WO1995014467A1 - Therapeutic guanidines - Google Patents

Therapeutic guanidines Download PDF

Info

Publication number
WO1995014467A1
WO1995014467A1 PCT/US1994/013541 US9413541W WO9514467A1 WO 1995014467 A1 WO1995014467 A1 WO 1995014467A1 US 9413541 W US9413541 W US 9413541W WO 9514467 A1 WO9514467 A1 WO 9514467A1
Authority
WO
WIPO (PCT)
Prior art keywords
acenaphthyl
methylguanidine
guanidine
substituted
bis
Prior art date
Application number
PCT/US1994/013541
Other languages
French (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
Original Assignee
Cambridge Neuroscience, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cambridge Neuroscience, Inc. filed Critical Cambridge Neuroscience, Inc.
Priority to EP95903152A priority Critical patent/EP0746316A4/en
Priority to JP7515219A priority patent/JPH09505600A/en
Priority to AU12122/95A priority patent/AU703138B2/en
Publication of WO1995014467A1 publication Critical patent/WO1995014467A1/en

Links

Classifications

    • 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

Abstract

The present invention provides N,N'-diaryl substituted guanidines having therapeutic utility. The compounds of the present invention are represented by formula (I), wherein R and R1 represent hydrogen or other group and Ar and Ar1 represent selected aryl groups, and at least one being acenaphthyl.

