WO1998029117A1

WO1998029117A1 - N-linked ureas and carbamates of heterocyclic thioesters

Info

Publication number: WO1998029117A1
Application number: PCT/US1997/024070
Authority: WO
Inventors: Gregory S. Hamilton; Jia-He Li; Wei Huang
Original assignee: Guilford Pharmaceuticals Inc.
Priority date: 1996-12-31
Filing date: 1997-12-23
Publication date: 1998-07-09
Also published as: US5935989A; HUP0002442A3; GT199800014A; CA2239781A1; ZA9711704B; BR9714092A; KR20000057488A; PA8444001A1; PL334372A1; IL129696A0; US6184243B1; BG103408A; AU721572B2; AU5724198A; CZ154699A3; HUP0002442A2; AR013909A1

Abstract

This invention relates to neurotrophic low molecular weight, small molecule N-linked ureas and carbamates of heterocyclic thioesters having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

Description

N-LINKED UREAS AND CARBAMATES OF HETEROCYCLIC THIQESTERS

This application is a continuation-in-part application of U.S. Patent Application Serial No. 08/775,535 filed December 31, 1995.

BACKGROUND OF THE INVENTION

1. Field of Invention This invention relates to neurotrophic low molecular weigh", small molecule N-linked ureas ar.d carbamates of heterocyclic thioester≤ having an. affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

2. Description of Related Art

The term immunophilin refers to a number cf proteins that serve as receptors for the principal im unosuppressant drugs, cyclosporin A (CsA) , FK505 and rapamycin. Known classes of immunophilins are cyclophilins and FK506 binding proteins, or FKBPs. Cyclosporin A binds to cyclophilin A while FK506 and rapamycin bind to FKBP12. These immunophilin-drug complexes interface with various intracellular signal transduction systems, especially the immune and nervous systems.

Immunophilins are known :: have pepϋidyi-prolvl isomerase (PPIase) , or rotamase, enzyme activity, .i has been determined that rotamase enzyme activitv plays a role in the catalyzation of the interconversion of the cis and trans isomers of peptide and protein substrates for the imπunophil r. proteins .

Immunophilins were originally discovered and studied in the immune tissue. It was initially postulated by those skilled m the art that inhibition of the immunophilins' rotamase activity leads to inhibition of T-cell proliferation, thereby causing the immunosuppressive activity exhibited by immunosuppressant drugs, such as cyclosporin A, FK505 and rapamycin. Further study has shown that the inhibition of rotamase activity, in and of itself, does not result in immunosuppressive activity. Schreiber et al . , Science, 1990, vol. 250, pp. 556- 559. Instead, immunosuppression appears to stem from the formulation of a complex of immunosuppressant drugs and immunophilins. It has been shown that the immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al., Call, 1991, vol. 66, pp. 307-315. In the case of FKBP-FK506 and cyclophilin-CsA, the immunophilin-drug complexes bind to the enzyme calcmeurin and inhibit the T-cell receptor signalling which leads to T-cell proliferation. Similarly, the immuno ilin-drug complex of FKBP-rapamvcm interacts with the RAFT1/FRAP protein and hic ts tne 11-2 recectcr signalling. Immunophilins have been founα to be present at high concentrations m tne central nervous system. Immunophilins are enricned 13-50 times mere in tne central nervous system than the immune system. Within neural tissues, immunophilins appear to influence nitric oxide syntr.es is, neurotransmitter release and neuronal process extension.

It has been found tnat picc olar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate neurite outgrowth PC12 cells and sensory neurons, namely dorsal root ganglion cells (DRGs) . Lyons et al . , Proc. of Na tl . . cad. Sci . , 1994, vol. 91, pp. 3191-3195. In whole animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve injury. Surprisingly, it has been found that certain compounds with a high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects. Furthermore, these rotamase inhibitors are devoid of immunosuppressive activity. These findings suggest the use of rotamase mnibitors in treating various peripheral neuropathies and enhancing neuronal regrowtn m the central nervous system (CMS) . Studi.es nave demonstrated that neuroαegenerative disorders such as Alzheimer's disease, Parkinson's disease, ana amyctrophic lateral sclerosis ΑLS) may occur αue to the loss, or decreaseα availac lit , of a neurotrophic substance specific for a particular population of neurons affected m the αisorαer.

Several neurotrop ic factors affecting specific neuronal populations m the central nervous system nave oeen identified. For example, it nas been hypotnesized that Alzheimer's αisease results from a decrease or loss of nerve grc«vtn factor (MGF, . It has thus been proposeα to treat Senile Dementia cf tne Alzheimer's Type (SDAT) patients with exogenous nerve growth factor or other neurotropnic proteins, such as brain derived growtn factor, glial denveα growth factor, ciliary neurotrophic factor and neurctrop -3, to increase the survival of degenerating neuronal populations . Clinical application of these proteins in various neurological disease states is nampered by difficulties the delivery and bioavailability of large proteins to nervous system targets. By contrast, immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity. However, when admmistered chronically, immunosuppressant αrugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of giomerular filtration and irreversible interstitial 5 fibrosis (Kopp et al., J. Ar.. Sec . Nepr.rol . , 1991, 1:162); neurological deficits, such as voluntar-, tremors, or non-specific cereoral angina, such as non- localized headaches (De Green et al . , N. Enςl . J. Med. , 1987, 317:861); and vascular hypertension with 0 complications resulting therefrom (Kanan et al., N. Engl . J. Med. , 1989, 321:1725).

In order to prevent the ≤iαe effects associated with use of the immunosuppressant compounds, the present invention provides r.on-immunosuppressive

15 compounds containing small molecule FKBP rotamase inhibitors for enhancing neurite outgrowth, and promoting neuronal growth ana regeneration various neuropathological situations wnere neuronal repair can be facilitated, including: peripheral nerve damage

' o caused by physical injury or disease state such as diabetes; physical damage to the central nervous system (spinal cord and cram) ; brain αamage associated with stroke; ana neurological disorders relating to neurodegeneration, such as Parkinson's

25 disease, SDAT (Alzheimer's α sease) , ana amyotropmc lateral sclerosis. SUMMARY OF THE INVENTION

The present invention relates to neurotroohic low molecular weight, small molecule compounds havmσ an affinity for FKBP-type im ur.ophilins . Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the e zyme activity associated with immunophilin proteins, particularly pept dyl- prolyl iso erase, or rotamase, enzyme activity. A key feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity in addition to their neurotrophic activity. Another significant feature is the novel addition of a thioester linkage and an unexpected increase in bioavailability and potency as compared to compounds lacking a thioester linkage.

Specifically, the present invention relates to a compound of formula I:

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

A and 3 are taken together with the nitrogen and carbon atoms to which they are respectively attached to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination cf CR,, o S, SC, S0_:, NH or NR₃;

X is either 0 or S;

Y is a direct bond to Z, a C_:-C₆ straight or branched chain alkyl, or a C_- ._; straight or branched chain alkenyl, wherein any of the carbon atoms of sa d alkyl or alkenyl are optionally substituted in one or 0 more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, amincalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said

15 alkyl or alkenyl are optionally replaced with 0, NH, NR , S, SO, or S0_:, wherein ?._ is selected from the group consisting of hydrogen, (C.-C₅j -straight or branched chain alkyl, (C₃-C._:) -straight or branched chain alkenyl or alkynyl, and (C_:-C,) bridging alkyl

? ^r) wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR-. and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;

25 Z is a direct bond, or a C-.-C straight or branched chain alkyl, or a C-C, straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkvl, thiocarbonyl, ester, thioester, alkoxy, alkencxv, cyano, nitro, imino, alkyiamino, amir.eaikvl, sulfhyαryl, thioalkyl, sulfer.yl, oxygen to form a carbcnyi, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR_:, S, SO, or S0_;, wherein ? is selected from the group consisting of hydrogen, (C.-C^; -straight or branched chain alkyl, (C_;.-C,-) -straight or branched chain alkenyl or alkynyl, and (C-_-C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR-_ and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;

C and D are independently: hydrogen, Ar, C_:-C₃ straight or branched chain alkyl, or C_:-C straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position (s) with C₃-C_j cycloalkyl, C₅-C₇ cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C_:-C. alkyl, C_-C. alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkencxy, cyano, nitro, imino, alkyiamino, aminoalkyl, sulfhydryl, thicalkyl, sulfcnyl, wherein any of the carbon atoms of said 5 alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR-, S, SO, or S0_;, wherein R₂ is selected from the group 0 consisting of hydrogen, (C-_.-C,) -straight or branched chain alkyl, (C₃-C;) -straight cr branched chain alkenyl or alkynyl, and (C_;-C ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR-_ and ending with one of the carbon

15 atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; W is oxygen or sulfur;

~ "i U is either 0 or N, wherein when U is 0, then R,_. is a lone pair of electrons and R₂ is selected from the group consisting of:

Ar as defined above, C₃-C₉ cycloalkyl, C_:-C._: straight or branched chain aikyi or alkenyl, or C_:-C₆

25 straight or branched chain alkyl or alkenyl substi_tuted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C^C- straight or branched chain alkyl, C_:-C₆ straight or branched chain alkenyl, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, iminc, alkylamino, aminoalkyl, sulfhydryi, thioalkyl, sulfonyi, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SC, S0_:, 0, or NR wherein R, is selected from the group consisting of hydrogen, (Ci-C -straight or branched chain alkyl, (C₃-C₅)- straight or branched chain alkenyl or alkynyl, and (C- C.) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR, and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C₃-C. cycloalkyl; and when U is N, R- and R are selected independently from the group consisting of: hydrogen, Ar as defined above, C-C, cycloalkyl, C--C straight or branched chain alkyl or alkenyl, or C_:-C_b- straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C_-C= straight or branched chain alkyl, C_:-C- straight or branched chain alkenyl, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, i ino, alkyla ino, aminoalkyl, sulfhydryl, thioalkyi, sulfon l, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, S3, S0_:, 0, or NR- wherein R_: is selected from the group consisting of hvdrogen, (C_:-C ι -straight or branched chain alkyl, (C₃-C₅)- straigh or branched chain alkenyl or alkynyl, and (C-- C) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C₂-C, cycloalkyl; or R and R_: may be taken together to form a heterocyclic ring. In preferred embodiments, Ar is a cyclic or fused cyclic ring and includes a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to five position (s) with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl, C_:-C₆ straight or branched chain alkyl, C-C₅ straight or branched chain alkenyl, C-C._; alkoxy, C_:-C₃ alkenyloxy, phencxy, benzyloxy, amino, thiocarbonyl, ester, thioester, cyano, i ino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonvl; wherein the individual ring sizes are 5-3 members; wherein the heterocyclic ring contains 1-4 heteroatom(s) selected from the group consisting of o, N, or S; wherein aromatic or tertiary alkyl amines are optionally oxidized to a corresponding N-oxide.

Particularly preferred Ar groups include phenyl, benzyl, naphthyl, pyrrolyl, pyrreliαmyi, pyrid yl, pyrimidinyl, punnyl, quinol yl, isoqu olmyl, furyl, thicphenyl, imidazolyl, oxazolyl, thiazclyl, pyrazoiyl, and thienyl.

Preferred heterocyclic groups may be selecteα from tne group consisting of pyrrolyl, pyrrolidinyl, pyridmyl, pyrimidinyl, punnyl, qumolmyl, isoqumolmyl, furyl, thicphenyl, imidazolyl, oxazolyl, thiazolyl, pyrazoiyl, thienyl, piperidinyl, and p perazmyl. A preferred embodiment of this invention is a compound of formula II:

or a pnar acεutically accεptacle salt, ester, or solva_te thereof, wherein:

E, F, G and H are independently CH₂, 0, S, SO, SO-, NH or NR, wherein at least two of E, F, G, and H are CH;

X is either 0 or S;

Y is a direct bond tc Z, a C_:-C₆ straight or brancned chain alkyl, or a C_;-C₅ straight or brancneα chain alkenyl, wherein any of tne carbon atoms of saiα alkyl or alkenyl are optionally substituted m one or more positions with ammo, halo, haloalkyl, thiocaroonyl, ester, thioester, alkoxy, aikenoxy, cyanc, nitro, imino, al ylammo, aminoalkyl, sulfnyαryl, thioalkyl, sulfonvl, oxygen to form a carbcnyl, or wherein any of tne carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR_;, 3, SO, or S0_:, wherein ?- is selected from the group consisting of hydrogen, (C^C -straight or branched chain alkyl, (C₃-C -straight or branched chain alkenyl or alkynyl, ana <C_:-C br agmg alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR,_ and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;

Z is a direct bond, or a C_:-C straight or brancned chain alkyl, or a C_.- . straight or brancheα chain alkenyl, wherein any of tne carbon atoms of sa α alkyl or alkenyl are optionally substituted m one or more positions with ammo, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenox.y, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonvl, oxygen to form a carbonyl, or wherein any of the carbon atoms cf said alkyl or alkenyl are optionally replaced with 0, NH, NR_;, S, SO, or S0_:, wherein R is selected from the group consisting of hydrogen, (C_:-C._;) -straight or branched chain alkyl, (C_:.-C- -straight or branched chain alkenyl or alkynyl, and ( €■_-€ , ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen cf NR,_ and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fusee to an Ar group; C and D are independently: hydrogen, Ar, C-_-C straight or branched chair, alkyl, or C_:-C- straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position (s) with C₃-C₉ cycloalkyl, C₅-C- cycloalkenyl, hydroxy!, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C_-C₅ alkyl, C_:-C₅ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioes_ter, alkoxy, aikenoxy, cyano, nitre, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonvl, wherein any of the carbon atoms of sa_'iα alkyl or alkenyl are optionally substituted m one or more positions with oxygen to form a carbcnyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR_:, S, SO, or S0_:, wherein R_ is selected from the group consisting of hydrogen, (C-_-T) -straight or branched chain alkyl, (C₃-C -straight or branched chain alkenyl or alkynyl, and (C_:-C bπαgmg alkyl wherein saiα bridging alkyl forms a heterocyclic ring starting w tn the nitrogen of NR,_. and ending with one of tne carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; wherein Ar is an aryl or neteroaryl moiety which is substituted or unsubstituted; W is oxygen or sulfur;

