EP0587670A1 - Ligands des recepteurs pcp et leur utilisation - Google Patents

Ligands des recepteurs pcp et leur utilisation

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Publication number
EP0587670A1
EP0587670A1 EP92911577A EP92911577A EP0587670A1 EP 0587670 A1 EP0587670 A1 EP 0587670A1 EP 92911577 A EP92911577 A EP 92911577A EP 92911577 A EP92911577 A EP 92911577A EP 0587670 A1 EP0587670 A1 EP 0587670A1
Authority
EP
European Patent Office
Prior art keywords
dibenzo
dihydro
cycloheptene
iminomethano
compound
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Withdrawn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
EP92911577A
Other languages
German (de)
English (en)
Other versions
EP0587670A4 (fr
Inventor
Eckard Weber
John F. W. Keana
Peter Barmettler
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.)
Oregon State Board of Higher Education
Oregon State
Original Assignee
Oregon State Board of Higher Education
Oregon State
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Publication date
Application filed by Oregon State Board of Higher Education, Oregon State filed Critical Oregon State Board of Higher Education
Publication of EP0587670A1 publication Critical patent/EP0587670A1/fr
Publication of EP0587670A4 publication Critical patent/EP0587670A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • A61P25/28—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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention is in the field of pharmaceutical compositions which are useful for the prevention and/or treatment of neurodegradation and other neuropathological conditions in animals.
  • the amino acid L-glutamate is widely thought to act as a chemical transmitter substance at excitatory synapses within the central nervous system. Neuronal responses to glutamate are complex and appear to be mediated by at least three different receptor types, i.e., KA, QA and
  • NMDA subtypes each being named for their relatively specific ligands, i.e., kainic acid, quisqualic acid and N-methyl-D-aspartic acid, respectively.
  • NMDA receptors are strongly involved in nerve cell death which occurs following brain ischemia or hypoxia. Upon the occurrence of ischemic/hypoxic brain insults such as those which occur during spinal or head trauma, stroke or heart attack, an excessive release of endogenous glutamate occurs from nerve terminals deprived of the energy supplies needed to retain the neurotransmitter. The excessive amounts of glutamate cause an over-stimulation of NMDA receptors on nearby neurons.
  • Associated with the NMDA receptors is an ion channel.
  • the recognition site, i.e., the NMDA receptor is external to the ion channel.
  • glutamate When glutamate interacts with the NMDA receptor, it causes the ion channel to open, thereby permitting a flow of cations across the cell membrane, e.g., Ca 2+ and Na + into the cell and K + out of the cell. It is believed that this flux of ions, especially the influx of Ca 2+ ions, caused by the interaction of glutamate with the NMDA receptor plays an important role in neuronal death. See, e.g., Rothman, S.M. and Olney, J.W., Trends in Neurosci. 10(7):299-302 (1987).
  • Agents which block responses to NMDA receptor activation therefore have potential therapeutic uses in the treatment of neurological disorders and nerve cell death resulting from hypoxia or hypoglycemia or following brain ischemia which occurs during stroke, trauma and heart attack.
  • a number of disorders of the nervous system are associated with neurodegeneration that may be caused by over-activation of NMDA receptors.
  • Antagonists of NMDA receptor-mediated responses have potential therefore for the treatment of such disorders as Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and Down's Syndrome.
  • PCP receptor a receptor site within the ion channel known as the PCP receptor. See Vincent, J.P., Kartalovski, B., Geneste, P., Kamenka, J.M. and Lazdunski, M., Proc. Natl. Acad Sci. USA 76:4678-4682 (1979); Zukin, S.R. and Zukin, R.S., Proc. Natl Acad. Sci. USA 76:5372-5376
  • Compounds which bind to the PCP receptor can act as ion channel blockers, thereby interrupting the flow of ions across the cell membrane. In this manner, agents which interact with the PCP receptor act as non-competitive blockers, reducing the agonist action of glutamate at the NMDA receptor.
