AU777188B2 - Heterocyclic thioesters and ketones - Google Patents

Description

0 N\ I P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A DIVISIONAL PATENT

ORIGINAL

TO BE COMPLETED BY APPLICANT Name of Applicant: GPI NIL HOLDINGS, INC.

Actual Inventor: HAMILTON, GREGORY LI, JIA-HE Address for Service: CALLINAN LAWRIE, 711 High Street, Kew, Victoria 3101, Australia Invention Title: HETEROCYCLIC THIOESTERS AND KETONES The following statement is a full description of this invention, including the best method of performing it known to me:- 06/08/01,gc12226spe.2 4 BACKGROUND OF THE INVENTION This application is a divisional application of Australian Patent Application No. 42590/97, the subject matter of which is herein incorporated.

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

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

06/08/01,gc12226.spe,32 4 a 1 2 Immunophilins are known to have peptidyl-prolyl isomerase (PPIase), or rotamase, enzyme activity. It has been determined that rotamase enzyme activity plays a role in the catalyzation of the interconversion of the cis and trans isomers of peptide and protein substrates for the immunophilin proteins.

Immunophilins were originally discovered and studied in the immune tissue. It was initially postulated by those skilled in the art that inhibition of the immunophilins' rotamase activity leads to inhibition of T-cell proliferation, thereby causing the immunosuppressive activity exhibited by immunosuppressant drugs, such as cyclosporin A, FK506 and rapamycin.

Further study has shown that the inhibition of rotamase 1 5 activity, in and of itself, does not result in immunosuppressive activity. Schreiber et al., Science, 1990, vol. 250, pp. 556-559. Instead, immunosuppression appears to stem from the formulation of a complex of immunosuppressant drug and immunophilin. It has been 20 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 cyclophilin-CsA, the immunophilin-drug complexes bind to the enzyme calcineurin and inhibit the T-cell receptor signalling which leads to T-cell proliferation. Similarly, the I I 3 immunophilin-drug complex of FKBP-rapamycin interacts with the RAFT1/FRAP protein and inhibits the IL-2 receptor signalling.

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 nitric oxide synthesis, neurotransmitter release and neuronal process extension.

It has been found that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate neurite outgrowth in PC12 cells and sensory neurons, namely dorsal root ganglion cells (DRGs). Lyons 15 et al., Proc. of Natl. Acad. Sci., 1994, vol. 91, pp.

3191-3195. In whole animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve injury.

Surprisingly, it has been found that certain 20 compounds with a high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects. Furthermore, these rotamase inhibitors are devoid of immunosuppressive activity. These findings suggest the use of rotamase inhibitors in treating various peripheral neuropathies and enhancing neuronal regrowth in the central nervous system (CNS). Studies I I 4 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 affecting 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 SDAT patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain derived growth factor, glial derived growth factor, ciliary 15 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 'in the delivery and bioavailability of large proteins to 20 nervous system targets. By contrast, immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity.

However, when administered chronically, immunosuppressant drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis (Kopp et al., J. Am. Soc. Nephrol., 1991, 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina, such as nonlocalized headaches (De Groen et al., N. Engl. J. Med., 1987, 317:861); and vascular hypertension with complications resulting therefrom (Kahan et al., N. Engl.

J. Med., 1989, 321:1725).

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 enhancing neurite outgrowth, and promoting neuronal growth and regeneration in various neuropathological situations where neuronal repair can be facilitated, including: peripheral nerve damage caused 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 neurological disorders relating to neurodegeneration, such as Parkinson's disease, SDAT 20 (Alzheimer's disease) and amyotrophic lateral sclerosis.

SUMMARY OF THE INVENTION The present invention relates to neurotrophic low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity. A key feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity in addition to their neurotrophic activity.

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

(CH

2 )n II N Z R1 0

X

N)h 0 R2 or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; X is O or S; 15 Z is selected from the group consisting of CH 2

CHRI

and C(RI) 2 R, is selected from the group consisting of CI-C straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, Ar 1 and mixtures thereof, wherein said R, is unsubstituted or substituted with halo, nitro, Cl-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, Cl-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ari or a mixture thereof;

R

2 is selected from the group consisting of CI-C9 I I

I

7 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C, cycloalkyl, C5-C7 cycloalkenyl and Arl; and Ar 1 is phenyl, benzyl, pyridyl,- fluorenyl, thioindolyl or naphthyl wherein said Ari is unsubstituted or substituted with halo, hydroxy, nitro, Ci-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, Ci-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.

The present invention also relates to a pharmaceutical composition comprising: an effective amount of the compound of formula II for effecting a neuronal activity; and (ii) a pharmaceutically acceptable carrier.

15 The present invention further relates to a method of effecting a neuronal activity in an animal, comprising: administering to the animal an effective amount of the compound of formula II.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1(A) is a representative photomicrograph of untreated sensory neurons.

FIG. 1(B) is a representative photomicrograph of compound 1 (10 pM) promoting neurite outgrowth in sensory neurons.

8 FIG. 1(C) is a representative photomicrograph of compound 1 (1 nM) promoting neurite outgrowth in sensory neurons.

FIG. 1(D) is a representative photomicrograph of compound 1 (1 pM) promoting neurite outgrowth in sensory neurons.

FIG. 2(A) is a representative photomicrograph of untreated sensory neurons.

FIG. 2(B) is a representative photomicrograph of compound 9 (10 pM) promoting neurite outgrowth in sensory neurons.

FIG. 2(C) is a representative photomicrograph of compound 9 (1 nM) promoting neurite outgrowth in sensory neurons.

S: 15 FIG. 2(D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons.

FIG. 3(A) is a representative photomicrograph of untreated sensory neurons.

20 FIG. 3(B) is a representative photomicrograph of compound 10 (10 pM) promoting neurite outgrowth in sensory neurons.

FIG. 3(C) is a representative photomicrograph of compound 9 (1 nM) promoting neurite outgrowth in sensory neurons.

FIG. 3(D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons.

FIG. 4 presents quantitation for the recovery of THpositive dopaminergic neurons in the striatum of animals receiving compounds 1, 9 and DETAILED DESCRIPTION OF THE INVENTION Definitions "Alkyl" refers to a branched or unbranched saturated hydrocarbon chain containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl and the like, unless therwise indicated.

15 "Alkoxy" refers to the group -OR wherein R is alkyl as herein defined. Preferably, R is a branched or unbranched saturated hydrocarbon chain containing 1 to 3 carbon atoms.

"Halo" refers to fluoro, chloro, bromo or iodo, 20 unless otherwise indicated.

"Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.

"Enantiomers" are a pair of stereoisomers that are nonsuperimposable mirror images of each other.

"Diastereoisomers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Nonracemic mixture" is a mixture containing unequal parts of individual enantiomers or stereoisomers.

"Pharmaceutically acceptable salt" refers to a salt of the inventive compounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. The salt can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of a base salt include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl- D-glucamine, and salts with amino acids such as arginine and lysine. Also, the basic nitrogen-containing groups 11 can be quarternized with agents including: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides.

"Phenyl" refers to any possible isomeric phenyl radical, optionally monosubstituted or multisubstituted with substituents selected from the group consisting of alkyl, alkoxy, hydroxy, halo and haloalkyl.

"Treating" refers to: preventing a disease, disorder or condition from occurring in an animal which may be predisposed to .*e 15 the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, arresting its development; and (iii) relieving the disease, disorder or condition, causing regression of the disease, disorder and/or condition.

