MXPA99002813A - Heterocyclic thioesters and ketones - Google Patents

Abstract

This invention relates to neurotrophic low molecular weight, small molecule heterocyclic thioesters and 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.

Description

KETONES AND HETEROCICLIC TIOESTERS This application is a continuation in part of the US patent application No. 08/721, 765, filed on September 25, 1996, the entire contents of which is incorporated by reference.

BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION This invention relates to small molecule, low molecular weight heterocyclic ketones and thioesters, having an affinity for FKBP type immunophilins, and their use as inhibitors of enzyme activity associated with immunophilin proteins, particularly activity of enzyme, peptidyl-prolyl isomerase or rotamase. 2. Description of the Related Art The term immunophilin refers to a number of proteins that serve as receptors for the major immunosuppressant drugs, cyclosporin A (CsA), FK506 and rapamycin. The known classes of immunophilins are cyclophilins and proteins that bind FK506, or FKBPs. Cyclosporin A binds to cyclophilin A, while FK506 and rapamycin bind to FKBP1 2. These inm-unofilin-drug complexes are interrelated with several intracellular signal transduction systems, especially the immune and nervous systems. Immunophilins are known to have peptidyl-prolyl isomerase (PPIase) enzyme activity, or rotamase. It has been determined that the rotamase enzyme activity plays a role in the catalysis of the interconversion of the cls and trans isomers of peptide and protein substrates for the immunophilin proteins. Originally, immunophilins were discovered and studied in the immune tissue. Initially, those skilled in the art postulated that the inhibition of the rotamase activity of the immunophilins leads to the inhibition of T cell proliferation, thereby causing the immunosuppressive activity exhibited by immunosuppressive drugs, such as cyclosporin a, FK506 and rapamycin. An additional study has shown that the inhibition of rotamase activity in and of itself does not result in immunosuppressive activity. Schreiber et al. , Science, 1990, vol. 250, pp. 556-559. Instead, immunosuppression appears to come from the formulation of an immunosuppressant drug complex and immunophilin. It has been shown that immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al. , Cell, 1 991, vol. 66, pp. 807-815. In the case of FKBP-FK506 and cyclophilin-CsA, the immunophilin-drug complexes bind to the calcinerurin enzyme and inhibit T cell receptor signaling, which leads to the proliferation of T cells. Similarly, the complex of immunophilin-FKBP-rapamycin drug interacts with the RAFT1 / FRAP protein and inhibits I-L-2 receptor signaling. It has been found that immunophilins are present in 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 the synthesis of nitric oxide, the release of neurotransmitters and the extension of the neuronal process. It has been found that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate the outgrowth of neurites in PC12 cells and sensory neurons, mainly dorsal root ganglia cells (DRGs). Lyons et al. , Proc. Of Nati. Acad. Sci., 1994, vol. 91, pp. 31 91-31 95. In whole animal experiments, it has been shown that FK506 stimulates nerve regeneration following injury to facial nerves. Surprisingly, it has been found that certain compounds with a high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects. Additionally, these rotamase inhibitors are devoid of immunosuppressant activity. These findings suggest the use of rotamase inhibitors to treat several peripheral neuropathies and to intensify neuronal regrowth in the central nervous system (CNS). Studies have shown that neurodegenerative disorders, such as, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS), can occur due to the loss or decreased availability of a specific neurotrophic substance for a particular population of neurons affected in the disorder. Several neurotrophic factors have been identified that affect specific neuronal populations. For example, a hypothesis has been formulated that Alzheimer's disease results from a decrease or loss of nerve growth factor (NGF). Thus, it has 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 neurotrophic factor and neurotropin-3, to increase the survival of neuronal populations of degeneration. The clinical application of these proteins in several neurological disease states is hampered by difficulties in the delivery and bioavailability of large proteins to nervous system targets. In contrast, immunosuppressant drugs with neurotrophic activity are relatively small and exhibit excellent bioavailability and specificity. However, when administered chronically, immunosuppressive 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, non-localized 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 the use of immunosuppressant compounds, the present invention provides non-immunosuppressive compounds containing rotamase inhibitors of small molecule FKBP to enhance neurite outgrowth, and promote neuronal growth and regeneration in various neuropathological situations, where Neuronal repair may be facilitated, including: peripheral nerve damage caused by physical injury or disease status, such as diabetes; physical damage to the central nervous system (spinal cord and brain); brain damage associated with stroke; and neurological disorders in relation to neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's disease) and amyotrophic lateral sclerosis.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to small molecule, low molecular weight, neurotrophic compounds that have an affinity for FKBP type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the enzymatic activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase enzyme activity, or rotamase. 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 I I: 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 S, CH2, CHRi and C (R?) 2; R-i is selected from the group consisting of straight or branched chain alkyl of C ^ Cs, straight or branched chain alkenyl of C2-C5, Ar! and mixtures thereof, wherein said Ri is unsubstituted or substituted with halo, nitro, straight or branched chain alkyl of Ci-Ce, straight or branched chain alkenyl of C2-C6, hydroxy, C ^ C ^ alkoxy ^ C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ari or a mixture thereof; R2 is selected from the group consisting of straight or branched chain alkyl of C | -C9, straight or branched chain alkenyl of C2-C9, cycloalkyl of C3-C8, cycloalkenyl of C5-C7 and Ar ^ and Ar-i is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said An is unsubstituted or substituted with halo, hydroxy, nitro, straight or branched chain alkyl of C ^ Ce, straight or branched chain alkenyl of C2-C6, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof. The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of the compound of claim 1 for effecting neuronal activity; and (i) a pharmaceutically acceptable carrier.

The present invention further relates to a method for effecting neuronal activity in an animal, comprising: administering to the animal an effective amount of the compound of formula BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 (A) is a photomicrograph representative of untreated sensory neurons. FIG. 1 (B) is a representative photomicrograph of compound 1 (10 pM) promoting neurite outgrowth in sensory neurons.

FIG. 1 (C) is a representative photomicrograph of compound 1 (1 nM) promoting the outgrowth of neurites in sensory neurons. FIG. 1 (D) is a representative photomicrograph of compound 1 (1 μM) promoting neurite outgrowth in sensory neurons. FIG. 2 (A) is a photomicrograph representative 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 the outgrowth of neurites in sensory neurons. FIG. 2 (D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons.

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

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 1 0 (1 nM) promoting neurite outgrowth in sensory neurons. FIG. 3 (D) is a representative photomicrograph of compound 1 0 (1 00 nM) promoting neurite outgrowth in sensory neurons.

FIG. 4 presents the quantification for the recovery of TH-positive dopaminergic neurons in the striatum of animals receiving compounds 1, 9 and 1 0.

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

"Halo" refers to fluoro, chloro, bromo or iodo, unless otherwise indicated. "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way that atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are images of mirrors that do not overlap one another. "Diastereoisomers" are stereoisomers which are not mirror images with one another. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal portions of individual stereoisomers or enantiomers. "Pharmaceutically acceptable salt" refers to a salt of the inventive compounds, which possesses the desired pharmacological activity and which is not biologically undesirable or otherwise undesirable. Salt can be formed with inorganic acids, such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camforate, camfosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, 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, salts of dicyclohexylamine, N -methyl-D-glucamine, and salts with amino acids, such as, arginine and lysine. In addition, the groups containing basic nitrogen can be quaternized 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. "Treatment" refers to: (i) preventing a disease, disorder or condition from occurring in an animal, which may be predisposed to the disease, disorder and / or condition, but which has not yet been diagnosed as having it; (ii) inhibit the disease, disorder or condition, that is, stop its development; and (iii) alleviating the disease, disorder or condition, i.e., causing the regression of the disease, disorder and / or condition.

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

FORM ULA I 0 In particular, this invention relates to a compound of formula I: 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 CH2, O, s, SO, S02, NH or NR2 in any chemically stable oxidation state; X is either O or S; Z is either S, CH2, Q, W or C (R1) 2; W and Y are independently O, S, CH2 or H2; Ri is straight or branched chain alkyl or alkenyl of which is substituted at one or more positions with (Ar -?) N, (Ar?) N connected by a straight or branched chain alkyl or alkenyl of C -? - C6 , C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a straight or branched chain alkyl or alkenyl of C? -C6, Ar2 or a combination thereof; n is 1 or 2; R2 is either straight or branched chain alkyl or alkenyl of Ci-C9, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar-i, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more positions with straight or branched chain C 1 -C 4 alkyl or alkenyl, hydroxyl or a combination thereof; Y Ar! and Ar2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three positions with straight chain halo, hydroxyl, nitro, trifluoromethyl, alkyl or alkenyl. or branched C? -C6, C? -C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the sizes of the individual ring are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S and a combination thereof. Suitable mono- and bicyclic, carbo- and heterocyclic rings include, without limitation, naphthyl, idolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.

