AU703138B2 - Therapeutic guanidines - Google Patents

Description

I -L WO 95/14467 PCT/IS94/13541 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 are highly s"ecialized 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 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, Neuron., 1:623 (1988); Choi, Cerebrov. and Brain Metab. Rev., 2:105 (1990); Albers, et al., Ann. Neurol., 25:398 (1989). Indeed, it is belieed 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 WO 95/14467 PCTIUS94/13541 -2associated with glutamate dehydrogenase deficiency and decreased glutamate catabolism, amyotrophic lateral sclerosis/Parkinsoniumdementia, Parkinson's disease, and Alzheimer's disease. Choi, D.W., Neuron, 1:623-634 (1988); Choi, Cereb. Brain Met., Rev.

2:105-147 (1990); Courtier et al., Lancet, 341:265-268 (1993); Appel, Trends Neurosci., 16:3-5 (1993).

In the mammalian brain, glutamate interacts with three major classes or receptors, N-methyl-D-aspartate ("NMDA") receptors, non-NMDA receptors and metabotropic receptors (Watkins, 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 MacDermott, Nature 321:519 (1986)). Thus, binding of glutamate to the NMDA receptor opens a cation-selective channel that is markedly permeable to Ca 2 leading to a large and rapid increase in intracellular Ca 2 Although 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 Ca2+-channels. The so-called "metabotropic receptor", on the other hand, is not associated with an ion channel but can promote the release of Ca 2 from intracellular stores via the second-messenger inositol triphosphate.

Irrespective of the triggering mechanism, prolonged elevation of 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 Ca2+-dependent proteases, lipases and endonucleases, free radical formation and lipid peroxidation of the cell membrane.

t WO 95/14467 PCT/1S94/13541 -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 overstimulation of NMDA receptors. Associated with the NMDA receptor is an ion channel. The recognition site, 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, Ca 2 and Na' into the cell and K out of the cell. It is believed that this flux of ions, especially the influx of Ca2+ ions, caused by the interaction of glutamate with the NMDA receptor, plays an important role in nerve cell death. See, Rothman, S.M. and Olney, 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, Epilepsia, 1):S29-S34 (1989); and Rogawski, 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 a-amino-3hydroxyl-5-methyl-4-isoazole propionic acid. These subclasses may be categorized as "non-NMDA" receptors.

WO 95/14467 PCT/US94/13541 -4- 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-NN'DA 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, 20:1627 (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 WO 95/14467 PCT/US94/13541 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 Cerebrov. Brain Metab., Rev. 1:165-211 (1990); Watkins, J.C. and Olverman, Trends Neurosci., 10:265-272 (1987)) and blockers of the ion channel of the NMDA receptor-channel complex (Meldrum, Cerebrovascular Brain Metab., Rev. 2:27-57 (1987); Choi, 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, 11th ed., 1989) has been reported. Olney, J.W. et al., Science, 244:1360-1362 (1989); Koek, W. and Colpaert, 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 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, 316:148-150 (1985)); Evans, M.C. et al., Neurosci.

Lett., 83:287-292 (1987); Ault, B. and Wang, Br. J.

~LI I

I

WO 95/14467 PCT/US94/13541 -6- Pharmacol., 87:695-703 (1986); Kaneko, et al., Arzneim- Forsch./Drug Res., 39:445-450 (1989); Malgouris, 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, J.

Pharmacol. Exp. Ther., 252:349-357 (1990); 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, et al., J. Neurosci., 9: 3720-3727 (1989); Miller, et al., New Anticonvulsant Drugs, Meldrum, B.S. and Porter R.J. (eds), London:John Libbey, 165-177 (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, 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, J. Chen, F.H. Sharp, and R.P. Simon, J. Cereb. Blood Flow and Metab., 13:88-97 (1993), Meldrum, et al., Brain Res., 593:1-6 and Stys, 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.

WO 95/14467 PCT/US94/13541 -7- As the cell depolarizes and reaches the threshold for action potential firing, Na channels are activated. Stys et al. (Stys, S.G.

Waxman, and B.R. Ransom, J. Neurosci., 12:430-439 (1992)) 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 1: Ar' N(R) N(R1) Ar

NH

(I)

wherein: R and R' 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 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 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;

I

WO 95/14467 PCT/US94/135411 -8- Ar and Ar' 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

RI

N N (IA)

NH

wherein: R and R' 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 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 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; WO 95/14467 PCT/US94/135.11 -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: R R 1 1 n Y NT

B

NH

wherein R, R' 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 IIA:

(R

2 n N. R R 1 I I (llA N N (IIA)

NH

wherein R, R' and Ar are the same as defined above for Formula IA, 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 2n

I

WO 95/14467 PCT/US94/1354 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 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 aminoalkyl 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 3acenapthyl moiety, particularly compounds of the following Formula

IIB:

R RI (R2) n I N N N N& (llB)

NH

wherein R, R' and Ar are the same as defined above for Formula IA, 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 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 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 aminoalkyl having from 1 to about 20 carbon atoms, or

M

I

WO 95/14467 PCITUS94/13541 -11 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 R 2 groups.

Preferred compounds of Formula I, IA, IB, IIA or ilB include disubstituted guanidines, where R and R 1 are each hydrogen, particularly where the group Ar and/or Ar' 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 where only one of R and R' are hydrogen) and tetrasubstituted guanidines where both R and R' are other than hydrogen), particularly where the group Ar and/or Ar' 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.

I

WO 95/14467 P(IT/S94/13541 12- 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 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 or, 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 WO 95/14467 PCTUS94113541 13disease, 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 thiat 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

I

WO 95/14467 PCT/US94/13541 14particularly 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, 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 pM 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 pM 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.

