I
p O p O

Ci 0=5=0 CHZ ) n R, ( CH2 ) n N - N
I H 0 Et3N, CH2C12 0=SI
=0 O
I
R' Thiols R-SH may be conveniently prepared from the corresponding readily available alcohols or halides via a two step replacement of halogen by sulfur, as described in Scheme V. Halides may be reacted with thiourea, and the corresponding alkyl thiouronium salts hydrolyzed to provide thiols RSH. If alcohols are used as the starting materials, they may be first converted to the corresponding halides by standard methods.

SCHEME V

1) S
PBr3 H2N "lk NH2 or R-OH R-Br R-SH
CBz4/Ph3P 2) OH

The compounds of formulas XXV to XXIX may be prepared by a variety of synthetic sequences that utilize established chemical transformations. The general pathway to the present compounds is described in Scheme VI. N-glyoxylproline derivatives may be prepared by reacting L-proline methyl ester with methyl oxalyl chloride as shown in Scheme VI. The resulting oxamates may be reacted with a variety of carbon nucleophiles to obtain intermediates compounds.

These intermediates are then reacted with a variety of alcohols, amides, or protected amino acid residues to obtain the propyl esters and amides of the invention.
SCHEME VI

0 OCH3 RLi or RMgX
N COOCH3 --- N -------~ I~y H

COCH3 LiOH COH Y-Z
N --f O 0 MeOH/H20 0 0 Coupling Method )--'--o 0 OCH3 OCHj Y-z R

The substituted alcohols may be prepared by a number of methods known to those skilled in the art of organic synthesis. As described in Scheme VII, alkyl or aryl aldehydes may be homologated to phenyl propanols by reaction with methyl(triphenyl-phosphoranylidene)acetate to provide a variety of trans-cinnamates; these latter may be reduced to the saturated alcohols by reaction with excess lithium aluminum hydride, or sequentially by reduction of the double bond by catalytic hydrogenation and reduction of the saturated ester by appropriate reducing agents.
Alternatively, the trans-cinnamates may be reduced to (E)-allylic alcohols by the use of dii.sobutylaluminum hydride.

SCHEME VII

Lithium aluminum Ph3P=CHCOOCH3 ~ COOCH3 hydzide R-CHO --- R - - R'OH
THF
/
Diisobutylaluminum H2, Lithium aluminum hydride Pd/C hydride or Diisobutylaluminum ~ hydzicie R~~OH
R--,/COOCH3 Longer chain alcohols may be prepared by homologation of benzylic and higher aldehydes.

Alternatively, these aldehydes may be prepared by conversion of the corresponding phenylacetic and higher acids, and phenethyl and higher alcohols.

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.

Ki 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., Nature, 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 TABLES IX to XVI.

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 re'-eases 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 Ki values.

In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL
of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/mi in 1 mM HC1) 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 IX

In Vitro Test Results - Formulas I to V
Compound K; (nM) 31 8.7 TABLE IX (continued) In Vitro Test Results - Formulas I to V
Compound Ki (nM) 38 8.9 TABLE IX (continued) In Vitro Test Results - Formulas I to V
Compound Ki nM

TABLE X

In Vitro Test Results - Formulas VI to IX
Compound Ki (nM) Table XI

In Vitro Test Results - Formulas X to XIV
Compound K; (nM) Parent (unoxidized) 7.5 compound of Example 6 95 (Example 6) 225 TABLE XII

In Vitro Test Results - Formulas XV to XIX
Compound K; nM
101 +++
102 ++
103 ++

104 ++
105 ++
106 +
107 ++
108 +++

109 +++
110 +{..}
111 ++
112 +++
113 +++

114 +++
115 +++
116 ++

Relative potencies of compounds are ranked according to the following scale: ++++ denotes Ki or ED50 < 1 nM; +++ denotes Ki or ED50 of 1-50 nM; ++ denotes Ki or ED 50 of 51-200 nM; + denotes K. or ED of 201-500 nM.

TABLE XIII

In Vitro Test Results - Formulas XX to XXIV
Compound Ki (nM) 117 +++

118 ++
119 ++
120 ++
121 ++
122 +

123 ++
124 +++
125 +++
126 +++
127 ++

128 +++
129 +++
130 +++
131 +++
132 ++

Relative potencies of compounds are ranked according to the following scale: ++++ denotes K; or ED50 < 1 nM; +++ denotes K; or ED50 of 1-50 nM; ++ denotes Ki or ED 50 of 51-200 nM; + denotes Ki or ED of 201-500 nM.

TABLE XIV

In Vitro Test Results - Formulas XXV to XXIX

O -Z
N

O

R

No. Z R' Ki 137 1,1-dimethylpropyl 3-phenylpropyl 42 138 3-phenyl-prop-2- 125 (E) -enyl 139 " 3-(3,4,5-tri-methoxyphenyl)propyl 200 140 " 3-(3,4,5-trimethoxy-phenyl)-prop-2-(E)-enyl 65 141 3 - (4 , 5 -methl-lenedioxv) -phenylpropyl 170 142 " 3-(4,5-methylenedioxy) phenylprop-2-(E)-enyl 160 143 " 3-cyclohexylpropyl 200 144 " 3-cyclohexylprop-2-(E)-enyl 600 145 (1R)-1,3-diphenyl-l-propyl 52 TABLE XIV (continued) In Vitro Test Results - Formulas XXV to XXIX
No. Z R i Ki 146 2-furanyl 3-phenylpropyl 4000 147 2-thienyl 92 148 2-thiazolyl 100 149 phenyl 1970 150 1,1-dimethylpropyl 3-(2,5-dimethoxy) phenylpropyl 250 151 3-(2,5-dimethoxy) phenylprop-2-(E)-enyl 450 152 2-(3,4,5-trimethoxy phenyl)ethyl 120 153 3-(3-pyridyl)propyl 5 154 3-(2-pyridyl)propyl 195 155 3-(4-pyridyl)propyl 23 156 cyclohexyl 3-phenylpropyl 82 157 tert-butyl " 95 158 cyclohexylethyl " 1025 159 cyclohexylethyl 3-(3-pyridyl)propyl 1400 160 tert-butyl 3-(3-pyridyl)propyl 3 161 1,1-dimethylpropyl 3,3-diphenylpropyl 5 162 cyclohexyl 3-(3-pyridyl)propyl 9 163 2-thienyl 3-(3-pyridyl)propyl 1000 164 tert-butyl 3,3-diphenylpropyl 5 165 cyclohexyl " 20 166 2-thienyl 150 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.

Dosaae 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 vitro 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 iliustrati,.Te of tre 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 (2S)-2-({1-oxo-5-phenyl}-pentyl-l-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine (1) (2S)-2-(1-oxo-4-t)henyl)butyl-N-benzvlpyrrolidine 1-chloro-4-phenylbutane (1.78 g; 10.5 mmol) in 20 , mL of THF was added to 0.24 g (10 mmol) of magnesium turnings in 50 mL of refluxing THF. After the addition was complete, the mixture was refluxed for an additional 5 hours, and then added slowly to a refluxing solution of N-benzyl-L-proline ethyl ester (2.30 g (10 mmol) in 100 mL of THF. After 2 hours of further reflux, the mixture was cooled and treated with 5 mL of 2 N HC1. The reaction mixture was diluted with ether (100 mL) and washed with saturated NaHCO3, water and brine. The organic phase was dried, concentrated and chromatographed, eluting with 5:1 CHZC1z:EtOAc to obtain 2.05 g (64%) of the ketone as an oil. 1H NMR (CDC13; 300 MHz) : 1.49-2.18 (m, 8H) ;
2.32-2.46 (m, 1H); 2.56-2.65 (m, 2H); 2.97-3.06 (m, 1H) ; 3.17-3.34 (m, 1H) ; 3.44-3.62 (m, 1H) ; 4.02-4.23 (m, 2H); 7.01-7.44 (m, 10H).
(2S)-2-(1-oxo-4-phenyl)butvlgyrrolidine The ketone compound (500 mg) and palladium hydroxide (20% on carbon, 50 mg) was hydrogenated at 40 psi in a Paar shaker overnight. The catalyst was removed by filtration and the solvent was removed in vacuo. The free amine was obtained as a yellow oil (230 mg; 100%). 'H NMR (CDC13; 300 MHz) : 1.75-2.34 (m, 10H) ; 2.55 (m, 2H) ; 2.95 (dm, 1H) ; 3.45-3.95 (m, 1H); 4.05 (m, 1H); 7.37 (m, 5H).
(2S)-2-(1-oxo-4-phenyl)butyl-l-(1 2-dioxo-2-methoxyethyl)pyrrolidine To a solution of (2S) -2- (1-oxo-4-phenyl)butylpyrrolidine (230 mg; 1.0 mmol) in CH2C12(20 mL) at 0 C was added dropwise methyloxalyl chloride (135 mg; 1.1 mmol) . After stirring at 0 C for 3 hours, the reaction was quenched with saturated NH4C1 and the organic phase was washed with water and brine and dried and concentrated. The crude residue was purified on a silica gel column, eluting with 20:1 CH2C12 : EtOAc to obtain 300 mg of the oxamate as a clear oil (98%) . 'H NMR (CDC13; 300 MHz) : 1.68 (m, 4H) ;

1.91-2.38 (m, 4H) ; 2.64 (t, 2H) ; 3.66-3.80 (m, 2H);
3.77, 3.85 (s, 3H total); 4.16 (m, 2H); 4.90 (m, 1H);
7.16 (m, 3H) ; 7.27 (m, 2H) .
(2S)-2-({1-oxo-5-phenyl}-pentyl-l-(3,3-dimethyl-1 2-dioxopentyl)pyrrolidine (1) To a solution of the oxamate above (250 mg; 0.79 mmol) in'anhydrous ether (15 mL), cooled to - 78 C, was added 1, 1 -dimethylpropyl -magnesium chloride (0.8 mL of a 1.0 M solution in ether; 0.8 mmol). After stirring the resulting mixture at -78 C for 2 hours, the reaction was quenched by the addition of 2 mL of saturated NH4C1, followed by 100 mL of EtOAc. The organic phase was washed with brine, dried, concentrated, and purified on a silica gel column, eluting with 50:1 CH2C12:EtOAc. Compound 1 was obtained as a clear oil, 120 mg. 1H NMR (CDC13, 300 MHz) b 0.87 (t, 3H, j = 7.5) ; 1.22 (s, 3H) ; 1.25 (s, 3H); 1.67 (m, 4H); 1.70-2.33 (m, 6H); 2.61 (t, 2H, }

= 7.1); 3.52 (m, 2H); 4.17 (t, 2H, j= 6.2); 4.52 (m, 1H) 7.16-7.49 (m, 5H). Analysis calculated for C22H31N03 - H2O: C, 70.37; H, 8.86; N, 3.73. Found:
70.48; H, 8.35; N, 3.69.

Example 2 Synthesis of 2-phenyl-l-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate (10) Methvl(2S)-1-(1,2-dioxo-2-methoxyethvl)-2-T)yrrolidinecarboxylate 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 min, 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 MgSO4 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) : b 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(750) of the oxamate as a colorless oil. 1H NMR (CDC13) : 6 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 (drr., 1H, j = 8.4, 3.4).

(2S)-1-(1,2-dioxo-3,3-dimethvlpentvl)-2-pyrrolidine-carboxylic acid A mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (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 HC1, 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) : 6 0.87 (t, 3H) ; 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); 3.53 (dd, 2H, j = 10.4, 7.3);
4.55 (dd, 1H, j = 8.6, 4.1).