FORM ULA II A preferred embodiment of this invention is a compound of formula I I: 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 S, CH2, CH R-i and C (R1) 2; Ri is selected from the group consisting of straight or branched chain alkyl of -CS -CS, straight or branched chain alkenyl of C2-C5, Ar-i and mixtures thereof, wherein said R1 is unsubstituted or substituted with halo , nitro, straight or branched chain alkyl of C? -C6, straight or branched chain alkenyl of C2-C6, hydroxy, C-? -C alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar! or a mixture thereof; R2 is selected from the group consisting of straight or branched chain alkyl of CrC9, straight or branched chain alkenyl of C2-C9, cycloalkyl of C3-C8, cycloalkenyl of C5-C7 and An; and An is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said An is unsubstituted or substituted with halo, hydroxy, nitro, straight or branched chain alkyl of Ci-Ce, straight or branched chain alkenyl of C2-C6, C1-C alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof. Specific examples of these modalities are presented in TABLE I.

TABLE I 1 1 O CH 2 3-phenylpropyl 3-3-dimethylpentyl 2 1 O CH 2 3- (3-pyridyl) propyl 3-3-dimethylpentyl 3 1 O CH 2 3-phenylpropyl tert-butyl 4 1 O CH 2 3- (3- pyridyl) propyl tert-butyl 5 1 O CH 2 3- (3-pyridyl) propyl Cichlorhexyl 6 1 O CH 2 3- (3-pyridyl) propyl Cyclopentyl 7 1 O CH 2 3- (3-pyridyl) propyl Cycloheptyl 8 1 O CH 2 2 - (9-fluorenyl) ethyl 3, 3-dimethylpentyl 9 1 OS 2-phenethyl 3-3-dimethylpentyl 1 0 2 OS 2-phenethyl 3,3-dimethylpentyl 1 1 1 OS Methyl (2-thioindole) 3,3-dimethylpentyl 1 2 1 OS 2-phenethyl Cisolhexyl 1 3 2 OS 2-phenethyl tert-butyl 14 2 0 S 2-phenethyl Phenyl 1 5 1 O CH 2 3- (4-methoxyphenyl) propyl 3,3-dimethylpentyl 1 6 2 O CH 2 4 - (4-methoxyphenyl) butyl 3,3-dimethylpentyl 1 7 2 O CH2 4-phenylbutyl 3, 3-dimethylpentyl 1 8 2 O CH2 4-phenylbutyl Phenyl 2 O CH2 4-phenylbutyl Cichlohexyl 1 S CH2 3-phenylpropyl 3,3 -dimethylpentyl 1 S S 2-phenethyl 3, 3-dimethylpentyl 2 S CH2 3-phenylpropyl 3,3-dimethylpentyl 2 S S 2-phenethyl 3, 3-dimethylpentyl 2 O CHR! 3-phenylpropyl 3,3-dimethylpentyl 2 O CH R! 3-phenylpropyl Cichlorhexyl 2 0 CHRi 3-phenypropyl Phenyl 2 O CH R! 3-phenylpropyl 3,4,5-trimethoxyphenyl 1 O S 2-phenethyl Cyclopentyl 2 O S 3-phenylpropyl tert-butyl 1 O S 3-phenylpropyl 3, 3-dimethylpentyl 1 O S 3- (3-pyridyl) propyl 3,3-dimethylpentyl 1 O S 3-phenylpropyl Cichlorhexyl 1 0 S 4-phenylbutyl Cichlorhexyl 1 O S 4-phenylbutyl 3,3-dimethylpentyl 1 O S 3- (3-pyridyl) propyl C yclohexyl 1 O S 3,3-diphenylpropyl 3,3-dimethylpentyl 1 or S 3,3-diphenylpropyl Cichlorhexyl 1 or S 3- (4-methoxyphenyl) propyl 3,3-dimethylpentyl 2 0 S 4-phenylbutyl tert-butyl 2 or S 1, 5-diphenylpentyl 3, 3-dimethylpentyl 2 or S 1, 5-diphenylpentyl Phenyl 2 0 S 3- (4-methoxyphenyl) propyl 3,3-dimethylpentyl 2 or S 3- (4-methoxypheni I) propyl Phenyl 2 O s 3- (4-methoxyphenyl) propyl 1 O s 3,3-di (4-fluoro) phenylpropyl 1 O s 4,4-di (4-fluoro) phenyl-butyl 1 O s 3- (1 -naphthyl) propyl 1 0 s 2,2- diphenylethyl 2 O s 2,2-diphenylethyl 2 O s 3,3-diphenylpropyl 1 O s 3- (4- {trifluoromethyl} - phenyl) propyl 1 O s 3- (2-naphthyl) propyl 2 O s 3- (1-naphthyl) propyl 1 0 s 3- (3-chloro) phenylpropyl 1 O s 3- (3- {trifluoromethyl} - phenyl) propyl 1 O s 3- (2-biphenyl) propyl 1 O s 3,3-dimethylpentyl 1 O s 3- (3-fluorophenyl) propyl 2 O s 4-phenylbutyl 2 0 s 3-phenylpropyl 1 O s 3- (2-chloro) phenylpropyl 2 O s 3- (3-chloro) phenylpropyl 2 O s 3- (2-fluoro) phenylpropyl 2 O s 3- (3-fluoro) phenyl propyl 1 S 3- (2,5-dimethoxyphenyl) -3,3-dimethylpentyl propyl 1 O CH 2 3 -phenylpropyl Cichlorhexyl 1 O CH 2 3-phenylethyl tert -butyl 2 O CH 2 4 -phenyl butyl C yclohexyl 2 O CH Ri 2-phenylethyl tert-butyl 1 O CH2 3,3-di (4-fluorophenyl) -3,3-dimethylpentyl propyl 2 O CH2 3-phenylpropyl 3, 3-dimethylpentyl The most preferred examples of TABLE I are called as follows: (2S) -2- ( { 1 -oxo-5-fenii.}. -pentyl-1 - (3,3-dimethyl-1,2-d-oxopentyl) pyrrol id i na 3-3-Dimeti 1-1 - [(2S) -2- (5- (3-pyridyl) pentanoyl) -1-pyrrolidine] -1,2-pentanedione (2S) -2- (. {1 -oxo-4-phenyl.} - butyl-1 - (3,3-dimethyl-1,2-dioxobutyl) pyrrolidine 1 - . 2 - (2,3-dimethyl-1,2-dioxopentyl) -2-piperidincarbothioate 2-phenyl-1-ethyl (2S) -1 - (3,3-dimeti I-1,2-dioxopentyl) -2- pyrrolidinecarbothioate of 2-f eni I-1-ethyl (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate (3-thioindolyl) methyl (2S) -1 - (2- cyclohexyl-1, 2-dioxopentyl) -2-pyrrolidinecarbothioate 2-f eni I-1-ethyl 1 - (2-f in i 1-1, 2-dioxoethyl) -2-piperidincarbothioate 2-phenyl-1-ethyl (2S) -1- (1-cyclopentyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 2-phenyl-1-ethyl 1- (3,3-dimethyl-1,2-dioxobutyl) -2-pyridine 3-f-n-1-propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3-phenyl-1-propyl (2S) -1- ncarbothioate (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3- (3-pyridyl) -1-propyl (2S) -1- (2-cyclohexyl-1,2-dioxoethyl) -2-pyrrolidinecarbothioate of 3-phenyl-1-propyl (2S) -1- (2-cyclohexyl-1,2-dioxoethyl) -2-pyrrolidinecarbotioate of 4-f in i-1-butyl (2S) -1- (3,3 -dimethyl-1, 2-dioxopentyl) -2-pyrrolidincarboxylate of 4-fe nyl-1-Butyl (2S) -1- (2-cyclohexyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3- (3-pyridyl) -1-propyl (2S) -1- (3,3-dimethyl) 1,3-diphenyl-1-propyl (2S) -1- (2-cyclohexyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3,3-diphenyl-1-pyrrolidinecarbothioate 3,3-diphenyl-1-propyl (2S) -1- (2-cyclohexyl-1,2-dioxopentyl) -2-pyrrolidinecarbotioate -propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3- (para-methoxyphenyl) -1-propyl 1- (1,2-dioxo-3,3- dimethyl butyl) -2-piperidinecarboxylate 4-f-enyl-1-butyl 1- (3,3-dimeti-1-1, 2-dioxopentyl) -2-piperidinecarbothioate 1,5-diphenyl-3-pentyl 1 - ( 3-phenyl-1,2-dioxoethyl) -2-piperidinecarbothioate 1,5-dif eni I-3-mercaptopentyl 1- (1,2-dioxo-3,3-dimethylpentyl) piperidin-2-carbothioate 3- ( para-methoxyphenyl) -1-propyl 1- (2-phenyl-1,2-dioxoethyl) piperidin-2-carbothioate of 3- (para-methoxyphenyl) -1-propyl 1- (3,3-dimethyl-1,2) -dioxopentyl) piperidin-2-carbothioate 3- (1-naphthyl) -1-propyl (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbotioate 3,3-di ( para-fluoro) phenyl) -1-pr opyl 1 - (3, 3-d-methyl-2-oxo-pentane) -2-pyrrolidine incarbothioate of 4,4-di (para-fluorophenyl) butyl (2S) -1- (3, 3-di meti l-2-oxo petanoyl) -2-pi rro I id incarbothioate of 3- (1-naphthyl) propyl (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) tetrahydro-1 H -2-pyrrolcarbothioate 2,2-diphenylethyl (2S) -1 - (3,3-di-methyl-l-2-oxopentanoyl) -2-pi perid 2,2-diphenylethyl incarbothioate 1- (3,3-dimethyl) -2-oxopentanoyl) -2-piperidincarbothioate of 3,3-diphenylpropyl (2S) -1- (3, 3-d im eti l-2-oxopentanoi I) -2-pi rro I id incarbothioate of 3- [4 - (trifluoromethyl) phenyl] propyl 52 (2S) -1 - (3, 3 (dimethyl-2-oxopentanoyl) -2- pyrrolidinecarbothioate 3- (2-naphthyl) propyl 53 (2R, S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate 3- ( 2- naphthyl) propyl 54 (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2- pyrrolidincarbothioate 3- (3-chlorophenyl) propyl 55 (2S) -1- (3, 3 -dim eti l-2-oxopentanoyl) -2-pi rro I id incarbothioate of 3- [3- (trifluoromethyl (phenyl) propyl 56 (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2- 3- (1-biphenyl) propyl pyrrolidinecarbothioate 57 (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2- pyrrolidinecarbothioate 3- (2-fluorophenyl) propyl 58 (2S) -1- ( 3, 3-di meti l-2-oxopentanoyl) -2-pi rro I id incarbothioate of 3- (3-fluorophenyl) propyl 59 1 - (3, 3-di meti l-2-oxo penta no il) -2 -piperidyl 4-phenylbutyl incarbothioate 60 1 - (3, 3-di meti l-2-oxopentanoyl) -2-piperid 3-phenylpropyl incarbothioate 61 (2 S) -1- (3, 3-d im eti l- 2-oxopentanoyl) -2-pi rro I id 3- (2-chlorophenyl) propyl incarbothioate 62 1 - (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate 3- (2- c) lorophenyl) propyl 63 1- (3- (2-fluorophenyl) propyl-1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate 3 - (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate) - (3- fluorophenyl) propyl 65 (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (3,4-dimethoxyphenyl) propyl 66 (2S) -2- (. { 1-oxo-4-phenyl} -butyl-1- (2-cyclohexyl-1,2-dioxoethyl) pyrrolidine 67 2- ( { 1-oxo-4-phenyl} - butyl-1 - (3,3-dimethyl-1,2-dioxobutyl I) pyrrolidine 68 2- (. {1-oxo-6- phenyl.}., -butyl-1- (3,3-dimeti-1-1, 2-dioxobutyl) pyrrole id: 69 2- ( { 1-oxo- [2- { 2'-phenyl}. ethyl] -4-phenyl.} - butyl-1- (3,3-dimethyl-1,2-dioxobutyl) piperidine 70 1- { (2S) -2- [5,5- di (4-fluorophenyl) pentanoyl] -2-pyrrolidin.} - 3,3-dimethyl-1,2-pentanedione 71 3,3-dimethyl-1- [2- (4-phenylpentanoyl) piperidine] -1,2 -pentanedione FORMULA III Another preferred embodiment is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein: A, B, C and D are independently CH2, O, S, SO, S02, NH or NR2; X is O or S; Z is S, CH2, CHRi or C (R -,) 2; Ri is straight or branched chain alkyl or alkenyl of C? -C6, which is substituted at one or more positions with (Ar?) N, (Ar?) N connected by a straight or branched chain alkyl or alkenyl of C C6, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a straight or branched chain alkyl or alkenyl of C -CQ, Ar2 or a combination thereof; n is 1 or 2; R2 is either straight or branched chain alkyl or alkenyl of C ^ C9, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, or Ar-i, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted at one or more positions with straight or branched chain alkyl or alkenyl of C1-C4, hydroxyl or a combination thereof; Y Ar-i 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 positions with halo, hydroxyl, nitro, trifluoromethyl, alkyl or alkenyl straight or branched chain of C ^ Ce, CI-C4 alkoxy, Ci-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the sizes of the individual rings are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S and a combination thereof. Particularly preferred compounds of formula I I are presented in TABLE I I.