I

WO 95/14467 PCT/US94/13541 15 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 irceptor 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 llB) are F, CI, Br and I. Preferred alkyl groups include having 1 to about 12 carbon atoms, more preferably 1 to about 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-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 12 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 aminoalkyl 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

_I_

WO 95/14467 PCT/US94/13541 16preferably 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 (SO 2 groups, more typically one sulfono group, and from 1 to about 12 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, quinolinyl including 8-quinolinyl, indolinyl including 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 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 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, 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 12 carbon atoms or

I

WO 95/14467 PCT/US94/13541 17from 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 12 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 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 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 12 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, iso-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, above-mentioned aryl groups substituted by one or more C-C12, or C1-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 I Yflk-I WO 95/14467 PICT/US94/13541 18trifluoromethyl. 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, 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 Iy 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, CF 3 acyl, C-C, alkyl, C2- C, alkenyl, C2-C6 alkynyl, alkoxy, C6-C,1 aryl, C2-C 6 dialkoxymethyl, cyano, C3-C, cycloalkyl, C3-C, heterocycloalkyl, C3-C,1 dialkylaminoalkyl, carboxy, C2-C, carboxylic acid, carboxamido, C1-C, haloalkyl, C 1

-C

6 haloalkylthio, allyl, C,-C 20 aralkyl, a C3-C6 heterocycloalkyl ring fused to a benzene ring, alkylthio, arylthio, haloalkoxy, amino, Ci-C. alkylamino, C2-C16 dialkylamino, carbamoyl, C1-C, N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl, and the like.

Particularly preferred R and R' 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.

Preferred R 2 groups of compounds of the invention include halo, substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsub-

M

WO 95/14467 PCT/US94/13541 19stituted alkylthio, and substituted or unsubstituted alkylsulfinyl.

Preferred substituted alkyl R 2 groups include haloalkyl 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 3,4,5substituted 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, haloalkyl such as fluoroalkyl including trifluromethyl, chloroalkyl and bromoalkyl, haloalkoxy including fluoroalkoxy such as trifluoromethoxy, and carobocylic aryl, particularly substituted or unsubstituted phenyl.

Specifically preferred Ar and/or Ar 1 groups for Formula I, IA, IB, IIA, o IlB include the following: halophenyl such as fluorophenyl, WO 95114467 Pwr/US9411 354 I 20 chlorophenyl, bromophenyl and lodophenyl including dibromophenyl, 4-chiorophenyl, 2,3-dichlorophenyl, 3,4dichiorophenyl, 2,3,4-trichlorophenyl, 3,4,5-trichlorophenyl, 2,3,4,5tetrachlorophenyl, 2,3,5,6-tetrachiorophenyl, 3-iodophenyl, and the like; alkylphenyl such as 2,3-dimethylphenyl, 3-isopropyiphenyl, tertbutylphenyl including 3-tert-butylphenyl, 4-tert-butyiphenyl, cyclohexylphenyl including 4-cyclohexylphenyl, sec-butylphenyl including 4-sec-butylphenyl, adamantylphenyl including 3adamantyiphenyl and 4-adamantylphenyl, and the like; haloalkylphenyl including fluoro, bromo, and chioroalkyiphenyl such as trifluoromethylphenyl, particularly 4-trifluoromethylphenyl; alkoxyphenyl including 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-nbutoxyphenyl and the like; nitrophenyl such as 3-nitrophenyl, 4nitrophenyl and the like; substituted and unsubstituted bi-phenyl such 1 5 as 2-bi-phenyl, 3-bi-phenyl, 4-bi-phenyl and the like; substituted and unsubstituted aralkylphenyl including aralkylphenyl having 1 to about about carbon atoms and preferably an aryl substituent of phenyl such as e.g. (1 '-methyl-2'-phenylethyl)phenyl CH 5

CH

2

CH(CH

3

)CH

5 such as 3-(1'-methyl-2'-phenylethyl)phenyl and 4- (1 '-methyl-2'-phenylethyl)phenyl, phenethylphenyl (i.e.

CH

5

CH

2

CH

2

C

6

H

6 such as 3-phenethylphenyl and 4-phenethylphenyl and the like; substituted and unsubstituted aralkylaminophenyl such as e.g. (mono-phenylC 1 6 alkylene)aminophen'/l or (di-phenylC 1 ,alkylene)aminophenyl such as N-d ibenzyl) amino phenyl, (N,Ndiphenethylene)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

M

WO 95/14467 PCT/US94113541 21 (alkyleneoxyaryl)phenyl such as (C,alkyleneoxyaryl)phenyl, particularly substituted and unsubstituted ,alkyleneoxyphenyl)phenyl such as substituted or unsubstituted benzyloxymethylenephenyl including such groups having one or more C,.,alkyl, halo-C 1 6 ,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 indole)phenyl, phenyl substituted by benzothiazole such as 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 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, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiazolyl, and benzimidazolyl. Typically preferred heteroaromatic-substituted phenyl substituents include those phenyl substituents indepe' ently substituted at one or more ring positions, more typicaliy 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' groups of Formula I, IA, IB, IIA, or 1lB also include substituted and unsubstituted naphthyl; and substituted and unsubstituted acenaphthyl including 3-acenaphthyl and acenaphthyl.