Compounds of the Invention The neurotrophic low molecular weight, small molecule FKBP inhibitor compounds of this invention have 12 an affinity for FKBP-type immunophilins, such as FKBP12.

When the neurotrophic compounds of this invention are bound to an FKBP-type immunophilin, they have been found to inhibit the prolyl-peptidyl cis-trans isomerase activity, or rotamase, activity of the binding protein and unexpectedly stimulate neurite growth.

FORMULA I In particular, this invention relates to a compound of formula I:

A

2 to which they are respectfully attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH or

NR

2 in any chemically stable oxidation state; X is either O or S; Z is either CH 2 CHR, or C(Rt)2; 13 W and Y are independently O, S, CH 2 or H,; R, is Ci-C 6 straight or branched chain alkyl or alkenyl, which is substituted in one or more position(s) with (Ar) n, (Ar) n connected by a C 1

-C

6 straight or branched chain alkyl or alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a Ci-C 6 straight or branched chain alkyl or alkenyl, Ar 2 or a combination thereof; n is 1 or 2;

R

2 is either C1-C9 straight or branched chain alkyl or alkenyl, C3-C, cycloalkyl, C5-C7 cycloalkenyl or Ari, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and 15 Ari and Ar 2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C straight or branched chain alkyl or alkenyl, Ci-C4 20 alkoxy, Ci-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S and a combination thereof.

Suitable mono- and bicyclic, carbo- and heterocyclic 14 rings include, without limitation, naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.

FORMULA II A preferred embodiment of this invention is a compound of formula II:

(CH

2 )n II N ZR1 0o X R2 or pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; X is O or S; Z is selected from the group consisting of CH 2 CHRi 15 and C(R) 2 RI is selected from the group consisting of Ci-C straight or branched chain alkyl, C 2 -Cs straight or branched chain alkenyl, Ari and mixtures thereof, wherein said R, is unsubstituted or substituted with halo, nitro, Cl-C 6 straight or branched chain alkyl, C 2

-C

6 straight or branched chain alkenyl, hydroxy, Ci-C 4 alkoxy, C 2

-C

4 alkenyloxy, phenoxy, benzyloxy, amino, Ar 1 or a mixture thereof;

R

2 is selected from the group consisting of C 1

-C

9 straight or branched chain alkyl, C 2

-C

9 straight or branched chain alkenyl, C3-C8 cycloalkyl, 05-07 cycloalkenyl and Ar 1 and Ar 1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl wherein said Ar 1 is unsubstituted or substituted with halo, trifluoromethyl, hydroxy, nitro, Cl-C6 straight or branched chain alkyl, 02-06 straight or branched chain alkenyl, 01-04 alkoxy, 02-04 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.

Specific in TABLE I.

examples of these embodiments are presented TABLE I '9 9.

9 9 9*9 9 9 99.9 9 9 9 99 9 9.9.

9 .999 No.

15 1 2 3 4 5 20 6 7 8 16 17 18 19 22 z

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2 3-Phenylpropyl 3-(3-Pyridyl)propyl 3-Phenylpropyl 3-(3-Pyridyl)propyl 3-(3-Pyridyl)propyl 3-(3-Pyridyl)propyl 3-(3-Pyridyl)propyl 2-(9-Fluorenyl)ethyl 3-(4-Methoxyphenyl)propyl 4-(4-Methoxyphenyl)butyl 4-Phenylbutyl 4-Phenylbutyl 4-Phenylbutyl 3-Phenyipropyl 3-Phenylpropyl 1,1-Dimnethyipropyl 1, 1 -Dimethyipropyl tert-Butyl tert-Butyl Cyclohexyl Cyclopentyl Cycloheptyl 1,1 -Dimethyipropyl 1, -Dimethyipropyl 1 1 -Dimethyipropyl 1, 1 -Dimethylpropyl Phenyl tert-Butyl 1,1-Dimethyipropyl 1, 1 -Dimethylpropyl 16 24 2 0 CHR, 3-Phenyipropyl 2 0 CHR 1 3-Phenyipropyl 26 2 0 CHR 1 3-Phenyipropyl 27 2 0 CHR 1 3-Phenyipropyl 66 1 0 CH 2 3-Phenyipropyl 67 1 0 CH 2 2-Phenylethyl 68 2 0 CH 2 4-Phenylbutyl 69 2 0 CHRI 2-Phenylethyl 1 0 CH 2 3,3-Di(4-fluorophenyl)propyl 71 2 0 CH 2 3-Phenyipropyl 1, 1-Dimethyipropyl Cyclohexyl Phenyl 3 Cyclohexyl tert-Butyl Cyclohexyl tert-Butyl 1, 1-Dimethyipropyl 1, 1-Dirnethyipropyl 0 0 0@e 0 0 *000 a S.

06940 0 00 06 The most preferred examples of TABLE I are named as follows: 1 (28)-3 ,3-dimethyl- 1-j2-(5-phenylpentanoyl) pyrrolidinyllpentane- 1,2-dione 2 (25)-3 ,3-dimnethyl-l1-[2-(5-(3-pyridyl)pentanoyl) pyrrolidinyllpentane- 1,2dione 3 (25)-2-(l1-oxo-5-phenyl)-pentyl-l1-(3, 3-dimethyl- 1,2-dioxobutyl)pyrrolidine 66 (2S) 1-Oxo-5-phenyl) pentyl-1- (2-Cyclohexyl-1, 2dioxoethyl) pyrrolidine 67 2-(1-Oxo-4-phenyl)-butyl-1-(3,3-dimethyi-1,2dioxobutyl) pyrrolidine 68 2-(1-Oxo-6-phenyl)-hexyl-1-(2-Cyclohexyi-1,2dioxoethyl) piperidine 69 2-({1-Oxo-[2-{2'--phernyilethyi]-4*-phenyl}-butyl-1- 3-dimethyl-1, 2-clioxobutyl) piperidine (2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl]-1-(3,3 dimethyl-1, 2-pentanedione) pyrrolidine 17 71 3,3-Dimethyl-1-[2-(5-phenylpentanoyl)piperidino]- 1,2-pentanedione FORMULA III Another preferred embodiment is a compound of formula III:

B-C

AN Z

N

00 1 0

III

2 or a pharmaceutically acceptable salt thereof, wherein: 0 0 oo 15 A, B, C and D are independently

CH

2 O, S, SO, SO2, NH or NR,; e*t: X is O or S; Z is CH 2 CHR, or C(Ri) 2 RI is Ci-C6 straight or branched chain alkyl or o* 20 alkenyl, which is substituted in one or more position(s) with (Arl)n, (Arl)n connected by a Ci-C6 straight or branched chain alkyl or alkenyl, C3-C, cycloalkyl, C3-C8 ease cycloalkyl connected by a Ci-C6 straight or branched chain alkyl or alkenyl, Ar 2 or a combination thereof; n is 1 or 2;

R

2 is either Ci-C, straight or branched chain alkyl or alkenyl, C 3 cycloalkyl, C 5 -C7 cycloalkenyl or Ar,, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C 4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and Arl and Ar 2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl or alkenyl, C 1

-C

4 alkoxy, C 1

-C

4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group 15 consisting of O, N, S and a combination thereof.

Particularly preferred compounds of formula III are presented in TABLE II.

