HK1025739A

HK1025739A - N-oxides of heterocyclic esters, amides, thioesters and ketones

Info

Publication number: HK1025739A
Application number: HK00104955.5A
Authority: HK
Inventors: S. Hamilton Gregory; P. Steiner Joseph; S. Burak Eric
Original assignee: Gpi Nil Holdings, Inc.
Priority date: 1997-02-28
Filing date: 1998-02-26
Publication date: 2000-11-24

Description

N-oxides of heterocyclic esters, amides, thioesters and ketones

no marking

Background

1. Field of the invention

The present invention relates to neurotrophic low molecular weight, small molecule N-oxides of heterocyclic esters having an affinity for FKBP-type immunophilins, and their use as inhibitors of enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

2. Description of the related Art

The term immunophilins is a series of proteins that act as receptors for the major immunosuppressant drugs, cyclosporin a (csa), FK506, and rapamycin. A known class of immunophilins is KF506, or FKBPs, of cyclophilins and connexins. Cyclosporin a binds cyclophilin a when FK506 and rapamycin are bound to FKBP 12. These immunophilin-drug complexes have various intracellular signal transduction systems, especially the interfaces of the immune and nervous systems.

Immunophilins are known to have peptidyl-prolyl isomerase (PPI enzyme), or rotamase, enzyme activity. In the case of immunophilin proteins, it has been determined that the enzymatic activity of rotamase enzymes plays a catalytic role in the interconversion of cis and trans isomers of peptide and protein materials.

Immunophilins were first discovered and studied in immune tissues. It was initially hypothesized by those skilled in the art that inhibition of the rotamase activity of immunophilins results in inhibition of T-cell proliferation, thereby resulting in immunosuppressive activity exhibited by immunosuppressant drugs such as cyclosporin a (csa), FK506, and rapamycin. It has also been found that inhibition of rotamase activity does not, on its own, produce immunosuppressive activity (Schreiber et al, Science, 1990, Vol. 250, pp. 556-559). In contrast, the immunosuppressive effect appears to be due to the formulation of a complex of the immunosuppressant drug and the immunophilin. The immunophilio-drug complexes have been shown to interact with ternary protein targets as their mode of action (Schreiber et al, Cell (Cell), 1991, vol 66, pp 807-815). In the case of FKBP-FK506 and cyclophilin-CsA, the immunophilin-drug complex binds to calcineurin and inhibits T-cell receptors signaling T-cell proliferation. Similarly, the immunophilin-drug complex of FKBP-rapamycin interacts with RAFT1/FRAP protein and inhibits signaling by IL-2 receptors.

Immunophilins have been found to be present in high concentrations in the central nervous system. The immunophilin is 10-50 times higher in the central nervous system than in the immune system. In neural tissue, immunophilins may affect the synthesis of nitrogen-containing oxides, the release of neurotransmitters and the spread of neuronal processes.

It has been found that micromolar concentrations of immunosuppressive agents, such as FK506 and rapamycin, stimulate the expression of PC₁2 cells and sensory neurons, i.e., ganglion cells (DRGs) of the posterior root of the spinal nerve (Lyons et al, Proc. of Natl. Acad. Sci., 1994, Vol. 91, p. 3191 3195). Throughout animal testing, FK506 has been shown to stimulate nerve regeneration following facial nerve injury.

Surprisingly, it has been found that certain compounds having a strong affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects. In addition, these rotamase inhibitors lack immunosuppressive activity. These findings have led to suggestions for the use of rotamase inhibitors to treat various peripheral neutropenia and to enhance neuronal regeneration in the Central Nervous System (CNS). Studies have demonstrated that neurodegenerative disorders such as alzheimer's disease, parkinson's disease and Amyotrophic Lateral Sclerosis (ALS) may result due to loss or reduction of the availability of neurotrophic substances specifically designed to affect specific populations of neurons in the disorder.

Several neurotrophic factors in the central nervous system that affect specific neuronal populations have been identified. For example, it has been postulated that Alzheimer's disease results from a reduction or loss of Nerve Growth Factor (NGF). Exogenous neurotrophins or other neurotrophins, such as brain derived auxin, glial derived auxin, ciliary neurotrophin and neurotrophin-3 have therefore been proposed for the treatment of patients with Alzheimer's disease (SDAT) for increasing the survival of the degenerating neuronal population.

The use of these proteins in the clinical treatment of various neurological diseases has been hampered by difficulties in the delivery and bioavailability of large proteins to the target nervous system. In contrast, immunosuppressant drugs with neurotrophic activity are relatively small molecules and exhibit excellent bioavailability and specificity. However, when administered continuously, immunosuppressant drugs exhibit a range of potentially serious side effects, including nephrotoxicity, such as damage to glomerular filtration and irreversible gap fibrosis (Kopp et al, j.am. soc. nephrol., 1991, 1: 162); neurological deficits such as involuntary tremor; or nonspecific cerebellar colic, such as non-localized headache (De Groen et al, N.Engl. J.Med., 1987, 317: 861); and hypertension, which can produce complications (Kahan et al, n.engl.j.med., 1989, 321: 1725).

To avoid the side effects associated with the use of immunosuppressant drugs, the present invention provides non-immunosuppressive compounds containing small molecule FKBP rotamase inhibitors for enhancing the natural development of axons, promoting neuronal growth and regeneration in a variety of neuropathological conditions, facilitating neuronal repair, including: peripheral nerve damage caused by physical injury or disease states such as diabetes; physical damage to the central nervous system (spinal cord and brain); brain damage caused by impact, and neuropathological disorders associated with neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's disease), and amyotrophic lateral sclerosis.

Summary of the invention

The present invention relates to neurotrophic low molecular weight, small molecule compounds having affinity for FKBP-type immunophilins. These neurotrophic compounds, once bound to a protein, are potent inhibitors of immunophilin-related enzyme activity, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity. A key feature of the compounds of the present invention is that they do not produce any potent immunosuppressive activity other than their neurotrophic activity. Another important feature is that the newly added oxidation at a particular amino group produces the corresponding N-oxide, which is unexpectedly increased in both bioavailability and potency compared to compounds lacking the N-oxide group.

