EP0746316A1 - Guanidines therapeutiques - Google Patents

Guanidines therapeutiques

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Publication number
EP0746316A1
EP0746316A1 EP95903152A EP95903152A EP0746316A1 EP 0746316 A1 EP0746316 A1 EP 0746316A1 EP 95903152 A EP95903152 A EP 95903152A EP 95903152 A EP95903152 A EP 95903152A EP 0746316 A1 EP0746316 A1 EP 0746316A1
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European Patent Office
Prior art keywords
acenaphthyl
methylguanidine
guanidine
substituted
bis
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.)
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Application number
EP95903152A
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German (de)
English (en)
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EP0746316A4 (fr
Inventor
Sharad Magar
Graham J. Durant
Lain-Yen Hu
Stanley M. Goldin
N. Laxma Reddy
James B. Fischer
Subbarao Katragadda
Andrew Gannett Knapp
Lee David Margolin
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.)
Cenes Pharmaceuticals Inc
Original Assignee
Cambridge Neuroscience Inc
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Publication of EP0746316A1 publication Critical patent/EP0746316A1/fr
Publication of EP0746316A4 publication Critical patent/EP0746316A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/20—Acenaphthenes; Hydrogenated acenaphthenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention pertains to certain substituted guanidines, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such guanidines.
  • Neurons of the mature central nervous system are highly specialized and in general do not replace themselves. Consequently, death or degeneration of cells in the nervous system can have far more serious consequences than cell death or degeneration in other organs. Abnormal neuronal death can be rapid and widespread as in traumatic brain injury, or can occur over many years among very specific populations of neurons as in chronic neurodegenerative diseases.
  • glutamate neurotoxicity is involved in acute injury to the nervous system as observed with seizure, hypoxia, hypoglycemia, and trauma, as well as in chronic degenerative diseases such as Huntington's disease, olivopontocerebellar atrophy - 2 -
  • glutamate In the mammalian brain, glutamate interacts with three major classes or receptors, i.e., N-methyl-D-aspartate ("NMDA") receptors, non-NMDA receptors and metabotropic receptors (Watkins, J.D., et al., Trends Neurosci. , 10:265 (1987); and Seeburg, TIPS, 141 :297 (1993)). While triggering distinctive postsynaptic responses, all three classes of glutamate receptors can act to increase the intracellular concentration of free Ca 2+ in nerve cells (A.B. MacDermott, Nature 321 :519 (1986)).
  • NMDA N-methyl-D-aspartate
  • binding of glutamate to the NMDA receptor opens a cation-selective channel that is markedly permeable to Ca + , leading to a large and rapid increase in intracellular Ca 2+ .
  • non-NMDA receptors are in most instances linked to cation channels that largely exclude calcium, they can indirectly promote Ca 2+ entry into neurons by depolarizing the cell membrane, which in turn opens voltage-activated Ca 2+ -channels.
  • the so-called "metabotropic receptor" is not associated with an ion channel but can promote the release of Ca 2+ from intracellular stores via the second-messenger inositol triphosphate.
  • cytosolic Ca 2+ is believed to be a key event in the initiation of neuronal destruction.
  • Adverse consequences of elevated intracellular Ca 2 + include derangement of mitochondrial respiration, activation of Ca 2+ -dependent proteases, lipases and endonucleases, free radical formation and lipid peroxidation of the cell membrane. - 3 -
  • the NMDA subtype of excitatory amino acid receptors is strongly involved in nerve cell death which occurs following brain or spinal chord ischemia.
  • ischemic brain insults such as stroke, heart attack or traumatic brain injury
  • an excessive release of endogenous glutamate occurs, resulting in the over- stimulation of NMDA receptors.
  • Associated with the NMDA receptor is an ion channel.
  • the recognition site, i.e., the NMDA receptor is external to the ion channel.
  • 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.
  • Non-NMDA receptors constitute a broad category of postsynaptic receptor sites which, as is the case for NMDA receptors, are directly linked to ion channels. Specifically, the receptor sites are physically part of specific ion channel proteins.
  • Non-NMDA receptors have been broadly characterized into two major subclasses based on compounds selective therefor: kainate receptors and AMPA/quisqualate receptors. See J.C. Watkins et al., Trends Neurosci. , 10:265 (1987).
  • AMPA is an abbreviation for ⁇ -amino-3- hydroxyl-5-methyl-4-isoazole propionic acid.
  • These subclasses may be categorized as "non-NMDA" receptors. Compared to NMDA receptors, non-NMDA receptors have received less pharmacological scrutiny — the existing antagonists are all competitive -- and in vivo research in this area has been hampered by the lack of drugs that cross the blood-brain barrier.
  • One such disorder is global cerebral ischemia, as occurs following cardiac arrest, drowning, and carbon monoxide poisoning.