TABLE No B X Ri 72 CH: CH; O 2-phenethyl 3, 3-dimethyl-pentyl 73 CH 2 S CH 2 O CH 2 3-phenylpropyl 3,3-dimethyl-pentyl 74 CH; CH; NH O 2-phenethyl 3, 3-dimethyl-pentyl 75 CH, S CH 2 S S 2-phenethyl 3, 3-dimethyl-pentyl FORMULA IV A preferred additional embodiment of this invention is a compound of formula IV: or a pharmaceutically acceptable salt thereof, wherein: A, B, C and D are independently CH2, O, S, SO, S02, NH or NR2; X is O or S; Z is S, CH2, CHR! or CÍR ^; Ri is straight or branched chain alkyl or alkenyl of C ^ Ce, which is substituted at one or more positions with (ArN, (Ar ^ n connected by a straight or branched chain alkyl or alkenyl of Ci-Ce, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a straight or branched chain alkyl or alkenyl of Ci-Cd, Ar2 or a combination thereof, n is 1 or 2, R2 is either alkyl or alkenyl of chain linear or branched Cr C, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or An, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted at one or more positions with straight chain alkyl or alkenyl or branched C -? - C4, hydroxyl or a combination thereof; Ar-i 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 positions with halo, hydroxyl, nitro, trifluoromethyl, alkyl or alkenyl straight or branched chain of C 1 -C 4 alkoxy, C 1 -C alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the sizes of individual rings are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S and a combination thereof. Particularly preferred compounds of formula IV are presented in TABLE I.

TABLE I 1 76 CH 2 CH n 2 O CH: CH 2 3-phenylpropyl 3,3-dimethyl pentyl 77 CH 2 CH 2 O CH; O S 2-phenethyl 3, 3-dimethyl pentyl 78 CH CH 2 CH; O CH 2 3-phenylpropyl 3,3-dimethylpentyl 79 CH 2 CH 2 CH; S 2-phenethyl 3, 3-dimethyl-pentyl The compounds of this invention possess asymmetric centers and can thus be produced as mixtures of stereoisomers or as individual stereoisomers. The individual stereoisomers can be obtained by using an optically active starting material, by solving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by solving the compound of formula (I). It is understood that 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 can thus be produced as mixtures of stereoisomers or as individual R and S stereoisomers. The individual enantiomers can be obtained by resolving a racemic or 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 stereoisomer S is very preferred due to its higher activity.