U is either 0 or N, wherein when U is 0, then R is a lone pair of electrons and R- is selected from the group consisting of: Ar as defined above, C₃-C, cycloalkyl, C.-C. straight or branched chain alkyl or alkenyl, or C_:-C. straight or branched chain alkyl or alkenyl substituted m one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C_:-C_: straight or branched chain ai.<yl, C_:-C straignt or branched chain alkenyl, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitre, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkvi, sulfonvl, substituted alkyl or alkenyl wherein anv cf the carbon atoms of the aikyi or alkenyl are optionally replaced with S, S3, SC_:, 0, or NR₂ wherein R₂ is selected from the group consisting of hydrogen, (C₁-C₅) -straight or branched chain alkyl, (C₃-C,_/- straight or branched chain alkenyl or alkynyl, and (C-- C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen cf MR- and ending with one of the carbon atoms of said aikyi or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C₃-C, cycloalkyl; and when U is N, ?.-_ and R₂ are selected independently from the group consisting of: hydrogen, Ar as defined above, C₃-C₉ cycloalkyl, C_:-C₅ straight or branched chain alkyl or a'lkenyl, or C,-C₃ straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C--C, straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonvl, substituted alkyl cr alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, S0₂, o, or NR, wherein R₂ is selected from the group consisting cf hydrogen, (C.-C^) -straight or branched chain alkyl, (C,-c.-) - straight or branched chain alkenyl or alkynyl, and (C-- C) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR, and ending with one cf the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C₃-C₃ cycloalkyl; or R_: and R₂ may be taken together to form a heterocyclic ring.

In preferred embodiments, Ar is a cyclic or fused cyclic ring and includes a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to five position(s) with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl, C_;-C₅ straight or branched chain alkyl, C-C₆ straight or branched chain alkenyl, C-_-C₆ alkoxy, C₂-C₆ alkenyloxy, phenoxy, benzyloxy, amino, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl; wherein the individual ring sizes are 5-3 members; wherein the heterocyclic ring contains 1-4 heteroatom(s) selected from the group consisting of 0, N, or S; wherein aromatic or tertiary alkyl amines are optionally oxidized to a corresponding N-oxide. Particularly preferred Ar groups include phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridmyl, pyrimiαinyl, punnyl, qumclmyl, isoqumolmyl, furyl, thiophenyl, imidazolyl, oxazolyl, tniazoiyi, pyrazoiyl, and thienyl.

Preferred heterocyclic groups may oe seiecteα from _tne group consisting of pyrrolyl, pyrrolidinyl, pvndmyl, pyrimidinyl, punnyl, qumolmyl, isoqumolmyl, furyl, tniephenyl, imidazolyl, oxazolyl, thiazolyl, pyrazoiyl, thienyl, pipεnαmyl, and piperazmyl.

Another prefεrreα εmbcαi ent is a compound cf formula III:

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

E, F, and G are independently CH_, 0, S, SO, SO_, NH or NR₃ wherein at least 2 cf E, F, and G are CH₂ ^;

X is either 0 or S;

Y is a direct bond to Z , a C.-C. straight or branched chain alkyl, or a C_.-C. stra gnt or brancheα

13 chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with ami o, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxv, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbcnyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR₂, 5, SO, or S0₂, wherein ?.- is selected from the group consisting of hydrogen, (C_:-C.-) -straight or branched chain alkyl, (C₃-C._:> -straight cr branched chain alkenyl or alkynyl, and (C-_-C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen cf NR_: and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;

Z is a direct bond, or a C_:-C, straight or branched chain alkyl, or a C_;-C₅ straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced witn o NH NR₂, S, SO, or S0₂, wherein ?^, is selected from the group consisting of hydrogen, (Cι_.-C₅) -straiαht or brancned chain alkyl, iC₃-C._: -straight or eranched chain alkenyl or alkynyl, and (C_:-C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen cf >!?_ and er.αmg with one of tne carbon atoms cf said al.<yl or alkenyl cnam, and wherein said heterocyclic ring is optionally fused to an Ar group;

C and D are independently: hyαrogen, Ar, C_:-C. straight or brancr.se chain alkyl, or C₂-C_b straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted m one or more position is) with C₃-C₉ cycloalkyl, C.-C- cycleal -:enyi, hydrcxyi, carbonyl oxygen, or Ar, wherein saiα alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C_:-C„ alkyl, C₂-C₅ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, immo, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted m one or more positions with oxygen to form a carocnyl, or wherein any of the carcon atoms of said al.-:yl or alkenyl are optionally replaced with 0, NH, NR>, s, SO or SC₂, wherein R₂ is selected from the group consisting of hydrogen, (C1_.-C₃) -straight or branched chain alkyl, (C₃-C₃) -straight cr branched chain alkenyl or alkynyl, and (d.-C,) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR,_. and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; is oxygen or sulfur;

U is either 0 or N, wherein when U is C, then R_: is a lone pair of electrons and R is selected from the group consisting of:

Ar as defined above, C₃-C₃ cycloalkyl, C_:-C₆ straight or branched chain alkyl or alkenyl, or d-C, straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, ammo, halo, haloalkyl, hydroxy, trifluoromethyi, d-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SC, S0₂, 0, or IT?.. where_»in R is selected from the group consisting of hvdreσer. (d-d; -straight or branched chain aikyi, (C,-C,)- straight or branched chain alkenyl or alkynyl, and (d- C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR. and ending with one of the carbon atoms of said aikyi or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or d-d cycloalkyl; and when U is N, R_: and P.- are selected independently from the group consisting cf: hydrogen, Ar as defined above, d-d cycloalkyl, C,_,- straight or branched chain alkyl or alkenyl, or d-d straight or branched chain alkyl cr alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, d-d straight or branched chain alkyl, d- straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitre, iminc, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyi wherein any of the carbon atoms of the alkyl or alkenyl^' are optionally replaced with S, SO, S0₂, 0, or N?._: wherein R₂ is selected from the group consisting of hydrogen, (C.-d_;} -straight or branched chain alkyl, (d-C₅) - straight or branched chain alkenyl or alkynyl, and (d- C) bridging alkyl wherein said bridging alkyl forms' -a heterocyclic ring starting witn the nitrogen of MR, and ending with one of the carbcr. atoms of said alkvl or alkenyl chain, and wherein saiα heterocyclic r ng s optionally fused to an Ar group or C-C₉ cycloalkyl; or R_x and R₂ may be taken together to form a heterocyclic ring.

In prεferreα embodiments, Ar is a cyclic or f sεα cyclic ring and includes a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring s either unsubstituted or substituted in one to five posιtιen(s) with halo, haloalkyl, hydroxyl, nitre, trifluoromethyl, d-d stra gnt or brancnεα chain alkyl, d-C_b straight or branched chain alkenyl, d-C₅ alkoxy, d-C₅ alkenyloxy, phenoxy, benzyloxy, ammo, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl; wherein the individual ring sizes are 5-3 members; wherein the heterocyclic ring contains 1-4 heteroatom(s) selected from the group consisting of 0, N, or S; wherein aromatic or tertiary alkyl amines are optionally oxidized to a corresponding N-oxide.

Particularly preferred Ar groups include phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridmyl, pyrimidinyl, punnyl, qumoimyl, isoqumolmyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazoiyl, and thienyl.

Preferred heterocyclic groups may be selec_te_d from the group consisting of pyrrolyl, pyrrolidinyl, pyridmyl, pyrimidinyl, punnyl, qumolinyl, isoqumolmyl, furyl, tn epnenyl, imidazolyl, oxazolyl, thiazolyl, pyrazol./l, tnienyi, piperidinyl, and piperazmyl .

A further particularly preferreα εmecαiment o_f this invention is a compound of formula IV:

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

X is either 0 or S;

Y is a direct bond to Z, a d-d straight or brancned chain alkyl, or a d-C straight or branched chain alkenyl, wherein any of tne carbon atoms of said alkyl or alkenyl are optionally substituted m one or more positions with ammo, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfcnyl, oxygen to form- -a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR₂, S, SO, or S0₂, wherein R₂ is selected from the group consisting of h^ydrogen, (d_-C₆) -straight or branched chain alkyl, (C-d_;. -straight or branched chain alkenyl or alkynyl, and id-C bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR-_ and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;

Z is a direct bond, or a d-C₃ straight or branched chain alkyl, or a d-d straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in .one or more positions with aminc, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR,, S, SO, or SO,, wherein ?. is selected from the group consisting of hydrogen, (d-d;) -straight or branched chain alkyl, (d-C,-/ -straight or branched chain alkenyl or alkynyl, and (d-C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic r-nα starting with the nitrogen of NR-_ and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring s optionally fusεα to an Ar group;

C and D are independently: r.ydrogen, Ar, d-C₃ straigr.t or oranched chain alkyl, or d-C, straight or crancned main alkenyl, wherein any cf the carbon atoms of said alkyl or alkenyl are optionally substituted m one or more position (s) with d-C₉ cycloalkyl, d-d cycloalkenyl, hydroxy!, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with d-C, alkyl, d-d alkenyl, hydroxy, ammo, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, immo, alkylamino, aminoalkyl, sulfhydryl, tnιoal.<yl, sulfonyl, wherein any of tne carbon atoms of saiα alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR₂, S, SO, or S0₂, wherein R₂ is selected from the group consisting of hydrogen, (d-d) -straight or brancned chain alkyl, (d-C -straight or branched chain alken^yl or alkynyl, and (C.-C bridging alkyl wherein saiα bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR^,, and ending w th one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar grouo_; wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; W is oxygen or sulfur;

U is either 0 or N, wherein when U is 0, then R- is a lone pa r of electrons and R_ is selected from the group consisting of:

Ar as defined above, d-d cycloalkyl, d-C, straight or branched chain alkyl or alkenyl, or C,-d straight or branched chain alkyl or alkenyl substituted m one or more positions with Ar, ammo, halo, haloalkyl, hydroxy, trifluoromethyl, d-C₅ straight or branched chain alkyl, d-C, straight or branched chain alkenyl, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitre, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, S0, 0, or NR₂ wherein

R₂ is selected from the group consisting of hydrogen,

(d-C,-) -straight or branched chain alkyl, (C₃-C )- straight or branched chain alkenyl or alkynyl, and (C_- C₄) bridging alkyl wherein sa d cridgmg alkyl forms a heterocyclic ring starting with the nitrogen of NR, ≤nd ending with one of the carbc atoms of said alkvl c alkenyl chain, and wherein said heterocyclic ring .₅ optionally fused to an Ar group cr C₃-C₉ cycloalkyl; and when U is N, R-_ and R are selected independently from the group consisting of: hydrogen, Ar as defined above, d-C₉ cycloalkyl, d-C,- straight or branched chain alkyl or alkenyl, or d-C,- straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, aminc, halo, haloalkyl, hydroxy, trifluoromethyl, d-C. straight or branched chain aikyi, d-d straight or branched chain alkenyl, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, S3, SG_;, 0, or NR₂ wherein R₂ is selected from the group consisting of hydrogen, (d-d) -straight or branched chain alkyl, (d-d;- straight or branched chain alkenyi or alkynyl, and (d- C„) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR_: and ending with one of the carbon atoms of said alkyl cr alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or d-C, cycloalkyl; R^,_ and R₂ may be taken together to form -a heterocyclic ring.

In preferred embodiments, Ar is a cyclic or fuseα cyclic ring and includes a cr.c-, bi- or tricvclic, carbo- or heterocyclic ring, wnerem the ring ₁₃ either unsubstituted or substituted m one to five position (s) with halo, haloal.<yi, hydroxyl, nitro, trifluoromethyl, d-C₃ straignt or branched chain alkyl, d-C, straignt or brancned chain alkenyi, C.-C. alKoxy, d-d alkenyloxy, phenoxy, benzyloxy, ammo, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfnyαryl, thιoai yl, ano sulfonyl; wherein the individual ring sizes are 5-3 members; wherein the heterocyclic ring contains 1-4 hetεroatom(s) selected from the group consisting of 0, N, or S; wherein aromatic cr tertiary alkyl amines are optionally oxidized to a corresponding N-oxiαe.

Particularly preferred Ar groups include pnenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridmyl, pyrimidinyl, punnyl, qumelmyl, isoqumolmyl, furyl, thiophεnyi, imidazolyl, oxazolyl, tniazolyi, pyrazoiyl, and thienyl.

Preferred heterocyclic groups may be selected from the group consisting of pyrrolyl, pyrrolidinyl, pyridmyl, pyrimidinyl, punnyl, qumelmyl, isoqumolmyl, furyl, thiopnenyl, imidazolyl, oxazolyl, thiazoiyl, pyrazoiyl, thienyl, piperidinvi, and piperazinyi.