Description

THERAPEUTIC GUANIDINES
BACKGROUND OF THE INVENTION
1 . Field of the Invention
The present invention pertains to certain substituted guanidines, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such guanidines.
2. Background
Neurons of the mature central nervous system ("CNS") 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.
Substantial evidence now points to pernicious overactivity of normal neurotransmitter systems as a contributory mechanism in many instances of pathological neuronal degeneration. In particular, overstimulation of neuronal receptors for L-glutamate, the brain's most prevalent excitatory amino acid ("EAA") neurotransmitter, has been recognized as a causal or exacerbating factor in several acute neurological disorders, and has been proposed to underlie a number of chronic neurodegenerative diseases as well. Choi, D.W., Neuron. , 1 :623 (1988); Choi, D.W., Cerebrov. and Brain Metab. Rev. , 2: 105 (1990); Albers, G.W., et al., Ann. Neurol. , 25:398 (1 989) . Indeed, it is believed that 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 -
associated with glutamate dehydrogenase deficiency and decreased glutamate catabolism, amyotrophic lateral sclerosis/Parkinsonium- dementia, Parkinson's disease, and Alzheimer's disease. Choi, D.W., Neuron, 1 :623-634 (1988); Choi, D.W., Cereb. Brain Met., Rev. 2: 105-147 (1990); Courtier et al., Lancet, 341 :265-268 ( 1 993); Appel, S.H., Trends Neurosci. , 16:3-5 (1993).
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 Ca2+ in nerve cells (A.B. MacDermott, Nature 321 :519 (1986)). Thus, 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 Ca2+ . Although non-NMDA receptors are in most instances linked to cation channels that largely exclude calcium, they can indirectly promote Ca2+ entry into neurons by depolarizing the cell membrane, which in turn opens voltage-activated Ca2+-channels. The so-called "metabotropic receptor", on the other hand, is not associated with an ion channel but can promote the release of Ca2+ from intracellular stores via the second-messenger inositol triphosphate.
Irrespective of the triggering mechanism, prolonged elevation of cytosolic Ca2+ is believed to be a key event in the initiation of neuronal destruction. Adverse consequences of elevated intracellular Ca2 + include derangement of mitochondrial respiration, activation of Ca2+-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. Upon the occurrence of 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. 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., Ca2+ and Na+ into the cell and K+ out of the cell. It is believed that this flux of ions, especially the influx of Ca2+ ions, caused by the interaction of glutamate with the NMDA receptor, plays an important role in nerve cell death. See, e.g., Rothman, S.M. and Olney, J.W., Trends in Neurosci. , 10(7):299-302 (1987). Additionally, excessive excitation of neurons occurs in epileptic seizures and it has been shown that over-activation of NMDA receptors contributes to the pathophysiology of epilepsy (Porter, R.J., Epilepsia, 30(Suppl. 1 ):S29-S34 (1989); and Rogawski, M.A., et al., Pharmacol. Rev. , 42:224-286 (1990)).
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 σ-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. Nonetheless, in vivo studies have clearly demonstrate that non-NMDA receptor agonists can be as excitotoxic as NMDA agonists, although longer exposures can be required. In addition, evidence from animal studies and from human epidemiological studies suggests that excitotoxicity mediated by non-NMDA receptors may be clinically important in certain pathologies. See M.D. Ginsberg et al., Stroke, 20: 1 627 (1989).
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. In contrast, 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).
At present, there is a critical need for effective treatments which limit the extent of nerve cell death following a stroke or traumatic brain injury. Recent advances in the understanding of the mechanisms underlying this nerve cell death have led to the hope that a drug treatment can be developed. Research and development efforts in this area have focussed on blocking the actions of glutamate that are mediated by the NMDA receptor-channel complex. Two approaches have been developed: competitive NMDA receptor antagonists (Choi D.W., Cerebrov. Brain Metab., Rev. 1 : 165-21 1 (1990); Watkins, J.C. and Olverman, H.J., Trends Neurosci. , 10:265-272 (1987)) and blockers of the ion channel of the NMDA receptor-channel complex (Meldrum, B., Cerebrovascular Brain Metab., Rev. 2:27-57 (1987); Choi, D.W., Cerebrovascular Brain Metab., Rev. 2: 105-147 (1987); and Kemp, J.A. et al. , Trends Neurosci. , 10:265-272 (1987)). However, some toxicity with certain ion-channel-blockers such as MK-801 (see Merck Index, monograph 3392, 1 1th ed., 1989) has been reported. Olney, J.W. et al., Science, 244: 1360-1362 (1989); Koek, W. and Colpaert, J., J. Pharmacol. Exp. Ther. , 252:349-357 (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 -
Pharmacol. , 87:695-703 (1986); Kaneko, T., et al., Arzneim- Forsch./Drug Res. , 39:445-450 (1989); Malgouris, C, et al., J. Neurosci. , 9:3720-3727 (1989); Jimonet, P. et al. BioOrgan. and Med. Chem. Lett. , 983-988 (1993); Wahl, F. et al., Eur. J. Pharmacol. , 230:209-214 (1993); Koek, J.W. and Colpaert, F.C., J. Pharmacol. Exp. Ther. , 252:349-357 (1 990); Kaneko, T. et al., Arzneim.-Forsch./Drug Res. , 39:445-450 (1989). Certain compounds said to inhibit glutamate release also have been reported to show anticonvulsant activity. Malgouris, C, et al., J. Neurosci. , 9: 3720-3727 (1989); Miller, et al., New Anticonvulsant Drugs, Meldrum, B.S. and Porter R.J. (eds), Londo John Libbey, 1 65-1 77 (1986).
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. As hypoxia develops, ATP depletion leads to an inability of the Na, K-ATPase to maintain the ion gradients which generate the normal membrane potential of resting nerve cells. As the cell depolarizes and reaches the threshold for action potential firing, Na channels are activated. Stys et al. (Stys, P.K., S.G. Waxman, and B.R. Ransom, J. Neurosci., 12:430-439 (1 992)) recently reported the development of Na channel hyperactivity in anoxia of central white matter and demonstrate in vitro the neuroprotective effect of the Na channel blockers tetrodotoxin (TTX) and saxitoxin (STX).
SUMMARY OF THE INVENTION The present invention provides N,N'-diaryl substituted guanidines of Formula I:
Ar1 - N(R) - C - N(R1) - Ar NH (I) wherein:
R and R1 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 aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; - 8 -
Ar and Ar1 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:
Figure imgf000010_0001
wherein:
R and R1 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 least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; - 9
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.
Another group of preferred compounds of the present invention include those represented by Formula IB:
Figure imgf000011_0001
wherein R, R1 and Ar are the same as defined above for
Formula IA, and pharmaceutically acceptable salts thereof.
In another aspect, preferred compounds of Formula I include those guanidines having an N- and/or N'-acenaphtyl substituent that comprise one or more ring substituents. In particular, preferred compounds include those of the following Formula UA:
Figure imgf000011_0002
wherein R, R1 and Ar are the same as defined above for Formula IA, each R2 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 -
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 substituted or unsubstituted aralkyl having at least about 5 ring atoms; n is an integer equal to 1 -9; and pharmaceutically acceptable salts thereof.
Also preferred are guanidines having a substituted 3- acenapthyl moiety, particularly compounds of the following Formula
Figure imgf000012_0001
wherein R, R1 and Ar are the same as defined above for Formula IA, each R2 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 - 1 1 -
substituted or unsubstituted aralkyl having at least about 5 ring atoms; 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 R2 groups.
Preferred compounds of Formula I, IA, IB, IIA or IIB include disubstituted guanidines, i.e., where R and R1 are each hydrogen, particularly where the group Ar and/or Ar1 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. Also preferred are tri-substituted guanidines (i.e., where only one of R and R1 are hydrogen) and tetra- substituted guanidines (i.e., where both R and R1 are other than hydrogen), particularly where the group Ar and/or Ar1 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.
Compounds of the invention may exist as any one of a number of tautomeric forms. Each of these tautomeric forms are within the scope of the invention. That is, 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.
Most of the especially preferred 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. As described above, 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.
The 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 -
disease, olivopontocerebellar atrophy, HIV-induced dementia and blindness or multi-infarct dementia. 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.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that 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. Accordingly, 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 -
particularly such administration to a mammal in need of such treatment. By such blockage of calcium channels of neuronal cells, conditions associated with excessive endogenous neurotransmitter release can be treated.
More particularly, some 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. Further and without wishing to be bound by theory, 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 μM 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 -
It has also been found that compounds of the invention, while effective modulators of neurotransmitter release as demonstrated e.g. in Example 64 which follows, exhibit relatively low affinity to the PCP and/or sigma receptors in typical PCP and sigma receptor binding assays. This suggests that compounds of the invention have a clearly distinct therapeutic mechanism of action relative to neuroprotective agents that exhibit high affinity for the PCP or sigma receptors.
Suitable halogen groups of compounds of the invention
(including compounds of Formulas I, IA, IB, IIA or IIB) are F, Cl, Br and I. Preferred alkyl groups include having 1 to about 1 2 carbon atoms, more preferably 1 to about 6 carbon atoms, such as methyl, ethyl, Λ-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 -
preferably 1 to about 6 carbons, and even more preferably 1 -3 carbon atoms. Secondary and tertiary amine groups are generally more preferred than primary amine moieties. Preferred 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. Preferred alkylsulfonyl groups have one or more sulfono (SO2) 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. 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. fused to a benzene ring); and substituted or unsubstituted tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl groups, pyrazinyl, coumarinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiazolyl, benzotriazolyl, and benzimidazolyl. 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 -
from 1 to about 6 carbon atoms; 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 those groups having one or more sulfinyl groups and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl such as those groups having one or more sulfono groups and from 1 to about 1 2 carbon atoms or from 1 to about 6 carbon atoms. Further suitable and preferred substituted moieties of compounds are disclosed herein.
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. Also preferred 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 C6 or Cn-C4 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 -
trifluoromethyl. 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.
Particularly preferred substituent groups of compounds of the invention include halogen, hydroxy, CF3, C,-Ce acyl, C Cβ alkyl, C2- C6 alkenyl, C2-Cβ alkynyl, C-|-Cβ alkoxy, C6-C18 aryl, C2-C6 dialkoxy- methyl, cyano, C3-Cβ cycloalkyl, C3-C6 heterocycloalkyl, C3-C15 dialkylaminoalkyl, carboxy, C2-C6 carboxylic acid, carboxamido, C^Ce haloalkyl, CrC6 haloalkylthio, allyl, C7-C20 aralkyl, a C3-C6 heterocycloalkyl ring fused to a benzene ring, CrC6 alkylthio, arylthio, Cι-Cβ haloalkoxy, amino, CrC6 alkylamino, C2-C15 dialkyl- amino, carbamoyl, C C6 N-alkylcarbamoyl, C2-C15 N,N-dialkyl- carbamoyl, nitro, C2-C15 dialkylsulfamoyl, and the like.
Particularly preferred R and R1 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 R1 groups.
Preferred R2 groups of compounds of the invention include halo, substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyi, substituted or unsubstituted alkoxy, substituted or unsub- - 19 -
stituted alkylthio, and substituted or unsubstituted alkylsulfinyl. Preferred substituted alkyl R2 groups include haloalkyi including fluoroalkyl such as fluoromethyl or fluoroethyl, particularly trifluoromethyl.
Typically preferred 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. at the 3 or 4 position; 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.
Specifically preferred Ar and/or Ar1 groups for Formula I, IA,
IB, IIA, or IIB include the following: halophenyl such as fluorophenyl, - 20 -
chlorophenyl, bromophenyl and iodophenyl including 2,5- dibromophenyl, 4-chiorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 2,3,4-trichlorophenyl, 3,4,5-trichlorophenyl, 2,3,4,5- tetrachlorophenyl, 2,3,5,6-tetrachlorophenyl, 3-iodophenyl, and the like; alkylphenyl such as 2,3-dimethylphenyl, 3-isopropylphenyl, tert- butylphenyl including 3-ferf-butylphenyl, 4-tert-butylphenyl, cyclohexylphenyl including 4-cyclohexylphenyl, sec-butylphenyl including 4-sec-butylphenyl, adamantylphenyl including 3- adamantylphenyl and 4-adamantylphenyl, and the like; haloalkylphenyl including fluoro, bromo, and chloroalkγlphenyl such as trifluoromethylphenyl, particularly 4-trifluoromethylphenyl; alkoxyphenyl including 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-/7- butoxyphenyl and the like; nitrophenyl such as 3-nitrophenyl, 4- nitrophenyl and the like; substituted and unsubstituted bi-phenyl such as 2-bi-phenyl, 3-bi-phenyl, 4-bi-phenyl and the like; substituted and unsubstituted aralkylphenyl including aralkylphenyl having 1 to about 10 about carbon atoms and preferably an aryl substituent of phenyl such as e.g. (1 '-methyl-2'-phenylethyl)phenyl (i.e., C6H5- CH2CH(CH3)C6H5-) such as 3-(1 '-methyl-2'-phenylethyl)phenyl and 4- (1 '-methyl-2'-phenylethyl)phenyl, phenethylphenyl (i.e.
C6H5CH2CH2C6H5-) such as 3-phenethylphenyl and 4-phenethylphenyl and the like; substituted and unsubstituted aralkylaminophenyl such as e.g. (mono-phenylC^ealkylenejaminophenyl or (di-phenylC,. βalkylene)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. 4-benzyloxyphenyl, 3-benzyloxyphenyl, dibenzyloxyphenyl such as 3-dibenzyloxyphenyl and 4-dibenzyloxyphenyl, and the like; substituted and unsubstituted - 21 -
(alkyleneoxyaryl)phenyl such as
Figure imgf000023_0001
particularly substituted and unsubstituted (C,. 6alkyleneoxyphenyl)phenyl such as substituted or unsubstituted benzyloxymethylenephenyl including such groups having one or more Chalky!, 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. fused to a benzene ring)), as well as phenyl substituted by one or more substituted or unsubstituted tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl groups, pyrazinyl, coumarinyl, tetrahydroquinoiinyl, tetrahydroisoquinolinyl, benzothiazolyl, and benzimidazolyl. Typically preferred 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 Ar1 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;