2-phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate (10) To a solution of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (241 mg;
1.0 mmol) in CHZClZ (10 mL) was added dicyclohexylcarbo-diimide (226 mg; 1.1 mmol) After stirring the resulting mixture for 5 minutes, the solution was cooled to 0 C and treated with a solution of phenyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2C12. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo;
the crude residue was purified by flash chromatography (10:1 hexane:EtOAc) to obtain 302 mg (84%) of compound = 25 10 as an oil. 'H NMR (CDC13, 300 MHz) : 6 0.85 (t, 3H, j = 7.5) ; 1.29 (s, 3H) ; 1.31 (s, 3H) ; 1.70-2.32 (m, 6H) ; 2.92 (t, 2H, ' = 7.4) ; 3.22(t, 2H, j = 7.4) ; 3.58 (m, 2H) ; 4.72 (m, 1H) ; 7.23-7.34 (m, 5H) . Analysis calculated for CZOH27N03S - 0.4 H20: C, 65.15; H, 7.60;
N, 3.80. Found: C, 65.41; H, 7.49; N, 3.72.

Example 3 Synthesis of 2-phenyl-l-ethyl (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate (9) Methyl 1-(1,2-dioxo-2-methoxvethyl)-2-piperidine-carboxylate A solution of methyl pipecolate hydrochloride (8.50 g; 47.31 mmol) in dry methylene chloride (100 mL) was cooled to 0 C and treated with triethylamine (10.5 g; 103 mmol; 2.1 eq) After stirring the formed slurry under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (8.50 g; 69.4 mmol) in methylene chloride (75 mL) was added dropwise. The resulting mixture was stirred at 0 C for 1,5 hours.
After filtering to remove solids, the organic phase was washed with water, dried over MgSO4 and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 9.34 g (86%) of the product as a reddish oil. Mixture of cis-trans amide rotamers;
data for trans rotamer given. 'H NMR (CDC13) : 6 1.22-1.45 (m, 2H); 1.67-1.78 (m, 3H); 2.29 (m, 1H); 3.33 (m, 1H) ; 3.55 (m, 1H) ; 3.76 (s, 3H) ; 3.85, 3.87 (s, 3H
total); 4.52 (dd, 1H).

Methyl 1-(1,2-dioxo-3,3-dimethvlpentyl)-2-piperidine-carboxylate A solution of methyl 1-(1,2-dioxo-2-methoxyethyl)-2-piperidinecarboxylate (3.80 g; 16.57 mmol) in 75 mL of tetrahydrofuran (THF) was cooled to -78 C and treated with 20.7 mL of a 1.0 M solution of 1,1-dimethyl-propylmagnesium 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 3.32 g (74%) of the oxamate as a colorless oil. 1H NMR (CDC13) S 0.88 (t, 3H) ; 1.21, 1.25 (s, 3H each); 1.35-1.80 (m, 7H); 2.35 (m, 1H);
3.24 (m, 1H) ; 3.41 (m, 1H) ; 3.76 (s, 3H) ; 5.32 (d, 1H).

1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidine-carboxylic acid A mixture of methyl 1-(1,2-dioxo-3,3-dimethylpentyl) -2-piperidinecarboxylate (3.30 g; 12.25 mmol), 1 N LiOH (15 mL), and methanol (60 mL) was stirred at 0 C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HC1, diluted with water, and extracted into 100 mL
of methylene chloride. The organic extract was washed with brine and concentrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification. 'H NMR (CDC13) : S 0.89 (t, 3H) ; 1.21, 1.24 (s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H);

3.22 (d, 1H); 3.42(m, 1H); 5.31 (d, 1H).
2-phenyl-l-ethyl (2S)-l-(3,3-dimethyl-l,2-dioxopentyl)-2-pyrrolidinecarbothioate (9) To a solution of 1-(1,2-dioxo-3,3-dimethylpentyl) -2-piperidine-carboxylic acid (255 mg;
1.0 mmol) in CH2C12 (10 mL) was added dicyclohexylcarbodiimide (226 mg; 1.1 mmol) After stirring the resulting mixture for 5 minutes, the solution was cooled to 0 C and treated with a solution of phenyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2C12. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo;
the crude residue was purified by flash chromatography (10:1 hexane:EtOAc) to obtain 300 mg (80%) of compound 9 as an oil. 'H NMR (CDC13, 300 MHz) : d 0.94 (t, 3H, j = 7.5); 1.27 (s, 3H); 1.30 (s, 3H); 1.34-1.88 (m, 7H) ; 2.45 (m, 1H) ; 2.90 (t, 2H, j = 7.7) ; 3.26 (t, 2H, j = 7.7); 3.27 (m, 1H) 3.38 (m, 1H) ; 5.34 (m, 1H) ;

7.24-7.36 (m, 5H) . Analysis calculated for C21HZ9NO3S:
C, 67.17; H, 7.78; N, 3.73. Found: C, 67.02; H, 7.83; N, 3.78.

Example 4 Synthesis of 3-phenyl-l-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxvlate (80) 1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)-carboxylate A solution of L-thioproline (1.51 g; 11.34 mmol)in 40 mL of dry methylene chloride was cooled to 0 C and treated with 3.3 mL (2.41 g; 23,81 mmol) of triethylamine. After stirring this mixture for 30 minutes, a solution of methyl oxalyl chloride (1.81 g;
14.74 mmol) was added dropwise. The resulting mixture was stirred at 0 C for 1.5 hours, filtered through Celite to remove solids, dried and concentrated. The crude material was purified on a silic gel column, eluting with 10% MeOH in methylene chloride, to obtain 2.0 g of the oxamate as an orange-yellow solid.
3-phenyl-l-propyl(2S)-1-(1,2-dioxo-2-methoxvethyl)2-(4-thiazolidine)carboxylate 1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)-carboxylate (500 mg; 2.25 mmol), 3-phenyl-i-propanol (465 mg; 3.42 mmol), dicyclohexylcarbodiimide (750 my;
3.65 mmol), 4-dimethylaminopyridine (95 mg; 0.75 mmol) and camphorsulfonic acid (175 mg; 0.75 mmol) in 30 mL
of methylene chloride were stirred together overnight.

The mixture was filtered through Celite to remove solids and chromatographed (25% ethyl acetate/hexane) to obtain 690 mg of material. 'H NMR (CDC13, 300 MHz) 61.92-2.01 (m, 2H) ; 2.61-2.69 (m, 2H) ; 3.34 (m, 1H) 4.11-4.25 (m, 2H) ; 4.73 (m, 1H) ; S.34 (m, 1H) ; 7.12 (m, 3H) ; 7.23 (m, 2H) .

3-phenyl-l-pronvl(2S)-1-(3,3-dimethvl-1 2-dioxopentvl)-2-(4-thiazolidine)carboxvlate (80) A solution of 3-phenyl-i-propyl (2S) -1- (1, 2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carboxylate (670 mg;
1.98 mmol) in tetrahydrofuran (10 mL) was cooled to -78 C and treated with 2.3 mL of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in ether. After stirring the mixture for 3 hours, it was poured into saturated ammonium chloride, extracted into ethyl acetate, and the organic phase was washed with water, dried and concentrated. The crude material was purified on a silica gel column, eluting with 25%

ethyl acetate in hexane, to obtain 380 mg of the compound of Example 4 as a yellow oil. 'H NMR (CDC13, 300 MHz) d 0.86 (t, 3H) ; 1.21 (s, 3H) ; 1.26 (s, 3H) ;
1.62-1.91 (m, 3H); 2.01 (m, 2H); 2.71 (m, 2H); 3.26-3.33 (m, 2H); 4.19 (m, 2H); 4.58 (m, 1H); 7.19 (m, 3H) ; 7.30 (m, 2H) . Analysis calculated for C20H27NO4S :
C, 63.63: H, 7 23; N, 3.71. Found: C, 64.29; H, 7.39; N, 3.46.

Example 5 Synthesis of 3-(3-pvridvl)-1-propyl(2S)-1-(3,3-dimethyl-Z,2-dioxopentyl)-2-(4-thiazolidi.ne) carboxylate (81) The compound of Example 5 was prepared according to the procedure of Example 4, using 3-(3-pyridyl)-1-propanol in the final step, to yield 3 - (3 -pyridyl) - 1 -propyl( 2 S) -1- ( 3 , 3 -dimethyl -1, 2 - dioxopentyl ) - 2 - ( 4 -thiazolidine)carboxylate. 1H NMR (CDC13, 300 MHz): 6 0.89 (t, 3H, j= 7.3); 1.25 (s, 3H); 1.28 (s, 3H);
1.77 (q, 2H, j 7.3); 2.03 (tt, 2H, j= 6.4, 7.5);
2.72 (t, 2H, j= 7.5) ; 3.20 (dd, 1H, j= 4.0, 11.8) ;
3.23 (dd, 1H, j 7.0, 11.8); 4.23 (t, 2H, j = 6.4);
4.55 (d, 2H, j= 8.9); 5.08 (dd, 1H, j = 4.0, 7.0);

7.24 (m, 1H) ; 8.48 (m, 2H). Analysis calculated for C19H26N204S - 0.5 H20: C, 58.89; H, 7.02; N, 7.23.
Found: C, 58.83; H, 7.05; N, 7.19.

ExamAle 6 Synthesis of 3-(3-pyridyl)-1-propyl (2S)-l-(3,3-Dimethyl-l,2-dioxopentyl)-2-Qyrrolidinecarboxylate, N-oxide (95) Methyl (2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmo1.) ir 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 MgSO4 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. 1H NMR (CDC13): 6 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-dimethylpentvl)-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. 'H NMR (CDC13) : 6 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).

(2S)-1-(1,2-dioxo-3,3-dimethvlpentyl)-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 HC1, 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. 1H NMR (CDC13) d 0.87 (t, 3H) ; 1.22, 1.25 (s, 3H each) ; 1.77 (dm, 2H) ; 2.02 (m, 2H) ; 2.17 (m, 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 (2S) -1- (3 3-dimethyl-1 2-dioxopentyl)-2-pyrrolidinecarboxvlate A mixture of (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (4.58 g;
19 mmol), 3-pyridinepropanol (3.91 g; 28.5 mmol), dicyclohexylcarbodiimide (6.27 g; 30.4 mmol), camphorsulfonic 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). 1H NMR (CDC13, 300 MHz): 6 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-PyridVl)-1-propyl (2S)-1-(3,3-dimethyl-1 2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide (95) 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 S7%-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 95 of Example 6. 'H NMR (CDC13, 300 MHz): 6 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 C20H28N205 - 0.75 H20: C, 61.60; H, 7.63; N, 7.18.
Found: C, 61.79; H, 7.58; N, 7.23.

