AU3506299A - Small molecule inhibitors of rotamase enzyme activity - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

PATENTS ACT 1990 COMPLETE

SPECIFICATION

r FOR A STANDARD PATENT

ORIGINAL

TO BE COMPLETED BY APPLICANT ame of Applicant: Sictual Inventor(s): Address for Service: Invention Title: GUILFORD PHARMACEUTICALS,

INC.

Gregory S. Hamilton; Joseph P. Steiner CALLINAN LAWRIE, 711 High Street, Kew, 3101, Victoria, Australia SMALL MOLECULE INHIBITORS OF ROTAMASE ENZYME

ACTIVITY

The following statement is a full description of this invention, including the best method of performing it known to me:- 15/06/99,LP10624.CS,1 SMALL MOLECULE INEIBITORS OF ROTAMASE ENZYME ACTIVITY BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to neurotrophic compounds having an-affinity for FKBP-type immunophilins, their 10 preparation and use as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity.

2. Description of the Prior Art 15 The term immunophilin refers to a number of i proteins that serve as receptors for the principal immunosuppressant drugs, cyclosporin A (CsA), FK506, and rapamycin. Known classes of immunophilins are cyclophilins, and FKS06 binding proteins, such as FKBP.

Cyclosporin A binds to cyclophilin while FK506 and rapamycin bind to FKBP. These immunophilin-drug complexes interface with a variety of intracellular signal transduction systems, especially in the immune system and the nervous system.

Immunophilins are known to have peptidyl-prolyl

I

isomerase (PPIase) or rotamase enzyme activity. It has been determined that rotamase activity has a role in the catalyzation of the interconversion of the cis and trans isomer of immunophilin proteins.

Immunophilins were originally discovered and studied in immune tissue. It was initially postulated by those skilled in the art that inhibition of the immunophilins rotamase activity leads to the inhibition of T-cell proliferation, thereby causing the immunosuppressive action exhibited by immunosuppressive drugs such as cyclosporin A, FK506, and rapamycin.

Further study has shown that the inhibition of rotamase activity, in and of itself, is not sufficient for immunosuppressant activity. Schreiber et al., Science, 1990 vol. 250 pp. 556-559. It has been shown that the immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al., Cell, 1991, vol. 66, pp. 807-815. In the case of FKBP-FK506 and FKBP-CsA, the drug-immunophilin complexes bind to the enzyme calcineurin, inhibitory Tcell receptor signalling leading to T-cell proliferation. Similarly, the complex of rapamycin and FKBP interacts with the RAFT1/FRAP protein and ihhibits signalling from the IL-2 receptor.

Immunophilins have been found to be present at high concentrations in the central nervous system.

Immunophilins are enriched 10-50 times more in the central nervous system than in the immune system.

Within neural tissues, immunophilins appear to influence neuronal process extension, nitric oxide synthesis, and neurotransmitter release.

It has been found that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate neurite out growth in PC12 cells and sensory nervous, namely dorsal root ganglion cells (DRGs).

Lyons et al., Proc. of Natl. Acad. Sci., 1994 vol. 91, pp. 3191-3195. In whole animal experiments, FK506 has 10 been shown to stimulate nerve regeneration following facial nerve injury and results in functional recovery in animals with sciatic nerve lesions.

Surprisingly, it has been found that drugs with a high affinity for FKBP are potent rotamase inhibitors causing a neurotrophic effect. Lyons et al. These findings suggest the use of immunosuppressants in treating various peripheral neuropathies and enhancing neuronal regrowth in the central nervous system (CNS).

Studies have demonstrated that neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) may occur due to the loss, or decreased availability, of a neurotrophic substance specific for a particular'.

population of neurons affected in the disorder.

Several neurotrophic factors effecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer's disease results from a decrease or loss of nerve growth factor (NGF). It has thus been proposed to treat Alzheimer's patients with exogenous nerve growth factor or other neurotrophic proteins such as brain derived nerve factor (BDNF), glial derived nerve factor, ciliary neurotrophic factor, and neurotropin-3 to increase the survival of degenerating neuronal populations.

Clinical application of these proteins in various neurological disease states is hampered by difficulties o 10 in 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 administered chronically, immunosuppressants exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis (Kopp et al., 1991, J. Am. Soc. Nephrol. 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina such as non-localized headaches (De Groen et al., 1987, N. Engl. J. Med. 317:861); and vascular hypertension with complications resulting therefrom (Kahan et al., 1989 N. Engl. J. Med. 321: 1725).

In order to prevent the side effects associated with use of the immunosuppressant compounds, the present invention provides non-immunosuppressive compounds containing small molecule FKBP rotamase inhibitors for promoting neuronal growth and regeneration in various neuropathological situations where neuronal repair can be facilitated including peripheral nerve damage by physical injury or disease state such as diabetes, physical damage to the central nervous system (spinal cord and brain) brain damage associated with stroke, and for the treatment of neurological disorders relating to neurodegeneration, 10 including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.

SUMMARY OF THE INVENTION The present invention relates to a novel class of neurotrophic compounds having an affinity for FKBP-type immunophilins. Once bound to this protein the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins and particularly rotamase enzyme activity, thereby stimulating neuronal regeneration and outgrowth. 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.

A preferred embodiment of this invention is a neurotrophic compound of the formula: 00 x where R, is selected from the group consisting of a C,-C, straight or branched chain alkyl or alkenyl group optionally substituted with C 3

-C

8 cycloalkyl, C 3 Or C. cycloalkyl, C,-C 7 cycloalkenyl, Ar,, where said alkyl, alkenyl, cycloalkyl or cycloalkeny. groups may be optionally substituted with C,-C 4 alkyl, C 1 C. alkenyl, or hydroxy, where Ar 1 is selected from the group consisting of 1-napthyl, 2-napthyl, 2indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consis ting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C3 1

-C

6 straight or branched alkyl or alkenyl, alkoxy or CI-C 4 alkenyloxy, phenoxy, benzyloxy, and amino; x is selected from the group consisting of oxygen, sulfur, methylene (CH 2 or H 2 Y is selected from the group consisting of oxygen or NR,, where

R

2 is hydrogen or C,-C 6 alkyl; and Z is H or is selected from the group consisting of C 2

-C

6 straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar, as defined above, C 3

-C

8 cycloalkyl, cycloalkyl connected by a C, -Cc straight or unbranched alkyl or alkenyl chain, and Ar 2 where Ar 2 is selected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3i thienyl, 2, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C, -C6 straight or branched alkyl or alkenyl, C 1

-C

4 alkoxy or C, -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; Z may also be the fragment: 0 -CH LX 2

-R

4 R3

'I

'i It' -i i^ where

R

3 is selected from the group consisting of straight or branched alkyl C-C optionally substituted with

C

3 cycloalkyl, or Ar, as defined above, and unsubstituted Arl;

X

2 is O or NRs, where R, is selected from the group consisting of hydrogen, C-C, straight or branched alkyl and alkenyl; R is selected from the group consisting of 10 phenyl, benzyl, Cl-Cs straight or branched alkyl or alkenyl, and C,-Cs straight or branched alkyl or alkenyl substituted with phenyl; or pharmaceutically acceptable salts or hydrates thereof.

Another preferred embodiment of this invention is a neurotrophic compound of the formula: CV

-Z

O

where R, is a C, straight or branched chain alkyl or alkenyl group optionally substituted with C3-C, cycloalkyl, C 3 or C5 cycloalkyl, C, cycloalkenyl, or Ar,, where said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C, -C4 alkyl, C, -C4 alkenyl, or hydroxy, and where Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, or 4pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, straight or branched alkyl or alkenyl, C, -C4 alkoxy or C4 alkenyloxy, phenoxy, ~benzyloxy, and amino; Z is H or is a C 2 straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar, as defined above, C3-C, cycloalkyl, cycloalkyl connected by a straight or unbranched alkyl or alkenyl chain, or Ar, where Ar, is selected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3thienyl, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C 1 straight or branched alkyl or alkenyl, alkoxy or C.-C, alkenyloxy, phenoxy, benzyloxy, and amino; or pharmaceutically acceptable salts or hydrates thereof.

Another preferred embodiment of the invention is a neurotrophic compound having an affinity for FKBP-type immunophilins which inhibit the rotamase activity of the immunophilin.

Another preferred embodiment of the present :*,invention is a method for treating a neurological disorder in an animal comprising administering a therapeutically effective amount of a compound having an affinity for FKBP-type immunophilins which inhibits the rotamase activity of the immunophilin.

Another preferred embodiment of the invention is a method of promoting neuronal regeneration and growth in mammals, comprising administering to a mammal an effective amount of a neurotrophic compound having an affinity for FKBP-type immunophilins which inhibits the rotamase activity of the immunophilin.

Yet another preferred embodiment of the invention is a method of preventing neurodegeneration in an animal comprising administering to an animal an effective amount of a neurotrophic compound having an

I

11 affinity for the FKBP-type immunophilins which inhibits rotamase activity of the immunophilin.

Another preferred embodiment is a neurotrophic N-glyoxyl prolyl ester compound of the formula: Q-z

N

O

0 where R, is a Ci-CF straight or branched chain alkyl or alkenyl group optionally substituted with C 3 to C 6 cycloalkyl, or Ar,, where Ar, is selected from the group consisting of 2furyl, 2-thienyl, or phenyl; X is selected from the group consisting of oxygen and sulphur; Y is oxygen; and Z is H or is a straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar, as defined above, C 3

-C

6 cycloalkyl, Ar 2 where Ar 2 is selected from the group consisting of or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen and CI-C, alkoxy.

Particularly preferred neurotrophic N-glyoxyl prolyl, ester compounds according to the above formula are selected from the group consisting of: 3-(2,S-dimethoxyphenyl)-l-propyI dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 3- (2,5-dimethoxyphenyl) -l-prop-2- -enyl. (2S) -1- 3-dimethyl-1, 2-dioxopentyl) -2-pyrrolidiner carboxylate, 2-(3,4,5-trimethoxyphenyl)-1-ethyl dimethyl -1,2 -dioxopentyl) -2 -pyrrolidinecarboxylate, 3-(3-Pyridyl)-1-propyl (2S) -1-(3,3-dimethyl-1,2dioxopentyl) -2 -pyrrolidinecarboxylate, 3-(2-Pyl-idyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2dioxopentyl) -2-pyrrolidinecarboxylate, 3-(4-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2dioxopentyl) -2 -pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2dioxoethyl) -2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S) -1-(2-cyclohexylethyl-1,2dioxoethyl) -2-pyrrolidinecarboxylate, 3- (3-pyridyl) -i-propyl (2S) -1-(2-cyclohexylethYl- 1, 2-dioxoethyl) -2-pyrrolidinecarboxylate, 3-(3-pyridyl)-1-propyl (MS-1-(2-tert-butyl-1,2dioxoethyl) -2 -pyrrolidinecarboxylate, 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-j,2dioxopentyl) -2 -pyrrolidinecarboxylate, 3- (3-pyridyl) -i-propyl (2S) -1-(2-cyclohexyl-I,2dioxoethyl) -2-pyrrolidiflecarboxylate, 3-(3-Pyridyl) -1-propyl (2S) ((2-thienyl] glyoxyl) pyrrolidinecarboxylate, 3,3-Diphelyl-1-propy. (2S)-l-(3,3-dirnethyl-i,2dioxobutyl) -2 -pyrrolidinecarboxylate, 3, 3-Diphenyl-i-propyl (2S) -l-cyclohexylglyoxyl- 2 -pyrrolidinecarboxylate, and 3, 3-Diphenyl-1-propyJ. (2S) -1-(2-thienyl)glyoxyl- 2 -pyrrolidinecarboxylate.

BRE ECITO O-IEDAIG Figure 1 is a photomicrograph of chick dorsal root gangl~ia treated with various concentrations of Example 17 as indicated. Figure 1 shows th~at Example 17 of the present invention potently promotes neurite outgrowth in sensory neuronal cultures. Explant cultures isolated form embryonic- day 9 10 chick dorsal root ganglia were treated with various concentrations of Example 17 as indicated. .Forty-eight hours later, the number of neurite with a length greater than one DRG explant was quantitated. The number of neurites.

expressed in untreated DRG's was subtracted form the neurite number of Example 17-treated samples to yield Example 17-dependent specific neurite outgrowth.

1 Micrographs of Example 17 treated DRG's, as well as quantitative dose-dependent neurite outgrowth elicited by Example 17 are presented.

Figure 2 is a graph showing quantitation of neurite outgrowth in chick dorsal root ganglia treated with various concentrations of Example 17 as indicated.