22 Specifically compounds of the invention are selected from: N-(5-acenaphthyl).N'-(2,3,4-trichflorophenyj)guafljdine; N-(5-acenaphthyl)-N'-(2, 3, 4 -trlchlorophenyl)-N-metlyguanlne; N-5ae a hh l-'(,,-rchoa h nl-'M tyg alie N-(5-acenaphthyl)-N'-(2,3,4-trlchorophenyl)-NN'-bismethylguanidine; N, N, N-(5-acenaphtiyl)-N'-(1 -anthracenyl)guanidlne; N-(5-acenaphthyl)-N'-(1 -anrhracenvll-N-methylguanidine; N-(5-acenaphthyl)-N'-( 1 -anthracenyl)-N'-methylguanidlne; 4Q**.N-(5-acenaphthyl)-N'-(1 -anthracenyl)-N,N'-bis-methylguanidine; na hhS-'(-etb tl e lg a iie N-(5-acenaphthyl)-N'-(4-.rert-butylphe-nyl)guN-tlguane;e 15N-(-acenaphthyl)-N'-(4-rert-butylphenyl)lN'methyluanidine; -N'-(4-rert-butylphenyl) -N'-berhylguangn Wi e N-(5-acenaphthyl)-N'-(4-cyclobutypheny)NN.ityguanidine; N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)guN-die;lunii N-5a e a hhlS'(-y lhx lh n l-'m til u die N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)-NNi-methylguanidine; u* 20N-(5i-acenaphthyl)-N'-(4-sccloheylpheny)gun-miehgunlie N-(5-acenaphi~hyl)-N'-(4-sccloheylphenyl)-Nmsmethylguadnedln N-(5-acenaphthyl)-N'-(4-sec-bu~ylphenyl)guNi'iehlunii 2S N-(5-acenaphlhyl)-N'-(4-sec-butylphenyl)-N,'-ehis-maniduine; e 2~N-(5-acenaphthyl)-N'-(4-sec-btylphenyl)-N-N'ebis-methigunidne N- (S-acena phthyI) meThox~yp henyI) -N'-methyl gua nidin a; N-(5-acenaphthyl)-N'-(4-methoxypheny?-NN'-methylguanilgnidne N- (5-acena phthyl)-N'- (2,3-dlchlora pheny1) quan id ine; WO 95/14467 1PCl1US9411354 I 23 N- (5-acena phthyi)-N'- 3-d ic hlo rop henylI)- N-meth ylIg uanid ine; N- (5-acenap hthyl)-N'- (2,3-d ichlIoro ph enyl)-N'-rmethy Igua nid ine; N- (5-acenaphthyl)-N'-(2, 3-d ichlorop he nyl) N'-bis-methy Ig ua nid ine; N- (5-acenaphthyl)-N'- (4-methoxy- 2-nap hthyl) Iguanid in e; N- (5-acena phthyl)- N'-(4-methoxy-2-nap hthyl)-N-methy Ig ua nid ine; phthyl)-N'- (4-methoxy- 2-na phthyl) -N'-methylg uan id ine; N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N, N'-bismethylguanidine; (3,4-d ichlorop he nyI) guanid ine; N- (5-acena phthyl)- (3,4-d ich lo rophe nyI)- N-methyl gua nid ine; N- (5-ace nap hthyl)- (3,4-d ic hlIoro phe nyl) -N'-methylg ua nid ine; N- (5-acenap hthy (3,4-dic hlorop he nyl)- N, N'-bis-methylgu anid ine; N- (5-acenap hthy (4-ch lo rop henyl) guan id ine; N- (5-ace nap lthy I)-N'-(4-chNo ro phenyl) -N-methyl gua nid ine; 1 5 N- (5-acen a phthylI)-N'- (4-ch lo rophe nyl)-N'-methyIg ua nid ine; (4-chlorop he nyl)-N, N'-bis-methy Igu an id ine; N- (5-acena phthyl)- (2-na phthyl) gua nid ine; N- (5-acenap hthyl)-N'-(2-na phthyl)-N-methyl gua nid ine; N- (5-ace nap hth yl -(2-nap hth y methyl g u a n id dine; N- (5-acenaphthyl)-N'- (2-nap hthyl)-N,N'-bis-methylg uanid ine; N- (5 -ace na phthyl)-N'- (6-q u inoilinyl) gu an idine; N- (5-ace na phthyl)-N'- (6-qu!noinyl) -N-methyIg ua nid in e; N- (5-ace na phthyl)-N'- (6-q uino linyl) -N'-methylIg ua nid ine; N- (5-acenaphthyl)-N'- (6-qu !no linyl)-N, N'-bis-methylg uanid ine; N- (5-acenaphthyI) nitro phe nyl) gu anid ine; N- (5-acena phthy1) (4-nitro phe nyl)-N-methylIg ua nid ine; N- (5-acen ap hthyl) (4-n itro phenyl) -N'-methyl gua nid ine; 5-acenaphthyl)-N'-(4-nitrop he nyl)-N, N'-bis-methylguanid mne; N- (5-acena phthyl-N'- (3-bi-phenyl) g uanid ine; N-(5-acenaphthyl-N'-(3-bi-phenyl)-N-methylguanidine; WO 95/14467 CISI34 24 N- (5-acenaphthyl-N'- bi- phenyl)- N'-methy Igu anidine; (3-bi-p he nyl)-N, N'-bis-methylguanidine; N- (5-acenap hthyl)-N'- 3-dimethylp he nyI) g uan idine; N- (5-acena phthyl) 3-d imethyl phe nyI)- N-methyl gua nid ine; N- (5-acena phthyl) (2,3-d imethy lphe nyl) -N'-methyl gua nid ine; -N'-(2,3-dimethylp he nyl)-N, N'-bis-methylgu an idine; N- (5-ace na phthyl)-N'- (2-bi- phenyl) guan idi ne; N- (5-ace nap hthyl)-N'- (2-bi- ph enyl)-N-methy Ig ua nid ine; N- (5-ace na phthyl)- N'-(2-bi-phenyl)- methyl gua nid ine; N- (5-acenaphthyl)-N'-(2-bi-phenyl)-N, N'-bis-methyl g uan idine; N- (5-ace na phthyl)-N'- 5-d ibra mo phenyl) gua nid ine; N- (5-acena phthylI)-N'- 5-d ibromo phe nyl)- N-methy Ig ua ni dine; N- ace naphthyl)-N'-(2, 5-dibromophenyl)-N'-methyiguanid ine; N-(5-acenaphthyl)-N'-(2, 5-dibromop he nyl)-N, N'-bis-methylgu an idin e; 1 5 N- (5-ace nap hthyl1) (3,4-d imethoxyphe nyl) gua nid ine; N- -(5-ace nap ht hyl di met ho xy phe eny 1) N methyl g u an id din e; N- (5-acena phthyl) (3,4-d imethoxyp heny N'-methyl gu anid ine; (3,4-dimethoxyphenyl)-N, N'-bismethylguanidine; N-(5-acenaphthyl)-N'-(4-methoxy-1 -naphthyl)-N-methylguanidine; N-(5-acenaphthyl)-N'-(4-methoxy- 1 -nap hthyl)-N'-methylgu anidine; N-(5-acenaphthyi)-N'-(4-methoxy-l -naphthyI) N'-dimethylIguanidine; N- (5-acenaphthyl)-N'-(4-chloro- 1 -naphthyI) gu an idine; N- (5-acenaphthyl)-N'-(4-chloro- 1 -nap hthyl)-N-methylguanidine; N- (5-acenaphthyl)-N'-(4-chloro- 1-nap hthyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(4-chloro-1 -naphthyl)-N, N'-bis-methylIguanidine; N- (5-ace na