IL128792A - Heterocyclic ketones and pharmaceutical compositions comprising same - Google Patents

Heterocyclic ketones and pharmaceutical compositions comprising same

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Publication number
IL128792A
IL128792A IL128792A IL12879299A IL128792A IL 128792 A IL128792 A IL 128792A IL 128792 A IL128792 A IL 128792A IL 12879299 A IL12879299 A IL 12879299A IL 128792 A IL128792 A IL 128792A
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IL
Israel
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compound
phenyl
dimethyl
group
neurological disorder
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IL128792A
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Hebrew (he)
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Guilford Pharm Inc
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Publication of IL128792A publication Critical patent/IL128792A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D211/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D211/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D211/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
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    • 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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    • C07D401/12—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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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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

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  • Hydrogenated Pyridines (AREA)
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Description

128792/4 HETEROCYCLIC KETONES AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME S GPI NIL Holdings, Inc. 128792/3 BACKGROUND OF THE INVENTION 1 Field of Invention This invention relates to neurotrophic low molecular weight, small molecule heterocyclic thioesters and ketones having an affinity for FKBP-type immunophilins, their use for the preparation of medicaments to be utilized as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-proplyl isomerase, or retamase, enzyme activity.; 2 Description of Related Art The term immunophilin refers to a number of proteins that serve as receptors for the principal immunsuppressant drugs, cyclosporin A (CsA), FK506 and rapamycin. Known classes of immunophilins are cyclophilins and FK506 binding proteins, or FKBPs. Cyclosporin A binds to cyclophilin A while FK506 and rapamycin bind to FKBP12. These immunophilin-drug complexes interface with various intracellular signal transduction systems, especially the immune and nervous systems.
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-celi 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 ana cf itself, does not result in immunosuppressive activity. Schreiber et al . , Science, 195C, vol. 25C, pp. 556-559. Instead, immunosuppression appears to stem from the formulation of a complex of immunosuppressant drug and immunophilin. It has been shown that the immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al . , Cell, 1951, vol. 66, pp. 807-815. In the case of FK3P-FK506 and cyclophilin-CsA, the immunophilin- drug complexes bind to the enzyme caicineurin and inhibit the T-cell receptor signalling which leads to T-cell proliferation. Similarly, 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 in the central nervous system than in the immune system. Within neural tissues, immunophilins appear to influence nitric oxide synthesis, neurotransmitter release -and neuronal process extension.
It has been found that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate neurite outgrowth in PC12 cells and sensory neurons, namely dorsal roc: ganglion cells (D Gs) . Lyons et al . , Proc . of Nazi. Acad. Sci . , 1994, vol. 91, pp. 21=1-2195. In whole animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve ir.j ry.
Surprisingly, has been found that certain compounds with a high affinity for FKBPs are potent rctamase inhibitors and exhibit excellent neurotrophic effects. Furthermore, these rotamase inhibitors are devoid of immunosuppressive activity. These findings suggest the use of rotamase inhibitors in treating various peripheral neuropathies and enhancing neuronal rearcwth in the central nervous system (CNS) . Studies have demonstrated that neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) , may occur due to the loss, or decreased availability, of a neurotrophic substance specific for a particular population of neurons affected in the disorder.
Several neurotrophic factors 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 cr 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.
Clinical application of these proteins in various neurological disease states is hampered by difficulties in the delivery and bioavailability of large proteins to nervous system targets. By contrast, immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity. However, when administered chronically, immunosuppressant drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of ciomerular filtration and irreversible interstitial fibrosis ( opp et al . , J. Am. Soc. Nephrol., 1991, 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina, such as non- localized headaches (De Groen et al., N. Engl. J. Med., 1987, 317:861); and vascular hypertension with complications resulting therefrom (Kahan et al . , jV. Engl . J. Med., 1989, 321:1725) .
To prevent the side effects associated with use of the immunosuppressant compounds, the present invention provides non- immunosuppressive compounds containing small molecule FKBP rotamase inhibitors for enhancing neurite outgrowth, and promoting neuronal growth and regeneration in various neuropathological situations where neuronal repair can be facilitated, including: peripheral nerve damage caused by physical injury or disease state such as diabetes,- physical damage to the central nervous system •spinal cord and brain) ; brain damage associated with stroke; and neurological disorders relating to ne rodegeneration, 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 an affinity for FKBP-type immunophilins . Once bound to these proteins , the neurotrophic compounds are potent 128792/3 e inhibitors of the enzyme activity associated with immunophilin proteins, par icularly 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. 128792/4 7 The present invention relates to a compound formula II: or pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; x is o z is selected from the group consisting of CH2, CHR^ and C(R2)2; Rj^ is C^-C8 straight or branched chain alkyl which is substituted with A^ ; R2 is selected from the group consisting of : - -C8 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-Ca cycloalkyl, -C5-C7 cycloalkenyl, and, -Arlf Arx is phenyl, pyridyl, fluorenyl benzo [b] thiophen, or naphthyl, wherein said Ar: is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C^-C8 straight or branched chain 128792/5 8 alkyl, C2-C6 straight or branched chain alkenyl C^-Q, alkoxy,C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof.
The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of the compound of formula II for effecting a neuronal activity; and (ii) a pharmaceutically acceptable carrier.
The present invention further relates to a medicament for performing a method of effecting a neuronal activity in an animal, comprising: administering to the animal an effective amount of the compound of formula II. 128792/5 The present invention relates also to the use of a compound of Formula II for the preparation of a medicament useful for effecting a neuronal activity in an animal excluding human beings .
The present invention also relates to a method for treatment of animals excluding human beings comprising administering one or more compound (s) of Formula II in an amount for effecting a neuronal activity, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder BRIEF DESCRIPTION OF THE DRAWINGS FIG 1A, 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 μΜ) promoting neurite outgrowth in sensory neurons .
FIG. 2(A) is a representative photomicrograph of nc eat d 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 S (1 nM) promoting neurite outgrowth in sensory neurons .
FIG. 2(D) is a representative photomicrograph of compound 3 (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 (1G pM) promoting neurite outgrowth in se sor-.' neurons.
FIG. 3(C) is a representative photomicrograph of compound 9 (l 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 ΤΉ-positive dopaminergic neurons in the striatum of animals receiving compounds 1, 9 and 10.
DETAILED DESCRIPTION OF THE INVENTION Definitions "Alkyl" refers :o a branched or unbranched saturated hydrocarbon chair, containing 1 cc 6 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, ceri-bucyi, n-per.ty , r.-hexy and the like, unless otherwise indicated.
"Aixoxy" refers :: the group -OR wherein R is alkyl as herein defined. Preferacly, R is a branched or n ranched saturated hydrocarccr. chain containing 1 to 3 carbon atoms .
"Halo" refers cc flucre, chioro, bromo or lodo , unless otherwise indicated.
"Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only m the way tr.e acorns 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 , o s ifate butyrate, citrate, camphorate, camphorsulfonate , cycicpentanepropionate , digluconate, codec ylsuif ate , e h nes ifonate, fumarate, gl coheptanoate , glycerophospha e, hemisulfate heptanoate, hexanoate, hydrochloride hydrobromide , hydroiodide , 2 -hydrcxyethanesulfonate , lactate, maleate, methanesulfonate , 2 -nap thalenesulfonate , nicotinate, oxalate, thiocyanate, tosylate and undecanoate . Examples cf a oase 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 crgar.ic bases such as dicyciohexyiamine salts, N-methyl- -ci camine , and salts with amino acids such as arginine and lysine. Also, Che basic nitrogen-containing grouDS can be quartemized with agents including : lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dxmethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides .
"Phenyl" refers to any possible isomeric phenyl radical, optionally monosubstituted or multisubstitu ed with subscituents selected from the group consisting of alkyl, alkoxy, hydroxy, halo and haloalkyl .
"Treating" refers :o: (i) preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet beer, diagnosed as havi g ι; ,· ;ii inhibiting t e disease, disorder or condition, i.e., arresting its development ; and (lii) relieving t disease, disorder or condition, i.e., causing regression of the disease, disorder and/or conditio .
Compounds of the Invention he neurotrophic low molecular weight, small le ? Ξ? inhibitor tomcc nds of this invention have 128792/2 14 An affinity for FKBP-type immunophilins , such as FKBP12. When the neurotrophic compounds of this invention are bound to an FKBP-type immunophilin, they have been found to inhibit the prolyl-peptidyl cis- trans isomerase activity of, or romatase, activity of the binding protein and unexpectedly stimulate neurite growth.