  • PCP receptor ligands include PCP [angel dust], i.e., phencyclidine, analogues such as 1-[1-(2-thienyI)-cyclohexyl]-piperidine (TCP), benzomorphan (sigma) opiates, dioxolanes and 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine (i.e., the drug MK-801, see U.S. Patent No. 4,399,141). See, also, Wong, E.H.F., Kemp, J.A.,
  • MK-801 is apparently the most potent selective PCP receptor ligand/NMDA channel blocker known to date.
  • R 1 , R 2 , R 3 , and R 4 are H
  • the compound is MK-801. This compound and derivatives thereof are the subject of a patent to Anderson et al., U.S. Patent No. 4,399,141 (1983).
  • muscle relaxants which are useful as muscle relaxants, antidepressants, anticonvulsants, and in the treatment of mixed anxiety-depression, minimal brain dysfunction, and extrapyramidal disorders.
  • Z represents a group selected from the group consisting of
  • This compound reportedly has hypotensive properties.
  • the compounds reportedly exhibit central nervous system depressant and anticonvulsant properties without causing ataxia.
  • These compounds are reportedly useful as stimulants and anticonvulsants.
  • These compounds are reportedly useful as minor tranquilizers, anticonvulsants, muscle relaxants, and in the treatment of extrapyramidal disorders such as Parkinson's disease.
  • These compounds are reportedly useful as minor tranquilizers, anticonvulsants, muscle relaxants, and in the treatment of extrapyramidal disorders such as Parkinson's disease.
  • the invention relates to a method of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, and hypoglycemia, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, comprising administering to an animal in need of such treatment a compound of the Formula (XVI):
  • R is hydrogen, C 2 -C 6 acyl, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkoxycarbonyl, C 7 -C 10 aralkyl, C 2 -C 6 alkenyl, C 3 -C 15 dialkylaminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkynyl, C 3 -C 15 trialkylsilyl, C 4 -C 10 alkylcycloalkyl, or C 3 -C 6 cycloalkyl;
  • R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 7 -C 10 aralkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 15 dialkylaminoalkyl;
  • X and Y are independently selected from the group consisting of a halogen such as chloro, fluoro, bromo, iodo, C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, e.g.
  • Z represents a group selected from
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aralkyl, C 4 -C 15 dialkylaminoalkyl, heterocycloalkyl, C 2 -C 6 acyl, aroyl, or aralkanoyl, and
  • R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, aralkyl or C 3 -C 15 dialkylaminoalkyl;
  • n is an integer selected from 0 (X or Y is hydrogen, respectively), 1, 2, 3, or 4;
  • Figure 1 depicts a graph showing the in vitro neuroprotective effect of ( ⁇ ) 10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (IDDC), (+) IDDC, N-methyl IDDC and a control sample on rat hippocampal cells treated with various concentrations of glutamate.
  • Figure 2 depicts a graph showing the in vivo neurotoxicity protective effect of (+)-IDDC at various dosage levels.
  • the invention relates to a method of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, and hypoglycemia, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Down's syndrome, comprising administering to an animal, i.e. a human, in need of such treatment a compound of the Formula (XVI):
  • R is hydrogen, C 2 -C 6 acyl, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkoxycarbonyl, C 7 -C 10 aralkyl, C 2 -C 6 alkenyl, C 3 -C 15 dialkylaminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkynyl, C 3 -C 15 trialkylsilyl, C 4 -C 10 alkylcycloalkyl, or C 3 -C 6 cycloalkyl;
  • R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 7 -C 10 aralkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 3 -C 15 dialkylaminoalkyl;
  • X and Y are independently selected from the group consisting of a halogen such as chloro, fluoro, bromo, iodo, C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, e.g.
  • a halogen such as chloro, fluoro, bromo, iodo, C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, e.g.
  • Z represents a group selected from
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aralkyl, C 4 -C 15 dialkylaminoalkyl, heterocycloalkyl, C 2 -C 6 acyl, aroyl, or aralkanoyl
  • R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, aralkyl or C 3 -C 15 dialkylaminoalkyl
  • n is an integer selected from 0 (X or Y is hydrogen, respectively), 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof;
  • said compound exhibits a high binding activity with respect to the PCP receptor in mammalian nerve cells, and is administered in an amount effective to treat or prevent said neuronal loss or to treat said disease.