phthylI)-N'- (3,4,5-trichlo ro phe nyl) gu an id ine; ap hthyl)-NI- 5-trichlo ro phe nyl) methyl gua nid ine; N- (5-acena phthyl) 5-trichlo ro phe ny 'methylIg ua nid ine; WO 95/1167 P(11U8941 3511 25 N-(5-acenaphthyl)-N'-(3,4, 5-trichlorophenyl)-N, N'-bismethyl gu an idine; 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-acenaphthyl)-N'-(4-bi-phenyl)-N, N'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)guanidine; N-(5-acenaphthyl)-N'-(2, 3,4, 5-tetrachlorophenyl )-N-methyiguanidine; N-(5-acenaphthyl)-N'-(2,3,4, N-(5-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)-N, N'-bismethylguanidine; N-(5-acenaphthyl)-N'-(3-isopropylphenyl)guanidine; N-(5-acenaphthyl)-N'-(3-isopropylplhenyl)-N-methylguanidine; )-N'-(3-isopropylphenyl)-N'-methylguanidine; 1 5 N-(5-acenaphthyl)-N'-(3-/sopropylphenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(3-tert-butylphenyl)guanidine; N-(5-acenaphthyl)-N'-(3-tert-butylphenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'-(3-tert-butylphenyl)-N'-methylguanidine; N-(5-acenaphthyl)--N'-(3-tert-butylphenyl)-N, f"'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)guanidine; N-(5-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)-N-methylguanidine; N-(5-acenaphthyl)-N'-(2,3, 5,6-tetrachlorophenyl)-N'-methylguianidine; N-(5-acenaphthyl)-N'-(2,3, 5, 6-tetrachlorophenyl)-N,N'-bismethyl g uan idine; N-(5-acenaphthyl)-N'-(3-iodophenyl)guanidine; N-(5-acenaphthyl)-N'-(3-iodophenyI)-N-methylguanidine; N-(5-acenaphthyl)-N'-(3-iodophenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(3-iodophenyl)-N, N'-bis-methyiguanidine; N-(5-acenaphthyl)-N'-(3-nitrophenyl)guanidine; N-(5-acenaphthyI)-N'-(3-nitrophenyl)-N-methylguanidine; WO 95/14467 P('T11S94111354 I -26 N- (5-acena phthyl) (3 -n itrophe nyl)-N'-methyl gua nid ine; nap hthyl)-N'-(3-nitrophenyl)-N, N'-bis-methylguanidine; N- (5-acena phthyl)-N'-(5-i nd oiinyl) gua nid ine; phthy (5-i nd olinyl)-N-methylIg ua nid ine; N- (5-acenap hthyl)-N'-(5 -ind olIinyl)-N'-methyl gua nid ine; N'-bis-methylg uanld ine; N- (5-acena phthylI)-N'-(3-a ce naphthyi) gua nid ine; N- (5-acena phthyl)-N'-(3-ace nap hthyl)-N-methyl gua nid ine; N- (5-acena phthylI)- (3-ace nap hthyl) -N'-methy Ig uan id ine; N- (5-acenaphthyl)-N'- (3-acenaphthyl)-N, N'-bis-methy Ig ua nid ine; N- (5-ace nap hthy)-N'-( 2-f Iuorenyl) g uan idine; N- (5-acenap hthy)-N'- (2-flIuore nyl)- N-methylIg uan id ine; N- (5-a cena phthy) (2-f Iuo re nyi)-N'-methyl gua n ine; -(2-fluorenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine; N- (5-ace nap hthyl)- n-b utoxy pheny)-N-mathylg ua nid ine; N- (5-ace nap hthy I) -N'-(-utox yph enfl) -methyl g uan idine; N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N, N'-bis-methlylguanidine; N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl) guanidine; N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-Nmethyiguanidine; N-(5-acenaphthyl)-N'-(3-(2-methoxy)d ibenzofuranyl)-N'methylguanidine; -,aphthy)-N'-(3-(2-methoxy)dibenzofuranyl)-N, N'-bismethylguanidine; N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)gualidifle; N-(5-acenaphthyl).N'-(9-hydroxy-2-fluorenyl)-N-methylguanidifle; N-(5-acenaphthyl)-N'-(9-hyd roxy-2-fluorenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluoreflyl)-N, N'-bismethylguanidine; mm WO 95/14467 P'CT/lS941/1 3541 27 N- (5-acena phthyl) -N'-(4-trif Iuoro methyl ph eny1) g uanid ine; N- (5-acena phthylI)-N'- (4-trif Iuoro methy Ip he nyl)- N-methy 1 a n id ine; N-(157-acena phthy 1) -N'-(4-trif Iuo romethyl phe nyI)- N'-metl g uan id ine; N-(5-acenaphthyl)-N'."-(4-trifluoromethylp he nyl)-N, N'-bismethylguanidine; N-(5-acenaphthyl)-N'-(4methylthiophen",I)guanidine; N-(5-acenaphthyl)-N'-(4-methylthiophenyfl-N-methyIguanidime; N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N'-methylguainidine; 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-acenaphthyI)-N'-(3--ec-butylphenyl)-N,N'-bis-methylguanidine; N -(3-ace nap hthy I) -(2,3,4-trio aro phen yl)g uanid in e; 1 5 N-(3-acenaphthyi)-N'-(2,3,4-trichloropheny)-N-methytguanidine; N-(3-acenaphthyi)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine; N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N, N'-bismethylguanidine; N, N'-bis (3-acenaphthyl)-N-methylguanidine; N, N'-bis(3-acenaphthy)-N, N'-bis-rethylguanid ine; N-(3-acenaphthyl)-N'-(l thracenyl)guanidine; N-(3-acenaphthyl)-N'-( I -a nth race nyl)-N-me-thyl guanidine; N-(3-acenaphthyl)-N'-( 1 -anthracenyl)-N'-methylguanidine; N-(3-acenaphthyl)-N'-( 1 -anthracenyl)-N, N'-bis-methylguaniidine; N-(3-acenaphthyI)-N'-(4-tert-butylphenyI) guanidine; N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)-N-methylguanidine; N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)-N'-methy~guanidine; N-(3-acenaphthy)-N'-(4-tert-butylphenyI)-N N'-bis-methylguanidine; N- (3-ace nap hthy I) (4-cycl10hex yiphen yI) g uan idine; N-3aeahhl-'(-ylheypey)Nmtygaiie