Example 7 Synthesis of 3-(3-Pyridyl)-l-propylmercaptyl 2S-1-[(2-methylbutyl)carbamovllAVrrolidine-2-carboxylate (101) 3-(3-Pvridvl)-1-protpylchloride To a solution of 3-(3-pyridyl)-1-propanol (10 g;
72.4 mmol) in chloroform (100 mL) was added dropwise a solution of thionyl chloride (12.9 g; 108.6 mmol) in chloroform (50 mL). The resulting mixture was refluxed for 1 hour, then poured into ice-cold 50%

aqueous potassium hydroxide (150 mL). The layers were separated, and the organic phase was dried, concentrated, and purified on a silica gel column, eluting with 40% ethylacetate in hexane, to obtain 10 g (65%) of the chloride as a clear oil. 'H NMR (300 MHz, CDC13) : S 2.02-2.11 (m, 2H) ; 2.77 (m, 2H) ; 3.51 (m, 2H) ; 7.20 (m, 1H) ; 7.49 (m, 1H) ; 8.45 (m, 2H).
3-(3-Pyridyl)-1-nronvlmercaptan A mixture of 3-(3-pyridyl)-1-propylchloride (3 g;
19.4 mmol) and thiourea (1.48 g; 19.4 mmol) in ethanol (10 mL) was refluxed for 24 hours. Aqueous sodium hydroxide, 15 mL of a 0.75 N solution, was added, and the mixture was refluxed for an additional 2 hours.
After cooling to room temperature, the solvent was removed in vacuo. Chromatographic purification of the crude thiol on a silica gel column eluting with 50%
ethyl acetate in hexane delivered 1.2 g of 3-(3-Pyridyl)-1-propylmercaptan as a clear liquid. 'H NMR

(300 MHz, CDC13) : 6 1.34 (m, 1H) ; 1.90 (m, 2H) ; 2.52 (m, 2H) ; 2.71 (m, 2H) ; 7.81 (m, 1H) ; 7.47 (m, 1H) ;
8.42 (m, 2H).

3-(3-Pyridyl)-1-propylmercaptyl N-(tert-butvloxycarbonyl)pyrrolidine-2-carboxvlate A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (3.0 g; 13.9 mmol); 3-(3-Pyridyl)-1-propylmercaptan (3.20 g; 20.9 mmol), dicyclohexylcarbodiimide (4.59 g; 22.24 mmol), camphorsulfonic acid (1.08 g; 4.63 mmol), and 4-dimethylaminopyridine (0.60 g; 4.63 mmol) in dry methylene chloride (100 mL) was stirred overnight.
The reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting with ethyl acetate to obtain 4.60 g (95%) of the thioester as a thick oil. 1H NMR
(300 MHz, CDC13): 6 1.45 (s, 9H); 1.70-2.05 (m, 5H);

2.32 (m, 1H) ; 2.71 (t, 2H) ; 2.85 (m, 2H) ; 3.50 (m, 2H) ; 4.18 (m, 1H) ; 7.24 (m, 1H) ; 7.51 (m, 1H) ; 8.48 (m, 2H).

3-(3-Pyridvl)-1-propylmercaptyl pyrrolidine-2-carboxylate A solution of 3-(3-Pyridyl)-1-mercaptyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (4.60 g;
13.1 mmol) in methylene chloride (60 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x). The combined organic extracts were dried and concentrated to yield 2.36 g(75%) of the free amine as a thick oil. 1H NMR (300 MHz, CDC13) : S 1.87-2.20 (m, 6H) 2.79 (m, 2H) 3.03-3.15 (m, 4H total); 3.84 (m, 1H) ; 7.32 (m, 1H) ; 7.60 (m, 1H) ; 8.57 (m, 2H) 3- (3-Pyridyl) -1-gropylmercaptyl 2S-1- [ (2-methylbutvl)carbamoylIpvrrolidine-2-carboxylate (101) A solution of 2-methylbutylamine (113 mg; 1.3 mmol) and triethylamine (132 mg; 1.3 mmol) in methylene chloride (5 mL) was added to a solution of triphosgene (128 mg; 0.43 mmol) in methylene chloride (5 mL). The resulting mixture was refluxed for 1 hour and r.hen cooled to room temperature. 3-(3-Pyridyl)-l-propylmercaptyl pyrrolidine-2-carboxylate (300 mg; 1.3 mmol) in 5 mL of methylene chloride was added and the resulting mixture was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 250 mg (55%) of the compound of Example 7 (Compound 101, Table VII) as an oil. '-H NMR (300 MHz, CDC13) : d 'H NMR (CDC13, 300 MHz): S 0.89-0.93 (m, 6H); 1.10-1.20 (m, 1H); 1.27 (s, 1H); 1.36-1.60 (m, 2H); 1.72 (s, 2H); 1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H); 2.92-3.54 (m, 6H); 4.45-4.47 (m, 1H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd, 1H);
8.46-8.48 (s, 2H).

Example 8 Synthesis of 3-(3-Pvridvl)-1-propyl 2S-1-[(1' 1'-Dimethylpropyl)carbamoyl]-pyrrolidine-2-carboxylate (102) Reaction of 3-(3-pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylate with the isocyanate generated from tert-amylamine and triphosgene, as described for Example 7, provided the compound of Example 8 (Compound 102, Table VII) in 62% yield. 'H
NMR (CDC13, 300 MHz) : b 0.83 (t, 3H) ; 1.27 (s, 6H) ;

1.64-1.71 (m, 2H) ; 1.91-2.02 (m, 7H); 2.66-2.71 (t, 2H); 2.85 (m, 2H); 3.29-3.42 (m, 2H); 4.11 (br, 1H);
4.37-4.41 (m, 1H) .

Example 9 Synthesis of 3-(3-pyridyl)-1-propylmercantyl 2S-1-[(cyclohexvl)thiocarbamovl]-pyrrolidine-2-carboxylate (107) A mixture of cyclohexylisothiocyanate (120 mg;

0.9 mmol), 3-(3-pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 160 mg (47%) of the compound of Example 9 (Compound 107, Table VII). 'H NMR (CDC13, 300 MHz): 6 1.16-1.40 (m, 6H) ; 1.50-1.71 (m, 4H) ;
1.95-2.08 (m, 7H); 2.70-2.75 (t, 2H); 3.03 (m,. 2H);
3.40-3.60 (m, 2H); 4.95-4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m, 1H).

Example 10 Synthesis of 3-(para-MethoxyPhenyl)-1-pro,pylmercaptyl(2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate (120) 3-(,o-Methoxytahenvl)-1-propylbromide To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0 C, was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3x) and brine (3x). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluting with 10%
EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide.

3-(p-Methoxyt)henyl)-1-propylmercaptan A mixture of 3-(p-methoxyphenyl)-1-propylbromide (14 g; 61. mmol) and thiourea (5.1 g; 67 mmol) in ethanol (150 mL) was refluxed for 48 hours.
Evaporation of the solvent provided a clear glassy compound, which was dissolved in 50 mL of water and treated with 100 mL of 40% aqueous sodium hydroxide.
After stirring the resulting mixture for two hours, the product was extracted into ether (3x), and the combined organic extracts were washed with sodium bicarbonate and brine, dried, and concentrated.
Chromatographic purification of the crude thiol on a silica gel column eluting with 2% either in hexane delivered 10.2 g of 3-(p-methoxyphenyl)- 1-propylmercaptan as a clear liquid. 1H NMR (300 MHz, CDC13) : 6 1.34 (t, 1H) ; 1.88-1.92 (m, 2H) ; 2.49-2.53 (m, 2H); 2.64-2.69 (m, 2H); 3.77 (s, 3H); 6.80-F.84 (m, 2H); 7.06-7.24 (m, 2H).
3-(p-Methoxyphenyl)-1-mercaptyl N-(tert-butyloxycarbonyl)pvrrolidine-2-carboxvlate A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (2.0 g; 9.29 mmol), 3-(p-methoxyphenyl)-1-propylmercaptan (1.86 g; 10.22 mmol), 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.96 g; 10.22 mmol), and 4-dimethylaminopyridine (catalytic) in dry methylene chloride (50 mL) was stirred overnight. The reaction mixture was diluted with methylene chloride (50 mL) and water 100 (mL), and the layers were separated. The organic phase was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated to provide 3.05 g of the product (100%) as a thick oil. 'H NMR (300 MHz, CDC13) : 6 1.15 (s, 9H) ; 1.84-2.31 (m, 6H) ; 2.61 (m, 2H) ; 2.83 (m, 2H) ; 3.51 (m, 2H) ; 3.75 (s, 3H) ; 6.79 (d, 2H, j = 8.04) ; 7.05 (m, 2H) .
3-(P-Methoxy,ohenyl)-1-mercaptyl pyrrolidine-2-carboxylate A solution of 3-(p-methoxyphenyl)-mercaptyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.0 g; 8.94 mmol) in methylene chloride (60 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x). The combined organic extracts were dried and concentrated to yield 1.73 g (69%) of the free amine as a thick oil. 'H NMR (300 MHz, CDC13) : 6 1.80-2.23 (m, 6H) ; 2.62 (m, 2H) ; 2.81 (m, 2H) ; 3.01 (m, 2H) ;

3.75 (s, 3H) ; 3 .89 (m, 1H) ; 6.81 (m, 2H) ; 7.06 (m, 2H).
3-(para-Methoxyphenyl)-i-propvlmercaptvl (2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate (120) A solution of 3-(p-methoxyphenyl)-i-mercaptyl pyrrolidine-2-carboxylate (567 mg; 2.03 mmol) and benzenesulfonyl chloride (358 mg; 2.03 mmol) in methylene chloride (5 mL) was treated with diisopropylethylamine (290 mg; 2.23 mmol) and stirred overnight at room temperature. The reaction mixture was filtered to remove solids and applied directly to a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 540 mg of Compound 120 (Table VIII) as a clear oil. 1H NMR (300 MHz, CDC13) : b 1.65-1.89 (m, 6H) ; 2.61 (t, 2H, j = 7.3) ; 2.87 (t, 2H, j = 7.6) ;
3.26 (m, 1H) ; 3.54 (m, 1H) ; 3.76 (s, 3H) ; 4.34 (dd, 1H, j = 2.7, 8.6); 6.79 (d, 2H, j = 8.7); 7.06 (d, 2H, j = 8.6) ; 7.49-7.59 (m, 3H) ; 7.86 (dd, 2H, j = 1.5, 6.8).

Example 11 Synthesis of 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(ar-toluenesulfonyl)pyrrolidine-2-carboxylate (121) A solution of 3-(p-Methoxyphenyl)-1-mercaptyl pyrrolidine-2-carboxylate (645 mg; 2.30 mmol) and cx-toluenesulfonyl chloride (440 mg; 2.30 mmol) in methylene chloride (5 mL) was treated with diisopropylethylamine (330 mg; 2.53 mmol) and stirred overnight at room temperature. Purification as described for Example 10 provided the compound of Example 11 (Compound 121, Table VIII) as a clear oil.
1H NMR (300 MHz, CDC13) : 6 1.65-2.25 (m, 8H) ; 2.65 (t, 2H); 2.89-2.96 (m, 2H); 3.55-3.73 (m, 2H); 3.80 (s, 3H); 4.32 (s, 2H); 4.70-4.81 (m, 1H); 6.83 (d, 2H);
7.09 (d, 2H); 7.14 (m, 3H); 7.26 (m, 2H).