  • the compounds having Formula (XVI) above may exist in racemic form or in the optically active stereoisomeric form.
  • the compounds having Formula (XVI) may exist in radiolabeled form, e.g. wherein the one or more of the atoms are substituted by 3 H, 11 C, 14 C, 18 F,
  • the compounds of the invention are those of Formula (XVI) wherein R is H, i.e., those having the following structural Formula (XVII):
  • R 1 , X, Y, Z and n are as defined above.
  • Typical C 1 -C 6 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, i-pentyl and hexyl groups.
  • Typical C 2 -C 6 acyl groups include acetyl, propanoyl, i-propanoyl, butanoyl, s-butanoyl, pentanoyl and hexanoyl groups.
  • Typical aryl groups include phenyl, naphthyl, phenanthryl and anthracyl groups.
  • Typical C 1 -C 6 alkoxycarbonyl groups include carbonyl substituted by methoxy, ethoxy, propanoxy, i-propanoxy, n-butanoxy, t-butanoxy, i- butanoxy, pentanoxy, and hexanoxy groups.
  • Typical aralkyl groups include the above-listed C 1 -C 6 alkyl groups substituted by phenyl, naphthyl, phenanthryl and anthracyl groups, e.g. benzyl, phenethyl, phenylpropyl, phenylisopropyl, and phenylbutyl.
  • Typical C 2 -C 6 alkenyl groups include vinyl, allyl, 2-butenyl, 2-pentenyl, and 2-hexenyl groups.
  • Typical C 2 -C 6 alkynyl groups include ethyhyl and propargyl groups.
  • Typical halo groups include fluorine, chlorine, bromine and iodine.
  • Typical aroyl groups include carbonyl substituted by phenyl, naphthyl, phenanthryl and anthracyl groups.
  • Typical aralkanoyl groups include carbonyl substituted by the above-listed aralkyl groups.
  • Typical aralkoxy groups include the above listed C 1 -C 6 alkoxy groups substituted by phenyl, naphthyl, phenanthyl and anthracyl groups.
  • Typical substituted aryl groups include the above-listed aryl groups substituted by halo, hydroxy, amino, and the like.
  • Typical heteroaryl groups include furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyrizinyl and oxazolyl groups.
  • Typical substituted heteroaryl groups include the above-listed heteroaryl groups substituted by halo, C 1 -C 6 alkyl and the like.
  • Typical C 5 -C 6 heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl and pyrrolidinyl groups.
  • Typical C 3 -C 15 -dialkylaminoalkyl groups include N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-dimethylaminopropyl and N,N-dimethylaminobutyl.
  • a most preferred compound wherein X, Y, R and R 1 are hydrogen (n is 0), is (+) and/or (-) 10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (IDDC) having the following Formula (XVIII):
  • a fourth preferred compound wherein X and Y are hydrogen and R and R 1 are CH 3 is (+) and/or (-) 5-methyl-N-methyl-10,5-(iminomethano)-10, 11-dihydro-5H- dibenzo[a,d]cycloheptene (5-methyl-N-methyl-IDDC) having the following Formula (XXI):
  • the compounds of the invention exhibit high binding activity with respect to the PCP receptor in mammalian nerve cells.
  • Compounds with especially high binding activity include those represented by Formulae (XVIII) - (XXI), above.