In particular to a compound shown in a formula I or a pharmaceutically acceptable salt thereof,wherein: a and B together with the nitrogen and carbon atoms to which they are attached form a 5-to 7-membered saturated or unsaturated heterocyclic ring consisting of CH₂、O、S、SO、SO₂NH, or NR₁Any combination thereof in any chemically stable oxidation state;

w is O, S, CH₂Or H₂；

R is a group consisting of C₃～C₈Cycloalkyl optionally substituted C₁～C₆Straight or branched alkyl or alkenyl, C₃Or C₅Cycloalkyl radical, C₅-C₇Cycloalkenyl radical or Ar₁Wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl may be substituted by C₁～C₄Alkyl radical, C₁～C₄Alkenyl or hydroxy optionally substituted, said Ar₁Is selected from the group consisting ofHydrogen, halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄1-naphthyl, 2-naphthyl, 1-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl with 1 to 3 substituents selected from the group consisting of alkenyloxy, phenoxy, benzyloxy and amino;

x is O, NH, NR₁、S、CH、CR₁Or C (R)₁)₂；

Y is a direct bond, or one or more positions are substituted by C₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₂S, SO or SO₂Optionally substituted, wherein R₂Selected from the group consisting of hydrogen, (C)₁～C₄) Straight or branched alkyl, (C)₃～C₄) Straight or branched alkenyl or alkynyl, and (C)₁～C₄) Bridged alkyl wherein a bridge is formed between the nitrogen and the carbon atom of said alkyl or alkenyl containing said heteroatom forming a ring, wherein said ring is optionally fused to an Ar group; and

z is an aromatic or tetraalkylamine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide, Ar is a mono-, di-or tricyclic carbonyl or heterocyclic ring, wherein 1-3 positions of said ring may or may not be substituted with halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄Alkoxy radical, C₁～C₄Alkenyloxy, phenoxy, benzyloxy, amino, or combinations thereof; wherein the size of a single ring is 5-6 membered ring; wherein the heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of O, N, S and combinations thereof, wherein at least one heteroatom is nitrogen; wherein the hydrocarbyl amine is oxidized to the corresponding N-oxide with the hydrocarbyl group being C in one or more positions₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₁S, SO or SO₂Optionally substituted; and

R₁is hydrogen, (C)₁～C₄) Straight or branched alkyl, (C)₃～C₄) Straight or branched alkenyl or alkynyl, or R₁Are defined as Y to Z.

Another preferred embodiment of the present invention is a compound of formula II or a pharmaceutically acceptable salt thereof,wherein E, F, G and H are each CH₂、O、S、SO、SO₂NH, or NR₁；

W is O, S, CH₂Or H₂；

R is a group consisting of C₃～C₈Cycloalkyl optionally substituted C₁～C₆Straight or branched alkyl or alkenyl, C₃Or C₅Cycloalkyl radical, C₅-C₇Cycloalkenyl radical or Ar₁Wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl may be substituted by C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,C₁～C₄Alkenyl or hydroxy optionally substituted, said Ar₁Is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄1-naphthyl, 2-naphthyl, 1-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl with 1 to 3 substituents selected from the group consisting of alkenyloxy, phenoxy, benzyloxy and amino;

x is O, NH, NR₁、S、CH、CR₁Or C (R)₁)₂；

z is an aromatic or tetraalkylamine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide, Ar is a mono-, di-or tricyclic carbonyl or heterocyclic ring, wherein 1-3 positions of said ring may or may not be substituted with halogenHydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄Alkoxy radical, C₁～C₄Alkenyloxy, phenoxy, benzyloxy, amino, or combinations thereof; wherein the size of a single ring is 5-6 membered ring; wherein the heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of O, N, S and combinations thereof, wherein at least one heteroatom is nitrogen; wherein the hydrocarbyl amine is oxidized to the corresponding N-oxide with the hydrocarbyl group being C in one or more positions₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₁S, SO or SO₂Optionally substituted; and

Another preferred embodiment of the invention are compounds of formula III and pharmaceutically acceptable salts thereof,wherein E, F and G are each CH₂、O、S、SO、SO₂NH, or NR₁；

W is O, S, CH₂Or H₂；

R is a group consisting of C₃～C₈Cycloalkyl optionally substituted C₁～C₆Straight or branched alkyl or alkenyl, C₃Or C₅Cycloalkyl radical, C₅-C₇CycloalkenesRadical or Ar₁Wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl may be substituted by C₁～C₄Alkyl radical, C₁～C₄Alkenyl or hydroxy optionally substituted, said Ar₁Is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄1-naphthyl, 2-naphthyl, 1-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl with 1 to 3 substituents selected from the group consisting of alkenyloxy, phenoxy, benzyloxy and amino;

x is O, NH, NR₁、S、CH、CR₁Or C (R)₁)₂；

z is an aromatic or tetraalkylamine oxidized to a corresponding N-oxide, wherein the aromatic amine is oxidized to a corresponding N-oxideAr of the compound is mono-, di-or tricyclic carbonyl or heterocycle, wherein 1-3 positions of the ring may or may not be substituted by halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄Alkoxy radical, C₁～C₄Alkenyloxy, phenoxy, benzyloxy, amino, or combinations thereof; wherein the size of a single ring is 5-6 membered ring; wherein the heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of O, N, S and combinations thereof, wherein at least one heteroatom is nitrogen; wherein the hydrocarbyl amine is oxidized to the corresponding N-oxide with the hydrocarbyl group being C in one or more positions₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₁S, SO or SO₂Optionally substituted; and