Methods for using the compounds of the invention The compounds of the present invention have affinity for the protein that binds FK506, particularly FKBP 12, 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 above reasons, the present invention further relates to a method for effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula I, I I, II or IV. In a preferred embodiment, the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder. Neurological disorders that can 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 hereditary muscular atrophy of the bulb; syndromes of invertebrate discs with hernia, broken or with prolapse; cervical spondylosis; plexus disorders; syndromes of thoracic outlet destruction; peripheral neuropathies, such as those caused by lead, dapsone, ticks, porphyria or Guillain-Barré syndrome; Alzheimer 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, traumatic brain injury, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder in relation to neurodegeneration. Examples of neurological disorders that are related to neurodegeneration are Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. For these purposes, the compounds can be administered orally, parenterally, by atomizer inhalation, topically, rectally, nasally, buccally, vaginally or via a reservoir implanted in dosage formulations containing carriers, auxiliaries and pharmaceutically acceptable vehicles, not toxic, conventional. The term parenteral, as used in the present, includes subcutaneous, intravenous, intramuscular, intraperitoneal, intraheal, intraventricular, intrasternal and intracranial injection or infusion techniques. To be therapeutically effective as central nervous system targets, compounds must easily penetrate the blood-brain barrier when administered peripherally. Compounds that can not penetrate the blood-brain barrier can be administered effectively by an intraventricular route. The compounds may be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing agents or humectants and suspending agents. Sterile injectable preparations can 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 vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as solvents or suspension media. For this purpose, any soft fixed oil, such as a synthetic mono- or diglyceride, can 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 suspensions or oil solutions may also contain long chain alcohol dispersants or diluents. Additionally, the compounds can be administered orally in the form of capsules, tablets, aqueous solutions or suspensions. The tablets may contain carriers, such as lactose and corn starch, and / or lubricating agents, such as magnesium stearate. The capsules may contain diluents including lactose and dried corn starch. The aqueous suspensions may contain emulsifying agents and suspending agents combined with the active ingredient. Oral dosage forms may also contain sweetening and / or flavoring and / or coloring agents. The compounds can also be administered rectally in the form of suppositories. These compositions can be prepared by mixing the medicament with a suitable non-irritating excipient, which is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the rectum to release the medicament. Such materials include cocoa butter, beeswax and polyethylene glycols. Additionally, the compounds can be administered topically, especially when the conditions directed for the treatment involve easily accessible areas or organs by topical application, including neurological disorders of the eye, the skin or the lower intestinal tract. Suitable topical formulations can be easily prepared for each of these areas. For topical application to the eye, or ophthalmic use, the compounds can be formulated as micronized suspensions in sterile, pH adjusted, isotonic solution, or, preferably, as a solution in sterile, pH adjusted, isotonic saline solution, either with or without a preservative, such as, benzylalkonium chloride. Alternatively, the compounds can be formulated into ointments, such as petrolatum, for ophthalmic use.

For topical application to the skin, the compounds may be formulated into suitable ointments containing the suspended or dissolved compounds 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 in 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, alcohol Cetearyl, 2-octyldodecanol, benzyl alcohol and water. Topical application to the lower intestinal tract can be done in rectal suppository formulations (see above) or in suitable enema formulations. Dosage levels in 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 being from about 0.1 mg to about 1,000 mg. The amount of active ingredient that can be combined with the carrier materials to produce a simple dosage form will vary depending on the host treated and the particular mode of administration. However, it is understood that a specific dose level for any particular patient depends on a variety of factors, including the activity of the specific compound; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; combination of medication; the severity of the particular disease that is 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 on the previously stated factors and the neurotrophic effectiveness of the drug combination.

Pharmaceutical Compositions of the Invention The present invention also relates to a pharmaceutical composition comprising: (i) a neurotrophically effective amount of the compound of formula I, I I, I, IV, and (ii) a pharmaceutically acceptable carrier. The above discussion which relates 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- (3,3-dimethyl-1, 2-dioxopentyl) pyrrolidine (1) (2S) -2- (1-oxo-4-phenyl) butyl-N-benzylpyrrolidine, 1-chloro-4-phenylbutane (1.78 g, 10.5 mmol) in 20 ml of THF was added to 0.24 g (10 mmol) of magnesium turnings in 50 ml. of refluxing THF After the addition was complete, the mixture was refluxed for an additional 5 hours, and then slowly added to a refluxing solution of N-benzyl-L-proline ethyl ester (2.30 g. 10 mmol)) in 100 ml of THF After 2 hours of further reflux, the mixture was cooled and treated with 5 ml of NCI 2N.The reaction mixture was diluted with ether (100 ml) and washed with NaHCO 3, Saturated, water and brine The organic phase was dried, concentrated and chromatographed, levigating with CH2Cl2: EtOAc 5: 1 to obtain 2.05 g (64%) of the ketone as an oil, 1 H NMR (CDCl 3, 300 MHz) : 1.49-2.18 (m, 8H), 2.32-2.46 (m, 1H), 2.56-2.65 (m, 2H), 2.97-3.06 (m, 1H); 3.17-3.34 (m, 1H); 3.44-3.62 (m, 1H); 4.02-4.23 (m, 2H); 7.01-7.44 (m, 10H). (2S) -2- (1-oxo-4-phenylbutylpyrrolidine.) The ketone compound (500 mg) and palladium hydroxide (20% on carbon, 50 mg) was hydrogenated at 2812 kg / cm2 on 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 (m, 10H); 2.55 (m, 2H); 2.95 (dm, 1H); 3.45-3.95 (m, 1H); 4.05 (m, 1H); 7.37 (m, 5H). (2S) -2- (1-Oxo-4-phenyl) butyl-1- (1,2-dioxo-2-methoxyethyl) pyrrolidine. To a solution of (2S) -2- (1-oxo-4-phenyl) butylpyrrolidine (230 mg, 1.0 mmol) in CH 2 Cl 2 (20 ml) at 0 ° C was added methylloxalyl chloride in the form of drops (135 mg; 1.1 mmol). After stirring at 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 column of silica gel, levigating with 20: 1 CH2Cl2: EtOAc to obtain 300 mg of the oxamate as a clear oil (98%), 1 H NMR (CDCl 3, 300 MHz): 1.68 (m, 4H ); 1.91-2.38 (m, 4H); 2.64 (t, 2H); 3.66-3.80 (m, 2H); 3.77, 3.85 (s, 3H total); 4.16 (m, 2H); 4.90 (m, 1H); 7.16 (m, 3H); 7.27 (m, 2H). (2S) -2 - ((1-oxo-5-phenyl) -pentyl-1- (3,3-dimethyl-1,2-dioxopentyl) pyrrolidine (1). To a solution of the above oxamate (250 mg; mmol) in anhydrous ether (15 ml), cooled to -78 ° C, was added 1,1-dimethylpropyl magnesium chloride (0.8 ml of a 1.0 M solution in ether, 0.8 mmol). -78 ° C for 2 hours, the reaction was quenched by the addition of 2 ml of saturated NH CI, followed by 100 ml of EtOAc The organic phase was washed with brine, dried, concentrated and purified on a gel column. silica, levigating with 50: 1 CH2Cl2: EtOAc Compound 1 was obtained as a clear oil, 120 mg, 1H NMR (CDCl3, 300 MHz): d 0.87 (t, 3H, J = 7.5); 1.22 (s, 3H ), 1.25 (s, 3H), 1.67 (m, 4H), 1.70-2.33 (m, 6H), 2.61 (t, 2H, J = 7.1), 3.52 (m, 2H), 4.17 (t, 2H, J = 6.2); 4. 52 (m, 1 H); 7.16-7.49 (m, 5H). Anal. Caled, for C22H3i N03 - H20: C, 70.37; H, 8.86; N, 3.73. Found: 70.48; H, 8.35; N, 3.69.