TABLE II No. A B C X Z R I R 2 73 CH 2 S CH 2 O CH, 3-phenylpropyl 3,3-dimethylpentyl FORMULA IV A further preferred embodiment of this invention is a compound of formula IV:

C

B 'D 1 O XN

IV

0 X R2 or a pharmaceutically acceptable salt thereof, wherein: 15 A, B, C and D are independently CH2, O, S, SO, SO 2

NH

or NR 2 X is O or S; Z is CH2, CHR, or C(Ri) 2 R, is Ci-C 6 straight or branched chain alkyl or alkenyl, which is substituted in one or more position(s) with (Arl)n, (Arl)n connected by a Ci-C, straight or branched chain alkyl or alkenyl, C3-C, cycloalkyl, C3-C, cycloalkyl connected by a CI-C6 straight or branched chain alkyl or alkenyl, Ar 2 or a combination thereof; n is 1 or 2;

R

2 is either Ci-C, straight or branched chain alkyl or alkenyl, C 3

-C

8 cycloalkyl, C 5

-C

7 cycloalkenyl or Ari, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C 4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and Ari and Ar 2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C 6 straight or branched chain alkyl or alkenyl, Ci-C 4 alkoxy, Ci-C 4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and -wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S and a combination thereof.

Particularly preferred compounds of formula IV are presented in TABLE III.

20 TABLE III No. A B C D X Z R, R 2 76 CH 2

CH

2 O CH 2 0 CH 2 3-phenylpropyl 3,3-dimethylpentyl 78 CH 2

CH

2 S CH 2 0 CH 2 3-phenylpropyl 3,3-dimethylpentyl The compounds of this invention possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual stereoisomers. The individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compound of formula It is understood that the individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers are encompassed by the scope of the present invention. The compounds of this invention possess at least one asymmetric center and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers. The individual enantiomers may be obtained by resolving a racemic or 15 non-racemic mixture of an intermediate at some appropriate stage of the synthesis. It is understood that the individual R- and S- stereoisomers as well as mixtures of stereoisomers are encompassed by this invention. The Sstereoisomer is most preferred due to its greater 20 activity.

Methods of Using the Compounds of the Invention The compounds of the present invention have an affinity for the FK506 binding protein, particularly FKBP12, which is present in the brain. When the inventive compounds bind to FKBP in the brain, they exhibit excellent neurotrophic activity. This activity is useful in the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathies.

For the foregoing reasons, the present invention further relates to a method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula I, II, III or

IV.

In a preferred embodiment, the neuronal activity is selected from the group consisting of stimulation of 15 damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

The neurological disorders that may be 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; herniated, ruptured or prolapsed invertebrate disk syndromes; cervical spondylosis; plexus disorders; thoracic outlet destruction syndromes; peripheral neuropathies such as those caused by lead, dapsone, ticks, porphyria or Guillain-Barr& syndrome; Alzheimer's disease; and Parkinson's disease.

The compounds of the present invention are particularly useful for treating a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

Examples of neurological disorders relating to neurodegeneration are Alzheimer's Disease, Parkinson's Disease and amyotrophic lateral sclerosis.

For these purposes, the compounds may be administered 15 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 compounds should readily penetrate the blood-brain barrier when peripherally administered.

Compounds which cannot penetrate the blood-brain barrier can be effectively administered by an intraventricular route.

The compounds may be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally-acceptable diluents or solvents, for example, as solutions in 1,3-butanediol.

Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium .ol• chloride solution. In addition, sterile, fixed oils are e conventionally employed as solvents or suspending mediums. For this purpose, any bland fixed oil such as a synthetic mono- or di-glyceride may be employed. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their polyoxyethylated versions, are useful in the preparation of injectables. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

Additionally, the compounds may be administered orally in the form of capsules, tablets, aqueous suspensions or solutions. Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate. Capsules may contain diluents including lactose and dried corn starch. Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient. The oral dosage forms may further contain sweetening and/or flavoring and/or coloring agents.

The compounds may also be administered rectally in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable nonirritating 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.

15 Furthermore, the compounds may be administered topically, especially when the conditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin or the lower intestinal tract.

Suitable topical formulations can be readily prepared for each of these areas.

For topical application to the eye, or ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as a solution in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, the compounds may be formulated into ointments, such as petrolatum, for ophthalmic use.

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

Topical application to the lower intestinal tract can be effected in a rectal suppository formulations (see above) or in suitable enema formulations.

Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It is understood, however, that a specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration.

The compounds can be administered with other 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 and the neurotrophic effectiveness of the drug combination.

**o Pharmaceutical Compositions of the Invention The present invention also relates to a pharmaceutical 20 composition comprising: a neurotrophically effective amount of the compound of formula I, II, III or IV, and (ii) a pharmaceutically acceptable carrier.

The above discussion relating to the utility and administration of the compounds of the present invention also applies to the pharmaceutical compositions of the present invention.

Examples The following examples are illustrative of the present invention and are not intended to be limitations thereon.

Unless otherwise specified, all percentages are based on 100% by weight of the final compound.

EXAMPLE 1 Synthesis of (2S)-2-(1-oxo-5-phenyl)-pentyl-1-(3,3dimethyl-1,2-dioxopentyl)pyrrolidine (1) (2S)-2-(l-oxo-5-phenyl)pentyl-N-benzylpvrrolidine. 1chloro-4-phenylbutane (1.78 g; 10.5 mmol) in 20 mL of THF was added to 0.24 g (10 mmol) of magnesium turnings in 15 mL of refluxing THF. After the addition was complete, the mixture was refluxed for an additional 5 hours, and then added slowly to a refluxing solution of N-benzyl-Lproline ethyl ester (2.30 g (10 mmol) in 100 mL of THF.

After 2 hours of further reflux, the mixture was cooled and treated with 5 mL of 2 N HC1. The reaction mixture was diluted with ether (100 mL) and washed with saturated NaHCO 3 water and brine. The organic phase was dried, concentrated and chromatographed, eluting with 5:1 CHC21:EtOAc to obtain 2.05 g of the ketone as an oil, 'H NMR (CDC13; 300 MHz): 1.49-2.18 8H); 2.32- 2.46 1H); 2.56-2.65 2H); 2.97-3.06 1H); 3.17- 3.34 (in, 1H); 3.44-3.62 (in, 1H); 4.02-4.23 (in, 2H); 7.01- 7.44 (in, (2S) -2-(l-oxo-5-phenvl)rentylP~rroidile. The ketone compound (500 mg) and palladium hydroxide (20% on carbon, 50 mng) was hydrogenated at 40 psi in a Paar shaker overnight. The catalyst was removed by filtration and the solvent was removed in vacuo. The free amine was obtained as a yellow oil (230 mg; 100%), 1 H NMR (CDCl 3 300 MHz): 1.75-2.34 (in, 10H); 2.55 (mn, 2H); 2.95 (dmn, 1H); 3.45-3.95 (mn, 1H); 4.05 (in, 1H); 7.37 (mn, (2S)-2-(l-oxo-5-phenvl)pentvl--(1,2dioxo- 2 methoxvethyl)Pyrrolidile. To a solution of oxo- 5-phenyl) pent ylpyrrol idine (230 ing; 1.0 mrnol) in

CH

2 Cl 2 (20 inL) at 0 0 C was added dropwise iethyloxalyl chloride (135 ing; 1.1 minol). After stirring at 0 0 C for 3 hours, the reaction was quenched with saturated NH 4 Cl and the organic phase was washed with water and brine and dried and concentrated. The crude residue was purified on a silica gel column, eluting with 20:1 CH 2 C1 2 :EtOAc to obtain 300 mg of the oxamate as a clear oil 'H NMR ***(CDCl 3 300 MHz): 1.68 (in, 4H); 1.91-2.38 4H); 2.64 2H) 3. 66-3. 80 (mn, 2H) 3. 77, 3. 85 3H total); 4. 16 (in, 2 H) 4. 90 (in, 1 H) 7. 16 (in, 3 H) 7. 27 (in, 2 H).