A further particularly preferred embodiment of the present invention is a compound of formula IV or a pharmaceutically acceptable salt thereof,wherein n is 1, 2 or 3 to form a 5-to 7-membered heterocyclic ring;

w is O, S, CH₂Or H₂；

R is a group consisting of C₃～C₈Cycloalkyl optionally substituted C₁～C₆Straight or branched chain alkanesRadical or alkenyl, C₃Or C₅Cycloalkyl radical, C₅-C₇Cycloalkenyl radical or Ar₁Wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl may be substituted by C₁～C₄Alkyl radical, C₁～C₄Alkenyl or hydroxy optionally substituted, said Ar₁Is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄1-naphthyl, 2-naphthyl, 1-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl with 1 to 3 substituents selected from the group consisting of alkenyloxy, phenoxy, benzyloxy and amino;

x is O, NH, NR₁、S、CH、CR₁Or C (R)₁)₂；

z is oxidized to a corresponding N-An aromatic or tetraalkylamine of an oxide wherein the aromatic amine is Ar oxidized to a corresponding N-oxide, Ar is a mono-, di-or tricyclic carbonyl or heterocycle wherein 1 to 3 positions of said ring may or may not be substituted with halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄Alkoxy radical, C₁～C₄Alkenyloxy, phenoxy, benzyloxy, amino, or combinations thereof; wherein the size of a single ring is 5-6 membered ring; wherein the heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of O, N, S and combinations thereof, wherein at least one heteroatom is nitrogen; wherein the hydrocarbyl amine is oxidized to the corresponding N-oxide with the hydrocarbyl group being C in one or more positions₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₁S, SO or SO₂Optionally substituted; and

In a preferred embodiment, Ar is selected from the group consisting of pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyridazinyl, quinolinyl, isoquinolinyl.

Particularly preferred compounds of the invention include:

(2S) -1- (3, 3-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (2-pyridinyl) -1-propyl ester, N-oxide;

(2S) -1- (3, 3-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridinyl) -1-propyl ester, N-oxide;

(2S) -1- (3, 3-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (4-pyridinyl) -1-propyl ester, N-oxide;

(2S) -1- (1, 1-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (2-quinolinyl) -1-propyl ester, N-oxide;

(2S) -1- (1, 1-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (3-quinolinyl) -1-propyl ester, N-oxide;

(2S) -1- (1, 1-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (4-quinolinyl) -1-propyl ester, N-oxide.

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

The invention still further includes methods of using the compounds of the invention. A preferred embodiment includes a method of stimulating an injured neuron in an animal, the method comprising:

the animal is administered a neurotrophic effective amount of a compound of the present invention.

Another preferred embodiment of the present invention includes a method of promoting neuronal regeneration in an animal comprising:

Another embodiment of the invention encompasses a method of preventing neurodegeneration in an animal comprising:

Another embodiment of the invention encompasses a method of treating a neurological disorder in an animal comprising:

Neuropathological disorders which the compounds of the present invention may be particularly useful for treating are selected from the group consisting of peripheral nerve damage caused by physical injury or disease state, physical damage to the brain and spinal cord; brain damage caused by impact, and neuropathological disorders associated with neurodegeneration. Examples of such neuropathological disorders involving neurodegeneration are Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Brief description of the drawings of the invention

FIG. 1 is a bar graph showing MPTP-toxicity for preventing striatal TH nerve distribution density by parallel dosing. FIG. 1 shows that the compound of the invention administered at 4 mg/kg significantly prevented MPTP-toxicity in the striatal nerves. Detailed description of the invention

Definition of

"alkyl", unless otherwise defined, refers to a branched or unbranched saturated hydrocarbon chain having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

"alkoxy" means an-OR group, wherein R is an alkyl group as defined above. Preferably, R is a branched or unbranched saturated hydrocarbon chain having 1 to 3 carbon atoms.

"halogen" means, unless otherwise defined, fluorine, chlorine, bromine or iodine.

"phenyl" includes all possible isomeric phenyl groups, optionally mono-or polysubstituted, the substituents being selected from the group consisting of alkyl, alkoxy, hydroxy, halogen and haloalkyl.

The term "C₁～C₆"and similar terms found in standard chemical nomenclature when used for alkyl and alkenyl chains, are understood by those skilled in the art to include chains such as C₁～C₃、C₁～C₄、C₁～C₅、C₁～C₆、C₂～C₄、C₂～C₅、C₂～C₆、C₃～C₅、C₃～C₆、C₄～C₆And their isomers.

The term "pharmaceutically acceptable salt" refers to salts of the subject compounds that possess the desired pharmaceutical activity without biologically or otherwise undesirable activity. The salts may be formed with inorganic acids such as acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, caproates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, oxalates, thiocyanates, tosylates, and undecanoates. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylammonium salts, N-methyl-D-glucamine, and amino acid salts such as arginine and lysine, and the like. The nitrogen-containing basic groups may be formed into quaternary ammonium salts with reagents such as lower alkyl halides, chloro, bromo, and iodo methyl, ethyl, propyl, and butyl, dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain alkyl halides such as chloro, bromo, and iodo decyl, dodecyl, tetradecyl, and octadecyl, halogenated aromatic alkyls such as benzyl bromide and phenethyl bromide, and others. Thereby obtaining a water or oil soluble or dispersible product.

The compounds of the present invention have at least one asymmetric center and thus can produce mixtures of stereoisomers or individual enantiomers or diastereomers. The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of the intermediate at some suitable stage of the synthesis, using optically active starting materials, or by resolution of the compounds of formula (I). It is understood that the individual stereoisomers as well as mixtures of stereoisomers (racemic and non-racemic) are included within the scope of the present invention. The S stereoisomer of the 1-position atom of formula I is most preferred because of its higher activity.

"isomers" are different compounds having the same molecular formula.

"stereoisomers" are isomers that differ only in the way the atoms are arranged in space.

"enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other.

"diastereomers" are stereoisomers that do not mirror each other.

A "racemic mixture" is a mixture containing equal parts of an individual enantiomer, and a "non-racemic mixture" is a mixture containing unequal parts of individual enantiomers or stereoisomers.

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

(i) preventing the occurrence of a disease or condition, which may be pre-treated before the disease and/or condition has not been diagnosed;

(ii) inhibiting said disease and/or condition, i.e. arresting its development; or

(iii) Alleviating the disease and/or condition and causing regression of the disease and/or condition.