Figure 2 shows that Example 17 of the present invention potently promotes neurite outgrowth in sensory neuronal cultures. Explant cultures isolated form embryonic day 10 9 10 chick dorsal root ganglia were treated with various concentrations of Example 17 as indicated.

Forty-eight hours later, the number of neurite with a length greater than one DRG explant was quantitated.

The number of neurites expressed in untreated DRG's was subtracted form the neurite number of Example 17-treated samples to yield Example 17-dependent specific neurite outgrowth. Quantitative dose-dependent neurite outgrowth elicited by Example 17 is presented.

Figure 3 is a photomicrograph of rat sciatic nerve sections. Figure 3 shows that Example 1 of the present invention promotes neuronal regeneration following sciatic nerve lesions. Sciatic nerves of 150 g male Sprague-Dawley rats were crushed at the level of the hips. Example 1 (30 mg/kg Inactive (30 mg/kg or intralipid vehicle was administered once daily for the next 21 days. Animals were sacrificed, sciatic nerves removed and nerve segments 2 mm distal to the crush site were sectioned and stained with Holmes silver stain (to assess axon number) and Luxol fast blue (to assess remyelination). The micrographs show sciatic nerve sections of sham operated rats, vehicle-treated lesioned animals, Example 1 and Inactive treated at 630x magnification, four animals per group.

Figure 4 is a graph of HH] -CFT binding per Ag of Striatal Membrane Protein. Figure 4 shows that 10 neuroimmunophilin ligands of the present invention promote recovery of dopamine neurons following MPTP treatment of mice. CD1 mice (25 g) were treated daily with 30 mg/kg MPTP for 5 days. The animals were also treated daily with intralipid vehicle, Example 1 (100 mg/kg or Example 17 (40, 20, 10 mg/kg s.c., Sas indicated) concurrently with the MPTP and continued for an additional 5 days. After eighteen days, the mice were sacrificed, striata from 5 animals per group were pooled and processed into a washed membrane preparation. Binding of [3H]-CFT to these striated membrane preparations of various groups was quantitated to determine dopamine transporter levels on viable nerve terminals. Binding in the presence of 10 jM unlabelled CFT provided on estimate of nonspecific binding, which was subtracted from the total binding to quantitative specific [3H]-CFT bound. Binding was normalized to the protein content of the striatal membranes from each experimental group. Coronal and saggital brain sections from MPTP and drug treated animals were stained with anti-tyrosine hydroxylase (TH) Ig to quantitate striatal, medial forebrain bundle axonal and nigral levels of TH, which is indicative of functional dopaminergic neurons.

Figure 5 is a bar graph of 3 H]-CFT plotted for 200 Ag of membrane protein. Figure 5 shows that neuroimmunophilin ligands of the present invention promote recovery of dopamine neurons following MPTP treatment of mice in accordance with the procedure described in Figure 4.

SFigure 6 is a photomicrograph, at 630x magnification, of coronal and saggital brain sections.

Figure 6 shows brain sections from MPTP and drug treated animals stained with anti-tyrosine hydroxylase (TH) Ig to quantitate striatal levels of TH, which is indicative of functional dopaminergic neurons.

Figure 7 is a photomicrograph, at magnification, of coronal and saggital brain sections.

Figure 7 shows brain sections from MPTP and drug treated animals stained with anti-tyrosine hydroxylase (TH) Ig to quantitate nigral levels of TH, which is indicative of functional dopaminergic neurons.

Figure 8 is a photomicrograph, at 400x magnification, of coronal and saggital brain sections.

Figure 8 shows brain sections from MPTP and drug treated animals stained with anti-tyrosine hydroxylase (TH) Ig to quantitate medial forebrain bundle axonal levels of TH, which is indicative of functional dopaminergic neurons.

DETAILED DESCRIPTION OF THE INVENTION The novel neurotrophic compounds of this invention are relatively small molecules in relation to other known compounds which bind to FKBP-type immunophilins, such as rapamycin, FK506, and cyclosporin.

The neurotrophic compounds of this invention have an affinity for the FK506 binding proteins such as ooe• 10 FKBP-12. When the neurotrophic compounds of the invention are bound to the FKBP, they have been found to unexpectedly inhibit the prolyl- peptidyl cis-trans isomerase activity, or rotamase activity of the binding protein and stimulate neurite growth, while not exhibiting an immunosuppressant.effect.

More particularly, this invention relates to a novel class of neurotrophic compounds represented by the formula:

M

18 Where

R

1 is a C 1

-C

9 straight or branched chain alkyl or alkenyl group optionally substituted with C3-C8 cycloalkyl, C3 or C 5 cycloalkyl, C5-C7 cycloalkenyl, or Ar 1 where said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C 1

-C

4 alkyl, C 1 -C4 alkenyl, or hydroxy, and where Arl is selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3furyl, 2-thienyl, 3-thienyl, 3- or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of 10 hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C 1 -C6 straight or branched alkyl or alkenyl, C1-C4 alkoxy or C1-C4 alkenyloxy, phenoxy, benzyloxy, and amino; X is oxygen or sulfur; Y is oxygen or NR 2 where R 2 is hydrogen or C1-C6 alkyl; and Z is a C2-C 6 straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar 1 as defined above, C3-C 8 cycloalkyl, cycloalkyl connected by a C1-C6 straight or unbranched alkyl or alkenyl chain, or Ar 2 where Ar 2 is selected from the group consisting of 2-indolyl, 3indolyl, 2- furyl, 3-furyl, 2- thiazolyl, 2-thienyl, 3- thienyl, or 4-pyridyl, and S phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or alkenyl, C1-C4 alkoxy or C 1 -C4 alkenyloxy, phenoxy, benzyloxy, and amino; 15/06/99, Ip9427.pgsl8-19,18 19 Z may also be the fragment: 0

R

R3 5 where R 3 is selected from the group consisting of straight or branched alkyl C 1

-C

8 optionally substituted with C 3

-C

8 cycloalkyl, or Ar 1 as defined above, and unsubstituted Ar 1

*X

2 isO0 or NR 5 where R 5 is selected from the 15/06/99. Ip9427.pgsIS-19.l9 group consisting of hydrogen, cl-C 6 straight or branched alkyl. and alkenyl; R, is selected from the group consisting of phenyl, benzyl, CL-Cs straight or branched S alkyl. or alkenyl, and Cl-Cs straight or branched alkyl or alkeny. substituted with phenyl; or pharmaceutically acceptable salts or hydrates thereof.

Preferred compounds have the following formula: toS Swher RI i tagtorbace can.-y oraknlgopotonlysbtttdwt whereey, rA, hresi akl alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C,-C 4 alkyl, CQ-C, alkenyl, or hydroxy, and where Ar 1 is selected from the group consisting of l-napthyl, 2-napthyl, 2-indolyl, 3 -iridolyl, 2-furyl, 3-fury., 2- thiazolyl, 2-thieny., 3- S thienyl, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl,

CI-C

6 straight or branched alkyl. or alkenyl, CI-C, alkoxy or C,too, C 4 alkenyloxy, phenoxy, benzyloxy, and amino; *z is a C 2

-C

6 straight or branched chain alkyl.

or alkenyl, wherein the alk yl chain is substituted in one or more positions with Ar, as defined above, C3-CS cycloalkyl, 'boo cycloalky. connected by a Cl-C, straight or unbranched alkyl. or alkenyl chain, or A-r 2 where Ar 2 is selected from the group consisting of 2-indolyl, 3-indolyl, 2fury., 3-fury., 2- thiazolyl, 2-thienyl, 3thienyl, or 4-pyridy., or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl,

C

1

,-C

6 straight or branched alkyl or alkenyl, C 1

-C

4 alkoxy or C 1

C

4 alkenyloxy, phenoxy, benzyloxy, and amino; or pharmaceutically acceptable salts or 22 hydrates thereof.

Preferred neurotrophic N-glyoxyl prolyl ester compounds have the formula: N

°-Z

R

1 .:2 5 where R, is a Cl-Cs straight or branched chain alkyl or alkenyl group optionally substituted with

C

3 to C, cycloalkyl, or Ar, where Ar is selected from the group consisting of 2furyl, 2-thienyl, or phenyl; X is selected from the group consisting of oxygen and sulfur; Y is oxygen; and Z is a straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar 1 as defined above, C3-C cycloalkyl, Ar 2 where Ar, is selected from the group consisting of or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen and C,-C 4 alkoxy.

The compounds of this invention exist as stereoisomeric forms, either enantiomers or diastereoisomers. The stereochemistry at position 1 (Formula 1) is R or S, with S preferred. Included within the scope of the invention are the enantiomers, 10 the racemic form, and diastereoisomeric mixtures.

Enantiomers as well as diastereoisomers can be separated by methods known to those skilled in the art.

It is known that immunophilins such as FKBP preferentially recognize peptide substrates containing Xaa-Pro-Yaa motifs, where Xaa and Yaa are lipophilic amino acid residues. Schreiber et al. 1990 J. Org.

Chem. 55, 4984-4986; Harrison and Stein, 1990 Biochemistry, 29, 3813-3816. Thus modified prolyl peptidomimetic compounds bearing lipophilic substituents should bind with high affinity to the hydrophobic core of the FKBP active site and inhibit its rotamase activity.

Preferred compounds of the present invention include R, groups which are not stereochemically bulky in relation to the known shape and size of the hydrophobic core of the FKBP active site. -Thus, very large and/or highly substituted R, groups would bind with less affinity to the FKBP active Site.

Preferred compounds of the invention include: 3-phenyl-1-propyl (2S) -1-(3,3-diiethyl-1,2dioxopentyl) 2 -pyrrolidinecarboxylate, 3-phenyl-l-prop-2-(E)-eny. 2 S)-1-(3,3..dimethyl- 1, 2-dioxopentyl) 2 -pyrrolidinecarboxylate, 3-(3,4,5-trimethoxyphenyl)-1..propyi dimethyl- 1, 2-dioxopentyl) -2 -pyrrolidinecarboxylate, 3- (3,4,5-trimethoxyphenyl)-1-prop2-(E).enl (2S) 1- 3-dimethyl-i, 2-dioxopentyl) 2 -pyrrolidine carboxylate, 3-(4,5-methylenedioxyphenyl)-..propyl (25) -1-13,3dimethyl-i, 2-dioxopentyl) -2 -pyrrolidinecarboxylate, 3- (4,5-methylenediox-yphenyl) -J-prop-2- -enyl (2S) -1-(3,3-dimethyl-1,2-dioxopentyl) -2pyrrolidinecarboxylate, 3-cyclohexyl-1-propyl (25) (3,3-dimethyl-1,2dioxopentyl) 2 -pyrrolidinecarboxylate, 3-cyclohexyl-l-prop-2- -enyl (2S) :00: 20 dimethyl-i, 2-dioxopentyl) 2 -pyrrolidinecarboxylate, (lR) -1,3-diphenyl-1-propyl (25) -1-(3,3-dimethyl- 1, 2-dioxopentyl) -2-pyrrol-idinecarboxylate, 3-phenyl-1-propy. (25) (1,2-dioxo-2-L2furanyl ethyl-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (25) (1,2-dicxo-2- [2thienyl ethyl-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S) 2-dioxo-2- [2thiazolyl ethyl-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl C2S) -1-(1,2-dioxo-2 phenyl) ethyl -2 -pyrrol.idinecarboxylate, 3-(2,5-dimethoxyphenyl)-l-propyl dimethyl-1, 2-dioxopentyl) 2 -pyrrolidinecarboxylate, 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-j- (3 ,3-dirnethyl-1, 2-dioxopentyl) 2 -pyrroljdine.

carboxyvlate, 2-(3,4,5-trimethoxphenyl)-..ethyi dimetlayl-1, 2-dioxopentyl) 2 -pyrrolidinecarboxylate, 10 3-(3-Pyridyl2'-l-propyl 2 S)-l-(3,3-dimethyl-1,2dioxopentyl) -2 -pyrrol idinecarboxylate, 3-(2-Pyridyl)-1-propy. 2 S)-1-(3,3-dimethyl..,2dioxopentyl) -2 -pyrrol'idinecarboxylate, 3-(4-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2- 15 dioxopentyl) -2-pyrrolidinecarboxylate, 3-phenyl-1-pr-opyl (2S) -1-(2-cyclohexyl-1,2dioxoethyl) -2 -pyrrolidinecarboxylate, 3-pheriyl-1-propyl 2 S)-1-(2-cyclohexylethyl-1,2-.

dioxoethyl) -2 -pyrrolidinecarboxylate, 3- (3-pyridyl) -1-propyl (2S) -1-(2-cyclohexylethyl- 1,2 -dioxoethyl) -2 -pyrrolidinecarboxylate, 3-(3-pyridyl)-1-propyl (2S)-l-(2-tert-butyl-1,2dioxoethyl) -2-pyrrolidinecarboxylate, 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2dioxopenty.) -2 -pyrrolidinecarboxylate, 3-(3-pyridyl)-1-propyl 2 S)-1-(2-cyclohexyl-1,2dioxoethyl) -2 -pyrrolidinecarboxylate, 3-(3-Pyridyl)-l-propy. 2 S-N-([2-thienyl] glyoxyl) pyrrolidinecarboxylate, 3,3-Diphenyl-1-propy. 2 SY-l-(3,3-dimethyl..1,2 dioxobutyl) -2-pyrrolidinecarboxylate, 3 ,3-Diphenyl-1-propyl (2S) -l-cyclohexylglyoxy>- 2 -pyrrolidinecarboxcylate, 3,3-Diphenyl-1-propy. (2S) -1-(2-thienyl)glyoxyl- 2-pyrrolidinecarboxylate.