  • Transient, severe interruption of the cerebral blood supply in animal causes a syndrome of selective neuronal necrosis, in which degeneration occurs among special populations of vulnerable neurons (including neocortical layers 3, 5 and 6, pyramidal cells in hippocampal zones CA1 and CA3, and small and medium sized striatal neurons).
  • the time course of this degeneration is also regionally variable, and can range from a few hours (striatum) to several days (hippocampus).
  • NMDA antagonists generally have not proven highly effective in animal models of global ischemia; indeed, it has been suggested that positive results obtained using NMDA antagonists may largely be artifactual.
  • the competitive non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (“NBQX") is dramatically effective in preventing delayed neuronal degeneration following transient forebrain ischemia in both gerbils and rats. See, M.J. Sheardown et al., Science, 247:571 -574 (1990).
  • NMDA antagonists also have been shown to inhibit memory acquisition. Morris, R.G.M., in Excitat. A.A. 's in Health and Disease, D. Lodge (ed.), Wiley, 297- 320 (1988).
  • Blockers of neurotransmitter release have received some attention as potential neuroprotective agents. See Meldrum, B., Cerebrovascular and Brain Metab., Rev. 2: 27-57 (1990); Dolphin, A.C. Nature, 316: 148-1 50 (1985)); Evans, M.C. et al., Neurosci. Lett. , 83:287-292 (1987); Ault, B. and Wang, CM., Br. J. - 6 -
  • nimodipine Calcium antagonists such as nimodipine have been reported to act both as cerebral vasodilators (Wong, M.C.W. and Haley, E.C. Jr., Stroke, 24:31 -36 ( 1989)), and to block calcium entry into neurons (Scriabine, A., Adv. Neurosurg. (1990)). Modest improvement in the outcome of stroke has been observed in clinical trials. Gelmers, H.J. et al., N. Eng. J. Med. , 318:203-207 (1988). While there are significant cardiovascular side effects, nimodipine appears less toxic than certain NMDA antagonists.
  • Antagonists of voltage-gated Na channels can exhibit neuroprotective properties. Graham, S.H., J. Chen, F.H. Sharp, and R.P. Simon, J. Cereb. Blood Flow and Metab. , 13:88-97 (1 993), Meldrum, B.S., et al., Brain Res. , 593: 1 -6 and Stys, P.K., S.G. Waxman, and B.R. Ransom, J. Neurosci. , 12:430-439 ( 1992). In stroke, sustained hypoxia in the "core region" results from occlusion of the blood supply by a clot.
  • the present invention provides N,N'-diaryl substituted guanidines of Formula I:
  • R and R 1 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted
  • Ar and Ar 1 are each independently selected from the group consisting of substituted or unsubstituted carbocyclic aryl having at least 5 carbon atoms, and substituted or unsubstituted heteroaromatic group having 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of the Formula I include those represented by Formula IA:
  • R and R 1 are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at
  • Ar is selected from the group consisting of substituted or unsubstituted carbocyclic aryl having at least 5 carbon atoms, and substituted or unsubstituted heteroaromatic group having 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; and pharmaceutically acceptable salts thereof.
  • R, R 1 and Ar are the same as defined above for
  • preferred compounds of Formula I include those guanidines having an N- and/or N'-acenaphtyl substituent that comprise one or more ring substituents.
  • preferred compounds include those of the following Formula UA:
  • each R 2 substituent is independently halogen, hydroxyl, cyano, isocyanato, nitro, amino, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 - 10 -
  • n is an integer equal to 1 -9; and pharmaceutically acceptable salts thereof.
  • guanidines having a substituted 3- acenapthyl moiety particularly compounds of the following Formula
  • each R 2 substituent is independently halogen, hydroxyl, cyano, isocyanato, nitro, amino, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyi having from 1 to about 20 carbon atoms, or -
  • n is an integer equal to 1 -9; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of Formulas IIA or IIB include those where n is 1 , 2 or 3, and more preferably n is 1 or 2.
  • Compounds of Formula IIA or IIB are preferably substituted at the 3, 4, 5, 6, 7 and/or 8 positions of the acenaphthyl group by one or more R 2 groups.
  • Preferred compounds of Formula I, IA, IB, IIA or IIB include disubstituted guanidines, i.e., where R and R 1 are each hydrogen, particularly where the group Ar and/or Ar 1 is a heterocyclic group or a substituted or unsubstituted carbocyclic aryl group such as unsubstituted and substituted biphenyl and unsubstituted or substituted phenyl including mono-substituted phenyl, di-substituted phenyl and tri-substituted phenyl.
  • tri-substituted guanidines i.e., where only one of R and R 1 are hydrogen
  • tetra- substituted guanidines i.e., where both R and R 1 are other than hydrogen
  • the group Ar and/or Ar 1 is a heterocyclic group or a substituted or unsubstituted carbocyclic aryl group such as unsubstituted and substituted biphenyl and unsubstituted and substituted phenyl including mono-substituted phenyl, di-substituted phenyl and tri-substituted phenyl.