The term "effect" in direct relation to "affecting neuronal activity" refers to producing or bringing about a desired effect or result, including but not limited to stimulating neurons, promoting regeneration, preventing degeneration and treating disorders.

The nomenclature used for the compounds of the invention is as follows, taking the compound of formula IV as an example.

A compound of the present invention, particularly of formula IV, wherein n is 1, R is 1, 1-dimethylpentyl, X is O, Y is (CH)₂)₃And Z is 3-pyridyl-N-oxide, designated (2S) -1- (3, 3-dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl ester, N-oxide. Compounds of the invention

The neurotrophic low molecular weight, small molecule KFBP inhibitor compounds of the present invention have an affinity for FKBP-type immunophilins such as FKBP 12. When a neurotrophic compound of the present invention binds to an FKBP-type immunophilin, it is found to inhibit the prolyl peptidyl cis-trans isomerase activity or rotamase enzyme activity of the binding protein and unexpectedly stimulate axonal growth.

Table 1 lists specific examples of these embodiments.

TABLE 1

The most preferred compounds of formula IV are:

The compounds of the present invention exist as stereoisomers, either enantiomers or diastereomers. Mixtures of enantiomers, racemic forms and diastereomers are within the scope of the invention. Enantiomers and diastereomers may be separated by methods known to those skilled in the art. Methods of use of the compounds of the invention

The compounds of the invention have affinity for FK506 binding proteins, in particular FKBP12, present in neuronal tissue. The compounds of the present invention exhibit excellent neurotrophic activity when bound to FKBP in neurons. This activity can be used to stimulate damaged neurons, promote neuronal regeneration, prevent neurodegeneration, and treat a variety of neuropathological disorders known to be caused by neuronal degeneration and peripheral neuropathy.

For the foregoing reasons, the present invention further relates to a method of affecting neuronal activity in an animal, comprising:

administering to the animal a neurotrophic effective amount of a compound of formula I, II, II, or IV.

In a preferred embodiment, the activity of the neuron is selected from the group consisting of stimulating an injured neuron, promoting neuronal regeneration, preventing and arresting neurodegeneration, and treating a neuropathological disorder.

Neuropathological disorders that may be treated include, but are not limited to: trigeminal neuralgia, glossopharyngeal neuralgia, muscular dystrophy, amyotrophic lateral sclerosis, chronic anterior cord poliomyelitis, progressive bulbar hereditary anterior cord poliomyelitis, hernia, explosive or prolapsed spinal cord syndrome, cervical spondylosis, plexus disorders (vascular or neurological), chest destructive syndrome, peripheral neuropathy caused by lead, dapsone, ticks, porphyria or guillain-barre syndrome, alzheimer's disease and parkinson's disease.

The compounds of the invention are particularly useful for treating neuropathological disorders selected from the group consisting of peripheral neuropathies caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, brain damage caused by impact, and neuropathological disorders associated with neurodegeneration. Examples of neuropathological disorders associated with neurodegeneration are Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Pharmaceutical compositions and formulations

For these purposes, the compounds of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, intrathecally or by implantation of a reservoir in a dosage formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion techniques.

For effective treatment of central nervous system targets, the compounds of the present invention should readily penetrate cerebral thrombosis when administered peripherally. Compounds that do not permeate cerebral thrombosis may be administered effectively through the ventricular circulation or other suitable delivery system suitable for administration to the brain.

The compounds of the present invention may be administered in the form of sterile injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fatty oils are conventionally employed as a solvent or suspending vehicle. Any mixed fatty oil may be used for this purpose including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, and especially polyoxyethylene modifications thereof, are suitable for use in the injectable formulations. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant.

The compounds may be administered orally in the form of capsules, tablets, aqueous suspensions or solutions. Tablets may contain carriers such as lactose and cereal starches, and/or lubricating agents such as magnesium stearate. The capsules may contain a diluent comprising lactose and dried cereal starch. Aqueous suspensions may contain emulsifying and suspending agents in admixture with the active ingredient. The oral dosage form may further comprise sweeteners and/or flavours and/or colouring agents.

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

The compounds of the present invention may also be administered topically, particularly for the treatment of neuropathological disorders in areas and organs readily accessible by topical administration, including the eye, skin or lower intestinal tract. Suitable topical formulations for use in these areas are readily prepared.

For topical application to the eye or for ocular use, the compounds may be formulated as a particulate suspension in isotonic, pH adjusted, sterile saline, or preferably as a solution in isotonic, pH adjusted, sterile saline, with or without a preservative such as benzyl alkonium chloride. In addition, for ophthalmic use, the compounds of the present invention may be formulated in an ointment such as petrolatum.

For topical application to the skin, the compound may be formulated in a suitable ointment containing the compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds may be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitol monostearate, tween 60, cetyl esters wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.

Topical administration to the lower intestinal tract can be effected by a rectal suppository formulation (see above) or by a suitable enema formulation.

Dosage levels of the active ingredient compounds useful in the treatment of the above-mentioned diseases are in the range of about 0.1 mg to about 10,000 mg, with dosage levels in the range of about 0.1 mg to about 1,000 mg being preferred. The amount of active ingredient that can be combined with the carrier to form a single dosage form will vary depending upon the patient being treated and the particular mode of administration.

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

The compounds can be administered in combination with other neurotrophic agents such as Neurotrophic Growth Factor (NGF), glial-derived growth factor, brain-derived growth factor, ciliary neurotrophin and neurotrophin-3. The dosage level of the other neurotrophic agent will depend on the factors described above and the neurotrophic effectiveness of the agent.