Particularly preferred neurotrophic N-glyoxyl prolyl ester compounds are selected from the group consisting of: 3-(2,5-dimethoxyphenyl)-l-propyl (S--33 dimethyl 2-dioxopentyl) -2 -pyrrolidinecarboxylate, 1s 3- 5-dimethoxyphenyl) -1-prop-2- -enyl (2S)-1- 3-dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 2-(3,4,5-trimethoxyphenyl)-1-ethyl dimethyl-i, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 3- (3-Pyridyl)-i-propyl (2S)-1-(3,3-dimethyl-1,2dioxopentyl) -2 -pyrrolidinecarboxylate, 3-(2-Pyridyl)-1-propy. (2S)-l-(3,3-dimethyl-1,2dioxopentyl) -2 -pyrrolidinecarboxylate, 3-(4-Pyridyl)-1-propyl (2S)-1-.(3,3-dimethyl-1,2dioxopentyl) -2-pyrrolidinecarboxylate, 3-phenyl-l-propy. (2S)-1-C2-tert-butyl-1,2dioxoethyl) -2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S) -1-(2-cyclohexylethyl-1,2dioxoethyl) -2 -pyrrolidinecarboxylate, 3-(3-pyridyl) -1-propyl (2S) 2 -cYclohexylethyl- 1, 2- dioxoethyl) -2 -pyrrol idinecarboxylate, 3-(3-pyridyl)-l-propyl (MS-1-(2-tert-butyl-, 2 dioxoethyl) -2-pyrrolidinecarboxylate, dioxopentyl) -2 -pyrrol idinecarboxylate, 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexy-,2.

dioxoethyl) -2 -pyrrolidinecarboxylate, 10 3-(3-Pyridyl) -1-propy. 2-thienyll glyoxyl) pyrrolidinecarboxylate, 3,3-Diphenyl-1-propy. (2S)-1-(3,3-dimethyl-1,2dioxobutyl) -2-pyrrolidinecarboxylate, 3,3 -Diphenyl-1-propyl (2S) -1-cyclohexy].glyoxyl 2-pyrrolidinecarboxylate, and 3,3-Diphenyl-1-propy. (2S) -1-(2-thienyl)glyoxyl- 2 -pyrrol idinecarboxylate.

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsuif ate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemissulfate heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- 28 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2 -naphthalensulfonate, nicotinate, oxalate, pamoate, pectinate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts 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 dicyclohexylamine salts,

N-

methyl-D-glucamine, and salts with amino acids such as S: 10 arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, nad butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, S. 15 dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

20 The neurotrophic compounds of this invention can be periodically administered to a patient undergoing treatment for neurological disorders or for other reasons in which it is desirable to stimulate neironal regeneration and growth, such as in various peripheral neuropathic and neurological disorders relating to neurodegeneration. The compounds of this invention can also be administered to mammals other than humans for treatment of various mammalian neurological disorders.

~~L~I

The novel compounds of the present invention are potent inhibitors of rotamase activity and possess an excellent degree of neurotrophic activity. This activity is useful in the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and in the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathies. The neurological disorders that may be 10 treated include but are not limited to: trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, 15 herniated, ruptured or prolapsed invertabrae disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathic such as those caused by lead, dapsone, ticks, prophyria, or Gullain-Barr4 syndrome, 20 Alzheimer's disease, and Parkinson's disease.

For these purposes the compounds of the present 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, intraventricularly, intrasternal and intracranial injection or infusion techniques.

To be effective therapeutically as central nervous system targets the immunophilin-drug complex should readily penetrate the blood-brain barrier when peripherally administered. Compounds of this invention which cannot penetrate the blood-brain barrier can be effectively administered by an intraventricular route.

10 The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleaginous suspension.

This suspension may be formulated according to techniques know in the art using suitable dispersing or 15 wetting agents and suspending agents. The sterile a injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable 20 vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.

Fatty acids such as oleic acid and its glyceride derivatives find use in the preparation of injectables, olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

The compounds may be administered orally in the form of capsules or tablets, for example, or as an aqueous suspension or solution. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral 10 administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or 15 flavoring and/or coloring agents may be added.

The compounds of this invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non- 20 irritating 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 optically, 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 ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions is 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.

10 For application topically to the skin, the compounds can be formulated in a suitable ointment containing the compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, 15 propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in, for example, a mixture of one or more of 20 the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, 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 of about .1mg to about 10,000 mg. of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1mg 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, 10 general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated and form of administration.

The compounds can be administered with other a 15 neurotrophic agents such as neurotrophic growth factor (NGF), glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor, and neurotropin-3. The dosage level of other neurotrophic drugs will depend upon the factors previously stated 20 and the neurotrophic effectiveness of the drug combination.

EK Test Procedure Inhibition of the peptidyl-prolyl isomerase'- (rotamase) activity of the inventive compounds can be evaluated by known methods described in the literature (Harding, M.W. et al. Nature 341: 758-760 (1989); Holt et al. J. Am. Chem. Soc. 115: 9923-9938). These values are obtained as apparent Ki's and are presented in Table I. The cis-trans isomerization of an alanineproline bond in a model substrate, N-succinyl-Ala-Ala- Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of 10 inhibitor concentration to yield the apparent K, values.

In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCI), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCi, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml in 1 mM HC1) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35 mM LiCI in trifluoroethanol).

The absorbance at 390 nm versus time is monitored for 90 sec using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.

The data for these experiments is presented in Table I.

Table I 'N

R

0 ~0 0 No. R a a. a 2 3 1, 1-dimethylpropy.

3- phenylpropyl 3-phienyl-prop-2- -enyl 3- (3,45-trimethoxyphenyl) propyl 3- (3,4,9 -trimethoxypheny1l -prop-2- CE) -enyl 3- phenylpropy.

3- 3- cyclohexyipropy.

3-cyclohexylprop-2- enyl (iR) 3-diphenyl-1propyl 3 -phenylpropyl 125 9 10 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 2- furanyl 2 thienyl 2- thiazolyl phenyl 1, 1-dimethyipropyl to cyclohexyl tert -butyl cyclohexylethyl cyclohexylethyl tert-butyl 1, i-dimethylpropyl cyclohexyl 2- thienyl tert-butyl cyclohexy.

2- thienyl

I

200 600 52 4000 92 1970 250 3 5- dimethoxy) phenyipropy.

3- phenylprop-2- CE) -enyl 2- (3,4,5-trimethoxy phxenyl) ethyl 3 (3 -pyridyl) propyl 3 (2 -pyridyl) propy.

3- (4-pyridyl) propyl 3 -phenyipropyl 3993-prdl)poy 3 (3 -pyridyl) propyl 3,3 -diphenyipropyl 3 (3 -pyridyl) propyl 3 (3 -pyridyl) propyl 3, 3-diphenyipropyl 120 195 23 82 1025 1400 3 9 1000 In mammalian cells, FKBP-12 complexes with the inositol triphosphate receptor (IP 3 R) and the ryanodine receptor (RyR). It is believed that the neurotrophic compounds of this invention disassociates FKBP-12 from these complexes causing the calcium channel to become "leaky" (Cameron et al., 1995). Calcium fluxes are involved in neurite extensions so that the IP 3

R

receptor and the ryanodine receptor might be involved in the neurotrophic effects of drugs. Since the drugs 10 bind to the same site as FKBP-12 as the IP 3 R receptor, one could assume that the drugs displace the channels from FKBP-12.

Chick Dorsal Root Ganglion Cultures and Neurite Outgrowth Dorsal root ganglia were dissected from chick embryos of ten day gestation. Whole ganglion explants were cultured on thin layer Matrigel-coated 12 well plates with Liebovitz L15 plus high glucose media supplemented with 2mM glutamine and 10% fetal calf serum, and also containing 10 iM cytosine 3-D arabinofuranoside (Ara C) at 37 0 C in an environment containing 5% CO,. Twenty-four hours later, the DRGs were treated with various concentrations of nerve growth factor, immunophilin ligands or combinations of NFG plus drugs. Forty-eight hours after drug treatment, the ganglia were visualized under phase contrast or Hoffman Modulation contrast with a Zeiss Axiovert inverted microscope. Photomicrographs of the C.

C

CCC

explants were made, and rieurite 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 are presented in Table II. Representative photomicrographs for Example 17 are shown in Figure 1; a dose response curve for 10 this Example is given in Figure 2.

Neurite Outgrowth in Chick DRG Example No. EDso, neurite outgrowth, nM 1 53 15 2 105 3 149 4 190 5 6 20 10 0.46 11 0.015 14 2 0.8 16 0.015 17 0.05 18 19 6 0.13 21 0.025 22 0.66 23 1100 24 0.014 0.50 26 2 27 S00 28 0.50 29 100 Sciatic Nerve Axotomy Six-week old male Sprague-Dawley rats were 1 anesthetized, and the sciatic nerve exposed and crushed, at the level of the hip, by forceps. Test compounds or vehicle were administered subcutaneously just prior to the lesion and daily for the following 18 days. Sections of the sciatic nerve were stained with Holmes silver stain.to quantify the number of axons, and Luxol fast blue to quantify the level of myelination. Eighteen days after lesion, there was a significant decrease in the number of axons decrease as compared to non-lesioned control) and degree of myelination (90% decrease as compared to nonlesioned control) in animal treated with vehicle.

Administration of Example 1 (30 mg/kg just prior to the lesion and daily for 18 days following the lesion, resulted in significant regeneration of both axon number decrease as compared to non-lesioned control) and the degree of myelination (50% decrease as compared to control) as compared to vehicle treated animals. The significant efficacy of Example 1 is consistent with its potent activity in inhibiting rotamase activity and stimulating neurite outgrowth in chick DRGs. These results are shown in Figure 3. "Sham" denotes control animals that received vehicle but'were not lesioned; "Vehicle" denotes animals that were lesioned and received only vehicle no drug).

Example 1 showed a striking similarity to the sham treated animals, demonstrating the powerful neuroregenerative effects of these compounds in vivo.

39 Inactive is a compound that is inactive as an FKBP12 inhibitor. Animals treated with this compound resembled the vehicle-treated lesioned animals, consistent with the neuroregenerative results observed with Example 1 being directly caused by its inhibition of FKBP12.

Quantitation for these data are shown in Table III.

Table III Treatment Axon Number Myelin Level Control) 10 Sham 100 100 Lesion: Vehicle 50 Example 1 100 (30 mg/ kg s.c.) Inactive 25 (30 mg/kg s.c.) MPTP Model of Parkinson's Disease in Mice MPTP lesioning of dopaminergic neurons in mice was used as an animal model of Parkinson's Disease. Four week old male CDI white mice were dosed i.p. with mg/kg of MPTP for 5 days. Example 17(10-40 mg/kg), or vehicle, were administered s.c. along with the MPTP for days, as well as for an additional 5 days following cessation of MPTP treatment. At 18 days following MPTP treatment, the animals were sacrificed and the striata were dissected and homogenized. Binding of (3H]CFT, a radioligand for the dopamine transporter, to the stiatal membranes was done to quantitate the level of the dopamine transporter (DAT) following lesion and drug treatment. Immunostaining was performed on saggital and coronal brain sections using anti-tyrosine hydoxylase Ig to quantitate survival and recovery of dopaminergic neurons. In animals treated with MPTP and vehicle, a substantial loss of functional dopaminergic terminals was observed as compared to non-lesioned animals. Lesioned animals receiving Example 17 showed a nearly quantitative recovery of TH-stained dopaminergic neurons.