I

NV() 9?5114.107 IM IU')4/1354 I 28 N- (3-acenaphthyl)-N'-(4-cyciohexyiphenyl)-N'-methylgu anidine; N- (3-acenaphthyl)-N'-(4-cycohexyIphenyl)-N, N'-bis-methylguanidine; N- (3-ace nap hthyl)-N'-(4-sec-butylphenyI) guanidine; N- (3-acenap, i-wivl-i '-(4-sec-butylphanyl)-N-methylguanidine; N- (3-acenaphti ,,N'-(4-sec-butylphenyl)-N'-methylguanidine; N- (3-acenaphthyl)-N'-(4-sec-butylphenyl)-N, N'-bis-methylguanidine; N- (3-acenaphthyl)-N'-(4-methoxyphenyl)guanidino; N- (3-acenaphthyl)-N'-(4-methoxyphenyl)-N-methylguanidine; N- (3-acenaphthyl)-N'-(4-methoxyphenyl)-N'-methylguanidine; 1 0 N- acen a phthyl)- methoxyphenyl)- N, N'-bis-methylguanidine; N- (3-acenaphthyl)-N'-(2,3-dichlorophenyl)guanidine; N- ace nap hthyl)- 3-d ichlorop henylI)- N-methylIg ua nid ine; N-(3-acenaphthyl)-N'-(2,3-dichiorophenyl)-N'-methylguanidine; N- (3 -ace nap hthyl)-N'- (2,3-d ichlo ro phe nyl)-N, N'-bis-methylguanidine 1 5 N- (3-acenaphthyi)-N'-(4-methoxy-2-naphthyl) guanidine; N- ace nap hthyl)- methoxy-2-na phthyI)- N- methygua n Wine; N- (3-acena pht hyi)-N'-(4-methoxy-2-na phthyl1) -N'-methylg9u a [id ine; N- (3-acenaphthyi)-N'-(4-methoxy-2-naphthyl)-N, N'-bismethylguanidine; N-(3-acenaphthyl)-N'-(3,4-dichlorophenyl)guanidine; N- (3-acenaphthyl)-N'-(3,4-dichlorophenyl)-N-methylguanidine; N- (3-acenaphthyl)-N'-(3, 4-dichilorophenyI)-N-methylguanidine:, N- (3-ace naphthyi)-N'-(3, 4-dichlorophenyl)-N, N '-bis-methylguanidine; N- (3-acenaphthyl)-N'-(4-chlorophenyl)guan*Idine; N- (3-acenaphthyl)-N'-(4-chlorophenyl)-N-metthylgujanidine; 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; WO095/14467 ICT/1JS94/1I3541 -29 N-(3-acenaphthyl)-N'-(2-naphthyl)-N, N'-bis-methy Iguanidine; N- (3-acenap hthyl)-N'- (6-quino linyI) guanid ine; N- (3-acena phthyI)- (6-q uinolinyl)-N-methylIg ua nid ine; N- (3-ace nap hthyl) (6-q uino linyl) methylg ua nid ine; N-(3-acenaphthyl)-N'- (6-quinolinyl)-N, N'-bis-methylIgu anid ine; N- (3-acena phthyl)-N'-(4-nitro phenyl) gua nid ine; N-(3-acenaphthyi)-N'-(4-nitro phe nyl)-N-methylgua nid mne; N- (3-acena phthyl)-N'- (4-nitro phe nyl)-N'-methy Ig ua nid ine; N-(3-acenaphthyl)-N'- (4-nitrop he nyl)-N, N'-bis-methylg ua nidi ne; N- (3-acena phthyl-N'- (3-bi-phe nyl) guanidi ne; N- (3-ace nap hthyi-N'- bi-p henyi)-N-methyl guan id ine; N- (3-ace na phthyl-N'- (3-bi-p he ny1) methy Ig ua nid ine; N-(3-acenaphthyl-N'-(3-bi-phenyl)-N, N'-bis-methylguanidine; N- (3-acenaphthyl)-N'- 3-dimethylp he nyI) guanid ine; N- (3-ace na phthylI)- (2,3-d imethylpheny1) -N-methylIg u anid ine; N- (3-ace nap hthyl)-N'- (2,3-d imethylpheny1) N-methy g uani d ine; N-(3-acenaphthyl)-N'-(2,3-dimothylp he nyl)-N, N'-bis-methyIg uanidine; N (3-ace na p hthy bi- ph eny I) g u an i din e; N- (3-acena phthyl)- he nyl) -N-methyl gua nid ine; N-(3-acena phthyl)- (2-bi-p he nyl)-N'-methyl gua n idine; N-(3-acenaphthyl)-N'-(2-bi-phenyI) N'-bis-methylIgua nid in e; N- (3-acena phthylI)- 5-d ib ro mophe ny1) gua nid ine; N- (3-acenaphthyl)-N'- 5-dibromophenyl)-N-methy Igua nid in e; N- (3-acena phthyl)- 5-d ibro mop he nyI)- methyl gu an id ine; N-(3-acenaphthyl)-N'-(2,5-dibromophenyl)-N, N-bis-methylguanidine; N- (3-acena phthyl)- (3,4-d !met hoxyp he nyl) gua nid ine; N- (3-acena phthyl)-N'- (3,4-d imethoxyp he nyl) -N-methyl gua nid ine; N- (3-ace nap hthyl) (3,4-d imethoxy ph eny 1) meth y Ig uanid in e; N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N, N'-bismethylguanidine; WO 95/14467 PICTIUS94/1354 I 30 N-(3-acenaphthyi)-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-chioro-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-methyiguanidine; N-(3-acenaphthyi)-N'-(3,4, N-(3-acenaphthyl)-N'-(3,4, N-(3-acenaphthyl)-N'-(3,4, N-(3-acenaphthyi)-N'-(3,4, 5-trichlorophenyl)-N, N'-bismethylguanidine; N-(3-acenaphthyl)-N'-(4-bi-phenyi)guanidine; N-(3-acenaphthyl)-N'-(4-bi-phenyl)-N-methylguanidine; 1 5 N-(3-acenaphthyl)-N'-(4-bi-phenyl)-N'-methylguanidine; N- (3-acenaphthyl)-N'-(4-bi-phenyl)-N, N'-bis-methylguanidinc; N-(3-acenaphthyl)-N'-(2,3,4, N-(3-acenaphthyl)-N'-(2, 3,4, N-(3-acenaphthyl)-N'-(2,3,4, N-(3-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)-N,N'-bismethyiguanidine; N-(3-acenaphthyl)-N'-(3-isopropylphenyl)guanidine; N-(3-acenaphthyl)-N'-(3-/soprop)ylphenyl)-N-methylguanidine; N- (3-ace nap ht hy I) -(3-/sop rap yiphen yl -N'-methyl g uan idine; N-(3-acenaphthyl)-N'-(3-/sopropylphenyl)-N N'-bis3-methylguanidine; N -(3-ace nap hthyI) tert- butylp hen yI) g uan idine; N-(3-acenaphthyl)-N'-(3-tert-butylphenyl)-N-methylguanidine; N-(3-acenaphthy!)