Specific examples of these compounds are presented in Table I: TABLE I X Z R, R2 1 0 CH2 3-Phenylpropyl 1,1-Dknethy Ipropyl 1 0 CH2 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 1 0 CH2 3-Phenylpropyl tert-Butyl 1 0 CH2 3-(3-Pyridyl)propyl tert-Butyl 1 0 CH2 3-(3-Pyridyl)propyl Cyclo exyl 1 0 CH2 3-(3-Pyridyl)propyl Cyclopentyl 1 0 CH2 3-(3-Pyridyl)propyl Cycloheptyl 1 0 CH2 2-(9-Fluorer.yl)et yl 1,1-Dimethylpropyl 1 0 S 2-Phenethyl 1,1-Dimethylpropyl 2 0 S 2-Phenethyl 1,1-Dimethylpropyl / 16 128792/2 fethyl (2-benzD [b] thiophen) 11 1 0 "s Methyl(2 h-te-ffid le-> 1, 1-Dimethy Ipropy 1 12 1 0 s 2-Phenethyl Cyclohexyl 13 2 0 s 2-Phenethyl tert-Butyl 14 2 0 s 2-Phenethyl Phenyl 1 0 CHj 3-(4-Methoxyphenyl)propyl 1, 1-Dimethy Ipropy 1 16 2 0 CH2 4-(4-Methoxyphenyl)butyl 1,1-Dimethylpropyl 17 2 0 CH2 4-Phenylbutyl 1, 1-Dimethy Ipropy 1 18 2 0 CH2 4-Phenylbutyl Phenyl 19 2 0 CH2 4-Phenylbutyl tert-Butyl 1 s CH2 3-Phenylpropyl 1,1-Dimethylpropyl 21 1 s S 2-Phenethyl 1,1-Dimethylpropyl 22 2 s CH2 3-Phenylpropyl 1,1-Dimethylpropyl 23 2 . S - S 2-Phenethyl 1,1-Dimethylpropyl 24 2 0 CHR, 3-Phenylpropyl 1,1-Dimethylpropyl 2 0 CHR, 3-Phenylpropyl Cyclohexyl 26 2 0 CHR, 3-Phenylpropyl Phenyl 27 2 0 CHR, 3-Phenylpropyl 3 ,4,5 -Trimethoxypheny 1 28 1 0 JS 2-Phenethyl Cyclopentyl 29 2 0 s 3-Phenylpropyl tert-Butyl i 0 s 3-Phenylpropyl 1,1-Dimethylpropyl 31 1 0 S ' 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 32 1 0 s 3-Phenylpropyl Cyclohexyl 33 1 0 s 4-Phenylbutyl Cyclohexyl 3 1 0 s 4-Phenylbutyl 1,1-Dimethylpropyl 1 0 s 3-(3-Pyridyl)propyl Cyclohexyl 36 1 0 s 3,3-Diphenylpropyl 1 , 1-Dimethy Ipropy 1 37 1 0 s 3,3-Diphenylpropyl Cyclohexyl 38 0 s 3-(4-Methoxyphenyl) 1,1-Dimethylpropyl 1 propyl - - t l 17 1 28792/2 40 2 0 s 1 ,5-Diphenyl-3-pentyl 1 ,1-Dimethylpropyl 41 2 0 s 1 ,5-Diphenyl-3-pentyl Phenyl 42 2 0 s 3 -(4-Methoxypheny 1) 1,1-Dimethylpropyl propyl 43 2 0 s 3-(4-Methoxyphenyl) Phenyl propyl 44 2 0 s 3-(l-Naphthyl)propyl 1,1-Dimethylpropyl 45 1 0 s 3 ,3-Di(4-fluoro)phenyl- 1,1-Dimethylpropyl propyl 46 1 0 s 4 ,4-Di(4-fluoro)phenyl- 1 ,1-Dimethylpropyl butyl 47 1 0 s 3-(l-Naphthyl)propyl 1,1-Dimethylpropyl 48 1 0 s 2,2-Diphenylethyl 1 , 1-Dimethylpropyl 49 2 0 s 2,2-Diphenylethyl 1,1-Dimethylpropyl 50 2 0 s 3,3-Diphenylpropyl 1 , 1-Dimethylpropyl 51 1 0 s 3-(4-{Trifluoromethyl}- 1,1-Dimethylpropyl phenyl)propyl 52 1 0 s 3-(2-Naphthyl)propyl 1 ,1-Dimethylpropyl 53 2 0 s 3-(l-Naphthyl)propyl 1,1-Dimethylpropyl 54 1 0 . s 3-(3-Chloro)phenylpropyl 1 , 1-Dimethylpropyl 55 1 0 s 3-(3-{Trifluoromethyl}- 1 , 1-Dimethylpropyl phenyl)propyl 56 1 0 s 3-(2-Biphenyl)propyl 1,1-Dimethylpropyl 57 1 0 s 3-(2-Fluorophenyl)propyl 1 , 1-Dimethylpropyl 58 1 0 s 3-(3-Fluorophenyl)propyl 1 , 1-Dimethylpropyl 59 2 0 s 4-Phenylbutyl 1 ,1-Dimethylpropyl 60 2 0 s 3-Phenylpropyl 1 , 1-Dimethylpropyl 61 1 0 s 3-(2-Chloro)phenylpropyl 1,1-Dimethylpropyl 62 2 0 s 3-(3-Chloro)phenylpropyl 1 , 1-Dimethylpropyl 63 2 0 s 3-(2-Fluoro)phenylpropyl 1 , 1-Dimethylpropyl 18 128792/2 64 2 0 s 3-(3-Fluoro)phenylpropyl 1,1-Dimethylpropyl 65 1 0 s 3-(3 ,4-Dimethoxyphenyl)- 1,1-Dimethylpropyl propyl 66 1 0 CH2 3-Phenylpropyl Cyclohexyl 67 1 0 CH2 2-Phenylethyl tert-Butyl 68 2 0 CH2 4-Phenylbutyl Cyclohexyl 69 2 0 CHR, 2-Phenylethyl tert-Butyl 70 1 0 CH2 3 ,3-Di(4-fluorophenyl)- 1,1-Dimethylpropyl propyl 71 2 0 CH2 3-Phenylpropyl 1,1-Dimethylpropyl The most preferred examples of TABLE I are named as follows: 1 (2S") - 3,3-dimethyl-l-[2-(5-phenylpentanoyl) pyrrolidinyl] pentane-1, 2-dione 2 (2S) -3, 3-dimethyl-l- [2- (5- (3-pyridyl) pentanoyl) pyrrolidinyl ] pentane-1 , 2-dione 3 - (2S) -2- (l-oxo-5-phenyl) -pentyl-1- (3, 3-dimethyl-l, 2-..„ dioxobutyl) pyrrolidine 9 2-Phenyl-l-ethyl ( 2S) -1- ( 3 , 3-dimethyl-l , 2- dioxopentyl) -2-pyrrolidinecarbothioate 2-Phenyl-l-ethyl 1- (3, 3-dimethyl-l, 2-dioxopentyl) - 2-piperidinecarbothioate 11 1- { 2-benzo [b] thiophen-3-ylmethylthio ) carbonyl] pyrrolidinyl } -3 , 3-dimethylpentane-l , 2-dione 12 2-Phenyl-l-ethyl ( 2 S) -1- ( 2 -cyclohexyl- 1 , 2 - dioxoethyl ) -2-pyrrolidinecarbothioate 19 128792/2 2-Phenyl-l-ethyl 1- (2-phenyl-l, 2-dioxoethyl ) -2-piperidinecarbothioate 2- Phenyl-l-ethyl (2S) -1- ( 2-cyclopentyl-l , 2-dioxoethyl ) -2-pyrrolidinecarbothioate 3-Phenyl-1 -propyl 1- ( 3, 3-dimethyl-l, 2-dioxobutyl) - 2-piperidinecarbothioate 3 - Phenyl- 1 -propyl (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarbothioate 3- (3-Pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarbothioate 3- Phenyl-l -propyl (2S) -1- ( 2-cyclohexyl-l , 2-dioxoethyl) -2-pyrrolidinecarbothioate 4 - Phenyl- 1 -butyl (2S) -1- (2-cyclohexyl-l, 2-dioxoethyl ) -2-pyrrolidinecarbothioate 4 -Phenyl- 1 -butyl (2S) -1- (3, 3-dimethyl-l , 2-dioxopentyl ) -2-pyrrolidinecarbbthioate 3- (3-Pyridyl) -1-propyl (2S) -1- (2-cyclohexyl-l, 2-dioxoethyl ) -2-pyrrolidinecarbothioate 3, 3-Diphenyl-l-propyl (2S) -1- ( 3 , 3-dimethyl-l , 2-dioxopentyl) -2-pyrrolidinecarbothioate 3, 3-Diphenyl-l-prppyl (2S) -1- (2-cyclohexyl-l, 2-dioxoethyl) -2-pyrrolidinecarbothioate 3- (para-Methoxyphenyl ) -1-propyl (2S) -1- (3,3-dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarbothioate 4- Phenyl-l-butyl 1- (1, 2-dioxo-3, 3-dimethylbutyl) -2-piperidinecarbothioate 128792/2 l,5-Diphenyl-3-pentyl l-(3,3-dimethyl-l,2-dioxopentyl ) -2-piperidinecarbothioate 1, 5-Diphenyl-3-pentyl 1- (2-phenyl-l, 2-dioxoethyl ) - 2-piperidinecarbothioate 3- (para-Methoxyphenyl ) -1-propyl 1- (1, 2-dioxo-3, 3-dimethylpentyl) piperidine-2-carbothioate 3- (para-Methoxyphenyl) -1-propyl 1- (2-phenyl-l, 2-dioxoethyl ) piperidine-2-carbothioate 3- (1-Naphthyl) -1-propyl 1- (3, 3-dimethyl- 1 , 2-dioxopentyl) piperidine-2-carbothioate 3, 3-Di {para-fluoro) phenyl-l-propyl · (2S)-l-(3,3-dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarbothioate 4, 4-Di (para-fluorophenyl) butyl 1- (3, 3-dimethyl-2-oxopentanoyl ) -2-pyrrolidinecarbothioate 3- (1-Naphthyl) -1-propyl (2S) -1- (3, 3-dimethyl-2-' oxopentanoyl) -2-pyrrolidinecarbothioate 2 ,.2-Diphenylethyl (2S) -1- ( 3, 3 -dimethy1 - 2 -oxopentanoyl ) -2-pyrrolidinecarbothioate 2.2- Diphenylethyl (2S) -1- (3, 3 -dimethy1 - 2 -oxopentanoyl) -2-piperidinecarbothioate 3.3-Diphenylpropyl 1- (3, 3-dimethyl-2-oxopentanoyl) - 2-piperidinecarbothioate 3- [4- (Trifluoromethyl) phenyl] propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (2-Naphthyl) propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl ) -2-pyrrolidinecarbothioate 2i 128792/2 3-(l-Naphthyl) -1 -propyl 1- (3, 3 -dime thy1-2 -oxopentanoyl ) -2-piperidinecarbothioate 3- (3-Chlorophenyl) propyl (2S) -1- ( 3 , 3-dimethyl-2-oxopentanoyl ) -2-pyrrolidinecarbothioate 3- [3- (Trifluoromethyl) phenyl] propyl (2S) -1- (3, 3-dimethy1-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- ( 2 -Biphenyl) propyl (25) -1- (3, 3-dimethyl-2-oxopentanoyl ) -2-pyrrolidinecarbothioate 3- (2-Fluorophenyl) propyl (2S) -1- ( 3 , 3-dimethyl-2-oxopentanoyl ) -2-pyrrolidinecarbothioate 3- (3-Fluorophenyl) propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl ) -2-pyrrolidinecarbothioate 4-Phenylbutyl 1- (3, 3-dimethyl-2-oxopentanoyl ) -2-piperidinecarbothioate 3-Phenylpropyl 1- ( 3, 3-dimethyl-2-oxopentanoyl ) -2-piperidinecarbothioate 3- (2-Chlorophenyl) propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbothioate 3- (3-Chlorophenyl) -1-propyl 1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate 3- (2-Fluorophenyl) propyl l-(3, 3 -dimethy1-2 -oxopentanoyl) -2-piperidinecarbothioate 3-(3-Fluorophenyl)propyl 1- ( 3 , 3 -dimethy1-2-oxopentanoyl) -2-piperidinecarbothioate · 3- (3, 4-Dimethoxyphenyl) propyl (2S) -1- (3, 3-dimethyl- 2-oxopentanoyl ) -2-pyrrolidinecarbothioate 22 128792/2 66 (2S)-2-( l-0xo-5-phenyl)pentyl-l- (2-Cyclohexyl-l, 2- dioxoethyl) pyrrolidine 67 2- ( 1-Oxo- 4 -phenyl ) -butyl- 1- (3, 3-dimethyl-l, 2- dioxobutyl) pyrrolidine . 68 2- ( 1-Oxo- 6 -phenyl ) -hexyl-1- (2-Cyclohexyl-l , 2- dioxoethyl) piperidine 69 2- ( { 1-Oxo- [2-{2 ' -phenyl } ethyl ] - -phenyl } -butyl-1- (3, 3-dimethyl-l, 2-dioxobutyl) piperidine 70 (2S) -2 - [5, 5-di ( 4 -Fluorophenyl ) pentanoyl ] -1- (3, 3 dimethyl-1, 2-pentanedione) pyrrolidine 71 3, 3-Dimethyl-1- [2- ( 5-phenylpentanoyl ) piperidino] - 1, 2-pentanedione FORMULA III Another preferred embodiment is a compound formula III: or a pharmaceutically acceptable salt thereof, wherein: A, B, C and D are independently CH2, 0, S, SO, S0a, H or NR2; X is 0 or S; Rj, is Cl-C6 straight or branched chain alkyl or alkenyl, which is substituted in one or more position (s) with (Ar,)n, (Arx)n connected by a CJ^ - CJ straight or branched chain alkyl or alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a -Cj straight- or branched chain alkyl or alkenyl, Ar, or a combination thereof; n is 1 or 2 ; R: is either C.-C6 straight or branched chain alkyl or alkenyl, C3-C3 cycloalkyl, C5-C, cycloalkenyl or Arlt wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted cr substituted in one or more position (si with C.- , straight or branched chain alkyl cr alkenyl, hydroxy! cr a combination thereof; and Ar■ and Ar; are independently a mono-, bi- or tricyclic, carbo- cr heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxy!, nitro, trifluoromethyl , ;-C3 straight or branched chain alkyl or alkenyl, C,-C4 aikoxy, C.-C, alkenylcxy, pher.oxy, benzyloxy, amino or a combination thereof,- wherein the individual ring sizes are 5-5 members; and wherein the heterocyclic ring contains 1-6 heteroatom ( s ! selected from the group consisting of 0, N, S and a combination thereof.
Particularly preferred compounds of formula III are presented in TABLE II .
TABLE II No. B X 72 CH, S CH, 0 -phenethyl 3,3-dimethyl pentyl CH, S CH, 0 -phenylpropyl 3 , 3 -dimethyl pentyl 74 CH, CH, NH O -phenethyl 3,3-dimethyl pentyl 75 CH- S CH, S -phenethyl 3,3-dimethyl pentyl FORMULA IV A further preferred embodiment of this invention is a c mpound of formula IV: or a pharmaceutically acceptable salt thereof, wherein: A, B, C and D are independently CH2, 0, S, SO, S02/ NH or R2 ; X is 0 or S; Z is S , CH2 , CHRX or C (Ri, ) 2 ; R, is - C5 straight or branched chain alkyl or alkenyl, which is substituted in one or more position (s) with (Ar:)n, (Ar n connected by a C^ - Cg straight or branched chain alkyl or alkenyl, C3-Ce cycloalkyl, C3-C8 cycioalkyl connected by a C,-C6 straight or branched chain alkyl or alkenyl, Ar, or a combination thereof; n is 1 or 2 ; R2 is either - Cg straight or branched chain alkyl or alkenyl, C3-C3 cycioalkyl, C3-C7 cycloalkenyl or Arx, wherein said alkyl, alkenyl, cycioalkyl or cycloalkenyl s either unsubs icuted or substituted in one or more positio (s) with C.-C, straight or- branched chain alkyl or alkenyl, hydroxy 1 or a combination thereof; and Ar. and Ar2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl , Cj-C¾ straight or branched chain alkyl or alkenyl, C-^-C, alkoxy, C.-C, 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.
Particularly preferred compounds of formula IV are presented in TABLE III.
TABLE ΙΠ No. A B C D X z R2 76 CH: CH: 0 CH2 0 CH, 3-phenylpropyl 3,3-dimethylpentyl 77 CH: CH: 0 CH: 0 S 2-phenethyl 3,3-dimethylpentyl 78 CH: CH: S CH; 0 CH; 3-phenylpropyl 3,3-dimethylpentyl 79 CH: CH: S CH, 0 S 2-phenethyl 3,3-dimethylpentyl The compounds of this invention possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual stereoisomers.' The individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemio 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 or the present invention. The compounds of this invention possess at least one asymmetric center and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers . The individual enantiomers may be obtained by resolving a racemic or 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 .
Methods of Using the Compounds of the Invention The ' compounds of the present invention have an affinity for the FK506 binding protein, particularly FK3P12, which is present in the brain. When the inventive compounds bind to FKBP in the brain, they exhibit excellent neurotrophic activity. This activity is useful in the stimulation of damaged neurons, the promotion cf neuronal regeneration, the prevention of ne rodegeneratio , and the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathies.