As discussed above, the compounds of the invention have affinity for FK506 binding proteins, particularly FKBP 12. Inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of this affinity. Ki test procedure

Inhibition of the prolyl peptidyl isomerase (rotamase) activity of the compounds of the invention can be assessed by known methods described in the literature (Harding et al, Nature, 1989, 341: 758. sup. 760; Holt et al, J.S.Chem.Soc., 115: 9923. sup. 9938). These values obtained are clear Ki's and are listed in Table II. Cis-trans isomerization of alanine-proline bound in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, was monitored by chymotrypsin-coupled spectrophotometric analysis, which releases p-nitroanilide from the cis substrate. Inhibition of the reaction by the addition of different concentrations of inhibitor was measured and the data was analyzed as a function of inhibitor concentration for changes in the first order rate constant to calculate clear Ki values.

To a plastic cuvette, 950 ml of frozen test buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 ml of FKBP (2.5 mM dithiothreitol), 25 ml of chymotrypsin (50 mg/ml in 1 mM HCl) and 10 ml of test compound in dimethylsulfoxide at different concentrations were added. The reaction was initiated by the addition of 5 ml of the zymolyte (succinyl-Ala-Phe-Pro-Phe-p-nitroanilide, 5 mg/ml in 2.35 mmol of LiCl in trifluoroethanol).

The absorbance was measured at 390 nm with a spectrophotometer over time and the rate constant was determined from the absorbance data obtained over time. These test data for representative compounds are listed in table II under the Ki column.

The neurotrophic effects of the compounds of the present invention can be demonstrated in vitro cell bioassay as described below. Chick Dorsal Root Ganglion (DRG) cultures and axon growth

Dorsal root ganglia were excised from chick embryos at 10 days of gestation. At 37 deg.C, 5% CO₂Whole ganglion explants were cultured in the environment on Matrigel-coated 12-well thin plates with Liebovitz L15 plus high glucose medium supplemented with 2 millimoles of glutamine and 10% fetal calf serum and also containing 10 micromoles of cytosine beta-D-arabinofuranoside (Ara C). After 24 hours, the DRGs were treated with various immunophilin ligands. 48 hours after administration atGanglia were observed under phase contrast or under a hofmann modulator with a Zeiss Axiovert transition microscope. Micrographs of the explants were made and axon growth quantified. Total axons were counted as positive for the ratio of axon diameter to DRG, for each experimental condition. 3-4 DRGs were cultured per well. Each treatment was performed in duplicate.

In vitro tests can prove the unexpectedly large metabolic stability of the N-oxides of the invention. In studies to directly estimate the metabolic rate of N-oxide, a murine liver microsome identification described below was used as the first model for metabolism. The data presented comparing the N-oxide of example 1 with its parent (unoxidized) compound shows that the N-oxide has a longer half-life than its parent compound. Furthermore, studies using purified esterase (described in detail below) demonstrated that example 1 underwent limited in vitro deesterification during the course of the study, while its precursor compound (unoxidized parent compound) underwent significant degradation under the same reaction conditions. Method for identifying microsome

Various liver microsomes are provided by suppliers. The microsomes are characterized prior to shipment. The reaction mixture contained microsomes, 5. mu.M MgCl, 1 mM NADP, 4 mM glucose-6-phosphate (G-6-P), and 1 unit/4 ml glucose-6-phosphate dehydrogenase (G-6-P DH). For all studies, the final microsomal protein concentration was 0.2 mg/ml. Incubate for 1 hour in a shaking water bath (37 ℃). The reaction was terminated by transferring a portion of the reaction mixture, placing it in a test tube with an equal volume of acetonitrile, and performing a biological assay using the internal standard method. The results of these experiments were taken as the half-life (t) of the compound_1/2) Are listed in Table II. Activity of esterase

Purified rabbit liver esterase was purchased from Sigma. 5 units of enzyme were placed in 2 ml of 0.05M Tris (Tris (hydroxymethyl) aminomethane) buffer (pH 7.5). The culture was carried out for 2 hours. The reaction was terminated by transferring a portion of the reaction mixture into a test tube with an equal volume of acetonitrile and bioanalyzed by the internal standard method. The results of these experiments are presented in table II as the enzymatic degradation rate of the compounds.

The results of these in vitro experiments for (2S) -1- (3, 3-dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridinyl) -1-propyl ester (parent) are set forth in Table II.

TABLE II

Compound (I)	K_I(nM)	ED₅₀(nM)	T_1/2(minutes)	Esterase degradation (pmol min/mg/protein)
Compound (I)	K_I(nM)	ED₅₀(nM)	T_1/2(minutes)	Esterase degradation (pmol min/mg/protein)	Mother body	7.5	0.05	8.1	7521
EXAMPLE 1	225	2.3	42.8	367	Mother body	7.5	0.05	8.1	7521

MPTP model of Parkinson's disease

The significant neurotrophic and neuroregenerative therapeutic effects of the compounds of the invention can be further demonstrated in animal models of neurodegenerative diseases. MPTP damage of murine dopamine neurons was used as an animal model for parkinson's disease. 4-month-old CD1 white male mice were dosed intraperitoneally with 30 mg/kg MPTP for 5 days. Test compound (4 mg/kg) or vehicle was administered subcutaneously with MPTP for 5 days and again for 5 days after cessation of MPTP treatment. At 18 days post MPTP treatment, the animals were slaughtered and the striatum dissected and perfusion fixed. Radial and coronal brain sections were immunostained with 1 gram of anti-tyrosine hydroxylase to quantify dopamine neuron survival and regeneration. In animals treated with MPTP and vehicle, a large loss of functional dopamine end-points was observed when compared to non-injured animals. Injured animals that absorbed the test compound showed significant regeneration of TH-stained dopamine neurons. This animal model shows a quantification of the rate of regeneration of TH positive dopamine neurons in the striatum of animals that take up the compounds of the invention. Data representative of inhibited and injured animals that did not receive the test drug is also presented, in contrast to data from animals that received the compound of the invention. Figure 1 lists data for animals representing inhibition and injury without absorption of the test drug and controls with the parent compound of the invention and the animal data of example 1. It is evident that, although example 1 shows lower efficacy in vitro, it shows very high efficacy in an in vivo model of neurodegeneration due to its unexpectedly better bioavailability and pharmacokinetics. Examples