  • IDDC (+) and/or (-) 10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
  • novel IDDC derivatives which may be used in the practice of the invention include (-)-3-Chloro-5-(iminomethano)-10,11-dihydro-5H-dibenzo- [a,d]cycloheptene, (+) 3-Chloro-5-(iminomethano)-10,11-dihydro5H-dibenzo-[a,d]cycloheptene, (-)-N-methyl-3-Chloro-5-(iminomethano)- 10,11-dihydro-5H-dibenzo-[a,d]cycloheptene, (+)-N-methyl-3-Chloro-5- (iminomethano)-10,11-dihydro-5H-dibenzo-[a,d]cycloheptene, 3-iodo-5- (iminomethano)-10,11-dihydro-5H-dibenzo-[a,d]cycloheptene, N-methyl-3- iodo-5
  • this invention relates to a method of ameliorating the neurotoxic effect induced by glutamate interacting with the NMDA receptor of a nerve cell, comprising the administration, to an animal, e.g., a human being, exhibiting symptoms of or susceptible to such neurotoxic effect, of a compound of the invention which has a high affinity for the
  • compositions of the invention may be administered prophylactically, for example, before a surgical procedure or other treatment which may be expected to cause reduced blood flow to the brain or spinal cord, thereby, preventing or ameliorating neurodegradation.
  • the pharmaceutical compositions of the invention may also be administered after trauma to, for example, the head or spinal cord to prevent or ameliorate the resulting neurodegeneration which may result therefrom.
  • a number of disorders of the nervous system are associated with neurodegradation that may be caused by over-activation of NMDA receptors. Therefore, agents which block responses to NMDA receptor activation have therapeutic use in the treatment of neurological disorders and also in the prevention of nerve cell death resulting from hypoxia or hypoglycemia or following brain ischemia which occurs during stroke, trauma and heart attack. Antagonists of NMDA receptor-mediated responses also are useful for the treatment of such disorders as Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and Down's Syndrome.
  • the invention also relates to a method of inhibiting NMDA receptor ion channel-related neurotoxicity comprising administering to an animal a compound of Formula (XVI) which possesses a high affinity for the PCP receptor of a nerve cell, in an amount effective to inhibit the neurotoxicity.
  • a compound of Formula (XVI) which possesses a high affinity for the PCP receptor of a nerve cell, in an amount effective to inhibit the neurotoxicity.
  • the compounds are tested to determine their ability to displace tritiated-TCP and tritiated-MK-801 which are used to label PCP receptors. Evaluating the competitive displacement binding data, the preferred compounds are those which exhibit a high affinity (i.e., low IC 50 value) for the PCP receptors.
  • an IC 50 value of at most about 1000 nM, preferably at most about 500 nM indicates a high binding affinity.
  • the term "high affinity" is intended to mean a compound which exhibits an IC 50 value of at most about 1000 nM.
  • the compounds are evaluated with respect to their ability to block the ion channel of the NMDA receptor channel complex and thereby inhibit Ca 2+ and Na + ion flow into the nerve cell.
  • the ion channels are opened by activating the NMDA receptor. Ion flow is determined by measuring the passage of electrical current, i.e., a use-dependant decrease in electrical current indicates blocking of the ion channel due to binding of a ligand at a site within the channel.
  • a use-dependent block means that as more NMDA receptor- channel complexes are activated by glutamate, blockage of the channels by the non-competitive blocking agent become more effective.
  • EAA receptors are exposed in vitro to glutamate and the particular compound under investigation.
  • the survival percentage of cells indicates the ability of the compound to protect against glutamate-induced neuronal death.
  • NMDA injection into one cerebral hemisphere causes injury which resembles the lesion produced by hypoxia-ischemia.
  • the ability of compounds to limit the NMDA-induced lesion is a measure of their neuroprotective properties; since the compounds may be administered intraperitoneally, the model can also provide information about a compound's ability to cross the blood-brain barrier.
  • the compounds having Formula (XVI) are prepared according to Scheme I shown below, for example, by heating the diaryl derivative having Formula (XXII) with bromoacetaldehyde diethylacetal in a polar aprotic solvent.
  • Polar aprotic solvents which can be used for this purpose include N,N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO).
  • the temperature of the reaction mixture may range from 70°C to 120°C.
  • the product having the Formula (XXIII) is then treated with an acid such as trifluoromethanesulfonic acid or 70% perchloric acid in a solvent such as chloroform or dichloromethane at ambient temperature to give a compound having the Formula (XXIV).
  • This compound may then be derivatized at the nitrogen atom with a suitable electrophile to give the compound represented by Formula (XVI).