-N'-(3-tert-butylphenyl)-N'-methylguanidine; i'q-(3-acenaphthyl)-N'-(3-tert-butylphenyl)-N, N'-bis-methylguanidine; N-(3-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)guanidine; WO 95114467 P('T1U594/ 13541 31 N- (3-acena phthyl)- 3,5, 6-tetrac hlorop he nyl)- N-methy Ig u anid ine; N- (3-acena phthyl)- 5, 6-tetrachlo ro phe nyl)-N'-methylg ua nid ine; N- (3-acenaphthyl)-N'- 3,5, 6-tetrach lorophenyl)-N, N'-bismethyl gu anid in e; N- (3-ace na phthyl)-N'- (3-iodo phe nyl) guanid ine; N- (3-acenap hthyl)-N'- (3-io do phe nyl)-N-methyigu an idine; N- (3-ace na phthyI) '(3-id do p heny yI) -methyl g ua an i ne; N-(3-acenaphthyl)-N'-(3-iodophenyl)-N, N'-bis-methylguanid ine; N- (3-acenap hthyl)-N'- (3-nitropheny I) guanid ine; N- (3-ace nap hthyfl)-N'- nitro phenyl)- N- methyl gua nid ine; N- (3-ace nap hthyl)-N'- (3-nitro phe nyl)- N'-methylIg ua nid ine; N-(3-ace nap hthyl)-N'- (3-nitrop he nyl)-N, N'-bis-methy Iguanidine; N- (3-acenaphthyl)-N'- (5-indolinyl) guanldine; N- (3-acena phthyl)- (5-indoinyl)-N- methylg ua nid ine; 1 5 N- (3-acenap hthyl)-N'- (5-indolinyl)-N'-methylg ua nidine; N-(3-acenaphthyl)-N'- (5-indolinyl)-N, N'-bis-methylguanidine; N-(3-acenaphthy)-N'-(2-f Iuorenyl) guanidine; N- (3-ace nap hthy)- (2-f luo renyI)- N-met hylg ua nid ine; N- (3-acenaphthy)-N'- (2-flIuorenyl)-N'-methylg ua nid ine; N-(3-acenaphthy)-N'-(2-f luorenyl)-N, N'-bis-methylg uanid ine; N- (3-acena phthyl)- n- butoxyp henyl) gua nid ine; N- (3-acenaphthyl)- 4- n- butoxyp henyl)- N- methy Ig ua nid in e; N- (3-ace nap hthyl)-N'- n-b utoxy pheny N'-methylg ua nid ine; N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N, N'-bis-methylguanidine; N- (3-acena phthyl)- methoxy) dibenzof ura ny1) g uanid ine; N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzof uranyl)-Nmethylguanidine; N- (3-acena phthylI)- methoxy)d ibenzof ura nyl)- N'methylguanidine; WO 95/14467 Pcrus4/1354 I 32 N- (3-acenaphthyl)-N'-(3-(2-methoxy)d ibenzof uranyl)-N, N'-bismethylguanidine; N- (3-acenaphthyl)- N'-19-hyd roxy- 2-f Iuorenyl) guanid ine; N- (3-ace na phthy I) hyd roxy- 2-f lu ore ny I) N-rnethylI g u an id dine; N- (3-ace na phthyl) hyd roxy- 2-f IuorenylI)-N'-methyl gua nid ine; N- (3-acenaphthyl)-N'-(9-hydroxy-2-f luorenyl)-N, N'-bismethylguanidine; N-(3-acenaphthyl)-N'- (4-triflIuoromethylphenyl) gua nidine; N- (3-ace nap hthyl)-N'-(4-tri flIuoro methyl phe nyl) -N-methyl gua nid ine; N- (3-acenaphthylI)- (4-trif luoromethylp he nyl0-N'-methy lguanid in e; N-(3-acenaphthyl)-N'-(4-triflIuoromethylphenyl)-N, N'-bismethylguanidine; N-(3-acenaphthyl)-N'-(4methylthiophenyl)guanidine; N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N-methylguanidine; 1 5 N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N'-methylguanidine; N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N, N'-bis-methylguanid me; N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)gLuanidine; N-(3-acenaphthyl)-N'-(3-sec-butylplhenyl)-N-methylguanidine; N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N'-methylguanidine; N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N,N'-bis-methylguaniidinie; N -ace nap hthy I) -(4-ben zyl0xy ph en yl) gu an idine; (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-ace nap hthy -(4-ada ma nty Iph en y 1) uan idine; 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'-phenylethyi)phenyl)guanidine; WO 95/14467 PCT1US94/1354 I 33 N- (5-ace na p hthy (3 ,4-tet ra ii fl p he fl) g u an id dine; N- (5-ace na phthyl)-N'- (7-be nzyltetra Ii nyl phe ny1) gua nid ine; N-(5-acenaphthyl)-N'-(3,4-dibenzyI oxyphenyl)guanidine; N-(5-acenaphthyl)-N'-(3-1 ethoxy)phenyl)propanyl)phenyl)guanidine; N-(5-acenaphthyl)-N'-(3-(N m 1 N"-dibenzy)aminophenyl)guanidine; N-(5-acenaphthyl)-N'-(3-(l '-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-ace nap hthy phe nethyIp hen yI) gu an idine; N-(3-acenaphthyl)-N'-(4-adamantylphenyl)guanidine; N-(3-acenaphthyl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine; N- (3-ace nap hthy I) -(4-ben zyl oxy ph enyl -methyl g u an id dine; N- (3-ace nap hthyl)- bip henyl)-N'- methylg ua nid ine; N-(3-acenaphthyl)-N'-(3-(l1'-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 etho xy )phe nyI) prop anyI) p he ny) g ua n idine; 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)phenylguanidinie; IIElsD WO 95/14467 IPCITUS94/13541 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 R 2 groups defined above for Formulas IIA and lIB.