EXAMPLE 2 Synthesis of 1 - (3,3-d-methyl-1,2-dioxopentyl) -2-piperid incarbothioate of 2-phenyl-1-ethyl (9) (2S) -1 - (1 .2- d-Oxo-2-methoxy-P-2-pi-methyl-dicarboxylate methyl ester A solution of L-proline methyl ester hydrochloride (3.08 g, 18.60 mmol) in dry methylene chloride at 0 ° C was cooled and treated with triethylamine (3.92 g, 38.74 mmol, 2.1 eq) After stirring the paste formed under a nitrogen atmosphere for 1 5 min, a solution of methyl oxalyl chloride (3.20 g, 26.1 mmol) in methylene chloride was added. The resulting mixture was stirred at 0 ° C for 1.5 hours After filtering to remove the solids, the organic phase was washed with water, dried over MgSO.sub.2 and concentrated. a column of silica gel, levigating with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil, mixture of cis-trans amide rotamers, data for rotamer t rans given 1 H NMR (CDCl 3): d 1 .93 (dm, 2H); 2.1 7 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.70, 3.84 (s, 3H total); 4.86 (dd, 1 H, J = 8.4, 3.3). .2 S) -1 - (1,2-dioxo-3,3-dimethylpentyl) -2-pi rro I methylcarboxylate. A solution of methyl (2S) -1 - (1, 2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g, 0.90 mmol) in 30 ml of tetrahydrofuran (THF) was cooled to -78 ° C and it was treated with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 ° C for three hours, the mixture was poured into saturated ammonium chloride (100 ml) and extracted into ethyl acetate. The organic phase was washed with water, dried and concentrated, and the crude material obtained on removal of the solvent was purified on a column of silica gel, levigating with 25% ethyl acetate in hexane to obtain 2.10 g (75%). ) of oxamate as a colorless oil, 1 H NMR (CDCl 3): d 0.88 (t, 3H); 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J = 8.4, 3.4). (2S) -1- (1, 2-dioxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxylic acid. A mixture of methyl (2S) -1- (1, 2-dioxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxylate (2.10 g, 8.23 mmol), 1N LiOH (15 ml), and methanol (50 ml) was stirred. ) at 0 ° C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 ml of methylene chloride. The organic extract was washed with brine and concentrated to give 1.73 g (87%) of white solid as snow, which did not require further purification, 1 H NMR (CDCl 3): d 0.87 (t, 3 H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, 1H, J = 8.6, 4.1). 1 - (3, 3-dim eti 1-1, 2-d ioxopentyl) -2-piperidincarbothioate 2-phenyl-1-ethyl (9). Dicyclohexylcarbodiimide (226 mg, 1.1 mmol) was added to a solution of (2S) -1- (1,2-dioxo-3,3-dimethylpentyl) -2-pyrrolidincarboxylic acid (241 mg, 1.0 mmol) in CH2Cl2. After stirring the resulting mixture for 5 minutes, the solution was cooled to 0 ° C and treated with a solution of phenyl mercaptan (1 38 mg, 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2Cl2. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo; the crude residue was purified by flash chromatography (1 0: 1 hexane: EtOAc) to obtain 302 mg (84%) of 9 as an oil, 1 H NMR (CDCl 3, 300 MHz): d 0.85 (t, 3H, J = 7.5); 1.29 (s, 3H); 1.31 (s, 3H); 1 .70-2.32 (m, 6H); 2.92 (t, 2H, J = 7.4); 3.22 (t, 2H, J = 7.4); 3.58 (m, 2H); 4.72 (m, 1 H); 7.23-7.34 (m, 5H). Anal. Caled, for C20H27NO3S - 0.4 H20: C, 65.15; H, 7.60; N, 3.80. Found: C, 65.41; H, 7.49; N, 3.72.

EX EM PLO 3 Synthesis of (2S.-1 - (3.3-d imeti 1-1.2-di oxo pentyl -2-pi rro I id 2-phenyl-1-ethyl incarbothioate (10) 1 - (1 Methyl 2-dioxo-2-methoxyethyl) -2-piperidinecarboxylate A solution of methyl pipelhate hydrochloride (8.50 g, 47.31 mmol) in dry methylene chloride (1000 ml) was cooled to 0 ° C and treated with triethylamine (10.5 g, 11.0 mmol, 2.1 eq) After stirring the paste formed under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (8.50 g, 60.4 mmol) in methylene chloride was added. (75 ml) in the form of drops The resulting mixture was stirred at 0 ° C for 1.5 hours After filtering to remove the solids, the organic phase was washed with water, dried over MgSO4 and concentrated. crude was purified on a column of silica gel, levigating with 50% ethyl acetate in hexane, to obtain 9.34 g (86%) of the product as a reddish oil.

Mixture of cis-trans amide rotamers; data for trans rotamer dice. 1 H NMR (CDCl 3): d 1.22-1.45 (m, 2H); 1.67-1.78 (m, 3H); 2.29 (m, 1H); 3.33 (m, 1H); 3.55 (m, 1H); 3.76 (s, 3H); 3.85, 3.87 (s, 3H total); 4.52 (dd, 1H). 1- (1,2-dioxo-3,3-dimethylethyl) -2-piperidinecarboxylate methyl. A solution of methyl 1- (1,2-dioxo-2-methoxyethyl) -2-piperidinecarboxylate (3.80 g, 16.57 mmol) in 75 ml of tetrahydrofuran (THF) was cooled to -78 ° C and treated with 20.7 ml. of a 1.0 M solution of 1,1-dimethyl-propylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 ° C for three hours, the mixture was poured into saturated ammonium chloride (100 ml) and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated, and the crude material obtained on the solvent removal was purified on a column of silica gel, levigating with 25% ethyl acetate in hexane, to obtain 3.32 g (74 g. %) of the oxamate as a colorless oil, 1 H NMR (CDCl 3): d 0.88 (t, 3H); 1.21, 1.25 (s, 3H each); 1.35-1.80 (m, 7H); 2.35 (m, 1H); 3.24 (m, 1H); 3.41 (m, 1H); 3.76 (s, 3H); 5.32 (d, 1H). 1- (1, 2-d-Oxo-3,3-dimethylpenti0-2-piperidn-carboxylic acid.) A mixture of 1- (1,2-dioxo-3,3-dimethylpentyl) was stirred. Methyl-2-pperidinecarboxylate (3.30 g, 12.25 mmol), 1 N LiOH (15 mL), and methanol (60 mL) at 0 ° C for 30 minutes and at room temperature overnight The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 ml of methylene chloride.The organic extract was washed with brine and concentrated to give 2.80 g (87%) of white solid as snow, which required additional purification, 1H NMR (CDCI3): d 0.89 (t, 3H), 1.21, 1.24 (s, 3H each), 1.42-1.85 (m, 7H), 2.35 (m, 1H), 3.22 (d, 1H ); 3.42 (m, 1H); 5.31 (d, 1H). (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbotioate of 2-f eni I-1-ethyl ( 10) Dicyclohexylcarbodiimide (226 mg, 1.1 mmol) was added to a solution of 1- (1,2-dioxo-3,3-dimethylpentyl) -2-piperidinecarboxylic acid (255 mg, 1.0 mmol) in CH 2 Cl 2. (10 ml) After stirring the mixture resulted for 5 minutes, the solution was cooled to 0 ° C and treated with a phenyl mercaptan solution (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2Cl2. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo; the crude residue was purified by flash chromatography (10: 1 hexane: EtOAc) to obtain 300 mg (80%) of 10 as an oil, 1 H NMR (CDCIs, 300 MHz): d 0.94 (t, 3H, J = 7.5); 1.27 (s, 3H); 1.30 (s, 3H); 1.34-1.88 (m, 7H); 2.45 (m, 1H); 2.90 (t, 2H, J = 7.7); 3.26 (t, 2H; J = 7.7); 3.27 (m, 1H); 3.38 (m, 1H); 5.34 (m, 1H); 7.24-7.36 (m, 5H). Anal. Caled, for C2? H2gN03S: C, 67.17; H, 7.78; N, 3.73. Found: C, 67.02; H, 7.83; N, 3.78. As discussed above, the compounds of the present invention have an affinity for the protein that binds FK506, particularly FKBP12. The inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of this affinity.

K i test procedure The 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, 1: 5: 9923-9938). These values are obtained as apparent K's and are presented in Table IV for the representative compounds. The cis-trans isomerization of an alanine-proline ligature in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a coupled chymotrypsin assay, which releases para-nitroanilide of 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 are analyzed as a change in the first order rate constant as a function of inhibitor concentration to produce the apparent K i values. 950 ml of ice-cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 ml of FKBP (2.5 mM in 10 mM Tris-CI pH 7.5, 1 mM NaCl, dithiothreitol 1 were added to a plastic test tube. mM, 25 mL of chymotrypsin (50 mg / mL in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe) -Pro-Phe-para-nitroanilide, 5 mg / ml in 2.35 mM LiCl in trifluoroethanol.) Absorbance is monitored at 390 nm versus time for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance data versus time.

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

Chicken dorsal root ganglia cultures and neurite outgrowths The neurotrophic effects of the FKBP inhibitor compounds were demonstrated by evaluating the ability of the compounds to promote neurite outgrowth in chicken sensory neurons cultured from dorsal root ganglia. The dorsal root ganglia were dissected from 10-day-old chicken embryos. Whole ganglia explantations were cultured in 12-well plates coated with thin-layer Matrigel with Liebovitz L1 5 plus high glucose medium supplemented with 2 mM glutamine and 10% fetal calf serum, and also containing 1.0 μM cytosine. β-D arabinofuranoside (Ara C) at 37 ° C in an environment containing 5% C02. Twenty-four hours later, the DRGs were treated with various concentrations of nerve growth factor, immunophilin ligands or combinations of drugs plus NFG. Forty-eight hours after the drug treatment, the nodes under phase contrast or Hoffman Modulation contrast were visualized with an inverted Zeiss Axiovert microscope. The photomicrographs of the explantations were made and the neurite outgrowth was quantified. Neurites larger in diameter than DRG were counted as positive, with total number of neurites quantified for each experimental condition. Three to four DRGs were grown per cavity, and each treatment was performed in duplicate. Dose-response curves were generated from which ED50 values were obtained. The results of these experiments are presented in Table IV under the column "ED50". Representative photomicrographs of untreated sensory neurons (control) and of compounds 1 (10 pM, 1 nM, 1 μM), 9 (10 pM, 1 nM, 1 00 nM) and 10 (10 pM, 1 nM, 100 nM) ) promoting neurite outgrowth in sensory neurons are shown in FIGs 1 (AD), 2 (AD) and 3 (AD), respectively.