Examule 12 Synthesis of 3-(para-Methoxvnhenvl)-1-Propylmercaptyl(2S)-N-(a-toluenesulfonyl)pyrrolidine-2-carboxylate (122) A solution of 3-(p-methoxyphenyl)-1-mercaptyl pyrrolidine-2-carboxylate (567 mg; 2.30 mmol) and p-toluenesulfonyl chloride (425 mg; 2.23 mmol) in methylene chloride (5 mL) was stirred overnight at room temperature. Purification as described for Example 10 provided the compound of Example 12 (Compound 122, Table VIII) as a clear oil. 'H NMR (300 MHz, CDC13) : S 1.67-1.94 (m, 6H); 2.40 (s, 3H); 2.61 (t, 2H, j = 7.3) ; 2.84 (m, 2H, j = 7.2) ; 3.22 (m, 1H) ;
3.52 (m, 1H); 3.76 (s, 3H); 4.32 (dd, 1H, J-2.9, 8.5);
6.79 (d, 2H, j = 6.5); 7.07 (d, 2H, j = 6.5); 7.29 (d, 2H, j = 6.5) ; 7.74 (d, 2H, j = 6.5) Example 13 Synthesis of 1,5-Diphenyl-3-pentylmercaptyl N-(para-toluenesulfonyl)pipecolate (134) 3-Phenyl-l-probanal Oxalyl chloride (2.90 g; 2.29 mmol) in methylene chloride (50 mL), cooled to -78 C, was treated with dimethylsulfoxide (3.4 mL) in 10 mL of methylene chloride. After stirring for 5 min, 3-phenyl-l-propanol (2.72 g; 20 mmol) in 20 mL of methylene chloride was added, and the resulting mixture was stirred at -78 C for 15 min, treated with 14 mL of triethylamine, stirred an additional 15 min, and poured into 100 mL of water. The layers were separated, the organic phase was dried and concentrated, and the crude residue was purified on a silica gel column, eluting with 10% ethyl acetate in hexane, to obtain 1.27 g (47%) of the aldehyde as a clear oil. iH NMR (300 MHz, CDC13): 6 2.80 (m, 2H);
2.98 (m, 2H); 7.27 (m, 5H); 9.81 (2, 1H).
1,5-Diphenyl-3-pentanol A solution of 2- (bromoethyl) benzene (1.73 g; 9.33 mmol) in diethylether (10 mL) was added to a stirred slurry of magnesium turnings (250 mg; 10.18 mmol) in 5 mL of ether. The reaction was initiated with a heat gun, and after the addition was complete the mixture was heated on an oil bath for 30 min. 3-Phenyl-l-propanal (1.25 g; 9.33 mmol) was added in 10 mL of ether, and reflux was continued for 1 hour. The reaction was cooled and quenched with saturated ammonium chloride, extracted into 2x ethyl acetate, and the combined organic portions were dried and concentrated. Chromatographic purification on a silica gel column (10% ethyl acetate in hexane) delivered 1.42 g(63%) of the diphenyl alcohol. 'H NMR
(300 MHz, CDC13) : 6 1.84 (m, 4H) ; 2. 61-2.76 (m, 4H) ;

3.65 (m, 1H); 7.19-7.29 (m, 10H).
1,5-Diphenyl-3-bromopentane To a solution of 1,5-diphenyl-3-pentanol (1.20 g (5 mmol) and carbon tetrabromide (1.67 g; 5 mmol) in methylene chloride (20 mL) was added triphenylphosphine (1.31 g; 5 mmol) portionwise, at 0 C. After stirring at room temperature for 18 hours, the mixture was concentrated, triturated with ether, and the solids removed by filtration. The filtrate was passed through a plug of silica gel, eluting with hexane:methylene chloride, 10:1, to give 1.35 g (90%) of the bromide as an oil which was used without further purification. 1H NMR (300 MHz, CDC13) : b 2.11-2.18 (m, 4H) ; 2.73 (m, 2H) ; 2.86 (m, 2H) ; 3.95 (m, 1H); 7.16-7.30 (m, 10H).

1,5-Diphenvl-3 -pentylmercaptan Using the procedure described in Example 10 for the conversion of bromides to thiols, 1,5-diphenyl-3-bromopentane was converted to 1,5-diphenyl-3-pentylmercaptan in 35% overall yield. 'H NMR (300 MHz, .~_DC13) : 6 1. 79 (m, 2H) ; 1. 98 (m, 2H) ; 2. 7 1 (m, 3F'.) 2.80 (m, 2H); 7.16-7.28 (m, 10H).
1,5-Diphenyl-3-pentvlmercapty1 N-(tert-butvloxycarbonvl)pyrrolidine-2-carboxylate A mixture of N-(tert-butyloxycarbonyl)-(S)-pipecolic acid (2.11 g; 9.29 mmol) , 1,5-diphenyl-3-pentylmercaptan (2.58 g; 10.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.96 g; 10.22 mmol) and 4-dimethylaminopyridine (catalytic) in dry methylene chloride (50 mL) was stirred overnight. the reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated to provide 870 mg (20%) of the product as a thick oil, which was used without further purification.

1,5-Diphenyl-3-pentylmercaptyl pyrrolidine-2-carboxylate A solution of 1,5-diphenyl-3-pentylmercaptyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (850 mg; 1.8 mmol) in methylene chloride (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride. The combined organic extracts were dried and concentrated to yield 480 mg (72%) of the free amine as a thick oil, which was used without further purification.

1,5-Diphenyl-3-pentylmercaptyl N-(para-toluenesulfonyl)pipecolate (134) 1,5-Diphenyl-3-pentylmercaptyl N-(para-toluenesulfonyl)pipecolate(18) was prepared from 1,5-diphenyl-3-pentylmercaptyl pyrrolidine-2-carboxylate and para-toluenesulfonyl chloride as described for Example 12, in 65% yield. 'H NMR (CDC13, 300 MHz) b 0.80 (m, 4H) 1.23-1.97 (m, 5H) ; 2.15 (d, 1H); 2.61-2.69 (m, 4H) ; 3.23 (m, 1H) ; 3.44 (dm, 1H) ; 4.27 (s, 2H) ; 4.53 (d, 1H, j = 4.5) ; 5.06 (m, 1H) ; 7.16-7.34 (m, 15H) Example 14 Synthesis of 3-phenyl-1-propvl (2S)-1-(3,3-dimethvl-1,2-dioxopentyl)-2-pyrrolidinecarboxvlate (137) Methyl (2S)-1-(1,2-dioxo-2-methoxvethvl)-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 min, 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 MgSO4 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. 1H NMR (CDC13) : d 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. 'H NMR (CDC13) : d 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).

Synthesis of (2S)-1-(1,2-dioxo-3,3-dimethvlpentyl)-2-pyrrolidinecarboxylic acid A mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxylate (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
HC1, 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 (s, 3H each) ; 1.77 (dm, 2H) ; 2.02 (m, 2H) ; 2.17 (m, IH) ; 2.25 (m, 1H); 3.53 (dd, 2H, j = 10.4, 7.3);
4.55 (dd, 1H, j = 8.6, 4.1) .

3-Phenyl-l-propvl (2S)-1-(3 3-dimethyl-1 2-dioxopentyl)-2-pyrrolidinecarboxvlate (137) A mixture of (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidine-carboxylic acid (600 mg;
2.49 mmol), 3-phenyl-l-propanol (508 mg; 3.73 rnmol), dicyclohexylcarbodiimide (822 mg; 3.98 mmol), camphorsulfonic acid (190 mg; 0.8 mmol) and 4-dimethylaminopyridine (100 mg; 0.8 mmol) in methylene chloride (20 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo, and the crude material was purified on a flash column (25% ethyl acetate in hexane) to obtain 720 mg (80%) of Example 14 as a colorless oil. 1H NMR (CDC13) : d 0.84 (t, 3H) ; 1.19 (s, 3H); 1.23 (s, 3H); 1.70 (dm, 2H); 1.98 (m, 5H);
2.22 (m, 1H); 2.64 (m, 2H) ; 3.47 (m, 2H) ; 4.14 (m, 2H); 4.51 (d, 1H); 7.16 (m, 3H); 7.26 (m, 2H).

Example 15 The method of Example 14 was utilized to prepare the following illustrative compounds.

Compound 138: 3-phenyl-l-prop-2- (E) -enyl (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 80%. 'H NMR (360 Mhz, CDC13) : d 0.86 (t, 3H) ; 1.21 (s, 3H) ; 1.25 (s, 3H) ; 1.54-2.10 (m, 5H) ; 2.10-2.37 (m, 1H) ; 3.52-3.55 (m, 2H) ; 4.56 (dd, 1H, j = 3.8, 8.9) ; 4.78-4.83 (m, 2H) ; 6.27 (m, 1H) ; 6.67 (dd, 1H, j = 15.9); 7.13-7.50 (m, 5H).

Compound 139: 3-(3,4,5-trimethoxyphenyl)-i-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 61%. 'H NMR (CDC13): d 0.84 (t, 3H);
1.15 (s, 3H) ; 1.24 (s, 3H) ; 1.71 (dm, 2H) ; 1.98 (m, 5H) ; 2.24 (m, 1H) ; 2.63 (m, 2H); 3.51 (t, 2H); 3.79 (s, 3H) ; 3.83 (s, 3H) ; 4.14 (m, 2H) ; 4.52 (m, 1H) 6.36 (s, 2H).

Compound 140: 3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine carboxylate, 66%. 'H NMR (CDC13) : d 0.85 (t, 3H) ; 1.22 (s, 3H) 1.25 (s, 3H) 1.50-2.11 (m, 5H) ; 2 .11-2 .40 (m, 1H) ; 3.55 (m, 2H) ; ? .85 (s, 3H) ;
3.88 (s, 6H) ; 4.56 (dd, 1H) ; 4.81 (m, 2H); 6.22 (m, 1H) ; 6.58 (d, 1H, j = 16) ; 6.63 (s, 2H).

Compound 141: 3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 82%. 1H NMR (360 MHz, CDC13) : d 0.86 (t, 3H) ; 1.22 (s, 3H) ; 1.25 (s, 3H) ; 1.60-2.10 (m, 5H) ;

3.36-3.79 (m, 2H); 4.53 (dd, 1H, j= 3.8, 8.6); 4.61-4.89 (m, 2H); 5.96 (s, 2H); 6.10 (m, 1H); 6.57 (dd, 1H, j 6.2, 15.8); 6.75 (d, 1H, j= 8.0); 6.83 (dd, 1H, j= 1.3, 8.0); 6.93 (s, 1H).

Compound 142: 3- (4,5-methylenedioxyphenyl) -1-prop-2-(E)-enyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate, 82%. 1H NMR (360 MHz, CDC13) :
d 0.86 (t, 3H); 1.22 (s, 3H); 1.25 (s, 3H);. 1.60-2.10 (m, 5H) ; 2.10-2.39 (m, 1H); 3.36-3.79 (m, 2H) ; 4.53 (dd, 1H, j = 3.8, 8.6); 4.61-4.89 (m, 2H); 5.96 (s, 2H); 6.10 (m, 1H); 6.57 (dd, 1H, j= 6.2, 15.8); 6.75 (d, 1H, j = 8.0) ; 6.83 (dd, 1H, j= 1.3, 8.0) ; 6.93 (s, 1H).

Compound 144: 3-cyclohexyl-l-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 92%. 1H NMR (360 MHz, CDC13) : d 0.86 (t, 3H); 1.13-1.40 (m + 2 singlets, 9H total); 1.50-1.87 (m, 8H) ; 1.87-2.44 (m, 6H) ; 3.34-3.82 (m, 2H) ; 4.40-4.76 (m, 3H); 5.35-5.60 (m, 1H); 5.60-5.82 (dd, 1H, ~
= 6.5, 16).

Compound 145: (1R) -1, 3-Diphenyl-l-propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 90%. 'H NMR (360 MHz, CDC13) : d 0.85 (t, 3H) ; 1.20 (s, 3H); 1.23 (s, 3H); 1.49-2.39 (m, 7H); 2.46-2.86 (m, 2H); 3.25-3.80 (m, 2H); 4.42-4.82 (m, 1H); 5.82 (td, 1H, j = 1.8, 6.7) ; 7.05-7.21 (m, 3H) ; 7.21-7.46 (m, 7H) .