Figures 4 and 5 show the quantitation in DAT 10 levels, whereas figures 6-8 are photomicrographs showing the regenerative effects of Example 17 in this model. Figure 4 demonstrates the significant recovery in functional dopaminergic terminals, as assayed by [3H]-CFT binding, relative to animals receiving MPTP but not the Guilford compounds. Figure 5 gives this data in bar graph form. It is shown that animals receiving 40 mg/kg of Example 17 in addition to MPTP manifested a greater than 90% recovery of [3H]-CFT binding. As shown in Figures 6-8, immunostaining for tyrosine hydroxylase (a marker of viable dopaminergic neurons) in the striatum, the nigra, and the medial forebrain bundle, shows a clear and marked recovery of functional neurons in animals that received Example 17, as compared to animals that received lesioning agent but no drug (MPTP/Vehicle).

The following examples are illustrative of preferred embodiments of the invention and are not to be construed as limiting the invention thereto. All preferred embodiments of the invention and are not to be construed as limiting the invention thereto. All polymer molecular weights are mean average molecular weights. All percentages are based on the percent by weight of the final delivery system or formulation prepared unless otherwise indicated and all totals equal 100% by weight.

EXAMPLES

The inventive compounds may be prepared by a 10 variety of synthetic sequences that utilize established chemical transformations. The general pathway to the present compounds is described in Scheme 1. Nglyoxylproline derivatives may be prepared by reacting L-proline methyl ester with methyl oxalyl chloride as shown in Scheme I. The resulting oxamates may be reacted with a variety of carbon nucleophiles to obtain intermediates compounds. These intermediates are then reacted with a variety of alcohols, amides, or protected amino acid residues to obtain the propyl esters and amides of the invention.

C C cc RL cr rMrX

CCH

NMeCH/H 2 0 N ci~m~~o 0 a

R

EXAMPLE 1 Synthesis of 3-phenyl-1-propyl (2S) -1-(3,3-dimethyl- 1, 2-dioxopentyl) -2-pyrrolidinecarboxylate (Example 1).

Synthesis of methyl (2S)-1-(1,2-dioxo-2methoxyethyl) -2-pyrrolidinecarboxylate.

5 A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in dry methylene chloride was cooled to 0 0 C and treated with triethylamine (3.92 g; 38.74 MMol; 2.1 eq). After stirring the formed slurry under a nitrogen atmosphere for 15 min, a soluti6n of methyl oxaly. chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0 0 C for 1.5 hr. After filtering to remove solids, the organic phase was washed with water, dried over MgSO, and concentrated.

The crude residue was purified on a silica gel column, eluting with S0W ethyl acetate in hexane, to obtain 3.52 g (88k) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotarner given. 1H NNR (CDCl 3 :d 93 (dmn, 2H) ;2.17 Cm, 2H1) 3.62 (in, 2H) 3.71. 3H1); 3 .79, 3 .84 3H total); 4.86 (dd, 1H1, J 8.4, 3.3).

Synthesis of methyl (2S) -1-(l,2-dioxo-3,3.

dimethylpentyl) -2-pyrrolidinecarboxylate.

A solution of methyl (2S)-1-C1,2-djoxo-2inethoxyethy.) -2-pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 niL of tetrahydrofuran (THF) was cooled to -78 0 C and treated with 14.2 niL of a 1.0 M solution of 1,1-dimethylpropylmagnesiui chloride in THF. After stirring the resulting homogeneous mixture at -78 0 C for three hours, the mixture was poured into saturated ammoniumn chloride (100 inL) and extracted into ethyl acetate. The organic phase was washed with water, e dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 251W ethyl acetate in hexane, to obtain 2.10 g (75t) of the oxamate as a colorless oil. 'H NNR (CDCl 3 Id 0.88 Ct, 3H) 17.22, 1.26 3H1 each); 1.75 (din, 2H1); 1.87-2.10 Cm, 3H1); 2.23 11) 3.54 2H1); 3.76 3H); 4.52 (drn, 111, J 8.4, 3.4).

Synthesis of (2S)-1-C1,2-dioxo-3,3dimethylpentyl) -2-pyrrolidinecarboxylic acid.

A mixture of methyl (2S)-1-(l,2-dioxo.3,3.

dimethylpentyl) -2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N~ LiOH (15 mL), and methanol (50 mL) was stirred at 0 0 C for 30 min and at room temperature overnight. The mixture was acidified to pH 1 with I N HC1, diluted with water, and extracted into 100 niL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (8726) of snowwhite solid which did not require further purification.

'IH NNR (CD)Cl 3 :d 0 87 3 H) 1. 22, 1. 25 3 H each); 1..77 (din, 2H); 2.02 (in, 2H); 2.17 (mn, IH); 2.25 (mn, 1H); 3.53 (dd, 2H, J 10.4,- 4.55 (dd, IR, J 4.1).

Synthesis of 3-phenyl-1-propyl (2S) dimethyl- 1,2 -dioxopentyl) -2 -pyrrolidinecarboxylate (Example A mixture of (2S)-3-(1,2-dioxo-3,3dimethylpentyl) -2-pyrrolidine-carboxylic acid (600 mg; 2.49 inmol), 3-phenyl-1-propanol (508 mng; 3.73 minol), dicyclohexylcarbodiimide (822 mg; 3.98 inmol), camphorsulphonic acid (19-C mg; 0.8 mmol) and 4dimethylaminopyridine (100 mug; 0.8 mmol) in methylene chloride (20 niL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered tb~rbugh Celite to remove solids and concentrated in vacuo, and the crude material was purified on a flash column (251s ethyl acetate in hexane) to obtain 720 mug of Example 1 as a colorless oil. 1 H NMR (CDCl 3 d 0. 84 1.19 3H); 1.23 3H); 1.70 (din, 2H); 1 9 SH) 2. 22 1H) 2. 64 2H) 3.4 7 2H); 4.14 Cm, 2H) 4.51 Cd, 1H); 7.16 Cm, 3H); 7.25 2H) The method of Example 1 was utilized to prepare the following illustrative examples: S Example 2: 3-phenyl-l-prop-2-CE)-enyl dimethy-1,2-dioxopentyl)- 2 -pyrrolidinecarboylate, '11 NvR (360 Mhz, CDCl 3 d 0.86 3H); 1.21 (s, 3H); 1.25 Cs, 3H); 1.54-2.10 Cm, 5H); 2.10-2.37 Cm, 1H); 3.52-3.55 2H); 4.56 (dd, 1H, J 3.8, 8.9); 4.78-4.83 2H); 6.27 Cm, 1H); 6.67 (dd, 1H, j 15.9); 7.13-7;50 51)..

Example 3: 3-(3,4,5-trimethoxyphenyl)-i-propyl (2S)-1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 61%, 11 NMR (CDC13): d 0.84 t, 3H); 1.15 1s 3H); 1.24 Cs, 3H); 1.71 (dm, 2H); 1.98 2.24 Cm, 1H); 2.63 Cm, 21); 3.51 Ct, 2H); 3.79 Cs, 3H); 3.83 Cs, 3H) 4.14 Cm, 2H) 4.52 Cm, 1H) 6.36 Cs, 2H).

Example 4: 3-(3,4,5-trimethoxyphenyl)--prop-2-CE)-enyl (2S)-1-3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine carboxylate, 66%, 'H NNR (CDCl 2 d 0.85 Ct, 3H) 1.22 3H); 1.25 Cs, 31); 1.50-2.11 Cm, SH); 2.11-2.40 Cm, 1H); 3.55 Cm, 2H); 3.85 Cs, 3H); 3.88 Cs, 6H); 4.56 (dd, 1H); 4.81 Cm, 2H); 6.22 Cm, 1H); 6.58 11, J 16); 6.63 Cs, 2H).

Example 5: 3-C4,5-methylenedioxyphenyl)-1-propyl C2S)- 1-C3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-

~I~

carboxylate,82%, 'H NMR (360 MIYz, CDC1) d 0.86 1.22 3H); 1.25 3H); 1.60-2.10 3.36-3.79 2H); 4.53 (dd, 1H, J 3.8, 4.61- 4.89 Cm, 2H); 5.96 2H); 6.10 Cm, 1H); 6.57 dd, IH, J 6.2, 15.8); 6.75 Cd, 1W, J 6.83 dd, JH, j 1.3, 6.93 ii).

Example 6: 3-( 4 ,5 -methylenediocyphenyl )-J-prop-2-. enyl (2S)-l-(3,3-dimethyl-12-dixopentyl)-2pyrrolidinecarboxylate,82g, 'E NMR (360 MHz, CDC1 3 d 310 0.86 3H); 1.22 s, 31); 1.25 3H); 1.60-2.10 (m, SH); 2.10-2.39 1W); 3.36-3.79 Cm, 2H); 4.53 (dd, 1H, J 3.8, 4.61-4.89 m, 2H); 5.96 s, 2H); 6.10 Cm, 1W); 6.57 (dd, 1H, J 6.2, 15.8); 6.75 (d, 3-H, J 6.83 Cdd, 1W, J 1.3, 6.93 Cs, 1H).

Example 8: 3 -cyclohexyl-l-prop-2-(E)-enyl dimethyl-1,2-dioxopentyl)- 2 -pyrrolidinecarboxylate 92%, IH NMR (360 MHz, CDC1 3 d 0.86 t, 3H); 1.13-1.40 Cm 2 singlets, 9H total); 1.50-1.87 8H); 1.87- 2.44 6H); 3.34-3.82 Cm, 2H); 4.40-4.76 Cm, 3H); 5.35-5.60 5.60-5.82 (dd, 1H, J 6.5, 16).

Example 9: (1R)-1,3-Diphenyl.1.propyl dimethyl-1,2-dioxopentyl)- 2 -pyrrolidinecarboxylat', 'H NMR (360 MHz, CDC1 3 d 0.85 t, 3H) 1.20 (s, 3H); 1.23 Cs, 3H); 1.49-2.39 7H); 2.46-2.86 (m, 2H); 3.25-3.80 2H); 4.42-4.82 Cm, 1H); 5.82 (td, 1W, J 1.8, 7.05-7.21 3H); 7.21-7.46 (m, 7H).

Example 10: 3-phenyl-l-propyl (2S)-1-(1,2-dioxo-2-[ 2 furanyl] )ethyl-2-pyrrolidinecarboxylate, 99%, 1 H NMR (300 MFz, CDC1 3 d 1.66-2.41 6H); 2.72 2H, j 3.75 2H); 4.21 2H); 4.61 IH); 6.58 1H); 7.16-7.29 Cm, SH); 7.73 2H).

Example 11: 3-phenyl-l-propyl C1,2-dioxo-2- 2thienyl) )ethyl-2-pyrrolidinecarboxylate, 81*, 'H NMR (300 MFz, CDC1 3 d 1.88-2.41 6H); 2.72 (dm, 2H); 3.72 2H); 4.05 1H); 4.22 (in, IH); 4.64 1H); 7.13-7.29 6H) 7.75 (dm, 1H) 8.05 1H).

Example 13: 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2phenyl) ethyl-2-pyrrolidinecarboxylate, 99V, 'H NMR (300 MHz, CDC1.): d 1.97-2.32 6H); 2.74 Ct, 2H, J3 3.57 2H); 4.24 Cm, 2H); 4.67 Cm, 1H); 6.95- 7.28 SN); 7.51-7.64 3H); 8.03-8.09 2H).

Example 14: 3- (2,5-dimethoxyphenyl) -1-propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 99k, IH NMR (300 MHz, CDC13). d 0.87 Ct, 3H); 1.22 Cs, 3H) *1.26 Cs, 3H) 1.69 2H) 1.96 (m, 5H); 2.24 IH); 2.68 2H); 3.55 2H); 3.75 Cs, 3H); 3.77 3H); 4.17 Cm, 2H); 4.53 Cd, 1H); 6.72 (m, 3H).

Example 15: 3- 5-dimethoxyphenyl) -I-prop-2- -enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 99%, IN NvR (300 MHz, CDC1 3 d 0.87. t., 3H; 1.22 3H); 1.26 3H); 1.67 Cm, 2H); 1.78 Cm, IN); 2.07 Cm, 2H); 2.26 3.52 2H); 3.78 Cs, 3H); 3.80 Cs, 3H); 4.54 IH); 4.81 2H); 6.29 (dt, 1H, J 15.9); 6.98 Cs, IH).