MPTP Model of Parkinson's Disease The remarkable neuro-regenerative and neurotrophic effects of the compounds of the present invention were further demonstrated in an animal model of neurodegenerative disease. Dopaminergic neuron MPTP lesions were used in mice as an animal model of Parkinson's Disease. I.p. white CD1 male mice, of four weeks with 30 mg / kg of MPTP during 5 days. The test compounds (4 mg / kg), or vehicle, were administered s.c. together with MPTP for 5 days, as well as for about 5 additional days following the cessation of MPTP treatment. At 18 days following the MPTP treatment, the animals were sacrificed and the striata was dried and homogenized. Immunostaining was performed on the sagittal and coronal cerebral sections using anti-tyrosine hydroxylase 1 g to quantify the survival and recovery of dopaminergic neurons.

In animals treated with MPTP and vehicle, a substantial loss of functional dopaminergic terminals was observed, compared with non-injured animals. The injured animals that received test compounds showed a significant recovery of dopaminergic neurons stained with TH. The results of these experiments are presented in TABLE IV under the column "% recovery of TH". Quantification for the recovery of TH-positive dopaminergic neurons in the striatum of animals that received compounds 1, 9 and 1 0, and for representative injured and control animals that did not receive the test drugs, is presented in FIG. Four.

TABLE IV Results of in vitro tests Example # Ki, nM ED50, nM% recovery of TH 1 31 0.4 23 2 210 3 85 9 104 0.5 61 10 12 0.8 54 11 299 0.36 53 12 442 0.025 14 3 3 3111333 0 0 0 ... 999 48 28 1 1 1000888 0 0 0 ... 999 41 29 5 5 5999 0 0 0 ... 000000333 50 11 1111 00 0 ... 000000000222555 65 31 88 8 ... 777 --- 31 32 33 3666222 _- ~ _ 52 33 1698 - 34 3 344 0 0..99 48 62 ~ 36 7 7 --- 56 37 68 - 38 8 8..99 0 0..001111 37.32 39 347 ~ 40 1226 41 366 - 42 28 - 43 259 - 44 1 18888 - 25 45 31 - 46 757 - 47 2 211 - 50 48 1 12277 - 28 49 1334 - 50 5 555 -__ 62 51 33 52 6 53 261 54 37 55 30 56 880 57 57 58 79 59 962 60 90 61 139 62 1 96 63 82 64 163 65 68 66 306 38 67 1 77 68 284 69 49 23 70 457 25 71 788 All publications and patents identified above are incorporated herein by reference.

It will be obvious that the invention being described in this way, can be varied in many ways. Such variations should not be considered as a departure from the spirit and scope of the invention and it is intended that all such modifications be included within the scope of the following claims.

Claims (60)