The following examples are illustrative of the invention and are not intended to be limiting. Example 1

Synthesis of (2S) -1- (3, 3-methyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl ester, N-oxide (1)

(2S) -1- (1, 2-dioxy-2-methoxyethyl) -2-pyrrolidinecarboxylic acid methyl ester

A solution of L-proline methyl ester hydrogen chloride (3.08 g, 18.60 mmol) in chloroform was cooled to 0 deg.C and triethylamine (3.92 g, 38 mmol)74 millimill, 2.1 equivalents). After stirring for 15 minutes under a nitrogen blanket to form a slurry, a solution of methyloxalyl chloride (3.20 g, 26.12 mmol) in dichloromethane (45 ml) was added dropwise to the reaction solution. The resulting mixture was stirred at 0 ℃ for 1.5 hours. After removing the solids by filtration, the organic phase was washed with water, dried over magnesium sulfate and concentrated. The resulting crude residue was purified by silica gel column eluting with 50% ethyl acetate in hexane to give 3.52 g (88%) of the product as a red oil. The data for cis-trans amide rotamer mixture and trans-rotamer are as follows:¹HNMR(CDCl₃) (ii) a δ 1.93(dm, 2H); 2.17(m, 2H); 3.62(m, 2H); 3.71(m, 3H); 3.79, 3.84(s, 3H all); 4.86(dd, 1H, J ═ 8.4, 3.3).

(2S) -1- (1, 2-dioxy-3, 3-dimethoxypentyl) -2-pyrrolidinecarboxylic acid methyl ester

A solution of methyl (2S) -1- (1, 2-dioxy-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 ml of Tetrahydrofuran (THF) was cooled to-78 deg.C and treated with 14.2 ml of a 1.0 mol solution of 1, 1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at-78 ℃ for 3 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 product obtained after removal of the solvent was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to give 2.10 g (75%) of oxamate as a colorless oil.¹HNMR(CDCl₃): δ 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-dioxy-3, 3-dimethoxypentyl) -2-pyrrolidinecarboxylic acid

A mixture of methyl (2S) -1- (1, 2-dioxy-3, 3-dimethoxypentyl) -2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1N LiOH (15 ml), and methanol (50 ml) was stirred at 0 ℃ for 30 minutes and at room temperature overnight. Mixing the above materialsThe material was acidified with 1N HCl to PH 1, diluted with water and extracted with 100 ml dichloromethane. The organic phase was washed with brine solution and the organic solution was concentrated to give 1.73 g (87%) of a snow white solid without further purification.¹H NMR(CDCl₃): δ 0.87(t, 3H); 1.22, 1.25(s, 3H each); 1.77(dm, 2H); 2.02(m, 2H); 2.17(m, 1H); 2.25(m, 1H); 3.53(dd, 2H, J ═ 10.4, 7.3); 4.55(dd, 1H, J ═ 8.6, 4.1).

(2S) -1- (3, 3-methyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl ester

A mixture of (2S) -1- (1, 2-dioxy-3, 3-dimethoxypentyl) -2-pyrrolidinecarboxylic acid (4.68 g; 19 mmol), 3-pyridylpropanol (3.91 g; 28.5 mmol), dicyclohexylcarbodiimide (6.27 g, 30.4 mmol), camphorsulfonic acid (1.47 g, 6.33 mmol) and 4-dimethylaminopyridine (773 mg; 6.33 mmol) in dichloromethane (100 ml) was stirred under nitrogen overnight. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo. The crude product was triturated with several portions of ether, the ether portion was filtered through Celite to remove solids and concentrated under vacuum. The concentrated filtrate was purified on a flash column (gradient eluent from 25% ethyl acetate in hexane to pure ethyl acetate) to afford 5.47 g (80%) of GPI 1046 (partial hydrate) as a colorless oil.¹H NMR(CDCl₃300 MHz): δ 0.85(t, 3H); 1.23, 1.26(s, 3H each); 1.63-1.89(m, 2H); 1.90-2.30(m, 4H); 2.30-2.50(m, 1H); 2.72(t, 2H); 3.53(m, 2H); 4.19(m, 2H); 4.53(m, 1H); 7.22(m, 1H); 7.53(dd, 1H); 8.45. elemental analysis: c₂₀H₂₈NO₄·0.25H₂Calculated value of O: c, 65.83; h, 7.87; and N, 7.68. Test values are: c, 66.01; h, 7.85; and N, 7.64.

(2S) -1- (3, 3-methyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl ester, N-oxide

(2S) -1- (3, 3-methyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridinyl) -1-propyl ester was stirred at room temperatureA solution of the ester (190 mg, 0.52 mmol) and m-chloroperbenzoic acid (160 mg 57% -86% material, 0.53 mmol) in dichloromethane (20 ml) for 3 hours. The reaction mixture was diluted with dichloromethane and washed twice with 1N NaOH. The organic extract was dried and concentrated. The resulting crude product was chromatographed, eluting with 10% methanol in ethyl acetate to give 130 mg of the compound of example 1.¹HNMR(CDCl₃300 MHz): δ 0.83(t, 3H); 1.21(s, 3H); 1.25(s, 3H); 1.75-2.23(m, 8H); 2.69(t, 2H, J ═ 7.5); 3.52(t, 2H, J ═ 6.3); 4.17(dd, 2H, J ═ 6.3); 4.51(m, 1H); 7.16-7.22(m, 2H); 8.06-8.11(m, 2H). Elemental analysis: c₂₀H₂₈N₂O₅·0.75H₂Calculated value of O: c, 61.60; h, 7.63; and N, 7.18. Test values are: c, 61.79; h, 7.58; and N, 7.23.