Particularly preferred compounds of the preser- invention are selected from the group consisting of: 3-Phenyiprepyl (2S) -I- ( 1-cyclohexylcarbamoyl) -I- pyrreiidinecarbcthiate (17);

Phenethyi (2S) -N- (cyclohexylcarbamoyl) -2- pyrrelidinecarbothiate (13);

3- (2, 3, 5-Trimethylp e yij rop l 1- (1- adamantylcarbamoyl) -2-pyrrolidinecarbothioate (19);

3- ( 2, 3 , 5-Trimethyi hen ylj propyi 1 -

( cyclohexylcarbamoyl) -2-pyrrolidinecarbothioate (20, ;

3 - ( 3-Fluorophenyi ) propyl ( 2 S ) - 1 -

(Cyclohexylcarbamoyl) -2-pyrrel dinecarbcthicate (21 ; 3- (2-Fluorophe yl) propyl ( 2 S .■ - 1 - ! 1 - adamantylcarbamoyl) -2-pyrroiidinecarbothioate (22) ;

3- ( 2-Fluorophen yl j propyi ( 2 S ) - 1 -

(cyclohexylcarbamoyl) -2-pyrrolidinecarbothicate (23 ;

3- ( 4-Methylphenyl ) propyl ( 2 S ) - 1 - (cyclohexylcarbamoyl) -2-pyrrclidinecarbothioate (24, ;

3- (4-Methylphenyl) ?ropyl (2S) -1- (1- adamantylcarbamoyl) -2-pyrroIidinecarbothioate (25) ;

3- (4-Methylphenyl) propyl (2S) -l- (tεrt- butylcarbamoyl) -2-pyrrolidinεcarbcthioate (26) ; 3- ( 2-Chlorophenyl ) propyl ( 2 S ) - 1 - cyclohexylcarbamoyl) -2-pyrrolidinecarbothioate (27, ; 3-(3,5-Dιmethoxyphenyl)prcpyl (2S)-l-( [ (IS) -1- fi_ naphthyl⁾ ethyl] -carbamoyl ^}-2-pyrrolidmecarbothιoate

(28) ;

3, 3-Dιphe ylpro yl (2S) -1- [ (1, 1, 3, 3- tetram.ethylbutyi⁾ carbamoyl] -2-pyrrolidmecarbothιoa_te

(29) ;

3-Cyclohexylpropyl •' 2 S ) - 1 - [ ( 2 , 6 - diiscprepylphenyl) carbamoyl] -2-pyrroiιdmecarocthιoate (31) ; 3-Cyclohexylpropyl (2Sj -1- (hexylcarbamoyl) -2- pyrrelidmecarbothioate (32);

3 , 3-Dιphenylpropyi ( 2S ) -l- [ ( 2 , 4- dimethcxyphenyl) carbamoyl] -2-pyrrolidmecarbothιoate (33) ; 3-(3,5-Dιmethoxyphenyl)prepyi (2S) -1- { [ ( IS, 2R) -2- p h e y l - c y c l o p r o p i ; c a r b a mo y l ] - 2 - pyrrolidmecarbothioate (34);

3 - P h e n y l p r o p y l ( 2 S ) - l - [ { 2 , 4 -

Dimethoxyphenyl) carbamoyl] -2-pyrrolιdmecarbothιoate (35);

3-Phenylpropyl (2S) -1- ( 1- damantylcarbamoyl) -2- pyrroiidmecarbothioate (36);

3-Phenylpropyl (2S) -1- ( 1-cyclohexylcarbamoyl) -2- pyrroiidmecarbothioate (37) ^• 3-?henylpropyi (2S) -1- [ 1-aαamantylammo) (thioxo) - methyl] -2-pyrrolιdmecarbothιeate (38) ; 3- ( 3 , 4 , 5-Trimethoxyphenyl) propyl (2S₎ -.1- ⁽hexyicarbamoyl⁾ -2-pyrrolidinecarbothioate (39) ;

3- ⁽3, 4, 5-Trimethoxyphenyl)propyl (23) -1- ⁽benzyicarbamoyi ^• -2-pyrrolidinecarbothioate (40) ; 3-Phenylpropyl (2S) -1- (dimethylcarbamcyl) -2- pyrrciidinecarbothioate (41) ;

3-?henylpropyl ⁽2S⁾ -1- ; l-pyrrolidinyicarbamoyl) - 2-pyrrolidinecarbothioate (42, ;

3-?henylprepyl (2S) -1- ^'morphilmccarbamovl' -2- pyrrolidinecarbothioate (43);

3-Phenylpropyl (2S) -1- (diisopropylcarbamoyl) -2- pyrrclidinecarbcthioate (44);

3-Phenylpropyl (2S) -1- [methyl (phenyl) carbamoyl] - 2-pyrrolidinecarbothioate (45) ; and 3-Phenylpropyl (2S) -1- (diphenylcarbamoyl) -2- pyrrolidir.ecarbcthioate .

The present invention also relates to a pharmaceutical composition comprising a neurotrophically effective amount of the compound of formula I, II, III or IV, and a pharmaceutically acceptable carrier.

The present invention further relates to a method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of the compound of formula I, TT J-.T or IV.

The present invention further relates to the use of any cf the compounds of Formula I, II, m, iv o m Table I below in the preparation of a medicamen_t for tne treatment of a disease such as peripheral neuropathy caused by physical injury or disease sta_te, physical damage to the bram, physical damage to the spinal cere, stroke associated witn bram damage, Alzheimer's Disease, Parkinson's Disease, ana amyotropnic lateral sclerosis.

The present invention also contemplates processes for manufacturing the novel compounds, particularly the processes delineated belcw m Schemes 1 and 2.

DETAILED DESCRIPTION OF THE INVENTION Definitions "Alkyl" means a branched cr unbranched saturated hydrocarbon chain comprising a designated number of carbon atoms. For example, C_-C, straight or branched alkyl hydrocarbon chain contains 1 to 6 carbon atoms, and includes but is not limited to substituents such as methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, cert-butyl, n-pentyl, n-hexyl, and the like, unless otherwise indicated.

"Alkenyl" means a brancned or unbranched unsaturated hydrocarbon chain comprising a designated number of carbon atoms. For example, d-C straiαh_t c branched alkenyl hydrocarbon chain contains 2 to 6 carbcn atoms having at least one dcuble bond, and includes but is not limited to substituents such as ethenyl, propenyl, iso-prcpenyi, butenyl, isc-buter.vl, tert-butenyl, n-pentenyl, n-hexenyl, and the like, unless otherwise indicated.

"Alkoxy" means the group -OR wherein R is alkvl as herein defined. Preferably, R is a branched er unbranched saturated hydrocarbon chain containing 1 to 6 carbcn atoms .

"Ar" means an aryl or heteroaryl moiety which is substituted or unsubstituted, especially a cyclic or fused cyclic ring and includes a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to five position (s) with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl, d-d straight or branched chain alkyl, d-d straight or branched chain alkenyl, d- alkoxy, C₂-C₅ alkenyloxy, phenoxy, benzyloxy, amino, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl; wherein the individual ring sizes are 5-5 members; wherein the heterocyclic ring contains 1-4 heteroatom(s) selected from the group consisting of 3, N, or 3; wherein aromatic or tertiary alkyl amines a're optionally oxidized to a corresponding N-oxi e. Particularly preferred aryl or heteroaryl moieties include but are not limited to pnenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyriαmyl, pyrimidinyl, punnyl, qumelmyl, isoqumolmyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazoiyl, and thienyl.

"Halo" means at least one fluoro, chlore, bromc, or lodo moiety, unless otherwise indicated.

"Phenyl" includes all possible lsomeric phenyl radicals, optionally monosuostiteted or muiti-suosti- tuted with substituents selected from the group consisting of ammo, hale, haloalkyl, hydroxy, trifluoromethyl, d-d straignt or branched chain alkyl, d-d straight or brancned chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, NR₂ wherein R, is selected from the group consisting of hydrogen, (d- d) -straight or branched chain alkyl, (d-dj -straight or branched chain alkenyl cr alkynyl, and (d-C bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR_: and ending with one of the carbcn atoms of said alkyl cr alkenyl chain, and wherein saiα heterocyclic ring is optionally fused to an Ar group.

The term "pharmaceutically acceptable salt, ester, or solvate" refers to salts, esters, or solvates of the subject compounds which possess _the desired pharmacological activity and which are neither biologically nor otherwise undesirable. The salt, ester, or solvates can be formed with inorganic acids such as acetate, adipate, alginate, asparta_te, benzcate, benzenesulfonate, bisuifatε, butyrate, citrate, camphorate, campho sul fonate , cyclcpentanepropionate, digiuconate, dodecyisulfate, ethanesulfonate, fumarate, glucoheptanoate, giuconate, glycerephosphate, hemisulfate, hεptanoatε, hexanoate, hydrochloride hydrobromide, hydroiodide, 2- hydroxyethanesul fonate , lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotmate, oxalate, sulfate, thiocyanate, tosyiate and undecanoate. Base salt, ester, or solvates include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salt with organic bases such as dicyclohexylammε salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternizεd with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, hromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

The compounds of this invention may possess at least one asymmetric center and thus can be produced as mixtures of stereoisomers or as individual enantiomers or diastereomers . The individual stereoisomers may be obtained by using an optically active starting material, by resolving a race ic or non-racεmic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of formula (I, . It is understood that the individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers are encompassed by the scope of the present invention. The S- sterecisomer at atom 1 of formula I is most preferred due to its greater activity.

"Isomers" are different compounds that have the same molecular formula and includes cyclic isomers such as (iso)indole and other isomeric forms of cyclic moieties.

"Stereoisomers" are isomers that differ only in the way the atoms are arrangeα m space.

"Enantiomers" are a pair of stereoiscmers tha_t are non-supeπmposable mirror images of eacn ether.

"Diastereoisomers" are stereoisomers w cn are not mirror images of each other.

"Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Ncn-racemie mixt is a mixture containing individual enantiomers or stereoisomers. The term "preventing neurocegeneratior." as used herein includes the aoiiity to prevent neurocegeneration m patients newly diagnosed as having a neurodegenerative disease, or at r sk cf developing a new degenerative disease ana for preventing further neurodegeneration m patients who are already suffering from cr have symptoms of a neurodegenerative disease.

The term "treatment" as used herein covers any treatment of a disease and/or condition m an animal, particularly a human, and includes:

(l) preventing a disease and/or condition frcr occurring in a subject which may be predisposed to the disease and/or condition but has not yet been diag^¬ nosed as having it; (n) inhibiting the disease and/or i.e., arresting its development; or

33 (iii) relieving the disease and/or condition, i.e., causing regression of the disease and/or condi_¬ tion.

The system used in naming the compounds of _the present invention is shown below, using a compound of formula IV as an example.

A compound of the present invention, especially Formula IV, wherein n is 1, X is 0, Y is (CH₂)-, Z is CH, C is 3-pyridyi, D is H, W is 0, ϋ is N, Pi is H and R2 is 2-methylbutyl, is named 3- ( 3-pyridyl) -1- propylmercaptyl (2s) -1- [ (2-methylbutyl) carbamoyl] pyrroiidine-2-carboxylate .

Compounds of the Invention The neurotrophic low molecular weight, small molecule FKBP inhibitor compounds of this invention have an affinity for FKBP-type immunophilins, such as FKBP12. When the neurotrophic compounds of this invention are bound to an FKBP-type immunophilin, they have been found to inhibit the prolyl-peptidyl cis- trans isomerase activity, or rotamase, activity of the binding protein and unexpectedly stimulate neurite growth.