Example 16: 2 -(3,4,5-trimethoxyphenyl) -l-ethyl (2S)-j- (3,3-dimethyl-1,2-dioxoentyl)- 2 -pyrrolidinecarboxylate, 97k, IH NNR (300 MHz, CDC1) d 0.84 Ct, 3H); 1.15 3H); 1.24 3H); 1.71 (dm, 2H); 1.98 SH); 2.24 2.63 2H); 3.51 2H); 3.79 3H); 3.83 3H); 4.14 2H); 4.52 lI); 6.36 2H).

Example 17: 3-(3-Pyridyl)-i-propy. dinethyl-i,2-dioxopentyl)- 2 -pyrrolidinecarboxylate, 1 H NMR (CDC1 3 300 M14z) d 0.85 3H) 1.23, 1.26 3H each); 1.63-1.89 2H); 1.90-2.30 (m, 4H); 2.30-2.50 lI); 2.72 2H); 3.53 2H); 4.19 2H); 4.53 1H); 7.22 1K); 7.53 (dd, 11); 8.45.

Example 18: 3-(2-Pyridyl)-1-propyl diiethyl-1,2-dioxopentyl)-2 -pyrrlidinecarboxylate, 88!, )H NMR (CDCl 3 300 MHz): d 0.84 3H); 1.22, 1.27 3H each); 1.68-2.32 81); 2.88 2H, J 3.52 2H); 4.20 2H); 4.51 1H); 7.09- 7.19 2H); 7.59 1H); 8.53 1H, J 4.9).

Example 19: 3-(4-Pyridyl)-1-propyl dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, IH NMR (CDCl3, 300 MHz): d 6.92-6.80 6.28 1H); 5.25 IH, J 4.12 1H); 4.08 (s, 3H); 3.79 3H); 3.30 2H); 2.33 1H); 1.85- 1.22 1.25 3H); 1.23 3H); 0.89 3H, J Example 20: 3-phenyl-1-propyl 2 S)-1-(2-cyclohexyl-1,2dioxoethyl) -2-pyrrolidinecarboxylate, 91k, 1H NMR (CDC1 3 300 MHz): d 1.09-1.33 5H) 1.62-2.33 (m, 12H); 2.69 2H, J 3.15 111); 3.68 (m, 21); 4.16 2H); 4.53, 4.84 11 total); 7.19 (M, 3H); 7.29 2H).

Example 21: 3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2dioxoethyl) -2-pyrrolidinecarboxylate, 92%, 'H NMR *i (CDC1 3 300 MHz): d 1.29 9H); 1.94-2.03 51); 2.21 1H); 2.69 2H); 3.50-3.52 2H); 4.16 (i, 2H); 4.53 1H); 7.19 311); 7.30 2H).

Example 22: 3-phenyl-1-propyl (2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 97%, 'H NMvlR (CDC1 3 300 MHz): d 0.88 2H); 1.16 4H); 1.43-1.51 2H); 1.67 5H); 1.94-2.01 6H); 2.66-2.87 4H); 3.62-3.77 2H); 4..5 2H); 4.86 11); 7.17-7.32 SH).

Example 23: 3-(3-pyridyl)-1-propyl (2S) -1-(2-cyclohexylethyl-1, 2-dioxoethyl) -2-pyrrolidinecarboxylate, 70%, IH NMR (CDC1 3 300 MHz): d 0.87 2H); 1.16 (m, 4H); 1.49 2H); 1.68 41); 1.95-2.32 7H); 2.71 2H); 2.85 2H); 3.63-3.78 2H); 4.19 (m, 2H); 5.30 1H); 7.23 1H); 7.53 1H); 8:46 (M, 2H).

Example 24: 3-(3-pyridyl)-1-propyl (2S)-1-(2-tertbutyl-1,2-dioxoethyl)-2-pyrrolidinecarboCylate, 83%, 'H NMR (CDC1 3 300 MHz): d 1.29 9H); 1.95-2.04 (i, 2.31 1H); 2.72 2H, J 3.52 m, 21); 4.18 Cm, 2H); 4.52 Cm, lH); 7.19-7.25 1H); 7.53 (m, IH); 8.46 2H).

Example 25: 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl- 1, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 99!, 'H NMR (CDC1 3 300 MHz): d 0.85 3H); 1.21, 1.26 Cs, 3H each); 1.68-2.04 5H); 2.31 1H); 2.40 2H); 3.51 2H); 4.08 3H); 4.52 1H); 7.18-7.31 (m, Example 26: 3-(3-pyridyl)-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 88%, 1

H

NMR (CDC1 3 300 MHz): d 1.24-1.28 SH); 1.88-2.35 11H); 2.72 2H, J 3.00-3.33 (di, lE); 3-.69 2H); 4.19 2H); 4.55 lB); 7.20-7.24 (m, 1H); 7.53 1R); 8.47 2H).

Example 27: 3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl) glyoxyl)pyrrolidinecarboxylate, 49k, 1H NMR (CDC1 3 300 MHz): d 1.81-2.39 6H); 2.72 (dm, 2H); 3.73 2H); 4.21 2H); 4.95 1H); 7.19 2H); 7.61 1H); 7.80 1H); 8.04 1H); 8.46 2H).

Example 28: 3,3-Diphenyl-l-propyl (2S)-l-(3,3-dimethyl- 1,2-dioxobutyl)-2-pyrrolidinecarboxylate, 99%, 'H NMR (CDC13, 300 MHz): d 1.27 9H); 1.96 2H); 2.44 4H); 3.49 1H); 3.64 1H); 4.08 4.53 (dd, IH); 7.24 Example 29: 3,3-Diphefyl-1-propyl (2S)-1-cyclohexyl glyoxyl-2-pyrrolidinecarboxylate, 911, 'H NMR (CDC- 3 300 MHz): d 1.32 6H); 1.54-2.41 10H); 3.20 (dm, 1H); 3.69 2H); 4.12 4H); 4.52 lH); 7.28 (Mn, i0H).

Example 30: 3, 3-Dipheriyl-i-propyl (2S) -1-(2-thienyl) glyo~xyl-2-pyrrolidilecarboxylate, 75k, 'Hl NM (CDC1 3 300 mHz): d 2.04 (mn, 3H); 2.26 (mn, 2H1); 2.48 IH) 3.70 (mn, 2H1); 3.82-4.18 (in, 3H1 total); 4.64 (mn, 1H1); 7.25 (mn, 11H); 7.76 (dd, lH); 8.03 (in, 1H1).

The requisite substituted alcohols may be prepared by a number of methods known to those skilled in the art of organic synthesis.. As described in Scheme 11, ~.10 alkyl or aryl aldehydes may be homnologated to phenyl propanols by reaction with methyl (triphenylphosphoralylidefle)acetate to provide a variety of trans-cinnamates; these :latter may be reduced to the saturated alcohols by reaction with excess lithium aluminum hydride, or sequentially by reduction of the double bond by catalytic hydrogenation and reduction of the saturated ester by appropriate reducing agents. Alternatively, the trans-cinnamates may be reduced to (E)-allylic alcohols by the use of diisobutylaluninumf hydride.

Uchium aluminum PCOPh 3 P CHC'OOCH 3 R COH hydride R O

THIF

H

2 Lithium aluminumA Oiisobuoyalumi/num Pd/C hydride or hydride IDisobutylalurninum hydride R O)H R

COH

Scheme 11 Longer chain alcohols may be prepared by homologation of benzylic and higher aldehydes.

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

General procedure for the synthesis of acrylic esters, exemplified for methyl (3,3,5-trimethoxy)trans-cinnamate: A solution of 3,4,5-trimethoxybenzaldehyde (5.0 g; 10 25.48 mmol) and methyl (triphenyl- 0 phosphoranylidene)acetate (10.0 g; 29.91 mmol) in tetrahydrofuran (250 mL) was refluxed overnight. After cooling, the reaction mixture was diluted with.200 mL of ethyl acetate and washed with 2 x 200 mL of water, dried, and concentrated in vacuo. The crude residue was chromatographed on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 5.63 g of the cinnamate as a white crystalline solid, 1 H NMR (300 Mhz; CDC1 3 d 3.78 3H); 3.85 6H); 6.32 (d, 1H,J 16); 6.72 2H); 7.59 1H, J- 16).

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

A solution of methyl (3,3,5-trimethoxy)-transcinnamate (1.81 g; 7.17 mmol).in tetrahydrofuran mL) was added in a dropwise manner to a solution of lithium aluminum hydride (14 mmol) in THF (35 mL), with stirring and under an argon atmosphere. After the addition was complete, the mixture was heated to for 4 hours. After cooling, it was quenched by the careful addition of 15 mL of 2N NaCH followed by 50 mL of water. The resulting mixture was filtered through Celite to remove solids, and the filter cake was washed with ethyl acetate. The combined organic fractions were washed with water, dried, concentrated in vacuo, and purified on a silica gel column, eluting with ethyl i* t acetate to obtain 0.86 g of the alcohol as a 10 clear oil, IH NMR (300 Mhz; CDCI) d 1.23 (br, IH); 1.87 2H); 2.61 2H, J 3.66 2H); 3.80 *e o* 3H); 3.83 6H); 6.40 2H).

General procedure for the synthesis of trans- S. ~allylic alcohols from acrylic esters. Exemplified for (3,4,5-trimethoxy)phenylprop-2- (E)-enol.

ft A solution of methyl (3,3,5-trimethoxy)-trans-

S

cinnamate (1.35 g; 5.35 mmol) in toluene (25 mL) was 0* cooled to -100C and treated with a solution of jdiisobutylaluminum hydride in toluene (11.25 mL of a 1.0 M solution; 11.25 mmol). The reaction mixture was stirred for 3 hrs at 0°C and then quenched with 3 mL of methanol followed by 1 N HCl until the pH was 1. The reaction mixture was extracted into ethyl acetate and the organic phase was washed with water, dried and concentrated. Purification on a silica gel column eluting with 25V ethyl acetate in hexane furnished 0.96 g of a thick oil, 1H NMR (360 Mhz; CDC13) d 3.85 3H); 3.87 6H) 4.32 2H, J 6.29 (dt, 1H, J 15.8, 6.54 1H, J 15.8); 6.61 2H).

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

0 The present application is a divisional application of Australian application No.

61062/96. The specification of which as published prior to acceptance is incorporated herein by reference.

*o 0 *0.

0

Claims (71)

1. Use of a nieurotrophic compound of the formula: :.or a pharmaceutically acceptable salt or hydrate thereof, where R, represents a CI-C 9 straight or branched chain alkyl. or alkenyl group *:.optionally substituted with C3-CO cycloalkyl,' -C 3 or C5 cycloalkyl, -C 5 cycloalkenyl, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C 1 -C 4 alkyl,C-C alkenyl, or hydroxy, or Ar 1 where Ar 1 is selected from the group consisting of l-naphthyl, 2-naphthyl, 2-indolyl, 3-indoly., 2-furyl, 3-furyl,

2-thiazol.yl, 2-thienyl, 3-thienyl, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C 1 -Cfi straight or branched alkyl or alkenyl, C 1 -C 4 alkoxy or C 1 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; X is oxygen or sulfur; Y is oxygen or NR 2 where R 2 is hydrogen or Cl-C. alkyl; and Z represents -a C 2 -C 6 straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar 1 as defined above, cycloalkyl, -cycloalkyl connected by a C 3 straight or unbranched alkyl or alkenyl chain, or -Ar 2 where Ar 2 is selected from the group consisting of 2- indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3- thienyl, or 4-pyricdyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromnethyl, C,-C 6 straight or branched alkyl or alkenyl, Cj- C 4 alkoxy or CI-C 4 alkenyloxy, phenoxy, benzyloxy, and amino; the fragment: CH -X 2 -R 4 H3 where R 3 is selected from straight or branched Ci-C 8 alkyl optionally substituted with C-CO cycloalkyl or Arl as defined S above, and unsubstituted Arl; X 2 is O or NR 5 where R, is selected from hydrogen, Ci-Cf straight or branched alkyl and alkenyl; R, is selected from the group consisting of phenyl, benzyl, C 1 -C5 straight or branched alkyl or alkenyl, and straight or branched alkyl or alkenyl substituted with phenyl, for promoting a neuronal growth and regeneration, for treating a neurological disorder, or for preventing neurodegeneration. 2. The use of claim 1 for stimulating growth of damaged peripheral nerves.