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); C.A. Maryanoff, et al., J. Org. Chem., 51:1882 (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 und PCT/US92/01050.

More particularly, the synthesis of the diaryl substituted guanidines of the invention is typically achieved by condensing a salt WO 95/14467 PCT/US94/13541 35 of an arylamine with a substituted aryl cyanamide such as 3acenaphthy! 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 Pd/C-H 2 NH N02 HAc Mixture of 5 &3

NH

2 2.

NH

2 CNBr/EtOAc_ NHCN

NH

2 HBr Ar -NHz+tX C&H5CH3 or CHsCl reflux

H

II I

NH

*HX

In step 1 of the above Scheme, a mixture of b- and 3-nitroacenaphthene 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. 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.

-1

I

WO 95/1,1467 PCT/UIS94/13541 36- SCHEME-2: PREPARATION OF N-ALKYL AND N,N'-DIALKYL N,N'- DI-ARYL GUANIDINES NHCN NaH/THF

N.

R-X

R

1 NH HX Are C6H5C1/AC13 reflux SR R N NAr

NH

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-3acenaphthyl-N-alkyl cyanamide (suitably prepared as discussed above) is treated with a salt of an aryl amine (for synthesis of trisubstituted 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 AIC 3 catalyst. 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.

I

WO 95/14167 PCITUS94/13541I -37- Such substituted cyanamide reagents can be readily prepared. For example, a substituted acenaphthyl derivative can be nitrated treatment with HNO 3 /H2SO 4 to provide a 3-nitroacephthyl or 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, haloacenaphthalene such as 3-fluoroacenaphthalene, 3chloroacenaphthalene, 3-bromoacenaphthalene, 4fluoroacenaphthalene, 4-chloroacenaphthalene, 4bromoacenaphthalene, 4-fluoroacenaphthalene, 4chloroacenaphthalene, and 4-bromoacenaphthalene; alkanoylacenaphthalene such as 4-acetylacenaphthalene; alkoxynaphthalene such as 4-methoxyacenaphthalene; acenaphthalene, 3-acid; 5-acenaphthalene, ethanol; acenaphthalene, methanol; alkenylacenaphthalene such as 3-(1methylpropenyl)acenaphthalene; 5-acenaphthalenecarboxanilide; and the like.