(2S) -oxo-5-phenyll-pentyl-l 3-dimethl-1, 2dioxopentyl)ipvrrolidine To a solution of the oxamate above (250 mg; 0.79 iniol) in anhydrous ether mL), cooled to 78 0 C, was added 1,1-dimethylpropylmagnesium chloride (0.8 mL of a 1.0 M solution in ether; 0.8 mmol). After stirring the resulting mixture at -78 0

C

for 2 hours, the reaction was quenched by the addition of 2 mL of saturated NH 4 C1, followed by 100 mL of EtOAc.

The organic phase was washed with brine, dried, concentrated, and purified on a silica gel column, eluting with 50:1 CH 2 Cl 2 :EtOAc. Compound 1 was obtained as a clear oil, 120 mg, 'H NMR (CDC13, 300 MHz): 6 0.87 3H, J= 7 1.

2 2 3H); 1.25 3H); 1.67 4H); 1.70-2.33 6H); 2.61 2H, 3.52 2H); 4.17 2H, J=6.

2 4.52 1H); 7.16-7.49 5H). Anal.

Calcd. for C 2 2

H

31

NO

3

H

2 0: C, 70.37; H, 8.86; N, 3.73.

Found: 70.48; H, 8.35; N, 3.69.

As discussed above, the compounds of the present invention have an affinity for the FK506 binding protein, particularly FKBP12. The inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP may be 20 measured as an indicator of this affinity.

K

i 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 et al., Nature, 1989, 341:758-760; Holt et al. J. Am. Chem.

Soc., 115:9923-9938). These values are obtained as apparent Ki's and are presented for representative compounds in Table IV. The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl- Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent K i 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 NaC1, 1 mM 15 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-Phepara-nitroanilide, 5 mg/mL in 2.35 mM LiCl in 20 trifluoroethanol).

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

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

Chick Dorsal Root Ganglion Cultures and Neurite Outgrowth The neurotrophic effects of the FKBP inhibitor compounds were demonstrated by evaluating the ability of the compounds to promote neurite outgrowth in cultured chick sensory neurons from dorsal root ganglia. 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 15 plus high glucose media supplemented with 2 mM glutamine and 10% fetal calf serum, and also containing 10 pM cytosine B-D arabinofuranoside (Ara C) at 370C in an environment containing 5% CO2. 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 explants were made, and neurite outgrowth was quantitated. Neurites longer than the DRG diameter were counted as positive, with total number of neurites quantitated per each experimental condition. Three to four DRGs are cultured per well, and each treatment was performed in duplicate.

Dose-response curves were generated from which EDo 0 values were obtained. The results of these experiments are presented in Table IV under the column Representative photomicrographs of untreated (control) sensory neurons and of compounds 1 (10 pM, 1 nM, 1 pM), 9 (10 pM, 1 nM, 100 nM) and 10 (10 pM, 1 nM, 100 nM) promoting neurite outgrowth in sensory neurons are shown in FIG.'s 2(A-D) and respectively.

MPTP Model of Parkinson's Disease 15 The remarkable neurotrophic and neuroregenerative effects of the present inventive compounds were further demonstrated in an animal model of neurodegenerative disease. MPTP lesioning of dopaminergic neurons in mice was used as an animal model of Parkinson's Disease. Four week old male CD1 white mice were dosed i.p. with mg/kg of MPTP for 5 days. Test compounds (4 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. Immunostaining was performed on saggital and coronal brain sections using anti-tyrosine hydroxylase 1 g 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 nonlesioned animals. Lesioned animals receiving test compounds showed a significant recovery of TH-stained dopaminergic neurons.

The results of these experiments are presented in TABLE IV under the column TH recovery". Quantitation for the recovery of TH-positive dopaminergic neurons in the striatum of animals receiving compounds 1, 9 and and for representative control and lesioned animals not receiving the test drugs, are presented in FIG. 4.

TABLE IV In Vitro Test Results Example Ki, nM ED50, nM TH recovery 1 31 0.4 23 2 210 3 85 66 306 5 38 67 177 68 284 69 49 23 457 71 788 All publications and patents identified above are hereby incorporated by reference.

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

6*69.0 Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.

Claims (53)

1. A compound of formula I: A' Z'R "\R 1 X WX R2 or a pharmaceutically acceptable salt thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH 2 O, S, SO, SO 2 NH, or NR 2 in any chemically stable oxidation state; 10 X is either O or S; Z is selected from the group consisting of CH 2 CHRI, or C(Ri)2; W and Y are independently O, S, CH 2 or H 2 RI is selected from the group consisting of: -CI-C 6 straight or branched chain alkyl substituted in one or more 15 position(s) with (Ari)n, -C 2 -C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl)n, -C 3 -C 8 cycloalkyl, -CI-C 8 cycloalkyl connected by a CI.C 6 straight or branched chain alkyl or a C 2 -C 6 straight or branched 21/06/04,atl2226.specipgs.doc.2 -37- chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -Ci-C 9 straight or branched chain alkyl, -C 2 -C 9 straight or branched chain alkenyl, -C 3 -C 8 cycloalkyl, -C 5 -C 7 cycloalkenyl, and -Arl, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C,-C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C,-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic -38- ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; provided that when Z is CH2, Ri is ethyl, X is 0, and A and B are taken together to form a piperidine ring, then R 2 is not 1,1- dimethylpropyl.

2. The compound of claim 1, wherein said Ar and Ar 2 are independently selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.

3. A compound of formula II: Z(CH 2 )n N z R I R 1 O X R2 or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; X is O or S; Z is selected from the group consisting of CH 2 CHRi, and C(R) )2; RI is selected from the group consisting of: -C 1 -C 5 straight or branched chain alkyl, -39- -C 2 -C 5 straight or branched chain alkenyl, and -Ari, wherein said R, is unsubstituted or substituted in one or more positions with halo, nitro, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, hydroxy, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, Arl, or a combination thereof; R 2 is selected from the group consisting of: -CI-C 9 straight or branched chain alkyl, -C 2 -C 9 straight or branched chain alkenyl, -C 3 -C 8 cycloalkyl, -C 5 -C 7 cycloalkenyl, and -Arl, rI Arl is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Cl-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; provided that when Z is CH 2 R, is ethyl, X is 0, and n is 2, then R 2 is not 1,1-dimethylpropyl.

4. The compound of claim 3, wherein: n is 1; and X is 0. The compound of claim 4, wherein Z is CR 2

6. The compound of claim 5, which is selected from the group consisting of: (2S) (l-Oxo-5-phenyl) pentyl-l- 3-dimethyl-1, 2- dioxopentyl) pyrrolidine; 3,3-Dimethyl-1-[(2S)-l-(5-(3-pyridyl)pentanoyl)-l- P~pyrrolidine] 2-pentanedione; (2S)-2-(1-Oxo-4-phenyl)butyl-1-(3,3-dimethyl-1,2- dioxobutyl) pyrrolidine; (2S) 1-Oxo-4-phenyl )butyl-1- (2-cyclohexyl) -1,2- dioxoethyl)pyrrolidine; 2- (1-Oxo-4-phenyl) butyl-l- 3-dimethyl-1, 2- dioxobutyl)pyrrolidine; and (2S)-2-[5,5-di (4-Fluorophenyl)pentanoyl]-2-pyrrolidine}- 3, 3-dimethyl-1, 2-pentanedione.

