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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
  • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
  • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• 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 pep idyl-prolyl isomerase, or rotamase, enzyme activity.
• immunophilin refers to a number of proteins that serve as receptors for the principal immunosuppressant drugs, cyclosporin A (CsA) , FK506 and rapamycin.
• CsA cyclosporin A
• FKBPs FKBPs
• Cyclosporin A binds to cyclophilin A while FK506 and rapamycin bind to FKBP12.
• FKBP12 FKBP12.
• Immunophilins are known to have peptidyl-prolyl isomerase (PPIase) , or rotamase, enzyme activity. It has been determined that rotamase enzyme activity plays a role in the catalyzation of the interconversion of the cis and trans isomers of peptide and protein substrates for the immunophilin proteins.
• Immunophilins were originally discovered and studied in the immune tissue. It was initially postulated by those skilled in the art that inhibition of the immunophilins' rotamase activity leads to inhibition of T-cell proliferation, thereby causing the immunosuppressive activity exhibited by immunosuppressant drugs, such as cyclosporin A, FK506 and rapamycin. Further study has shown that the inhibition of rotamase activity, in and of itself, does not result in immunosuppressive activity. Schreiber et al . , Science , 1990, vol. 250, pp. 556-559. Instead, immunosuppression appears to stem from the formulation of a complex of immunosuppressant drug and immunophilin.
• immunosuppressant drugs such as cyclosporin A, FK506 and rapamycin.
• the immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al . , Cell , 1991, vol. 66, pp. 807-815.
• the immunophilin-drug complexes bind to the enzyme calcineurin and inhibit the T-cell receptor signalling which leads to T-cell proliferation.
• the immunophilin-drug complex of FKBP-rapamycin interacts with the RAFT1/FRAP protein and inhibits the IL-2 receptor signalling.
• Immunophilins have been found to be present at high concentrations in the central nervous system. Immunophilins are enriched 10-50 times more m the central nervous system than in the immune system. Within neural tissues, immunophilins appear to influence nitric oxide synthesis, neurotransmitter release and neuronal process extension.
• neurotrophic factors affecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer's disease results from a decrease or loss of nerve growth factor (NGF) . It has thus been proposed to treat SDAT patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain derived growth factor, glial derived growth factor, ciliary neurotrophic factor and neurotropin-3 , to increase the survival of degenerating neuronal populations.
• NGF nerve growth factor
• immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity.
• immunosuppressant drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis ⁇ Kopp et al . , J. Am. Soc . Nephrol . , 1991, 1:162 ) ; neurological deficits, such as involuntary tremors, or non-specific cerebral angina, such as non- localized headaches (De Groen et al . , iV.
• the present invention provides non- immunosuppressive compounds containing small molecule FKBP rotamase inhibitors for enhancing neurite outgrowth, and promoting neuronal growth and regeneration in various neuropathological situations where neuronal repair can be facilitated, including: peripheral nerve damage caused by physical injury or disease state such as diabetes; physical damage to the central nervous system
• brain spinal cord and brain
• brain damage associated with stroke and neurological disorders relating to neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's disease) and amyotrophic lateral sclerosis.
• the present invention relates to neurotrophic low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
• immunophilin proteins particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
• a key feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity in addition to their neurotrophic activity.
• the present invention relates to a compound of formula II:
• n 1 or 2 ;
• X is 0 or S
• Z is selected from the group consisting of S, CH 2 , CH , and C(R.) 2 ;
• R x is selected from the group consisting of C -Cc, straight or branched chain alkyl, C 2 -C 5 straight or branched chain alkenyl, Ar x and mixtures thereof, wherein said R x is unsubstituted or substituted with halo, nitro, C-C 6 straight or branched chain alkyl, C 2 -C 3 straight or branched chain alkenyl, hydroxy, Cj_-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, ammo, Ax 1 or a mixture thereof;
• R 2 is selected from the group consisting of C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkenyl and Ar : ;
• Ar is phenyl, benzyl, pyridyl , fluorenyl , thioindolyl or naphthyl wherein said Ar x is unsubstituted or substituted with halo, hydroxy, nitro, C--C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, -C. alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, ammo or a mixture thereof.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising: (l) an effective amount of tne compound of claim 1 for effecting a neuronal activity; and (11) a pharmaceutically acceptable carrier.