3. The use of claim 1, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.

4. The use of claim 3, wherein the neurological disorder related to neurodegeneration is Alzheimer's disease. The use of claim 3, wherein the neurological disorder related to neurodegeneration is Parkinson's Disease-

6. The use of claim 3, wherein the neurological disorder related to neurodegeneratioi is arnyotrophic lateral sclerosis.

7. The use of claim 1 wherein Z and R, are lipophilic .:groups. The use of claim 1 wherein the compounid is selected from: 3-phenyl-l-propyl (2S)-1-(3,3-dimethyl-l,2-dioxopefltyl)-2- pyrrolidinecarboxylate; 3-(3-pyridyl)-l-propyl (2S)-1-3,3-dimethyl-l,2-dioxopefltyl)- 2-pyrrolidinecarboxylate; 3-phenyl-l-prop-2'-(E)-enyl (2S)-l-(3,3-dimethyl-l,2- dioxopentyl) -2-pyrrolidinecarboxylate; 3-(3,4,5-trimethoxyphenyl) -1-propyl (2S)-l-(3,3-dimethyl- 1, 2-dioxopentyl) -2-pyrrolidinecarboxylate; 3-(3,,4,5-trimethoxyphelyl)-1-prop-2-(E)-elyl dirnethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate; 3-(4,5--dichloropheflyl)-1-propyl (2S)-l-(3,3-dirnethyl-1,2- dioxopentyl) -2-pyrrolidinecarboxylate; 3-(4,5-dichlorophenyl)-1-prop-2-(E)-enyl dirnethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate; 3- (4,5-methylefedioxypheIyll-propyI (3,3-dimethyl- 1, 2-dioxopentyl) -2-pyrcrolidiflecarboxylate; 5-methylenedioxyphelyl) -1-prop-2-(E)-enyI (3,3- dimethyJ.-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate; 3-cyclohexyl-1-propyl (2S)-1-(3,3-dirnethyl-1,2-dioxopeltYl) :*2-pyrrolidinecarboxylate; 3-cyclohexyl-1-prop-2-(E)-elYl (3,3-dimethyl--1,2- *dioxopentyl) -2-pyrrolidinecarboxylate; (1R)-1,3-diphenyl-1-propyl (2S)-1-(3,3-dirnethyl-1,2- dioxopentyl) -2-pyrrolidinecarboxylate; (1R)-1,3-diphenyl--prop-2-(E)-ely2 (2S)-1-(3,3-diinethyl- 1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (IR) -1-cyclohexyl-3-phenyl-1-propyl (2S) -1-13, 3-dimethyl- 1, 2-dioxopentyl) -2-pyrrolidinecarboXYlate; dirnethyl-1, 2-dioxopenty.) -2-pyrrolidinecarboxylate; (1R)-1-(4,5-dichlorophenyl)--phelYl-l-propy1 dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate; 3-phenyl-1-propyl (1,2-dioxo-2-cyclohexyl)ethyl-2- pyrrolidinecarboxylate; 3-phenyl-l-propyl (2S)-1-(1,2-dioxo-4-cyc1ohexyl)butYl- 2 pyrrolidinecarboxylate; 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-furanylJ )ethyJ,-2- pyrrolidinecafboxylate; 3-phenyl-1-propy. (2S)-l-(1,2-dioxo-2--[2-thienyl] )ethyl-2- .~:pyrrolidinecarboxylate; 3-phenyl-1-propyl (2S) -l-(1,2-dioxo-2-[2-thiazolyll )ethyl-2- .2 pyrrolidinecarboxylate; 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2- pyrrolidinecarboxylate; l,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-l,2-dioxopeityl)- 2-pyrrolidiriecarboxylate; 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4- hydroxybutyl) -2-pyrrolidinecarboxylate; 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-l,2-dioxopentyl)-2- pyrrolidinecarboxylate; 1- 3-dirnethyl-1, 2-clioxopenty.) -L-proline] -L phenylalanine ethyl ester; 1-tl-(3,3--dimethyl-l,2-dioxopentyl)-L-proline--L leucine ethyl ester; 1- 3-dimethyl-l, 2-dioxopenty1) -L-proline] -L phenylgJlycine ethyl ester; 1- 3-dirnethyl-1, 2-dioxopentyl) -L-prolinel-L phenylalanine pheniyl ester; 1- 3-dimfethyl-l, 2-dioxopentyl) -L-proline] -L phenylalanine benzyl ester; and i-[l-(3,3-dimethyl-1,2-dioxopeltyl)-L-prolile)-L isoleucine ethyl ester.

9. Use of a neurotrophic compound of the formula: N Z 0 0 or a pharmaceutically acceptable salt or hydrate thereof, where R, represents a straight or branched chain alkyl or alkenyl group optionally substituted with Cj-CR cycloalkyl, C 3 or C5 cycloalkyl, C5-C, cycloalkenyl, where said alkyl, alkenyl, cycloalkyl, or cycloalkanyl groups may be optionally substituted with Cl-C 4 alkyl, C 2 *-C 4 alkenyl, or hydroxy, or Ar,, where Ar 1 is selected from the group consisting of l-naphthy-, 2-naphthyl, 2-indolyl, 3-iridolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, or 4-pyridyl, anda phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, *hydiroxyl, nitro, trifluoromethyl, CI-C 6 straight or branched alkyl or alkenyl, C 1 C 4 alkoxy or CI-C 4 alkenyloxy, phenoxy, *:benzyloxy, and amino; Z represents a C 2 -C 6 straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar, as defined above, -C 3 -Cg cycloalkyl, -cycloalkyl connected by a Cl-CE straight or unbranched alkyl or alkenyl chain, or Ar 2 where Ar 2 is selected from the group consisting of 2- indolyl, 3-indolyl, 2-fury)., 3-furyl, 2-thiazolyl, 2-thienyl, 3- thienyl, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, Cj-C 6 straight or branched alkyl or alkenyl, Cj- C 4 alkoxy or CI-C 4 alkenyloxy, phenoxy, benzyloxy, and amino, for promoting neuronal growth and regeneration, for treating a neurological disorder, or for preventing neurodegeneration. The use of claim 9 wherein Ri is selected from the group consisting of CI-C 9 straight or branched chain alkyl, 2- cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl.

11. The use of claim 9 for stimulating growth of damaged peripheral nerves.

12. The use of claim 9, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.

13. The use of claim 9, wherein the neurological disorder related to neurodegeneration is Alzheimer's disease.

14. The use of claim 9, wherein the neurological disorder related to neurodegeneration is Parkinson's Disease. The use of claim 9, wherein the neurological disorder related to neurodegeneration is amyotrophic lateral sclerosis.

16. The use of claim 9 wherein Z and Ri are lipophilic groups.

17. Use of a neurotrophic compound of the formula; H N NI-z 0 0~0 E wheer R3Z is thee d fragment: onisig ftaihto brncedC-C akl ptonly ubttuedwihC3C8cclaay or Ar as dfinedabove and nsubsitue Il R4 is selected from the group consisting of staight orny C- aklotnalklo susttuedl with C,-C. 8 cycloalkyl orarche aky defne abovend nsubstituted heyl consisoting ofehyrognl growth stdraigtnrerainhe fortrean neurological disorder, or for preventing neurodegeneration.

18. The use of claim 17 for stimulating growth of damaged peripheral nerves.

19. The use of claim 17, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.

20. The use of claim 17, wherein the neurological disorder related to neurodegeneration is Alzheimer's disease.

21. The use of claim 17, wherein the neurological disorder related to neurodegeneration is Parkinson's Disease.

22. The use of claim 17, wherein the neurological disorder related to neurodegeneration is amyotrophic lateral sclerosis.

23. The use of claim 17 wherein Z and Ri are lipophilic groups.

24. Use of a neurotrophic N-glyoxyl prolyl ester compound of the formula: N Z or a pharmaceutically acceptable salt or hydrate thereof, where RI represents a Ci-C 5 straight or branched chain alkyl or alkenyl group optionally substituted with C 3 cycloalkyl, or Arl, where Arl is selected from the group consisting of 2-furyl, 2-thienyl, and phenyl; and X is selected from the group consisting of oxygen and sulfur; Y is oxygen; and Z represents a straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar 1 as defined above, S- C 3 -C 6 cycloalkyl, or Ar 2 where Ar 2 is selected from or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen and C 1 -C 4 alkoxy, for promoting neuronal growth and regeneration, for treating a neurological disorder, or for preventing neurodegeneration. The use of claim 24 for stimulating growth of damaged peripheral nerves.

26. The use of claim 24, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.

27. The use of claim 24, wherein the neurological disorder related to neurodegeneration is Alzheimer's disease.

28. The use of claim 24, wherein the neurological disorder related to neurodegeneration is Parkinson's Disease.

29. The use of claim 24, wherein the neurological disorder ~related to neurodegeneration is amyotrophic lateral sclerosis. The use of claim 24 wherein Z and R, are lipophilic groups.

31. The use of claim 24 wherein the compound is selected from- 3-(2,5-dirnethoxyphenyl)-1-propy1 (2S)-1-(3,3-dimethyl-1,2- dioxopentyl) -2-pyrrolidinecarboxylate; 3-phenyl-1-propyl (2-tert-butyl-1,2-dioxoethyl) -2- pyrrolidinecarboxylate; 3-phenyl-1-propyJ- (2S)-1-(2-cyclohexylethy1-1,2-dioxoethyl)- 2-pyrrolidiniecarboxylate; 3- (3-pyridyl)-l-propyl (2S)-1-(2-cYClohexylethyl1,2 dioxoethyl} -2-pyrrolidinecarboxylate; 3- (3-pyridyl)-1-propyl (2S)-l-(2-tert-butyJl-1,2-dioxoethy1) 2-pyrrolidinecarboxylate; 3, 3-diphenyl-1-propyl (2S) 3-dimethy1-1,2-dioxopeltyl) 2-pyrrolidiflecarboxylate; 3-(3-pyridyl)-1-propyl (2S)-l-(2-cycohxy-1,2-dioxoethyl) 2-pyrrolidiriecarboxylate; 3-(3-pyridyl)-1-propyl [2-thienyl~glyoxyl) pyrrolidinecarboxylate; 3,3-diphenyl-1-propyl (2S)-l-(3,3-dirnethyl-1,2-dioxobutyl)- 2-pyrrolidinecarboxy)late; 3, 3-diphenyl) -1-propyl (2S) -1-cyclohexylglyoxyl- 2 pyrrolidinecarboxylate; and 3,3-diphenyl-1-propyl (2S)-1-(2-thienyl)gJ~yoxy1-2- pyrrolidinecarboxylate.

32. Uise of a neurotrophic compound of the formula: 0 N N or a pharmaceutically acceptabl.e salt or hydrate thereof, where R, represents a CI-C 9 straight of branched chain alkyl. or alkernyl group to. optionally substituted with C.-C 8 cycloalkyl, to. 9 or C 5 cycloalkyl, -C 5 -C 7 cycloalkenyl, 9 9 04*6 ,where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C,-C 4 alkyl, Cl-c~, 0:0*0: alkenyl, or hydroxy, or Arl, where Ar 1 is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolylt 2-furyJ, 3-furyl, 2-thiazoly., 2-thienyl, 3-thienyl, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, Cj-C 6 straight or branched alkyl or alkenyl, Cl-C 4 alkoxy or CI-C 4 alkenyloxy, phenoxy, benzyloxy, and amino; X is oxygen or sulfur; Y is oxygen or NR 2 where R 2 is hydrogen or Cj-C 6 alkyl; and Z represents -a C 2 -CG straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in Qne or more positions with Ar 1 as def ined above, C 3 -Cg cycloalkyl, -cycloalkyl connected by a C 1 -C 6 straight or unbranched alkyl. or alkenyl chain, or -Ar 2 where Ar 2 is selected from the group consisting of 2- indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3- &goo thienyl, ur '-pyridyl, and phenyl, having onc to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, CI-C6 straight or branched alkyl or alkenyl, Cj- C 4 alkoxy or Cl-C 4 alkenyloxy, phenoxy, benzyloxy, and amino; the fragment; 0 -C H X 2 -R 4 X 3 where R 3 is selected from straight or branched C,-C 8 alkyl optionally substituted with cycloalkyl or Ar, as defined above, and unsubstituted Ar,; X 2 is O or NRs, where Rs is selected from hydrogen, C,-C, straight or branched alkyl and alkenyl; R 4 is selected from the group consisting of phenyl, benzyl, C,-C 5 straight or branched alkyl or alkenyl, and straight or branched alkyl or alkenyl substituted with phenyl, in the preparation of a medicament for promoting neuronal growth and regeneration, for treating a neurological disorder, or for preventing neurodegeneration.

33. The use of claim 32 for stimulating growth of damaged peripheral nerves.

34. The use of claim 32, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration. The use of claim 34, wherein the neurological disorder related to neurodegeneration is Alzheimer's disease.