7. The compound of claim 3, wherein: n is 2; and X is 0. -41

8. The compound of claim 7, wherein Z is CR 2

9. The compound of claim 8, which is selected from the group consisting of: 2- 1-Oxo-6-phenyl I-hexyl-l- 3-dimethyl-l, 2-dioxobutyl) piperidine; 3,3-Dimethyl-l- (4-phenylbutanoyl)piperidino]-1,2- pentanedione; and 3, 3-Dimethyl-l- (5-phenylpentanoyl)piperidino] -1,2- pentanedione. The compound of claim 7, wherein Z is CHRj.

11. The compound of claim 10, which is selected from the group consisting of: 2-({1-Oxo-[2-{2'-phenyllethyllj-4-phenyl}-butyl-l-(3,3- dimethyl-l, 2-dioxobutyl) piperidine.

12. A compound which is 3,3-Dimethyl-l-((2S)-2-(5-(3- pyridyl)pentanoyl)-1-pyrrolidine]-1,2-pentanedione.

13. A compound which is 2-(1-Oxo-4-phenyl)butyl-l-(3,3- dimethyl-1, 2-dioxobutyl) pyrrolidine. -42-

14. A compound of formula III: B-C A Z.RI O X III R2 or a pharmaceutically acceptable salt thereof, wherein: A, B, and C are independently CH2, O, S, SO, SO 2 NH, or NR 2 X is O or S; Z is selected from the group consisting of CH2, CHRi, and C(Ri) 2; RI is selected from the group consisting of: -C 1 straight or branched chain alkyl substituted in one or more position(s) with (Arl)n, -C 2 -C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl), -C 3 cycloalkyl, -C 3 -C 8 cycloalkyl connected by a Cl-C 6 straight or branched chain alkyl or a C 2 -C 6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -Cj-C 9 straight or branched chain alkyl, -43- -C 2 -C 9 straight or branched chain alkenyl, -C3-C, cycloalkyl, -C5-C7 cycloalkenyl, and -Ar, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C 4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar, are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, Ci-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof. The compound of claim 14, wherein the compound is 2-(3-Phenylpropanoyl)-1-(3,3-dimethyl-l,2-dioxopentyl)-(4- -44- thiazolidine).

16. A compound of formula IV: C B/ 'D A Z II R IV O X 0 R2 or a pharmaceutically acceptable salt thereof, wherein: A, B, C, and D are independently CH 2 O, S, SO, SO2, NH, or NR 2 X is O or S; 4. Z is selected from the group consisting of CH 2 CHRi, and C (Ri) 2; RI is selected from the group consisting of: straight or branched chain alkyl substituted in one or more position(s) with (Arl), -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl), -C3-C, cycloalkyl, -C3-C, cycloalkyl connected by a C-C6 straight or branched chain alkyl or a Cz-C, straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -Ci-C 9 straight or branched chain alkyl, -C 2 -C 9 straight or branched chain alkenyl, -C 3 -C 8 cycloalkyl, -C 5 -C 7 cycloalkenyl, and -Ari, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar 1 and Ar 2 are independently a mono-, bi-, or tricyclic, S: carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; -46- provided that when Z is CH2, Ri is ethyl, X is O, and A, B, C, and D are all CH2, then R 2 is not l,l-dimethylpropyl.

17. The compound of claim 16, selected from the group consisting of: 2-(l-Oxo-5-phenyl)pentyl-l-(3,3-dimethyl-l,2-dioxopentyl) morpholine; and 2 -(l-Oxo-5-phenyl)pentyl-l-(3,3-dimethyl-l,2-dioxopentyl) thiomorpholine.

18. A pharmaceutical composition comprising: an effective amount of a compound of formula I: A Z R2 or a pharmaceutically acceptable salt thereof, wherein: A and B, together with the nitrogen and carbon atoms to Swhich they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2 O, S, SO, SO NH, or NR 2 in any chemically stable oxidation state; -47- X is either O or S; Z is selected from the group consisting of CH 2 CHRi, or C(RI)2; W and Y are independently O, S, CH 2 or H 2 RI is selected from the group consisting of: -Ci-C 6 straight or branched chain alkyl substituted in one or more position(s) with (Arj)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Arj), -C3-C, cycloalkyl, -C3-C 8 cycloalkyl connected by a Ci-C, straight or branched chain alkyl or a C2-C 6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -Ci-C9 straight or branched chain alkyl, C9 straight or branched chain alkenyl, -C3-C cycloalkyl, -Cs-C cycloalkenyl, and -Ar 1 wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C-C4 -48- straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Arl and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising: an effective amount of a compound of formula II: (CH 2 )n -1 N R I o x or a pharmaceutically acceptable salt thereof, wherein: -49- n is 1 or 2; X is O or S; Z is selected from the group consisting of CH 2 CHRi, and C(Ri) 2; R, is selected from the group consisting of: -Ci-Cs straight or branched chain alkyl, -C 2 -C 5 straight or branched chain alkenyl, and -Arl, wherein said R, is unsubstituted or substituted in one or more positions with halo, nitro, Cl-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, hydroxy, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, Ari, or a combination thereof; R 2 is selected from the group consisting of: -Ci-C 9 straight or branched chain alkyl, -C*-C 9 straight or branched chain alkenyl, -C 3 -C 8 cycloalkyl, -C 5 -C 7 cycloalkenyl, and -Ar, Ar, is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ari is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C,-C 6 straight or branched chain alkyl, 50 C 2 -C 6 straight or branched chain alkenyl, Cl-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; and (ii) a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 19, wherein said compound is selected from the group consisting of: (2S) (1-Oxo-5-phenyl) pentyl-l- 3-dimethyl-l, 2- dioxopentyl) pyrrolidine; 3,3-Dimethyl---[ (2S)-1-(5-(3-pyridyl)pentanoyl)-1- pyrrolidine] 2-pentanedione; (2S)-2-(1-Oxo-4-phenyl)butyl-l-(3,3-dimethyl-l,2- dioxobutyl) pyrrolidine; (2S) ({l-Oxo-4-phenyl }butyl-l- (2-cyclohexyl) -1,2- dioxoethyl)pyrrolidine; 2-(l-Oxo-4-phenyl)butyl-1-(3,3-dimethyl-1,2- dioxobutyl)pyrrolidine; (2S)-2-[5,5-di(4-E'luorophenyl)pentanoyl]-2-pyrrolidine}- 3, 3-dimethyl-1, 2-pentanedione; 2-({1-Oxo-6-phenyl}-hexyl-1-(3,3-dimethyl-1,2-dioxobutyl) piperidine; 3, 3-Dimethyl-1- (4-phenylbutanoyl)piperidino] -1,2- pentanedione; 3, 3-Dimethyl-1- (5-phenylpentanoyl) piperidino] 2- -51- pentanedione; and 2-({l-Oxo-[2-{2'-phenyl}ethyl]-4-phenyl}-butyl-l-(3,3- dimethyl-1,2-dioxobutyl)piperidine.