N,N'-bis(5-acenaphthyl)-N-methylguanidine; N,N'-bis(5-acenaphthyl)-N,N'-bis-methylguanidine;
N- 5-acenaphthyl)-N'- ((1 -anthracenyDguanidine;
N- 5-acenaphthyl)-N'- ((1 -anthracenyD-N-methylguanidine;
N-| 5-acenaphthyl)-N'- ((l -anthracenyl)-N'-methylguanidine;
N- 5-acenaphthyl)-N'- ((1 -anthracenyl)-N,N'-bis-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-re/?-butylphenyl)guanidine;
N- 5-acenaphthyl)-N'- ((4-tert-butylphenyl)-N-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-fert-butylphenyl)-N'-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-rert-butylphenyl)-N,N'-bis-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-cyclohexylphenyl)guanidine;
N- 5-acenaphthyl)-N'- ((4-cyclohexylphenyl)-N-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-cyclohexylphenyl)-N'-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-cyclohexylphenyl)-N,N'-bis-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-sec-butylphenyl)guanidine;
N- 5-acenaphthyl)-N'- ((4-sec-butylphenyl)-N-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-sec-butylphenyl)-N'-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-sec-butylphenyl)-N,N'-bis-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-methoxyphenyl)guanidine;
N- 5-acenaphthyl)-N'- ((4-methoxyphenyl)-N-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-methoxyphenyl)-N'-methylguanidine;
N- 5-acenaphthyl)-N'- ((4-methoxyphenyl)-N,N'-bis-methylguanidine;
N- 5-acenaphthyl)-N'- ((2,3-dichlorophenyl)guanidine; - 23
N-(5-acenaphthyl)-N'- 2,3-dichlorophenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 2,3-dichlorophenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 2,3-dichlorophenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'- 4-methoxy-2-naphthyl)guanidine; N-(5-acenaphthyl)-N'- 4-methoxy-2-naphthyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 4-methoxy-2-naphthyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 4-methoxy-2-naphthyl)-N,N'-bis- methylguanidine; N-(5-acenaphthyl)-N'- 3,4-dichlorophenyl)guanidine; N-(5-acenaphthyl)-N'- 3,4-dichlorophenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 3,4-dichlorophenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 3,4-dichlorophenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'- 4-chlorophenyl)guanidine; N-(5-acenaphthyl)-N'- 4-chlorophenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 4-chlorophenyl)-N'-methylguanidine;
N 5-acenaphthyl)-N'- 4-chlorophenyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl)-N'- 2-naphthyl)guanidine; N 5-acenaphthyl)-N'- 2-naphthyl)-N-methylguanidine; N 5-acenaphthyl)-N'- 2-naphthyl)-N'-methylguanidine; N 5-acenaphthyl)-N'- 2-naphthyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl)-N'- 6-quinolinyl)guanidine; N 5-acenaphthyl)-N'- 6-quinolinyl)-N-methylguanidine; N 5-acenaphthyl)-N'- 6-quinolinyl)-N'-methylguanidine; N 5-acenaphthyl)-N'- 6-quinolinyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl)-N'- 4-nitrophenyl)guanidine; N 5-acenaphthyl)-N'- 4-nitrophenyl)-N-methylguanidine; N 5-acenaphthyl)-N'- 4-nitrophenyl)-N'-methylguanidine; N 5-acenaphthyl)-N'- 4-nitrophenyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl-N'-(3-bi-phenyl)guanidine; N 5-acenaphthyl-N'-(3-bi-phenyl)-N-methylguanidine; - 24
N-(5-acenaphthyl N'-(3-bi-phenyl)-N'-methylguanidine; N-(5-acenaphthyl N'-(3-bi-phenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl -N'- 2,3-dimethylphenyl)guanidine; N-(5-acenaphthyl -N'- 2,3-dimethylphenyl)-N-methylguanidine; N-(5-acenaphthyl -N'- 2,3-dimethylphenyl)-N'-methylguanidine; N-(5-acenaphthyl -N'- 2,3-dimethylphenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl -N'- 2-bi-phenyl)guanidine; N-(5-acenaphthyl -N'- 2-bi-phenyl)-N-methylguanidine; N-(5-acenaphthyl ■N'- 2-bi-phenyl)-N'-methylguanidine; N-(5-acenaphthyl ■N'- 2-bi-phenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl -N'- 2,5-dibromophenyl)guanidine; N-(5-acenaphthyl -N'- 2,5-dibromophenyl)-N-methylguanidine; N-(5-acenaphthyl -N'- 2,5-dibromophenyl)-N'-methylguanidine; N-(5-acenaphthyl -N'- 2,5-dibromophenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl -N'- 3,4-dimethoxyphenyl)guanidine; N-(5-acenaphthyl -N'- 3,4-dimethoxyphenyl)-N-methylguanidine; N-(5-acenaphthyl -N'- 3,4-dimethoxyphenyl)-N'-methylguanidine; N-(5-acenaphthyl -N'- 3,4-dimethoxyphenyl)-N,N'-bis- methylguanidine; N-(5-acenaphthyl -N'- 4-methoxy-1 -naphthyi)-N-methylguanidine; N-(5-acenaphthyl -N'- 4-methoxy-1-naphthyl)-N'-methylguanidine; N-(5-acenaphthyl -N'- 4-methoxy-1 -naphthyl)-N,N'-dimethylguanidine; N-(5-acenaphthyl -N'- 4-chloro-1 -naphthyl)guanidine; N-(5-acenaphthyl -N'- 4-chloro-1 -naphthyl)-N-methylguanidine; N-(5-acenaphthyl -N'- 4-chloro-1-naphthyl)-N'-methylguanidine; N-(5-acenaphthyl -N'- 4-chloro-1 -naphthyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl -N'- 3,4,5-trichlorophenyl)guanidine; N-(5-acenaphthyl -N'- 3,4,5-trichlorophenyl)-N-methylguanidine; N-(5-acenaphthyl -N'- 3,4,5-trichlorophenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N' (3,4,5-trichlorophenyl)-N,N'-bis- methylguanidine; N-(5-acenaρhthyl)-N'- 4-bi-phenyl)guanidine; N-(5-acenaphthyl)-N'- 4-bi-phenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 4-bi-phenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 4-bi-phenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'- 2,3,4,5-tetrachlorophenyDguanidine; N-(5-acenaphthyl)-N'- 2,3,4,5-tetrachlorophenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 2,3,4,5-tetrachlorophenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 2,3,4,5-tetrachlorophenyl)-N,N'-bis- methylguanidine; N-(5-acenaphthyl)-N'- 3-/sopropylphenyl)guanidine; N-(5-acenaphthyl)-N'- 3-/sopropylphenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 3- sopropylphenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 3- sopropylphenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'- 3-rerf-butylphenyl)guanidine; N-(5-acenaphthyl)-N'- 3-tert-butylphenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 3-terf-butylphenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 3-ferr-butylphenyl)-N,N'-bis-methylguanidine; N-(5-acenaρhthyl)-N'- 2,3,5,6-tetrachlorophenyDguanidine; N-(5-acenaphthyl)-N'- 2,3,5,6-tetrachlorophenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 2,3,5,6-tetrachlorophenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 2,3,5,6-tetrachlorophenyl)-N,N'-bis- methylguanidine; N-(5-acenaphthyl)-N'- 3-iodophenyl)guanidine; N-(5-acenaphthyl)-N'- 3-iodophenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'- 3-iodophenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 3-iodophenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'- 3-nitrophenyl)guanidine; N-(5-acenaphthyl)-N'- 3-nitrophenyl)-N-methylguanidine; - 26 -
N-(5-acenaphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-nitrophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(5-indolinyl)guanidine;
N-(5-acenaphthyl)-N'-(5-indolinyl)-N-methylguanidine; N-(5-acenaphthyl)-N'-(5-indolinyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(5-indolinyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)guanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)guanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N'-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)guanidine; N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N- methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N'- methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N,N'-bis- methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)guanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N,N'-bis- methylguanidine; - 27 -
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N,N'-bis- methylguanidine; N-(5-acenaphthyl)-N'-(4- methylthiophenyljguanidine;
N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)guanidine; N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3 4-trichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N,N'-bis- methylguanidine;
N,N'-bis(3-acenaphthyl)-N-methylguanidine; N,N'-bis{3-acenaphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(1 -anthracenyl)guanidine;
N-(3-acenaphthyl)-N'-(1 -anthracenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(1 -anthracenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(1 -anthracenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl)-N'-(4-rert-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-te/ -butylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-rert-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-cyclohexylphenyl)guanidine; N-(3-acenaphthyl)-N'-(4-cyclohexylphenyl)-N-methylguanidine; - 28
N-(3-acenaphthyl N' 4-cyclohexylphenyl)-N'-methylguanidine; N-(3-acenaphthyl N' 4-cyclohexylphenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl N'- 4-sec-butylphenyl)guanidine; N-(3-acenaphthyl N'- 4-sec-butylphenyl)-N-methylguanidine; N-(3-acenaphthyl ■N'- 4-sec-butylphenyl)-N'-methylguanidine; N-(3-acenaphthyl N'- 4-sec-butylphenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl •N'- 4-methoxyphenyl)guanidine; N-(3-acenaphthyl •N'- 4-methoxyphenyl)-N-methylguanidine; N-(3-acenaphthyl N'- 4-methoxyphenyl)-N'-methylguanidine; N-(3-acenaphthyl ■N'- 4-methoxyphenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl •N'- 2,3-dichlorophenyl)guanidine; N-(3-acenaphthyl •N'- 2,3-dichlorophenyl)-N-methylguanidine; N-(3-acenaphthyl ■N'- 2,3-dichlorophenyl)-N'-methylguanidine; N-(3-acenaphthyl •N'- 2,3-dichlorophenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl -N'- 4-methoxy-2-naphthyl)guanidine; N-(3-acenaphthyl -N'- 4-methoxy-2-naphthyl)-N-methylguanidine; N-(3-acenaphthyl -N'- 4-methoxy-2-naphthyl)-N'-methylguanidine; N-(3-acenaphthyl -N'- 4-methoxy-2-naphthyl)-N,N'-bis- methylguanidine; N-(3-acenaphthyl -N'- 3,4-dichlorophenyl)guanidine; N-(3-acenaphthyl -N'- 3,4-dichlorophenyl)-N-methylguanidine; N-(3-acenaphthyl -N'- 3,4-dichlorophenyl)-N'-methylguanidine; N-(3-acenaphthyl -N'- 3,4-dichlorophenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl -N'- 4-chlorophenyl)guanidine; N-(3-acenaphthyl ■N'- 4-chlorophenyl)-N-methylguanidine; N-(3-acenaphthyl •N'- 4-chlorophenyl)-N'-methylguanidine; N-(3-acenaphthyl -N'- 4-chlorophenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl -N'- 2-naphthyl)guanidine; N-(3-acenaphthyl -N'- 2-naphthyl)-N-methylguanidine; N-(3-acenaphthyl -N'- 2-naphthyl)-N'-methylguanidine; - 29 -
N-(3-acenaphthyl)-N'-(2-naphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(6-quinolinyl)guanidine;
N-(3-acenaphthyl)-N'-(6-quinolinyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(6-quinolinyl)-N'-methylguanidine; N-(3-acenaphthyl)-N'-(6-quinolinyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-nitrophenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-nitrophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-nitrophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-nitrophenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl-N'-(3-bi-phenyl)guanidine;
N-(3-acenaphthyl-N'-(3-bi-phenyl)-N-methylguanidine;
N-(3-acenaphthyl-N'-(3-bi-phenyl)-N'-methylguanidine;
N-(3-acenaphthyl-N'-(3-bi-phenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dimethylphenyl)guanidine; N-(3-acenaphthyl)-N'-(2,3-dimethylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dimethylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dimethylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2-bi-phenyl)guanidine;
N-(3-acenaphthyl)-N'-(2-bi-phenyl)-N-methylguanidine; N-(3-acenaphthyl)-N'-(2-bi-phenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2-bi-phenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,5-dibromophenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,5-dibromophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,5-dibromophenyl)-N'-methylguanidine; N-(3-acenaphthyl)-N'-(2 5-dibromophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N,N'-bis- methylguanidine; N-(3-acenaphthyl) -N'-( 4-methoxy-1-naphthyl)-N-methylguanidine;
N-(3-acenaphthyl) -N'-( 4-methoxy-1 -naphthyl)-N'-methylguanidine;
N-(3-acenaphthyl) -N'-( 4-methoxy-1 -naphthyl)-N,N'-dimethylguanidine;
N-(3-acenaphthyl) -N'-( 4-chloro-1 -naphthyl)guanidine; N-(3-acenaphthyl) -N'-( 4-chloro-1 -naphthyl)-N-methylguanidine;
N-(3-acenaphthyl) -N'-( 4-chloro-1 -naphthyl)-N'-methylguanidine;
N-(3-acenaphthyl) -N'-( 4-chloro-1 -naphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl) -N'-( 3,4,5-trichlorophenyDguanidine;
N-(3-acenaphthyl) -N'-( 3,4,5-trichlorophenyl)-N-methylguanidine; N-(3-acenaphthyl) -N'-( 3,4,5-trichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl) -N'-( 3,4,5-trichlorophenyl)-N,N'-bis- methylguanidine;
N-(3-acenaphthyl) -N'-( 4-bi-phenyl)guanidine;
N-(3-acenaphthyl) -N'-( 4-bi-phenyl)-N-methylguanidine; N-(3-acenaphthyl) -N'-( 4-bi-phenyl)-N'-methylguanidine;
N-(3-acenaphthyl) -N'-( 4-bi-phenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl) -N'-( 2,3,4,5-tetrachlorophenyDguanidine;
N-(3-acenaphthyl) -N'-( 2,3,4,5-tetrachlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl) -N'-( 2,3,4,5-tetrachlorpphenyl)-N'-methylguanidine; N-(3-acenaphthyl) -N'-( 2,3,4,5-tetrachlorophenyl)-N,N'-bis- methylguanidine;
N-(3-acenaphthyl) -N'-( 3-/sopropylphenyl)guanidine;
N-(3-acenaphthyl) -N'-( 3- sopropylphenyl)-N-methylguanidine;
N-(3-acenaphthyl) -N'-{ 3- sopropylphenyI)-N'-methylguanidine; N-(3-acenaphthyl) -N'-( 3-/sopropylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl) -N'-( 3-fe/?-butylphenyl)guanidine;
N-(3-acenaphthyl) -N'-( 3-ferf-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl) -N'-( 3-terf-butylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl) -N'-( 3-ferf-butylphenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl) -N'-( 2,3,5,6-tetrachlorophenyDguanidine; - 31 -
N-(3-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)-N,N'-bis- methylguanidine; N-(3-acenaphthyl)-N'-(3-iodophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-iodophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-iodophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-iodophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)guanidine; N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)guanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)-N-methylguanidine; N-(3-acenaphthyl)-N'-(5-indolinyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)guanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N'-methylguanidine; N-(3-acenaphthy)-N'-(2-fluorenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)guanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N- methylguanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N'- methylguanidine; - 32
N-(3-acenaphthyl)-N'-(3"-(2-methoxy)dibenzofuranyl)-N,N'-bis- methylguanidine;
N-(3-acenaphthyl -N'-(9-hydroxy-2-fluorenyl)guanidine; N-(3-acenaphthyl -N'-(9-hydroxy-2-fluorenyl)-N-methylguanidine; N-(3-acenaphthyl -N'-(9-hydroxy-2-fluorenyl)-N'-methyiguanidine; N-(3-acenaphthyl -N'-(9-hydroxy-2-fluorenyl)-N,N'-bis- methylguanidine; N-(3-acenaphthyl -N'-(4-trifluoromethylphenyl)guanidine; N-(3-acenaphthyl -N'-(4-trifluoromethylphenyl)-N-methylguanidine; N-(3-acenaphthyl -N'-(4-trifluoromethylphenyl)-N'-methylguanidine; N-(3-acenaphthyl -N'-(4-trifluoromethylphenyl)-N,N'-bis- methylguanidine; N-(3-acenaphthyl)-N'-(4- methylthiophenyl guanidine; N-(3-acenaphthyl -N'-(4-methylthiophenyl)-N-methylguanidine; N-(3-acenaphthyl -N'-(4-methylthiophenyl)-N'-methylguanidine; N-(3-acenaphthyl -N'-(4-methylthiophenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl -N'-(3-sec-butylphenyl)guanidine; N-(3-acenaphthyl -N'-(3-sec-butylphenyl)-N-methylguanidine; N-(3-acenaphthyl -N'-(3-sec-butylphenyl)-N'-methylguanidine; N-(3-acenaphthyl -N'-(3-sec-butylphenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl -N'-(4-benzyloxyphenyl)guanidine; N-(5-acenaphthyl -N'-(3-benzyloxyphenyl)guanidine; N-(5-acenaphthyl -N'-(3-sec-butylphenyl)guanidine; N-(5-acenaphthyl -N'-(2-anthracenyl)guanidine; N-(5-acenaphthyl -N'-(3-phenethylphenyl)guanidine; N-(5-acenaphthyl -N'-(4-adamantylphenyl)guanidine; N-(5-acenaphthyl -N'-(3-benzyloxyphenyl)-N'-methylguanidine; N-(5-acenaphthyl -N'-(4-benzyloxyphenyl)-N'-methylguanidine; N-(5-acenaphthyl -N'-(3-biphenyl)-N'-methylguanidine; N-(5-acenaphthyl -N'-(3-(1 '-methyl-2'-phenylethyl)phenyl)guanidine; - 33 -