Claims

1. A compound shown in formula I and a pharmaceutically acceptable salt thereof,wherein: a and B together with the nitrogen and carbon atoms to which they are attached form a 5-to 7-membered saturated or unsaturated heterocyclic ring consisting of CH₂、O、S、SO、SO₂NH or NR₁Any combination thereof in any chemically stable oxidation state;

w is O, S, CH₂Or H₂；

R is a group consisting of C₃～C₈Cycloalkyl optionally substituted C₁～C₆Straight or branched alkyl or alkenyl, C₃Or C₅Cycloalkyl radical, C₅-C₇Cycloalkenyl radical or Ar₁Wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl may be substituted by C₁～C₄Alkyl radical, C₁～C₄Alkenyl or hydroxy optionally substituted, said Ar₁Is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄1-naphthyl, 2-naphthyl, 1-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl with 1 to 3 substituents selected from the group consisting of alkenyloxy, phenoxy, benzyloxy and amino;

x is O, NH, NR₁、S、CH、CR₁Or C (R)₁)₂；

Y is a direct bond, or one or more positions are substituted by C₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₂S, SO or SO₂Optionally substituted, wherein R₂Selected from the group consisting of hydrogen, (C)₁～C₄) Straight or branched alkyl, (C)₃～C₄) Straight or branched alkenyl or alkynyl, and wherein a bridge is formed between the nitrogen and the carbon atom of said alkyl or alkenyl containing said heteroatom forming a ring and wherein said ring is optionally fused to an Ar group (C)₁～C₄) Bridged alkyl groups; and

z is an aromatic or tetraalkylamine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide, Ar is a carbonyl or heterocycle of one-, two-, or three-membered ring, wherein 1-3 positions of said ring may or may not be substituted with halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄Alkoxy radical, C₁～C₄Alkenyloxy, phenoxy, benzyloxy, amino, or combinations thereof; wherein the size of a single ring is 5-6 membered ring; wherein the heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of O, N, S and combinations thereof, wherein at least one heteroatom is nitrogen; wherein the hydrocarbyl amine is oxidized to the corresponding N-oxide with the hydrocarbyl group being C in one or more positions₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₁S, SO or SO₂Optionally substituted;

ar is selected from the group consisting of pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyridazinyl, quinolinyl, and isoquinolinyl; and the combination of (a) and (b),

2. The compound of claim 1 having an affinity for FKBP-type immunophilins.

3. The compound of claim 2, wherein the FKBP-type immunophilin is KFBP 12.

4. The compound of claim 1, which is capable of inhibiting rotamase activity.

5. A pharmaceutical composition comprising a neurotrophic effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A method of stimulating injured neurons in an animal, the method comprising: administering to an animal a neurotrophic effective amount of a compound of claim 1.

7. A method of promoting neuronal regrowth in an animal comprising: administering to an animal a neurotrophic effective amount of a compound of claim 1.

8. A method of preventing neurodegeneration in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 1.

9. A method of treating a neurological disorder in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 1.

10. The method of claim 9, wherein said neurological disorder is 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, brain damage caused by impact, and neuropathological disorders associated with neurodegeneration.

11. The method of claim 10, wherein said neuropathological disorder associated with neurodegeneration is selected from the group consisting of alzheimer's disease, parkinson's disease, and amyotrophic lateral sclerosis.

12. A compound shown in formula II and its pharmaceutically acceptable salt,

wherein E, F, G and H are each CH₂、O、S、SO、SO₂NH, or NR₁；

W is O, S, CH₂Or H₂；

x is O, NH, NR₁、S、CH、CR₁Or C (R)₁)₂；

Y is a direct bond, or one or more positions are substituted by C₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₂S, SO or SO₂Without forcingIs substituted, wherein R₂Selected from the group consisting of hydrogen, (C)₁～C₄) Straight or branched alkyl, (C)₃～C₄) Straight or branched alkenyl or alkynyl, and (C)₁～C₄) Bridged alkyl wherein a bridge is formed between the nitrogen and the carbon atom of said alkyl or alkenyl containing said heteroatom forming a ring, wherein said ring is optionally fused to an Ar group; and

z is an aromatic or tetraalkylamine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide, Ar is a mono-, di-or tricyclic carbonyl or heterocyclic ring, wherein 1-3 positions of said ring may or may not be substituted with halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄Alkoxy radical, C₁～C₄Alkenyloxy, phenoxy, benzyloxy, amino, or combinations thereof; wherein the size of a single ring is 5-6 membered ring; wherein the heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of O, N, S and combinations thereof, wherein at least one heteroatom is nitrogen; wherein the hydrocarbyl amine is oxidized to the corresponding N-oxide with the hydrocarbyl group being C in one or more positions₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₁S, SO or SO₂Optionally substituted;

R₁is hydrogen, (C)₁～C₄) A straight or branched alkyl group,(C₃～C₄) Straight or branched alkenyl or alkynyl, or R₁Are defined as Y to Z.

13. The compound of claim 12 having an affinity for FKBP-type immunophilins.

14. The compound of claim 13, wherein the FKBP-type immunophilin is KFBP 12.

15. The compound of claim 12, which is capable of inhibiting rotamase activity.

16. A pharmaceutical composition comprising a neurotrophic effective amount of a compound of claim 12 and a pharmaceutically acceptable carrier.

17. A method of stimulating injured neurons in an animal, the method comprising: administering to an animal a neurotrophic effective amount of a compound of claim 12.

18. A method of promoting neuronal regrowth in an animal comprising: administering to an animal a neurotrophic effective amount of a compound of claim 12.

19. A method of preventing neurodegeneration in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 12.

20. A method of treating a neurological disorder in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 12.

21. The method of claim 20, wherein said neurological disorder is 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, brain damage caused by impact, and neuropathological disorders associated with neurodegeneration.

22. The method of claim 21, wherein said neuropathological disorder associated with neurodegeneration is selected from the group consisting of alzheimer's disease, parkinson's disease, and amyotrophic lateral sclerosis.