21. A pharmaceutical composition comprising: an effective amount of a compound of formula III: B-C A Z X III 00 R2 or a pharmaceutically acceptable salt thereof, wherein: SA, B, and C are independently CH2, O, S, SO, SO 2 NH, or NR 2 X is O or S; Z is selected from the group consisting of CH 2 CHRi, and C(Ri) 2; S• RI is selected from the group consisting of: -Ci-C 6 straight or branched chain alkyl substituted in one or more position(s) with (Arl)n, -C 2 -C 6 straight or branched chain alkenyl substituted in one or mo: position(s) with (Ari)n, -C 3 -C 8 cycloalkyl, -C 3 -C 8 cycloalkyl connected by a Ci-C 6 straight or branched chain alkyl or a C 2 -C 6 straight or branched -52- chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -CI-C 9 straight or branched chain alkyl, -C 2 -C 9 straight or branched chain alkenyl, -C 3 -C 8 cycloalkyl, -C 5 -C7 cycloalkenyl, and -Arl, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C 1 -C 4 *t straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, Ci-C4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are members; and wherein the heterocyclic -53- ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.

22. The pharmaceutical composition of claim 21, wherein said compound is 2-(3-Phenylpropanoyl)-l-(3,3-dimethyl-l,2- dioxopentyl)-(4-thiazolidine).

23. A pharmaceutical composition comprising: an effective cmount of a compound of formula IV: C B 'D IIV O X Z 9* 9 0o or a pharmaceutically ccceptable salt thereof, wherein: 0 A, B, C, and D arc independently CH 2 O, S, SO, SO 2 NH, or NR 2 X is 0 or S; Z is selected fro. the group consisting of CH 2 CHRi, and C(RI) 2; RI is selected from the group consisting of: -C1-C6 straig ,t or branched chain alkyl substituted in one or more *osition(s) with -54- -C 2 -C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arj),, -C 3 cycloalkyl, -C 3 -C 8 cycloalkyl connected by a Ci-C 6 straight or branched chain alkyl or a C 2 -C 6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -Ci-C 9 straight or branched chain alkyl, -C-2C 9 straight or branched chain alkenyl, -C 3 -C 8 cycloalkyl, -C 5 -C 7 cycloalkenyl, and Arl, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C 1 -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar 1 and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23, wherein said compound is selected from the group consisting of: 2-(l-Oxo-5-phenyl)pentyl1--(3,3-dimethyl-1,2-dioxopentyl) morpholine; and 2-(l-Oxo-5-phenyl)pentyl-l- (3,3-dimethyl-1,2-dioxopentyl) thiomorpholine.

25. The pharmaceutical composition according to any of to claims 18-24, further comprising one or more additional S* neurotrophic agent(s). *o

26. The pharmaceutical composition of claim 25, wherein said one or more additional neurotrophic agent(s) is/are independently selected from the group consisting of neurotrophic growth factor (NGF), glial derived growth factor, brain derived -56- growth factor, ciliary neurotrophic factor and neurotropin- 3

27. The pharmaceutical composition of claim 26, wherein said one or more additional neurotrophic agent(s) is neurotrophic growth factor (NGF).

28. A method for effecting a neuronal activity in an animal comprising: administering to the animal an effective amount of a compound of formula I: A N Z N Z R .W R 2 or a pharmaceutically acceptable salt thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered *saturated or unsaturated heterocyclic ring containing any combination of CH 2 O, S, SO, SO2, NH, or NR 2 in any chemically stable oxidation state; X is either O or S; Z is selected from the group consisting of CH 2 CHRi, or C(R) 2; -57- W and Y are independently O, S, CH 2 or H 2 R, is selected from the group consisting of: -Cl-C 6 straight or branched chain alkyl substituted in one or more position(s) with (Arl),, -C 2 -C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl), -C 3 -C 8 cycloalkyl, -C 3 -C 8 cycloalkyl connected by a Cl-C 6 straight or branched chain alkyl or a C 2 -C 6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: straight or branched chain alkyl, -C-C 9 straight or branched chain alkenyl, *S -C 3 -C 8 cycloalkyl, -C 5 cycloalkenyl, and -Ari, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with CI-C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and -58- Ari and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, CI-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.

29. A method for effecting a neuronal activity in an animal, comprising: administering to the animal an effective amount of a compound of formula II: (CH2)n N "RI 0 X 0 II or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; X is 0 or S; -59- Z is selected from the group consisting of CH 2 CHRi, and C(Ri) 2; RI is selected from the group consisting of: straight or branched chain alkyl, -C-2-C straight or branched chain alkenyl, and -Ar wherein said Ri is unsubstituted or substituted in one or more positions with halo, nitro, C,-C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, hydroxy, C,-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Arl, or a combination thereof; R 2 is selected from the group consisting of: -Ci-C, straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C 5 -C 7 cycloalkenyl, and -Ar, Ari is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar 1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, Cl-C, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Cl-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof. The method of claim 29, wherein said compound is selected from the group consisting of: (2S) (1-Oxo-5-phenyl) pentyl-l- 3-dimethyl-1, 2- dioxopentyl) pyrrolidine; pyrrolidine] 2-pentanediole; (2S) (l-Oxo-4-phenyl) butyl-1- 3-dimethyl-1, 2- dioxobutyl) pyrrolidine; (2S) -Oxo-4-phenyl }butyl-l- (2-cyclohexyl) -1,2- dioxoethyl) pyrrolidine; 2- (l-Oxo-4-phenyl) butyl-1- 3-dimethyl-1, 2- **dioxobutyl)pyrrolidile; 4. (2S) -2-[15,5-di (4-Fluorophenyl)pentafloyl-2pyrrolidineV- 3, 3-dimethyl-l, 2-pentanedione; 2- ({l-Oxo-6-phenyl}-hexylil (3,3-dimethyl-1,2-dioxobutyl) pipe ridine; 3, 3-Dimethyl-1- (4-phenylbutanoyl) piperidino] -1,2- pentanedione; 3, 3-Dimethyl-1- (5-phenylpentanoyl) piperidino] -1,2- pentanedione; and 2-(1Oxo-[2-{2'-phenyllethyl]-4-pheryl-butyll( 3 3 dimethyl-1, 2-dioxobutyl)piperidine. -61-

31. A method for effecting a neuronal activity in an animal, comprising: administering to the animal an effective amount of the compound of formula III: B-C A Z O X III 0 R2 or a pharmaceutically acceptable salt thereof, wherein: A, B, and C are independently CH2, O, S, SO, SO 2 NH, or NR 2 X is O or S; Z is selected from the group consisting of CH 2 CHR 1 and is selected from the group consisting of: -Cl-C 6 straight or branched chain alkyl substituted in one or more position(s) with (Arl)n, in one or more position(s) with (Arl), *-C 3 cycloalkyl, -C 3 cycloalkyl connected by a C 1 -C 6 straight or S* branched chain alkyl or a C 2 -C 6 straight or branched chain alkenyl, and -Ar 2 -62- n is 1 or 2; R 2 is selected from the group consisting of: -CI-C 9 straight or branched chain alkyl, -C 2 -C 9 straight or branched chain alkenyl, -C 3 -C 8 cycloalkyl, -C 5 -C 7 cycloalkenyl, and -Ari, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted Sin one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, CI-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof. -63-

32. The method of claim 31, wherein said compound is 2-(3- Phenylpropanoyl)-1-(3,3-dimethyl-1,2-dioxopentyl)-(4- thiazolidine)

33. A method for effecting a neuronal activity in an animal comprising: administering to the animal an effective amount of the compound of formula IV: C B D AN ZRI 0 X 0 R 2 or a pharmaceutically acceptable salt thereof, wherein: A, B, C, and D are independently CH2, O, S, SO, SO 2 NH, or NR 2 X is O or S; Z is selected from the group consisting of CH 2 CHRi, and C(R )2; R, is selected from the group consisting of: -Ci-C 6 straight or branched chain alkyl substituted in one or more position(s) with (Arl)n, -C--C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl), -64- -C 3 -C 8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -Ci-C 9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C, cycloalkyl, -C 5 cycloalkenyl, and -Arl, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl. is either unsubstituted or substituted in one or more position(s) with C 1 -C 4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.