Compound 146: 3-phenyl-l-propyl (2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate, 99$. 'H
NMR (300 MHz, CDC13) : d 1.66-2.41 (m, 6H) ; 2.72 (t, 2H, j = 7.5); 3.75 (m, 2H) ; 4.21 (m, 2H) ; 4.61 (m, 1H); 6.58 (m, 1H); 7.16-7.29 (m, 5H); 7.73 (m, 2H).

Compound 147: 3-phenyl-l-propyl (2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate, 81%. 1H
NMR (300 MHz, CDC13) : d 1. 88-2 .41 (m, 6H) ; 2.72 (dm, 2H) ; 3.72 (m, 2H) ; 4. 05 (m, 1H) ; 4.22 (m, 1H) ; 4. 64 (m, 1H); 7.13-7.29 (m, 6H); 7.75 (dm, 1H); 8.05 (m, 1H).

Compound 149: 3-phenyl-l-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate, 99%. 'H NMR
(300 MHz, CDC13) : d 1.97-2.32 (m, 6H) ; 2.74 (t, 2H, ~

= 7.5); 3.57 (m, 2H) ; 4.24 (m, 2H) ; 4.67 (m, 1H);
6.95-7.28 (m, 5H); 7.51-7.64 (m, 3H); 8.03-8.09 (m, 2H).

Compound 150: 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 99%. 'H NMR (300 MHz, CDC13) : d 0.87 (t, 3H) ; 1.22 (s, 3H) ; 1.26 (s, 3H) ; 1.69 (m, 2H) ; 1.96 (m, 5H); 2.24 (m, 1H) ; 2.68 (m, 2H); 3.55 (m, 2H);

3.75 (s, 3H) ; 3.77 (s, 3H) ; 4.17 (m, 2H) ; 4.53 (d, 1H); 6.72 (m, 3H).

Compound 151: 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dirnethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 99%. 'H NMR (300 MHz, CDC13):
d 0.87 (t, 3H) ; 1.22 (s, 3H) ; 1.26 (s, 3H) ; 1.67 (m, 2H) ; 1.78 (m, 1H) ; 2.07 (m, 2H) ; 2.26 (m, 1H) ; 3.52 (m, 2H) ; 3.78 (s, 3H) ; 3.80 (s, 3H) ; 4.54 (m, 1H) 4.81 (m, 2H) ; 6.29 (dt, 1H, j = 15.9); 6.98 (s, 1H) Compound 152: 2-(3,4,5-trimethoxyphenyl)-i-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 97%. 'H NMR (300 MHz, CDC13) : d 0.84 (t, 3H) ; 1.15 (s, 3H) ; 1.24 (s, 3H) ; 1.71 (dm, 2H) ; 1.98 (m, 5H) ; 2.24 (m, 1H) ; 2.63 (m, 2H) ; 3.51 (t, 2H) 3.79 (s, 3H); 3.83 (s, 3H) ; 4.14 (m, 2H) ; 4.52 (m, 1H) ; 6.36 (s, 2H).

Compound 153: 3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylare, 80%. 1H NMR (CDC13, 300 MHz) : d 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.

Compound 154: 3- ( 2- Pyri dyl )-1- propyl ( 2 S) -1- ( 3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 88%. 1H NMR (CDC13, 300 MHz) : d 0.84 (t, 3H) ; 1.22, 1.27 (s, 3H each); 1.68-2.32 (m, 8H); 2.88 (t, 2H, 7.5); 3.52 (m, 2H); 4.20 (m, 2H); 4.51 (m, 1H); 7.09-7.19 (m, 2H) ; 7.59 (m, 1H) ; 8.53 (d, 1H, j = 4.9).
Compound 155: 3- ( 4 - Pyridyl ) -1-propyl ( 2 S) -1- ( 3 , 3 -dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 91%. 'H NMR (CDC13, 300 MHz) : d 6. 92-6.80 (m, 4H) 6.28 (m, 1H) ; 5.25 (d, 1H, j = 5.7) ; 4 .12 (m, 1H) 4.08 (s, 3H) 3.79 (s, 3H) ; 3.30 (m, 2H) ; 2.33 (m, 1H); 1.85-1.22 (m, 7H) ; 1.25 (s, 3H) ; 1.23 (s, 3H) 0.89 (t, 3H, j = 7.5).

Compound 156: 3-phenyl-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 91%. 'H NMR
(CDC13, 300 MHz) : d 1.09-1.33 (m, 5H) ; 1.62-2.33 (m, 12H); 2.69 (t, 2H, j = 7.5); 3.15 (dm, 1H); 3.68 (m, 2H); 4.16 (m, 2H); 4.53, 4.84 (d, 1H total); 7.19 (m, 3H) ; 7.29 ;m, 2H) .

Compound 157: 3-phenyl-i-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 92%. 'H NMR
(CDC13, 300 MHz) : d 1.29 (s, 9H) ; 1.94-2.03 (m, 5H) ;

2.21 (m, 1H); 2.69 (m, 2H); 3.50-3.52 (m, 2H); 4.16 (m, 2H) ; 4.53 (m, 1H) ; 7.19 (m, 3H) ; 7.30 (m, 2H).

Compound 158: 3-phenyl-l-propyl (2S)-1-(2-cyclohexyl-ethyl-l,2-dioxoethyl)-2-pyrrolidinecarboxylate, 97%.
'H NMR (CDC1õ 300 MHz) d 0.88 (m, 2H) ; 1.16 (m, 4H) 1.43-1.51 (m, 2H); 1.67 (m, 5H); 1.94-2.01 (m, 6H);

2.66-2.87 (m, 4H); 3.62-3.77 (m, 2H); 4.15 (m, 2H);
4.86 (m, iH) ; 7.17-7.32 (m, 5H).

Compound 159: 3- (3-pyridyl) -1-propyl (2S) -1- (2-cyclo-hexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 70%. 'H NMR (CDC13, 300 MHz) d 0.87 (m, 2H) ; 1.16 (m, 4H) ; 1.49 (m, 2H) ; 1.68 (m, 4H) ; 1.95-2.32 (m, 7H) ; 2.71 (m, 2H) ; 2.85 (m, 2H) ; 3.63-3.78 (m, 2H) 4.19 (m, 2H) ; 5.30 (m, 1H) ; 7.23 (m, 1H) ; 7.53 (m, 1H); 8.46 (m, 2H).

Compound 160: 3- (3-pyridyl) -1-propyl (2S) -1- (2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 83%.
1H NMR (CDC13, 300 MHz) : d 1.29 (s, 9H) ; 1.95-2.04 (m, 5H); 2.31 (m, 1H); 2.72 (t, 2H, j = 7.5); 3.52 (m, 2H) ; 4. 18 (m, 2H) ; 4.52 (m, 1H) ; 7. 19-7.25 (m, 1H) 7.53 (m, 1H) ; 8.46 (m, 2H) .

Compound 161: 3, 3-diphenyl -1-propyl ( 2 S) -1- ( 3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 99%. 'H NMR (CDC13, 300 MHz) : d 0.85 (t, 3H) ; 1.21, 1.26 (s, 3H each) ; 1.68-2.04 (m, 5H) ; 2.31 (m, 1H) 2.40 (m, 2H); 3.51 (m, 2H); 4.08 (m, 3H); 4.52 (m, 1H) ; 7.18-7.31 (m, 10H) Compound 162: 3- (3-pyridyl) -1-propyl (2S) -1- (2-cyclo-hexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 88%.
1H NMR (CDC13, 300 MHz) : d 1.24-1.28 (m, 5H) ; 1.88-2.35 (m, 11H); 2.72 (t, 2H, j = 7.5); 3.00-3.33 (dm, 1H) ; 3.69 (m, 2H) ; 4.19 (m, 2H) ; 4.55 (m, 1H) ; 7.20-7.24 (m, 1H) ; 7.53 (m, 1H) ; 8.47 (m, 2H) .

Compound 163: 3- (3-Pyridyl) -1-propyl (2S) -N- ( [2-thienyl] glyoxyl)pyrrolidinecarboxylate, 49%. 'H NMR
(CDC13, 300 MHz) : d 1.81-2.39 (m, 6H) ; 2.72 (dm, 2H) 3.73 (m, 2H); 4.21 (m, 2H); 4.95 (m, 1H); 7.19 (m, 2H) ; 7.61 (m, 1H) ; 7. 80 (d, 1H) ; 8.04 (d, iH) ; 8.46 (m, 2H).

Compound 164: 3,3-Diphenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate, 99 0. 'H NMR (CDC13, 300 MHz) : d 1.27 (s, 9H) ; 1.96 (m, 2H) ; 2.44 (m, 4H) ; 3.49 (m, 1H) ; 3.64 (m, 1H) 4.08 (m, 4H) ; 4.53 (dd, 1H) ; 7.24 (m, lOH) .

C'ompound 165: 3,3-Diphenyl-l-propyl (2S) -1-cyclohexyl glyoxyl-2-pyrrolidinecarboxylate, 91%. 'H NMR (CDC13, 300 MHz): d 1.32 (m, 6H) ; 1.54-2.41 (m, 10H) ; 3.20 (dm, 1H); 3.69 (m, 2H); 4.12 (m, 4H); 4.52 (d, 1H);
7.28 (m, 10H).

Compound 166: 3,3-Diphenyl-l-propyl (2S)-1-(2-thienyl) glyoxyl-2-pyrrolidinecarboxylate, 75%. 'H NMR

(CDC13, 300 MHz) d 2.04 (m, 3H); 2.26 (m, 2H); 2.48 (m, 1H); 3.70 (m, 2H); 3.82-4.18 (m, 3H total); 4.64 (m, 1H); 7.25 (m, 11H); 7.76 (dd, 1H); 8.03 (m, 1H).

Examvle 16 General procedure for the synthesis of acrylic esters, exemplified for methyl (3,3,5-trimethoxy)-trans-cinnamate.

A solution of 3,4,5-trimethoxybenzaldehyde (5.0 g; 25.48 mmol) and methyl (triphenyl-phosphoranylidene) acetate (10.0 g; 29.91 mmol) in tetrahydrofuran (250 mL) was refluxed overnight.
After cooling, the reaction mixture was diluted with 200 mL of ethyl acetate and washed with 2 x 200 mL of water, dried, and concentrated in vacuo. The crude residue was chromatographed on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 5.63 g (88%) of the cinnamate as a white crystalline solid. 1H NMR (300 Mhz; CDC13) : d 3.78 (s, 3H) ; 3.85 (s, 6H); 6.32 (d, 1H, 16); 6.72 (s, 2H); 7.59 (d, 1H, j = 16).

Example 17 General procedure for the synthesis of saturated alcohols from acrylic esters, exemplified for (3,4,5-trimethoxy) phenylpropanol.

A solution of methyl (3,3,5-trimethoxy)-trans-cinnamate (1.81 g; 7.17 mmol) in tetrahydrofuran (30 mL) was added in a dropwise manner to a solution of lithium aluminum hydride (14 mmol) in THF (35 mL), with stirring and under an argon atmosphere. After the addition was complete, the mixture was heated to 75 C for 4 hours. After cooling, it was quenched by the careful addition of 15 mL of 2 N NaOH followed by 50 mL of water. The resulting mixture was filtered through Celite to remove solids, and the filter cake was washed with ethyl acetate. The combined organic fractions were washed with water, dried, concentrated in vacuo, and purified on a silica gel column, eluting with ethyl acetate to obtain 0.86 g(53%) of the alcohol as a clear oil. 'H NMR (300 Mhz; CDC13) : d 1.23 (br, 1H) ; 1.87 (m, 2H) ; 2.61 (t, 2H, j = 7.1) ;

3.66 (t, 2H) 3.80 (s, 3H) 3.83 (s, 6H) ; 6.40 (s, 2H).