  • Formulas I, IA, IB, IIA and IIB include the tautomeric isomers of the specified guanidines.
  • Preferred compounds of the invention modulate, particularly inhibit, the release of a neurotransmitter, preferably glutamate. More preferably the preferred substituted guanidines modulate, particularly inhibit, neurotransmitter (e.g., glutamate) release from ischemic neuronal cells, especially mammalian cells such as human neuronal cells.
  • guanidines of Formulas IA, IB, IIA or IIB above will be active in the K-evoked glutamate release assay and veratridine induced glutamate release assay, as discussed more fully infra.
  • these especially preferred compounds include a 3-acenaphthyl or 5-acenaphthyl group on one guanidine nitrogen and either a substituted or unsubstituted aryl group, particularly a phenyl group, on the second guanidine nitrogen.
  • N,N'-diaryl substituted guanidines of the present invention are useful for a number of therapeutic applications, including treatment of those diseases that result from modulation of a particular neurotransmitter system and that can be counteracted by one or more of the substituted guanidines of the invention which act either on the same or another class of neurotransmitters.
  • the present invention includes methods for treatment and/or prophylaxis of neurological conditions such as epilepsy, neurodegenerative conditions and/or nerve cell death resulting from hypoxia, hypoglycemia, brain or spinal chord ischemia, brain or spinal chord trauma, stroke, heart attack, drowning or carbon monoxide poisoning.
  • Compounds of the invention also are useful to treat and/or prevent various neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, Korsakoff's - 13 -
  • Compounds of the invention also may be used to treat anxiety, e.g. by administration to subjects susceptible to generalized anxiety disorder.
  • Compounds of the invention also will utility for the treatment of epilepsy.
  • Compounds of the invention will have particular utility for treatment of global cerebral ischemia as may occur following cardiac arrest, drowning and carbon monoxide poisoning.
  • the methods of treatment (which include prophylactic therapy) of the invention generally comprise administration of a therapeutically effective amount of one or more compounds of Formula I, IA, IB, IIA or IIB to an animal, including a mammal, particularly a human.
  • the invention also provides pharmaceutical compositions that comprise one or more compounds of Formula I and a suitable carrier.
  • compounds of the invention have the ability to modulate, i.e. inhibit or potentiate the release of neurotransmitter(s), or decrease or preferably lengthen the time course of action of neurotransmitter(s), from neuronal tissue. It has thus been found that the compounds will have utility to treat or prevent those pathophysiologic conditions which result from excessive or inadequate release of neurotransmitters. It is thought that substituted guanidines of the invention mediate the inhibition of neurotransmitter release by blocking presynaptic calcium channels and/or sodium channels.
  • the invention provides methods for blockage of voltage sensitive calcium channels and sodium channels of neuronal cells, particularly mammalian cells such as human neuronal cells, comprising the administration to the cells an effective amount of a compound(s) of Formula I, IA, IB, IIA or IIB - 14 -
  • disorders such as neuronal damage in stroke may be alleviated by inhibiting the release of excitatory amino acids such as glutamate.
  • Some disorders such as depression may be alleviated by inhibiting the release of inhibitory neurotransmitters such as gamma-aminobutyric acid.
  • inhibiting the release of an excitatory neurotransmitter such as glutamate by administration of a compound of the invention may indirectly potentiate the release or subsequent actions of an inhibitory transmitter such as gamma-aminobutyric acid, and thus the compound of the invention may treat disorders known to be alleviated by more direct potentiation of inhibitory neurotransmission, e.g., anxiety or insomnia.
  • Compounds of the invention may be considered effective inhibitors of neurotransmitter release if the compound causes at least about a 50% inhibition of neurotransmitter, such as glutamate, at a concentration of about 100 M according to the protocol disclosed in Example 64 below. More preferably the compound will cause at least about a 50% inhibition of neurotransmitter, such as glutamate, at a concentration of about 30 ⁇ M according to the protocol disclosed in Example 64 below.
  • Compounds of the invention may modulate release of neurotransmitters that include glutamate, dopamine, norepinephrine, glycine, aspartate and serotonin, particularly glutamate. - 1 5 -
  • alkyl groups include having 1 to about 1 2 carbon atoms, more preferably 1 to about 6 carbon atoms, such as methyl, ethyl, ⁇ -propyl, /so-propyl, 7-butyl, f-butyl, /so-butyl, sec-butyl, pentyl and hexyl groups.
  • Preferred alkenyl and alkynyl groups include those groups having one or more unsaturated linkages, preferably one or two unsaturated linkages and from 2 to about 1 2 carbon atoms, more preferably 2 to about 6 carbon atoms, still more preferably 2 to about 3 or 4 carbon atoms.
  • Each of the terms alkyl, alkenyl and alkynyl as used herein refer to both cyclic and noncyclic groups, although typically straight or branched chain noncyclic groups are generally more preferred.
  • Preferred alkoxy groups of compounds of the invention include groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbons.