Specific exemplifications of these embodiments are presented in TABLE I. TABLE I: COMPOUNDS

No n W Y Z C D Rl R2

1 1 0 (CH₂) CH 3-Pyridyl H H 2-Meth leutyl 2 1 0 (CK )_: CH 3-?yridyl H H 1,1- dimeth l ropyl 3 1 0 (CH,)₂ CH 4-Methoxy H H 1,1- phenyl di e h I ropy1

4 1 0 CH, CH Phenyl H H 1,1- dimeth I ropy1

5 1 S (CH,)_: CH 4-Methoxy H H Cyclohexyl phenyl

6 1 0 (CH₂)₂ CH 3-Pyridyl H H Cyclohexyl

7 1 S (CH₂)₂ CH 3-Pyridyl H H Cycichexyi 8 1 S (CH,)₂ CH 3-Pyridyl H H 1-Adamantyl

9 1 S (CH₂)₂ CH 3-Pyridyl H H 1,1- dimethyl ropyi

10 1 0 (CH₂)₂ CH Phenyl Phenyl H 1,1- di eth-., Ipropyi

11 2 0 (CH,)₂ CH Phenyl H H 1,1- di ethylpropyl

12 2 0 (CH₂), CH Phenyl H H Phenyl 13 2 0 DirectCH 2-Phenyl 2-?henylH Phenyl Bond ethyl ethyl

14 2 0 DirectCH 2-Phenyl 2-PhenylH Cyclohexyl

Bond ethyl ethyl

15 2 S DirectCH 2-Phenyl 2-?henylH Cyclohexyl

Bond ethyl ethyl

16 2 0 (CH,)₂ CH 4-Methoxy H H Cycichexyi phenyl

17 1 0 (CH,)_: CH Phenyl H H Cyclohexyl No n w V Z C D Rl R2

13 1 0 H: CH Phenyl H H Cyclohexyl

19 1 0 (CH,) , CH 2,3,5 Tri H H Adamantyl methylphenyl

20 1 0 (CH₂) CH 2,3,5 Tri K H Cyclohexyl methylphenyl

21 1 c (CH_:) ₂ CH 3-Fluoro H H Cyclohexyl phenyl

22 _ 0 (CH₂) , CH 2-Fluoro H H Adamantyl phenyl

23 1 0 (CH₂) , CH 2-Fluoro H H Cyclohexyl phenyl

24 1 o (CH,) ₂ CH 4 -Methyl H K Cyclohexyl phenyl

25 1 0 (CH ) CH 4-Methyl H H Adamantyl phenyl

26 1 0 (CH_:) , CH 4-Methyl H H Tert-butyl phenyl

27 1 0 (CH^,) CH 2-Chloro H H Cyclohexyl phenyl

23 1 0 (CH_;) , CH 3, 5-Dimeth K H 1-Naptnylethyl oxyphenyl

29 1 0 (CH,) , CH Phenyl Phenyl H 1,1,3,3- Tetramethylbutyl

31 1 0 (CH,) ₂ CH Cyclohexyl H H 2, 6-Diisopropyl phenyl

32 1 0 (CH,;i_; CH Cyclohexyl H H Hexyl

33 1 0 (CH ;ι CH Phenyl Phenyl H 2, 4-D metncxy phenyl

34 1 0 (CH,: 1, CH 3, 5-Dimeth H H 2-Phenylcyclo oxyphenyl propyl

35 1 0 (CH,: ) CH Phenyl H H 2, 4-Dimethoxy phenyl

36 1 0 (CH,: ), CH Phenyl H H ^■ Adamantyl

37 1 0 (CH, )₂ CH Phenyl H H Cyclohexyl

38 1 0 (CH, ): CH Phenyl H H Adamantyl

39 1 0 (CH, ), CH (3,4,5- H H Hexyl

Trimethoxy) phenyl

40 1 0 (CH;}; CH (3,4,5- H Benzy]

Trimethoxy) phenyl No n W Y Z C D Rl R2

41 1 0 (CH,), CH Phenyl H CH, CH,

42 1 0 (CH )₂ CH Phenyl R_:,R₂= -c:-:_:-cκ,-cκ,-

CH,- (cyclic) ^"

43 1 0 (CH,), CH Phenyl H R,,R-= -Ch--CH,-C-CI- CH₂- (cyclic) ^"

44 1 0 (CH,)₂ CE Phenyl H R_:=R₂=Diismrepyl

45 1 0 (CH), CH Phenyl H CH, Phenyl

46 1 0 (CH,), CH Phenyl H R^R—Pher.vl

The compounds of the present invention exist Ξ_S stereoisomeric forms, either enantiomers or diastereoisomers . Included w thm the scope of the invention are the enantiomers, t e racemic form, arα diastereoisomεric mixtures. Enantiomers and diastereoisomers can be separated by methods known to those skilled in the art.

Methods of Using the Compounds of the Invention The compounds of the present invention have an affinity for tne FK506 binding protein, particularly FKBP12, wr.ic is present m tne neuronal tissue. When the inventive compounds emd to FKBP in neuronal tissue, they exhibit excellent neurotrophic activity. This activity is useful in the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathies. For the foregoing reasons, the present invention further relates to a method of effecting a neuronal activity m an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula I, II, III or IV. In a preferred embodiment, the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neuredegeneration and treatment of neurological disorder .

The compounds of the present invention are particularly useful for preventing neurodegeneration in patients suffering from a neurodegenerative disease or who have symptoms of a neurodegenerative disease. The compounds are also useful for preventing neurodegeneration in patients newly diagnosed as having a neurodegenerative disease or at risk fcr developing a neurodegenerative disease. These compounds are also useful for, but not limited to, preventing neurodegeneration in patients suffering from Parkinson's disease or having symptoms of Parkinson's disease. These treatment methods are exemplified in the MPTP Model and data described herein.

The neurological disorders that may be treated include but are not limited to: trigeminal neuralgia; glossopharyngeal neuralgia; Bell's Palsy; mvasthenia gravis; muscular dystrophy; amyotrophic lateral sclerosis; progressive muscular atrophy; progressive bulbar inherited muscular atrophy; hermated; ruptured or prolapsed invertebrate disk- syndromes; cervical spondylesis; plexus disorders_; thoracic outlet destruction syndromes; peripheral neuropathic such as those caused by lead, oapsone, ticks, porpnyπa, or Guillam-Sarre syndrome; Alzheimer's disease; and Par-:mscr.'s disease.

The compounds of the present invention are particularly useful for treating a neurological disorder selected from the group consisting of: peripheral neuropathy caused ey physical injury or disease state, physical damage to tne bram, physical damage to the spinal cord, stroke associated with bram damage, and neurological disorder relating to neurodegeneration. Examples of neurological disorders relating to neurodegeneration are Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

Pharmaceutical Compositions of the Invention The present invention also relates to a pharma- ceutical composition comprising:

(l) a neurotrophically effective amount of the compound of formula I, II, III or IV, and (ii) a pharmaceutically acceptable carrier. The above αiscussion relating to the utility and administration of the compounds of the present invention also applies to the pharmaceutical compositions of the present invention.

The term "pharmaceutically acceptable carrier" as used herein refers to any carrier, diluent, excipient, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbant, preservative, surfactant, colorant, flavorant, or sweetener.

For these purposes the compounds of the presen_t invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non- toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneally, intrathecally, intraventπcularly, intrasterr.al and mtracranial injection or infusion techniques.

For oral administration, the compounds of the present invention may be provided in any suitable dosage form known in the art. For example, the compositions may be incorporated into tablets, powders, granules, beads, chewable lozenges, capsules, liquids, aqueous suspensions cr solutions, or similar dosage forms, using conventional equipment and techniques known m the art. Tablet dosage forms are preferred. Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate. Capsules may contain diluents including lactose and dried corn starch. Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient.

When preparing dosage form incorporating the compositions cf the invention, the compounds may also be blended with conventional excipients such as binders, including gelatin, pregεlatinized starch, and the like; lubricants, such as hydrogenated vegetable oil, stearic acid, and the like; diluents, such as lactose, mannose, and sucrose; disintegrants, such as carboxymethylcellulose and sodium starch glycolate; suspending agents, such as povidone, " polyvinyl alcohol, and the like; abscrbants, such as silicon dioxide; preservatives, such as methylparaben, propylparaben, and sodium benzoate; surfactants, such as sodium lauryl sulfate, polysorbate 80, and the like; colorants such as F.D.& C. dyes and lakes; flavorants; and sweeteners .

Compositions and methods cf the invention also may utilize controlled release technology. Thus, for example, the inventive compounds may be incorporated into a hydrophcbic polymer matrix for'- controlled release over a period of days. Such controlled release films are well known to the art. Particularly preferred are trar.sdermal delivery systems. Other examples of pclymers commonly employed for this purpose that may be used in the present invention include ncndegradable ethylene- vinyl acetate copolymer and degradable lactic acid- glycolic acid copolymers which may be used externally or internally. Certain h drogels such as poly (hydroxyethylmethacrylate cr pely (v yialcohoi also may be useful, but for shorter release cycles then the other polymer releases systems, such as those mentioned above. To be effective therapeuticaily as central nervous system targets, the compounds of the present invention should readily penetrate the blood-brain barrier when peripherally administered. Compounds which cannot penetrate the blccd-brain barrier can be effectively administered by an mcraventricular route or other appropriate delivery system suitable for administration to the brain.

The compounds of the present invention may be administered in the form of sterile injectablε preparations, for example, as sterile injectable aqueous cr oleaginous suspensions. These

43 suspensions may be formulateα according to techniques known m the art using suitable dispersing or wetting agents and suspending agents. The sterile mjectable preparations may also ee sterile mjectable solutions or suspensions m non- toxic parenterally-acceptabie diluents or solvents, for example, as solutions m 1, 3-butanedιol . Among the acceptable vehicles and solvents mat may be employee are water, Ringer's solution and lsotomc sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as solvents or suspending mediums. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glyceπdes . Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially m their polyoxyethylated versions, are useful m the preparation of injectables. These oil solutions or suspensions may also contain long-cham alcohol diluents or dispersants.

The compounds of this invention may also be administered rectally in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irπtatmg excipient which is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa-- butter, beeswax and polyethylene glycols.

The compounds of this invention may also be administered topically, especially when the conditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas.

For topical application to the eye, er ophthalmic use, the compounds can be formulated as micronized suspensions in isctenic, pH adjusted sterile saline, cr, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively for the ophthalmic uses the compounds may be formulated in an ointment such as petrolatum. For topical application to the skin, the compounds can be formulated in a suitable ointment containing the compound suspended cr dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, ^• white petrolatum, propylene glycol, polycxyethyiene polyoxypropylene compound, emulsifying wax and Wcater. Alternatively, the compounds can be formulated in a suitable lotion cr cream 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 esters wax, cetearyl alcohol, 2- octyidodecanol, benzyl alcohol and water.

Topical application for the lower intestinal tract an be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.

Dosage levels on the order cf 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 amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It is understood, however, that a specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated and form cf administration.

The compounds can be administered with other neurotrophic agents such as neurotrophic growth factcr (NGF) , giial derived growth factor, brain derived growth factor, ciliary neurotrophic factor, and neurotropin-3. The dosage level of other neurctrephic drugs will depend upon the factors previously stated and the neurotrophic effectiveness of the drug combination.

The present invention relates to the use of any of the compounds seen in Table I in the preparation cf a medicament for the treatment of a disease such as peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis . The present invention also contemplates processes for manufacturing the novel compounds, particularly the processes delineated in schemes 1 and 2.

The novel compounds of this invention may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathway depicted belcv. As described by Scheme 1, cyclic ammo acids 1 protected by suitable blocking groups P on the ammo acid nitrogen may be reacted with thicis RSH to generate thioesters 2. After removal cf the protecting group, the free amme 3 may oe reacted with a variety of lsecyanates or isothiocyanates tc provide the final ureas or thioureas, respectively.

R-SH Deprotect

Coupling Method

?

SCHEME 1 Isocyanates (R'NCO) or isethiocyanates (R'NCS)- 4 may be conveniently prepared from the corresponding readily available amines by reaction with phosgene or thiophcsgene, as depicted m Scheme 2.

SCHEME 2

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 3. 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

Examples

The following examples are illustrative of the present invention and are net intended to be limitations thereon, unless otherwise specified, all percentages are based on 100% by weight of the final compound.

EXAMPL; 1

Synthesis of 3- ⁽ 3-Pyridyl) -l-oropylmercaptyl 2S-1- r (2-me hylbutyl⁾ carbamoyl 1 yrrolidine-2-carbox late (1)

3- ( 3-PyridvH -1-orooylchloride

To a solution of 3- ( 3-pyridyl) -1-propancl (10 g; 72.4 mmol) in chloroform (100 itiL) 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 in_to 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, eiuting with 40% ethylacetate m hexar.e, to obtain 10 g (65%) of the chloride as a clear oil, ^:H NMR ',300 MHZ, CDC1₃) : δ 2.02-2. II ( , 2H ; 2.77 ;_m, 2H) ; 3.51 (m, 2H) ; 7.20 (m, IHj ; 7.49 (m, IH) ; 3.45 (m, 2H) .

3- '3-PyridvD -1-oropylmercaptan

A mixture of 3- ( 3-pyricyl) -1-prcpylchlcr de (3 g; 19.4 mmol) and thiourea -,1. 3 g; 19.4 mmol, m ethanol (10 mL) was refluxed for 24 hours. Aqueous sodium hydroxide, 15 L of a 0.75 N solution, was added, and the mixture was refluxed for ar. additional 2 hrs . After cooling to room temperature, the solvent was removed in vacuo . Chromatographic purification of the crude thioi on a silica gel column eiuting with 50% ethyl acetate in hexar.e delivered 1.2 g of 3- (3-Pyridyl) -1-propyimercaptan as a clear liquid ^:H NMR (300 MHZ, CDCl,i : δ 1.34 (m, IH) ; 1.90 (m, 2H) ; 2.52 (m, 2H) ; 2.71 (m, 2H) ; 7.31 (m, IH) ; 7.47 (m, IH) ; 8.42 ( , 2H) .

30 3- ( 3-Pyridyl -l-orooylmercaotyl N- ( tsr-~

A mixture of N- ( tert-butylyoxycarbonyl; - (S) - proline (3.0 g; 13.9 mmol); 3- ( 3-Pyridyl) -1- pro yimercaptan (3.20 g; 20.9 mmol), dicyciehexylcarbcdiimide (4.59 g; 22.24 m ci) , camphersuifonic acid (1.03 g; 4.63 mmci), and 4- dimethylaminopyridine (0.60 g; 4.63 mmol) in dry methylene chloride (100 L) was stirred overnight. The reaction mixture was diluted with methylene chloride (50 mL) and water (100 L) , 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 eiuting with ethyl acetate to obtain 4.60 g (95%) of the thioester as a thick oil, '-H NMR (300 MHZ, CDCl,): δ 1.45 (s, 9H) ; 1.70-2.05 (m, 5K) ; 2.32 (m, IH) ; 2.71 (t, 2H) ; 2.85 ( , 2H) ; 3.50 (m, 2H) ; 4.18 (m, IH) ; 7.24 (m, IH) ; 7.51 (m, IH) ; 3.48 (m, 2H) .