For the foregoing reasons , the present invention further relates to a method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound cf formula I, II, III or I .
In a preferred embodiment, the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.
The neurological disorders that may be treated include but are not limited to: trigeminal neuralgia; glossopharyngeal neuralgia; Bell's Palsy; myasthenia gravis; muscular dystrophy; amyotrophic lateral sclerosis; progressive muscular atrophy; progressive bulbar inherited muscular atrophy; herniated, ruptured or prolapsed invertebrate disk syndromes; cervical spondylosis; plexus disorders; thoracic outlet destruction syndromes; peripheral neuropathies such as those caused by lead, dapsone, ticks, porphyria or Guil ain-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. Examples of neurological disorders relating to neurodegeneration are Alzheimer's Disease, Parkinson's Disease and amyotrophic lateral sclerosis .
For these purposes, the compounds may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneally , intrathecally , ir.traventricularly, intrastemal and intracranial injection or infusion techniques.
To be effective therapeutically as central nervous system targets, the compounds should readily penetrate the blood-brain barrier when peripherally administered. Compounds which cannot penetrate the blood-brain barrier can be effectively administered by an intraventricular r nts .
The compounds may be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally-acceptable diluents cr solvents, for examDle, as solutions in 1 , 3 -butanediol .
T/ 97/1 8 Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conven ionally employed as solvents or suspending mediums. For this purpose, any bland fixed oil such as a synthetic mono- or di-glyceride may be employed. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their pclyoxyethylated versions, are useful in the preparation of injectabies. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.
Additionally, the compounds may be administered orally in the form of capsules, tablets, aqueous suspensions or solutions. Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate. Capsules may contain diluents including lactose and dried corn starch. Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient. The oral dosage forms may further contain sweetening and/or flavoring and/or coloring agents.
The compounds may also be administered rectally in the form of suppositories. These compositions can be preoared by mixing the drug with a suitable non-irricaring excipie t which is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
Furthermore, the compounds may be administered topically, especially when the conditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin or the lower intestinal tract. Suitable topical formulations can be readily prepared for each of these areas .
For topical application to the eye, or ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as a solution in isotonic, pH adjusted sterile saline, either with or without a preservative such as be zyialkonium chloride. Alternatively, the compounds may be formulated into ointments, such as petrolatum, for ophthalmic use.
For topical application to the skin, the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, pciyoxyethyiene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate , polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Topical application to the lower intestinal tract can be effected in a rectal suppository formulations (see above) or in suitable enema formulations.
Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host created and the particular mode cf administration.
It is understood, however, that a specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration .
The compounds can be administered with other neurotrcchic agents such as neurotrophic growth factor (NGF: , glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor and neurotropin-3. The dosage level of other neurotrophic drugs will depend upon the factors previously stated and the neurotrophic effectiveness of the drug combination.
Pharmaceutical Compositions of the Invention The present invention also relates to a pharmaceutical composition comprising: (i) a neurotrophically effective amount of the compound of formula I, II, III or IV, and (ii) a pharmaceutically acceptable carrier.
The above discussion relating to the utility and administra ion of the compounds of the present invention also applies to the pharmaceutical compositions of the c ssen invention.
Examples The following examples are illustrative of the present invention and are r.c intended to be limitations thereon. Unless otherwise specified, all percentages are based on 100% by weight cf the final compound. 3 128792/2 EXAMPLE 1 Synthesis of (2S) -2- (1-oxo-5-phenyl) -pentyl-1- (3 , 3- dimethyl-1 , 2-dioxopentyl) pyrrolidine ( 1 ) (2S) -2- ( 1-oxo-5-phenyl ) pentyl-N-benzylpyrrolidine. l-chloro-4-phenylbutane (1.78 g; 10.5 mmol) in 20 mL of THF was added to 0.24 g (10 mmol) of magnesium turnings, in 50 mL of refluxing THF. After the addition was complete, the mixture was r.efluxed for an additional 5 hours, and then added slowly to a refluxing solution of N-benzyl-L-proline ethyl ester (2.30 g (10 mmol) in 100 mL of THF. After 2 hours of further reflux, the mixture was cooled and treated with 5 mL of 2 N HC1. The reaction mixture was diluted with ether (100 mL) and washed with saturated NaHC03, water and brine. The organic phase was dried, concentrated and chromatographed, eluting with 5:1 CH2Cl2:EtOAc to obtain 2.05 g (64%) of the ketone as an oil, ¾ NMR (CDC13; 300 MHz): 1.49-2.18 (m, 8H) ; 2.32-2.46 (m, 1H) ; 2.56-2.65 (m, 2H) ; 2.97-3.06 (m, 1H) ; 3.17-3.34. (m, 1H) ; 3.44-3.62 (m, 1H) ; 4.02-4.23 (m, 2H) ; 7.01-7.44 (m, 10H) . (25) -2- ( l-oxo-5-phenyl) pentylpyrrolidine . The ketone compound (500 mg) and palladium hydroxide (20% on carbon, 50 mg) was hydrogenated at 40 psi in a Paar shaker overnight. The catalyst was removed by filtration and the solvent was removed in vacuo. The free amine was obtained as a yellow oil (230 mg; 100%), XH NMR (CDC13; 128792/2 300 MHz): 1.75-2.34 (m, 10H) ; 2.55 (m, 2H) ; 2.95 (dm, 1H); 3.45-3.95 (m, 1H) ; 4.05 (m, 1H) ; 7.37 (m, 5H) . (2S)-2-(l-oxo-5-phenyl)pentyl-l-(l,2-dioxo-2-methoxyethyl ) pyrrolidine . To a solution of (2S)-2-(l-oxo-5-phenyl) pentylpyrrolidine (230 mg; 1.0 mmol) in CH2C12(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„C1 and the organic phase was washed with water and brine and dried and concentrated. The crude residue was purified on a silica gel column, eluting with 20:1 CH2Cl2:EtOAc to obtain 300 mg of the oxamate as a clear oil (98%), H NMR (CDC13; 300 MHz): 1.68 (m, 4H) ; 1.91-2.38 (m, 4H) ; 2.64 (t, 2H) ; 3.66-3.80 (m, 2H) ; 3.77, 3.85 (s, 3H total); 4.16 (m, 2H) ; 4.90 (m, 1H) ; 7.16 (m, 3H) ; 7.27 (m, 2H) . (25) -2- ( f l-oxo-5-phenyl I -pentyl-1- ( 3 , 3-dimethyl-l , 2-dioxopentyl) pyrrolidine (1). To a solution of the oxamate above (250 mg; 0.79 mmol) in anhydrous ether (15 mL) , cooled to - 78°C, was added 1 , 1-dimethylpropyl-magnesium chloride (0.8 mL of a 1.0 M solution in ether; 0.8 mmol). After stirring the resulting mixture at -78°C for 2 hours, the reaction was quenched by the addition of 2 mL of saturated NH4C1, followed by 100 mL of EtOAc. The organic phase was washed with brine, dried, concentrated, and purified on a silica gel column, eluting with 50:1 CH2C12 : EtOAc . Compound 1 was obtained 3β 128792/2 as a clear oil, 120 mg, :H NMR (CDC13, 300 MHz): δ 0.87 (t, 3H, 1.22 (s, 3H) ; 1.25 (s, 3H) ; 1.67 (m, 4H) ; 1.70-2.33 (m, 6H) ; 2.61 (t, 2H, ; 3.52 (m, 2H) ; 4.17 (t, 2H, J=6.2); 4.52 (m, 1H) ; 7.16-7.49 (m, 5H) . Anal. Calcd. for C22H31N03 - H20 : C, 70.37; H, 8.86; N, 3.73. Found: 70.48; H, 8.35; N, 3.69.
EXAMPLE 2 Synthesis of 2-phenyl-1-ethyl 1- (3 , 3-dimethyl-l , 2- dioxopentyl) -2-pyrrolidinecarbothioate (9) Methyl (2S) -1- (1, 2-dioxo-2-methoxyethyl) -2 -pyrrolidinecarboxylate . A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in dry methylene chloride was cooled to 0°C and treated with triethylamine (3.92 g; '38.74 mmol; 2.1 eq) . After stirring the formed slurry under a nitrogen atmosphere for 15 min, a solution of methyl oxalyl chloride" (3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hour. After filtering to remove solids, the organic phase was washed with water, dried over 'MgS04 and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. λΗ NMR (CDC13) : δ 1.93 (dm, 2H) ; 2.17 (m, 2H) ; 3.62 (m, 2H) ; 3.71 (s, 3H) ; 1 S97/15832 37 3.79, 3.84 (s, 3H total) ; 4.86 (dd, 1H, J -8 . 4 , 3.3).
Me hyl (2S) -1- fl.2-dioxo-3.3 -dime hylnentyl ¾ - s> - p rrolidinecarboxylate . 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 l, l-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 °C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel cclum., eluting with 25% ethyl acetate in hexane, to cbcain 2.10 g (75%) of the oxamate as a colorless oil, "H NMR (CDC13) : δ 0.88 (t, 3H) ; 1.22, 1.26 (s, 3H each) ; i.75(cm, 2H) ; 1.87-2.10 (m, 3H) ; 2.23 (m, 1H) ; 3.54 (m, 2H) ; 3.76 (s, 3H) ; 4.52 (dm, 1H, J=8.4, 3.4). ?2S' -1- (1, 2-dioxo-3 , 3 -dimethylpentyl) -2 -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 mL) was stirred at 0°C for 30 minutes and at room temperature overnight . The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with 38 128792/2 brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification, H NMR (CDC13) : 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, 4.1) . 2-phenyl-l-ethyl 1- ( 3 , 3-dimethyl-l .2-dioxopentyl ) -2-pyrrolidinecarbothioate (9) . To a solution of (2S)-1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylic acid (241 mg; 1.0 mmol) in CH2C12 (10 mL) was added dicyclohexylcarbodiimide (226 mg; 1.1 mmol). After stirring the resulting mixture for 5 minutes, the solution was cooled to 0°C and treated with a solution of phenethyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2C12. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration .and the filtrate was concentrated in vacuo; ■ the crude residue was purified by flash chromatography (10:1 hexane : EtOAc) to obtain 302 mg (84%) of 9 as an oil, H NMR (CDC13, 300 MHz): δ 0.85 (t, 3H, J=7.5); 1.29 (s, 3H) ; 1.31 (s, 3H) ; 1.70-2.32 (m, 6H) ; 2.92 (t, 2H, J=7.4); 3.22(t, 2H, 3.58 (m, 2H) ; 4.72 (m, 1H) ; 7.23-7.34 (m, 5H) . Anal. Calcd. for C20H27NO3S - 0.4H2O: C, 65.15; H, 7.60; N, 3.80. Found: C, 65.41; H, 7.49; N, 3.72. 39 128792/2 EXAMPLE 3 Synthesis of 2-phenyl-1-ethyl (2S)-l-(3,3- dimethyl-1 , 2-dioxopentyl) -2-piperidinecarbothioate (10) Methyl 1- (1, 2-dioxo-2-methoxyethyl) -2-piperidine-carboxylate . A solution of methyl pipecolate hydrochloride (8.50 g; 47.31 mmol) in dry methylene chloride (100 mL) was cooled to 0°C and treated with triethylamine (10.5 g; 103 mmol; 2.1 eq) . After stirring the formed slurry under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (8.50 g; 69.4 mmol) in methylene chloride (75 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hours. After filtering to remove solids, the organic phase was washed with water, dried over MgS04 and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 9.34. g (86%") 'of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. *H NMR (CDC13) : δ 1.22-1.45 (m, 2H) ; 1.67-1.78 (m, 3H) ; 2.29 (m, 1H) ; 3.33 (m, ' 1H) ; 3.55 (m, 1H) ; 3.76 (s, 3H) ; 3.85, 3.87 (s, 3H total); 4.52 (dd, 1H) .
Methyl 1- (1, 2-dioxo-3, 3-dimethylpentyl ) -2-piperidine -carboxylate . A solution of methyl 1- ( 1 , 2-dioxo-2-methoxyethyl ) -2-piperidinecarboxylate (3.80 g; 16.57 mmol) in 75 mL of tetrahydrofuran (THF) was cooled to - 78 °C and treated with 20.7 mL of a 1.0 M solution of 1,1- dimethyl-propylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 °C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.32 g (74%) of the oxamate as a colorless oil, XH NMR (CDClj) : 6 0.88 (t, 3H) ; 1.21, 1.25 (s, 3H each) ; 1.35-1.80 (m, 7H) ; 2.35 (m, 1H) ; 3.24 (m, 1H) ; 3.41 (m, 1H) ; 3.76 (s, 3H) ; 5.32 (d, 1H) . 1 - Ί .2-cioxo-3 , 3-dimet hyloentyl ) - 2 -p jperidine - arboxylic acid. A mixcure of methyl 1- ( 1 , 2-dioxo-3 , 3 -dimethyipentyl) -2 -piperidinecarboxylate (3.30 g; 12.25 rnmci) , 1 N LiOK (15 mL) , and methanol (60 mL) was stirred a: 0°C f r 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride . The organic extract was washed with brine and concentrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification, ¾ NMR (CDCi,) : 0 0.89 (t, 3K) ; 1.21, 1.24 (s, 3H each) ; 1.42-1.55 (m, 7K) ; 2.35 (m, 1H) ; 3.22 (d, 1H) ; 3.42 (m, 1H) ; 128792/2 2-phenyl-l-ethyl (25) -1- (3, 3-dimethyl-l , 2- dioxopentyl) -2-piperidinecarbothioate (10) . To a solution of 1- ( 1 , 2-dioxo-3 , 3-dimethylpentyl ) -2- piperidine-carboxylic acid (255 mg; 1.0 mmol) in GH2C12 (10 mL) was added dicyclohexylcarbodiimide (226 mg; 1.1 mmol) . After stirring the resulting mixture for 5 minutes, the solution was cooled to 0°C and treated with a solution of phenethyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2C12. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo; the crude residue was purified by flash chromatography (10:1 hexane:EtOAc) to obtain 300 mg (80%) of 10 as an oil, 1H N R (CDC13, .300 MHz) : d 0.94 (t, 3H, J=7.5); 1.27 (s, 3H) ; 1.30 -(s, .3H) ; 1.34-1.88 (m, 7H) ; 2.45 (m, 1H) ; 2.90 (t, 2H-, ■ ; 3.26 (t, 2H, J=7.7); 3.27 (m, 1H) ; 3.38 (m, 1H) ; 5.34 (m, 1H) ; 7.24-7.36 (m, 5H) . Anal. Calcd. for C21H29N03S: C, 67.17; H, 7.78; N, 3.73. Found: - C, 67.02; H, 7.83; N, 3.78.
As discussed above, the compounds of the present invention have an affinity for the 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.
Kt Test Procedure Inhibition of the peptidyl -prolyl isomerase (rotamase) activity of the inventive compounds can be evaluated by known methods described in the literature (Harding et al . , Nature, 1989, 341:758-760; Holt et al . J. Am. Che . Soc, 115:9923-9938) . These values are obtained as apparent Kt's and are presented for representative compounds in Table IV. The cis- rans isomerization of an alanine -proline bond- in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin- coupled assay, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data s analyzed as a change in first -order rate constant as a function of inhibitor concentration to yield the apparent K. values.
In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES , pH 7.8, 100 mM NaCl) , 10 mL of FKB? (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl , 1 mM dithiothreitol ) , 25 mL of chymotrypsin (50 mg/ml in 1 mM KC1 ) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate ( succinyl -Ala-Phe-Pro-Phe-para -r.ttroaniiide , 5 mg/mL in 2.35 mM LiCl in 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 data for these experiments for representative compounds are presented in Table IV under the column " Ki " .
The neurotrophic effects of the compounds of the present invention can be demonstrated in cellular biological experiments in vitro, as described below.
Chick Dorsal Root Ganglion Cultures and Neurite Outgrowth The neurotrophic effects of the FKBP inhibitor compounds were demonstrated by evaluating the ability of the compounds to promote neurite outgrowth in cultured chick sensory neurcns 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 μΜ cytcsine β-D arabinofuranoside (Ara C) at 37°C in an environment containing 5% CO: . Twenty- four hours later, the DRGs were treated with various concentrations of nerve growth factor, immunophilin ligands or combinations of NFG plus drugs. Forty-eight hours after drug treatment, the ganglia were visualized under phase contrast or Hoffman Modulation contrast with a Zeiss Axiovert inverted microscope. Photomicrographs of the explants were made, and neurite outgrowth was quantitated. Neurites longer than the DRG diameter were counted as positive, with total number of neurites quantitated per each experimental condition. Three to four DRGs are cultured per well, and each treatment was performed in duplicate.
Dose-response curves were generated from which EDS0 values were obtained. The results of these experiments are presented in Table IV under the column "ED50". Representative photomicrographs of untreated (control) sensory neurons and of compounds 1 (10 pM, 1 nM, l μΜ) , 9 (10 pM, 1 nM, .100 nM) and 10 (10 pM, 1 nM, 100 nM) promoting neurite outgrowth in sensory neurons are shown in FIG. 's i(A-D), 2 (A-D) and 3 (A-D) , respectively.
MPTP Model of Parkinson's Disease The remarkable neurotrophic and neuroregenerative effects cf the present inventive compounds were further demonstrated in an animal model of neurodegenerative disease. MPT? lesioning of dopaminergic neurons in mice was used as an animal model of Parkinson's Disease. Four week old male CD1 white mice were dosed i.p. with 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. At 18 days following MPTP treatment, the animals were sacrificed and the striata were dissected and homogenized. Immunostaining was performed on saggital and coronal brain sections using anti -tyrosine hydroxylase 1 g to quantitate survival and recovery of dopaminergic neurons . In animals treated with M?T? and vehicle, a substantial loss of functional' dopaminergic terminals was observed as compared to non-lesioned animals. Lesioned animals receiving test compounds showed a significant recovery of TH-stained dopaminergic neurons .
The results of these experiments are presented in TABLE IV under the column " TH recovery". Quantitation for the recovery cf TH -positive dopaminergic neurons in the striatum cf animals receiving compounds 1, 9 and 10, and for representative control and lesioned animals not receiving the test drugs, are presented in FIG. 4.
TABLE IV In Vitro Test Results Example # i. nM ED50. nM % TH recovery 1 31 0.4 23 2 210 85 104 0.5 61 12 0.8 54 1 299 0.36 53 2 442 0.025 4 313 0.9 48 8 108 0.9 41 9 59 0.003 50 0 11 0.00025 65 1 8.7 -- 31 2 362 -- 52 3 1698 4 34 0.9 48 62 6 7 - 56 7 68 8 8.9 0.011 37.32 PC17US97/15832 47 39 347 40 1226 41 366 42 28 43 259 44 188 25 45 31 46 757 47 21 50 48 127 28 49 1334 50 55 62 51 33 52 6 53 261 54 37 55 30 56 880 57 57 58 79 59 962 60 90 128792/2 48 61 139 62 196 63 82 84 163 65 68 66 306 5 38 67 177 68 284 69 49 - 23 70 457 - 25 71 788 All publications and patents identified above are hereby incorporated by reference.
All those parts which are not covered by the claims are given for illustrative purposes only.

Claims (9)

1. 28792/3 1. A compound of formula II: or pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; x is O ; z is selected from the group consisting of CH2, ■ HR1 and C(R2)2; R: is ^-Cj straight or branched chain alkyl which is substituted with Ar1 ; R2 is selected from the group consisting of : -C^-C8 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C3-C7 cycloalkenyl , and, -Arx, Arl is phenyl, pyridyl, fluorenyl benzo [b] thiophen, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, Cx-C6 straight or branched chain 128792/3 49A alkyl, C2-C6 straight or branched chain alkenyl C^ ^ alkoxy,C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof .
2. The compound of claim 1, wherein n is 1.
3. The compound of claim 2, wherein 2 is CH2. 128792/2 - 50 - Δ compound of Claim 3, which selected from group consisting of: (23) -2- { { l-0xo-5-phenyl } -pentyl) -1- ( 3, 3-dintiethyl-l, 2-dioxopentyl) pyrrolidine; 3, 3-Dimethyl-l- [ (2S) -2- (5- ( 3-pyridyl ) pentanoyl ) -1-pyrrolidine]-l,2-pentanedione; (2S) -2- ( {l-Oxo- -phenyl } -butyl) -1- (3, 3-dimethyl-l , 2-dioxobutyl) pyrrolidine; (2S) -2- ( (l-Oxo- -phenyl) -butyl) -1- (2-cyclohexyl-l, 2-dioxoethyl ) pyrrolidine; 2- ( { l-0xo-4-phenyl)-butyl) -1- (3, 3-dimethyl-l , 2-dioxobutyl ) pyrrolidine; and l-{ (2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl] -2-pyrrolidine } -3, 3-dimethyl-l, 2-pentanedione , or a pharmaceutically acceptable salt thereof. 5. The compound of Claim 1, wherein n is 2. 6. The compound of claim 5, which is selected group consisting of: 2- ( { l-0xo-6-phenyl}-hexyl-l- ( 3 , 3-dimethyl-l , 2-dioxobutyl ) piperidi'ne; and 3, 3-Dimethyl-l- [2- ( 4-phenylpentanoyl ) piperidino] pentanedione, or a pharmaceutically acceptable salt thereof. 7. The compound of Claim 1, wherein Z is CHRi . 8. The compound of Claim 7, which is 2- ( { 1-Oxo- [2- { phenyl ! ethyl] - -phenyl ) -butyl ) -1- [3, 3-dimethyl-l, 2- 128792/2 - 51 - dio:-:obu l 1 pipericline , or a pharmaceutically acceptable salt thereof . 9. A pharmaceutical composition comprising: i) an effective amount of one or more compound(s) as defined in any one of claims 1-3 for effecting a neuronal activity; and ii) a pharmaceutically acceptable carrier. 10. The pharmaceutical composition according to claim 9, further comprising one or more additional neurotrophic agent (s) . 11. The pharmaceutical composition, according to claim 10, wherein said one or more additional neurotrophic agent (s) is/are independently selected from the group consisting of nerve growth factor (NGF) , glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor and neurotrophin-3. 12. The pharmaceutical composition according to claim 11, wherein said one or more additional neurotrophic agent (s) is nerve growth factor (NGF) . 13. A compound of formula II as defined in any one of claims 1 to 3 for use as a medicament. 1
4. Use of a compound as defined in any one of claims 1 to 3 for the preparation of a medicament substantially as described in the specification. 1
5. The use according to claim 14, wherein the medicament is useful for effecting a neuronal activity in an animal xcluding human beings. 128792/2 - 52 - 1
6. The use according to claim 15, wherein 'the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder . 1
7. The use according to claim 16, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration. 1
8. The use according to claim 17, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis. 1
9. A method for treatment of animals excluding human ^ beings, comprising administering one or more compound (s) as defined in any one of claims 1 to 8 in an amount for effecting a neuronal activity. 20. The method according to claim 19, wherein the ^ neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neuroclegenera Lion and treatment of neurological disorder. I 21. The method according to claim 20, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration. 128792/2 method according to claim 21, wherein th neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis. THE APPLICANT 0 Viiihak Hess & Partners
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Families Citing this family (63)

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Publication number Priority date Publication date Assignee Title
US6509477B1 (en) 1998-11-12 2003-01-21 Guilford Pharmaceuticals Inc. Small molecule inhibitors of rotamase enzyme activity
US5859031A (en) 1995-06-07 1999-01-12 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
US6291510B1 (en) 1995-06-07 2001-09-18 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
US6218424B1 (en) * 1996-09-25 2001-04-17 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
US5801187A (en) 1996-09-25 1998-09-01 Gpi-Nil Holdings, Inc. Heterocyclic esters and amides
US5935989A (en) 1996-12-31 1999-08-10 Gpi Nil Holdings Inc. N-linked ureas and carbamates of heterocyclic thioesters
SK57899A3 (en) * 1996-12-31 2000-05-16 Guilford Pharm Inc N-linked ureas and carbamates of heterocyclic thioesters
US5721256A (en) * 1997-02-12 1998-02-24 Gpi Nil Holdings, Inc. Method of using neurotrophic sulfonamide compounds
US5846979A (en) * 1997-02-28 1998-12-08 Gpi Nil Holdings, Inc. N-oxides of heterocyclic esters, amides, thioesters, and ketones
US5945441A (en) * 1997-06-04 1999-08-31 Gpi Nil Holdings, Inc. Pyrrolidine carboxylate hair revitalizing agents
US6274602B1 (en) * 1998-06-03 2001-08-14 Gpi Nil Holdings, Inc. Heterocyclic thioester and ketone hair growth compositions and uses
US6852496B1 (en) * 1997-08-12 2005-02-08 Oregon Health And Science University Methods of screening for agents that promote nerve cell growth
US6096762A (en) * 1998-06-02 2000-08-01 Bristol-Myers Squibb Company Neurotrophic difluoroamide agents
CA2334204A1 (en) * 1998-06-03 1999-12-09 Gpi Nil Holdings, Inc. Heterocyclic ester and amide hair growth compositions and uses
EP1083872A1 (en) * 1998-06-03 2001-03-21 GPI NIL Holdings, Inc. Pipecolic acid derivative hair growth compositions and uses
NZ508462A (en) * 1998-06-03 2004-02-27 Guilford Pharm Inc Aza-heterocyclic compounds used to treat neurological disorders and hair loss
US6331537B1 (en) 1998-06-03 2001-12-18 Gpi Nil Holdings, Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
JP2002516844A (en) * 1998-06-03 2002-06-11 ジーピーアイ エヌアイエル ホールディングス， インコーポレイテッド Heterocyclic thioester and ketone hair growth compositions and uses
JP2002516904A (en) 1998-06-03 2002-06-11 ジーピーアイ ニル ホールディングス インコーポレイテッド N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
ATE257009T1 (en) * 1998-06-03 2004-01-15 Guilford Pharm Inc USE OF A COMPOUND FOR PRODUCING A MEDICATION FOR TREATING ALOPECIA OR PROMOTING HAIR GROWTH IN ANIMALS
AU756912B2 (en) * 1998-07-17 2003-01-23 Agouron Pharmaceuticals, Inc. Compounds, compositions, and methods for stimulating neuronal growth and elongation
GB9815880D0 (en) * 1998-07-21 1998-09-16 Pfizer Ltd Heterocycles
US7265150B1 (en) * 1998-08-14 2007-09-04 Gpi Nil Holdings Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds for vision and memory disorders
US6506788B1 (en) * 1998-08-14 2003-01-14 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders
EP1105112A2 (en) * 1998-08-14 2001-06-13 GPI NIL Holdings, Inc. Compositions and uses for vision and memory disorders
US6384056B1 (en) * 1998-08-14 2002-05-07 Gpi Nil Holdings, Inc. Heterocyclic thioesters or ketones for vision and memory disorders
US6376517B1 (en) * 1998-08-14 2002-04-23 Gpi Nil Holdings, Inc. Pipecolic acid derivatives for vision and memory disorders
US7338976B1 (en) * 1998-08-14 2008-03-04 Gpi Nil Holdings, Inc. Heterocyclic esters or amides for vision and memory disorders
US6218423B1 (en) * 1998-08-14 2001-04-17 Gpi Nil Holdings, Inc. Pyrrolidine derivatives for vision and memory disorders
US6339101B1 (en) * 1998-08-14 2002-01-15 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or isosteres for vision and memory disorders
US6337340B1 (en) * 1998-08-14 2002-01-08 Gpi Nil Holdings, Inc. Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders
US6462072B1 (en) 1998-09-21 2002-10-08 Gpi Nil Holdings, Inc. Cyclic ester or amide derivatives
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
US6228872B1 (en) 1998-11-12 2001-05-08 Bristol-Myers Squibb Company Neurotrophic diamide and carbamate agents
JP4708567B2 (en) * 1998-12-03 2011-06-22 ジーピーアイ ニル ホールディングス インコーポレイテッド Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
US6284779B1 (en) 1999-02-03 2001-09-04 Schering Aktiiengesellschaft Heteroaromatic compounds
WO2000046181A1 (en) * 1999-02-03 2000-08-10 Schering Aktiengesellschaft Carboxylic acid derivatives, process for their preparation and their use as rotamase enzyme activity inhibitors
WO2001004091A1 (en) 1999-07-09 2001-01-18 Ortho-Mcneil Pharmaceutical, Inc. Neurotrophic 2-azetidinecarboxylic acid derivatives, and related compositions and methods
JP2003504367A (en) 1999-07-09 2003-02-04 オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド Neurotrophic pyrrolidines and piperidines, and related compositions and methods
US6323215B1 (en) 1999-07-09 2001-11-27 Ortho-Mcneil Pharmaceutical, Inc. Neurotrophic tetrahydroisoquinolines and tetrahydrothienopyridines, and related compositions and methods
WO2001008685A1 (en) * 1999-07-30 2001-02-08 Vertex Pharmaceuticals Incorporated Acyclic and cyclic amine derivatives
US6593292B1 (en) 1999-08-24 2003-07-15 Cellgate, Inc. Compositions and methods for enhancing drug delivery across and into epithelial tissues
CA2383086A1 (en) * 1999-09-08 2001-03-15 Joseph P. Steiner Non-peptidic cyclophilin binding compounds and their use
US6417189B1 (en) 1999-11-12 2002-07-09 Gpi Nil Holdings, Inc. AZA compounds, pharmaceutical compositions and methods of use
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
AR034103A1 (en) * 1999-11-12 2004-02-04 Alcon Inc PHARMACEUTICAL COMPOSITION THAT INCLUDES NEUROPHILINE LIGANDS FOR THE TREATMENT OF EYE CONDITIONS
GT200000203A (en) 1999-12-01 2002-05-24 COMPOUNDS, COMPOSITIONS AND METHODS TO STIMULATE THE GROWTH AND ELONGATION OF NEURONS.
US6818643B1 (en) 1999-12-08 2004-11-16 Bristol-Myers Squibb Company Neurotrophic bicyclic diamides
ATE319712T1 (en) 1999-12-21 2006-03-15 Mgi Gp Inc HYDANTOIN DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE THEREOF
US6656971B2 (en) 2001-01-25 2003-12-02 Guilford Pharmaceuticals Inc. Trisubstituted carbocyclic cyclophilin binding compounds and their use
US6593362B2 (en) 2001-05-21 2003-07-15 Guilford Pharmaceuticals Inc. Non-peptidic cyclophilin binding compounds and their use
JP2005500270A (en) * 2001-05-29 2005-01-06 ギルフォード ファーマシュウティカルズ インコーポレイテッド Method for treating nerve injury that has occurred as a result of surgery
DE10150203A1 (en) * 2001-10-12 2003-04-17 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitor in treatment of cancer
WO2003093258A2 (en) * 2002-05-03 2003-11-13 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Novel spiro ketone and carboxylic acid derivatives as specific inhibitors for (po3h2) ser/(po3h2)thr-pro-specific peptidyl-prolyl-cis/trans-isomerases
KR101255074B1 (en) * 2003-10-01 2013-04-16 아돌로 코포레이션 Spirocyclic heterocyclic derivatives and methods of their use
US7780973B2 (en) * 2003-12-15 2010-08-24 Ethicon Endo-Surgery, Inc. Method and device for minimally invasive implantation of biomaterial
US20050142161A1 (en) * 2003-12-30 2005-06-30 Freeman Lynetta J. Collagen matrix for soft tissue augmentation
US20060189551A1 (en) * 2004-10-04 2006-08-24 Duke University Combination therapies for fungal pathogens
US7598261B2 (en) * 2005-03-31 2009-10-06 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
US7576207B2 (en) 2006-04-06 2009-08-18 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
JP2010503669A (en) * 2006-09-12 2010-02-04 アドラー コーポレーション Use of N-containing spiro compounds to enhance cognitive function
WO2008137476A1 (en) * 2007-05-04 2008-11-13 Burnham Institute For Medical Research Arylthioacetamide carboxylate derivatives as fkbp inhibitors for the treatment of neurological diseases

Family Cites Families (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL58849A (en) * 1978-12-11 1983-03-31 Merck & Co Inc Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them
US4310461A (en) * 1980-06-23 1982-01-12 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4390695A (en) * 1980-06-23 1983-06-28 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4578474A (en) * 1980-06-23 1986-03-25 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4950649A (en) * 1980-09-12 1990-08-21 University Of Illinois Didemnins and nordidemnins
GR75019B (en) * 1980-09-17 1984-07-12 Univ Miami
ZA817261B (en) * 1980-10-23 1982-09-29 Schering Corp Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them
DE19575012I2 (en) * 1980-10-23 2002-01-24 Schering Corp Carboxyalkyl dipeptides Process for their preparation and medicaments containing them
US4766110A (en) * 1981-08-21 1988-08-23 Ryan James W Novel complex amido and imido derivatives of carboxyalkyl peptides
ZA826022B (en) * 1981-08-21 1983-08-31 Univ Miami Novel complex amido and imido derivatives of carboxyalkyl peptides and thioethers and ethers of peptides
DE3360065D1 (en) * 1982-03-08 1985-03-28 Schering Corp Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them
AU563282B2 (en) * 1982-09-13 1987-07-02 Nippon Kayaku Kabushiki Kaisha Pyrrolidino and piperidino derivatives and condensed derivatives thereof
US4574079A (en) * 1983-05-27 1986-03-04 Gavras Haralambos P Radiolabeled angiotensin converting enzyme inhibitors for radiolabeling mammalian organ sites
US4593102A (en) * 1984-04-10 1986-06-03 A. H. Robins Company, Inc. N-[(amino)alkyl]-1-pyrrolidine, 1-piperidine and 1-homopiperidinecarboxamides (and thiocarboxamides) with sulfur linked substitution in the 2, 3 or 4-position
DE3508251A1 (en) * 1985-03-08 1986-09-11 Merck Patent Gmbh, 6100 Darmstadt Dipeptides
CN86101850A (en) * 1985-03-22 1987-02-04 森得克斯(美国)有限公司 N, the manufacture method and the purposes of N '-dialkyl group guanidine radicals dipeptides
ATE70048T1 (en) * 1986-09-10 1991-12-15 Syntex Inc SELECTIVE AMIDINATION OF DIAMINES.
IT1206078B (en) * 1987-06-03 1989-04-14 Polifarma Spa PROCEDURE FOR THE PRODUCTION OF 3-INDOLPIRUVIC ACID AND ITS DERIVATIVES THEIR PHARMACEUTICAL USE
US5187156A (en) * 1988-03-16 1993-02-16 Fujisawa Pharmaceutical Co., Ltd. Peptide compounds, processes for preparation thereof and pharmaceutical composition comprising the same
US5232923A (en) * 1988-03-18 1993-08-03 Mitsui Toatsu Chemicals, Incorporated Catechol derivatives and pharmaceutical preparations containing same
IL90872A0 (en) * 1988-07-08 1990-02-09 Smithkline Beckman Corp Retroviral protease binding peptides
DE3931051A1 (en) * 1988-09-22 1990-03-29 Hoechst Ag New herbicidal amine salts of herbicidal acids
US5166317A (en) * 1988-10-31 1992-11-24 Houston Biotechnology Incorporated Neurotrophic factor
EP0378318A1 (en) * 1989-01-11 1990-07-18 Merck & Co. Inc. Process for synthesis of FK-506 and tricarbonyl intermediates
EP0423358A4 (en) * 1989-04-15 1992-05-06 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Postostatin and related compound thereof, or their salts
US5359138A (en) * 1989-04-15 1994-10-25 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Poststatin and related compounds or salts thereof
US5164525A (en) * 1989-06-30 1992-11-17 Merck & Co., Inc. Synthetic process for fk-506 type macrolide intermediates
US5215969A (en) * 1989-08-11 1993-06-01 Hahnemann University Dopaminergic neurotrophic factor for treatment of Parkinson's disease
NZ234883A (en) * 1989-08-22 1995-01-27 Merck Frosst Canada Inc Quinolin-2-ylmethoxy indole derivatives, preparation and pharmaceutical compositions thereof
GB8922026D0 (en) * 1989-09-29 1989-11-15 Pharma Mar Sa Novel anti-viral and cytotoxic agent
US5115098A (en) * 1990-02-28 1992-05-19 President And Fellows Of Harvard College End-blocked peptides inhibiting binding capacity of gp120
JPH04211648A (en) * 1990-07-27 1992-08-03 Nippon Kayaku Co Ltd Keto-acid amide derivative
DE4015255A1 (en) * 1990-05-12 1991-11-14 Hoechst Ag OXALYL-AMINOSA-E-LEED DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICAMENT FOR INHIBITING THE PROLYL HYDROXYLASE
US5192773A (en) * 1990-07-02 1993-03-09 Vertex Pharmaceuticals, Inc. Immunosuppressive compounds
WO1992003472A1 (en) * 1990-08-24 1992-03-05 The Upjohn Company Peptides containing amino-polyols as transition-state mimics
AU8727491A (en) * 1990-08-29 1992-03-30 Vertex Pharmaceuticals Incorporated Modified di- and tripeptidyl immunosuppressive compounds
GB2247456A (en) * 1990-09-03 1992-03-04 Fujisawa Pharmaceutical Co Tetrahydropyrane compounds, a process for their production and a pharmaceutical composition containing the same
JPH04149166A (en) * 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd Novel keto acid amide derivative
AU1677092A (en) * 1991-03-20 1992-10-21 Vertex Pharmaceuticals Incorporated Tetrahydroxyalkane derivatives as inhibitors of hiv aspartyl protease
IT1245712B (en) * 1991-04-09 1994-10-14 Boehringer Mannheim Italia USEFUL HETEROCYCLIC AMINES THERAPY OF ASTHMA AND AIRWAY INFLAMMATION
US5147877A (en) * 1991-04-18 1992-09-15 Merck & Co. Inc. Semi-synthetic immunosuppressive macrolides
AU2007192A (en) * 1991-05-08 1992-12-21 Vertex Pharmaceuticals Incorporated Rfkbp: a novel prolyl isomerase and rapamycin/fk506 binding protein
DE69229782T2 (en) * 1991-05-09 2000-04-27 Vertex Pharmaceuticals Inc., Cambridge NEW IMMUNE SUPPRESSIVE CONNECTIONS
MX9202466A (en) * 1991-05-24 1994-06-30 Vertex Pharma NOVELTY IMMUNOSUPPRESSIVE COMPOUNDS.
JPH05178824A (en) * 1991-08-05 1993-07-20 Takeda Chem Ind Ltd Asparagine derivative and its use
WO1993007269A1 (en) * 1991-10-11 1993-04-15 Vertex Pharmaceuticals Incorporated ISOLATION OF AN Mr 52,000 FK506 BINDING PROTEIN AND MOLECULAR CLONING OF A CORRESPONDING HUMAN cDNA
IL103394A0 (en) * 1991-10-11 1993-03-15 Ciba Geigy Pyrimidinyl and triazinyl ethers and thioethers,their preparation and their use as herbicides
WO1993013066A1 (en) * 1991-12-20 1993-07-08 Syntex (U.S.A.) Inc. Cyclic amides of 3-amino-2-hydroxy-carboxylic acids as hiv-protease inhibitors
WO1993023548A2 (en) * 1992-05-20 1993-11-25 Vertex Pharmaceuticals Incorporated METHOD OF DETECTING TISSUE-SPECIFIC FK506 BINDING PROTEIN MESSENGER RNAs AND USES THEREOF
IT1254373B (en) * 1992-05-29 1995-09-14 HETEROPROSTANOIDS, PROCEDURE FOR THEIR PREPARATION AND THEIR EMPLOYE THERAPEUTIC.
US5334719A (en) * 1992-06-17 1994-08-02 Merck Frosst Canada, Inc. Bicyclic(azaaromatic)indoles as inhibitors of leukotriene bisynthesis
IS2334B (en) * 1992-09-08 2008-02-15 Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) Aspartyl protease inhibitor of a new class of sulfonamides
NZ314207A (en) * 1992-09-28 2000-12-22 Vertex Pharma 1-(2-Oxoacetyl)-piperidine-2-carboxylic acid derivatives as multi drug resistant cancer cell sensitizers
JPH06172306A (en) * 1992-10-05 1994-06-21 Nissan Chem Ind Ltd Cyclic amide compound and herbicide
AU5748194A (en) * 1992-12-11 1994-07-04 Vertex Pharmaceuticals Incorporated Mannitol derivatives and their use as inhibitors of aspartyl protease
DE4302860A1 (en) * 1993-01-22 1994-08-04 Chemie Linz Deutschland N-Cyclic and N, N'dicyclic ureas
US5385918A (en) * 1993-02-09 1995-01-31 Miles Inc. Aminomethylene-peptides as immunosuppressants
US5252579A (en) * 1993-02-16 1993-10-12 American Home Products Corporation Macrocyclic immunomodulators
US5319098A (en) * 1993-05-18 1994-06-07 Celgene Corporation Process for the stereoselective preparation of L-alanyl-L-proline
IT1270882B (en) * 1993-10-05 1997-05-13 Isagro Srl FUNGICIDE-BASED OLIGOPEPTIDES
WO1995012572A1 (en) * 1993-11-04 1995-05-11 Abbott Laboratories Cyclobutane derivatives as inhibitors of squalene synthetase and protein farnesyltransferase
DE69512220T2 (en) * 1994-03-07 2000-03-16 Vertex Pharmaceuticals Inc. SULPHONAMIDE DERIVATIVES AS ASPARTYL PROTEASE INHIBITORS
US5744485A (en) * 1994-03-25 1998-04-28 Vertex Pharmaceuticals Incorporated Carbamates and ureas as modifiers of multi-drug resistance
US5716929A (en) * 1994-06-17 1998-02-10 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US5856116A (en) * 1994-06-17 1999-01-05 Vertex Pharmaceuticals, Incorporated Crystal structure and mutants of interleukin-1 beta converting enzyme
AU3367995A (en) * 1994-08-18 1996-03-14 Ariad Pharmaceuticals, Inc. New multimerizing agents
US5543423A (en) * 1994-11-16 1996-08-06 Vertex Pharmaceuticals, Incorporated Amino acid derivatives with improved multi-drug resistance activity
IL115685A (en) * 1994-11-16 2000-08-31 Vertex Pharma Amino acid derivatives pharmaceutical compositions containing the same and processes for the preparation thereof
US5621108A (en) * 1994-12-05 1997-04-15 Trustees Of The University Of Pennsylvania Processes and intermediates for preparing macrocycles
US5859031A (en) * 1995-06-07 1999-01-12 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
US6037370A (en) * 1995-06-08 2000-03-14 Vertex Pharmaceuticals Incorporated Methods and compositions for stimulating neurite growth
US5801197A (en) * 1995-10-31 1998-09-01 Gpi Nil Holdings, Inc. Rotamase enzyme activity inhibitors
US5717092A (en) * 1996-03-29 1998-02-10 Vertex Pharmaceuticals Inc. Compounds with improved multi-drug resistance activity

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