1. REVIVALATION IS 1 . A compound of formula I I: 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 S, CH2, CHR and CÍR ^; R? is selected from the group consisting of straight or branched chain alkyl of C ^ Cs, straight or branched chain alkenyl of C2-C5, An and mixtures thereof, wherein said R-is unsubstituted or substituted with halo, nitro, straight or branched chain alkyl of Ci-Ce, straight or branched chain alkenyl of C2-C6, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar! or a mixture thereof; R2 is selected from the group consisting of straight or branched chain alkenyl straight or branched chain alkyl of C2-Cg, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and A; and Ar! is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said An is unsubstituted or substituted with halo, hydroxy, nitro, straight or branched chain alkyl of straight or branched chain alkenyl of C2-C6, alkoxy of C -? - C, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.
2. 2. The compound of claim 1, wherein: n is 1; and X is O.
3. 3. The compound of claim 2, wherein Z is CH2.
4. 4. The compound of claim 3, which is selected from the group consisting of: (2S) -2- (. {1-oxo-5-phenyl}. -pentyl-1 - (3, 3-dimethyl) -1,2-dioxopentyl) pyrrolidine; 3,3-dimethyl-1 [(2S) -2- (5- (3-pyridyl) pentanoyl) -1-pyrrolidin] -1,2-pentanedione; (2S) -2- ( { 1 -oxo-4-phenyl.} - butyl-1 - (3,3-dimethyl-1,2-dioxobutyl) pyrrolidine; (2S) -2- ( { 1 -oxo-4-phenyl] -buti 1-1 - (2-cyclohexyl-1,2-dioxoethyl) pyrrole idine; 2- (. {1-oxo-4-phenyl}. -butyl-1 - ( 3,3-dimethyl-1,2-dioxobutyl) pyrrolidine; and 1 - { (2S) -2- [5, 5-di (4-fluorophenyl) pentanoyl] -2-pyrrolidin.} -3.3 dimethyl-1,2-pentanedione 5. The compound of claim 2, wherein Z is S. The compound of claim 5, which is selected from the group consisting of: 1- (3,3-) dimethyl-1, 2-dioxopentyl) -2-piperidincarbothioate 2-phenyl-1-ethyl; (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate (3-thioindolyl) methyl; (2S) -1 - (2-cyclohexyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 2-phenyl-1-ethyl lo; (2S) -1 - (1-cyclopentyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 2-phenyl-1-ethyl; (2S) -1 - (3,3-dimethyl-1,2-dioxopetnyl) -2-pyrrolidinecarbothioate 3-phenyl-1-propyl; (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3- (3-pyridyl) -1-propyl; (2S) -1- (2-cyclohexy 1-1, 2-dioxoethyl) -2-pi rro I id 3-phenyl-1-propyl incarbothioate; (2S) -1 - (2-cyclohexyl-1,2-dioxoethyl) -2-pyrrolidinecarbothioate 4-phenyl-1-butyl; (2 S) -1 - (3, 3-d i meti 1-1, 2-d ioxopentyl) -2-pi rro I id incarbothioate of 4-f in i I-1-butyl; (2S) -1 - (2-cyclohexyl-1,2-d-ioxopentyl) -2-pi rro I id incarbothioate of 3- (3-pyridyl) -1-propyl; (2 S) -1- (3, 3-d i meti 1-1, 2-d ioxopentyl) -2-pi rro I id incarbothioate of 3, 3-d ifen i 1-1 -propyl; (2S) -1 - (2-cyclohexyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3,3-diphenyl-1-propyl; (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate of 3- (para-methoxyphenyl) -1-propyl; (2S) -1 - (3,3-Dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3,3-di (para-fluoro) phenyl-1-propyl; 1 - (3, 3-d i met i l-2-oxopentane i l) -2-pi rrol id incarbothioate of 4, 4-di. { parafluorophenyl) butyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (1-naphthyl) propyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) tetrahydro-1H-2-pyrrolcarbothioate 2,2-diphenylethyl; (2S) -1- (3,3-Dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate of 3- [4- (trifluoro methyl) phenyl] I] propyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-naphthyl) propyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (3-chlorophenyl) propyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- [3- (trifluoromethyl) phenyl] propyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (1-biphenyl) propyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-fluorophenyl) propyl; (2 S) -1 - (3, 3-d i methy1-2-oxopentanoyl) -2-pyrro I id 3- (3-fluorophenyl) propyl incarbothioate; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-chlorophenyl) propyl; and (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate of 3- (3,4-dimethoxyphenyl) pro pyl. The compound of claim 1, wherein: n is 1; and X is S. 8. The compound of claim 7, wherein Z is CH2. 9. The compound of claim 7, wherein Z is S. 1 0. The compound of claim 1, wherein: n is 2; and X is O. 1 1. The compound of claim 10, wherein Z is CH2. The compound of claim 1, which is selected from the group consisting of: 2- (. {1-oxo-6-phenyl]. -hexyl-1 - (3, 3-d) Methyl-1,2-dioxobutyl I) piperidine, and 3,3-di met-1-1 [2- (4-phenylpentanoyl) piperidine] -1,2-pentanedione.1 3. The compound of claim 10 , wherein Z is S. The compound of claim 13, which is selected from the group consisting of: (2 S) -1 - (3, 3-di meti 1-1, 2-d ioxopentyl) - 2-pyrrolidyl 2-phenyl-1-ethyl incarbothioate; 1 - (2-f in i 1-1, 2-di oxoet il) -2-piperid 2-phenyl-1-ethyl incarbothioate; 1 - ( 3, 3-di meti 1-1, 2-d-ioxobutyl) -2-pperidiocarbonate 3-phenyl-1-propyl; 1 - . 1 - . 1 - . 1- (1, 2-dioxo-3,3-dimethylbutyl) -2-piperidinecarbotyioate 4-phenyl-1-butyl; 1 - (3, 3-d i meti 1-1, 2-d and oxopentayl) -2-piperid i-carbothioate of 1,5-diphenyl-3-pentyl; 1- (1,5-phenyl-1,2-dioxoethyl) -2-piperidinecarbothioate 1,5-diphenyl-3-mercaptopentyl; 1- (1, 2-dioxo-3,3-dimethylpentyl) piperidine-2-carbothioate of 3- (para-methoxyphenyl) -1-propyl; 1- (2-phenyl-1,2-dioxoethyl) piperidin-2-carbothioate of 3- (para-methoxyphenyl) -1-propyl; 3- (1-Naphthyl) -1-propyl 1- (3,3-dimethyl-1,2-dioxopentyl) piperidin-2-carbothioate; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 2,2-diphenylethyl; 1 - (3, 3-d i methy1-2-oxo pentane i) -2-piperid i-3,3-diphenylpropylcarbonate; (2R, S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3- (2-naphthyl) propyl; 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 4-phenylbutyl; 1 - (3, 3-d i methyl-2-oxo pentane i) -2-pi pe rid 3-phenylpropyl incarbothioate; 1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate 3- (2-chlorophenyl) propyl; 1 - (3, 3-d i methyl-2-oxo pentanyl) -2-pi pe rid i ncarbothioate of 3- (2-fluorophenyl) propyl; and 1- (3, 3-d i met i 1-2-oxo pentanoyl) -2-piperid incarbothioate of 3- (3-fluorophenyl) propyl. The compound of claim 1, wherein: n is 2; and X is S. 16. The compound of claim 15, wherein Z is CH2. 17. The compound of claim 1, wherein Z is S. 18. The compound of claim 1, wherein Z is CH R! . 19. The compound of claim 1 which is 2- (. {1-oxo- [2-. {2'-phenyl} ethyl] -4-phenyl}. -butyl-1- (3,3-dimethyl-1,2-dioxobutyl) piperidine. 20. A pharmaceutical composition comprising: (i) an effective amount of the compound of claim 1 for effecting a neuronal activity; and (ii) a pharmaceutically acceptable carrier. twenty-one . The pharmaceutical composition of claim 20, wherein, in said compound: n is 1; and X is O. 22. The pharmaceutical composition of claim 21, wherein, in said compound, Z is CH2. 23. The pharmaceutical composition of claim 22, wherein said compound is selected from the group consisting of: (2S) -2- (. {1-oxo-5-phenyl}. -pentyl-1 - (3, 3-dimethyl-1,2-dioxopentyl) pyrrolidine; 3,3-dimethyl-1 [(2S) -2- (5- (3-pyridyl) pentanoyl) -1-pyrrolidin] -1,2-pentanedione; (2S ) -2- ( { 1 -oxo-4-phenyl.} - butyl-1 - (3,3-dimethyl-1,2-dioxobutyl) pyrrolidine; (2S) -2- (. {1-oxo-4-phenyl} -butyl-1 - (2-cyclohexyl-1,2-dioxoethyl) pyrrolidine; 2- (. {1-oxo-4-phenyl}. -butyl-1 - (3,3-dimeti 1-1, 2-di oxo buti I) pyrro I id ina; and 1 - { (2S) -2- [5,5-di (4-f luorofenyl) pentanoyl] -2-pyrrolidin.} - 3,3-dimethyl-1,2-pentanedione 24. The pharmaceutical composition of claim 21, wherein, in said compound Z is S. 25. The pharmaceutical composition of the claim 24, wherein said compound is selected from the group consisting of: 1- (3, 3-di met i 1-1, 2-di oxopentyl) -2-piperid i 2-phenyl-1-ethylcarbonate; (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate (3-thioindolyl) methyl; (2 S) -1- (2-cyclohexy 1-1, 2-dioxopentyl) -2-pyrro I id i ncarbothioate of 2-f in 1-1-ethyl; (2S) -1- (1-cyclopentyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 2-phenyl-1-ethyl; (2S) -1- (3,3-dimethyl-1,2-dioxopetnyl) -2-pyrrolidinecarbothioate 3-phenyl-1-propyl; (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3- (3-pyridyl) -1-propyl; (2S) -1- (2-cyclohexyl-1,2-dioxoethyl) -2-pyrrolidinecarbotioate of 3-f in I-1-propyl; (2S) -1- (2-cyclohexyl-1,2-d-oxoethyl) -2-pyridylcarbodioate of 4-f in i-1-butyl; (2 S) -1 - (3,3-d-methyl-1,2-dioxopentyl) -2-pyrrolidincarbothioate 4-phenyl-1-butyl; (2S) -1- (2-cyclohexyl-1,2-dioxopentyl) -2-pyrrolidinocarboxylate 3- (3-pyridyl) -1-propyl; (2 S) -1 - (3, 3-d i meti 1-1, 2-d ioxopentyl) -2-pi rro I id incarbothioate of 3, 3-d ifen 1-1-propyl; (2S) -1- (2-cyclohexyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3,3-diphenyl-1-propyl; (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate of 3- (para-m-ethoxyphenyl) -1-prophenyl; (2S) -1- (3,3-Dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3,3-di (para-fluoro) phenyl-1-propyl; 1 - . 1 - . 1 - . 1 - . 1- (3, 3-dimethyl-2-oxopentanoyl) -2-pyrrole id 4,4-di (para-fluorophenyl) butylcarbothioate; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (1-naphthyl) propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) tetrahydro-1 H-2-pyrrolcarbothioate 2,2-diphenylethyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- [4- (trifluoromethyl) phenyl] propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-naphthyl) propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (3-chlorophenyl) propyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- [3- (trifluoromethyl) phenyl] propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (1-biphenyl) propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarboxylate 3- (2-fluorophenyl) propyl; (2S) -1- (3,3-dimethyl-2-oxopentane] -1) -2- pyrrolidino-3- (3-fluorophenyl) propyl ester; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-chlorophenyl) propyl; and 3- (3,4-dimethoxyphenyl) propyl (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate. 26. The pharmaceutical composition of claim 20, wherein, in said compound: n is 1; and X is S. 27. The pharmaceutical composition of claim 26, wherein, in said compound, Z is CH2. 