Example 18 General procedure for the synthesis of trans-allylic alcohols from acrylic esters, exemplified for (3,4,5-trimethoxy)phenylprop-2-(E)-enoi.

A solution of methyl (3,3,5-trimethoxy) -trans-cinnamate (1.35 g; 5.35 mmol) in toluene (25 mL) was cooled to -10 C and treated with a solution of diisobutylaluminum hydride in toluene (11.25 mL of a 1.0 M solution; 11.25 mmol). The reaction mixture was stirred for 3 hours at 0 C and then quenched with 3 mL
of methanol followed by 1 N HC1 until the pH was 1.

The reaction mixture was extracted into ethyl acetate and the organic phase was washed with water, dried and concentrated. Purification on a silica gel column eluting with 25% ethyl acetate in hexane furnished 0.96 g (80%) of a thick oil. 1H NMR (360 Mhz; CDC13):
d 3.85 (s, 3H); 3.87 (s, 6H) ; 4.32 (d, 2H, j= 5.6);
6.29 (dt, 1H, j = 15.8, 5.7), 6.54 (d, 1H, j= 15.8);
6.61 (s, 2H).

Examule 19 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 non-immunosuppressive neuroimmunophilin FKBP ligand, GPI

1046. 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 growch 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 M GPI 1046 (FIG. 3) or 30 M 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 M 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 M 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 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, GPI 1046, GPI 1312, GPI 1572, GPI 1389, GPI
1511, or GPI 1234) 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 5 (complete hair regrowth in shaved area).

FIG. 5 shows that after 14 days, the animals treated with vehicle exhibited the beginning of hair growth in small tufts. By contrast, most of the animals treated with the low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP
ligands exhibited dramatic hair growth.

Example 20 A lotion comprising the following composition may be prepared.

(%) 95% Ethanol 80.0 a non-immunosuppressive neuroimmunophilir. 10.0 FKBP ligand a-Tocopherol acetate 0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil purified water 9.0 perfume and dye q.s.
Into 95% ethanol are added a non-immunosuppressive neuroimmunophilin FKBP ligand, a-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 21 A lotion comprising the following composition shown may be prepared.

(%) 95% Ethanol 80.0 a non-immunosuppressive neuroimmunophilin 0.005 FKBP ligand Hinokitol 0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil Purified water 19.0 Perfume and dye q.s.
Into 95% ethanol are added a non-immunosuppressive neuroimmunophilin FKBP ligand, 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 22 An emulsion may be prepared from A phase and B
phase having the following compositions.

(A phase) (%) Whale wax 0.5 Cetanol 2.0 Petrolatum 5.0 Squalane 10.0 Polyoxyethylene (10 mole) monostearate 2.0 Sorbitan monooleate 1.0 a non-immunosuppressive neuroimmunophilin 0.01 FKBP ligand (B phase) (%) Glycerine 10.0 Purified water 69.0 Perfume, dye, and preservative q.s.
The A phase and the B phase are respectivelv 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.
Examule 23 A cream may be prepared from A phase and B phase having the following compositions.

(A Phase) (o) Fluid paraffin 5.0 Cetostearyl alcohol 5.5 Petrolatum 5.5 Glycerine monostearate 33.0 Polyoxyethylene (20 mole) 2-octyldodecyl 3.0 ether Propylparaben 0.3 (B Phase) ( o ) a non-immunosuppressive neuroimmunophilin 0.8 FKBP ligand Glycerine 7.0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium Hexametaphosphate 0.005 Purified water 44.895 The A phase is heated and melted, and maintained at 70 c . The B phase is added into the A phase and r.he 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 24 A liquid comprising the following composition may be prepared.

($) Polyoxyethylene butyl ether 20.0 Ethanol 50.0 a non-immunosuppressive neuroimmunophilin 0.001 FKBP ligand Propylene glycol 5.0 Polyoxyethylene hardened castor oil 0.4 derivative (ethylene oxide 80 mole adducts) Perfume q.s.
Purified water q.s.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a non-immunosuppressive neuroimmunophilin FKBP ligand, 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 25 A shampoo comprising the following composition may be prepared.
(%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betaine lauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0 Polyethylene glycol 5.0 a non-immunosuppressive neuroimmunophilin 5.0 FKBP ligand Ethanol 2.0 Perfume 0.3 Purified water 69.7 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 lauryldimethyl-aminoacetate. Then a mixture obtained by adding 5.0 g of a non-immunosuppressive neuroimmunophilin FKBP
ligand, 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 or_ce or twice per day.

Example 26 A patient is suffering from alopecia senilis. A
non-immunosuppressive neuroimmunophilin FKBP ligand or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.

Exaz=le 27 A patient is suffering from male pattern alopecia. A non-immunosuppressive neuroimmunophilin FKBP ligand or a pharmaceutical composition comprising the same may be administered to the patient.
Increased hair growth is expected to occur following treatment.

Examtple 28 A patient is suffering from alopecia areata. A
non-immunosuppressive neuroimmunophilin FKBP ligand or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 29 A patient is suffering from hair loss caused by skin lesions. A non-immunosuppressive neuroimmunophilin FKBP ligand or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 30 A patient is suffering from hair loss caused by tumors. A non-immunosuppressive neuroimmunophilin FKBP ligand or a pharmaceutical composition comprising the same may be administered to the patient.
Increased hair growth is expected to occur following treatment.

Example 31 A patient is suffering from hair loss caused by a systematic disorder, such as a nutritional disorder or an internal secretion disorder. A non-immunosuppressive neuroimmunophilin FKBP ligand or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.

Example 32 A patient is suffering from hair loss caused by chemotherapy. A non-immunosuppressive neuroimmunophilin FKBP ligand or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.

Examr)le 33 A patient is suffering from hair loss caused by radiation. A non-immunosuppressive neuroimmunophilin FKBP ligand 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 (5)

WE CLAIM:
1. Use of an effective amount of a non-immuno-suppressive neuroimmunophilin FKBP ligand for treating alopecia or promoting hair growth in an animal.
2. Use of a non-immunosuppressive neuroimmunophilin FKBP ligand in the manufacture of a medicament for treating alopecia or promoting hair growth in an animal.
3. The use of claim 1 or 2, wherein the neuroimmuno-philin FKBP is FKBP-12.
4. A pharmaceutical composition which comprises:
(i) an effective amount of a non-immunosuppressive neuroimmunophilin FKBP ligand for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4, wherein the neuroimmunophilin FKBP is FKBP-12.
CA002292910A 1997-06-04 1998-06-03 Hair growth compositions and uses Expired - Fee Related CA2292910C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/869,426 1997-06-04
US08/869,426 US5945441A (en) 1997-06-04 1997-06-04 Pyrrolidine carboxylate hair revitalizing agents
PCT/US1998/011237 WO1998055090A1 (en) 1997-06-04 1998-06-03 Hair growth compositions and uses

Publications (2)

Publication Number Publication Date
CA2292910A1 CA2292910A1 (en) 1998-12-10
CA2292910C true CA2292910C (en) 2008-09-02

Family

ID=25353537

Family Applications (2)

Application Number Title Priority Date Filing Date
CA002292965A Expired - Fee Related CA2292965C (en) 1997-06-04 1998-06-03 Pyrrolidine derivative hair growth compositions and uses
CA002292910A Expired - Fee Related CA2292910C (en) 1997-06-04 1998-06-03 Hair growth compositions and uses

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA002292965A Expired - Fee Related CA2292965C (en) 1997-06-04 1998-06-03 Pyrrolidine derivative hair growth compositions and uses

Country Status (12)

Country Link
US (10) US5945441A (en)
EP (3) EP1479373B1 (en)
JP (2) JP2002510302A (en)
AT (1) ATE275930T1 (en)
AU (2) AU7716998A (en)
CA (2) CA2292965C (en)
DE (2) DE69826267T2 (en)
ES (1) ES2229498T3 (en)
MX (1) MXPA99010886A (en)
TW (3) TW518220B (en)
WO (2) WO1998055090A1 (en)
ZA (3) ZA984621B (en)

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6218424B1 (en) * 1996-09-25 2001-04-17 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
US5846979A (en) * 1997-02-28 1998-12-08 Gpi Nil Holdings, Inc. N-oxides of heterocyclic esters, amides, thioesters, and ketones
US5945441A (en) 1997-06-04 1999-08-31 Gpi Nil Holdings, Inc. Pyrrolidine carboxylate hair revitalizing agents
US6274602B1 (en) * 1998-06-03 2001-08-14 Gpi Nil Holdings, Inc. Heterocyclic thioester and ketone hair growth compositions and uses
US20010049381A1 (en) * 1997-06-04 2001-12-06 Gpl Nil Holdings, Inc., Pyrrolidine derivative hair growth compositions and uses
AU770459B2 (en) * 1998-06-03 2004-02-19 Gpi Nil Holdings, Inc. Heterocyclic ester and amide hair growth compositions and uses
JP2002517383A (en) * 1998-06-03 2002-06-18 ジーピーアイ ニル ホールディングス インコーポレイテッド AZA-heterocyclic compounds used to treat neurological disorders and hair loss
WO1999062881A1 (en) * 1998-06-03 1999-12-09 Gpi Nil Holdings, Inc. Aza-heterocyclic compounds used to treat neurological disorders and hair loss
EA200001247A1 (en) * 1998-06-03 2001-08-27 Джи Пи Ай Нил Холдингс, Инк. N-BONDED SULPHONAMIDES OF N-HETEROCYCLIC CARBONIC ACIDS OR ISATERES OF CARBONIC ACIDS
US6429215B1 (en) 1998-06-03 2002-08-06 Gpi Nil Holdings, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6331537B1 (en) * 1998-06-03 2001-12-18 Gpi Nil Holdings, Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
US6337340B1 (en) * 1998-08-14 2002-01-08 Gpi Nil Holdings, Inc. Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders
US6506788B1 (en) * 1998-08-14 2003-01-14 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders
US6384056B1 (en) * 1998-08-14 2002-05-07 Gpi Nil Holdings, Inc. Heterocyclic thioesters or ketones for vision and memory disorders
US6218423B1 (en) * 1998-08-14 2001-04-17 Gpi Nil Holdings, Inc. Pyrrolidine derivatives for vision and memory disorders
US7338976B1 (en) * 1998-08-14 2008-03-04 Gpi Nil Holdings, Inc. Heterocyclic esters or amides for vision and memory disorders
US7410995B1 (en) * 1998-08-14 2008-08-12 Gpi Nil Holdings Inc. N-linked sulfonamide of heterocyclic thioesters for vision and memory disorders
US6462072B1 (en) * 1998-09-21 2002-10-08 Gpi Nil Holdings, Inc. Cyclic ester or amide derivatives
JP2002525302A (en) * 1998-09-30 2002-08-13 ザ、プロクター、エンド、ギャンブル、カンパニー Method of treating hair loss using ketoamides
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
NZ516888A (en) * 1999-07-30 2004-02-27 Vertex Pharma Acyclic and cyclic amine derivatives
AU6388500A (en) * 1999-08-05 2001-03-05 Procter & Gamble Company, The Multivalent sulfonamides
AU6611800A (en) * 1999-08-05 2001-03-05 Procter & Gamble Company, The Method of treating hair loss using multivalent ketoamides and amides
AU6387600A (en) * 1999-08-05 2001-03-05 Procter & Gamble Company, The Multivalent substituted ketoamides and amides
WO2001010838A1 (en) * 1999-08-05 2001-02-15 The Procter & Gamble Company Multivalent compounds
US6593362B2 (en) * 2001-05-21 2003-07-15 Guilford Pharmaceuticals Inc. Non-peptidic cyclophilin binding compounds and their use
US7169564B1 (en) * 2001-06-26 2007-01-30 Anaderm Research Corporation FKBP51/52 and CyP40-mediated mammalian hair growth
US7598278B2 (en) 2002-04-11 2009-10-06 L'oreal Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss
AU2003257143A1 (en) * 2002-07-31 2004-02-16 Shaklee Corporation A method for maximizing scalp health and inducing enhanced visual and tactile hair quality
EP3431464A3 (en) 2003-08-06 2019-07-31 Senomyx Inc. Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
EP1743621B1 (en) 2004-04-28 2014-03-05 Cosmo Oil Co., Ltd. Hair restorer
EP1838288A4 (en) * 2004-12-20 2010-08-04 Ariad Pharma Inc Therapeutic materials and methods
US20100022604A1 (en) * 2006-12-20 2010-01-28 Taisho Pharmaceutical Co., Ltd. Prophylactic or therapeutic agent for alopecia
US20080221115A1 (en) * 2007-02-26 2008-09-11 Liat Hayardeny-Nisimov Use of long-chain alcohol derivatives for the treatment of alopecia areata
TWI534142B (en) 2011-03-15 2016-05-21 大正製藥股份有限公司 Azole derivatives
JP6020396B2 (en) * 2012-09-12 2016-11-02 大正製薬株式会社 Medicaments containing azole derivatives
FR3030248B1 (en) 2014-12-22 2018-03-23 L'oreal PYRIDINE-DICARBOXYLIC ACID DERIVATIVE ASSOCIATION / PARTICULAR ANTIOXIDANT AGENT