N-(5-acenaphthyl)-N'-(3,4-tetralinylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(7-benzyltetralinylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3,4-dibenzyl oxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-1 -(4- ethoxy)phenyl)propanyl)phenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-(N",N"-dibenzyl)aminophenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-(1 '-benzylbutyl)phenyl)guanidine;
N-(5-acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl)phenylguanidine;
N-(5-acenaphthyl)-N'-(2-(2-indolyl)phenyl)guanidine; N-(5-acenaphthyl-N'-(3-bromophenyl)guanidine;
N-(5-acenaphyl)-N'-(2,3,4-trichlorophenyl)-N,N'-dimethylguanidine;
N-(5-acenaphthyl)-N'-(2,3,4-trichloro-phenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-(2'-benzothiazole-6'-methyl)phenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-benzoyloxyphenyl)guanidine; N-(3-acenaphthyl)-N'-(3-benzoyloxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(2-anthracenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-phenethylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-adamantylphenyl)guanidine; N-(3-acenaphthyl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-benzyloxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-biphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-(1 '-methyl-2'-phenylethyl)phenyl)guanidine;
N-(3-acenaphthyl)-N'-(3,4-tetralinylphenyl)guanidine; N-(3-acenaphthyl)-N'-(7-benzyltetralinylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-1 -(4- ethoxy)phenyl)propanyl)phenyl)guanidine;
N-(3-aceπaphthyl)-N'-(3-(N",N"-dibenzyl)aminophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-(1 '-benzylbutyl)phenyl)guanidine; N-(3-acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl)phenylguanidine; - 34 -
N-(3-acenaphthyl)-N'-(2-(2-indolyl)phenyl)guanidine; N-(3-acenaphthyl-N'-(3-bromophenyl)guanidine; N-(3-acenaphthyl)-N'-(3,4-dibenzyl oxyphenyl)guanidine; N-(3-acenapthyl)-N'-(2, 3, 4-trichlorophenyl)-N,N'-dimethyl guanidine; N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine; N-(3-acenaphthyl)-N'-(4-(2'-benzothiazole-6'-methyl)phenyl)guanidine; and pharmaceutically acceptable salts of said compounds.
Additional preferred compounds include those named above with one or more ring substituents on the acenaphthyl group thereof, particularly those R2 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.
Chem. , 13:924 (1948); G.J. Durant, et al., J. Med. Chem. , 28: 1414
(1985); CA. Maryanoff, et al., J. Org. Chem. , 51 : 1 882 (1986); M.P.
Kavanaugh, et al., Proc. Natl. Acad. Sci. USA, 85:2844-2848 (1988); E. Weber, et al., Proc. Natl. Acad. Sci. USA, 83:8784-8788
(1986); H.W.J. Cressman, Org. Syn. Coll., 3:608-609 (1955);
International Applications WO 91 /12797 and PCT/US92/01050.
More particularly, the synthesis of the diaryl substituted guanidines of the invention is typically achieved by condensing a salt - 35 -
of an 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. 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
Figure imgf000037_0001
Mixture of 5 &3
Figure imgf000037_0002
A* — NHg-HX HsCHsor Hjα reflux
Figure imgf000037_0003
In 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 H2 and suitable pressure such as 40 psi and the resulting amines are separated such as by recrystallization. In 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. 36 -
SCHEME-2: PREPARATION OF N-ALKYL AND N,N'-DIALKYL N,W- DI-ARYL GUANIDINES
Figure imgf000038_0001
Tri and tetra-substituted guanidines of the invention may be prepared as outlined in Scheme-2 above. As shown in the Scheme, 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 AICI3 cataiyst. The products can be purified by conventional means such as silica gel chromatography.
While in the above Schemes reaction of an unsubstituted acenaphthyl cyanamide is depicted, an acenapthyl cyanamide having one or more ring substituents can be reacted with a salt of an aryl amine by the same procedures of Schemes-1 and 2 as described above to provide compounds of the invention having a substituted acenaphthyl moiety, including compounds of Formula IIA or IIB. - 37 -
Such substituted cyanamide reagents can be readily prepared. For example, a substituted acenaphthyl derivative can be nitrated (e.g., treatment with HNO3/H2SO4) 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
(1992). The reaction products can be separated by recrystallization or chromatography if more than one isomer is generated from the nitration. Such 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; 5-acenaphthalenecarboxanilide; and the like.
If the ring substitutent of the acenaphthyl derivative includes a potentially reactive functionality (e.g. an unsaturated carbon-carbon bond that could be reduced during hydrogenation of the nitro group), a suitable protecting group can be employed that is later removed as will be known to those skilled in the synthesis art. - 38 -
In addition to nitration of a substituted acephthyl derivative, compounds of the invention having a substituted acenaphthyl moiety, including compounds of Formulas IIA or IIB, can be prepared by a number of other routes. Specifically, for preparation of other 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. Obraztsy, Tovarnye Znaki, (3), 96-7 (1982); J. P. Li, et al., US 78- 890736 (1978); N. S. Vorozhtsov, Zh. Org. Khim. , 8(2): 353-7
(1972); J. Wolinski et al., Rocz. Chem. , 44(9): 1721 -31 (1970); A. P. Karishin, et al., Zh. Obshch. Khim. , 39(9): 2098-101 ( 1 969); and V.V. Mezheritskii, et al., Zh. Org. Khim. , 27(10), 2198-204 ( 1991 ). Compounds prepared by such methods can be converted to an amine, if necessary, and then reacted with CNBr and an aryl amine as described above to provide guanidine derivatives having a substituted acenaphthyl moiety.
As discussed above, 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. As mentioned above, 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. One of ordinary - 39 -
skilled in the art can select those compounds which are effective or particularly effective modulators of neurotransmitter release using the procedures disclosed herein or in PCT/US92/01050 with no more than routine experimentation. For example, 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.
In particular, 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. 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 -
Korsakoff's disease, olivopontocerebellar atrophy, HIV-induced dementia and blindness or multi-infarct dementia. As disclosed by Dreyer et al., Science, 248:364-367 (1990), gp120 neurotoxicity is associated with increased levels of Ca2+ which are apparently mediated by excitatory amino acids binding at the NMDA receptor site. Though again not wishing to be bound by theory, compounds of the invention should have utility in treating HIV-induced dementia and blindness by means of preventing the release of excessive glutamate.
As noted above 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. Pretreatment of animals with the NMDA antagonist MK-801 (Merck Index, monograph 3392, 1 1th ed., 1989) 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.
At least some compounds of the invention will have utility in treating or preventing conditions treatable by the blockage of voltage- activated sodium channels as demonstrated by the results disclosed in Example 66 which follows. Accordingly, 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 -
amount of a compound of the invention, particularly by such administration to a mammal in need of such treatment. Conditions that can be treated by blockage of sodium channels will include, e.g., epilepsy. Moreover, 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.
It has been reported that 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)).
See also Price, M.T., et al., Soc. Neurosci. Abstr. , 16:377, abstr. 1 61 .1 6 (1990). 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. It is thus believed that compounds of the invention, especially charged or otherwise hydrophilic compounds of the invention with limited blood brain barrier permeability, 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. For example, for treatment of a stroke victim, 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.
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.
For parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Ampoules are convenient unit dosages.
For enteral application, particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, 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.
It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the particular site of - 44 -
administration, the subject's weight, age and general health, etc. Optimal administration rates for a given protocol of administration can be readily ascertained by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines. In general, 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. Such 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.
As with prior guanidines such as those reported in U.S. Patent
No. 1 ,41 1 ,713, the guanidines of the present invention should have utility as rubber accelerators.
All documents mentioned herein are incorporated herein by reference in their entirety.
The present invention will be further illustrated with reference to the following examples which aid in the understanding of the present invention, but which are not to be construed as limitations thereof. - 45 -
GENERAL COMMENTS
In the following examples, all percentages reported herein, unless otherwise specified, are percent by weight. All temperatures are expressed in degrees Celsius.
Melting points were determined in open capillary tubes on a Thomas-Hoover apparatus and are uncorrected. Thin-layer chromatography was performed on Merck silica gel 60 F254 (0.2 mm) or Baker-flex 1 B2-F silica gel plates. Guanidines were visualized on TLC with 254-nM UV light or as a blue spot with bromcresol spray reagent (Sigma Chemical Co.). Preparative TLC was performed on Analtech GF precoated silica gel (1000 μm) glass-backed plates (20 x 20 cm). The IR, 1H and 13C NMR spectra of all compounds were consistent with their assigned structures. NMR spectra were recorded on a General Electric QE-300 or Varian Gemini 300 and the chemical shifts were reported in ppm (δ) relative to the residual signal of the deuterated solvent (CHCI3, δ 7.26; CHD2OD, δ 3.30). Infrared spectra were recorded in CHCI3 (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 (1H) 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 wateπacetonitrile 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
where noted, by published procedures. Chlorobenzene was freshly distilled from CaH2 or anhydrous quality solvent (Sure Seal) supplied by Aldrich wa used. Ether (Et2O) and tetrahydrofuran (THF) were refluxed over sodium/benzophenone ketyl and freshly distilled under N2 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.
Example 1 : Preparation of N-(5-acenaphthyl)-N'-(2,3,4- trichlorophenyl)guanidine«HCI (METHOD-A (Scheme-1 ))
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. Ether (60 mL) was added to the residue and the mixture was stirred overnight. The solid was removed (more hydrobromide of 5-aminoacenaphthene) and the filtrate concentrated to approximately 20 mL and then diluted with warm cyclohexane (15 mL). Upon standing at room temperature, off white crystals were deposited. They were collected, washed with cyclohexane-ether (1 :1 ) and dried in vacuo to give 1 .5 g of pure product, mp 1 63-65 °C - 47 -
Step 2. Preparation of N-(5-acenaphthyl)-N'-(2.3.4- trichlorophenyl)guanidine*HCI
A mixture of 5-acenaphthyl cyanamide (0.194 g, 1 mmol) and 2,3,4-trichloroaniline hydrochloride (0.221 g, 0.95 mmol; prepared from 2,3,4-trichloroaniline and 1 .0N HCI-ether) were heated at reflux in 5 mL of chlorobenzene. Shortly after reflux temperature was reached all the solids had dissolved to give a clear solution. After a total of 2 hour reflux, the mixture was cooled to 20°C and allowed to stand for 24 hours. The solid was collected by filtration and washed with excess of methylene chloride and dried in vacuo at 40°C to give product (0.293 g, 68%) as an off white solid, mp: 208- 10°C; 'H NMR (CD3OD): δ 7.70-7.58 (m, 3H, Ar-H), 7.48 (d, 2H, J = 7.5Hz, Ar-H), 3.47-3.41 (m, 4H, 2 x CH2); HRMS 389.0220 (389.0253 calcd. for C19H14N3CI3); Anal Calcd. for C19H1SN3CI4
(427.15): C, 53.42; H, 3.54; N, 9.84; Cl, 33.2; Found: C, 53.25: H, 3.57; N, 9.67; Cl, 33.75.
Example 2: Preparation of N,N'-bis(5-acenaphthyl)-N-methyl guanidine-HCI (METHOD B (Scheme-2))
Part 1 . Preparation of N-methyl-N-5-acenaphthyl cyanamide
A solution of 5-acenaphthyl cyanamide ( 1 .5 g, 7.73 mmol) in THF (22 mL) was slowly added to a stirred suspension of sodium hydride (0.6 g, 15.1 mmol) in THF (8 mL) at room temperature. After 3 hour reflux, the reaction mixture was cooled to 20°C, methyl iodide (2.64 g, 18.6 mmol) wa added and stirred the contents at 20°C After 16 hours, the reaction was quenched by careful addition of methanol (15 mL) followed by water (35 mL). Extracted by methylene chloride (3 x 30 mL), dried over MgSO4 and the solvent was evaporated. The residue was purified on flash chromatography - 48 -
to yield the product (0.8 g, 50%) as a tan solid. TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.72.
Part 2. Preparation of N.N'-bis(5-acenaphthyl)-N-methyl αuanidine*HCI
Aluminum chloride (0.28 g, 2.1 1 mmol) was added to a stirred solution of N-5-acenaphthyl-N-methyl cyanamide (0.4 g, 1 .92 mmol) in chlorobenzene (5.8 mL) at 145 °C After 10 minutes 5- acenaphthene amine hydrochloride (0.39 g, 1 .29 mmol, prepared from 5-acenaphthene and 1 .0M HCI-ether) was added and continued reflux. After 20 hours, the reaction mixture was evaporated and the product was purified by flash chromatography to afford the title compound (0.41 g, 55%) as orange tint white solid; mp: 236°C; TLC (CH2CI2:CH3OH; 9: 1 ); Rf = 0.19; H NMR (CDCI3 + CD3OD): δ 7.61 -7.04 (m, 10H, Ar-H), 3.84-3.81 (m, 2H, CH2), 3.43-3.27 (m, 9H, 3 x CH2 and CH3); HRMS: 377.1897 (377.1892 calcd. for C2βH23N3).
Example 3: Preparation of N,N'-bis(5-acenaphthyl)-N,N'-bis- methyl guanidine'HCI (METHOD C (Scheme-2))
Part 1 . Preparation of N-methyl-N-5-acenaphthyl cyanamide Prepared as per part 1 in Method B of Example 2.
Part 2. Preparation of N-methyl-N-5-acenaphthyl amine
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.
BH3-THF solution (50 mL) was added dropwise to a stirred suspension of above formamide (6.07 g, 30.4 mmol) in THF ( 100 mL) at ice-bath temperature. After stirring the contents at 25 °C for 18 hours, the reaction mixture was concentrated to a volume of ca. 35 mL and the ethyl acetate (10 mL) was added at 10°C The mixture was quenched with 3N HCI solution and then basified with NaOH solution. It was extracted with methylene chloride (2 x 75 mL), dried (Na2SO4) and evaporated to give a tan colored solid (5.45 g). It was recrystallized from methanol to afford the title compound (2.85 g) as tan colored crystals; mp 102-03°C
Part 3. Preparation of N.N'-bis(5-acenaphthyl)-N.N'-bis-methyl guanidine*HCI
Aluminum chloride (0.21 g, 1 .58 mmol) was added to a stirred solution of N-5-acenaphthyl-N-methyl cyanamide (0.3 g, 1 .44 mmol) in chlorobenzene (7 mL) at 145°C After 10 minutes 5- acenaphthene-N-methyl amine hydrochloride (0.29 g, 1 .3 mmol; prepared from 5-acenaphthene-N-methyl amine and 1 .0M HCI-ether) was added and continued reflux. After 4 hours, the reaction mixture was evaporated on rotavap and the product was purified by flash chromatography to afford the title compound (0.25 g, 45%) as yellow solid; mp: 272°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.1 7; 'H NMR (CD3OD): <J 7.18 (bs, 5H, Ar-H), 6.78-6.73 (m, 5H, Ar-H), 3.47 (s, 6H, 2 x CH3), 3.24-3.19 (m, 4H, 2 x CH2), 3.04 (bs, 4H, 2 x CH2); HRMS: 391 .2051 (391 .2048 calcd. for C27H25N3). - 50 -
Examples 4-63
By methods indicated above, including by the specified Methods A-C of Examples 1 -3 respectively and using appropriately substituted reagents, the following named compounds were prepared having the indicated physical characteristics.
Example 4: N-(5-acenaphthyl)-N'-(1 -anthracenyl)guanidine»mesylate
Preparation: As per Method A of Example 1 . White solid; mp: 243-45°C; 1H NMR (CD3OD): δ 8.65-7.25 (m, 14H, Ar-H), 3.33- 3.20 (m, 4H, 2 x CH2), 2.25 (s, 3H, -CH3); Anal. Calcd. for C28H25N3-CH3SO3H: C, 69.54; H, 5.21 ; N, 8.69; Found: C, 69.33; H, 5.23; N, 8.55.
Example 5: N-(5-acenaphthyl)-N'-(4-tertbutylphenyl)guanidine*HCI
Preparation: As per Method A of Example 1 . White solid; TLC (CH2CI2:CH3OH; 9: 1 ): R, = 0.5; H NMR (CD3OD): δ 7.65-7.20 (m, 9H, Ar-H), 3.30 (m, 4H 2 x CH2), 1 .22 (s, 9H, 3 x CH3); HRMS: 343.2043 (343.2048 calcd. for C23H25N3).
Example 6: N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)guanldine»HCI
Preparation: As per Method A of Example 1 , except that 4- cyclohexylphenyl cyanamide was reacted with 5-acenaphthyl-1 - amine hydrochloride. White solid; mp: 232-34°C; 1H NMR (DMSO): δ 7.8-8.2 (m, 13H, Ar-H), 3.4-3.3 (m, 5H, 2 x CH2 and CH), 1 .8- 1 .15 (m, 10H, 5 x CH2); Anal. Calcd. for C25H28CIN3 (405.95): C, 73.96; H, 6.95; N, 10.35; Cl, 8.73; Found: C, 73.91 ; H, 6.96; N, 10.12; Cl, 8.56. - 51 -
Example 7: N-(5-acenaphthyl)-N'-(4-secbutylphenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . White solid; TLC (CH2CI2:CH3OH; 9: 1 ): Rf = 0.7; 1H NMR (CD3OD): δ 7.60-7.15 (m, 9H, Ar-H), 3.30 (m, 4H, 2 x CH2), 2.52 (q, 1 H, -CH), 1 .50 (m, 2H, - CH2), 1 .1 1 (d, 3H, CH3), 0.71 (t, 3H, CH3); HRMS: 343.2051 (343.2049 calcd. for C23H25N3).
Example 8: N-(5-acenaphthyl)-N'-(4-methoxyphenyl)guanidine*HBr
Preparation: As per Method A of Example 1 . Fluffy cream solid; mp: 187-200°C; TLC (CHCI3:CH3OH; 10: 1 ); Rf = 0.31 ; 'H NMR (CDCI3): δ 7.45-7.10 (m, 7H, Ar-H), 6.80 (d, 2H, J = 8Hz, Ar-H), 3.68 (s, 3H, OCH3), 3.38-3.22 (m, 4H, 2 x CH2); HRMS: 31 7.1 509 (317.1 528 calcd. for C20H19N3O); Anal. Calcd. for C20H20N3BrO
(398.30): C, 60.44; H, 5.08; N, 10.58; Found: C, 60.28; H, 5.14; N, 10.41 .
Example 9: N-(5-acenaphthyl)-N'(2,3-dichlorophenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . White (yellow tint) solid; mp: 124-30°C; TLC (CHCI3:CH3OH; 10: 1 ): R( = 0.18; 'H NMR (CDCI3): δ 7.59 (d, 1 H, J = 8Hz, Ar-H), 7.47 (t, 1 H, J = 8Hz, Ar- H), 7.36-7.14 (m, 6H, Ar-H), 3.40-3.25 (m, 4H, 2 x CH2); HRMS: 355.0647 (355.0643 calcd. for C19H15C12N3).
Example 10: N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)guanidine
Preparation: As per Method A of Example 1 . Light yellow solid; mp: 191 -92°C; TLC (CH2CI2:CH3OH; 9: 1 ): Rf = 0.51 ; 1H NMR (CD3OD + CDCI3): J 8.1 7 (d, 1 H, J = 8Hz, Ar-H), 7.73 (d, 1 H, J = 8Hz, Ar-H), 7.66 (d, 1 H, J = 8Hz, Ar-H), 7.57-7.26 (m, 7H, Ar-H), - 52 -
7.09 (d, 1H, J = 8Hz, Ar-H), 3.96 (s, 3H, OCH3), 3.43-3.35 (m, 4H, 2 x CH2); HRMS: 367.1680 (367.1685 calcd. for C24H21ON3).
Example 11 : N-(5-acenaphthyl)-N'-(3,4-dichlorophenyl)guanidine»HCI
Preparation: As per Method A of Example 1. White solid; mp:
> 300°C; TLC (CHCI3:CH3OH; 10:1): Rf = 0.27; 1H NMR (CDCI3): δ
7.55 (d, 1H, J = 8Hz Ar-H), 7.48 (t, 1H, J = 8Hz, Ar-H), 7.37 (d, 2H,
J = 8Hz, Ar-H), 7.30 (t, 2H, J = 8Hz, Ar-H), 7.19 (d, 1H, J = 7Hz, Ar- H), 7.13 (bd, 1H, Ar-H), 3.66-3.30 (m, 4H, 2 x CH2); HRMS:
355.0651 (355.0643 calcd. for C19H15CI2N3).
Example 12: N-(5-acenaphthyl)-N'-(4-chlorophenyl)guanidine»HBr
Preparation: As per Method A of Example 1, except N-4- chlorophenyl cyanamide was reacted with 5-acenaphthyl-1 -amine hydrobromide. White solid; mp: 216-17°C; 1H NMR (CDCI3): δ 7.65- 7.23 (m, 9H, Ar-H), 3.42-3.35 (m, 4H, 2 x CH2): 13C NMR (CDCI3): 147.81, 146.47, 140.09, 133.35, 132.11, 131.98, 129.90, 129.40, 127.48, 126.83, 126.70, 126.66124.65, 124.51, 120.52, 118.95, 30.49, 29.94; HRMS: 321.1039 (321.1033 calcd. for C19H1βN3CI).
Example 13: N-(5-acenaphthyl)-N'-(2-naphthyl)guanidine»HCI
Preparation: As per Method A of Example 1. Light yellow solid; mp: 200°C; TLC (CHCI3:CH3OH; 10:1): Rf = 0.14; 1H NMR (CDCI3+ CD3OD): £7.78-7.14 (m, 12H, Ar-H), 3.33-3.25 (m, 4H, 2 x CH2); HRMS: 337.1500 (337.1579 calcd. for C23H19N3). - 53 -
Example 14: N-(5-acenaphthyI)-N'(6-quinolinyl)guanidine»HCI
Preparation: As per Method A of Example 1 . White solid; mp: 242-44°C; TLC (CHCI3:MeOH 10: 1 ): R, = 0.2; H NMR (DMSO): δ 9.1 -7.3 (m, 1 1 H, Ar-H), 3.5-3.2 (m, 4H, 2 x CH2).
Example 15: N-(5-acenaphthyl)-N'-(4-nitrophenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . Off white solid; mp: 85-86°C; 'H NMR (CD3OD): δ 7.57-7.05 (m, 9H, Ar-H), 3.49- 3.43 (m, 4H, 2 x CH2); MS(CI): m/e 333 (M + 1 for the free base) .
Example 16: N-(5-acenaphthyl-N'-(3-bi-phenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . White cream solid; mp: 1 28-36°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.56; 1H NMR (CD3OD): δ 7.68-7.35 (m, 14H, Ar-H), 3.45-3.31 (m, 4H, 2 x CH2); HRMS: 363.1726 (363.1735 calcd. for C25H21N3).
Example 17: N-(5-acenaphthyl)-N'-(2,3-dimethylphenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . Light yellow solid; p: 199-207°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.38; 'H NMR (CD3OD): δ 7.68-7.58 (m, 2H, Ar-H), 7.48 (d, 1 H, J = 8Hz, Ar-H), 7.41 -7.36 (m, 2H, Ar-H), 7.23-7.1 6 (m, 3H, Ar-H), 3.45-3.39 (m, 4H, 2 x CH2), 2.34 (s, 3H, CH3), 2.28 (s, 3H, CH3); HRMS: 31 5.1717 (315.1735 calcd. for C21H21N3).
Example 18: N-(5-acenaphthyl)-N'-(2-bi-phenyl)guanidine*HBr
Preparation: As per Method A of Example 1 . White solid; mp: 141 -43°C; 'H NMR (CD3OD): δ 7.56-7.05 (m, 14H, Ar-H), 3.43- 3.31 (m, 4H, 2 x CH2); MS (El): m/e 364 (M + 1 for the free base); HRMS: 363.1737 (363.1735 calcd. for C25H21N3).
Example 19: N-(5-acenaphthyl)-N'-(2,5-dibromophenyl)guanidine*HCI
Preparation: As per Method A of Example 1 . Yellow tint solid; mp: 194-96°C; TLC (CHCI3:CH3OH; 9: 1 ): R, = 0.33; 1H NMR (CD3OD): δ 7.74-7.34 (m, 8H, Ar-H), 3.50-3.42 (m, 4H, 2 x CH2); HRMS: 442.9678 (442.9633 calcd. for C19H15Br2N3) .
Example 20: N-(5-acenaphthyl)-N'-(3,4-dimethoxyphenyl) guanidine'HCI
Preparation: As per Method A of Example 1 . Brown solid; mp: 1 52-55 °C; TLC (CHCI3:CH3OH; 10: 1 ): R, = 0.27; 1 H NMR (CD3OD): £ 7.70-7.58 (m, 2H, Ar-H), 7.47 (d, 1 H, J = Hz, Ar,H), 7.41 -7.35 (m, 2H, Ar-H), 7.04-6.92 (m, 3H, Ar-H), 3.85 (s, 3H, CH3), 3.84 (s, 3H, CH3), 3.47-3.44 (m, 2H, 2 x CH2); HRMS: 347.1637 (347.1 634 calcd. for C21H21O2N3).
Example 21 : N-(5-acenaphthyl)-N'-(4-methoxy-1 -naphthyl)-N- methylguanidine*HCI
Preparation: As per Method B of Example 2. Light yellow solid; mp: 158-59°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.25; 1H NMR (CD3OD): δ 8.30-6.90 (m, 1 1 H, Ar-H), 4.03 (s, 3H, OCH3), 3.64 (bs, 3H, N-CH3), 3.50-3.41 (m, 4H, 2 x CH2); HRMS: 381 .1850 (381 .1841 calcd. for C25H23ON3).
Example 22: N-(5-acenap thyl)-N'-(4-methoxy-1 -naphthyl)-N'-methyl guanidine'HCI
Preparation: As per Method B of Example 2, except that N- methyl-N-(4-methoxy-1 -naphthyl) cyanamide was reacted with 5- - 55 -
acenaphthyl-1 -amine hydrochloride. White solid; mp: 195-97°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.10; 1H NMR (CD3OD): (5 8.37 (d, 1 H, J = 8.4Hz, Ar-H), 7.95-7.28 (m, 9H, Ar-H), 7.05 (d, 1 H, J = 8.3Hz, Ar-H), 4.07 (s, 3H, OCH3), 3.60 (bs, 3H, N-CH3), 3.47-3.31 (m, 4H, 2 x CH2); HRMS: 381 .1840 (381 .1841 calcd. for C25H23ON3).
Example 23: N-{5-acenaphthyl)-N'-(4-methoxy-1 -naphthyl)- N,N'-dimethyl guanidine*HCI
Preparation: As per Method C of Example 3. White solid; mp:
210-12°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.34; 1H NMR (CD3OD): δ 7.95 (d, 1 H, Ar-H), 7.38-6.65 (m, 10H, Ar-H), 3.82 (s, 3H, OCH3), 3.48 (s, 3H, N-CH3), 3.42 (s, 3H, N-CH3), 3.25-3.18 (m, 2H, CH2), 3.04-2.65 (m, 2H, CH2); HRMS: 395.2005 (395.1998 calcd. for C26H25ON3).
Example 24: N-(5-acenaphthyI)-N'-(4-chloro-1 -naphthyl)guanidine»HCI
Preparation: As per Method A of Example 1 . White solid; mp: 258-60°C; 1H NMR (CD3OD); δ 8.38-8.35 (m, 1 H, Ar-H), 8.15-8.1 1
(m, 1 H, Ar-H), 7.81 -7.34 (m, 9H, Ar-H), 3.44-3.41 (m, 4H, 2 x CH2);
MS (El): m/e 372 (M + 1 for free base); Anal. Calcd. for C23H19CI2N3
(408.31 ): C, 57.65; H, 4.69; N, 10.29; Found: C, 67.58; H, 4.60;
N, 10.28; HPLC (CH3CN:H2O 50:50 with 0.1 % TFA): 99.9% pure.
Example 25: N-(5-acenaphthyl)-N'-(3,4,5-trichlorophenyl) guanidine*HCI
Preparation: As per Method A of Example 1 . White solid; mp: 234-36°C; TLC: Rf = 0.28 (CH2CI2/CH3OH: 9: 1 ); H NMR (CD3OD): δ 7.68-7.35 (m, 7H, Ar-H), 3.53-3,40 (m, 4H, 2 X CH2); HRMS: 381 .0251 (389.0253 calcd. for C19H14CI3N3); HPLC (CH3CN:H2O 50:50 with 0.1 % TFA): 95.5% pure. - 56 -
Example 26: N-(5-acenaphthyl)-N'-(4-bi-phenyl)guanidine-»CH3SO3H
Preparation: As per Method A of Example 1 . White solid; mp: 196-98°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.29, 1H NMR (CD3OD) δ 7.75-7.36 (m, 14H, Ar-H), 3.45 (bs, 4H, 2 X CH2), 2.69 (s, 3H, CH3); HRMS: 363.1737 (363.1735 calcd. for C25H21N3).
Example 27: N-(5-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl) guanidine»HCI
Preparation: As per Method A of Example 1 . White solid; mp:
223-25 °C; TLC (CH2CI2/CH2OH; 9: 1 ): R{ = 0.51 ; ,H NMR (CD3OD): δ 7.74-7.33 (m, 6H, Ar-H), 3.47-3.40 (m, 4H, 2 X CH2); Anal Calcd. for C19HI3CI4N3 (461 .59): C, 49.44; H, 3.06; N, 9.1 ; Found: C, 50.89; H, 3.1 5; N, 8.84; HRMS found: 422.9875 (422.9864 Calcd. for C19H13CI4N3); HPLC (CH3CN:H2O 45:55 with 0.1 % TFA): 95.5% pure.
Example 28: N-(5-acenaphthyl)-N'-(3-isopropylphenγl)guanidine*HCI
Preparation: As per Method A of Example 1 . White solid; mp:
149-51 °C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.28; ,H NMR (CD3OD): δ
7.66-7.19 (m, 9H, Ar-H), 3.44 (bs, 4H, 2 X CH2), 3.00-2.89 (m, 1 H,
-CH-), 1 .26 (d, 6H, J = 7Hz, 2 X CH3); HRMS: 329.1873 (329.1892 calcd. for C23H25N3).
Example 29: N-(5-acenaphthyl)-N'-(3-tert-butylphenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . White solid; mp: 176-78°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.26; 1H NMR (CD3OD): δ 7.68-7.28 (m, 9H, Ar-H), 3.45-3.44 (m, 4H, 2 X CH2), 1 .33 (s, 3H, CH3); HRMS: 343.2055 (343.2048 calcd. for C22H23N3). - 57 -
Example 30: N-(5-acenaphthyl)-N'-(2,3,5,6- tetrachlorophenyl)guanidine*CH3SO3H
Preparation: As per Method A of Example 1 . White solid; mp: 248-50°C; ,H NMR (CD3OD): δ 8.12-7.33 (m, 6H, Ar-H), 3.44-3.40 (m, 4H, 2 X CH2), 2.69 (s, 3H, CH3); MS (El): m/e 426 (M + 1 for the free base).
Example 31 : N-(5-acenaphthyl)-N'-(3-iodophenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . White solid; mp: 203-04°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.19; 'H NMR (CD3OD) : δ 7.76-7.58 (m, 4H, Ar-H), 7.47 (d, 1 H, J = 7.33Hz, Ar-H), 7.42-7.34 (m, 3H, Ar-H), 7.22 (t, 1 H, J = 8Hz, Ar-H), 3.45-3.44 (m, 4H, 2 X CH2); HRMS: 413.0395 (413.0389 calcd. for C19H16IN3).
Example 32: N-(5-acenaphthyl)-N'-(3-nitrophenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . Yellow solid; mp: 244-48°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.1 6; 'H NMR (CD3OD): δ 8.25-8.16 (m, 2H, Ar-H), 7.80-7.58 (m, 4H, Ar-H), 7.51 (d, 1 H, J = 7.24Hz, Ar-H), 7.41 (d, 1 H, J = 6.9Hz, Ar-H), 7.37 (d, 1 H, J = 7.4Hz, Ar-H); HRMS: 332.1276 (332.1273 calcd. for Cl9H1βN4O2).
Example 33: N-(5-acenaphthyl)-N'-(5-indolinyl)guanidine*HCI
Preparation: As per Method A of Example 1 . Yellow-white solid; mp: 147-48°C; TLC (CHCI3:CH3OH; 10: 1 ): Rf = 0.27; 1H NMR (CD3OD): δ 7.65-7.57 (m, 2H, Ar-H), 7.46 (d, 1 H, J = 7.3Hz, Ar-H), 7.41 -7.29 (m, 3H, Ar-H), 7.22 (bs, 1 H, Ar-H), 7.1 2 (dd, 1 H, J = 7.9 and 2.1 Hz, Ar-H), 3.47-3.43 (m, 4H, 2 X CH2), 2.92 (dd, 4H, - 58 -
J = 14.8 and 7.4Hz, 2 X Ar-CH2), 2.10 (m, 2H, CH2); HRMS: 327.1742 (327.1735 calcd. for C22H21N3).
Example 34: N-{5-acenaphthyl)-N'-(3-acenaphthyl) guanidine*CH3SO3H
Preparation: As per Method A of Example 1 . White solid; mp: 245°C, H NMR (300 MHz, CD3OD): δ 7.69-7.73 (m, 2H, Ar-H), 7.60-7.65 (m, 2H, Ar-H); 7.49-7.53 (m; 2H, Ar-H); 7.35-7.48 (m, 4H, Ar-H); 3.41-3.49 (m, 4H, 2 X CH2); 2.68 (s, 3H, CH3); MS (El): m/e 363 (M + for free base); Elemental analysis for C25H21N3*CH3SO3H-»2H2O: Calcd: C, 61 .62; H, 5.76; N, 8.28; S, 6.32; Found: C, 61 .77; H, 5.43; N, 8.22; S, 5.47; HPLC (AcCN: H2O 1 : 1 ): 99.3% pure.
Example 35: N-{5-acenaphthy)-N'-(2-fluorenyl)guanidine»HCI
Preparation: As per Method A of Example 1 . Buff white solid: mp: 239-240°C; 1H NMR (300 MHz, CD3OD): δ 7.90-7.92 (d, J = 8Hz, 1 H, Ar-H), 7.82-7.84 (d, J = 7Hz, 1 H, Ar-H) 7.69-7.72 (d, 1 H, J = 8Hz, Ar-H); 7.62-7.64 (m, 3H, Ar-H); 7.48-7.51 (d, J = 7.5Hz, 1 H, Ar-H); 7.29-7.41 (m, 5H, Ar-H); 3.95 (s, 2H, CH2); 3.40-3.47 (m, 4H, 2-CH2); MS (El): m/e 375 (M + for free base): Elemental analysis for C26H21N3-»HCI*0»25H2O: Calcd: C, 74.99; H, 5.44; N, 10.08; Found: C, 75.25; H, 5.44; N, 10.14.
Example 36: N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine*HCI
Preparation: As per Method A of Example 1 . Brownish solid; mp: 90°C; 1H NMR (300 MHz, CD3OD): δ 7.57-7.67 (m, 2H, Ar-H), 7.45-7.47 (d, J = 7.5Hz, 1 H, Ar-H); 7.34-7.40 (m, 2Hm Ar-H); 7.27- 7.30 (m, 2H, Ar-H); 6.99-7.02 (m, 2H, Ar-H); 3.97-4.02 (t, 2H, O- 59
CH2); 3.41-3.47 (m, 4H, 2-CH2); 1.71-1.78 (dt, 2H, CH2): 1 .46-1.54
(m, 2H, CH2); 0.95-1.00 (t, 3H, CH3); MS (El): m/e 359 (M + for free base); Elemental analysis for C23H25N3O»HCI»0-»75H2O: Calcd: C,
67,47; H, 6.77; N, 10.26; Found: C, 67.66; H, 6.67; N, 10.26.
Example 37: N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl) guanidine*HCI
Preparation: As per Method A of Example 1. White solid; mp: 230°C; 1H NMR (300 MHz, CD3OD): δ 8.06-8.09 (dd, J1 = 7.5Hz, J2 = 1.5Hz, 1 H, Ar-H), 7.80 (s, 1 H, Ar-H), 7.73-7.76 (d, J = 7.5Hz, 1 H, Ar-H), 7.60-7.65 (m, 3H, Ar-H), 7.46-7.56 (m, 2H, Ar-H), 7.34- 7.40 (m, 3H, Ar-H), 4.10 (s, 3H, O-CH3), 3.40-3.43 (m, 4H, 2-CH2); MS (El): m/e 407 (M + for free base); Elemental analysis for C26H21N3O2-»HCI-»0*25H2O: Calcd: C, 69,64; H, 5.06; N, 9.36; Found: C, 69.68; H, 4.98; N, 9.40.
Example 38: N-(5-acenaphthyl)-N'-(9-hydroxy-2- fluorenyl)guanidine»HCI
Preparation: As per Method A of Example 1. White solid; mp: 265°C; 1H NMR (300 MHz, CD3OD): δ 7.80-7.83 (d, J = 8Hz, 1 H, Ar-H), 7.69-7.74 (t, 2H, Ar-H), 7.60-7.64 (m, 3H, Ar-H), 7.49-7.52 (d, J = 7.5Hz, 1 H, Ar-H), 7.34-7.42 (m, 5H, Ar-H), 5.58 (s, 1 H, -OH), 3.45 (brs, 4H, 2-CH2); MS (El): m/e 391 (M + for free base);
Elemental analysis for C26H21N3O»HCI*0-»25H2O: Calcd: C, 72.22; H, 5.24; N, 9.7; Found: C, 72.35; H, 5.35; N, 9.58.
Example 39: N-(5-acenaphthyl)-N'-{4-trifluoromethylphenyl) guanidine'HCI
Preparation: As per Method A of Example 1. White solid; mp: 234-236°C; TLC (CH2CI2:CH3OH 9:1 ): Rf = 0.4; 1 H NMR (CDCI3): - 60-
7.70-7.25 (m, 9H, Ar-H), 3.46-3.38 (m, 4H, 2 X -CH2); MS(CI): m/e 356 (M + 1); Anal Calcd. for C2OH1βN3F3»HCI (391.82): C, 61.31; H, 4.37; N, 10.72; Found: C, 62.14; H, 4.34; N, 10.80.
Example 40: N-(5-acenaphthyl)-N'-(4-methylthiophenyl) guanidine*HCI
Preparation: As per Method A of Example 1. White solid; mp: 168-170°C; TLC (CH2CI2:CH3OH 9:1): Rf = 0.38; 1H NMR (CD3OD): 7.76-7.38 (m, 9H, Ar-H), 3.53-3.37 (m, 4H, 2 X -CH2), 2.57 (s, 3H, -SCH3); MS(CI): m/e 334 (M + 1); Anal. Calcd. for C20H19N3S»HCI (369.91): C, 64.94; H, 5.45; N, 11.36; Found: C, 64.38; H, 5.73; N, 11.05.
Example 41: N-(5-Acenaphthyl)-N'-(4-benzyloxyphenyl) guanidine»HCI
Light green foam; mp: 117-127°C; TLC (CH2CI2:CH3OH; 15:1): Rf = 0.50; 1H NMR (CD3OD): 7.646-7.094 (m, Ar-H, 14H), 5.127 (s, CH22H), 3.454-3.449 (m, CH2CH2, 4H); Anal. Calcd. for C26H23N3O-»HCI (429.95): C, 72.63; H, 5.63; N, 9.77; Found: C, 72.20; H, 5.70; N, 9.65.
Example 42: N-(5-Acenaphthyl)-N'-(3-benzyloxyphenyl)guanidine»HCI
Light green foam; mp: 94-98°C; TLC (CH2CI2:CH3OH; 15:1): R( = 0.50; 'H NMR (CD3OD): 7.639-6.981 (m, Ar-H, 14H), 5.117 (s, CH2, 2H), 3.451-3.344 (m, CH2CH2, 4H); Anal. Calcd. for C2βH23N3O-»HCI«0.5H2O (438.95): C, 71.07; H, 5.70; N, 9.57; Found: C, 71.44; H, 5.60; N, 9.83. - 61 -
Example 43: N-(5-Acenaphthyl)-N'-(3-benzyloxyphenyl) guanidine*Mesylate
Light yellow foam; mp: 90-98°C; TLC (AcOEt:CH3OH; 10:1): Rf = 0.30; 1H NMR (CDCI3): 7.647-7.268 (m, Ar-H, 11H), 6.956- 6.923 (m, Ar-H, 3H), 5.086 (s, CH2, 2H), 3.458-3.410 (m, CH2CH2, 4H), 2.857 (s, CH3, 3H); Anal. Calcd. for C27H27N3O4S (489.59): C, 66.24; H, 5.56; N, 8.58; Found: C, 66.99; H, 5.35; N, 8.74.
Example 44: N-(5-Acenaphthyl)-N'-(3-sec-butylphenyl) guanidine»Mesylate
White solid; mp: 136-138°C; TLC (CH2CI2: MeOH; 15:1): Rf = 0.31; 1H NMR (CD3OD): 7.668-7.164 (m, 9H, Ar-H), 3.483- 3.411 (m, CH2CH2, 4H), 2.655-2.627 (m, CH, 1H), 1.656-1.589 (m, CH2, 2H), 1.257-1.234 (d, J = 6.87Hz, CH3, 3H), 0.860-0.813 (m, CH3, 3H); Anal. Calcd. for C23H2βN3CI (379.93): C, 72.71; H, 6.90; N, 11.06; Found: C, 72.73; H, 6.75; N, 11.12.
Example 45: N-(5-Acenaphthyl)-N'-(2-anthracenyl)guanidine»HCI
Green solid; mp: 260-262°C; TLC (CH2CI2: MeOH; 15:1): Rf = 0.31; 1H NMR (CD3OD): 8.527-8.502 (d, Ar-H, J = 7.63Hz, 2H), 8.183-8.153 (d, Ar-H, J = 9.28Hz, 1H), 8.044 (s, br, Ar-H, 3H), 7.771-7.617 (m, Ar-H, 2H), 7.542-7.368 (m, 6H, Ar-H), 3.449- 3.418 (m, CH2CH2, 4H); Anal. Calcd. for C27H22N3CI (423.50): C, 76.50; H, 5.23; N, 9.91; Found: C, 76.33; H, 5.46; N, 9.70.
Example 46: N-(5-Acenaphthyl)-N'-(3-phenethylphenyl)guanidine*HCI
White solid; mp: 116-118°C; TLC (CH2CI2:MeOH; 15:1):
Rf = 0.31; 1H NMR (CD3OD): 7.645-7.156 (m, Ar-H, 14H), 4.233-
4.161 (q, CH, J = 7.14Hz, 1H), 3.478-3.414 (m, CH2CH2, 4H), - 62 -
1 .650-1 .626 (d, J = 7.20Hz, CH3, 3H); Anal. Calcd. for C27H26N3CI (427.98): C, 75.77; H, 6.12; N, 9.82; Found: C, 75.63; H, 5.98; N, 9.69.
Example 47: N-(5-Acenaphthyl)-N'-(4-adamantylphenyl)guanidine»HCI
White solid; mp: 240°C; TLC (CH2CI2:MeOH; 1 5: 1 ): Rf = 0.31 ; 'H NMR (CD3OD): 7.639-7.289 (m, Ar-H, 9H), 3.443-3.403 (m, CH2CH2, 4H), 2.086-1 .756 (m, CH's, 13H); Anal. Calcd. for C29H32N3CI (458.08): C, 76.04; H, 7.04; N, 9.1 7; Found: C, 75.97; H, 6.88; N, 9.06.
Example 48: N-{5-Acenaphthyl)-N'-(3-benzyloxyphenyl)-N'- methylguanidine»HCI
White solid; mp: 102-105 °C; TLC (CH2CI2: MeOH; 1 5: 1 ); Rf = 0.30; 1H NMR (CD3OD): 7.605-7.134 (m, 14H, Ar-H), 5.149 (s, CH2, 2H), 3.636 (s, CH3, 3H), 3.532-3.444 (m, CH2CH2, 4H); Anal. Calcd. for C27H2βN3CIO (443.98): C, 73.04; H, 5.98; N, 9.46; Found: C, 72.98; H, 5.95; N, 9.42.
Example 49: N-(5-Acenaphthyl)-N'-(4-benzyloxyphenyl)-N'- methylguanidine*HCI
White solid; mp: 108-1 10°C; TLC (CH2CI2:MeOH; 1 5: 1 );
Rf = 0.30; 'H NMR (CD3OD): 7.605-7.134 (m, 14H, Ar-H), 5.149 (s,
CH2, 2H), 3.536 (s, CH3, 3H), 3.532-3.444 (m, CH2CH2, 4H); Anal.
Calcd. for C27H26N3CIO (443.98): C, 73.04; H, 5.98; N, 9.46; Found:
C, 72.93; H, 6.00; N, 9.919. - 63 -
Example 50: N-(5-Acenaphthyl)-N'-(3-biphenyl)-N'- methylguanidine»HCI
White solid; mp: 217°C; TLC (CH2CI2:MeOH; 10:1): R, = 0.30; 1H NMR (CDCI3): 7.513-7.022 (m, 14H, Ar-H), 3.668 (s, CH3, 3H), 3.322-3.203 (m, CH2CH2, 4H); Anal. Calcd. for C26H24N3CI«2H2O (449.98): C, 69.40; H, 6.27; N, 9.34; Found: C, 69.25; H, 6.27; N, 9.48.
Example 51: N-(5-Acenaphthyl)-N'-(3-(1'-methyl-2'- phenyl)ethyl)guan.dine*HCI
White solid; mp: 106-108°C; TLC (CH2CI2:MeOH; 15:1) R( = 0.36; H NMR (CD3OD): 7.698-7.070 (m, 14H, Ar-H), 3.467- 3.312 (m, CH2CH2, 4H), 3.105-3.033 (m, CH, 1H), 2.928-2.810 (m, CH2, 2H), 1.267-1.244 (d, J = 6.87Hz, CH3, 3H); Anal. Calcd. for C28H28N3CI (442.00): C, 76.09; H, 6.39; N, 9.51; Found: C, 76.11; H, 6.55; N, 9.38.
Example 52: N-(5-Acenaphthyl)-N'-(3,4-tetralinylphenyl) guanidine»HCI
White solid; mp: 158-160°C; TLC (CH2CI2:MeOH; 15:1): R, = 0.36;1H NMR (CDCI3): 7.631-6.985 (m, 8H, Ar-H), 3.484-3.373 (m, CH2's, 4H), 2.747 (m, CH2, 2H), 1.793-1.784 (m, CH2,2H); Anal. Calcd. for C23H24CI (377.92): C, 73.10; H, 6.40; N, 11.12; Found: C, 72.88; H, 6.25; N, 11.03.
Example 53: N-(5-Acenaphthyl)-N'-(7-benzyltetralinyl)guanidine»HCI
White solid; mp: 161-162°C; TLC (AcOEt:MeOH; 10:1) Rf = 0.44; 1H NMR; 7.647-7.118 (m, Ar-H, 13H); Anal. Calcd. for C30H30N3CI-1/2H2O (477.04): C, 75.47; H, 6.50; N, 8.81; Found: C, 75.23; H, 6.28; N, 8.82. - 64 -
Example 54: N-(5-Acenaphthyl)-N'-(3,4-dibenzyloxyphenyl) guanidine»Mesylate
White solid; mp: 185-187°C; TLC (AcOEt:MeOH; 10: 1 ) Rf = 0.44; 'H NMR; 7.647-7.1 18 (m, Ar-H, 1 3H); Anal. Calcd . for C30H30N3O5S-»H2O (61 3.73): C, 66.54; H, 5.75; N, 6.85; Found: C, 66.86; H, 5.36; N, 6.92.
Example 55: N-(5-Acenaphthyl)-N'-(3-1-(4-ethoxy)phenyl)propanyl) phenyl)guanidine«Mesylate
White solid; mp: 93-95 °C; TLC (AcOet:MeOH; 10: 1 ) : R, = 0.0.49; 1H NMR; 7.636-7.575 (m, Ar-H, 2H), 7.41 6-7.1 28 (m, Ar-H, 1 1 H), 6.922 (s, Ar-H, 1 H), 6.871 -6.842 (d, Ar-H, J = 8.72Hz, 2H), 6.639-6.610 (d, Ar-H, J = 8.66Hz, 2H), 3.782-3.748 (q, OCH2, j = 7.40Hz, 2H), 3.498-3.417 (m, CH2CH2, 4H), 3.006-2.980 (m, CH, 1 H), 2.848 (s, CH3, 3H), 2.835-2.706 (m, CH2, 2H), 1 .31 7- 1 .193 (m, CH3, CH3, 6H); Anal. Calcd. for C31H35N3O4S (545.70): C, 68.23; H, 6.46; N, 7.70; Found: C, 68.30; H, 6.44; N, 7.85.
Example 56: N-(5-Acenaphthyl)-N'-(3-(N",N"-dibenzyl)aminophenyl) guanidine*Mesylate
White solid; mp: 150-152°C; TLC (AcOEt:MeOH; 10:1 ) Rf = 0.44; 1 H NMR; 7.568-7.174 (m, Ar-H, 1 7H), 6.745-6.530 (m, Ar-H, 2H), 4.697 (s, CH2, 2H), 3.497-3.413 (m, CH2CH2, 4H), 2.825 (s, CH3, 3H); HRMS: 482.2446 (482.628 calcd. for C33H30N4).
Example 57: N-(5-Acenaphthyl)-N'-(3-(1 '-benzylbutyl)phenyl) guanidine»Mesylate
White solid; mp: 90-92°C; TLC (AcOEt:MeOH; 10: 1 ); Rf = 0.48; NMR (CDCI3): 7.655-7.558 (m, Ar-H, 2H), 7.41 1 -7.269 (m, Ar-H, 5H), 7.1 69-6.800 (m, Ar-H, 7H), 3.492-3.414 (m, CH2CH2, 4H), 3.022-2.662 (m, CH2, CH, 3H), 2.842 (s, CH3, 3H),
1 .733-1 .695 (m, CH2, 2H), 1 .252-1 .176 (m, CH2, 2H), 0.895-0.847
(t, CH3, J = 7.28Hz); HRMS: 433.251 6 (433.5962 calcd. for 30H31N3).
Example 58: N-(5-Acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl) phenylguanidine*Mesylate
White solid; mp: 1 1 3-1 1 5 °C; TLC (AcOEt:MeOH; 10: 1 ): Rf = 0.39; 1H NMR (CDCI3): 7.681 -7.267 (m, Ar-H, 1 1 H), 6.904- 6.875 (d, Ar-H, J = 8.92Hz, 2H), 5.067 (s, CH2, 2H), 3.498-3.434 (m, CH2CH2, 4H), 2.856 (s, CH3, 3H), 1 .278 (s, tert-butyl, 9H); HRMS: 449.2452 (449.5956 calcd. for C30H31ON3).
Example 59: N-(5-Acenaphthyl)-N'-2(2-indolyl)phenylguanidine HCI
mp: 174-176°C; TLC: Rf = 0.32 (SiO2, CHCI3/MeOH = 10: 1 ); 1H NMR (CD3OD): δ ppm 6.86-7.83 (m, ARH, 14H), 3.30-3.40 (m, CH2, 4H); MS(EI): m/e 402.2 (M + : C27H22N4); Anal. (C,H,N; C27H22N4-»HCI): Calcd. (%): C, 70.33; H, 5.58; N, 12.16; Found (%): C, 70.01 ; H, 5.65; N, 1 1.56.
Example 60: N-(5-Acenaphthyl)-N'-(phenyl-3-bromo)guanidine HCI
mp: 204-205°C; TLC: Rf = 0.20 (SiO2, CHCI3/MeOH = 10: 1 );
1H NMR (CD3OD): δ ppm: 7.35-7.68 (m, ArH), 3.4-3.5 (m, CH2, 4H);
MS(EI): m/e 365.0 (M + : C19H16N3Br); Anal. (C,H,N;
C19H1βN3BR*HCI): Calcd. (%): C, 56.67; H, 4.25; N, 10.43; Found
(%): C, 56.49; H, 4.43; N, 10.18. Example 61 : N-(5-Acenaphyl)-N'-(2,3,4-trichlorophenyl)-N,N'dimethyl guanidine HCI
TLC: R, = 0.14 (SO2, CHCI3/MeOH = 10: 1 ); nH NMR (CD3OD) : δ ppm: 6.72-7.44 (m, ArH, 7H), 3.5-3.6 (s, CH3, 6H), 3.4-3.5 (m, CH2, 4H); MS(EI): m/e 418.0 (M+ : C21H18N3CI3); Anal. (C,H,N; C21H18N3CI3-»HCI): Calcd. (%): C, 55.41 ; H, 4.21 ; N, 9.23; Found (%): C, 55.26; H, 4.1 1 ; N, 9.03.
Example 62: N-(5-Acenaphyl)-N'-(2,3,4-trichlorophenyl)-N'- methylguanidine HCI
mp: 229-231 °C; TLC: R, = 0.19 (SiO2CHCI3/MeOH = 10: 1 ); H NMR (CD3OD): δ ppm: 7.54-7.70 (m, ArH, 4H), 7.33-7.40 (m, ArH, 3H); MS (El): m/e 403.1 (M + : C20H16N3CI3); Anal. (C,H,N;
C20H16N3CI3HCI): Calcd. (%): C, 54.45; H, 3.88; N, 9.52; Found (%): C, 54.23; H, 4.01 ; N, 9.36.
Example 63: N-(5-Acenaphyl)-N'-(4-(2'-benzothiazole-6'- methyl)phenyl)guanidine*HCI
mp: 244.5-246°C; TLC: R, = 0.23 (SiO2, CHCI3/MeOH = 10:1 ); H NMR (CD3OD): δ ppm 8.1 5-8.17 (m, ArH, 2H), 7.36-7.91 (m, ArH, 10H), 3.40-3.50 (m, CH2, 4H), 2.50 (s, CH3, 1 H); MS(EI): m/e 434.1 (M+ : C27H22N4S); Anal. (C,H,N; C27H22N4S-HCI): Calcd . (%): C, 68.85; H, 4.92; N, 1 1 .89; Found (%): C, 68.66; H, 4.91 ; N, 1 1 .86.
Example 64: Inhibition of Glutamate Release
Compounds were tested for inhibition of glutamate release. As shown by the data below, compounds of the invention blockers of glutamate release. The assay protocol was as described in PCT/US92/01050, specifically Examples 8-9 of that document. - 67 -
Briefly, the 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 μM or 3 μm. 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.
The relative levels of glutamate release in the presence of the specified compounds of the invention are shown in Table I and Table 1 A below. In those Tables, the tested compounds are identified by reference to corresponding Example No. and the following formula where the substituent groups R, R and R2 are specified in the Tables. The designation "NT" in the Tables indicates the compound was not tested in the specified assay.
A number of compounds identified in Table I and Table 1 A were also tested in a veratridine induced glutamate release assay and similar results of glutamate release inhibition were observed. The protocol of the veratridine induced glutamate release assay is described in Epilepsia, 27: 490-497 (1986).
TABLE I: INHIBITION OF GLUTAMATE RELEASE
Figure imgf000069_0001
68 -
Cmpd. % Block of Glu Rel of Ex.
No. R R1 R2 @ 10 μM @ 3 vM
1 2,3,4-trichlorophenyl H H NT 97
2 5-acenaphthyl H CH3 62 NT
3 5-acenaphthyl CH3 CH3 NT 53
4 1 -anthracenyl H H 95 85
5 4-tertbutylphenyl H H 100 49
6 4-cyclohexylphenyl H H NT 90
7 4-sβcbutylphenyl H H NT 84
8 4-methoxyphenyl H H 50 3
9 2,3-dichlorophenyl H H 86 47
10 4-OCH3-2-naphthyl H H 84 80
1 1 3,4-dichlorophenyl H H 82 NT
12 4-chlorophenyl H H 69 NT
13 2-naphthyl H H 81 NT
15 4-nitrophenyl H H 35 78
16 3-bi-phenyl H H NT 98
17 2,3-dimethylphenyl H H NT 46
18 2-bi-phenyl H H NT 54
19 2,5-dibromophenyl H H NT 46
20 3,4-dimethoxyphenyl H H NT 46
21 4-methoxy-1 -naphthyl CH3 H NT 54
22 4-methoxy-1 -naphthyl H CH3 NT 43
23 4-methoxy-1 -naphthyl CH3 CH3 NT 40
24 4-chloro-1 -naphthyl H H NT 75
25 3,4,5-trichlorophenyl H H NT 49
26 4-bi-phenyl H H NT 38
27 2,3,4,5-tetrachlorophenyl H H NT 37
28 3-isopropylphenyl H H NT 64
29 3-tertbutylphenyl H H NT 71 - 69 -
Figure imgf000071_0001
TABLE 1A: INHIBITION OF GLUTAMATE RELEASE
Cmpd. % Block of Glu Rel of Ex.
No. R R1 R2 @ 1 μm @ 0.3 μm
41 4-benzyloxyphenyl H H — 38
42 3-benzyloxyphenyl H H — 24
45 2-anthracenyl H H 44 —
46 3-phenethylphenyl H H 79 31
47 4-adamantylphenyl H H 20 —
48 3-benzyloxyphenyl H CH3 83 46
49 4-benzyloxyphenyl H CH3 44 1 1
50 3-(1 -methyl-2'-phenylethyl)phenyl) H H 72 —
51 3-biphenyl H CH3 47 —
53 7-benzyltetralinyl H H 100 —
56 3-(NB /N''-dibenzyl)aminophenyl H H — 7
57 3-(1 '-benzylbutyDphenyl H H — 23
58 3-(4-t-butylbenzoxymethylene)phenyl H H — 19
62 2,3,4-trichlorophenyl H CH3 - 1 5
Example 65: Ca-Flux Assay Compounds were also tested to determine where the Ca2+ dependent and independent components of glutamate release are related to the blockage of 45Ca uptake. Calcium uptake is one step in - 70 -
the cascade of events which occur in neuronal cell death from ischemia. See Bassaclough and Leach, Current Patents Ltd. , 2-21. The protocol of the Ca-flux assay is as follows and the results of the assay are shown in Table II below. 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 μM and incubated for 5 minutes at room temperature. 45Ca uptake was then measured by adding isotope in either LK or high potassium (1 50 mM KCl) containing buffer. After 5 seconds, the 45Ca flux was stopped with 0.9 mL quench solution (LK + 10 mM EGTA). The solution was filtered under vacuum and the filters washed with 1 5 mL of quench buffer. The effect of drug is expressed as % inhibition (or block) of control potassium-stimulated 45Ca influx. This method is an adaptation of the method disclosed by Nachsen and Blaustein, J. Physio/. , 361 :251 -268 (1985). Results of the assay are shown in Table II below. In Table II, the tested compounds are identified by reference to corresponding Example No. and the depicted structural formula where the substituent groups R, R1 and R2 are specified in Table II.
TABLE II: ACTIVITY IN THE Ca FLUX ASSAY
Figure imgf000072_0001
71
Block of
Cmpd. 45Ca @ 10μM Ex.
R R1 R2 % Block IC50 μM No.
5 4-tertbutylphenyl H H 50
6 4-cyclohexylphenyl H H 63
7 4-sec-butylphenyl H H 53
10 4-methoxy-2-naphthyl H H 43 6.35
1 6 3-bi-phenyl H H 7.18
39 4-trifluoromethyl H H 52
40 4-methylthio H H 46
Example 66: Sodium Channel Blockade Assay
The ability of compounds of the invention to block sodium channels of mammalian cells is exemplified by the data summarized in Table III below. The data demonstrates that at least some compounds of the invention block the saxitoxin binding site on voltage-activated Na channels which are believed to control glutamate release in vivo. The assay protocol was as described by F. Gusvosky, et al., Brain Research, 518: 101-106 (1990). The following solutions were prepared:
1 ) Stock Solution of the following composition (amounts of components expressed as grams/liter):
Component Amount 3 300 mmMM KKCCll 2.23
8 mM MgSO4 0.96
250 mM Hepes/Tris 59.57 (pH to 7.4 with Tris Base)
1 M Choline Chloride 139.60
18 mM CaCI2 1.99
The Stock Solution is made in ddH20, filtered and stored at room temperature for 4-6 weeks. The Hepes stock is kept refrigerated. - 72 -
2) Toxin: 1 mg of 1 mM Tetrodotoxin dissolved in 3.1 mis ddH20 (stored at 4°C).
3) Incubation Buffer of the following composition (amounts of components expressed as mis):
Component Amount
5.4 mM KCl 9.0
0.8 mM MgSO4 5.0
50 mM Hepes 10.0
130 mM Choline Chloride 6.5
19.5 mis of ddH2O and are added to the admixture followed by the addition of 0.049 grams of 5.5 mM glucose to provide the
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).
Component Amount
163 mM Choline Chloride 163
0.8 mM MgSO4 100
1.8 mM CaCI2 100
5.0 mM Hepes 20
617 mis of ddH2O and are added to the admixture to provide the Wash Buffer.
Synaptosome preparation
Synaptosomes were prepared as described in Example 8 of
PCT/US92/01050. The prepared synaptosomes are frozen in 1 ml aliquots (5% DMSO) at -80°C Preparation is thawed on ice immediately before assay and diluted to get approximately 1000 cpm for totals per filter (10-1 5 μg protein/filter to avoid any potential problems testing relatively lipophilic compounds that could be absorbed out of solution by the membranes). - 73 -
Assay
A test Assay is prepared of the following composition and having 200Λ final volume:
50Λ[3H]Saxitoxin: 5.9 nM (Amersham TRK.877) approximately a 1 :300 dilution of stock (the [3H]Saxitoxin is stored according to Amersham recommendations)
20Λ Compound of interest (diluted [10x] in ddH2O due to low solubility)
80Λ Incubation buffer 501 protein: 10-1 5 μg rat synaptosomes
This mixture is incubated for 30 minutes at 37°C, then filtered over Whatmann GF/C glass fiber filters, and washed 3X with 4 mis of Wash Buffer, and the filters punched filters to vials immediately upon completion of assay. [3H]STX is very unstable and can lose 3H when H2O evaporates while filters dry. 5 mis scintillation fluid (CytoScint ICN #882465) are added and the samples counted for 5 minutes each. Nonspecific binding is determined by 10 μM TTX and is about 5% of total binding at the above [protein].
In Table III, the tested compounds are identified by reference to the formula depicted below with the substituent groups of the tested compounds R, R1 and R2 specified in Table III. The tested compounds were in salt form, as indicated in the Table. TABLE III
Figure imgf000075_0001
- 74
Figure imgf000076_0001
75 -
Figure imgf000077_0001
The present invention has been described in detail, including the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of the present disclosure, may make modifications and/or improvements on this invention and still be within the scope and spirit of this invention as set forth in the following claims.

Claims

- 76 -
What is claimed is:
A compound having the formula:
Figure imgf000078_0001
wherein:
R and R1 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 alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyi 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 least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
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 - 77 -
rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; and pharmaceutically acceptable salts thereof.
2. A compound having the formula:
Figure imgf000079_0001
wherein:
R and R1 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 alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyi 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 least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; - 78 -
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.
3. A compound of claim 1 or 2 wherein Ar is phenyl independently substituted at one or more positions by halo, haloalkyi, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkoxy, nitro and substituted or unsubstituted carbocyclic aryl.
4. A compound of claim 1 or 2 where Ar is phenyl substituted by substituted or unsubstituted aralkyl, substituted or unsubstituted aralkylamino, substituted or unsubstituted aryloxy, substituted or unsubstituted alkyleneoxyaryl, or a substituted or unsubstituted heterocyclic group.
5. A compound of claim 1 or 2 wherein Ar is substituted or unsubstituted anthracenyl, substituted or unsubstituted indolinyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted bi-phenyl, substituted or unsubstituted dibenzofuranyl or substituted or unsubstituted tetralinyl.
6. A compound of claim 1 or 2 selected from the group of: 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; - 79
N-(5-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N,N'-bis- methylguanidine;
N,N'-bis(5-acenaphthyl)-N-methylguanidine;
N,N'-bis(5-acenaphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(1 -anthracenyl)guanidine;
N-(5-acenaphthyl)-N'-(1 -anthracenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(1-anthracenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(1-anthracenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-fe/τ-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-terf-butylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-terr-butylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-fe/ -butylphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-sec-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-sec-butylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-sec-butylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-sec-butylphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3-dichlorophenyl)guanidine;
N-(5-acenaphthyl)-N'-(2,3-dichlorophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3-dichlorophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3-dichlorophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)guanidine;
N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N-methylguanidine; 80 -
N-(5-acenaphthyl)-N'- 4-methoxy-2-naphthyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'- 4-methoxy-2-naphthyl)-N,N'-bis- methylguanidine;
N 5-acenaphthyl)-N'- 3,4-dichlorophenyl)guanidine; N 5-acenaphthyl)-N'- 3,4-dichlorophenyl)-N-methylguanidine; N 5-acenaphthyl)-N'- 3,4-dichlorophenyl)-N'-methylguanidine; N 5-acenaphthyl)-N'- 3,4-dichlorophenyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl)-N'- 4-chlorophenyl)guanidine; N 5-acenaphthyl)-N'- 4-chlorophenyl)-N-methylguanidine; N 5-acenaphthyl)-N'- 4-chlorophenyl)-N'-methylguanidine; N 5-acenaphthyl)-N'- 4-chlorophenyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl)-N'- 2-naphthyl)guanidine; N 5-acenaphthyl)-N'- 2-naphthyl)-N-methylguanidine; N 5-acenaphthyl)-N'- 2-naphthyl)-N'-methylguanidine; N 5-acenaphthyl)-N'- 2-naphthyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl)-N'- 6-quinolinyl)guanidine; N 5-acenaphthyl)-N'- 6-quinolinyl)-N-methylguanidine; N 5-acenaphthyl)-N'- 6-quinolinyl)-N'-methylguanidine; N 5-acenaphthyl)-N'- 6-quinolinyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl)-N'- 4-nitrophenyl)guanidine; N 5-acenaphthyl)-N'- 4-nitrophenyl)-N-methylguanidine; N 5-acenaphthyl)-N'- 4-nitrophenyl)-N'-methylguanidine; N 5-acenaphthyD-N'- 4-nitrophenyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl-N'-(3-bi-phenyl)guanidine; N 5-acenaphthyl-N'-(3-bi-phenyl)-N-methylguanidine; N 5-acenaphthyl-N'-(3-bi-phenyl)-N'-methylguanidine; N 5-acenaphthyl-N'-(3-bi-phenyl)-N,N'-bis-methylguanidine; N 5-acenaphthyl)-N'-(2,3-dimethylphenyl)guanidine; N 5-acenaphthyl)-N'-(2,3-dimethylphenyl)-N-methylguanidine; N 5-acenaphthyl)-N'-(2,3-dimethylphenyl)-N'-methylguanidine; 81
N-(5-acenaphthyl)-N'- 2,3-dimethylphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'- 2-bi-phenyl)guanidine;
N-(5-acenaphthyl)-N'- 2-bi-phenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'- 2-bi-phenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'- 2-bi-phenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'- 2,5-dibromophenyl)guanidine;
N-(5-acenaphthyl)-N'- 2,5-dibromophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'- 2,5-dibromophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'- 2,5-dibromophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'- 3,4-dimethoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'- 3,4-dimethoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'- 3,4-dimethoxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'- 3,4-dimethoxyphenyl)-N,N'-bis- methylguanidine;
N-(5-acenaphthyl)-N'- 4-methoxy-1 -naphthyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'- 4-methoxy-1 -naphthyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'- 4-methoxy-1 -naphthyl)-N,N'-dimethylguanidine;
N-(5-acenaphthyl)-N'- 4-chloro-1 -naphthyDguanidine;
N-(5-acenaphthyl)-N'- 4-chloro-1 -naphthyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'- 4-chloro-1 -naphthyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N' 4-chloro-1 -naphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'- 3,4,5-trichlorophenyOguanidine;
N-(5-acenaphthyl)-N' 3,4,5-trichlorophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N' 3,4,5-trichlorophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N' 3,4,5-trichlorophenyl)-N,N'-bis- methylguanidine;
N-(5-acenaphthyl)-N' 4-bi-phenyl)guanidine;
N-(5-acenaphthyl)-N' 4-bi-phenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N' 4-bi-phenyl)-N'-methylguanidine;
N-(5-acenaρhthyl)-N' 4-bi-phenyl)-N,N'-bis-methylguanidine; - 82
N-(5-acenaphthyl N'- 2,3,4,5-tetrachlorophenyDguanidine; N-(5-acenaphthyl •N'- 2,3,4,5-tetrachlorophenyl)-N-methylguanidine; N-(5-acenaphthyl N'- 2,3,4, 5-tetrachlorophenyl)-N'-methylguanidine; N-(5-acenaphthyl N'- 2,3,4,5-tetrachlorophenyl)-N,N'-bis- methylguanidine; N-(5-acenaphthyl N'- 3-/sopropylphenyl)guanidine; N-(5-acenaphthyl N'- 3-/sopropylphenyl)-N-methylguanidine; N-(5-acenaphthyl ■N'- 3-/sopropylphenyl)-N'-methylguanidine; N-(5-acenaphthyl N'- 3-/sopropylphenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl N'- 3-rert-butylphenyl)guanidine; N-(5-acenaphthyl N'- 3-tert-butylphenyl)-N-methylguanidine; N-(5-acenaphthyl N'- 3-rert-butylphenyl)-N'-methylguanidine; N-(5-acenaphthyl ■N'- 3-rerf-butylphenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl ■N'- 2,3,5,6-tetrachlorophenyDguanidine; N-(5-acenaphthyl N'- 2,3,5,6-tetrachlorophenyl)-N-methylguanidine; N-(5-acenaphthyl •N'- 2,3,5,6-tetrachlorophenyl)-N'-methylguanidine; N-(5-acenaphthyl N'- 2,3,5,6-tetrachlorophenyl)-N,N'-bis- methylguanidine; N-(5-acenaphthyl N'- 3-iodophenyl)guanidine; N-(5-acenaphthyl ■N'- 3-iodophenyl)-N-methylguanidine; N-(5-acenaphthyl •N'- 3-iodophenyl)-N'-methylguanidine; N-(5-acenaphthyl •N'- 3-iodophenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl •N'- 3-nitrophenyl)guanidine; N-(5-acenaphthyl ■N'- 3-nitrophenyl)-N-methylguanidine; N-(5-acenaphthyl •N'- 3-nitrophenyl)-N'-methylguanidine; N-(5-acenaphthyl ■N'- 3-nitrophenyl)-N,N'-bis-methyiguanidine; N-(5-acenaphthyl ■N'- 5-indolinyl)guanidine; N-(5-acenaphthyl ■N'- 5-indolinyl)-N-methylguanidine; N-(5-acenaphthyl •N'- 5-indolinyl)-N'-methylguanidine; N-(5-acenaphthyl ■N'- 5-indolinyl)-N,N'-bis-methylguanidine; - 83 -
N-(5-acenaphthyl)-N'-(3-acenaphthyl)guanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)guanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N'-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)guanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N- methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N'- methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N,N'-bis- methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)guanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N,N'-bis- methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N,N'-bis- methylguanidine; N-(5-acenaphthyl)-N'-(4- methylthiophenyDguanidine; 84 -
N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N,N'-bis- methylguanidine;
N,N'-bis(3-acenaphthyl)-N-methylguanidine;
N,N'-bis(3-acenaphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaρhthyl)-N' (1 -anthracenyOguanidine;
N-(3-acenaphthyl)-N' (1 -anthracenyD-N-methylguanidine;
N-(3-acenaphthyl)-N'- (l -anthracenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- (1 -anthracenyl)-N,N'-bis-methylguanidine;
N-(3-acenaρhthyl)-N'- (4-ferf-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'- (4-te/?-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- (4-terr-butylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N' (4-tert-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N' (4-cyclohexylphenyl)guanidine;
N-(3-acenaρhthyl)-N' (4-cyclohexylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N' (4-cyclohexylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- (4-cyclohexylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- (4-sec-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'- (4-sec-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- (4-sec-butylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- (4-sec-butylphenyl)-N,N'-bis-methylguanidine; - 85 -
N-(3-acenaρhthyl)-N'- 4-methoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'- 4-methoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 4-methoxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 4-methoxyphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 2,3-dichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'- 2,3-dichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 2,3-dichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 2,3-dichlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 4-methoxy-2-naphthyl)guanidine;
N-(3-acenaphthyl)-N'- 4-methoxy-2-naphthyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 4-methoxy-2-naphthyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 4-methoxy-2-naphthyl)-N,N'-bis- methylguanidine;
N-(3-acenaphthyl)-N'- 3,4-dichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'- 3,4-dichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 3,4-dichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 3,4-dichlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 4-chlorophenyl)guanidine;
N-(3-acenaphthyl)-N'- 4-chlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 4-chlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 4-chlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 2-naphthyl)guanidine;
N-(3-acenaphthyl)-N'- 2-naphthyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 2-naphthyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 2-naphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 6-quinolinyl)guanidine;
N-(3-acenaphthyl)-N'- 6-quinolinyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 6-quinolinyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 6-quinolinyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 4-nitrophenyl)guanidine; - 86 -
N- 3-acenaphthyl)-N'-(4-nitrophenyl)-N-methylguanidine; N- 3-acenaphthyl)-N'-(4-nitrophenyl)-N'-methylguanidine; N- 3-acenaphthyl)-N'-(4-nitrophenyl)-N,N'-bis-methylguanidine; N- 3-acenaphthyl-N'-(3-bi-phenyl)guanidine; N- 3-acenaphthyl-N'-(3-bi-phenyl)-N-methylguanidine; N- 3-acenaphthyl-N'-(3-bi-phenyl)-N'-methylguanidine; N- 3-acenaphthyl-N'-(3-bi-phenyl)-N,N'-bis-methylguanidine; N- 3-acenaphthyl)-N'- 2,3-dimethylphenyl)guanidine; N- 3-acenaphthyl)-N'- 2,3-dimethylphenyl)-N-methylguanidine; N- 3-acenaphthyl)-N'- 2,3-dimethylphenyl)-N'-methylguanidine; N- 3-acenaphthyD-N'- 2,3-dimethylphenyl)-N,N'-bis-methylguanidine; N- 3-acenaphthyU-N'- 2-bi-phenyi)guanidine; N- 3-acenaphthyl)-N'- 2-bi-phenyl)-N-methylguanidine; N- 3-acenaphthyl)-N'- 2-bi-phenyl)-N'-methylguanidine; N- 3-acenaphthyD-N'- 2-bi-phenyl)-N,N'-bis-methylguanidine; N- 3-acenaphthyl)-N'- 2,5-dibromophenyl)guanidine; N- 3-acenaphthyl)-N'- 2,5-dibromophenyl)-N-methylguanidine; N- 3-acenaphthyl)-N'- 2,5-dibromophenyl)-N'-methylguanidine; N- 3-acenaphthyl)-N'- 2,5-dibromophenyl)-N,N'-bis-methylguanidine; N- 3-acenaphthyl)-N'- 3,4-dimethoxyphenyl)guanidine; N- 3-acenaphthyl)-N'- 3,4-dimethoxyphenyl)-N-methylguanidine; N- 3-acenaphthyl)-N'- 3,4-dimethoxyphenyl)-N'-methylguanidine; N- 3-acenaphthyl)-N'- 3,4-dimethoxyphenyl)-N,N'-bis- methylguanidine;
N- 3-acenaphthyl)-N'- 4-methoxy-1 -naphthyl)-N-methylguanidine; N- 3-acenaphthyl)-N'- 4-methoxy-1 -naphthyl)-N'-methylguanidine; N- 3-acenaphthyl)-N'- 4-methoxy-1 -naphthyl)-N,N'-dimethylguanidine; N- 3-acenaphthyl)-N'- 4-chloro-1 -naphthyDguanidine; N- 3-acenaphthyl)-N'- 4-chloro-1 -naphthyl)-N-methylguanidine; N- 3-acenaphthyl)-N'- 4-chloro-1 -naphthyl)-N'-methylguanidine; 87 -
N-(3-acenaphthyl)-N'- 4-chloro-1 -naphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 3,4,5-trichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'- 3,4,5-trichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 3,4,5-trichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 3,4,5-trichlorophenyl)-N,N'-bis- methylguanidine;
N-(3-acenaphthyl)-N'- 4-bi-phenyl)guanidine;
N-(3-acenaphthyl)-N'- 4-bi-phenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 4-bi-phenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 4-bi-phenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 2,3,4,5-tetrachlorophenyDguanidine;
N-(3-acenaphthyl)-N'- 2,3,4,5-tetrachlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 2,3,4, 5-tetrachlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 2,3,4,5-tetrachlorophenyl)-N,N'-bis- methylguanidine;
N-(3-acenaphthyl)-N'- 3-/sopropylphenyl)guanidine;
N-(3-acenaphthyl)-N'- 3-/sopropylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 3-/sopropylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- 3-/sopropylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'- 3-ferf-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'- 3-feΛt-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 3-re/"f-butylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'- !3-tert-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaρhthyl)-N'- 2,3,5,6-tetrachlorophenyDguanidine;
N-(3-acenaphthyl)-N'- 2,3,5,6-tetrachiorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'- 2,3,5,6-tetrachlorophenyl)-N'-methylguanidine;
N-(3-acenaρhthyl)-N'- 2,3,5, 6-tetrachlorophenyl)-N,N'-bis- methylguanidine;
N-(3-acenaρhthyl)-N'- 3-iodophenyl)guanidine;
N-(3-acenaρhthyl)-N'- 3-iodophenyl)-N-methylguanidine; - 88 -
N-(3-acenaphthyl)-N'-(3-iodophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-iodophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)guanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)guanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N'-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)guanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N- methylguanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N'- methylguanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N,N'-bis- methylguanidine;
N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)guanidine;
N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N,N'-bis- methylguanidine; - 89 -
N-(3-acenaphthyl)-N'-(4-trifluoromethylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N,N'-bis- methylguanidine; N-(3-acenaphthyl)-N'-(4- methylthiophenyDguanidine;
N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N'-methylguanidine; and
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N,N'-bis-methylguanidine; and pharmaceutically acceptable salts of said compounds.
7. A compound of claim 1 or 2 selected from the group consisting of:
N-(5-acenaphthyl)-N'-(4-benzyloxyphenyl)guanidine; N-(5-acenaphthyl)-N'-(3-benzyloxyphenyl)guanidine; N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine; N-(5-acenaphthyl)-N'-(2-anthracenyl)guanidine; N-(5-acenaphthyl)-N'-(3-phenethylphenyl)guanidine; N-(5-acenaphthyl)-N'-(4-adamantylphenyl)guanidine; N-(5-acenaphthyl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(4-benzyloxyphenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(3-biphenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(3-(1 '-methyl-2'-phenylethyl)phenyl)guanidine; N-(5-acenaphthyl)-N'-(3,4-tetralinylphenyl)guanidine; N-(5-acenaphthyl)-N'-(7-benzyltetralinylphenyl)guanidine; - 90
N-(5-acenaphthyl)-N'-(3-1 -(4- ethoxy)phenyl)propanyl)phenyl)guanidine;
N- 5-acenaphthyl)-N'-(3-(N",N"-dibenzyl)aminophenyl)guanidine; N- 5-acenaphthyl)-N'-(3-(1 '-benzylbutyl)phenyl)guanidine; N- 5-acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl)phenylguanidine; N- 5-acenaphthyl)-N'-(2-(2-indolyl)phenyl)guanidine; N- 5-acenaphthyl-N'-(3-bromophenyl)guanidine; N- 5-acenaphyl)-N'-(2,3,4-trichlorophenyl)-N,N'-dimethylguanidine; N- 5-acenaphthyl)-N'-(2,3,4-trichloro-phenyl)-N'-methylguanidine; N- 5-acenaphthyl)-N'-(3,4-dibenzyloxyphenyl)guanidine; N- 5-acenaphthyl)-N'-(4-(2'-benzothiazole-6'-methyl)phenyl)guanidine; N- 3-acenaphthyl)-N'-(4-benzoyloxyphenyl)guanidine; N- 3-acenaphthyl)-N'-(3-benzoyloxyphenyl)guanidine; N- 3-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine; N- 3-acenaphthyl)-N'-(2-anthracenyl)guanidine; N- 3-acenaphthyl)-N'-(3-phenethylphenyl)guanidine; N- 3-acenaphthyl)-N'-(4-adamantylphenyl)guanidine; N- 3-acenaphthyl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine; N- 3-acenaphthyl)-N'-(4-benzyloxyphenyl)-N'-methylguanidine; N- 3-acenaphthyl)-N'-(3-biphenyl)-N'-methylguanidine; N- 3-acenaphthyl)-N'-(3-(1 '-methyl-2'-phenylethyl)phenyl)guanidine; N- 3-acenaphthyl)-N'-(3,4-tetralinylphenyl)guanidine; N- 3-acenaphthyl)-N'-(7-benzyltetralinylphenyl)guanidine; N- 3-acenaphthyl)-N'-(3-1 -(4- ethoxy)phenyl)propanyl)phenyl)guanidine;
N- 3-acenaphthyl)-N'-(3-(N",N"-dibenzyl)aminophenyl)guanidine; N- 3-acenaphthyl)-N'-(3-(1 '-benzylbutyl)phenyl)guanidine; N- 3-acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl)phenylguanidine; N- 3-acenaphthyl)-N'-(2-(2-indolyl)phenyl)guanidine; N- 3-acenaphhthyl-N'-(3-bromophenyl)guanidine; - 91 -
N-(3-acenaphthyl)-N'-(3,4-dibenzyloxyphenyl)guanidine; N-(3-acenapthyl)-N'-(2, 3, 4-trichlorophenyl)-N,N'-dimethyl guanidine; N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine; N-(3-acenaphthyl)-N'-(4-(2'-benzothiazole-6'-methyl)phenyl)guanidine; and pharmaceutically acceptable salts of said compounds.
8. A compound having the formula:
Figure imgf000093_0001
wherein:
R and R1 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 alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyi 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 least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; - 92 -
each R2 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 substituted or unsubstituted aralkyl having at least about 5 ring atoms; n is an integer equal to 1 , 2, 3, 4, 5, 7, 8 or 9;
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.
9. A compound having the formula:
Figure imgf000094_0001
wherein:
R and R1 are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, - 93 -
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 alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyi 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 least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; each R2 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 substituted or unsubstituted aralkyl having at least about 5 ring atoms; n is an integer equal to 1 , 2, 3, 4, 5, 6, 7, 8 or 9; - 94 -
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.
10. A method for treating or preventing a disorder of the nervous system in which the pathophysiology of the disorder involves excessive release of a neurotransmitter from neuronal cells comprising administering to a mammal exhibiting symptoms of said disorder or susceptible to said disorder an effective amount of a compound of claim 1 , 2, 8 or 9.
1 1 . The method of claim 10 wherein the disorder is 1 ) nausea resulting from chemotherapy, 2) epilepsy, 3) convulsions, 4) carbon monoxide poisoning, 5) cyanide poisoning, 6) toxic brain damage caused by tetrodotoxin or shell fish toxins, 7) amnesia, 8) migraine or river blindness, or 8) nerve cell death resulting from hypoxia, hypoglycemia, brain or spinal cord ischemia, brain or spinal cord trauma, stroke, heart attack, or drowning.
12. A method for treating or preventing nerve cell death comprising administering to a subject exhibiting symptoms of nerve cell death or susceptible to nerve cell death an effective amount of a compound of claim 1 , 2, 8 or 9.
13. A method for modulating the release of excess endogenous neurotransmitters from a subject comprising administering to the subject an effective amount of a compound of claim 1 , 2, 8 or 9. - 95 -
14. A method of blocking voltage sensitive calcium channels of mammalian neuronal cells comprising administering to the cells an effective amount of a compound of claim 1 , 2, 8 or 9.
15. A method of blocking voltage sensitive sodium channels of mammalian neuronal cells comprising administering to the cells an effective amount of a compound of claim 1 , 2, 8 or 9.
16. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 1 , 2, 8 or 9 and a pharmaceutically acceptable carrier.
PCT/US1994/013541 1993-11-22 1994-11-22 Therapeutic guanidines WO1995014467A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95903152A EP0746316A4 (en) 1993-11-22 1994-11-22 Therapeutic guanidines
JP7515219A JPH09505600A (en) 1993-11-22 1994-11-22 Therapeutic guanidines
AU12122/95A AU703138B2 (en) 1993-11-22 1994-11-22 Therapeutic guanidines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15593093A 1993-11-22 1993-11-22
US08/155,930 1993-11-22