  • Preferred thioalkyl groups include groups having one or more thioether linkages and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbons.
  • Preferred aminoalkyi groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more - 1 6 -
  • alkylsulfinyl groups have one or more sulfinyl (SO) groups, more typically one sulfinyl group, and from 1 to about 12 carbon atoms, more preferably 1 to about 6 carbons, and even more preferably 1 -3 carbon atoms.
  • SO sulfinyl
  • Preferred alkylsulfonyl groups have one or more sulfono (SO 2 ) groups, more typically one sulfono group, and from 1 to about 1 2 carbon atoms, more preferably 1 to about 6 carbons, and even more preferably 1 -3 carbon atoms.
  • SO 2 sulfono
  • Suitable heteroaromatic or heteroaryl and heteroalicyclic groups of compounds of the invention contain 1 -3 separate or fused rings and one or more N, O or S atoms and include, e.g., quinolinyl including 8-quinolinyl, indolinyl including 5-indolinyl, furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl and phthalimido groups all of which may be optionally independently substituted at one or more available positions including fused to a further cyclic group (e.g., quinolinyl including 8-quinolinyl, indolinyl including 5-indolinyl, furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl and phthalimido groups all of
  • Preferred aryl groups including carbocyclic aryl groups, include those having about 5 to about 20 carbons, more preferably about 1 to 3 separate or fused rings and from 6 to about 18 carbon atoms, such as phenyl, naphthyl, acenaphthyl, phenanthryl, anthracyl and fluorene groups.
  • Said substituted moieties of compounds of the invention may be substituted at one or more available positions by one or more suitable groups such as, e.g., halogen such as F, Cl, Br, or I; cyano; hydroxyl; nitro; azido; carboxy; carbocyclic aryl; alkyl groups including alkyl groups having from 1 to about 1 2 carbon atoms or - 17 -
  • suitable groups such as, e.g., halogen such as F, Cl, Br, or I; cyano; hydroxyl; nitro; azido; carboxy; carbocyclic aryl; alkyl groups including alkyl groups having from 1 to about 1 2 carbon atoms or - 17 -
  • alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon atoms or from 2 to about 6 carbon atoms; alkoxy groups such as those groups having one or more oxygen linkages and from 1 to about 1 2 carbon atoms or from 1 to about 6 carbon atoms; thioalkyl groups such as those groups having one or more thioether linkages and from 1 to about 1 2 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyi groups such as groups having one or more N atoms and from 1 to about 1 2 or 1 to about 6 carbon atoms; aminoalkylenearyl groups such as groups having one or more N atoms, such N atoms(s) by substitued by one or more alkylenearyl groups such as benzyl and the like with dibenzylamino being a particularly preferred substituent such as of phenyl or other aryl group; alkylsulfinyl such as
  • Specifically preferred substituted groups include carboxylic acyl or alkanoyl groups, preferably having from 1 to about 12 or 1 to about 6 carbon atoms such as acetyl, propanoyl, /so-propanoyl, butanoyl, sec-butanoyl, pentanoyl and hexanoyl groups.
  • substituted moieties are alkaryl groups which include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups, e.g., above-mentioned aryl groups substituted by one or more 0,-0, 2 , C C 6 or C n -C 4 alkyl groups such as phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl and phenylhexyl groups as well as the branched chain isomers thereof.
  • Haloalkyl are also preferred, particularly fluoroalkyl such as - 18 -
  • Aroyl groups are also preferred substituted groups such as carbonyl substituted by phenyl, naphthyl, acenaphthyl, phenanthryl, and anthracyl groups and carboxylic acyl groups substituted by one or more aryl groups, e.g., diphenylacetoxy and fluorenecarboxy groups.
  • Aralkanoyl groups are also preferred and include carbonyl substituted by the aralkyl groups described above.
  • Aralkoxy groups are also preferred substituted groups and include alkoxy groups substituted by phenyl, naphthyl, acenaphthyl, phenanthyl, and anthracyl groups.
  • Preferred substituted aryl groups include the above described aryl groups, particularly phenyl, substituted by halo, hydroxy, alkoxy, amino, and the like.
  • substituent groups of compounds of the invention include halogen, hydroxy, CF 3 , C,-C e acyl, C C ⁇ alkyl, C 2 - C 6 alkenyl, C 2 -C ⁇ alkynyl, C-
  • R and R 1 groups of compounds of the invention include hydrogen and substituted and unsubstituted alkyl, particularly methyl, ethyl, propyl and butyl. Hydrogen and methyl and ethyl are especially preferred R and R 1 groups.
  • R 2 groups of compounds of the invention include halo, substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyi, substituted or unsubstituted alkoxy, substituted or unsub- - 19 -
  • substituted alkyl R 2 groups include haloalkyi including fluoroalkyl such as fluoromethyl or fluoroethyl, particularly trifluoromethyl.