3- (3-Pyridyl) -1-propylmercaotyl oyrrolidine-2- carboxylate

A solution of 3- ( 3-?yridyl) -1-mercaptyl N- ( tert-butylyoxycarbonyl) pyrroiidine-2-carbcxylate (4.60 g; 13.1 mmol) in methylene chloride (60 L) and trifluoroacetic acid (6 ml⁾ was stirred at room temperature for three hours. Saturated potassium carbcr.atε was added until the pH was basic, and the reaction mixture was extracted with methylene chlcriάe (3x) . The combined organic extracts were dried and concentrated to yield 2.36 g (75%; of the free amine as a thick oil, ^'-^'-. NMR (30C MHZ, CDC1-.) : δ 1.8^"-2.20 (m, 6H) ; 2.79 ( , 2H ; 3.03-3.15 m, 4H total'; 3.34 (m, IH) ; 7.32 ( , IH) ; 7.50 ( , IH) ; 8.57 ( , 2H) .

3- < 3-Pyridyl⁾ -1-oropylmercaPtyl 25-1- ^~ 2- methylbutyl carbamoyll ρyrrolidine-2-carboxylate (1) 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 triphcsgene (123 mg; 0.43 mmol, m methylene chloride (5 mL) . The resulting mixture was refluxed for 1 hour and then cooled to room temperature. 3- (3-Pyridyl) -l-propylmercaptyl pyrrolidine-2- carboxylate (300 mg; 1.3 mmol) in 5 L 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 25C mg (55%) of the compound of Example 1 (1, Table I) as an oil, ^:κ NMR (300 MHZ, CDC1₃) : d ^lR NMR (CDC1₃, 300 MHZ) : δ 0.89-0.93 (m, 6H) ; 1.10-1.20 ( , IH) ; 1.27 (₅, IH) ; 1.36-1.50 (m, 2H) ; 1.72 (s, 2H) ; 1.97-2.23 (m, 5H) _; 2.70-2.75 (m, 2H) ; 2.92-3.54 ( , 5H) ; 4.45-4.47 _lm, IH) ; 7.21-7.29 (m, IH) ; 7.53-7.56 (dd, IH) ; 3.46- 8.48 (s, 2H) .

Example 2

Synthesis of 3- -Pyridyl -1-orcpyl 2S-1- f f 1 ' , 1 ' - 5 Dimethylcropyl⁾ carbamoyll oyrrolidine-2-carboxylate (2)

Reaction of 3- (3-pyridyi) -1-propylmercaptyl pyrroiidme-2-carboxylate with the isocyanate generated from terc-amylamine and triphosgene, as ^ described for Example 1, provided the compound of Example 2 (2, Table 1) in 62% yield, ^:H NMR (CDC1₃, 300 MHZ): δ 0.33 (t, 3H) ; 1.27 (s, 6H) ; 1.64-1.71 ( , 2H) ; 1.91-2.02 ( , 7H) ; 2.66-2.71 (t, 2H) ; 2.35 (m, 2H) ; 3.29-3.42 ( , 2H) ; 4.11 (br, IH) ; 4.37-4.4: 5 ( , IH; . Example 3

Synthesis of 3- ⁽ 3-pyrιdyl -l-orccylmercaotyl 7^.-' -

5 carbcxylate (7)

A mixture of cyclohexyliscth ecyanate 120 mg; 0.9 mmol), 3- (3-pyrιdyl) -1-propylmercaptyi pyrrclidme- 2-carboxylate (200 mg; 0.9 mmol) and triethylamine

10 (90 mg; 0.9 mmol) in 20 mL cf methylene mloride was the resulting mixture was stirred for 1 r.cur ana then partitioned between water a a a 1:1 mixture of ethyl acetate and hexane . The organic phase was dried, concentrated and purified by column

15 chromatography (50% ethyl acetate/hexane' to obtain 160 mg (47%) of the compound of Example 3 (7, Table I), -H NMR (CDCl,, 300 MHZ): δ 1.16-1.40 (m, 6H) ; 1.50-1.71 (m, 4H) ; 1.95-2.03 (m, 7H) ; 2.70-2.75 (t, 2H) ; 3.03 (m, 2H) ; 3.40-3.60 'm, 2H) ; 4.95-4.98 (d,

^ IH) ; 5.26-5.29 (d, IH) ; 7.1~-7.25 (m, IH; .

EXAMPLE 4 Synthesis of 3-Phenylorooyl ^f25'-l-M. 25 cyclohexylcarbamoyl) -

2-pyrrolidmecarbothιo te (17; The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a stick white solid, with a chemical formula of d-K ,N,0,S, a molecular weight of 375.55, ^:H NMR (CDC1₃, 300 MHZ > : δ 1.10-1.19 (m,4H); 1.30-1.33 (m, 3H) ; 1.61-1.71 (m,2H); 1.84-2.03 (m, 6H) ; 2.55 ( t, 2K, J=7.75) ; 2.37 (t,2H, =7.57) ; 3.33-3.39 ( , IH,; 3.46-3.50 ' , IH) ; 3.63-3.57 (m, IH) ; 4.13 (d, 2H, J=7.85) ; 4.55 (dd, IH, J=2.14, 6.05) ; 7.11-7.29 (m, 5H) . Thm Layer Chromatography yielded a result of R_; = 0.43 (50% ETOAc/Hexane) .

EXAMPLE 5 Synthesis of Phenethyl (2S -M- ι cv lohexylcarbamoyl) - 2-oy relιdinecarbothιoate (13)

The compound was prepared in accordance with the procedures used for the above examples and yielded an optically pure compound as a clear oil with a molecular formula of C_2:H,₂N,0₂S, molecular weight of 360.63, ^:H NMR (CDCI_:, 300 MHZ): δ 1.06- 1.33 (m, 7H); 1.61-1.72 ( , 2H) ; 1.93-2.13 (m, 4H) ; 2.84 (t,2H, J=7.57) ; 3.10 ( t, 2H, J=7.0 ) ; 3.33-3.35 (m,lH); 3.44-3.45 (m, IH) ; 3.64-3.67 (m, IH) ; 4.17 (bd, IH, J=7.94) ; 4.55 (bd, IH, =3.37 ) ; 7.20-7.31

(m, 5H) . Thm Layer Chrmoategraphy yielded a result o f R, = 0 . 13 ( 50 % Hexane : ETCAo

EXAMPLE 5

Synthesis of 3- ⁽2 , 3 , 5-Trimethylchenyl) prooyl 1-fi- adamar.tylcarbamσyl⁾ -2-pyrrolidinecarbothiata (19) The compound was prepared in accordance with the above examples and yielded an optically pure compound as a colorless oil with a molecular formui; of C₂₈H₄₀NO,S, molecular weight of 468.66, ^"-K NMR 0 (CDCl,, 300 MHZ) : δ 1.50 (s,3H); 1.67 (bs,5H); 1.32-

1.90 (m, 2H) ; 2.01 (s,6H); 2.15-2.20 (m, 4H) ; 2.10 (s,3H); 2.15 (s,3H); 2.19 (s,3H); 2.63 (t,2H, J=6.66) ; 3.30 (m, IH) ; 3.42 (m, IH) ; 4.15 (S,1K); 4.52 ( , IH) ; 7.01 (d, 2H, J=10.43 ) . Thin

15 Layer Chromatography yielded a result of R_:- = 0.32 (80% EtOAc/hexane) .

EXAMPLE

Synthesis of 3- (2 , 3 , 5-Trimethylohenyl) orooyl 1- " (cyclohexylcarbamoyl) -2-oyrrolidinecarbothioate (20: The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure ccmpound as a colorless oil with a molecular formula of C₂H₃₅N,OS-0.75 H₂0, 25 molecular weight of 430.13, ^"-H NMR (CDCl,, 300 MHZ): δ 1.06-1.19 (m,3H); 1.22-1.43 ( , 2H) ; 1.53-1.55

o (m,lH) ; 1.71-1.74 (m, 2H) ; 1.75-1.80 (m, 2H) ; 1.81- 1.85 (m, 3H) ; 1.96-2.03 (m, 2H) ; 2.10 (s,3H) ; 2.15 (s,3K) 2.20 (s,3H) ; 2.63 ( t, 2H, J=7.93 ) ; 2.90 (t,2H₎ ; 3.38 (q, IH) ; 3.40-3.43 (m, IH) ; 3.61-3.69 (m, IH) ; 4.19 (d,lH, J=3.22) ; 4.56 (d, IH) ; 6.95

(d, 2K, J=12.05) . Thin Layer Chromatography yielded a result of R_:- = 0.47 (30% EtCAc/hexane) .

EX.AMPLE 3 Synthesis of 3- f 3-Fluoropher.yl crooyl (2S)-1-

(Cyclohexylcarbamoyl⁾ -2-oyrrelidinecarbothioate (21)

The compound was prepared in accordance with the procedures used in the above examples an yielded an optically pure compound as a white solid with a molecular formula of C₂₁H₂,N₂C_:3F, a molecular weight of 392.56, ^'-H NMR (CDCl,, 300 MHZ): δ 1.07-1.43 (m, 6H) ; 1.63-1.73 (m, 2H) ; 1.37-2.09 (cm,7H); 2.67 (t,2H, J=7.46) ; 2.35 ( t, 2H, J=7.46) ; 3.35-3.37 (m, IH) ; 3.46-3.48 ( , IH) ; 3.65-3.67 (m, IH) ; 4.19 (d, IH, J=7.84) ; 4.55 (d, IH, J= .90) ; 6.84-6.95 (m, 3H) ; 7.21-7.24 ( , IH) . Thin Layer Chromatography yielded a result of R_:- = 0.19 (20% EtOAc/hexane) .

EXAMPLE 9 Synthesis of 3- ( 2-Fluorooher.^yl ' orcpyl (2S -1-(1- adaman ylcarbamoyl) -2-nyrrolidinecarbothioa e (22) The compound was prepared m accordance with the procedures used in the above examples and yielded an optically pure compound as a colorless oil with a molecular formula of C₂=H₃₃N,0,SF, a molecular weight of 444.64, -H NMR (CDCI₃, 300 MHZ): δ 1.65 (bs,5H); 1.99 (s,2H); 2.04 (bs, 6K) ; 2.06-2.19 (bs,6H); 2.25 (m, IH) ; 2.69 (t,2H;; 2.36 (t,2H); 3.42 (m, IK); 3.57 ( , IH) ; 4.25 (m, 2H; ; 4.57 (m, IH) ; 7.05 (m, 2H); 7.13 (m, 2H) . Thin Layer Chromatography yielded a result of R.- = 0.70 (ΞtOAc) .

EXAMPLE 10

(cyclohexylcarbamoyl⁾ -2-oyrrolidinecarbothioate (23) The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a white solid with a molecular formula of d_:H,N₂0,3F, a molecular weight of 392.55, ^lH NMR (CDCl,, 300 MHZ): δ 1.23- 1.32 .(m,3H); 1.41-1.49 (m, 3H) ; 1.74-1.82 (m, 2H) ; 1.93-2.09 (cm,6H); 2.15-2.23 ( , IH) ; 2.73 (t,2H); 2.94 (t,2H); 3.42-3.51 ( , IK) ; 3.54-3.61 (m, IH) ; 3.61-3.74 (m,lH); 4.24 (d, IH) ; 4.56 (d, IH) ; 6.91- 7.03 (m,2H); 7.15-7.24 (m, 2H) . Thin Layer Chromatography yielded a result cf R.- = 0.65. EXAMPLE 11 Synthesis of 3- (4-Methylohenyl) orooyl (2S -1- ( cyclohex^ylcarbamo^yl⁾ -2-oyr clidmecarbothioat-P (24₎ The Compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a white solid with a molecular formula of C,_:H₃₂N,O,S-0.25 EtOAc, a molecular weight of 410.60, ^"-H NMR (CDC1₃, 300 MHZ): δ 1.01-1.21 (m,3H); 1.30-1.44 (m, 2H) ; 1.61-1.69 (m,2H); 1.75-2.13 (cm,8H); 2.30 (s,3H); 2.53 (t,2H); 2.84 (t,2H); 3.61 (q,lH); 3.55-3.69 (m, IF.) ; 3.72- 3.76 (m,lH); 4.21 (d, IH) ; 4.59 (d, IH) ; 7.05-7.25 (m, H) . Thin Layer Chromatography yielded a result of R.- = 0.84 (30% EtOAc/hexane) .

EXAMPLE 12 Synthesis of 3- f 4-MethylPhenyl^ orooyl (2S)-1-(1- adamantylcarba oyl) -2-oyrrolidinecarbothioate (25) The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a colorless oil with a molecular formula of C,₅H₃₇N,O,S-0.10 EtOAc, a molecular weight of 450.46, ^lE NMR (CDCl,, 300 MHZ): δ 1.54 (s,5H); 1.66 (bs, 6H) ; 1.85 (q, IK) ; 2.03 (s,8H); 2.09 (s,4H); 2.63 (t,2H); 2.86 (t,2H); 3.33 (q,lH); 3.35 (m, IH) ; 4.03 (s,lH); 4.52 (d, IH) ; 7.03-7.14 ( , 4H) . Thin Layer Chromatography yielded a result of R_f = 0.68 (80% EtOAc/hexa e) .