34. The method of claim 33, wherein said compound is selected from the group consisting of: 2-(l-Oxo-5-phenyl)pentyl-l-(3,3-dimethyl-l,2-dioxopentyl) morpholine; and 2-(l-Oxo-5-phenyl)pentyl-l-(3,3-dimethyl-l,2-dioxopentyl) thiomorpholine.

35. The method according to any of claims 28-34, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration, and treatment of neurological disorder.

36. The method of claim 35, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating -66- to neurodegeneration.

37. The method of claim 36, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral scelerosis.

38. Use of a compound for treating a disease in an animal, wherein the compound is of formula I: A 1' ZR SRR 2 or a pharmaceutically acceptable salt thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH 2 O, S, S, S,02, NH, or NR 2 in any chemically stable oxidation state; X is either O or S; Z is selected from the group consisting of CH 2 CHR 1 or C(Ri)2; W and Y are independently O, S, CH2, or H 2 -67- RI is selected from the group consisting of: -C1-C, straight or branched chain alkyl substituted in one or more position(s) with (Arj)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Arj)n, -C3-C, cycloalkyl, -C3-C, cycloalkyl connected by a C 1 -C 6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: S-C: -C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C, cycloalkyl, cycloalkenyl, and -Ar 1 wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar, and Ar 2 are independently a mono-, bi-, or tricyclic, -68- carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Ci-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.

39. Use of a compound for treating a disease in an animal, S wherein the compound is of formula II: N R1 O: 0 X 0 X R2 II or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; X is O or S; Z is selected from the group consisting of CH2, CHRi, and C(Ri)2; RI is selected from the group consisting of: -69- -Ci-C 5 straight or branched chain alkyl, -C 2 -C 5 straight or branched chain alkenyl, and -Ari, wherein said R, is unsubstituted or substituted in one or more positions with halo, nitro, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, hydroxy, Ci-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, Arl, or a combination thereof; R 2 is selected from the group consisting of: -Cj-C 9 straight or branched chain alkyl, -C-C 9 straight or branched chain alkenyl, -C 3 -C 8 cycloalkyl, -C 5 -C7 cycloalkenyl, and -Ari, Ar 1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ari is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, alkoxy, "99* C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof. The use of claim 39, wherein said compound is selected 70 from the group consisting of: (2S) (l-Oxo-5-phenyl)peltYl-l- 3-dimethyl-1, 2- dioxopentyl) pyrrolidiie; 3, 3-Dimethyl-1- II(2S) (3-pyridyl) pentanoyl) -1- pyrrolidine] 2-pentanedione; (2S) (l-Oxo-4-pheflyl)butylil 3-dimethyl-1, 2- dioxobutyl) pyrrolidine; (2S) {-Oxo-4-phenyllbutYl-l (2-cyclohexyl) -1,2- dioxoethyl) pyrrolidine; 2- (l-Oxo-4-phenyl)butyl-l- 3-dimethyl-1, 2- dioxobutyl) pyrrolidine; (2S)-2-[5,5-di(4-Fluorophenyl)pentafoyl-2-pyrrolidinl- 3,3-dimethyl-1,2-peltanedione; piperidine; 3, 3-Dimethyl-1- (4-phenylbutanoyl) piperidino] -1,2- pentanedione; 3, 3-Dimethyl-1- (5-phenylpentaloyl) piperidino] -1,2- pentanedione; and 2-({1-Oxo-[2-{2'-phenyl}ethyl]-4-phefyly1butyl-l-( 3 3 dimethyl-l, 2-dioxobutyl) pipericiine.

41. Use of a compound for treating a disease in an animal, wherein the compound is of formula III: -71- I I III °0 x R2 or a pharmaceutically acceptable salt thereof, wherein: A, B, and C are independently CH 2 O, S, SO, SO 2 NH, or NR 2 X is O or S; Z is selected from the group consisting of CH 2 CHRi, and C(Ri) 2; RI is selected from the group consisting of: -Ci-C 6 straight or branched chain alkyl substituted in one or more position(s) with (Arl)n, e C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl)n, -C 3 cycloalkyl, -C 3 -C 8 cycloalkyl connected by a Cl-C 6 straight or branched chain alkyl or a C 2 -C 6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -C,-C 9 straight or branched chain alkyl, -C 2 -C 9 straight or branched chain alkenyl, -72- -C 3 -C 8 cycloalkyl, -C 5 -C7 cycloalkenyl, and -Ari, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Arl and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted *ee: 0 •in one to three position(s) with halo, hydroxyl, nitro, S trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ~ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof. 9 9 9

42. The use of claim 41, wherein said compound is 2-(3- Phenylpropanoyl)-1-(3,3-dimethyl-1,2-dioxopentyl)-(4- thiazolidine). -73-

43. Use of a compound for treating a disease in an animal, wherein the compound is of formula IV: C B 'D I IV 0 X 0 R2 or a pharmaceutically acceptable salt thereof, wherein: A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR 2 X is O or S; Z is selected from the group consisting of CH 2 CHRI, and C(Ri) 2; R, is selected from the group consisting of: -Ci-C 6 straight or branched chain alkyl substituted in goS one or more position(s) with (Arl)n, -C 2 -C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl)n, -C 3 cycloalkyl, 05 ~-C 3 -C 8 cycloalkyl connected by a Ci-C 6 straight or branched chain alkyl or a C 2 -C 6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; -74- R 2 is selected from the group consisting of: -CI-C 9 straight or branched chain alkyl, -C-2C 9 straight or branched chain alkenyl, -C 3 cycloalkyl, -C 5 -C 7 cycloalkenyl, and -Arl, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C 1 -C 4 straight or branched chain alkyl, C 2 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, Ci-C 6 straight or branched chain alkyl, C,-C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.

44. The use of claim 43, wherein said compound is selected from the group consisting of: 2-(l-Oxo-5-phenyl)pentyl-l-(3,3-dimethyl-l,2-dioxopentyl) morpholine; and 2-(l-Oxo-5-phenyl)pentyl-l-(3,3-dimethyl-l,2-dioxopentyl) thiomorpholine. Use of a compound for effecting a neuronal activity in an animal, wherein the compound is of formula I: B A.Z R R2 R2 combination of CH 2 O, S SSO, SO2, NH, or NR 2 in any o chemically stable oxidation state; X is either O or S; Z is selected from the group consisting of CH2t CHR 1 or C(Rj),; W and Y are independently O, S, Cd 2 or H 2 W and Y are independently O, S, CH 2 or H2; -76- RI is selected from the group consisting of: -Ci-C 6 straight or branched chain alkyl substituted in one or more position(s) with (Arl)n, -C 2 -C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl)n, -C 3 -C 8 cycloalkyl, -C 3 -C 8 cycloalkyl connected by a Ci-C 6 straight or branched chain alkyl or a C 2 -C 6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; R 2 is selected from the group consisting of: -C,-C 9 straight or branched chain alkyl, -C-2C 9 straight or branched chain alkenyl, -C 3 cycloalkyl, -C 5 -C cycloalkenyl, and -Ari, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C 1 -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar 2 are independently a mono-, bi-, or tricyclic, -77- carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Ci-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.