  • Ar substituents of compounds of Formula I, IA, IB, IIA or IIB are substituted and unsubstituted carboxylic groups, especially substituted and unsubstituted phenyl groups.
  • Phenyl groups having from 1 to 5 ring substitutents are particularly preferred including phenyl groups having a single ring substituent e.g.
  • disubstituted phenyl groups including a 2,3-substituted phenyl group, 2,4-substituted phenyl group, 2,5-substituted phenyl group, 2,6-substituted phenyl group, a 3,4-substituted phenyl group or a 3,5-substituted phenyl group; and trisubstituted phenyl groups including a 2,3,4-substituted phenyl group, a 2, 3,5-substituted phenyl group, a 2,3,6-substituted phenyl group and a 3,4,5- substituted phenyl group; and tetrasubstituted phenyl groups including a 2,3,4,5-substituted phenyl group, a 2,3,4,6-substituted pheny group and a 2,3,5,6-substituted phenyl group.
  • Preferred ring substituents of such substituted phenyl Ar groups include halogen, nitro, alkyl including alkyl having 1 to about 8 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, etc., alkoxy including alkoxy having 1 to about 8 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, etc., alkylthio such as methylthio and ethylthio, haloalkyi such as fluoroalkyl including trifluromethyl, chloroalkyi and bromoalkyl, haloalkoxy including fluoroalkoxy such as trifluoromethoxy, and carobocylic aryl, particularly substituted or unsubstituted phenyl.
  • IB, IIA, or IIB include the following: halophenyl such as fluorophenyl, - 20 -
  • C 6 H 5 CH 2 CH 2 C 6 H 5 - such as 3-phenethylphenyl and 4-phenethylphenyl and the like; substituted and unsubstituted aralkylaminophenyl such as e.g. (mono-phenylC ⁇ ealkylenejaminophenyl or (di-phenylC,.
  • ⁇ alkylene)aminophenyl such as (N,N-dibenzyl)aminophenyl, ⁇ N,N- diphenethylene)aminophenyl, N-methyl-N-benzylaminophenyl, and the like; substituted and unsubstituted aryloxyphenyl and aralkyloxyphenyl including substituted and unsubstituted phenoxyphenyl and benzyloxyphenyl such as e.g.
  • alkyleneoxyarylphenyl such as particularly substituted and unsubstituted (C,. 6 alkyleneoxyphenyl)phenyl such as substituted or unsubstituted benzyloxymethylenephenyl including such groups having one or more C h alky!, halo-C ⁇ alkylhalo, alkoxy, alkylthio or nitro benzyl ring substituents; substituted and unsubstituted heterocyclic-substituted phenyl, particularly heteroaromatic-substituted phenyl such as e.g.
  • phenyl substituted by indole such as 3-(2'-indole)phenyl and 4-(2'- indole)phenyl
  • phenyl substituted by benzothiazole such as 3-(2'- benzothiazole)phenyl, 4-(2-benzothiazole)phenyl, 3-(2'-benzothiazole- 6'-methyl)phenyl, 4- ⁇ 2-benzothiazole-6'-methyl)phenyl, and phenyl substituted by one or more indolinyl including 5-indolinyl, furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl and phthalimido groups (all of which may be optionally independently substituted at one or more available positions including fused to a further cyclic group (e.g.
  • heteroaromatic-substituted phenyl substituents include those phenyl substituents independently substituted at one or more ring positions, more typically one or two phenyl ring positions, by heteraromatic group(s) that each contains 1 - 3 rings, 3 to 8 ring members in each ring and 1 -3 N, O or S atoms.
  • Suitable Ar and/or Ar 1 groups of Formula I, IA, IB, IIA, or IIB also include substituted and unsubstituted naphthyl; and substituted and unsubstituted acenaphthyl including 3-acenaphthyl and 5- acenaphthyl. 22 -
  • Specifically preferred compounds of the invention include: N-(5-acenaphthyl)-N'-(2,3,4-trichlorophenyl)guanidine; N-(5-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N,N'-bis- methylguanidine;
  • Additional preferred compounds include those named above with one or more ring substituents on the acenaphthyl group thereof, particularly those R 2 groups defined above for Formulas IIA and IIB.
  • Specifically preferred pharmaceutically acceptable salts of said compounds include those compounds identified in the examples which follow, and 3-acenaphthyl derivatives of those exemplified compounds, i.e. compounds that contain 3-acenaphthyl group(s) in place of 5-acenaphthyl group(s).
  • Compounds of the invention can be prepared by reaction of an amine, typically an amine salt such as an amine hydrochloride, with a preformed substituted cyanamide. See S.R. Safer, et al., J. Org.
  • diaryl substituted guanidines of the invention is typically achieved by condensing a salt - 35 -
  • arylamine with a substituted aryl cyanamide such as 3- acenaphthyl or 5-acenaphthyl cyanamide in a suitable solvent, e.g. refluxing chlorobenzene or toluene, as shown in the Scheme-1 where Ar is as defined above.