36. The use of claim 34, wherein the neurological disorder related to neurodegeneration is Parkinson's Disease. 31. The use of claim 34, wherein the neurological disorder related to neurodegefleration is amyotrophic lateral sclerosis. 38, The use of claim 32 wherein Z and R, are lipophilic groups.

39. The use of claim 32 wherein the compound is selected from. 3-phenyll-Propyl (2S) -l-(3,3-dimethyl-1,2-dioxopentyl) -2- pyrroliclinecarboxYlate; 3-(3-pyridyl) -l-propyl (2S)-l-3,3.-dimethyl-1,2-dioxopentyl) 2-pyrrolidiflecarboxylate; 3-phenyllprop-2-(E)-enyl (2S)-l-(3,3-dimethyl-1, 2 dioxopentyl) -2-pyrrolidiflecarboxylate; 5-trimethoxypheflyl)l-Propyl (3,3-dimethyl- 1, 2-dioxopentyl) -2-pyrrolidinecarboxylate; 3 3 1 5-trimetoxyph yl)prop-2(E)-enyl diimethyl-1, 2-dioxopeityl) -2-pyrrolidinecarboxylate; 3-(4,5-dichloropheflyl)l 1propyl (2S)-l-(3,3-dimethyl-l,-i 2 dioxopentyl) -2-pyrrolidiflecarboxylate; 3 -(4,5-dichlorophefyl-V1prop- 2 (E)-enY1 dimethyl-1, 2-dioxopentyl) -2-pyrrolidiflecarbQxylate; 3- (4,5-~methylefledioxyphelyl) -1-propyl 3-dimethyl- 1, 2-dioxopenltJ) -2-pyrrolidiflecarboxylate; 3 4 5 -methyenedioxyphefl)prop?2(E)-enyl (3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidiflecarboxylate; 3-cyclohexyl--propyJ (2)l(,-dmty-,-dooetl- *2pyrrolidiflecarboxylate; 3-cyclohexyl-i-prop-2-(E)-enyl (2S)-1-(3,3dimethyl-1,2- ~.:~:dioxopeftylV2-pyrrolidilecarboxYlate; (1R)-1,3-diphefyl-propyl (2S)-1-(3,3-dimethyl12- dioxopentyl)-2-pyrroldilecarboxylate; (1R)-1,3-diphenyl-1prop-2-(E)-enyl (2S)-1-(3,3-d1methyl- l, 2 -dioxopentyl)-2-pyrroJlidinecarboxylate; (1R)-1-cycohexy13-phefl-l-propyl 3-diiethylV 1, 2-dioxopentYl) -2-pyrrolidilecar-boxylate; *(lR)-l-cycohexy-3phenyI1lprop-2(E)-enyl (3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidiflecarboxylate; (lR)-l-(4,5dichoropheny)3phenyll-propyl dimiethyl-1, 2-dioxopentyl) -2-pyrro3.idinecarboxylate; 3-phenyl-l-propyl (2S) -l-(l,2-dioxo-2-cyclohexyl)ethyl- 2 pyrrolidinecarboxylate; 3-phenyl--propyl (23) (,2-dioxo4ccohexy1)butyl- 2 pyrrolidinecarboxy)late; 3-phenyl--1-propyl (2S)-1-(1,2--dioxo-2-112-furanyl] )ethyl-2- pyrrolidinecarboxy-ate; 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-(2-thienyl))ethyl-2- pyrrolidinecarboxylate; 3-phenyl-1-propyl (2S)-l-(1,2-dioxo-2-t2-thiazolyl) )ethyl-2- *::pyrrolidinecarboxylate; ~~-pheny.-l-proyl (23) (1,2u.Loxo2-pLheflJethy4.-2- pyrrolidinecarboxylate; 1,7-diphenyl-4-heptyl (2S)-1-(3,3-dirnethyl-1,2-dioxopentyl)- 2-pyrrolidinecarboxylate; 3-phenyl-1-propyl (2S) 3-.dimethyJl-1, 2-dioxo'-4- hydroxybutyl) -2-pyrrolidinecarboxylate; 3-phenyl-1-propyl 3-direthyl-1,2-dioxopentyl)-2- pyrrolidinecarboxylate; 1- 3-dimethyl-l, 2-dioxopentyl) -L-proline] -L phenylalanine ethyl ester; 3-direthyl-1,2-dioxopentyl)-L-proline]-t leucine ethyl ester; 3-dirnethyl-1, 2-dioxopentyl) -L--proline] -L pheny1glycine ethyl ester; 1-ti- 3-dimethyl-1, 2-dioxopentyl) -L-prolinel -L phenylalanine phenyl ester; 1- 3-dimethyl-l,2-dioxopeltYl) -L-prolinel-L phenylalalife berizyl ester; and 1-[l-(3,3-dimethyl-1,2-dioxopeltyl)-L-proline1 -L isoleucine ethyl ester.

40. Use of a neurotrophic compound of the formula: 0 0 orapharmaceutically acceptable salt or hydrate thereof, where R, represents -a Cj-C 9 straight or branched chain alkyl or alkenyl group optionally substituted with C,-C 8 cycloalkyl, -C or C~s cyc-loalkyl, -CS-C, cycloalkenyl, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with Cj-C 4 alkyl, C 1 "-C 4 alkenyl, or hydroxy, or Ar 1 where Arl is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, or 4-pyridyl, and phenyl, having one to three substituerits which are independently selected from the group consisting of hydrogen, halogen, .hydroxyl, nitro, trifluoromethyl, CI-Cr, straight or branched alkyl or alkenyl, C 1 -C 4 alkoxy or CI-C 4 alkenyloxy, phenoxy, :benzyloxy, and amino; Z represents a C 2 -C 6 straight or branched chain alkyl or alkenyl, wherein the alkyl. chain is substituted in one or more positions with Ar, as defined above, -C 3 -C 8 I cycloalkyl, ~:-cycloalky]. connected by a CI-Cs straight or unbranched alkyl or alkenyl chain, or Ar 2 where Ar 2 is selected from the group consisting of 2- indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3- thienyl, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, Cj-C 6 straight or branched alkyl. or alkenyl, Cj- C, alkoxy or Cl-C 4 alkenyloxy, phenoxy, benzyloxy, and amino, in the preparation of a medicament for promoting neuronal growth and regeneration, for treating a neurological disorder, or for preventing neurodegeneration.

41. The use of claim 40 wherein RI is selected from the group consisting of CI-C, straight or branched chain alkyl, 2- cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl. S42. The use of claim 40 for stimulating growth of damaged peripheral nerves.

43. The use of claim 40, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, S and neurological pathologies related to neurodegeneration.

44. The use of claim 40, wherein the neurological disorder ~related to neurodegeneration is Alzheimer's disease. The use of claim 40, wherein the neurological disorder related to neurodegeneration is Parkinson's Disease.

46. The use of claim 40, wherein the neurological disorder related to neurodegeneration is amyotrophic lateral sclerosis.

47. The use of claim 40 wherein Z and RI are lipophilic groups.

48. Use of a neurotrophic compound of the formula: Sor pharmaceutically acceptable salts or hydrates thereof, where Z is the fragment: cc.. 0 SR C-CH R 4 where is selected from the group consisting of straight or c~-C 8 alkyl optionally substituted with CC 0 cycloalkyl branched C 3C or Ar 1 as defined above, and unsubstituted Ar 1 X. is 0 or where R5 is selected from the group consisting of hydrogen, C3-C. straight or branched alkyl and alkenyl; is selected from the group consisting of phenyl, benzyl, Cl-C. straight or branched alkyl or alkenyl, and Cj-C5 straight or branched alkyl or alkcenyl substituted with phenyl, in the preparation of a medicament for promoting neuronial growth and regeneration, for treating a neurological disorder, or for preventing neurodegeneration.

49. The use of claim 48 for stimulating growth of damaged peripheral nerves. The use of claim 48, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.

51. The use of claim 48, wherein the neurological disorder S: related to neurodegeneration is Alzheimer's disease.

52. The use of claim 48, wherein the neurological disorder 99* S related to neurodegeneration is Parkinson's Disease.

53. The use of claim 48, wherein the neurological disorder related to neurodegeneration is amyotrophic lateral sclerosis.

54. The use of claim 48, wherein Z and RI are lipophilic groups. Use of a neurotrophic compound of the formula: Y NZ or a pharmaceutically acceptable salt or hydrate thereof, where R, represents a c 1 -C5 straight or branched chain alkyl or alkeny- group optionally substituted with C 3 -C 6 cycloalkyi-, -or Ar 1 where Ar 1 is selected from the group consisting of 2-furyl, 2-thienyl, and phenyl; and X is selected from the group consisting of oxygen and sulfur; Y is oxygen; and *Z represents -a straight or branched chain alkyl or alkeriyl, wherein the alkyl chain is substituted in one or more positions with Ar 1 as defined above, C,-C 6 cycloalkyl, or Ar, where Ar 2 is selected from or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen and C,-C 4 alkoxy, in the preparation of a medicament for promoting neuronal growth and regeneration, for treating a neurological disorder, or for preventing neurodegeneration. 56, The use of claim 55 for stimulating growth of damvaged peripheral nerves.

57. The use of claim 55, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.

58. The use of claim 55, wherein the neurological disorder related to neurodegeneration is Alzheimer's disease.

59. The use of claim 55, wherein the neurological disorder related to neurodegefleration is Parkinson's Disease, The use of claim 55, wherein the neurological disorder related to neurodegeneration is amyotrophic lateral sclerosis. S.61. The use of claim 55 wherein Z and R, are lipophilic groups.

62. The use of claim 55 wherein the compound is selected from: 3-(2,5-dimethoxypheflyl)l-propyl (2S)-l-(3,3-dimfethyl-1, 2 dioxopentyl) -2-pyrrolidiflecarboxylate; 3 -(2,5-dimethoxypheyl)-l)1prop-2(E)-enyl dimethyl-l, 2-dioxopeityl) -2-pyrrolidinecarboxylate; 3-(3,4,5-trimfethoxyphefyl)-hlethyl (2S)-l-(3,3-dimethy~l1 2 dioxopefityl) -2-pyrrolidinecarboxylate; 3-phenyll-propyl (2S) -1-(2-tertbutyl1,2-dioxoethyl)- 2 pyrrolidinecarboxylate; 3-phenyl-1-propyl 2 -cyclohexylethyl-1,2-dioxoethyl)- 2-pyrrolidiflecarboxylate; 3-(3-pyridyl-1PrOPYl (2S)-1-(2-cylohexylethyl-, 2 dioxoethyl) -2-pyrrolidiflecarboxylate; 3-(3-pyridyl) -l-propy- (2S) l(-ycoey-12doxehl- 2-pyrrolidiflecarboxylate; ~3,3-diphelyl-1'-Propyl (23) -1-(3,3.-dimethyl-1,2-dioxobeftyl) 2-.pyrrolidinfecarboxylate; 3,(3-dphdyl)-1-propyl 2 S)-l-(cycohexylyxyl2i-ehl 2pyrrolidifecarboxylate;an pyrrolidifleCarboxylate; t~rt ialeuarbolial iodrer rvnignurdgnrt which comprises adminlisterinlg a therapeutically effective amount of a neurotrophic Ccompound of the formula: N Y 1%z S or a pharmaceutically acceptable salt or hydrate thereof, !~:where R, represents -a C 1 -C 9 straight or branched chain alkyl. or alkenyl group optionally substituted with C 3 cycloalkyl, C 3 Or C 5 cycloalkyl, C,,-C 7 cycJ.oalkenYl, where said alk~yl, alkeflyl, cycloalky., or cycloalkenyl groups may be optionally substituted with Cl-C 4 alkyl, C,-C 4 alkenyl, or hydroxy, or Arl, where Ar 1 is selected from the group consisting of 1-naphthYl, 2-naphthYl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thieflyl, 3-thiel, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromfethYl, Cj-c 6 straight or branched alkyl or alkenyl, C 1 -C4 ailkoxy or C 1 -Cakeyox, hnoy benzy)lQxy, and amino; X is oxygen or sulfur; Y is oxygen or NR 2 where is hydrogen or CI-CE alkcyl; and Z represents a C 2 -C 6 straight or branched chain alkyl. or alkenyl, ~.:wherein the alkyl chain is substituted in one or more positions with Arl as defined above, -C 3 -C 8 cycloalkyl, -cycloalkyl connected by a CI-CE straight or unbranched alkyl or a).kenyl chain, or Ar 2 where A\r 2 is selected from the group consisting of 2- thienyl, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, Cj-C6 straight or branched alkyl or alkenyl, Cj- C 4 alkoxy or CI-C 4 alkenyloxy, phenoxy, benzy3loxy, and amino; the fragment: 0 -CH I X 2 -R 4 3 where R, is selected from straight or branched Ci-C 8 alkyl optionally substituted with C 3 -C 8 cycloalkyl or Arl as defined above, and unsubstituted Arl; X 2 is 0 or NRs, where R 5 is selected from hydrogen, C 1 -C 6 ':straight or branched alkyl and alkenyl; R, is selected from the group consisting of phenyl, benzyl, C-C, straight or branched alkyl or alkenyl, and CI-C, straight or branched alkyl or alkenyl substituted with phenyl; in sufficient amounts to promote neuronal growth and regeneration, treat a neurological disorder, or prevent neurodegeneration.