• the present invention further relates to a method of effecting a neuronal activity an animal, comprising: administering to the animal an effective amount of the compound of formula II.
• FIG. 1(A) is a representative photomicrograph of untreated sensory neurons.
• FIG. KB 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 neurite outgrowth in sensory neurons .
• FIG. 1(D) is a representative photomicrograph of compound 1 (1 ⁇ M) promoting neurite outgrowth in sensory neurons .
• FIG. 2(A) is a representative photomicrograph of untreated sensory neurons.
• FIG. 2(B) is a representative photomicrograph of compound 9 ⁇ 10 pM) promoting neurite outgrowth in sensory neurons .
• FIG. 2(C) is a representative photomicrograph of compound 9 (1 nM) promoting neurite outgrowth in sensory neurons .
• FIG. 2(D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons.
• FIG. 3(A) is a representative photomicrograph of untreated sensory neurons.
• FIG. 3(B) is a representative photomicrograph of compound 10 (10 pM) promoting neurite outgrowth in sensory neurons.
• FIG. 3 ( C ) is a representative photomicrograph of compound 9 (1 nM) promoting neurite outgrowth in sensory- neurons .
• FIG. 3(D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons .
• FIG. 4 presents quantitation for the recovery of TH- positive dopaminergic neurons in the striatum of animals receiving compounds 1, 9 and 10.
• 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 alkyl as herein defined.
• 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 n the way the atoms are arranged in space. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other. “Diastereoisomers” are stereoisomers which are not mirror images of each other. “Racemic mixture” means a mixture containing equal parts of individual enantiomers. “Non- racemic mixture” is a mixture containing unequal parts of individual enantiomers or stereoisomers.
• “Pharmaceutically acceptable salt” refers to a salt of the inventive compounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable.
• the salt can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, ca phorsulfonate , cyclopentanepropionate, digluconate, dodecylsulfate, e t hane su 1 f ona t e , fumarate, glucoheptanoate , glycerophosphate , hemisulfate heptanoate, hexanoate, hydrochloride hydrobromide , hydroiodide, 2 -hydroxyethanesulfonate , lactate, maleate, methanesulfonate , 2-naphthalenesulfonate
• Examples of a base salt include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl- D-glucamine, and salts with amino acids such as arginine and lysme.
• the basic nitrogen-containing groups can be quarternized with agents including: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl , lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides .
• 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 steary
• Phenyl refers to any possible ls ⁇ meric phenyl radical, optionally monosubstituted or multisubstituted with substituents selected from the group consisting of alkyl, alkoxy, hydroxy, halo and haloalkyl . “Treating” refers to:
• the neurotrophic low molecular weight, small molecule FKBP inhibitor compounds of this invention have an affinity for FKBP-type immunophilins, such as FKBP12.
• FKBP-type immunophilins such as FKBP12.
• this invention relates to a compound of formula I :
• a and B together with the nitrogen and carbon atoms to which they are respectfully attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH 2 , O, S, SO, S0 2 , NH or NR 2 in any chemically stable oxidation state;
• X is either 0 or S; Z is either S, CH 2 , CHR ⁇ . or C(R 1 ) 2 ; W and Y are independently 0, S, CH 2 or H 2 ; R L is C l - C 6 straight or branched chain alkyl or alkenyl, which is substituted in one or more position (s) with (Ar ,., (ArJ.
• n is 1 or 2;
• R 2 is either C 1 -C 9 straight or branched chain alkyl or alkenyl, C 3 -C 9 cycloalkyl, C 5 -C 7 cycloalkenyl or Ar x , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more position (s) with -C 4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and
• Ar_ and Ar 2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position (s) with halo, hydroxyl, nitro, trifluoromethyl , C_-C 6 straight or branched chain alkyl or alkenyl, C x -C 4 alkoxy, C 1 -C 4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom (s) selected from the group consisting of O, N, S and a combination thereof.
• Suitable mono- and bicyclic, carbo- and heterocyclic rings include, without limitation, naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.