Family Cites Families (124)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2505114C3 (en) 1975-02-07 1979-06-13 Valentin Dr.Med. Koehler Scalp care products
US4070361A (en) 1977-04-21 1978-01-24 E. R. Squibb & Sons, Inc. Mercaptoalkylsulfonyl proline and pipecolic acid and esters thereof
IL58849A (en) 1978-12-11 1983-03-31 Merck & Co Inc Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them
US4578474A (en) * 1980-06-23 1986-03-25 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4390695A (en) 1980-06-23 1983-06-28 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4310461A (en) 1980-06-23 1982-01-12 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4950649A (en) 1980-09-12 1990-08-21 University Of Illinois Didemnins and nordidemnins
GR75019B (en) 1980-09-17 1984-07-12 Univ Miami
ZA817261B (en) * 1980-10-23 1982-09-29 Schering Corp Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them
DE3174844D1 (en) 1980-10-23 1986-07-24 Schering Corp Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them
ZA826022B (en) 1981-08-21 1983-08-31 Univ Miami Novel complex amido and imido derivatives of carboxyalkyl peptides and thioethers and ethers of peptides
US4438031A (en) 1982-02-24 1984-03-20 American Home Products Corporation N-(Alkylsulfonyl)-L-proline amide and N-(alkylsulfonyl)-2-carboxylic acid amide-indoline derivatives
DE3360065D1 (en) * 1982-03-08 1985-03-28 Schering Corp Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them
US4531964A (en) 1982-09-13 1985-07-30 Nippon Kayaku Kabushiki Kaisha Heterocyclic compound and a herbicidal composition containing said compound
US4574079A (en) * 1983-05-27 1986-03-04 Gavras Haralambos P Radiolabeled angiotensin converting enzyme inhibitors for radiolabeling mammalian organ sites
US4593102A (en) 1984-04-10 1986-06-03 A. H. Robins Company, Inc. N-[(amino)alkyl]-1-pyrrolidine, 1-piperidine and 1-homopiperidinecarboxamides (and thiocarboxamides) with sulfur linked substitution in the 2, 3 or 4-position
DE3508251A1 (en) * 1985-03-08 1986-09-11 Merck Patent Gmbh, 6100 Darmstadt Dipeptides
CN86101850A (en) 1985-03-22 1987-02-04 森得克斯(美国)有限公司 N, the manufacture method and the purposes of N '-dialkyl group guanidine radicals dipeptides
US5714510A (en) 1985-07-18 1998-02-03 Proctor; Peter H. Topical proxyl composition and method
US5472687A (en) * 1985-07-18 1995-12-05 Proctor; Peter H. Topical pyridine N-oxides
WO1988000040A1 (en) 1986-07-02 1988-01-14 American Health Products Corporation Topical hair growing composition and kit
DE3774975D1 (en) 1986-09-10 1992-01-16 Syntex Inc SELECTIVE AMIDINATION OF DIAMINES.
GB8630721D0 (en) * 1986-12-23 1987-02-04 Unilever Plc Cosmetic compositions
IT1206078B (en) 1987-06-03 1989-04-14 Polifarma Spa PROCEDURE FOR THE PRODUCTION OF 3-INDOLPIRUVIC ACID AND ITS DERIVATIVES THEIR PHARMACEUTICAL USE
LU86959A1 (en) * 1987-07-31 1989-03-08 Oreal NOVEL DERIVATIVES OF UREYLENE TRIAMINO-2,4,6 PYRIMIDINE OXIDE-3, THEIR PREPARATION AND THEIR USE IN COSMETICS AND DERMOPHARMACY
WO1989006234A1 (en) 1987-12-28 1989-07-13 Bazzano Gail S N,n-substituted amines and use thereof in hair growth promotion
GB2216003B (en) * 1988-02-18 1992-06-10 Toyama Chemical Co Ltd Hair restorer
US5187156A (en) 1988-03-16 1993-02-16 Fujisawa Pharmaceutical Co., Ltd. Peptide compounds, processes for preparation thereof and pharmaceutical composition comprising the same
IL90872A0 (en) 1988-07-08 1990-02-09 Smithkline Beckman Corp Retroviral protease binding peptides
US5342625A (en) * 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
DE3931051A1 (en) 1988-09-22 1990-03-29 Hoechst Ag New herbicidal amine salts of herbicidal acids
EP0378318A1 (en) 1989-01-11 1990-07-18 Merck & Co. Inc. Process for synthesis of FK-506 and tricarbonyl intermediates
US4996193A (en) * 1989-03-03 1991-02-26 The Regents Of The University Of California Combined topical and systemic method of administration of cyclosporine
US5359138A (en) * 1989-04-15 1994-10-25 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Poststatin and related compounds or salts thereof
US5162500A (en) 1989-04-15 1992-11-10 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Poststatin and related compounds or salts thereof
US5164525A (en) 1989-06-30 1992-11-17 Merck & Co., Inc. Synthetic process for fk-506 type macrolide intermediates
US5284826A (en) * 1989-07-24 1994-02-08 Sandoz Ltd. 0-hydroxyethyl and acyloxyethyl derivatives of [ser]8 cyclosporins
US5703088A (en) 1989-08-21 1997-12-30 Beth Israel Deaconess Medical Center, Inc. Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses
NZ234883A (en) * 1989-08-22 1995-01-27 Merck Frosst Canada Inc Quinolin-2-ylmethoxy indole derivatives, preparation and pharmaceutical compositions thereof
FR2651122B1 (en) 1989-08-29 1994-10-28 Oreal COMPOSITIONS FOR USE IN BRAKING HAIR LOSS AND INDUCING AND STIMULATING THEIR GROWTH, CONTAINING 2-AMINO PYRIMIDINE OXIDE-3 DERIVATIVES AND NEW AMINO-2 PYRIMIDINE OXIDE-3 DERIVATIVES.
GB8922026D0 (en) 1989-09-29 1989-11-15 Pharma Mar Sa Novel anti-viral and cytotoxic agent
KR0159766B1 (en) * 1989-10-16 1998-12-01 후지사와 토모키치로 Hair revitalizing agent
ES2084801T3 (en) 1990-02-19 1996-05-16 Ciba Geigy Ag ACIL COMPOUNDS.
US5115098A (en) * 1990-02-28 1992-05-19 President And Fellows Of Harvard College End-blocked peptides inhibiting binding capacity of gp120
JPH04211648A (en) 1990-07-27 1992-08-03 Nippon Kayaku Co Ltd Keto-acid amide derivative
DE4015255A1 (en) * 1990-05-12 1991-11-14 Hoechst Ag OXALYL-AMINOSA-E-LEED DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICAMENT FOR INHIBITING THE PROLYL HYDROXYLASE
US5192773A (en) 1990-07-02 1993-03-09 Vertex Pharmaceuticals, Inc. Immunosuppressive compounds
US5292747A (en) * 1990-08-07 1994-03-08 Hoffman-La Roche Inc. Substituted pyrroles
ES2104597T3 (en) 1990-08-14 1997-10-16 Kenneth M Hallam COMPOSITION FOR THE PROMOTION OF HAIR GROWTH.
AU8740991A (en) 1990-08-24 1992-03-17 Upjohn Company, The Peptides containing amino-polyols as transition-state mimics
WO1992004370A1 (en) 1990-08-29 1992-03-19 Vertex Pharmaceuticals Incorporated Modified di- and tripeptidyl immunosuppressive compounds
GB2247456A (en) * 1990-09-03 1992-03-04 Fujisawa Pharmaceutical Co Tetrahydropyrane compounds, a process for their production and a pharmaceutical composition containing the same
JPH04149166A (en) * 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd Novel keto acid amide derivative
FR2671082B1 (en) * 1990-12-28 1993-04-16 Oreal MULTI-COMPONENT AGENT OR KIT FOR PREPARING THE SULFO-CONJUGATED FORM OF PYRIMIDINO- OR TRIAZINO-N-OXIDE COMPOUNDS AND METHOD FOR IMPLEMENTING SAME.
AU1677092A (en) * 1991-03-20 1992-10-21 Vertex Pharmaceuticals Incorporated Tetrahydroxyalkane derivatives as inhibitors of hiv aspartyl protease
IT1245712B (en) 1991-04-09 1994-10-14 Boehringer Mannheim Italia USEFUL HETEROCYCLIC AMINES THERAPY OF ASTHMA AND AIRWAY INFLAMMATION
US5147877A (en) 1991-04-18 1992-09-15 Merck & Co. Inc. Semi-synthetic immunosuppressive macrolides
EP0584217A1 (en) * 1991-05-08 1994-03-02 Vertex Pharmaceuticals Incorporated Rfkbp: a novel prolyl isomerase and rapamycin/fk506 binding protein
DE69229782T2 (en) 1991-05-09 2000-04-27 Vertex Pharma NEW IMMUNE SUPPRESSIVE CONNECTIONS
US5620971A (en) 1991-05-09 1997-04-15 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
US5565560A (en) * 1991-05-13 1996-10-15 Merck & Co., Inc. O-Aryl,O-alkyl,O-alkenyl and O-alkynylmacrolides having immunosuppressive activity
MX9202466A (en) 1991-05-24 1994-06-30 Vertex Pharma NOVELTY IMMUNOSUPPRESSIVE COMPOUNDS.
FR2677884B1 (en) * 1991-06-20 1993-07-09 Oreal COMPOSITION FOR BRAKING HAIR LOSS BASED ON TRISUBSTITUTED N-OXIDE PYRIMIDINES OR THEIR SULFOCONJUGAL DERIVATIVES, NOVEL PYRIMIDINE N-OXIDE COMPOUNDS OR THEIR SULFOCONJUGAL DERIVATIVES.
JPH05178824A (en) 1991-08-05 1993-07-20 Takeda Chem Ind Ltd Asparagine derivative and its use
US5189042A (en) * 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
US5457111A (en) * 1991-09-05 1995-10-10 Abbott Laboratories Macrocyclic immunomodulators
US5208241A (en) * 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
MX9205821A (en) * 1991-10-11 1993-04-01 Ciba Geigy Ag PIRIMIDINIL- AND TRIAZINILETERES AND -TIOETERES AND PROCEDURE FOR THE PREPARATION.
WO1993007269A1 (en) * 1991-10-11 1993-04-15 Vertex Pharmaceuticals Incorporated ISOLATION OF AN Mr 52,000 FK506 BINDING PROTEIN AND MOLECULAR CLONING OF A CORRESPONDING HUMAN cDNA
AU3278293A (en) 1991-12-20 1993-07-28 Syntex (U.S.A.) Inc. Cyclic amides of 3-amino-2-hydroxy-carboxylic acids as hiv-protease inhibitors
GB9200245D0 (en) * 1992-01-07 1992-02-26 British Bio Technology Compounds
AU3477093A (en) 1992-01-27 1993-09-01 Merck & Co., Inc. 17beta -hydroxybenzoyl-4-aza-5alpha-androst-1-en-3-ones useful to treat baldness
WO1993018736A1 (en) 1992-03-19 1993-09-30 Armand Pardo Cosmetic hair care compositions for treating hair loss
CA2091194A1 (en) * 1992-04-08 1993-10-09 Richard D. Connell 2-oxo-ethyl derivatives as immunosuppressants
AU4388893A (en) 1992-05-20 1993-12-13 Vertex Pharmaceuticals Incorporated Method of detecting tissue-specific FK506 binding protein messenger RNAs and uses thereof
IT1254373B (en) * 1992-05-29 1995-09-14 HETEROPROSTANOIDS, PROCEDURE FOR THEIR PREPARATION AND THEIR EMPLOYE THERAPEUTIC.
US5284877A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkyl and alkenyl macrolides having immunosuppressive activity
US5284840A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkylidene macrolides having immunosuppressive activity
US5334719A (en) 1992-06-17 1994-08-02 Merck Frosst Canada, Inc. Bicyclic(azaaromatic)indoles as inhibitors of leukotriene bisynthesis
GB9216329D0 (en) 1992-07-31 1992-09-16 Erba Carlo Spa 17beta-substituted 4-aza-5alpha-androstan-3-one derivatives
IS2334B (en) 1992-09-08 2008-02-15 Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) Aspartyl protease inhibitor of a new class of sulfonamides
US5723490A (en) 1992-09-08 1998-03-03 Vertex Pharmaceuticals Incorporated THF-containing sulfonamide inhibitors of aspartyl protease
NZ314207A (en) 1992-09-28 2000-12-22 Vertex Pharma 1-(2-Oxoacetyl)-piperidine-2-carboxylic acid derivatives as multi drug resistant cancer cell sensitizers
US5258389A (en) * 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
AU5748194A (en) 1992-12-11 1994-07-04 Vertex Pharmaceuticals Incorporated Mannitol derivatives and their use as inhibitors of aspartyl protease
DE4302860A1 (en) 1993-01-22 1994-08-04 Chemie Linz Deutschland N-Cyclic and N, N'dicyclic ureas
US5385918A (en) * 1993-02-09 1995-01-31 Miles Inc. Aminomethylene-peptides as immunosuppressants
US5252579A (en) 1993-02-16 1993-10-12 American Home Products Corporation Macrocyclic immunomodulators
US5631017A (en) 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5837703A (en) * 1993-03-31 1998-11-17 Cell Therapeutics, Inc. Amino-alcohol substituted cyclic compounds
US5319098A (en) 1993-05-18 1994-06-07 Celgene Corporation Process for the stereoselective preparation of L-alanyl-L-proline
CA2167282A1 (en) 1993-07-16 1995-01-26 Gerald R. Crabtree Regulated apoptosis
US5482284A (en) 1993-08-09 1996-01-09 Vandever; Claude S. Golf address and stance teaching and practice device
IT1270882B (en) 1993-10-05 1997-05-13 Isagro Srl FUNGICIDE-BASED OLIGOPEPTIDES
DE69417925T2 (en) 1993-11-04 1999-11-25 Merck & Co Inc 7-SUBSTITUTED-4-AZA-STEROID DERIVATIVES AS 5-ALPHA REDUCTASE INHIBITORS
EP0677039B1 (en) 1993-11-04 1999-03-10 Abbott Laboratories Cyclobutane derivatives as inhibitors of squalene synthetase and protein farnesyltransferase
US5385908A (en) 1993-11-22 1995-01-31 American Home Products Corporation Hindered esters of rapamycin
MX9603909A (en) 1994-03-07 1997-03-29 Vertex Pharma Sulphonamide derivatives as aspartyl protease inhibitors.
US5744485A (en) 1994-03-25 1998-04-28 Vertex Pharmaceuticals Incorporated Carbamates and ureas as modifiers of multi-drug resistance
US5488816A (en) 1994-07-21 1996-02-06 Boehringer Mannheim Corporation Method and apparatus for manufacturing a coagulation assay device in a continuous manner
US5543423A (en) 1994-11-16 1996-08-06 Vertex Pharmaceuticals, Incorporated Amino acid derivatives with improved multi-drug resistance activity
US5506228A (en) * 1995-02-23 1996-04-09 Merck & Co., Inc. 2,6-diaryl pyridazinones with immunosuppressant activity
US5574011A (en) * 1995-04-04 1996-11-12 Tien; Henry C. Compositions and methods for the treatment of male-pattern baldness
US5691372A (en) 1995-04-19 1997-11-25 Vertex Pharmaceuticals Incorporated Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease
US5726184A (en) 1995-05-19 1998-03-10 Vertex Pharmaceuticals Incorporated Tetralin compounds with improved MDR activity
US5614547A (en) * 1995-06-07 1997-03-25 Guilford Pharmaceuticals Inc. Small molecule inhibitors of rotamase enzyme
US6037370A (en) * 1995-06-08 2000-03-14 Vertex Pharmaceuticals Incorporated Methods and compositions for stimulating neurite growth
US5801197A (en) * 1995-10-31 1998-09-01 Gpi Nil Holdings, Inc. Rotamase enzyme activity inhibitors
AU731826B2 (en) * 1996-02-28 2001-04-05 Ariad Pharmaceuticals, Inc. Synthetic Multimerizing Agents
US5717092A (en) * 1996-03-29 1998-02-10 Vertex Pharmaceuticals Inc. Compounds with improved multi-drug resistance activity
EP0823419A3 (en) 1996-08-09 2000-08-16 Takeda Chemical Industries, Ltd. Dimethylpropanediol compounds
US5786378A (en) * 1996-09-25 1998-07-28 Gpi Nil Holdings, Inc. Heterocyclic thioesters
US5840736A (en) 1996-11-13 1998-11-24 Vertex Pharmaceuticals Incorporated Methods and compositions for stimulating neurite growth
US5780484A (en) 1996-11-13 1998-07-14 Vertex Pharmaceuticals Incorporated Methods for stimulating neurite growth with piperidine compounds
US5811434A (en) 1996-11-13 1998-09-22 Vertex Pharmacueticals Incorporated Methods and compositions for stimulating neurite growth
WO1998024805A1 (en) 1996-12-06 1998-06-11 Vertex Pharmaceuticals Incorporated INHIBITORS OF INTERLEUKIN-1β CONVERTING ENZYME
US5874449A (en) * 1996-12-31 1999-02-23 Gpi Nil Holdings, Inc. N-linked sulfonamides of heterocyclic thioesters
JP2002515051A (en) * 1996-12-31 2002-05-21 ジーピーアイ エヌアイエル ホールディングス インコーポレイテッド N-linked sulfonamides of heterocyclic thioesters
US5945441A (en) * 1997-06-04 1999-08-31 Gpi Nil Holdings, Inc. Pyrrolidine carboxylate hair revitalizing agents
US6187784B1 (en) * 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Pipecolic acid derivative hair growth compositions and uses
US6271244B1 (en) * 1998-06-03 2001-08-07 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6187796B1 (en) * 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Sulfone hair growth compositions and uses
US6172087B1 (en) * 1998-06-03 2001-01-09 Gpi Nil Holding, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6218423B1 (en) * 1998-08-14 2001-04-17 Gpi Nil Holdings, Inc. Pyrrolidine derivatives for vision and memory disorders