  • a suitable solvent e.g. refluxing chlorobenzene or toluene
  • the cyanamide can be suitably prepared by reduction of the corresponding nitro-substituted aryl to an amine, followed by treatment with cyanogen bromide as shown in the following Scheme.
  • SCHEME-1 PREPARATION OF N,N'-DI-ARYLGUANIDINES
  • step 1 of the above Scheme a mixture of b- and 3-nitro- acenaphthene is reduced with Pd/C in suitable solvent such as ethyl acetate under H 2 and suitable pressure such as 40 psi and the resulting amines are separated such as by recrystallization.
  • step 2 the desired amino acenaphthene is treated with cyanogen bromide in suitable solvent such as ethyl acetate to give N-acenaphthyl cyanamide and acenaphthyl amine hydrobromide salt.
  • This cyanamide is subsequently reacted with substituted arylamine salts in a suitable solvent with heat such as refluxing chlorobenzene or toluene to give the final product.
  • Tri and tetra-substituted guanidines of the invention may be prepared as outlined in Scheme-2 above.
  • an arylcyanamide such as N-5-acenaphthyl-N-alkyl cyanamide or N-3- acenaphthyl-N-alkyl cyanamide (suitably prepared as discussed above) is treated with a salt of an aryl amine (for synthesis of tri- substituted guanidine) or salt of N-alkyl aryl amine (for synthesis of tetra-substituted guanidine) in a suitable solvent such as chlorobenzene in the presence of AICI 3 cataiyst.
  • the products can be purified by conventional means such as silica gel chromatography.
  • Such substituted cyanamide reagents can be readily prepared.
  • a substituted acenaphthyl derivative can be nitrated (e.g., treatment with HNO 3 /H2SO 4 ) to provide a 3-nitroacephthyl or 5- nitroacephthyl having one or more additional ring substituents. See the procedure of M.D. Vareny, et al., J. Med. Chem. , 35: 671
  • reaction products can be separated by recrystallization or chromatography if more than one isomer is generated from the nitration.
  • a substituted nitro derivative can then be reduced to the amine by hydrogenation, the amine then reacted with cyanogen bromide and then an arylamine salt as described above to provide a compound of Formula IIA or IIB.
  • Suitable substituted acenaphthyl derivatives that can be nitrated and further reacted in such manner include, e.g., haloacenaphthalene such as 3-fluoroacenaphthalene, 3- chloroacenaphthalene, 3-bromoacenaphthalene, 4- fluoroacenaphthalene, 4-chloroacenaphthalene, 4- bromoacenaphthalene, 4-fluoroacenaphthalene, 4- chloroacenaphthalene, and 4-bromoacenaphthalene; alkanoylacenaphthalene such as 4-acetylacenaphthalene; alkoxynaphthalene such as 4-methoxyacenaphthalene; acenaphthalene, 3-acid; 5-acenaphthalene, ethanol; 5- acenaphthalene, methanol; alkenylacenaphthalene such as 3-U - methylpropenyOacenaphthalene
  • a suitable protecting group can be employed that is later removed as will be known to those skilled in the synthesis art.
  • compounds of the invention having a substituted acenaphthyl moiety can be prepared by a number of other routes.
  • acenaphthyl derivatives having an amine or amine-precursor group and one or more additional ring substituents see V.N. Komissarov, Zh. Org. Khim. , 26(5): 1 106-10 (1 990); L. Skulski, et al., Pol. J. Chem. , 55(9): 1809-24 (1981 ); A. F. Pozharskii, Isobret. Prom.
  • the N,N'-diaryl substituted guanidines of the invention are useful for a number of therapeutic applications, including treatment of those diseases that result from modulation of a particular neurotransmitter system that can be counteracted by one or more of the substituted guanidines of the invention.
  • modulation of neurotransmitter release involves either the inhibition of neurotransmitter release, the potentiation of neurotransmitter release, or the increase or decrease of the time course of action of neurotransmitter release from neuronal tissue.
  • Neurotransmitters which may be modulated by compounds of the invention include, but are not limited to, glutamate, dopamine, norepinephrine, glycine, aspartate and serotonin.
  • compounds for the prevention of neuronal death can be evaluated in vivo in one or more variations of the rat middle cerebral artery occlusion model. Such models are generally considered to be particularly predictive of neuroprotective efficacy in stroke. See Ginsburg, et al., Stroke, 20:1627-1642 (1989). Efficacy of lead compounds also may be assessed in the 4-vessel occlusion model of global ischemia. See Pulsinelli, et al., Stroke: 19:913-941 (1988) and PCT/US92/01050.
  • the invention provides methods for treatment and/or prophylaxis of neurological conditions such as epilepsy, neurodegenerative conditions and/or nerve cell death resulting from e.g. hypoxia, hypoglycemia, brain or spinal chord ischemia, brain or spinal chord trauma, stroke, heart attack, drowning or carbon monoxide poisoning.
  • neurological conditions such as epilepsy, neurodegenerative conditions and/or nerve cell death resulting from e.g. hypoxia, hypoglycemia, brain or spinal chord ischemia, brain or spinal chord trauma, stroke, heart attack, drowning or carbon monoxide poisoning.
  • Typical candidates for treatment include heart attack, stroke, brain or spinal cord injury patients, patients undergoing major surgery where brain ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream.
  • the invention also provides methods to treat and/or prevent various neurodegenerative diseases of a subject such as an animal, particularly a human, by administering a therapeutically effective amount of one or more compounds of the invention.
  • Typical neurodegenerative diseases that can be treated and/or prevented include Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, - 40 -
  • the invention provides methods of treating Korsakoff's disease, a chronic alcoholism-induced condition, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the disease.
  • a subject including a mammal, particularly a human
  • one or more compounds of the invention in an amount effective to treat the disease.
  • Pretreatment of animals with the NMDA antagonist MK-801 markedly attenuates the extent of cell loss, hemorrhages and amino acid changes in a rat model of Korsakoff's disease. See P.J. Langlais, et al., Soc. Neurosci. Abstr. , 14:774 (1988). Therefore, compounds of the invention have utility for the attenuation of cell loss, hemorrhages and amino acid changes associated with Korsakoff's disease.
  • the invention provides methods for blockage of voltage sensitive sodium channels of neuronal cells, particularly mammalian cells such as human neuronal cells, comprising the administration to the cells of an effective - 41 -
  • Conditions that can be treated by blockage of sodium channels will include, e.g., epilepsy.
  • some compounds of the invention will block sodium channels in addition to presynaptic calcium channels. This dual action potentially may be particularly desirable for neuroprotective therapies.
  • NMDA antagonists which do not cross the blood/brain barrier may be used to alleviate certain undesirable side effects of cancer chemotherapy, e.g. nausea and emesis (A. Fink-Jensen et al., Neurosci. Lett. , 137(2): 1 73 (1992)).
  • Compounds of the invention particularly those compounds that are charged such as in the form of a pharmaceutically acceptable salt, and those compounds that otherwise are hydrophilic such as compounds that comprise one or more polar functionalities e.g. carboxy, amino, hydroxy and the like, may have comparatively limited ability to cross the blood brain barrier.
  • compounds of the invention will be clinically useful to ameliorate the side effects associated with chemotherapy, particularly cancer thermotherapy, that may be experienced by a mammal, particularly a human receiving such chemotherapy.
  • the compound of the invention would be typically administered to the subject in coordination with the chemotherapy regime. - 42 -
  • Compounds of the invention may be used in therapy in conjunction with other medicaments.
  • one or more compounds of the invention may be suitably administered together with a pharmaceutical targeted for interaction in the blood clotting mechanism such as streptokinase, TPA and urokinase.
  • the compounds of this invention can be administered intranasally, orally or by injection, e.g., intramuscular, intraperitoneal, subcutaneous or intravenous injection, or by transdermal, intraocular or enteral means.
  • the optimal dose can be determined by conventional means including the assays of Examples 64-65 which follow.
  • Guanidines of the present invention are suitably administered to a subject in the protonated and water-soluble form, e.g., as a pharmaceutically acceptable salt of an organic or inorganic acid, e.g., hydrochloride, hydrobromide, sulfate, hemi-sulfate, mesylate, gluconate, phosphate, nitrate, acetate, oxalate, citrate, maleate, etc., prepared by procedures such as those disclosed in the examples which follow.
  • an organic or inorganic acid e.g., hydrochloride, hydrobromide, sulfate, hemi-sulfate, mesylate, gluconate, phosphate, nitrate, acetate, oxalate, citrate, maleate, etc.
  • the compounds of this invention can be employed, either alone or in combination with one or more other therapeutic agents as discussed above, as a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, - 43 -
  • viscous paraffin perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • solutions preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Ampoules are convenient unit dosages.
  • tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like are particularly suitable, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • Intravenous or parenteral administration e.g., sub-cutaneous, intraperitoneal or intramuscular administration are generally preferred.
  • a suitable effective dose of one or more compounds of Formula I, Formula IA, Formula IB, Formula IIA or Formula IIB, particularly when using the more potent compound(s) of Formula I, Formula IA, Formula IB, Formula IIA or Formula IIB will be in the range of from 0.5 to 50 milligrams per kilogram bodyweight of recipient per day, preferably in the range of 1 to 10 milligrams per kilogram bodyweight of recipient per day.
  • the desired dose is suitably administered once daily, or several sub-doses, e.g., 2 to 4 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
  • sub-doses may be administered as unit dosage forms, e.g., containing from 0.25 to 25 milligrams of compound(s) of Formula I, Formula IA, Formula IB, Formula IIA or Formula IIB per unit dosage, preferably from 0.5 to 5 milligrams per unit dosage.
  • the guanidines of the present invention should have utility as rubber accelerators.
  • NMR spectra were recorded on a General Electric QE-300 or Varian Gemini 300 and the chemical shifts were reported in ppm ( ⁇ ) relative to the residual signal of the deuterated solvent (CHCI 3 , ⁇ 7.26; CHD 2 OD, ⁇ 3.30).
  • Infrared spectra were recorded in CHCI 3 (unless otherwise noted) on a Nicolet 5DXB FT-IR or Perkin-Elmer model 1420. All new compounds were analyzed either for C, H, and N elemental analyses or for exact mass. Compounds analyzed for exact mass were further analyzed by HPLC and/or 300 MHz NMR spectrometer ( 1 H) for their purity.
  • Elemental analyses were performed by Desert Analytics (Tucson, AZ) or Galbraith Laboratories (Knoxville, TN). High Resolution Mass spectra (HRMS) were recorded on a Finnegan MAT 90. HPLC were performed on a C18 reverse phase column using 50:50 wate ⁇ acetonitrile with 0.1 % TFA as the mobile phase. BrCN was obtained from Aldrich Chemical Co., and was used as received. All starting amines were obtained from commercial sources and were purified by standard procedures before use, or they were prepared, - 46
  • Chlorobenzene was freshly distilled from CaH 2 or anhydrous quality solvent (Sure Seal) supplied by Aldrich wa used.
  • Ether (Et 2 O) and tetrahydrofuran (THF) were refluxed over sodium/benzophenone ketyl and freshly distilled under N 2 before their use or anhydrous quality solvents (Sure Seal) supplied by Aldrich were used. All other solvents were reagent grade.
  • Alkyl- and arylcyanamides were prepared as described above and according to published procedures (e.g., PCT/US92/01050) by reaction of the amines with BrCN in ether.
  • Step 1 5-Acenaphthyl cyanamide 5-Aminoacenaphthene (7.0 g, 41 .4 mmol) was dissolved in a mixture of ether (100 Ml) and ethyl acetate (25 Ml). To this solution was added 5.2 mL of a 5M solution of cyanogen bromide in acetonitrile (25.6 mmol of cyanogen bromide). The solution was stirred overnight, with the gradual appearance of gray precipitate. The solid was removed by filtration (the hydrobromide of 5- aminoacenaphthene) and the resulting filtrate concentrated in vacuo to afford a semi-solid residue.
  • 5-Acenaphthene amine (5.8 g, 34.3 mmol) was dissolved in warm formic acid (97%, 25 mL) and refiuxed. After 7 hours, the reaction mixture was cooled to 25 °C and then let is stand in refrigerator for 1 2 hours. The solid was filtered and washed with acetonitrile and then air-dried to afford the formamide (6.65 g), which was used in the next step without further purification.
  • test compound is first dissolved in methanol to make a stock of 20 mM.
  • This solution is diluted into the basal buffer as well as high-K + buffer to give the required concentration of the compound as specified in Table I below, i.e., 10 ⁇ M or 3 ⁇ m. All solutions including the controls are made to have the same concentration of methanol. Methanol concentration never exceeded 0.3% (v/v) of buffers.
  • Synaptosomes were first exposed to the compound during the wash before superfusion and also during the entire superfusion protocol. The total time synaptosomes were exposed to the test organic compounds before the glutamate release was ⁇ 25 sec.
  • Example 65 Ca-Flux Assay Compounds were also tested to determine where the Ca 2+ dependent and independent components of glutamate release are related to the blockage of 45 Ca uptake. Calcium uptake is one step in - 70 -
  • Rat brain synaptosomes were prepared according to Hajos, Brain Res. , 93:485 (1975). Synaptosomes were suspended in low potassium "LK" buffer (containing 3 mM KCl) at 2 mg/ml. Test compounds in LK were added to synaptosomes to a final concentration of 10 ⁇ M and incubated for 5 minutes at room temperature. 45 Ca uptake was then measured by adding isotope in either LK or high potassium (1 50 mM KCl) containing buffer.
  • the Stock Solution is made in ddH 2 0, filtered and stored at room temperature for 4-6 weeks.
  • the Hepes stock is kept refrigerated. - 72 -
  • Incubation Buffer The Incubation Buffer is made on the day of the assay. 4) Wash Buffer of the following composition (amounts of components expressed as mis).
  • test Assay is prepared of the following composition and having 200 ⁇ final volume:
  • the tested compounds are identified by reference to the formula depicted below with the substituent groups of the tested compounds R, R 1 and R 2 specified in Table III.
  • the tested compounds were in salt form, as indicated in the Table. TABLE III

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Abstract

La présente invention décrit des guanidines à substitution N,N'-diaryle ayant une utilité thérapeutique. Les composés de la présente invention sont représentés par la formule (I) dans laquelle R et R1 représentent hydrogène ou un autre groupe, et Ar et Ar1 représentent des groupes aryle choisis dont au moins un est acénaphtyle.
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