Publications (1)

Publication Number Publication Date
WO1995014467A1 true WO1995014467A1 (en) 1995-06-01

Family

ID=22557352

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/013541 WO1995014467A1 (en) 1993-11-22 1994-11-22 Therapeutic guanidines

Country Status (6)

Country Link
EP (1) EP0746316A4 (en)
JP (1) JPH09505600A (en)
AU (1) AU703138B2 (en)
CA (1) CA2177084A1 (en)
WO (1) WO1995014467A1 (en)
ZA (1) ZA949253B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0959887A1 (en) * 1996-08-09 1999-12-01 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use
US6514990B2 (en) 1996-02-15 2003-02-04 Scion Pharmaceuticals, Inc. Pharmaceutically active compounds and methods of use
EP4057003A1 (en) * 2021-03-12 2022-09-14 Universidad de Castilla la Mancha Selective sulfate anion detection using guanylated fluorophores

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242198B1 (en) 1996-07-25 2001-06-05 Cambridge Neuroscience, Inc. Methods of treatment of eye trauma and disorders

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906779A (en) * 1986-07-10 1990-03-06 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists
WO1990014067A2 (en) * 1989-05-02 1990-11-29 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Methods for treating anxiety with sigma receptor ligands
WO1991018868A1 (en) * 1990-05-25 1991-12-12 STATE OF OREGON, acting by and through the OREGON STATE BOARD OF HIGHER EDUCATION, acting for and onbehalf of the OREGON HEALTH SCIENCES UNIVERSITY Substituted guanidines having high binding to the sigma receptor and the use thereof
WO1992014697A1 (en) * 1991-02-08 1992-09-03 Cambridge Neuroscience, Inc. Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906779A (en) * 1986-07-10 1990-03-06 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists
WO1990014067A2 (en) * 1989-05-02 1990-11-29 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Methods for treating anxiety with sigma receptor ligands
WO1991018868A1 (en) * 1990-05-25 1991-12-12 STATE OF OREGON, acting by and through the OREGON STATE BOARD OF HIGHER EDUCATION, acting for and onbehalf of the OREGON HEALTH SCIENCES UNIVERSITY Substituted guanidines having high binding to the sigma receptor and the use thereof
WO1992014697A1 (en) * 1991-02-08 1992-09-03 Cambridge Neuroscience, Inc. Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0746316A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6514990B2 (en) 1996-02-15 2003-02-04 Scion Pharmaceuticals, Inc. Pharmaceutically active compounds and methods of use
US6770668B2 (en) 1996-02-15 2004-08-03 N. Laxma Reddy Pharmaceutically active compounds and methods of use
EP0959887A1 (en) * 1996-08-09 1999-12-01 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use
EP0959887A4 (en) * 1996-08-09 2003-01-08 Cambridge Neuroscience Inc Pharmaceutically active compounds and methods of use
EP4057003A1 (en) * 2021-03-12 2022-09-14 Universidad de Castilla la Mancha Selective sulfate anion detection using guanylated fluorophores
WO2022189677A1 (en) * 2021-03-12 2022-09-15 Universidad De Castilla-La Mancha Selective sulfate anion detection using guanylated fluorophores

Also Published As

Publication number Publication date
AU703138B2 (en) 1999-03-18
EP0746316A4 (en) 1997-12-10
CA2177084A1 (en) 1995-06-01
JPH09505600A (en) 1997-06-03
EP0746316A1 (en) 1996-12-11
ZA949253B (en) 1996-01-04
AU1212295A (en) 1995-06-13

Similar Documents

Publication Publication Date Title
US6174924B1 (en) Therapeutic guanidines
US5767162A (en) Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US6153604A (en) Therapeutic substituted guanidines
US6251948B1 (en) Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists
JP4108127B2 (en) Compounds having anti-inflammatory and immunosuppressive activity
SK19495A3 (en) Pharmaceutical compositions
PL148590B1 (en) Method of obtaining novel derivatives of 2-amino-5-hydroxy-4-methylpyrimidine
US6156741A (en) Therapeutic substituted guanidines
US5847006A (en) Therapeutic guanidines
EP0746316A1 (en) Therapeutic guanidines
US6143791A (en) Therapeutic guanidines
HU211517A9 (en) 2-amino-1,2,3,4-tetrahydronaphthalene derivatives active on the cardiovascular system, processes for their preparation and pharmaceutical compositions containing them
US7351743B1 (en) Therapeutic guanidines
US5294638A (en) Phenyalkylaminoalkyl compounds and pharmaceutical compositions containing them
US4971985A (en) Pyridylketoxime ether compound and pharmaceutical composition containing it
US6787569B1 (en) Therapeutic guanidines
US4163053A (en) Anti-hypertensive 5-[2-(substituted anilinoalkylamino)-1-hydroxyalkyl]salicylamides
AU3222699A (en) Therapeutic guanidines
AU1010702A (en) Therapeutics Guanidines
EP0223598B1 (en) Catecholamine derivatives, processes for their preparation and pharmaceutical compositions thereof
AU647034B2 (en) Novel diamine compounds and cerebral protective drugs containing the same

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 08454927

Country of ref document: US

AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2177084

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1995903152

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1995903152

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1995903152

Country of ref document: EP