Also Published As

Publication number Publication date
TW501931B (en) 2002-09-11
JP2002510302A (en) 2002-04-02
MXPA99010886A (en) 2003-08-01
US6191125B1 (en) 2001-02-20
DE69826267D1 (en) 2004-10-21
ZA984778B (en) 1999-02-24
CA2292965C (en) 2007-11-13
EP0983054A1 (en) 2000-03-08
TW518220B (en) 2003-01-21
US5945441A (en) 1999-08-31
US6004993A (en) 1999-12-21
US20020037924A1 (en) 2002-03-28
US6177455B1 (en) 2001-01-23
US6187806B1 (en) 2001-02-13
CA2292965A1 (en) 1998-12-10
JP2002510301A (en) 2002-04-02
ATE275930T1 (en) 2004-10-15
US6239164B1 (en) 2001-05-29
WO1998055090A1 (en) 1998-12-10
US6194440B1 (en) 2001-02-27
EP0998263A1 (en) 2000-05-10
AU7716998A (en) 1998-12-21
ZA984621B (en) 1999-02-24
US20010036952A1 (en) 2001-11-01
EP0983054B1 (en) 2004-09-15
WO1998055091A1 (en) 1998-12-10
CA2292910A1 (en) 1998-12-10
TW490307B (en) 2002-06-11
EP1479373B1 (en) 2007-01-10
US20010029263A1 (en) 2001-10-11
JP4068164B2 (en) 2008-03-26
AU751057B2 (en) 2002-08-08
ES2229498T3 (en) 2005-04-16
EP1479373A1 (en) 2004-11-24
DE69826267T2 (en) 2005-11-17
DE69836878D1 (en) 2007-02-22
AU7716498A (en) 1998-12-21
ZA984783B (en) 1999-02-24

Similar Documents

Publication Publication Date Title
CA2292910C (en) Hair growth compositions and uses
AU764032B2 (en) Small molecule carbamate or urea hair growth compositions and uses
US6943187B2 (en) Pyrrolidine derivative hair growth compositions and uses
US6271244B1 (en) N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6429215B1 (en) N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6274602B1 (en) Heterocyclic thioester and ketone hair growth compositions and uses
AU759286B2 (en) N-linked sulfonamide of heterocyclic thioester hair growth compounds and uses
US20020010205A1 (en) N-linked sulfone of heterocyclic thioester hair growth compositions and uses
EP1083873B1 (en) Heterocyclic thioester and ketone hair growth compositions and uses
CA2333693A1 (en) N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
AU8252898A (en) N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
MXPA00011942A (en) N-linked sulfonamide of heterocyclic thioester hair growth compounds and uses

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed