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EP1204657A1 - Derives de piperidine et de pyrrolidine ayant une activite neuronale - Google Patents

Derives de piperidine et de pyrrolidine ayant une activite neuronale

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Publication number
EP1204657A1
EP1204657A1 EP00957534A EP00957534A EP1204657A1 EP 1204657 A1 EP1204657 A1 EP 1204657A1 EP 00957534 A EP00957534 A EP 00957534A EP 00957534 A EP00957534 A EP 00957534A EP 1204657 A1 EP1204657 A1 EP 1204657A1
Authority
EP
European Patent Office
Prior art keywords
pyrrolidine
pyridyl
glyoxyloyl
phenyl
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00957534A
Other languages
German (de)
English (en)
Inventor
Thomas Brumby
Fiona Mcdonald
Herbert Schneider
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Vertex Pharmaceuticals Inc
Original Assignee
Schering AG
Vertex Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE1999139707 external-priority patent/DE19939707A1/de
Application filed by Schering AG, Vertex Pharmaceuticals Inc filed Critical Schering AG
Publication of EP1204657A1 publication Critical patent/EP1204657A1/fr
Withdrawn legal-status Critical Current

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the invention relates to piperidine and pyrrolidine derivatives, the process for their production and their use in pharmaceutical agents.
  • FKBP FK506 binding protein
  • FK506 (Tacrolimus) , an immunosuppressive drug, has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al . (1994)] .
  • This compound has also been shown to be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher, Nature. 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerve [B . Gold et al . , J. Neurosci .. 15, pp. 7509-16 (1995)] .
  • immunosuppressive compounds have obvious drawbacks.
  • prolonged treatment with these compounds can cause nephrocoxicity [Kopp et al . , J. Am. Soc. Nephrol . , 1, p. 162 (1991)], neurological deficits [P. C. DeGroen et al . , N. En ⁇ . J . Med . , 317, p. 861 (1987)] and vascular hypertension [Kahan et al . , N. En ⁇ . J. Med.. 321, p. 1725 (1989)].
  • piperidine and pyrrolidine derivatives have immunosuppressive and non- immunosuppressive properties.
  • WO 96/40633 describes that N-glyoxyl-propylester compounds, which have an affinity to FKBP receptors, have a neurotrophic action and stimulate neuronal regeneration as inhibitors of the FKBP-rotamase .
  • neuronal activity includes stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of a neurological disorder.
  • the compounds of this invention have activity in both peripheral nerves and the central nervous system. Applicants have discovered diverse genera of compound with neuronal activity which do not bind to FKBP, and which do not have multi-drug resistance reversal activity. Without being bound by theory, applicants believe that the compounds disclosed m this application exert their neuronal activity by increasing cytoplasmic Ca 2+ concentrations. This is likely achieved by interaction, either direct or indirect, with a calcium release channel, such as the ryanodine receptor or the inositol 1,4,5- trisphosphate receptor, in the endoplasmic reticulum of the nerve cell.
  • a calcium release channel such as the ryanodine receptor or the inositol 1,4,5- trisphosphate receptor
  • the invention provides a method of stimulating nerve growth or preventing neurodegeneration by contacting nerve cells with a compound that : a. increases cytoplasmic Ca 2+ concentration or binds to the ryanodine receptor; b. does not bind to FKBP; and c. does not possess MDR reversal activity.
  • the present invention provides a compounds that : a. has neuronal activity; b. increases cytoplasmic Ca 2+ concentration or bind to the ryanodine receptor; c. does not bind to FKBP; and d. does not possess MDR reversal activity.
  • cytoplasmic Ca concentration means a detectable increase m channel current recorded m the single channel recording assay described below m the presence of such a compound as compared to an appropriate control.
  • increases cytoplasmic Ca 2+ concentration means a detectable shift in the fluorescence spectrum in the cell assay described herein.
  • ryanodine receptor means that the compound specifically competes with ryanodine for binding to microsomes in the assay described below.
  • does not bind FKBP means that the compound demonstrates a Ki of 10 ⁇ M or greater in at least one of the rotamase inhibitory assays described below.
  • does not possess MDR reversal activity means that at a concentration of 2.5 ⁇ M, the compound has an MDR ratio of less than 7.0, and preferably less than 3.0 in at least one of the MDR assays described below.
  • Single-channel recording experiments are useful to determine if the compounds of this invention cause the requisite increase in cytoplasmic Ca 2+ concentration. These experiments are conducted as described in E. Kaftan et al . , Circulation Research, 78, pp. 990-997 (1996), the disclosure of which is herein incorporated by reference.
  • Single channel recordings are conducted under voltage clamp conditions with a pair of Ag/AgCl electrodes contacting the solutions via CsCl junctions.
  • Vesicles are added to the cis chamber and fused with planar lipid bilayers composed of phosphatidylethanolamine/phosphatidylcholine (3:1, 30 mg/ml m decane, Avanti Polar Lipids) .
  • Ryanodine binding may be measured by incubating microsomal protein with 3 H-ryanodine in buffer containing 36 mM Tris pH 7.2 and 50 mM KC1 in the absence or presence of test compounds. Controls for maximum binding were done in the presence of 0.72 mM ATP and 36 ⁇ M CaCl 2 . Nonspecific binding was measured in the presence of 25 ⁇ M unlabeled ryanodine. Binding reactions were incubated for 2 hours at room temperature, and then centrifuged for 15 minutes at 30,000 x g. The pellets were solubilized and the radioactivity was measured by scintillation counting.
  • the flux of cytoplasmic Ca 2 ' into the cell can be followed fluorescently.
  • neuronal cells can be incubated with NGF and a calcium binding fluorescent dye, such as Fura-2, m a calcium-containing buffer.
  • a calcium binding fluorescent dye such as Fura-2, m a calcium-containing buffer.
  • Cells are imaged continuously both before and after the addition of a test compound of this invention
  • the difference m fluorescent intensity before and after the addition of compounds is then plotted as a ratio of fluorescence units at 340 nm and 380 n .
  • Testing a compound of this invention to confirm that it binds to FKBP12 with a Ki of 10 ⁇ M or higher may be achieved using several assays known in the art. In particular, those compounds may be assayed for their ability (or lack thereof) to inhibit rotamase.
  • Examples of assays that measure inhibition of FKBP12 rotamase activity are those in which the isomerization of an artificial substrate -- N-succinyl-Ala-Ala-Pro-Phe-p- nitroanilide -- is followed spectrophotometrically [M. W. Harding et al., Nature. 341, pp. 758-60 (1989); by J. J. Siekierka et al., Nature. 341, pp. 755-57 (1989); and S. T. Park et al . , J. Biol . Chem. , 267, pp. 3316-24 (1992)].
  • the assay includes the cis form of the substrate, FKBP12, the compound to be tested and
  • Chymotrypsin is able to cleave p-nitroanilide from the trans form of the substrate, but not the cis form. Release
  • FKBP binding assays include a competitive LH20 binding assay using labeled FK-506 as a reporting ligand. These have been described by M. W. Harding et al . , Nature , 341, pp. 758-60 (1989) and by J. J. Siekierka et al . , Nature . 341, pp. 755-57 (1989) .
  • any of the assays described m United States patents 5,543,423, 5,717,092, 5,726,184 or 5,744,485, the disclosures of which are herein incorporated by reference m their entireties, may be utilized.
  • cell lines which are known to be resistant to particular drug are employed. These cell lines include, but are not limited to, the L1210, P388D, HL60 and MCF7 cell lines. Alternatively, resistant cell lines may be developed. The cell line is exposed to the drug to which it is resistant, or to the test compound; cell viability is then measured and compared to the viability of cells which are exposed to the drug in the presence of the test compound ("MDR ratio”) .
  • the compounds of Formula I are metabolically stable and pass through the blood-brain barriers and stimulate the neurite growth by itself or in combination with neuronal growth factors. Since the new compounds also do not show any significant side effects, they are suitable for treatment of the various neuropathological diseases, which are affected by neuronal regeneration and growth, such as, e.g., peripheral nervous disturbances, which are caused by physical damages or diseases such as diabetes; physical damages of the central nervous system (e.g., of the brain or spinal cord); strokes; neurological disorders by neurodegenerations such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis.
  • peripheral nervous disturbances which are caused by physical damages or diseases such as diabetes
  • the central nervous system e.g., of the brain or spinal cord
  • strokes e.g., strokes
  • neurological disorders by neurodegenerations such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis.
  • the invention relates to the compounds of Formula I and their physiologically compatible salts
  • R 2 means straight -chain or branched Cj-Cg alkyl, which can be substituted with phenyl or halogenated phenyl
  • R 3 means straight-chain or branched Ci-Cg alkyl, straight- chain or branched C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, cyclohexylmethyl , whereby the alkyl, alkenyl, cycloalkyl and cycloalkenyl radical can be substituted by the same or a different component in one to two places with Ar, or R 2 and R 3 together with the N atom form a 5- to 7-membered heterocycle, which can be saturated or unsaturated and can be substituted with
  • the compounds of Formula I can be present as stereoisomers, geometric isomers or stable tautomers .
  • the invention comprises all possible isomers, such as E- and Z-isomers, S- and R- enantiomers, diastereomers , racemates and mixtures thereof.
  • the stereochemistry of the CH group, which carries substituent R 3 can be R or preferably S.
  • the physiologically compatible salts can be formed with inorganic and organic acids, such as, for example, oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p- toluenesulfonic acid, methanesulfonic acid, i.a.
  • inorganic and organic acids such as, for example, oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p- toluenesulfonic acid, methanesulfonic acid, i.a.
  • alkyl means a straight -chain or branched alkyl group, such as, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl , n-hexyl, sec-hexyl, heptyl , octyl , nonyl .
  • the alkenyl substituents contain at least one double bond, such as, for example, the following radicals: vinyl, 2 -propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-methyl -1-propenyl , 2 -methyl - 2 -propenyl, 3 -methyl -2 -propenyl , l-penten-3 -yl , n-hexenyl, 1- hepten-4-yl .
  • Cycloalkyl is defined in each case as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl .
  • Cycloalkenyl means, e.g., cyclopentenyl , cyclohexenyl and cycloheptenyl .
  • halogen means fluorine, chlorine, bromine or iodine .
  • alkyl radical is halogenated
  • one or more hydrogens can be replaced with halogen, e.g., 2 , 2 , 2- trifluorethyl as especially 4 , 4 , 5 , 5 , 5-pentafluoropentyl .
  • Ar is defined as 1- and 2-naphthyl, biphenyl, indenyl and preferably phenyl .
  • Ar is a monocyclic or bicyclic heteroaromatic compound, which in each ring contains 5 to 6 ring links and 1 to 4 heteroatoms and which can be partially hydrogenated; Ar preferably means a 5- or 6- ring, which contains 1 to 3 heteroatoms, and which can have a benzene ring annelated, whereby the bonding generally takes place with carbon atoms .
  • heteroaromatic compounds can be mentioned: furyl , thienyl , pyridyl , pyrrolyl, oxazolyl, thiazolyl, isothiazolyl , imidazolyl , pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl, pyrimidinyl , pyrazinyl, indolyl, benzimidazolyl , benzothiophenyl , quinolinyl, isoquinolinyl , quinoxalinyl , 1 , 2 , 3 , 4-tetrahydroquinolinyl , and benzothiazolyl .
  • 2-, 3- and 4 -pyridyl, 2- and 3 -thienyl, 2- and 3 -indolyl and 2-, 4- and 5 -thiazolyl are especially preferred.
  • R 1 Preferred embodiments of R 1 are Ar, straight-chain or branched Cj-C-, alkyl, which can be substituted with Ar or E, and C 3 -C cycloalkyl, which can be substituted with Ar or E, whereby in the case of cycloalkyl E, it especially means C--C, alkyl.
  • phenyl that is optionally substituted with E and straigh -chain or branched C :- ,-, preferably, C 3 -C 7 alkyl that is optionally substituted with E.
  • R 2 is methyl, ethyl and optionally benzyl that is substituted with halogen in the aromatic compound in one to three places .
  • R 3 is straight -chain or branched Ci-Cg alkyl, which can be substituted in one to two places with Ar, whereby Ar can be substituted in one to three places with E.
  • R 2 and R 3 together with the nitrogen atom form a heterocycle the latter is preferably saturated and has 5 to 7 ring links; pyrrolidine and piperidine are especially preferred.
  • E preferably means halogen, hydroxy, nitro, CF 3 , CN, C : -C 4 alkoxy and C ⁇ -C 4 alkyl.
  • R are straight-chain or branched alkyl, which optionally is substituted in one to four places with Ar or Ar optionally substituted with E.
  • R 4 in the meaning of a straight - chain or branched alkyl radical, which is substituted in one to two places with Ar .
  • R 4 with the structure
  • the invention also relates to the use of the compounds of Formula I for the production of a pharmaceutical agent for the stimulation of neuronal activity.
  • the compounds of Formula I are suitable for stimulation of neurite growth in nerve cells, for promotion of neuronal regeneration, for prevention of neurodegeneration, for treatment of neurological diseases such as neurodegeneration and for treatment of peripheral neuropathies.
  • the compounds of Formula I With the compounds of Formula I, the prevention and treatment of neuron cell death, which is triggered by a variety of diseases or physical trauma, is made possible.
  • the methods of stimulating nerve growth and preventing neurodegeneration disclosed herein employ the above compounds either alone or in combination with a neuronal growth factor. The methods are useful in treating or preventing nerve damage caused by various neurological diseases and physical traumas and also in ex vivo nerve regeneration.
  • Diseases which can be treated according to the invention with the compounds of Formula I or can be prevented with them, are especially trigeminal neuralgia, Collet-Sicard syndrome, Bell's palsy, myasthenia gravis, muscular dystrophy, muscle damage, progressive muscular atrophy, peripheral neurophathies , peripheral myelin disorders, Alzheimer's disease, Guillain- Barre syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Tourette ' s syndrome, multiple sclerosis, central myelin disorders, stroke, ischemia, neural degenerative diseases, trauma and Huntington's disease.
  • the invention also relates to the use of compounds of Formula IA and their physiologically compatible salts
  • R 1 , R 2 , R 3 , R 4 and X have the meaning that is mentioned above , and
  • the compounds of Formulas I and IA can be administered m one formulation or m separate formulations m combination with a neurotrophic factor or alone.
  • the term "neurotrophic factor” relates to compounds that stimulate the growth and the proliferation of nerve cells. Numerous neurotrophic factors are known, such as, for example, NGF, BNDF, aFGF, bFGF, PDGF, BDNF, GDNF, CNTF, NT- 3, NT-4/5 and IGF-1 and its derivatives, such as glGF-1 and Des (1-3 ) IGF-1.
  • NGF neurotrophic factor
  • the compounds according to the invention are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient contains vehicles, adjuvants and/or additives that are suitable for enteral or parenteral administration.
  • the administration can be done orally or sublingually as a solid m the form of capsules or tablets or as a liquid m the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or m the form of injection solutions that optionally also can be admmsitered subcutaneously, intramuscularly or intravenously, or topically or mtrathecally .
  • the inert organic and inorganic carrier materials that are known to one skilled m the art are suitable, such as, e.g., water, gelatin, gum arable, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc
  • preservatives, stabilizers, wetting agents, emulsifiers or salts for changing the osmotic pressure or buffers can optionally be contained.
  • Topical application is defined as transdermal patches, ophthalmic preparations, and aerosols for inhalation.
  • surface-active adjuvants such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof as well as liposomes or components thereof can also be used.
  • tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders such as, for example, lactose, corn or potato starch
  • talc and/or hydrocarbon vehicles or binders such as, for example, lactose, corn or potato starch
  • the administration can also be done in liquid form, such as, for example, as a juice, to which a sweetener is optionally added.
  • the dosage of the active ingredients can vary based on the method of administration, age and weight of the patient, type and severity of the disease that is to be treated and similar factors.
  • the daily dose is 0.01-100 mg/kg of body weight/day, whereby the dose can be given as a single dose that is to be administered once or divided into two or more daily doses.
  • the neurotrophic factor is preferably administered m a dose of 0.01 ⁇ g - 100 mg/kg/day together with the above-mentioned dose of the active ingredients.
  • the neurotrophic action of the compounds of Formula I and their physiologically compatible salts can be determined according to methods by W. E. Lyons et al . , Proc. Natl. Acad. Sci. USA, 91, pages 3191-95 (1994) .
  • the production of the compounds of Formula I is characterized in that a compound of Formula II
  • P is a protective group
  • R 2 and R 3 have the above- mentioned meanings
  • A means a reactive leaving group
  • a) is reacted with H-XR 4 , in which X is S, NH or NR 6 , and R 4 and R 5 have the above-mentioned meaning, and then is optionally oxidized to sulfoxide or sulfone
  • b) amino protective group P is cleaved off
  • Y-R 1 is introduced and optionally the isomers are separated, and the salts are formed.
  • R , R ⁇ and P have the above-mentioned meaning, a) being reacted with A-R', b) R 4 optionally being further modified by, e.g., C-C- linking reactions, such as, e.g., Heck reaction and/or hydrogenation, c) amino protective group P being cleaved off, d) Y-R 1 being introduced and optionally the isomers being separated and the salts being formed.
  • C-C- linking reactions such as, e.g., Heck reaction and/or hydrogenation
  • amino protective group P being cleaved off
  • Y-R 1 being introduced and optionally the isomers being separated and the salts being formed.
  • a compound of Formula III can also, however, be reacted with, for example, a ketone, ketal or enol ether, to a compound of Formula IV
  • R 2 , R 3 and P have the above-mentioned meaning, and R and R' are selected such that the desired radical R 4 is formed in the above-mentioned meaning, and then b) optionally the double bond is hydrogenated, c) amino protective group P is cleaved off, d) Y-R 1 is introduced, and optionally the isomers are separated, and the salts are formed .
  • protective group P all known amino protective groups are suitable, such as alkoxycarbonyl groups, such as BOC, and trimethylsilylalkoxycarbonyl groups, such as TeOC, i.a.
  • the thiolation, animation and alkylation are carried out m the usual way in the presence of bases, such as sodium hydride in polar solvents or in substances at room temperature or elevated temperature .
  • active group A for example, tosylate, mesylate, halogen or triflate is suitable.
  • cleavage of the amino protective group and the subsequent introduction of Y-R 1 is carried out according to known methods, which are described in, for example, US 5,721,256 and WO 98/29117 and WO 98/13355.
  • oxidation to sulfones or sulfoxides can be carried out according to the methods that are known to one skilled in the art, which are described in, for example, Methoden der Organichen Chemie [Methods of Organic Chemistry] (Houben-Weyl) , Editors D. Klamann, Thieme Stuttgart New York 1985, Volume Ell (Organic Sulfur Compounds) 702 ff and 1194 ff.
  • the production of the enol ether can be carried out, for example, according to the process that is described in Methoden der Organischen Chemie (Houben-Weyl), Thieme Stuttgart 1965, Volume Vl/3 (Oxygen Compounds) 90 ff .
  • optically active compounds of Formula I can be obtained with optically active starting materials or by separation according to commonly used methods, such as, for example, crystallization, chromatography or salt formation m the enantiomers or E/Z-isomers in the intermediate or final stages.
  • the presently disclosed compounds advantageously possess neuronal activity, without interfering with other pathways known to be affected by structurally similar compounds.
  • the nerve growth activity of the compounds of this invention may be initially assayed using several cell culture assays known in the art.
  • the compounds of this invention may be tested m neurite outgrowth assay using pheochromocytoma PC12 cells as described by Lyons et al . , PNAS , 91, pp. 3191-3195 (1994) .
  • a similar assay may be carried out m SH-SY5Y human neuroblastoma cells.
  • the chick dorsal root ganglia assay described m United States patent 5,614,547 or m G. S. Hamilton et al . , Bioorg. Med. Chem. Lett., (1997) and references cited therein, may be utilized.
  • the compounds of this invention may also be assayed for nerve growth activity m vivo using a mouse model of Parkinson's
  • Diseases which are treatable include, but are not limited to, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, progressive bulbar inherited muscular trophy, herniated, ruptured or prolapsed invertebrae disk syndrome's, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, such as those caused by lead, dapsone, ticks, or porphyria, other peripheral myelin disorders, Alzheimer's disease, Gullain-Barre syndrome, Parkinson's disease and other Parkmsonian disorders, ALS, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, neuropathy associated with diabetes, spinal cord injuries, facial nerve crush and other trauma, chemotherapy- and other medication- induced neuropathies and Huntmgton'
  • the method is used to stimulate nerve growth ex vivo .
  • the compounds or compositions described above can be applied directly to the nerve cells m culture. This aspect of the invention is useful for ex vivo nerve regeneration.
  • the method of stimulating neurite outgrowth or preventing neurodegeneration comprises the additional step of treating a patient or ex vivo nerve cells in culture with a neurotrophic factor, such as those contained in the compositions of this invention described above.
  • the product that is obtained is dissolved m 10 ml of 1,2- dichloroethane and 0.11 ml (0.80 mmol) of triethylamine, mixed with 113 mg (0.80 mmol) of cyclohexylisothiocyanate and heated at 80°C for 26 hours. After cooling, it is dispersed between 2N NaOH and CH 2 C1 2 , the aqueous phase is extracted again, the combined extracts are dried on Na 2 S0 4 , and concentrated by evaporation in a vacuum. The solvent is drawn off, and the residue is chromatographed (hexane - hexane/ethyl acetate 6:4) .
  • (2S)-1 ,1 -Dimethylethyl-2-(3-(3-pyridyl)propylthiomethyl)-pyrrolidine-1 - carboxylate 11.25g (57.6 mmol) of S-(3-(3-pyridyl)propyl)-acetate are dissolved in 576 ml ethanol containing 1 M sodium ethylate (576 mmol) and stirred overnight at room temperature. Then 34.83g (98 mmol) boc-prolinol tosylate in 50 ml ethanol and a catalytic quantity potassium iodide are added and the mixture brought to reflux for 2.5h. It is then allowed to cool and left over night at RT.
  • the organic phase is separated.
  • the aqueous phase is saturated with NaCl, the pH readjusted to 1 1 and reextracted with CH 2 CI 2 .
  • the aqueous phase is made basic with 2N NaOH and extracted a third time.
  • the combined organic phases are dried over Na 2 S0 4 and concentrated in vacuo. 3.66 g (>100%) raw product is obtained.
  • (2S)-1 ,1 -Dimethylethyl-2-(3-phenylpropylsulfonylmethyl)-pyrrolidlne-1 - carboxylate 13.1 g (39 mmol) of (2S)-1 , 1 -Dimethylethyl-2-(3-ph ⁇ nylpropylthiomethyl)- pyrrolidine-1 -carboxylate are dissolved in 300 ml CH 2 CI 2 and 21.2g (86 mmol) mCPBA (70% active ingredient) added at 0 °C and the reaction stirred over night at ambient temperature. The mixture is then extracted with 1M NaOH and the aqueous phase reextracted with dichioromethane.
  • (2S)-1 ,1 -Dimethylethyl-2-(2-(2-pyridyI)ethylsulfonylmethyl)-pyrrolidin ⁇ -1 ⁇ carboxylate 3.22 g (10 mmol) of (2S)-1 ,1-Dimethylethyl-2-(2-(2-pyridyl)ethylthiomethyl)- pyrrolidine-1 -carboxylate are dissolved in 70 ml CH 2 CI 2 and 4.93g (20 mmol) mCPBA (70% active ingredient) added at 0 °C and the reaction stirred over night at ambient temperature.
  • N-Methyl-N-[((2S)-3-(4-Ethoxyphenyl)-1-((3- pyridyl)propylsulfo ⁇ yl)-2-propyl)]-3,4,5-trimethoxyphenylglyoxylamide is obtained.

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Abstract

La présente invention concerne des composés de formule (I), ainsi que les procédés permettant leur production et que leur utilisation comme produits pharmaceutiques.
EP00957534A 1999-08-18 2000-08-18 Derives de piperidine et de pyrrolidine ayant une activite neuronale Withdrawn EP1204657A1 (fr)

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DE1999139707 DE19939707A1 (de) 1999-08-18 1999-08-18 Piperidin- und Pyrrolidin-Derivate
DE19939707 1999-08-18
US15056899P 1999-08-25 1999-08-25
US150568P 1999-08-25
PCT/US2000/022617 WO2001012622A1 (fr) 1999-08-18 2000-08-18 Derives de piperidine et de pyrrolidine ayant une activite neuronale

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JPH02235862A (ja) * 1989-03-08 1990-09-18 Sapporo Breweries Ltd 新規なピロリジン誘導体及びそれを含有する薬剤
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