• n 1 or 2 ;
• X is 0 or S
• Z is selected from the group consisting of S, CH 2 , CHR- L and C (R x ) 2 ;
• R is selected from the group consisting of C, -C 5 straight or branched chain alkyl, C 2 -C 3 straight or branched chain alkenyl, Ar : and mixtures thereof, wherein said Ri is unsubstituted or substituted with halo, nitro, C ⁇ C ⁇ straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, hydroxy, C ⁇ C. alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, Ar : or a mixture thereof;
• R 2 is selected from the group consisting of C ⁇ C g straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 2 -C 3 cycloalkyl, C s -C 7 cycloalkenyl and Ar j _; and
• Ar is phenyl, benzyl, pyridyl , fluorenyl, thioindolyl or naphthyl wherein said Ar x is unsubstituted or substituted with halo, hydroxy, nitro, C 1 -C 6 straight or branched chain alkyl, C 2 - C 6 straight or branched chain alkenyl, C ⁇ - ⁇ alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.
• TABLE I The most preferred examples of TABLE I are named as follows : 1 (25) -2 - ⁇ ⁇ l-Oxo-5-phenyl ⁇ -pentyl-1- (3 , 3-dimethyl- 1 , 2 -dioxopentyl ) pyrrolidine
• A, B , C and D are independently CH 2 , 0 , S , SO , S0 2 , NH or NR 2 ;
• X is 0 or S ;
• Z is S, CH 2 , CHR X or C(R 2 ;
• R. is C 1 - C 6 straight or branched chain alkyl or alkenyl, which is substituted in one or more position (s) with ( n , (Ar n connected by a C l - C 6 straight or branched chain alkyl or alkenyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl connected by a C l -C 6 straight or branched chain alkyl or alkenyl, Ar 2 or a combination thereof; n is 1 or 2;
• R 2 is either C 1 -C 9 straight or branched chain alkyl or alkenyl, C 3 -C 9 cycloalkyl, C s -C 7 cycloalkenyl or Ar x , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more positio (s) with C L -C 4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and
• Ar : and Ar 2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position (s) with halo, hydroxyl, nitro, trifluoromethyl , C ] _ - C i straight or branched chain alkyl or alkenyl, C,-C 4 alkoxy, -C 4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroato (s) selected from the group consisting of 0, N, S and a combination thereof.
• A, B, C and D are independently CH 2 , 0, S, SO, S0 2/ NH or NR 2 ;
• X is 0 or S
• Z is S, CH 2 , CHR, or C(R 1 ) 2 ;
• R is C,-C ⁇ straight or branched chain alkyl or alkenyl, which is substituted in one or more position (s) with ⁇ Ar. j,, (Ar,). connected by a C 1 ⁇ 6 straight or branched chain alkyl or alkenyl, C 3 -C ⁇ cycloalkyl, C 3 -C 8 cycloalkyl connected by a C -C 6 straight or branched chain alkyl or alkenyl, Ar 2 or a combination thereof; n is 1 or 2 ;
• R 2 is either 0,-0,, straight or branched chain alkyl or alkenyl, C,-C 9 cycloalkyl, C 5 -C 7 cycloalkenyl or Ar ⁇ , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more position (s) with -C, straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and
• Ar, and Ar 2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl , C x -C € straight or branched chain alkyl or alkenyl, C ⁇ -C 4 alkoxy, C : -C 4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom (s) selected from the group consisting of 0, N, S and a combination thereof.
• the compounds of th s invention possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual stereoisomers.
• the individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compound of formula (I) . It is understood that the individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers are encompassed by the scope of the present invention.
• the compounds of this invention possess at least one asymmetric center and thus can be produced as mixtures of stereoisomers or as individual R- and ⁇ -stereoisomers .
• the individual enantiomers may 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 S- stereoisomer is most preferred due to its greater activity.
• the compounds of the present invention have an affinity for the FK506 binding protein, particularly FKBP12, which is present in the brain.
• FKBP12 FK506 binding protein
• 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 neurodegeneracion, and the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathies.
• the present invention further relates to a method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula I, II, III or IV.