EXAMPLE 13 Synthesis of 3- ' 4-Methylohenyl ' orooyl 2S)-l-^°_'-_'-- butylcarba ovl⁾ -2-ovrrolidinecarbcthJ e--e (25)

The compound was prepared in accordance wi_th the procedures used in the above examples and yielded an optically pure compound as a colorless oil with a molecular formula of C₀H₃₀N₂35-0.3 H,0, a molecular weight of 367.94, ^:H NMR (CDCl,, 300 MHZ): δ 1.45 (s,9H); 1.82-1.91 ( , 2H, ; 1.95-2.13 ( , 4H) ; 2.31 (s,3H); 2.76 (t,2H); 2.39 (t,2H); 3.41-3.43 (m,lK); 3.46-3.49 ( , IH) ; 4.24 lbs, IK^'; 4.61 (d, IH) ; 7.09-7.12 (m,4H). Thin Layer Chromato raphy yielded a result of R, = 0.50 (50% EtOAc/hexane, .

EXAMPLE 14 Synthesis of 3- (2-Chloroohenyl 'orooyl 2S)-1- cyclohexylcarbamoyl) -2-oyrrolidir.ecarbcchioate (27) The Compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a light foam with a molecular formula of d_:H_2?N₂0₂SCl, a molecular weight of 403.99, ^:H NMR (CDCl,, 400 MHZ): δ 1.05- 1.42 (m,7H); 1.61-1.78 (m, 3H) ; 1.33-2.17 (m, 5H) ; 2.87 (t,2H); 3.05 (q,2H); 3.42 (q,lH); 3.57 ( , IH_{) ;}. 3.61-3.67 ( , IH); 4.21 (d, IK) ; 4.64 (d, IH) ; 7.20- 7.31 (m,3H); 7.56-7.59 (m, IH) . Thin Layer Chromatography yielded a result of R_:- = 0.78 (EtOAc) .

EXAMPLE 15 Synthesis of 3- l 3 , 5-Dimethoχyoher.yl ) prooyl < 2?. ) - ι - f r (IS) -1- (l-naohthyl⁾ ethyll -carbamoyl ■ -?.- oyrrolidinecarbothioate (28)

The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a colorless oil with a molecular formula of C_:3H₃N₂O₃S-0.75 H,0- 0.60 EtOAc, a molecular weight of 573.04, ^:H NMR (CDCl,, 400 MHZ) : δ 1.65 (d, 3H, J=6.76) ; 1.33-1.96 (m,2H); 1.99-2.07 ( , 3H) ; 2.50 ( t, 2K, J=7.51 ) ; 2.85 (t,2H, J=7.27) ; 3.29-3.63 (m, 2K) ; 3.73 (s,6H); 4.56 (d,lH, J=6.10) ; 4.76 (d, IH, J=7.51) ; 5.78-5.79 (m, IH) ; 6.29-6.32 (m, 3H) ; 7.40-7.76 (m, 4H) ; 7.31 (d,lH, J=6.90) ; 7.33 (d, IH, J=7.35) ; 8.17 (d, IH, J=7.72) . Thin Layer Chromatography yielded a result of R.- = 0.09 (50% EtOAc/hexane).

EXAMPLE 15

Synthesis of 3 , 3-Diohenylproo^yl (2S ⁾ -1- r ( 1 , 1 , 3 , 3- tetramethylbutyl carbamoyl 1 -2- pyrrolidinecarbothioate (29)

The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure ccmpound as a colorless oil with a molecular formula of C₂₃H₀N,C-S-0.25 EtOA.c, molecular weight of 502.74, ^:H NMR (CDCl,, 400 MHZ): δ 0.88 ( t, 2H, J=6.57) ; 1.02 (s,9H); 1.41 (s,3H); 1.42 (s,3H); 1.81 (d, IH, J=14.90) ; 1.65 (d, IH, J=14.90) ; 2.04-2.07 (m, IH) ; 2.29

(q,2H, J=7.83) ; 2.77 ( t, 2K, J=δ .97) ; 3.29-3.30 ( , IK) ; 3.40-3.42 (m, IH); 4.00 ( t, IK, J=7.83) ; 4.32 (s,lH); 4.53 (dd, IH, J=1.96,7.92) ; 7.10-7.27 (m, 10H) . Thin Layer Chromatography yielded a result of R_; = 0.43 (50% EtOAc/hexane) .

EXAMPLE 17 Synthesis of 3-Cvclohexylprooyl (2S) -1- ^r ( 2 , 6- diisoorooylphenyl) carbamoyll -2- oyrrolidinecarbothioate (31)

The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a white solid with a molecular formula of C_:-K-N_;0₂S, a molecular weight of 458.58, ^:H NMR (CDCl,, 400 MHZ): δ 0.76- 0.91 (m, 2H) ; 1.15-1.43 ( , 13H) ; 1.59-1.61 (m, 2H); 1.63-1.82 (m, 5H) ; 2.09-2.36 (m, 4H) ; 2.83 (t,2H); 3.24 (t,2H); 3.51-3.79 (m, 2H) ; 4.67-4.71 (m, IH) 7.15-7.20 (m,2H); 7.26-7.31 ( , IK) . Thin Layer Chromatography yielded a result of R.- = 0.72 (50% 5 EtOA-c/hexane) .

EXAMPLE 13 Synthesis of 3-Cvcloheχ^yloropyl <2S⁾-1- (hexylcarbamoyl⁾ -2-oyrrolidinecarbothioate (32) 0 The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a colorless oil with a molecular formula of C₂₁H_3eN₂O,S-0.05 H₂0, a molecular weight of 483.51, ^"-H NMR ( CDC1₃, 400 MHZ): 15 δ 0.76-0.91 (m, 2H) ; 1.15-1.43 (m, 13H) ; 1.59-1.61 (m, 2H) ; 1.63-1.32 ( , 5H) ; 2.09-2.36 (m, 4H) ; 2.83 (t,2H); 3.24 (t,2H); 3.51-3.79 ( , 2H) ; 4.67-4.71 (m,lH); 7.15-7.20 (m, 2H) ; 7.26-7.31 (m, IH) . Thin Layer Chromatography yielded a result of R_; = 0.35 "0 (50% EtOAc/hexane) .

EXAMPLE 19 Synthesis of 3 , 3-Diohenylorooyl (2S ) -1- f (2 , 4- dimethoxyphenyl) carbamoyll -2-pyrrolidinscarbothioate 25 (33)

The compound was prepared in accordance with the procedures used in the above ex aples and yielded an optically pure ccmpound as a white solid with a molecular formula of C₂₃H₃₂N,O.S, molecular weight of 504.33, ^:H NMR (CDCl,, 400 MHZ;: δ 2.05- 5 2.19 (m, 4H); 2.30 (q, 2H, J=8.05) ; 2.73

(td,2H, J=2.89,7.10) ; 3.53 (q, IH, J=7.57 ; 3.55-3.75 (m, IK); 3.77 (2,3H); 3.30 (s,3H); 3.99 (t, IK, J=7.76) ; 4.65 (dd, IK, =2.03, 3.12 ; 6.43-6.45 (m, 2H) ; 7.14-7.23 (m, 10H) ; 3.05 (d, IH, 1=9. Ξ : . Thm 10 Layer Chromatography yielded a result of R.- = 0.53 (EtOAc) .

EXAMPLE 20 15 Synthesis of 3- ( 3 , 5-Dimethoχyp'ner.yl) orooyl (25) -1- f r (IS, 2?) -2-phenyl-cvclopropyli carbamcyll -2- oyrrolidinecarbothioate (34)

The compound was prepare m accordance with the procedures used in the above examples and yielded an "0 optically active compound as an oil with a molecular formula of C₂₆H₃₂N₂O₄S-0.4 H,0, a molecular weight of

475.82, ^lE NMR (CDCl,, 300 MHZ): δ 0.86-0.33 (m, IH) ;

1.12-1.21 ( , 2K); 1.82-1.92 (m, 2H) ; 1.94-2.02

(m,2H); 2.05-2.12 (m, 2K) ; 2.50 ( t, 2H, J=7.86) ; 2.84 25 (dt,2H, J=7.04) ; 3.33-3.35 (m, IH) ; 3.46-3.43 (m, IH) ;

3.75 (s,6H); 4.53 (d, IH, J=6.35 ) ; 4.97 bs,lK); 5.23- 6.32 (m,2K); 7.12-7.25 (m, 6K) . Thin Layer Chromatography yielded a result of R.- = 0.65 (90% EtOAc/hexane) .

EXAMPLE 1

Synthesis of 3-Phenylorooyl '25 ) -1- r 17 , 4- Dimethoxyphenyl⁾ carbamoyl 1 -2-o-rrolidinecarbot.hi n - (35)

The compound was prepared in accordance with the procedures used in the above examples and yielded an optically active compound as an o l with a molecular formula of C₂₃K₂₃N-0₄S, a molecular weight of 428.57, ^:H NMR (CDCl,, 300 MHZ): δ 1.35-1.90 (m, 2H); 2.05-2.19 (m, 4H) ; 2.57 ( t, 2H, J=7.52 ) ; 2.87 (t,2H, J=6.61) ; 3.53-3.68 ( , IH) ; 3.72-3.75 (m, IH) ; 3.77 (s,3H); 3.83 (s,3H); 4.53 (dd, IH, J=2.16, 8.11) ; 6.43-5.46 (m, 2H); 6.80 (s,lK); 7.14-7.19 (m, 3H) ; 7.24-7.28 (m, IH) ; 3.06 (d, IH, J=7.81 ) . Thm Layer Chromatography yielded a result of R_:- = 0.45 (50% EtOAc/hexane) .

EXAMPLE 22 Synthesis of 3-Phenyloropyl ⁽2S⁾-1-(1- adamantylcarbamoyl⁾ -2-oyrrolidmecarbothioate (36) The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a colorless oil with a molecular formula of C,₅H₃₄N,0₂S, a molecular weight of 426.64, ^:H NMR (CDC1 , 300 MHZ₎: δ 1.59-1.65 (m,6H); 1.83-2.14 (m, 14H) ; 2.63 (t,2K, J=7.57) ; 2.86 ( t, 2K, J=7.22 ) ; 3.33-3.45 (m, IK_{) ;} 4.12 (d,2K, J=7.12) ; 4.53 (dd, IH, J=2.16, 8.16) ; 7.12- 7.29 (m, 5K) . Thin Layer Chromatography yielded a result of R, = 0.65 (50% EtOA.c/hexane) .

EXAMPLE 23 Synthesis of 3-Phenylorooyl '2S'-1-(1- cyclehexylcarbamoyl⁾ -2-oyrrolidinecarbothicate (37) The compound was prepared in accordance with the procedures used in the above examples and yielded an optically pure compound as a sticky white solid with a molecular formula of C_:H_3CN₂0,S, a molecular weight of 375.56, ^"-H NMR (CDCl,, 300 MHZ): δ 1.10-1.19 (m,4H); 1.30-1.38 (m, 3H) ; 1.61-1.71 (m, 2K); 1.84-2.03 (m, 6H) ; 2.65 ( t, 2H,

; 2.37 (t,2H, J=7.57) ; 3.33-3.39 (m, IK) ; 3.46-3.50 (m, IH) ; 3.63-3.67 (m, IH) ; 4.18 (d, 2H, J=7.35) ; 4.55 (dd, IH, J=2.14, 6.05) ; 7.11-7.29 (m, 5H) . Thin Layer Chromatography yielded a result of R_:- = 0.43 (50% EtOA.c/hexane) . K Test Procedure

Inhibition of the peptiαyl-prolyl isomerase (rotamase) activity of the inventive compounds can be evaluated by known methods described in the literature (Harding, et al., .Vature, 1989, 341:753- 760; Holt et al. J. Am. Cham . See , 115:9923-9933). These values are obtained as apparent Ki ' s and are presented in Table II. The cis -zrans isomerization of an alanme-prolme bond m a model substrate, N- succmyl-A.la-Ala-Pro-Phe-p-n troanιlιde, is monitored spεctrophotometrically m a chymotrypsin- coupled assay, which releases para-nitroanilide from the tra s form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor s determined, and the data is analyzed as a change m 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 L of FKBP (2.5 mM m 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol) , 25 mL of chymotrypsin (50 mg/ml m 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 (succmyl-Ala-Phe-Prc- Phe-p≤ra-nitroanilide, 5 mg/ml in 2.35 mM LiCl in trifluoroethanol) .

The absorbance at 390 n versus time is monitored for 90 seconds using a spectrophotcmeter and the rate constants are determined from the absorbance versus time data files.

The data for these experiments for representative compounds are presented in Table II under the column "Ki". The neurotrophic effects of the compounds of the present invention can be demonstrated in cellular biological experiments in vitro, as described below.

Chick Dorsal Root Ganglion

Cultures and Neurite Outgrowth Dorsal root ganglia were dissected from chick embryos of ten day gestation. Whole ganglion explar.ts were cultured on thin layer Matrigel-coatεd 12 well plates with Liebovitz L15 plus high glucose media supplemented with 2 mM giutamine and 10% fetal calf serum, and also containing 10 uM cytosine β-D arabinofuranoside (Ara C) at 37°c in an environment containing 5% CO, . Twenty- four hours later, the DRGs were treated with various immunophilin ligands. Forty-eight hours after drug treatment, the ganglia were visualized under phase contrast or Hoffman Modulation contrast with a Zeiss A_xiovert inverted microscope. Photomicrographs cf the explants were made, and neurite outgrowth was quantitated. Neurites longer than the DRG diameter were counted as positive, with total number of neurites quantitated per each experimental condition. Three to four DRGs are cultured per well, and each treatment was performed in duplicate. The data for these experiments for representative compounds are presented in Table II under the column "ED=₀".