28. The pharmaceutical composition of claim 26, wherein, in said compound, Z is S. 29. The pharmaceutical composition of claim 20, wherein, in said compound: n is 2; and X is O. 30. The pharmaceutical composition of claim 29, wherein, in said compound, Z is CH. 31 The pharmaceutical composition of claim 30, wherein said compound is selected from the group consisting of: 2- (. {1-oxo-6-phenyl} -hexyl-1 - (3,3-dimethyl- 1,2-dioxobutyl) piperidine, and 3,3-dimethyl-1 [2- (4-phenylpentanoyl) pperidine] -1, 2-pentanedione 32. The pharmaceutical composition of claim 29, wherein, in said compound, Z is S. The pharmaceutical composition of claim 32, wherein said compound is selected from the group consisting of: (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2- 2-phenyl-1-ethyl pyrrolidinecarbothioate; 2 - phenyl-1-ethyl-1- (2-phenyl-1,2-dioxoethyl) -2-piperidinecarbothioate; 1- (3-phenyl-1-propyl) -1- (3,3-dimethyl-1,2-dioxobutyl) -2-piperidinecarbothioate; 1- (1, 2-dioxo-3,3-dimethylbutyl) -2-piperidinecarbotyioate 4-phenyl-1-butyl; 1 - (3, 3-d-meti 1-1, 2-d-ioxopentayl) -2-piperid incarbothioate 1,5-diphenyl-3-pentyl; 1- (1,5-phenyl-1,2-dioxoethyl) -2-piperidinecarbothioate 1,5-diphenyl-3-mercaptopentyl; 1- (1, 2-dioxo-3,3-dimethylpentyl) piperidine-2-carbothioate of 3- (para-methoxyphenyl) -1-propyl; 1- (2-phenyl-1,2-dioxoethyl) piperidin-2-carbothioate of 3- (para-methoxyphenyl) -1-propyl; 3- (1-Naphthyl) -1-propyl 1- (3,3-dimethyl-1,2-dioxopentyl) piperidin-2-carbothioate; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 2,2-diphenylethyl; 3,3-diphenylpropyl 1,3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate; (2R, S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3- (2-naphthyl) propyl; 1 - (3, 3-d i m eti l-2-oxo pentane i l) -2-pi pe rid i ncarbotioate of 4-f in i I butyl; 1 - (3, 3-d i m eti l-2-oxo pentane i l) -2-piperid i 3-phenylpropylcarbothioate; 3- (2-chlorophenyl) propyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3- (2-chlorophenyl) propyl; 1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3- (2-fluorophenyl) propyl; and 3- (3-fluorophenyl) propyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate. 34. The pharmaceutical composition of claim 20, wherein, in said compound: n is 2; and X is S. 35. The pharmaceutical composition of claim 34, wherein, in said compound, Z is CH2. 36. The pharmaceutical composition of claim 34, wherein, in said compound, Z is S. 37. The pharmaceutical composition of claim 34, wherein, in said compound, Z is CHRi. 38. The pharmaceutical composition of claim 37, wherein said compound is 2- (. {1-oxo- [2-. {2'-phenyl} ethyl] -4-phenyl} -butyl- 1- (3, 3-dimethyl-1,2-dioxobutyl) piperidine 39. A method for effecting neuronal activity in an animal, comprising: administering to the animal an effective amount of the compound of claim 1. 40. The method of claim 39, 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 41. The method of claim 40, wherein the neurological disorder is selects from the group consisting of peripheral neuropathy caused by physical injury or disease status, traumatic brain injury, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder related to neurodegeneration. of claim 41, wherein the neurological disorder in relation to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. 43. The method of claim 39, wherein, in said compound: n is 1; and X is O. 44. The method of claim 43, wherein, in said compound, Z is CH2. 45. The method of claim 43, wherein said compound is selected from the group consisting of: (2S) -2- (. {1-oxo-5-phenyl}. -pentyl-1 - (3, 3-dimethyl-1,2-d-ioxo pentyl) pyrrole id i; 3,3-dimethyl-1 [(2S) -2- (5- (3-pyridyl) pentanoyl) -1-pyrrolidine] -1, 2 -pentanodone; (2S) -2- ( { 1 -oxo-4-phenyl}. Butyl-1 - (3,3-dimethyl-1,2-dioxobutyl) pyrrolidine; (2S) -2- ( { 1-oxo-4-phenyl] -butyl-1 - (2-cyclohexyl-1,2-dioxoethyl) pyrrolidine; 2- (. {1-oxo-4-phenyl} -buty 1-1 - (3 , 3-d imethyl-1, 2-dioxobutyl) pi rrol idine, and 1 - { (2 S) -2- [5,5-di (4-f luorofenyl) pentanoyl] -2-pyrrolidine.} - 3, 3-dimethyl-1,2-pentanedione 46. The method of claim 43, wherein, in said compound, Z is S. 47. The method of claim 46, wherein said compound is selected from a group consisting of: 1- (2,3-dimethyl-1,2-dioxopentyl) -2-piperidinecarbothioate 2-phenyl-1-ethyl; (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate (3-thioindolyl) methyl; (2 S) -1- (2-cyclohexy 1-1,2-dioxopentyl) -2-pi rro I id i ncarbothioate of 2-f in i I-1-ethyl; (2S) -1- (1-cyclopentyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 2-phenyl-1-ethyl; (2S) -1- (3,3-dimethyl-1,2-dioxopetnyl) -2-pyrrolidinecarbothioate 3-phenyl-1-propyl; (2S) -1- (3,3-d-imethyl-1,2-d -ioxopentyl) -2-pyrrolidincarbothioate 3- (3-pyridyl) -1-propyl; (2 S) -1- (2-cyclohexy 1-1,2-dioxoethyl) -2-pi rro I id i ncarbotioate of 3-f in i I-1-propyl; (2S) -1- (2-cyclohexyl-1,2-dioxoethyl) -2-pyrrolidinecarboxylate 4-phenyl-1-butyl; (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 4-phenyl-1-butyl; (2S) -1- (2-cyclohexyl-1,2-d -ioxopentyl) -2-pyrro I id i ncarbothioate of 3- (3-pyridyl) -1-propyl; (2S) -1- (3,3-Dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate of 3, 3-d ifen i 1-1-propyl; (2S) -1- (2-cyclohexyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3,3-diphenyl-1-propyl; (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarbothioate 3- (para-methoxyphenyl) -1-propyl; (2 S) -1 - (3, 3-d i meti 1-1, 2-dioxopentyl) -2-pyrrolidincarbothioate of 3,3-di (para-fluoro) phenyl-1-propyl; 1 - . 1- (3, 3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate of 4,4-di (para-fluorophenyl) butyl; (2 S) -1 - (3, 3-d i meti l-2-oxopentanoyl) -2-p i rro lidi ncarbotioate of 3- (1-naphthyl) propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) tetrahydro-1 H-2-pyrrolcarbothioate 2,2-diphenylethyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- [4- (trifluoromethyl) phenyl] propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-naphthyl) propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidincarbothioate 3- (3-chlorophenyl) propyl; (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- [3- (trifluoromethyl) phenyl] propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (1-biphenyl) propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-fluorophenyl) propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (3-fluorophenyl) propyl; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-chlorophenyl) propyl; and (2S) -1- (3, 3-d i methy1-2-oxopentanoyl) -2-pyrrolidone 3- (3,4-dimethoxyphenyl) propylcarbonate. 48. The method of claim 39, wherein, in said compound: n is 1; and X is S. 49. The method of claim 48, wherein, in said compound, Z is CH2. 50. The method of claim 48, wherein Z is S. 51. The method of claim 39, wherein, in said compound: n is 2; and X is O. 52. The method of claim 51, wherein, in said compound, Z is CH2. 53. The method of claim 52, wherein said compound is selected from the group consisting of: 2- (. {1-oxo-6-phenyl}. -hexyl-1 - (3,3-dimethyl-1) , 2-dioxobutyl) piperidine, and 3,3-di met i 1-1 [2- (4-phenylpentanoyl) piperidine] -1, 2-pentanedione 54. The method of claim 51, wherein, in said compound , Z is S. 55. The method of claim 54, wherein said compound is selected from the group consisting of: (2 S) -1 - (3, 3-d-meti 1-1, 2-d-ioxopentyl) -2-pyrro I id i ncarbothioate 2-phenyl-1-ethyl; 1- (2-phenyl-1,2-dioxoethyl) -2-piperidinecarboxylate 2-phenyl-1-ethyl; 1 - (3, 3-dimethyl-1,2-dioxobutyl) -2-piperidyl 3-phenyl-1-propylcarbothioate; 1 - . 1 - . 1 - . 1- (1, 2-dioxo-3,3-dimethylbutyl) -2-piperidinecarbotyioate 4-phenyl-1-butyl; 1 - (3, 3-d i met i 1-1, 2-d ioxopental) -2-piperid i-carbothioate of 1,5-dif in il-3-pentyl; 1- (1,5-phenyl-1,2-dioxoethyl) -2-piperidinecarbothioate 1,5-diphenyl-3-mercaptopentyl; 1- (1, 2-dioxo-3,3-dimethylpentyl) piperidine-2-carbothioate of 3- (para-methoxyphenyl) -1-propyl; 1- (2-phenyl-1,2-dioxoethyl) piperidin-2-carbothioate of 3- (para-methoxyphenyl) -1-propyl; 1- (3- (1-naphthyl) -1-propyl 1- (3,3-dimethyl-1,2-dioxopentyl) piperidin-2-carbothioic acid ester; (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 2,2-diphenylethyl; 1 - (3, 3-d i met i 1-2-oxo pentane i) -2-piperid i -carbothioate of 3,3-diphenylpropyl; (2R, S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3- (2-naphthyl) propyl; 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 4-phenylbutyl; 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3-phenylpropyl; 3- (2-chlorophenyl) propyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3- (2-chlorophenyl) propyl; 1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3- (2-fluorophenyl) propyl; and 3- (3-fluorophenyl) propyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate. 56. The method of claim 39, wherein, in said compound: n is 2; and X is S. 57. The method of claim 56, wherein, in said compound, Z is CH2. 58. The method of claim 56, wherein, in said compound, Z is S. 59. The method of claim 56, wherein, in said compound, Z is CH Ri. 60. The method of claim 59, wherein said compound is 2- (. {1-oxo- [2-. {2'-phenyl} ethyl] -4-phenyl.} - butyl-1. - (3,3-dimethyl-1,2-dioxobutyl) piperidine. SUMMARY This invention relates to small molecule, low molecular weight heterocyclic ketones and thioesters, which have an affinity for FKBP type immunophilins, and their use as inhibitors of enzyme activity associated with immunophilin proteins, particularly peptidyl enzyme activity -prolyl isomerase, or rotamase.