  • the N-methyl derivative may be prepared by reaction of (XXIV) with formaldehyde and sodium borohydride.
  • the nitrogen of Formula (XXIV) maybe reacted with an alkyl halide, alkanoyl halide, or other suitable electrophile.
  • (XVI) may be prepared by selecting an appropriately substituted diaryl derivative (XXII) which may be prepared by electrophilic substitution on the phenyl ring(s) according to methods known to those skilled in the art.
  • the 5-substituted derivatives of Formula (XVI) may be prepared according to Scheme II shown below, for example, by treatment of the diaryl derivative (XXII) with an alkynyl derivative (XXV) such as 3-bromo-1-propyne in an alcohohc medium containing a base such as potassium carbonate to give the substituted N-propargyl-1,2-diarylethylamine (XXVI).
  • Z is a carbon atom bearing a hydroxy group
  • the hydroxy group may be protected by a suitable hydroxy protecting group such as benzyl and the like.
  • Treatment of (XXVI) with an acid such as trifluoromethanesulfonic acid gives a compound having formula (XXVII).
  • This product may be further derivatized at the nitrogen or hydroxy group (where Z is substituted by alkoxy or acyloxy) by treatment with an appropriate electrophile, as discussed above.
  • optical isomers of the compound having Formula (XVI) may be separated by classical resolution techniques by, for example, formation of a salt of the amino group of Formula (XVI) with an optically active acid.
  • a particularly preferred acid for this purpose is (+)-di-p-toluoyl-D-tartaric acid.
  • the resulting diastereoisomeric salt may then be separated by crystallization, chromatography, or by taking advantage of the differing solubilities of the two diastereoisomeric salts.
  • the free base may then be isolated by treatment with a base such as aqueous ammonia and extraction with an organic solvent
  • the optical isomers may be prepared by resolution of the diaryl derivative (XXII).
  • 1,2-diphenylethylamine may be resolved by preparation of corresponding diastereoisomeric salt with an optically active acid.
  • a particularly preferred acid for this purpose is L- (+)-tartaric acid.
  • the diastereoisomeric salt may be separated by crystallization followed by isolation of the free base as discussed above.
  • the optically active 1,2-diphenylethylamine may then be carried through the reaction sequence shown in Scheme I or 13 to give the optically active product having Formula (XVI).
  • (+)-IDDC absolute configuration of (+)-IDDC as follows.
  • (-)-1,2-Diphenyl-ethylamine had already been shown (M. Nakazaki et al., Bull. Soc. Chem. Japan 36:316 (1963)) to have the R-absolute configuration.
  • (+)-IDDC from (R)(-)-1,2-diphenylethylamine the R-configuration is retained and it becomes C-10 in the IDDC molecule.
  • (+)-IDDC is R at C-10. Owing to the geometric constraints imposed on the molecule by the bicyclic ring structure, the absolute configuration at C-5 in (+)-IDDC must then be S.
  • the full name of (+)-IDDC is therefore (+)-10(R),5(S)-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
  • Acid addition salts are formed by mixing a solution of a compound having Formula (XVI) with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
  • the pharmaceutical compositions of the invention may comprise the compound of Formula (XVI) at a unit dose level of about 0.01 to about 500 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day.
  • a unit dose level of about 0.01 to about 500 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day.
  • the compound having Formula (XVI) may be administered at a unit dosage level of from about 0.01 to about 500 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof on a regimen of 1-4 times per day.
  • a unit dosage level of from about 0.01 to about 500 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof on a regimen of 1-4 times per day.
  • the exact treatment level will depend upon the case history of the animal, e.g., human being, that is treated. The precise treatment level can be determined by one of ordinary skill in the art without undue experimentation.
  • compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
  • animals Foremost among such animals are humans, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the new pharmaceutical preparations may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, are present at a concentration of from about 0.01 to 99 percent, together with the excipient.
  • compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetyl- cellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments maybe added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • N-(2,2-diethoxyethyl)-diphenylethylamine was prepared according to the procedure of Takayama, H., Chem. Lett. 865 (1978). To a stirred solution of 1,2-diphenylethylamine (3.94 g, 20.0 mmol, Aldrich Co., used as received) in N,N-dimethylformamide (DMF) (10 ml) at 80-90°C was added dropwise over 1 h freshly distilled bromoacetaldehyde diethylacetal
  • N-(2,2-diethoxyethyl)-diphenylethylamine 5.29 g, 84%): bp 150-160°C/0.50 mm; 1 H NMR (CDCl 3 ) ⁇ 1.10 (t, 3), 1.12 (t, 3), 1.70 (bs, 1), 2.50 (dd, 1), 2.58 (dd, 1) 2.91 (dd, 1), 2.98 (dd, 1), 3.39 (dt, 1), 3.44 (dt, 1), 3.54 (dt, 1), 3.59 (dt, 1), 3.86 (dd, 1), 4.53 (dd, 1), 7.16-7.40 (m, 10); 13 C NMR (CDCl 3 ) ⁇ 15.5 (q), 45.5 (t), 50.0 (t), 62.0 (t), 62.2 (t), 64.9 (d), 102.0 (d), 126.5,
  • (+)-IDDC was tested for its ability to achieve use-dependent blockage of NMDA-induced (+ glycine) responses on rat hippocampal neurons maintained in cell culture. This compound produced a result very similar to the use dependent blocking action exhibited by MK-801.
  • Hippocampal neurons were obtained from the CA1 region of the hippocampus from 1-3 day-old-newborn rats (Long-Evans). Small blocks of tissue (>1mm 3 ) were incubated in papain (20 units ml -1 ; Worthington-Cooper) for 30 minutes. The tissue was dissociated into a single cell suspension by trituration with a fire-polished Pasteur pipette in complete growth medium (Earle's MEM, 20 mM glucose, 50 units/tail penicillin/streptomycin, 5% heat-inactivated fetal calf serum, Serum Extender from Collaborative Research) containing 2.5 mg/ml bovine serum albumin and 2.5 mg/ml trypsin inhibitor (Sigma).
  • complete growth medium Earle's MEM, 20 mM glucose, 50 units/tail penicillin/streptomycin, 5% heat-inactivated fetal calf serum, Serum Extender from Collaborative Research
  • the cells were plated onto glass coverslips coated with collagen/poly-D-lysine. Cultures were fed every 3 days by replacing half the volume of medium. Arabinosylcytosine (5 ⁇ 10 -6 M) was added to the cultures for 1 or 2 days during the first week after plating to suppress the proliferation of non-neuronal cells. All electrophysiology experiments were performed with the whole- cell mode of patch clamp recording [Hamill, O.D., Marty, A., Neher, E., Sakman, B., and Sigworth, F.J., Pflugers Arch. 391:85-100 (1981)] from neurons grown for 1-3 weeks in culture. Agonists and agonist/antagonist combinations were applied by a U-tube tool (Fenwick et al., J. Physiol
  • the external solution contained (in mM) NaCl 140, KCl 3.5, CaCl 2 1, glucose 5, picrotoxinin 0.02, tetrodotoxin (TTX) 5 ⁇ 10 -4 , and N-2-hydroxyethyl- piperazme-N'-2-ethanesulfonic acid (HEPES) 10.
  • the pH of this solution was adjusted to 7.4 with NaOH.
  • the internal (patch electrode) solution contained (mM) Cs-methanesulfonate 120, CsCl 10, ethyleneglycol-bis-(ß- aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) 10, HEPES 10 (pH adjusted to 7.0 with CsOH).
  • Membrane current was filtered at 4000 Hz (-3dB; 8-pole Bessel) and recorded on magnetic tape for later analysis. Experiments were performed at room temperature (20-25oC).
  • [ 3 H]Kainate and [ 3 H]CPP and [ 3 H]AMPA were purchased from Dupont/NEN (Boston, MA)].
  • (+) N-methyl IDDC (10 uM) inhibited the NMDA current in a use-dependent and voltage-dependent manner. Serial applications evoked progressively smaller currents. Inhibition by (+) N- methyl IDDC was reversed only with prolonged or repeated application of NMDA The rate of recovery from blockade by (+) N-methyl IDDC was somewhat more rapid than the rate of recovery of responses following MK-801. This observation is consistent with the observation that (+) N-methyl IDDC has a lower affinity than MK-801 for the PCP receptor.
  • Dissociated rat hippocampal cultures were prepared using a modification of the method of Huettner and Baughman [Huettner, J.E. and Baugham, R.W., J. Neurosci. 3:144-3060 (1986)].
  • the cortices were removed from 1-3 day post-natal rats (Sprague-Dawley) that had been anesthetized with chloral hydrate, and the hippocampi were dissected out and placed in Cl- free dissociation medium supplemented with 1 mM kynurenic acid and 10 mM MgSO 4 (Choi, D.W., J. Neurosci. 7:369-379 (1987)).
  • the hippocampi were washed in the dissociation medium, then incubated for 2 ⁇ 20 minutes at 37°C in dissociation medium containing 10 units/ml of Papain (Worthington). After the enzyme treatment, the tissue was incubated for three 5-minute periods at 37°C with 10 mg/ml trypsin inhibitor (Sigma type II-0).
  • the cells were dissociated by trituration in growth medium and plated as 0.15 ml droplets of cell suspension onto the center of 35 mm
  • the cells were maintained in a medium that was similar to the growth medium but without the fetal bovine serum.
  • the medium was changed on a weekly schedule, replacing two-thirds the volume with fresh medium.
  • the only glutamate present in the media was that contained in the calf serum which gave a final concentration of 12 uM.
  • control salt solution similar to that reported in Choi, D.W., Maulicci-Gedde, M. and Viriegstein, A.R., J. Neurosci. 7:257-268 (1987), but with 10 mM HEPES substituted for Tris-HCl and buffered for pH 7.4 at 34°C.
  • the cultures were washed twice with CSS and then incubated for 5 minutes in CSS containing 1 uM glycine and the compound to be tested (the controls had 1 uM glycine only).
  • Glycine was included since it has been shown to potentiate the effects of glutamate at the NMDA site [Johnson, J.W.
  • FIG. 1 depicts a graph showing the in vitro neuroprotective effect of ( ⁇ )-IDDC, (+)-IDDC, N-methyl IDDC and a control sample on rat hippocampal cells treated with various concentrations of glutamate.
  • cultures tested with 5 uM ( ⁇ )-IDDC, 5 uM (+)-IDDC and 10 uM N-methyl IDDC exhibited enhanced cell survival when compared to control values.
  • Example 8 In Vivo Neurotoxicity Assay The experimental model of McDonald, J.W., et al., supra, was employed with the single alteration in protocol of an intraperitoneal injection of the test compound 15 minutes following, rather than preceding, the cerebral NMDA injection. As shown in Figure 2, (+)-IDDC was found, in dosages ranging from about 0.30 to 60 ⁇ Mol/kg of body weight, to protect against the lesions caused by NMDA injection.
  • IDDC in vitro and in vivo neuroprotective properties
  • Example 9 The preparation of Aryl-substituted IDDC derivatives The following is an experimental description of syntheses of some racemic substituted IDDC's and one optically active IDDC derivative.
  • the synthesis for each substituted IDDC began with a Friedel-Crafts reaction of an appropriate phenylacetyl chloride with an appropriate aromatic substrate.
  • the resulting desoxybenzoin was then converted to its methyl oxime ether using the method of Sing (Sing, P.J., Org. Chem. 44:843 (1979)).
  • the syn- and anti- isomers were usually not separated, but reacted together with borane-tetrahydrofuran complex to give the corresponding amines, according to the method of Feuer and Braunstein.
  • the resulting bi-phasic solution was refluxed with vigorous magnetic stirring overnight, and allowed to cool to room temperature. Hexanes (50 ml) were added, and the layers separated. The aqueous portion was extracted with hexanes (1 ⁇ 50 ml).
  • the reaction mixture was concentrated in vacuo to a pale yellow residue, which was taken up in methylene chloride (10 ml) and 10% NaOH (5 ml). The layers were separated and the organic layer washed with 10% NaOH (2 ⁇ 10 ml) and brine (1 ⁇ 10 ml), and dried over potassium carbonate. Evaporation of the solvent afforded a white residue, which was purified by preparative thin layer chromatography (1000 micron thickness, silica gel) using 8% methanol/ethyl acetate as eluant (the methanol contained 1% concentrated ammonium hydroxide).
  • the amine 15 was isolated as 1.263 g of a clear, colorless syrup (86% yield): R f 0.20 (5% methanol/chloroform); IR (CDCl 3 ) 3376 (w), 3316 (w), 3068 (w), 3031 (w), 3007 (w), 2965 (m), 2940 (m), 2910 (m), 2834 (m), 1614 (m), 1584
  • 4- Chlorophenylacetyl chloride was prepared as described before. To a suspension of aluminum chloride (1.27 g, 9.52 mmol) and anisole (1.4 g, 12.9 mmol) in CH 2 Cl 2 (40 ml) under nitrogen was added 4- chlorophenylacetyl chloride (1.8 g, 9.52 mmol) over a period of 30 minutes as a solution in CH 2 Cl 2 at room temperature. The resulting clear, pale yellow solution was refluxed for 18 hours. After cooling to room temperature, the resulting solution was poured into 100 ml ice water.
  • 3-Chloro-7-methoxy-IDDC 1-(N-Ethyl-(2,2-ethoxy))-amino-1-(4-methoxyphenyl)-2-(4-chlorophenyl)ethane (180 mg, 0.54 mmol) and perchloric acid (5 ml of 70% solution) were mixed together at room temperature under nitrogen. The resulting white mixture was stirred at room temperature for 60 hours, followed by quench and basification with ice and 10% NaOH. The resulting cloudy mixture was extracted with methylene chloride (25 ml, 3 times), and the combined extracts were washed with brine (10 ml) and dried over sodium sulfate.
  • 3-Fluoro-IDDC 1-(N-Ethyl-(2,2-ethoxy))-amino-2-(4- fluorophenyl)-1-phenylethane (100 mg, 1.51 mmol) and perchloric acid (12 ml of 70% solution) were mixed together at room temperature under nitrogen. The resulting white mixture was stirred at room temperature for 48 hours, followed by quench and basification with ice and 10% NaOH. The resulting cloudy mixture was extracted with methylene chloride (25 ml, 3 times), and the combined extracts were washed with brine (10 ml) and dried over sodium sulfate.
  • 4-Bromophenylacetyl chloride A mixture of 4-bromophenylacetic acid (6.45 g, 30 mmol) and phosphorous trichloride (4.12 g, 30 mmol) in a round bottom flask under nitrogen was heated to 50°C, for 30 min, and at 100°C for 3 hr and then it was allowed to cool to room temperature.
  • a septum was placed on the flask with a nitrogen inlet, and the flask was immersed in an oil bath at 150°C. After 5 hours of stirring, the heat was removed and the reaction mixture allowed to achieve room temperature. Water (5 ml) and ethyl acetate (5 ml) were added with stirring. The liquid portion was removed by pipette, and the residual solids rinsed with ethyl acetate (3 ⁇ 5 ml). All the liquids were combined and hexanes (10 ml) were added. The layers were separated and the organic portion was dried over sodium sulfate.
  • the IDDC analogs of the invention exhibit high binding to the PCP receptor.

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Abstract

L'invention concerne du 5-(iminométhano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptène et ses dérivés. L'invention concerne également l'utilisation de tels composés pour le traitement ou la prévention de la dépopulation neuronale dans l'ischémie, l'hypoxie, les lésions cérébrales ou de la moelle épinière, ainsi que pour le traitement de la maladie d'Alzheimer, de la sclérose latérale amyotrophique, de la maladie d'Huntington et du syndrome de Down.
EP92911577A 1991-04-29 1992-04-29 Ligands des recepteurs pcp et leur utilisation. Withdrawn EP0587670A4 (fr)

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