23. A compound of formula III and pharmaceutically acceptable salts thereof,wherein E, F and G are each CH₂、O、S、SO、SO₂NH, or NR₁；

W is O, S, CH₂Or H₂；

x is O, NH, NR₁、S、CH、CR₁Or C (R)₁)₂；

Y is a direct bond, or one or more positions are substituted by C₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇Cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar not strongPreparation of substituted C₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar groups may be replaced by O, NH, NR₂S, SO or SO₂Optionally substituted, wherein R₂Selected from the group consisting of hydrogen, (C)₁～C₄) Straight or branched alkyl, (C)₃～C₄) Straight or branched alkenyl or alkynyl, and (C)₁～C₄) Bridged alkyl wherein a bridge is formed between the nitrogen and the carbon atom of said alkyl or alkenyl containing said heteroatom forming a ring, wherein said ring is optionally fused to an Ar group; and

z is an aromatic or tetraalkylamine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide, Ar is a mono-, di-or tricyclic carbonyl or heterocyclic ring, wherein 1-3 positions of said ring may or may not be substituted with halogen, hydroxy, nitro, trifluoromethyl, C₁～C₆Straight or branched alkyl or alkenyl, C₁～C₄Alkoxy radical, C₁～C₄Alkenyloxy, phenoxy, benzyloxy, amino, or combinations thereof; wherein the size of a single ring is 5-6 membered ring; wherein the heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of O, N, S and combinations thereof, wherein at least one heteroatom is nitrogen; wherein the hydrocarbyl amine is oxidized to the corresponding N-oxide with the hydrocarbyl group being C in one or more positions₁～C₆Straight or branched alkyl or alkenyl, or C₃～C₈Cycloalkyl, or C₅-C₇C optionally substituted by cycloalkenyl, or hydroxy, or carbonyl oxygen, or Ar₁～C₆Straight-chain or branched alkyl or alkenyl, in which the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar groups may be replaced by C₁～C₄Alkyl radical, C₁～C₄Alkenyl, or hydroxy, or carbonyl oxygen, optionally substituted, or wherein said alkyl isAny carbon atom on the alkenyl, cycloalkyl, cycloalkenyl or Ar group may be replaced by O, NH, NR₁S, SO or SO₂Optionally substituted;

R₁is hydrogen, (C)₁～C₄) Straight or branched alkyl, (C)₃～C₆) Straight or branched alkenyl or alkynyl, or R₁Are defined as Y to Z.

24. The compound of claim 23 having an affinity for FKBP-type immunophilins.

25. The compound of claim 24, wherein the FKBP-type immunophilin is KFBP 12.

26. The compound of claim 23, which is capable of inhibiting rotamase activity.

27. A pharmaceutical composition comprising a neurotrophic effective amount of a compound of claim 23 and a pharmaceutically acceptable carrier.

28. A method of stimulating injured neurons in an animal, the method comprising: administering to an animal a neurotrophic effective amount of a compound of claim 23.

29. A method of promoting neuronal regrowth in an animal comprising: administering to an animal a neurotrophic effective amount of a compound of claim 23.

30. A method of preventing neurodegeneration in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 23.

31. A method of treating a neurological disorder in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 23.

32. The method of claim 31, wherein said neurological disorder is 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, brain damage caused by impact, and neuropathological disorders associated with neurodegeneration.

33. The method of claim 32, wherein said neuropathological disorder associated with neurodegeneration is selected from the group consisting of alzheimer's disease, parkinson's disease, and amyotrophic lateral sclerosis.

34. A compound of formula IV or a pharmaceutically acceptable salt thereof,wherein n is 1, 2 or 3 to form a 5-to 7-membered heterocyclic ring;

w is O, S, CH₂Or H₂；

x is O, NH, NR₁、S、CH、CR₁Or C (R)₁)₂；

35. The compound of claim 34 having an affinity for FKBP-type immunophilins.

36. The compound of claim 35, wherein the FKBP-type immunophilin is KFBP 12.

37. The compound of claim 34, which is capable of inhibiting rotamase activity.

38. A pharmaceutical composition comprising a neurotrophic effective amount of a compound of claim 34 and a pharmaceutically acceptable carrier.

39. A method of stimulating injured neurons in an animal, the method comprising: administering to an animal a neurotrophic effective amount of a compound of claim 34.

40. A method of promoting neuronal regrowth in an animal comprising: administering to an animal a neurotrophic effective amount of a compound of claim 34.

41. A method of preventing neurodegeneration in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 34.

42. A method of treating a neurological disorder in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 34.

43. The method of claim 42, wherein said neurological disorder is 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, brain damage caused by impact, and neuropathological disorders associated with neurodegeneration.

44. The method of claim 43, wherein said neuropathological disorder associated with neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

45. A compound selected from the group consisting of

(2S) -1- (1, 1-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (2-pyridinyl) -1-propyl ester, N-oxide;

(2S) -1- (1, 1-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridinyl) -1-propyl ester, N-oxide;

(2S) -1- (1, 1-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (4-pyridinyl) -1-propyl ester, N-oxide;

(2S) -1- (1, 1-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (3-quinolinyl) -1-propyl ester, N-oxide; and

(2S) -1- (1, 1-dimethyl-1, 2-dioxy-pentyl) -2-pyrrolidinecarboxylic acid 3- (4-quinolinyl) -1-propyl ester, N-oxide

In the group consisting of.

46. The compound of claim 45 having affinity for FKBP-type immunophilins.

47. The compound of claim 46, wherein the FKBP-type immunophilin is KFBP 12.

48. The compound of claim 45, which is capable of inhibiting rotamase activity.

49. A pharmaceutical composition comprising a neurotrophic effective amount of a compound of claim 45 and a pharmaceutically acceptable carrier.

50. A method of stimulating injured neurons in an animal, the method comprising: administering to an animal a neurotrophic effective amount of a compound of claim 45.

51. A method of promoting neuronal regrowth in an animal comprising: administering to an animal a neurotrophic effective amount of a compound of claim 45.

52. A method of preventing neurodegeneration in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 45.

53. A method of treating a neurological disorder in an animal, comprising: administering to an animal a neurotrophic effective amount of a compound of claim 45.

54. The method of claim 53, wherein said neurological disorder is 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, brain damage caused by impact, and neuropathological disorders associated with neurodegeneration.

55. The method of claim 54, wherein said neuropathological disorder associated with neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.