64. The method of claim 63 for stimulating growth of damaged peripheral nerves. The method of claim 63, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.

66. The method of claim 65, wherein the neurological disorder related to rneurodegeneratiofl is Alzheimner's disease.

67. The method of claim 65, wherein the neurological disorder related to neurodegefleration is Parkinson's Disease.

68. The method of claim 65, wherein the neurological disorder related to neurodegeneration is amyotrophic lateral sclerosis.

69. The method of claim 63 wherein Z and R, are lipophilic :groups. The method of claim 63 wherein the compound is selected :.from: 3-phenyl-1-propyl (2S) -l-i3,3-dimethyl-l,2-dioxopeltyl) -2- pyrrolidinecarboxylate; 2-pyrrolidinecarboxylate; 3-phenyl-l-prop-2-(E)eyl (2S)-1-(3,3-cU-methyl-l, 2 dioxopentyl) -2-pyrrolidinecarboxylate; 3- (3,4,5-trimethoxyphenyl)-l-propyl (2S)-l-(3,3-dimethyl- 1, 2-dioxopentyl) -2-pyrrolidinecarboxylate; 4,5-trimethoxyphenyl)-l-prop- 2 -(E)-eny1 (2S)-1l-(3,3- dimethyl-l, 2-dioxopentyl) -2-pyrrolidiflecarboxylate; 3-(4,5-dichloropheflyl)-l-propyl (2S)-l-(3,3--dimethyl-l, 2 dioxopentyl) 2pyrroidinecarboxylateI 3-(4,5-dich~orphefyl)prop-2-(E)enyI dimethyl-1, 2-dioxopentyl) -2-pyrrolidiflecarboxylate; 3-(4,5-methylernedioxyphefylY)l-propyI (2S) 3-dinethyl- 1, 2-dioxopentyl) -2-pyrrolidilecarboxyJlate; 3-(4,5-methylefedioxypheylY)-prop- 2 -(E)-enyl dimethyl-1, 2-dioxopenty-2-pyrrolidinecarboxyJlate; S. U 3-cyclohexyl-1-propyl (2S) 3-dimethyl-1, 2-dioxopenty.) .2-pyrrolidiirLecarboxylate; 3-cyclohexy1-l-prop-2-(E)-elyl (2S)-1-(3,3-dimethyl-1,2- dioxopentyl)-2-pyrrolidirnecarboxylate; (1R)-1,3--diphenyl-1-propy). 3-dirnethyl-1,2- 00.1, 2ioxopenty2l) 2-prroiidicarbxylate (1R)-1,cyciohexy1l-l-phefl--PrOPeyl 3-dimethyl- o1, 2-dioxopeltyl) -2-pyrrolidinecarboxylate; to,(R--ylhxy--hnllpoy P(3,3dietyl dimethyl-1, 2-dioxopentyl) -2-pyrrolidifecarboxylate; (1R)-1-(4,5-dichlorophefyl)3phefyl-llpropyI dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate; 3-phenyJl-1-PrQPY1 2 2 dioxo-2 cyclohexyl) ethyl 2- pyrrolidinecarboxylate; 3-phenyl-l-PrOPYl (2)l(,-ix--ylhxlbtl2 pyrrolidinecarboxyJlate; 3-phenyl-1-propyl 2 S)-1-(1,2-dioxo-2-[2-furanyl] )ethyl-2- pyrrolidiflecarboxylate; 3-phenyl-l-Propyl 2 S)-l-(1,2-dioxo-2-[2thienyl] )ethyl-2- pyrrolidinecarboxylate; .2 pyrrolidinecarboxylate; *3-phenyll-propy)- 2 Sh1l-(1,2-dioxo-2-phenyl)ethyl- 2 pyrrolidinecarboxylate; 1,7-diphefyl14-heptyl (2S) 3-d~fimthyl-1,2-dioxopentyl) 2-pyrrolidiflecarboxylate; 3-phenyl-l-Propyl (2S)-l-(3,3-dimethyl-1,2dioxo- 4 hydroxybutyl) 2 -pyrrolidinecarboxylate; 3-phenyl-l-propyl 3-dimethyl-1,2-dioxopefltyl)- 2 pyrrolidiflecarboxYlate; 1-11-(3, 3 -dimethy-1,2dioxopenty)VLproline]-L phenylalalife ethyl ester; 3 -dimethy-1,2-diOopentylYL-proline] -L leucifle ethyl ester; 1- 3-dimethyl-1, 2-dioxopentyl) -L-prolil]-L phenylg.ycifle ethyl ester; 1- 3-diinethyl-l, 2-dioxoperityl) -L-prolifl-L phenylalalife phenyl ester; 1- 3-dimethyl-l, 2-dioxopentyl) -L-prolfl-L phenylalalife benzyl ester; and 3 3 -dimethy-1,2-dioxopentyl)L-proline]L isoleucile ethyl ester.

71. A method of promoting neuronal growth and regeneration, treating a neurological disorder, or preventing neurodegefleration which comprises administerinlg a therapeutically effective amounirt of a neurotrophic compound of the formula: 00 or a pharmaceutically acceptable salt or hydrate thereof, where R, represents a CI-C 9 straight or branched chain alkyl or alkenyl group optionally substituted with C 3 -CU cycloalky-, or C 5 cycloalkyl, C5-C 7 cycloalkeny-, where said alkyl, alkenyl, cycloalkcyl, or cycloalkenll groups may be optionally substituted with Cl-C4 alkyl, Cl-C 4 alkenyl, or hydroxy, or Ar,, where Ar 1 is selected from the group consisting of l-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thieflyl, 3-thieflyl, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethYJ., Cj-C 6 straight or branched alkyl or alkeflyl, CI-C 4 alkoxy or Cl-C 4 alkenyloxy, phenoxy, benzyloxy, and amino; Z represents -a CV,-C 6 straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Arl as def ined above, C:,-C 0 cycloalkyl, -cycloalkyl connected by a CI-C 6 straight or unbranched alkyl. or alkenyl chain, or -Cn Ar 2 where Ar, is selected from the group consisting of 2- indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3- thienyl, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, Ci-C, straight or branched alkyl or alkenyl, Ci- C 4 alkoxy or C 1 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino, in sufficient amounts to promote neuronal growth and regeneration, treat a neurological disorder, or prevent Sneurodegeneration.

72. The method of claim 71 wherein R is selected from the group consisting of straight or branched chain alkyl, 2- cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and S4-hydroxybutyl.

73. The method of claim 71 for stimulating growth of S damaged peripheral nerves.

74. The method of claim 71, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration. The method of claim 71, wherein the neurological disordler related to neurodegefleration is Alzheimer' s disease.- 76, The method of claim 71, wherein the neurological disorder related to neu~rodegefleratiofl is Parkinson's Disease.

77. The method of claim 71, wherein the neurological disorder related to neurodegefleration is amyotrophic lateral sclerosis.

78. The method of claim 71 wherein Z and R, are lipophilic groups.

79. A method of promoting neuronal growth and regeneration, **~*treating a neurological disorder, or preventing neurodegefleration :which comprises administering a therapeutically effective amount of a neurotrophic compound of the formula: H N 0 or pharmaceutically acceptable salts or hydrates thereof, where Z is the fragment; 0 -CH X 2 -R 4 I R 3 where R 3 is selected from the group consisting of straight or branched C 1 alkyl optionally substituted with C 3 -C 8 cycloalkyl or Arl as defined above, and unsubstituted Arl; X, is O or NR,, where Rs is selected from the group consisting of hydrogen, CI-C, straight or branched alkyl and alkenyl; R 4 is selected from the group consisting of phenyl, benzyl, CI-Cs straight or branched alkyl or alkenyl, and straight or branched alkyl or alkenyl substituted with phenyl, in sufficient S amounts to promote neuronal growth and regeneration, treat a neurological disorder, or prevent neurodegeneration.

80. The method of claim 79 for stimulating growth of damaged peripheral nerves.

81. The method of claim 79, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.

82. The method of claim 79, wherein the neurological disorder related to neurodegeneration is Alzheimer's disease.

83. The method of claim 79, wherein the neurological disorder related to neurodegeneration is Parkinson's Disease.

84. The method of claim 79, wherein the neurological disorder related to neurodegeneration is amyotrophic lateral sclerosis. The method of claim 79 wherein Z and Ri are lipophilic groups.

86. A method of promoting neuronal growth and regeneration, treating a neurological disorder, or preventing neurodegeneration which comprises administering a therapeutically effective amount of a neurotrophic compound of the formula: N• Y \K x or a pharmaceutically acceptable salt or hydrate thereof, where RI represents a Ci-C 5 straight or branched chain alkyl or alkenyl group optionally substituted with C 3 -C 6 cycloalkyl, 0<- or Arl, where Arl is selected from the group consisting of 2-furyl, 2-thienyl, and phenyl; and X is selected from the group consisting of oxygen and sulfur; Y is oxygen; and Z represents a straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar 1 as 4* defined above, cycloalkyl, or Ar 2 where Ar 2 is selected from or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen and CI-C, alkoxy, in sufficient amounts to promote neuronal growth and regeneration, treat a neurological disorder, or prevent neurodegeneration.

87. The method of claim 86 for stimulating growth of damaged peripheral nerves.

88. The method of claim 86, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegenerat ion.

89. The method of claim 86, wherein the neurological disorder related to neurodegerieration is Alzheimner's disease. The method of claim 86, wherein the neurological disorder related to neurodegeneration is Parkinson's Disease.

91. The method of claim 86, wherein the neurological disorder related to neurodegerieration is amyotrophic lateral sclerosis.

92. The method of claim 86 wherein Z and R, are lipophilic groups.

93. The method of claim 86 wherein the compound is selected from, 3-(2,5-dimethoxypheflyl)-l-Propyl (2S)-l-(3,3-dimethyl-l,2- dioxopentyl) -2-pyrroli-dinecarboxylate; 3-(2,5-dimethoxyphenyl-l-prop-2-(E)-enyl dirnethyl--, 2-dioxopentyl) -2-pyrrolidiflecarboxylate; dioxoperityl) -2-pyrrolidinecarboxyJlate; 3-phenyl-l-propyl (2S)-1-(2tert-butyl-,2-dioxoethyl) -2- pyrrolidinecarboxylate; 3-phenyl-1--propyl 2 s)1I(2-cyclohexylethyl-1,2dioxoethyl) 2-pyrrolidinecarboxylate; dioxoethyl) -2-pyrrolidinecarboxylate; 3-(3-pyridyl)-1-propyl (2-tert-butyl-1,2-dioxoethyl)- 2-pyrrolidinecarboxylate; 3,3-diphenyl-l-propyl (2S)-l-(3,3-dimethyl-1,2-dioxopentyl) 2-pyrrolidinecarboxylate; 3-(3-pyridyl)-1--propyl (2-cyclohexyl-1,2-dioxoethyl)- 2-pyrrolidinecarboxylate; 3-(3-pyridyl)-l-propyl [2-thieriyl~glyoxyl) pyrrolidinecarboxylate; 3,3-diphenyl-l-propyl (2S)-1-(3,3-dimethyl-l,2-dioxobutyl)- 2-pyr rolidinecarboxylatei 3, 3-diphenyl) -1-propyl (2S) -1-cyclohexylglyoxyl-2- pyrrolidinecarboxylate; and 3,3-diphenyl-1-propyl (2S)-1-(2-thieny)glyoxyl-2- De pyrrolidinecarboxylate. *0:00

94. The use according to claim 1 or claim 32, or the method according to claim 63 substantially as hereinbefore described with reference to any of the examples. DATED this 15'h day of June, 1999. GUIILFORD PHARMACEUTICALS, INC. By their Patent Attorneys: CALLINAN LAWRIE