46. Use of a compound for effecting a neuronal activity in an animal, wherein the compound is of formula II: N R 0 X O R2 II ~or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; X is 0 or S; Z is selected from the group consisting of CH 2 CHRi, and C(Ri)2; R, is selected from the group consisting of: -78- -Ci-C 5 straight or branched chain alkyl, -C 2 -C 5 straight or branched chain alkenyl, and -Ari, wherein said R, is unsubstituted or substituted in one or more positions with halo, nitro, Ci-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, hydroxy, Cl-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, Ari, or a combination thereof; R 2 is selected from the group consisting of: -Ci-C 9 straight or branched chain alkyl, -C-C 9 straight or branched chain alkenyl, -C 3 cycloalkyl, -C 5 -C 7 cycloalkenyl, and -Ari, SAri is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar 1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, CI-C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, CI-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof.

47. The use of claim 46, wherein said compound is selected 79 from the group consisting of: (2S) (1-Oxo-5-phenyl) pentyl-l- 3-dimethyl-1, 2- dioxopentyl) pyrrolidine; 3, 3-Dimethyl-l- (3-pyridyl) pentanoyl) -1- pyrrolidine] 2-pentanedione; (2S) (1-Oxo-4-phenyl) butyl-l- 3-dimethyl-l, 2- dioxobutyl) pyrrolidine; (2S) {1-Oxo-4-phenyl }butyl-l- (2-cyclohexyl) -1,2- dioxoethyl) pyrrolidine; 2- (l-Oxo-4-phenyl) butyl-l- 3-dimethyl-1, 2- dioxobutyl) pyrrolidine; (2S)-2-I5,5di(4-Fuorophenyl)pentanoyl]-2-pyrrolidine}- a. 3, 3-dimethyl-1, 2-pentanedione; 2- -Oxo-6-phenyl)I-hexyl-l- 3-dimethyl-l, 2-dioxobutyl) piperidine; 3, 3-Dimethyl-l- (4-phenylbutanoyl) piperidino] -1,2- pentanedione; 3, 3-Dimethyl-l- (5-phenylpentanoyl) pipericino] -1,2- pentanedione; and 2-({1-Oxo-[2-{2'-phenyl~ethyl-4phenyly1butylli 3 3 dimethyl-1, 2-dioxobutyl) piperidine.

48. Use of a compound for effecting a neuronal activity in an animal, wherein the compound is of formula III: B-C A Z O X III R2 or a pharmaceutically acceptable salt thereof, wherein: A, B, and C are independently CH 2 O, S, SO, SO2, NH, or NR 2 X is O or S; Z is selected from the group consisting of CH 2 CHRi, and C(RI)2; RI is selected from the group consisting of: -Cl-C 6 straight or branched chain alkyl substituted in one or more position(s) with (Arl), C 2 -C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arj)n, -C 3 -C 8 cycloalkyl, -C 3 -C 8 cycloalkyl connected by a Ci-C straight or branched chain alkyl or a C 2 -C 6 straight or branched chain alkenyl, and -Ar 2 .n is 1 or 2; R 2 is selected from the group consisting of: -CI-C 9 straight or branched chain alkyl, -C-C 9 straight or branched chain alkenyl, -81 -C 3 cycloalkyl, -C 5 cycloalkenyl, and -Arl, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.

49. The use of claim 48, wherein said compound is 2-(3- Phenylpropanoyl)-1-(3,3-dimethyl-l,2-dioxopentyl)-(4- thiazolidine). -82- Use of a compound for effecting a neuronal activity in an animal, wherein the compound is of formula IV: C B 'D A 1 IV R2 or a pharmaceutically acceptable salt thereof, wherein: A, B, C, and D are independently CH 2 O, S, SO, SO2, NH, or NR 2 X is O or S; Z is selected from the group consisting of CH 2 CHRi, and .c(Ri) 2 R, is selected from the group consisting of: -Cl-C6 straight or branched chain alkyl substituted in one or more position(s) with (Arl)n, -C 2 -C 6 straight or branched chain alkenyl substituted in one or more position(s) with (Arl)n, -C3-C, cycloalkyl, -C3-C cycloalkyl connected by a CI-C, straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar 2 n is 1 or 2; -83- R 2 is selected from the group consisting of: straight or branched chain alkyl, -C2-C, straight or branched chain alkenyl, -C3-C, cycloalkyl, cycloalkenyl, and -Arl, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with Ci-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ari and Ar 2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, CI-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof. -84-

51. The use of claim 50, wherein said compound is selected from the group consisting of: 2-(l-Oxo-5-phenyl)pentyl-l-(3,3-dimethyl-1,2-dioxopentyl) morpholine; and 2-(l-Oxo-5-phenyl)pentyl-l-(3,3-dimethyl-1,2-dioxopentyl) thiomorpholine.

52. The use according to any of claims 45-51, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration, and treatment of neurological disorder.

53. The use of claim 52, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

54. The use of claim 53, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral scelerosis. A process of preparing a compound of the formula: comprising reacting a compound having formula R 1 -Cl and magnesium with a compound having the formula: ORa I II P 0 C. C C o C ro o *o wherein n is 1 or 2; Ra is a Ci-C6 alkyl; P is a benzyl group; and RI is a Ci-C 6 straight or branched chain alkyl substituted with phenyl.

56. A process of preparing a compound of the formula: comprising hydrogenating a compound of the formula: -86- r r N RI 1 P 0 with palladium hydroxide, wherein n is 1 or 2; P is a benzyl group; and R, is a Ci-C 6 straight or branched chain alkyl substituted with phenyl.

57. A process of preparing a compound of the formula: S)n o R 1 N o 0 ORb comprising reacting a compound of formula: S)n R 1 H 0 with Rb-oxalyl chloride, wherein Rb is CI-C 6 alkyl; n is 1 or 2; and R, is a Cl-C 6 straight or branched chain alkyl substituted with phenyl. -87-

58. A process of preparing a compound of the formula: comprising reacting a compound of the formula: with a compound of the formula R 2 -Mg-X, wherein X is chlorine, bromine, or iodine; Rb is Ci-C 6 alkyl; n is 1 or 2; R, is a Cl-C 6 straight or branched chain alkyl substituted with phenyl; and R 2 is a Ci-C 9 straight or branched chain alkyl. -88-

59. The compound of any one of claims 1 to 17, substantially as hereindescribed with reference to any one of the Examples. The pharmaceutical composition of any one of claims 18 to 27, substantially hereindescribed with reference to any one of the Examples.

61. The method of any one of claims 28 to 37, substantially hereindescribed with reference to any one of the Examples.

62. The use of the compounds of any one of claims 38 to 54 or 59, substantially hereindescribed with reference to any one of the Examples.

63. The process of claim 55 or 58, substantially hereindescribed with reference to any one of the Examples. Dated this 7 t h day of August, 2001. GPI NIL HOLDINGS, INC. By their Patent Attorneys: CALLINAN LAWRIE e 06/08101.gc12226.spe.88