• 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.
• the neurological disorders include but are not limited to: trigeminal neuralgia; glossopharyngeal neuralgia; Bell's Palsy; myasthenia gravis; muscular dystrophy; amyotrophic lateral sclerosis; progressive muscular atrophy; progressive bulbar inherited muscular atrophy; herniated, ruptured or prolapsed invertebrate disk syndromes,- cervical spondylosis; plexus disorders; thoracic outlet destruction syndromes; peripheral neuropathies such as those caused by lead, dapsone , ticks, porphyria or Guillain-Barre syndrome; Alzheimer's disease,- and Parkinson's disease.
• the compounds of the present invention are particularly useful for treating a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.
• a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.
• Examples of neurological disorders relating to neurode ⁇ eneration are Alzheimer's Disease, Parkinson's Disease and amyotrophic lateral sclerosis.
• the compounds may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles .
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneally, mtrathecally , traventricularly, intrastemal and mtracranial injection or infusion techniques.
• the compounds should readily penetrate the blood-bra barrier when peripherally administered. Compounds whicn cannot penetrate the blood-bram barrier can be effectively administered by an mtraventricular route .
• the compounds may be administered in the form of sterile mjectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known the art using suitable dispersing or wetting agents and suspending agents.
• the sterile mjectable preparations may also be sterile mjectable solutions or suspensions non-toxic parenterally-acceptable diluents or solvents, for example, as solutions m 1, 3-butaned ⁇ ol .
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and lsotomc sodium chloride solution.
• sterile, fixed oils are conventionally employed as solvents or suspending mediums.
• any bland fixed oil such as a synthetic mono- or di-glyceride may be employed
• Fatty acids such as oleic acid and its glyce ⁇ de derivatives, including olive oil and castor oil, especially m their polyoxyethylated versions, are useful m the preparation of injectables.
• These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.
• the compounds may be administered orally in the form of capsules, tablets, aqueous suspensions or solutions Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate .
• Capsules may contain diluents including lactose and dried corn starch.
• Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient.
• the oral dosage forms may further contain sweetening and/or flavoring and/or coloring agents.
• the compounds may also be administered rectally the form of suppositories.
• These compositions can be prepared by mixing the drug with a suitable non- irritating excipient whicn is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug.
• a suitable non- irritating excipient whicn is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug.
• Such materials include cocoa butter, beeswax and polyethylene glycols .
• the compounds may be administered topically, especially when the conditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin or the lower intestinal tract. Suitable topical formulations can be readily prepared for each of these areas .
• the compounds can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as a solution isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
• the compounds may be formulated into ointments, such as petrolatum, for ophthalmic use.
• the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved m, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate , polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol , benzyl alcohol and water.
• Topical application to the lower intestinal tract can be effected in a rectal suppository formulations (see above) or in suitable enema formulations.
• Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration .
• the compounds can be administered with other neurotrophic agents such as neurotrophic growth factor (NGF) , glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor and neurotropin-3.
• NGF neurotrophic growth factor
• the dosage level of other neurotrophic drugs will depend upon the factors previously stated and the neurotrophic effectiveness of the drug combination.
• compositions of the Invention also relates to a pharmaceutical composition comprising:
• (25) -2- fl-oxo-4-ohenyl)butyl-l- (1,2-dioxn-?- methoxyethyl ) pyrrolidine .
• (25) -2- (1- oxo-4-phenyl) butylpyrrolidine (230 mg; 1.0 mmol) in CH,C1 2 (20 mL) at 0°C was added dropwise methyloxalyl chloride (135 mg; 1.1 mmol) . After stirring at 0°C for 3 hours, the reaction was quenched with saturated NH 4 C1 and the organic phase was washed with water and brine and dried and concentrated.
• Methyl ( 25 ) -1- (1 , 2-dioxo-3 , 3-dimethylpentyl) -2- p yrrolidinecarboxylate A solution of methyl (25) -1- (1, 2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78°C and treated with 14.2 mL of a 1.0 M solution of 1, 1-dimethylpropylmagnesium chloride in THF.