TABLE II -'a)

In Vitro Test Pesulr.s

Ex. Nc. Ki,nM^r

1 +++

2 +÷

3 ++

4 ++

5 ++

6 +

7 + +

8 +++

9 +++

10 +++

11 ++

12 +++

13 +++

14 ++÷

15 +++

16 ++

18 *

19 *

20 +

21 *

22 +

23 *

24

25 +

26 *

27 *

28 +

29 *

31 *

32 *

TABLE 1Kb)

In Vitro Test Results

Ex. NO- ED50.nM-

1 ++++

2 +++

3 +++

4 ++

5 4-++

6 ++

7 +++

8 ++++

9 ++++

10 +++

11 +++

12 +++ 13 ++++ 14 +++ 15 ++++ 16 ++

Table life⁾: Numerical In Vitro Test Results

Ex . c . Ki,nM^~

18 5231 19 10,000

20 665

21 795

22 347

23 545 24 605

25 209

26 739

27 1494

28 8094 29 5147

3i ιo,:oo

32 3343

33 10,000

34 2757 35 10,000

36 285

37 601

38 659

39 31 40 82

41 722

42 525

43 3735

44 10,000 t. Relative potencies of compcunds are ranked according to the following scale: +τ-- denotes Ki or ED50 < 1 nM; +-r+ denotes K or ED50 of 1-50 nM;

++ denotes Ki or ED 50 of 51-200 nM; + denotes Ki o: ED of 201-500 nM; * denotes K or ED50 of > 500nM. MPTP Model of Parkinson's Disease The remarkable neurotrophic and neuroregenerative effects of the present inventive compounds can be further demonstrated in an animal model cf neurodegenerative disease. MPT? lesienmc of dopa mergic neurons m mice is used as an animal model of Parkinson's Disease. Four week old male CD1 white mice are doseα i.e. witn 30 mg/kg of MPT? for 5 days. Test compounds ' mg/kg), cr veniole, are administered s.c. along with the MPT? for 5 days, as well as for an additional 5 days following cessation of MPT? treatment. A.t 13 days following MPT? treatment, the animals are sacrificed a a the stπata are αissected ana perfus en-flxea. Immunostammg is performed cn saggital and coronal bram sections using anti-tyrcsme hydroxylase I g to quantitate survival and recovery of dopammergic neurons. In animals treated with MPT? and ver.icle, a substantial loss of functional dopammergic terminals is observed as compareα to non-les ened animals. Lεsioned animals receiving test compounds show a significant recovery of TH-sta ed dopammergic neurons. Data from this model presents quantitation for the recovery of TH-positive dopammergic neurons in the striatum of animals receiving the compounds of the present invention. Data from representative control and lesioned animals not receiving the test drugs also presents quantitation of effects in the absence of the compcunds of the present invention. The phrase "preventing neurodegeneration" relates to the remarkable ability of the compcunds of the present invention to significantly prevent nerve αamage when the compounds are given concurrently with a lesionmg agent, such as MPTP. This also provides a reasonable correlation between the scope of the claims and the ability to prevent neurodegeneration m patients newly diagnosed as having a neurodegenerative disease, or at risk of developing a neurodegenerative disease. The compounds also provide methods for preventing further neurodegeneration patients who are already suffering from or have symptoms of a neuroαegenerative disease.

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 ail such modifications are intended to be included within the scope of tne following claims.

Claims

WHAT IS CLAIMED IS

1. A. compound of formula I

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

A. and B are taken together with the nitrogen and carbon atoms to which they are respectively attached to form a 5-7 me bered saturated or unsaturated heterocyclic ring containing any combination of CH,, 0, 5, 30, SO,, NH or NR, ; X is either 0 or S; Y is a direct bond to Z, a d-d- straight or branched chain alkyl, or a d-d straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with C, NH, NR,, S, SO, or SO^,, wherein R_ is selected from the.. group consisting of hydrogen, (C_-C₅) -straight or brancned chain alkyl, (C-C₅) -straight or branched chain alkenyl cr alkynyl, ana (C_-C bridging alkvl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR_: and ending with one of tne carbon atoms of said alkyl or alkenyi chain, and wnerem sa α neterocyclic r ng is optionally fused to an A.r groip; Z is a direct bond, or a C_-d straignt or branched chain alkyl, or a d-d straight or brancheα chain alkenyl, wnerem any cf the caroon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with ammo, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, tnicalkyl, sulfon_l, oxygen to form a carbonyl, or wherein any of tne carbon atoms of saiα alkyl or alkenyl are optionally replaced with 0, NH, NR,, S, SO, or SO,, wherein R_: is selected from the group consisting of hydrogen, ^C_-C₆) -straignt or branched chain alkyl, (C-C₅) -straight or branched chain alkenyl or alkynyl, and (d-C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrcge of NR and ending with one of tne carbon atoms of said alk/1 cr alkenyi chain, and wherein said heterocyclic ring is optionally fused to an Ar group; C and D are independently: hydrogen, A.r, d-C, straight or branched chain alkyl, or d-d straight or branched chain alkenyl, wherein any of the carbon atoms cf said alkyl or alkenyl are optionally substituted in one or more position (s) with d-C₃ cycloalkyl, d-C- cycloalkenyl, hydrcxyl, carbonyl oxygen, or A.r, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with d-d alkyl, d-d alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally- substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR,, S, SO, or S0_:, wherein ?. is selected from the group consisting of hydrogen, (d- d) -straight or branched chain alkyl, (d-d) - straight or branched chain alkenyl or alkynyl, and (d-C.) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of MR- and ending with one cf the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group; wnerem A.r is an aryl or heteroaryl moiety which is substituted or unsucst tuted; TJ is oxygen or sulfur;

U is either 0 or N, wherein when U is 0, then R_: is a lone pair of electrons and R, is selected from the group consisting of: A.r as defined above, d-d cycloalkyl, d-C₅ straignt or branched chain al yl or alkenyl, or C -C. straignt or branched chain al.yl or alkenyl substituted m one or more positions with Ar, ammo, halo, haloalkyl, hydroxy, trifluoromethyl, d-C₅ straight or branched chain alkyl, d-d straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, al-.er.oxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO,, 0, or NR, wnerem R, is selected from the group consisting of hydrogen, (d-d) -straight or branched chain alkyl, (d-C₆) -straight cr branched chain alkenyl or alkynyl, and (d-C_, bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen cf NR_: and e ding with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic rir.g is optionally fused to an Ar group or d-d cyclcalkvl; and when U is N, R_: and ?._- are selected independently from the group consisting of: hydrogen, A.r as defined above, d-d cycloalkyl, d-d straight or branched chain alkyl or alkenyl, or d-d straight or branched chain alkyl or alkenyl substituted in one or more positions with A.r, ammo, halo, haloalkyl, hydroxy, trifluoromethyl, Z- -C straight or branched chain alkyl, d-d straight or branched chain alkenyi, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with Ξ, SO, SO,, Z , or NR₂ wherein R, is selected from the group consisting of hydrogen, (d_L-C₆) -straight or branched chain alkyl, (C,-C₃) -straight or branched chain alkenyl or alkynyl, and (d-C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR_: and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic rir.e is

34 optionally fused to an Ar group or C,-d cycloalkyl; or R_x and R, may be take together to form a heterocyclic ring.

2. The compound of claim 1, wherein the mcr.o- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of naphthyl, indoiyl, furyl, thiazoiyl, thienyl, pyridyl, and phenyl.

3. The compound of claim 1, wherein the compound has an affinity for FKBP-type immunophilins.

4. The compound of claim 3, wherein the FK3?-type immunophilins are FKBP12.

5. The compound of claim 1, wherein the compound inhibits rotamase enzyme activity.

6. The compound of claim 1, wherein the compound is selected from the group consisting of:

3-Phenylpropyi (2S) -1- ( 1-cyclohexylcarbamoyl) - 2-pyrrolidinecarbothiate (17);

Phenethyl (2S) -N- (cyclohexylcarbamoyl) -2- pyrrolidinecarbothiate (18); 3- (2, 3, 5-Trimethylphenyl) propyl 1-(1- adamantylcarba oyl) -2-pyrrolidinecarbothioate (19) ; 3- (2, 3, 5-Tπmethylphenyl , propyl 1- ( cyclohexylcarbamoyl) -2-pyrrolι inecarbcthioate

(20) ;

3- (3-Fluorophenyl) propyl (2S) -1- (Cyclohexylcarbamoyl) -2-pyrrolιdinεcarbothιoate

(21) ;

3- (2-Fluorophenyl) propyl 2S)-1- 1- adamantylcarbamoyl) -2-pyrrol αmecarcoth oate 22 ,- 3- (2-Fluorophenyl) propyl ,'2S) -1- (cyclohexylcarbamoyl) -2-pyrrol dinecarbothιoate

(23) ;

3- (4-Methyiphenyl) propyl (23) -1- ( cyclohexylcarbamoyl) -2-pyrrolidinecarbothioate

(24) ; 3- (4-Methylphenyl) propyl ;2S)-l-'l- adamantylcarba oyl) -2-pyrrolιdmecarbothιoate !2Ξ: ;

3- (4-Methylphenyl) propyl 25) -1- ; tert- butylcarbamoyl) -2-pyrrolidinεcarbcthιoate (26) ; 3- (2-Chlorophenyl) propyl (2S) -1- cyclohexylcarbamoyl) -2-pyrrolidmecarbothιoate 2~); 3- (3, 5-Dimethoxyphenyl) propyl 2S)-1-([(1S;-1- (1-naphthyl) ethyl] -carbamoyl} -2- pyrrolidinecarbothioate (23) ;

3, 3-Dιphenylpropyl (2S) -1- ['1,1,3,2- tetramethylbutyl) carbamoyl] -2- pyrrolidinecarbothioate (29) ;

36 3-Cyclohexylpropyl (2Sj -1- [(2,6- dnsopropylphenyl) carbamoyl] -2- pyrrolidmecarbothioate (31) ;

3-CyclohexyIpropyl (2S) -1- (hexylcarbamcyi) -2- pyrrolidmecarocthicate (32);

3, 3-Dιphenylpropyl (2S) -1- [(2,4- dimethoxyphenyl) carbamoyl] -2-pyrrolιdmecarbothιoate (33) ;

3- (3, 5-Dιmethcxyphenyl) ropyl (2S)-l-ι[(15,2R)- 2-pher.yl-cyclopropyl] carbamoyl] -2- pyrroiidmecarbothioate (34);

3-?henylproρyl (2S ) -1- [ (2, 4- Dimetncxyphenyl) carbamoyl] -2-pyrrolιdmecarbothιoate (35) ; 3-Phenylpropyl (2S) -1- ( 1-adamantylcarbamoyl) -2- pyrrolidmecarbothioate (36) ;

3-Phenylpropyl (2S)-1- I-cyclohexylcarbamoyl) - 2-pyrroiιdmecarcothιoate (37, ;

3-Phenylpropyl (2S) -1- [ 1-adamantylammo) (thioxo) -methyl] -2-pyrrolιdmecarbothιoate (38); 3- (3, 4, 5-Tπmethoxyphenyl) propyl (2S) -1- (hexylcarbamoyl) -2-pyrrolιdmecarbothιoate (39) ;

3- (3, 4, 5-Tπmethoxyphenyl) propyl (2S) -1- (benzylcarbamoyl) -2-pyrrolιdιnecarbothιoate (40) ; 3-Phenylpropyl (2S) -1- (α methylcarbamoyl j -2- pyrroliαmecarbothioate (41); 3-Phenylpropyl ⁽2S⁾ -1- ' 1-pyrrolιαmylcaroonyl.).- 2-pyrrolιdmecarbothιoate (42 ;

3-Phenylpropyl (2S) -1- imcrphilmccarbcr.yl) -2- pyrrolidmecarbothioate (43); 3-Phenylpropyl ⁽23⁾ -1- lαnsoprop lcarcamovl) -2- pyrrolidmecarbothioate (44^v;

3-Phenylpropyl (2S)-1- [ ethyl (phenyl) carbamoyl] -2-pyrrolidmecarbothιoate (45); and 3-Phenylpropyl (2S) -1- ι αipnenylcaroamoyl , -2- pyrrolidmecarbc hioatε (46).

7. A. pharmaceutical composition comprising a neurotrophically effective a cunt of the compound of claim 1 and a pharmaceutically acceptable carrier.

3. A method of effecting a neuronal activity m an animal, comprising: administering to the animal a neurotropnically effective amount of the compound of claim 1.

9. The method of claim 8, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion cf neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder .

10. The method of claim 9, wherein the neurologic, disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage tc the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

11. The method of claim 10, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

12 . A. compound o f formula I I

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

39 E, F, G and H are independently CH,, C, S, SO,_,. SO,, NH or NR, wherein at least two of E, F, G, and H are CH_:;

X is either 0 or S; Y is a direct bond to Z, a d- straight cr branched chain alkyl, cr a d-d straight or branched chain alkenyl, wherein any cf the carbon atoms of said alkyl or alkenyl are optionally substituted in one cr more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbcnyl, cr wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR,, 3, SO, or SO,, wherein R_; is selected from the group consisting of hydrogen, (d-d) -straight or branched chain alkyl, (d-d) -straight or branched chain alkenyi or alkynyl, and (d-C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR_: and ending with one of the carbcn atoms of said alkyl cr alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group;

Z is a direct bond, or a d-d straight or branched chain alkyl, or a d-d- straight or branched chain alkenyl, wherein any cf the carbon atoms of said alkyl or alkenyl are optionally substituted in one cr more positions with ammo, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyanc, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbcnyl, or wherein any of the carbcn atoms of said aikyi or alkenyl are optionally replaced with 0, NH, NR_:, S, SO, or SO,, wherein ?._: is selected from the group consisting of hydrogen,

-straight or branched chain alkyl, (d-d) -straight or branched chain alkenyl or alkynyl, and ^'. Z-_-C ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR,_ and ending with one of the carbon atoms of said alkyl cr alkenyi chain, and wherein said heterocyclic ring is optionally fused to an Ar group; C and D are independently: hydrogen, A.r, d-C₆ straight or branched chain alkyl, or C,-C₅ straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position (s) with d- cycloalkyl, C₅-C₇ cycloalkenyl, hydroxyl, carbonyl oxygen, cr A.r, wherein said alkyl, alkenyl, cycloalkyl cr cycloalkenyl groups are optionally substituted with d-C₅ alkyl, d-d alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, immo, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionall substituted in one or more positions with oxygen to form a carbonyl, or wherein any cf tne carbon atoms of saiα alkyl or alkenyl are optionally replaced with 0, NH, NR_:, S, SO, or 3d, wnerem R, is selected from the group consisting of nydrogen, (C - C₅) -straight or brancheα cnam al.<yl, (C-C₅) - straignt or branched cnam al enyl or alkynyl, and (d-C bridging alkyl wherein saiα oπdgmg alkyl forms a heterocyclic ring starting ,;ιth the nitrogen of NR_: and ending with one of the caroon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fuseα to an A.r group; wherein Ar is an aryl cr neteroaryl moiety which is substituted or unsubstituted; w is oxygen or sulfur;

U is either 0 or N, wherein when U is 0, then R_x is a lone pair of electrons and P_ is selected from the group consisting of:

A.r as defined above, C_.-d cycloalkyl, C_.-d straignt or branched chain al yl or al<enyl, or C -C straignt or branched chain alkyl cr alkenyl substituted in one or more positions w th Ar, ammo, halo, haloalkyl, hydroxy, trifluoromethyl, C -c_o straight or branched chain alkyl, C₂-C₅ straight or brancned chain alkenyl, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitre, immo, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or al.<enyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with 3, SO, SO , 0, or NP₂ wherein R₂ is selecteα from the group consisting of hydrogen, (d-d; -straight or branched chain alkyl, (C₃-C₆) -straight or branched chain alkenyl or alkynyl, and (d-C.,, bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR_: and ending with one of the carbon atoms cf said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group or C -C. cycloalkyl; and when U is N, R. and ?_ are selected independently from the group consisting of: hydrogen, Ar as defined above, C₂-C₃ cycloalkyl, C₁-C₃ straight or branched chain alkyl or alkenyl, or d-d straight or branched chain alkyl or alkenyl substituted m one or more positions with A.r, amino, halo, haloalkyl, hydroxy, trifluoromethyl, d-d straiont or branched chain alkyl, C_-C straignt or branched chain alkenyl, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbcn atoms of the alkyl or alkenyl are optionally replaced with S, SO, 50,, o, or NR_; wherein R, is selected from the group consisting of hydrogen, (d-d, -straight or branched chain alkyl, (d-C₃) -straight or branched chain alkenyl or alkynyl, and (d-C. bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR,_. and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group or C₃-C₅ cycloalkyl; or R-_ and R, may be taken together to form a heterocyclic ring.

13. The compound of claim 12, wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl .

14. The compound cf claim 12, wherein the compound has an affinity for FKBP-type immunophilins.

15. The compound of claim 14, wherein the FKBP- ype immunophilins are FKBP12.

16. The compound of claim 12, wnerem the compoun_d inhicits rotamase enzyme activity.

17. A pharmaceutical composition comprising a nεurotropnically effective amount of the compound of claim 12 and a pnarmaceutically acceptaole carrier.

18. A. method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrcpnιcall_, effective amount of the compound of claim 12.

19. The method of claim 13, wnerem the neuronal activity is selected from tne group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder .

20. The method of claim 19, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury cr disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

21. The method of claim 2 1 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

22. A. compound of formula III

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

Ξ, F, and G are independently CH,, 0, S, SO, SO,, NH or NR, wherein at least 2 of E, F, and G are CH,; X is either 0 or S;

Y is a direct bond to Z, a d-C₆ straight or branched chain alkyl, or a d-d straight or branched chain alkenyl, wherein any of the carbcn atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms cf said alkyl or alkenyl are optionally replaced with 0, NH, NR,, S, SO, or SC, wherein R_: is selected frem the group consisting of hydrogen, td_-d) -straight cr branched chain alkyl, (C~d) -straight or branched chain alkenyl or alkynyl, and (d-C₄) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR,. and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group;

Z is a direct bond, cr a C-_.-C₅ straight or branched chain alkyl, or a d-d straight or branched chain alkenyi, wherein any of the carbon atoms cf said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR,, 3, SO, or SC_;, wherein R, is selected from the group consisting of hydrogen, ;d_-d) -straight or branched chain alkyl, (d-C.;) -straight or branched chain alkenyl or alkynyl, and (d-C.,) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen cf NR-. and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group; c and D are independently: hydrogen, A.r, d-d straight or branched chain alkyl, or d-d straight or branched chain al.<enyl,.. wherein any of the carbon atoms of saiα alkyl or alkenyl are optionally substituted m one or more position (s) with C₃-C₈ cycloalkyl, d-d cycloalkenyl, hydroxyi, carbonyl oxygen, or A.r, wherein said alkyl, alkenyl, cycloalkyl cr cycloalkenyl groups are optionally substituted with d- alkyl, C,-C₃ alkenyi, hydroxy, am o, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, immo, alkylamino, aminoalkyl, sulfhydryl, tmoalkyl, sulfonyl, wherein any of tne carbon atoms of said alkyl or alkenyl are optionally substituted m one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR₂, S, SO, or SO,, wherein R, is selecteα from the group consisting of hydrogen, (d- C_s) -straight or oranched chain alkyl, (C_.-C - straight or branched chain alkenyl or alkynyl, and (d-C.j bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of MR_: and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group; wherein A.r is an aryl or heteroaryl moiety which is substituted or unsubstituted; W is oxygen or sulfur;

U is either 0 or N, wherein when U is 0, then R_: is a lone pair of electrons and R, is selected from the group consisting of:

A.r as defined above, d-d cycloalkyl, d-C₃ straight or branched chain alkyl cr alkenyi, cr d-d straight or branched chain alkyl or alkenyi substituted in one or more positions with A.r, amino, halo, haloalkyl, hydroxy, trifluoromethyl, d- straight cr branched chain alkyl, d-d straight or branched chain alkenyi, carbonyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO,, 0, or NR₂ wherein R, is selected from the group consisting of hydrogen, (d-d) -straight or branched chain alkyl, (d-d) -straight cr branched chain alkenyl or alkynyl, and (d-C bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR,. and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C,-C₉ cycloalkyl; and when U is N, R_: and ?- are selectee independently from the group consisting of: hydrogen, Ar as defined aoove, d-C, cycloalkyl, d-C, straight or branched chain alkyl or alkenyl, cr C_:-C, straight or branched chain alkyl or alkenyl substituted in one or more positions with A.r, ammo, halo, haloalkyl, hydroxy, trifluoromethyl, d-C₆ straight or branched chain alkyl, d-d straignt or branched chain alkenyl, carbcnyl, thiocarbonyl, ester, thioester, alkoxy, alκenoxy, cyano, nitro, immo, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of tne carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO,, 0, or NR, wherein R, is selected from the group consisting of hydrogen, (d-d) -straight or branched chain alkyl, (C_.-d) -straight or branched chain alkenyl or alkynyl, and (d-d) oπdging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR,. and ending with one of the carbon atoms cf said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C,-C₈ cycloalkyl; or R_x and R, may be taken together to form a heterocyclic ring.

23. The compound of claim 22, wherein A.r is selected from the group consisting of naphthyl, lndolyi, furyl, thiazolyl, thienyl, pyridyl, and phenyl . ς

24. The compound of claim 22, wnerem tne compcunα has an affinity for FKBP-type immunophilins.

25. The compound of claim 24, wherein tne FKBP-type 0 immunophilins are FKBP12.

26. The compound of claim 22, wherein the compound inhibits rotamase enzyme activity.

5 27. A. pharmaceutical composition comprising a neurotrophically effective amount of the ccmpound of claim 22 and a pharmaceutically acceptable carrier.

28. A. method of effecting a neuronal activity in an 0 animal, comprising: administering to the animal a neurotrophically effective amount of the compound of claim 22.

29. The method of claim 23, wnerem the neuronal 5 activity is selected from the group consisting of stimulation of damaged neurons, promotion of

.02 neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

30. The method of claim 29, wnerem the neurological disorder is selected from the group consisting of peripheral neuropathy caused cy physical injury or disease state, physical damage _t; the bram, physical damage to tne spinal cord, stroke associated with bram damage, and neurological disorder relating to neurodegeneration.

31. The method of claim 30, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotropnic lateral sclerosis.

32. A. compound of formula IV:

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

X is either 0 or S;

Y is a direct bond to Z, a C-_.-C₃ straight or branched chain alkyl, or a C_-d straight cr branche_d chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted m one cr more positions with ammo, halo, haloalkyl, thiocarbonyl, ester, tnioester, alkoxy, aikenoxy, cyano, nitro, immo, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR,, S, SO, or SO,, wherein R- is selected from the group consisting of hydrogen, (d-C₃) -straight or branched chain alkyl, (d-d) -straight or branched chain alkenyl or alkynyl, and C.-C bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR_: and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;

Z is a direct bond, or a C-_-C_β straight or branched chain alkyl, or a C,-C, straight or branched chain alkenyl, wherein any of tne carbon atoms of said al yl cr alkenyl are optionally substituted m one or more positions with ammo, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, immo, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR₂, S, SO, or S0_:, wherein P_ is selected from the group consisting of hydrogen, (d-C -straight or branched chain alkyl, (C₃-C₆) -straight or branched chain alkenyl or alkynyl, and (C_.-C bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR,_. and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; C and D are independently: hydrogen, Ar, C_.-C straight or branched chain alkyl, or d-C₆ straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted m one or more position (s) with C₃-C₈ cycloalkyl, d-d cycloalkenyl, hydroxyl, carbonyl oxygen, or A.r, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C_.-C₆ alkyl, d-d alkenyl, hydroxy, ammo, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyanc, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbcn atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbcn atoms of said alkyl or alkenyl are optionally replaced with 0, NH, NR₂, S, SO, or S0₂, wherein R₂ is selected from the group consisting of hydrogen, (d- C₆) -straight or branched chain alkyl, (C₃-d)- straight or branched chain alkenyl or alkynyl, and (d-C ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR-. and ending with one cf the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group; wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; W is oxygen or sulfur; U is either 0 or N, wherein when U is 0, then

Ri. is a lone pair of electrons and R_^ is selected from the group consisting of:

Ar as defined above, d-C, cycloalkyl, d-C₅ straight or branched chain alkyl or alkenyl, or d-d straight or branched chain alkyl or alkenyl substituted in one or more positions with A.r, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C--C₅ straight or branched chain alkyl, C,-C₅ straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, 30₂, 0, or NR, wherein R is selected from the group consisting of hydrogen, (d-d) -straight or branched chain alkyl, (C₃-C₆) -straight cr branched chain alkenyl or alkynyl, and (d-d) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrcgen of NR, and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C₃-C₃ cycloalkyl; and when U is N, R, and P., are selected independently from the group consisting of: hydrogen, A.r as defined above, C₃-C₃ cycloalkyl, d-C₆ straight or branched chain alkyl or alkenyl, or d-C₃ straight or branched chain alkyl or alkenyl substituted in one or more positions with A.r, amino, halo, haloalkyl, hydroxy, trifluoromethyl, d-C₅ straight or branched chain alkyl, d-d straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, aikenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenvl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO,, o, or NR₂ wherein R, is selected from the group consisting of hydrogen, (d-d; -straight or branched chain alkyl, (d-d) -straight cr branched chain alkenyl or alkynyl, and ( -d) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the ni regen of NR, and ending with one of the carbon atoms cf said- alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an A.r group or d-d cycloalkyl; or R-_ and R, may be taken together to form a heterocyclic ring.

33. The compound of claim 32, wherein A.r is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl .

34. The compound of claim 32, wherein the compound has an affinity for FKBP-type immunophilins.

35. The compound of claim 34, wherein the FKBP-type

10! lm unopnilins are FKBP12.

36. The ccmpound of claim 32, wherein the ccmpoun_d inhibits rotamase enzyme activity.

37. A. pnarmaceutical composition comprising a neurotrophically effective amount cf the compound of claim 32 and a pharmaceutically acceptable carrier.

33. A. method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotropnically effective amount of the compound of claim 32.

39. The method of claim 38, wnerem the neuronal activity is selected from tne group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

40. The method of claim 39, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused cy pnysicai injury or disease state, physical αamage to the bram, physical damage to the spinal corα, stroke associated with bram damage, and neurological disorder relating to neurodegeneration.

41. The method of claim 40, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.