• THF tetrahydrofuran
• (25) -1- (1, 2-dioxo-3 , 3 -dimethylpentyl) -2 -pyrrolidine- carboxylic acid A mixture of methyl (25) -1- (1 , 2-dioxo- 3 , 3-dimethylpentyl) -2 -pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 mL) , and methanol (50 L) was stirred at 0°C for 30 minutes and at room temperature overnight . The mixture was acidified to pH 1 with 1 N HC1 , diluted with water, and extracted into 100 mL of methylene chloride.
• Methyl 1- (1 , 2-QJOXO-3 , 3 -dimethyloentyl) -2-pjperidine- carboxylate A solution of methyl 1- (1 , 2-dioxo-2- methoxye ⁇ hyl) -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.
• THF tetrahydrofuran
• the compounds of the present invention have an affinity for the FK506 binding protein, particularly FKBP12.
• the inhibition of the prolyl peptidyl cis - trans isomerase activity of FKBP may be measured as an indicator of this affinity.
• Inhibition of the peptidyl -prolyl isomerase (rotamase) activity of the inventive compounds can be evaluated by known methods described m the literature (Harding et al . , Na ture , 1989, 341:758-760; Holt et al . J " . Am. Che/77. Soc . , 115:9923-9938) . These values are obtained as apparent K x 's and are presented for representative compounds Table IV.
• the cis - rans lsomerization of an alanme-prolme bond in a model substrate, N-succmyl-Ala-Ala-Pro-Phe-p-nitroanilide is monitored spectrophotometrically in a chymotrypsin- coupled assay, which releases para-mtroanilide from the trans form of the substrate.
• the inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change n first-order rate constant as a function of inhibitor concentration to yield the apparent K ⁇ values .
• a plastic cuvette In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl) , 10 mL of FKBP (2.5 mM 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol) , 25 mL of chymotrypsin (50 mg/ml m 1 mM HCl) and 10 L of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succmyl-Ala-Phe-Pro-Phe- para-mtroanilide, 5 mg/mL 2.35 mM LiCl trifluoroethanol) .
• substrate succmyl-Ala-Phe-Pro-Phe- para-mtroanilide, 5 mg/mL 2.35 mM LiCl trifluoroethanol
• the absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.
• the neurotrophic effects of the compounds of the present invention can be demonstrated in cellular biological experiments in vi tro , as described below.
• Chick Dorsal Root Ganglion Cultures and Neurite Outgrowth The neurotrophic effects of the FKBP inhibitor compounds were demonstrated by evaluating the ability of the compounds to promote neurite outgrowth in cultured chick sensory neurons from dorsal root ganglia.
• Dorsal root ganglia were dissected from chick embryos of ten day gestation.
• Whole ganglion explants were cultured on thin layer Matrigel-coated 12 well plates with Liebovitz L15 plus high glucose media supplemented with 2 mM glutamine and 10% fetal calf serum, and also containing 10 ⁇ M cytosine ⁇ -D arabinofuranoside (Ara C) at 37°C in an environment containing 5% CO, .
• Ara C cytosine ⁇ -D arabinofuranoside
• the DRGs were treaced with various concentrations of nerve growth factor, immunophilin ligands or combinations of NFG plus drugs.
• the ganglia were visualized under phase contrast or Hoffman Modulation contrast with a Zeiss Ax overt inverted microscope Photomicrographs of the explants were made, and neurite outgrowth was quantitated. Neurites longer than the DRG diameter were counted as positive, with total number of neurites quantitated per each experimental condition.
• Three to four DRGs are cultured per well, and each treatment was performed duplicate.
• MPTP Model of Parkinson's Disease The remarkable neurotrophic and neuroregenerative effects of the present inventive compounds were further demonstrated m an animal model of neurodegenerative disease MPTP lesionmg of dopammergic neurons in mice was used as an animal model of Parkinson's Disease.
• Four week old male CD1 white mice were dosed i.p. with 30 mg/kg of MPTP for 5 days.
• Test compounds ⁇ 4 mg/kg) . or vehicle were administered s.c. along with the MPTP for 5 days, as well as for an additional 5 days following cessation of MPTP treatment.
• the animals were sacrificed and the striata were dissected and homogenized.

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