If the ring substitutent of the acenaphthyl derivative includes a potentially reactive functionality 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.

I WO 95/14467 PICT/US94/13541 -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): 1106-10 (1990); L. Skulski, et al., Pol. J.

Chem., 55(9): 1809-24 (1981); A. F. Pozharskii, Isobret. Prom.

Obraztsy, Tovarnye Znaki, 96-7 (1982); J. P. Li, et al., US 78- 890736 (1978); N. S. Vorozhtsov, Zh. Org. Khim., 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 (1969); 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

II

WO 95/14467 PCI1US94/13541 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, WO 95/14467 PCT/US94/1354 I 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), gpl20 neurotoxicity is associated with increased levels of Ca 2 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, 11th 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 voltageactivated 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 WO 95/14467 PCT/US94/135411 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 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 Fink-Jensen et al., Neurosci. Lett., 137(2):173 (1992)).

See also Price, et al., Soc. Neurosci. Abstr., 16:377, abstr. 161.16 (1990). Compounds of the invention, particularly those compounds that are charged s ich 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.

I

I

WO) 5/14.167 PCT'lllS94/13541 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, 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, 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, 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 pharmace .tically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid,

IIL~SI-

WO 95/14467 PCT/US94/13541 -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, 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, by microencapsulation, multiple coatings, etc.

Intravenous or parenteral administration, 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 II i

I

WO 95/14467 iPCTUS94/13541 -44administration, 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 liB, particularly when using the more potent compound(s) of Formula I, Formula IA, FormulailB, Formula IIA or Formula lIB 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, 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, containing from 0.25 to 25 milligrams of compound(s) of Formula I, Formula IA, Formula IB, Formula IIA or Formula lIB 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. 1,411,713, 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.

WO 95/14467 PCT/US94/13541 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 F 25 4 (0.2 mm) or Baker-flex 1B2-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 Preparative TLC was performed on Analtech GF precoated silica gel (1000 pm) glass-backed plates (20 x cm). The IR, 1H and 3 C 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 relative to the residual signal of the deuterated solvent (CHCI 3 6 7.26; CHD 2 OD, 6 3.30). Infrared spectra were recorded in CHCI 3 (unless otherwise noted) on a Nicolet 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 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 water: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,

I

WO 95/14467 PCT/US94/13541 46 where noted, by published procedures. 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. Alkyland arylcyanamides were prepared as described above and according to published procedures PCT/US92/01050) by reaction of the amines with BrCN in ether.

Example 1: Preparation of N-(5-acenaphthyl)-N'-(2,3,4trichlorophenyl)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 MI) and ethyl acetate (25 MI). 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 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 and dried in vacuo to give 1.5 g of pure product, mp 163-65 0

C.

WO 95/14467 PICT1US94/13541 47 Ste e2. Preparation of N-(5-acenaphthvl)-N'-(2,3,4trichlorophenyl)quanidine*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 0 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 to give product (0.293 g, 68%) as an off white solid, mp: 208- 100C; 'H NMR (CD 3 OD): J 7.70-7.58 3H, Ar-H), 7.48 2H, Ar-H), 3.47-3.41 4H, 2 x CH 2 HRMS 389.0220 (389.0253 calcd. for C 19

H,

4

N

3 Anal Calcd. for C 9 ,Hi 5 NaCI 4 (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 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 200C, methyl iodide (2.64 g, 18.6 mmol) wa added and stirred the contents at 200C. 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 MgS04 and the solvent was evaporated. The residue was purified on flash chromatography WO 95/14467 PCT/US94/13541 48 to yield the product (0.8 g, 50%) as a tan solid. TLC (CHCI:CH 3

OH;

10:1): R,=0.72.

Part 2. Preparation of auanidine*HCI Aluminum chloride (0.28 g, 2.11 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 1450C. After 10 minutes acenaphthene amine hydrochloride (0.39 g, 1.29 mmol, prepared from 5-acenaphthene and 1.OM 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: 2360C; TLC (CH 2

CI

2 :CHO3H; R,=0.19; 'H NMR (CDCl 3

CD

3 OD): 6 7.61-7.04 10H, Ar-H), 3.84-3.81 2H, CH 2 3.43-3.27 (m, 9H, 3 x CH 2 and CH 3 HRMS: 377.1897 (377.1892 calcd. for

C

26

H

2 3

N

3 Example 3: Preparation of methyl guanidine*HCI (METHOD C (Scheme-2)) Part 1. Preparation of N-methvl-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 amine (5.8 g, 34.3 mmol) was dissolved in warm formic acid 25 mL) and refluxed. After 7 hours, the reaction mixture was cooled to 250C and then let is stand in refrigerator for 12 hours. The solid was filtered and washed with WO 95/14467 PCT/US94113541 49 acetonitrile and then air-dried to afford the formamide (6.65 g), which was used in the next step without further purification.

BH

3 -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 250C for 18 hours, the reaction mixture was concentrated to a volume of ca.

mL and the ethyl acetate (10 mL) was added at 100C. The mixture was quenched with 3N HCI solution and then basified with NaOH solution. It was extracted with methylene chloride (2 x mL), dried (Na 2

SO

4 and evaporated to give a tan colored solid (5.45 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 quanidine*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 1450C. After 10 minutes acenaphthene-N-methyl amine hydrochloride (0.29 g, 1.3 mmol; prepared from 5-acenaphthene-N-methyl amine and 1.OM 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: 2720C; TLC (CHCI':CH 3 OH; 10:1): R,=0.17; 'H NMR (CD 3 OD): 6 7.18 (bs, 5H, Ar-H), 6.78-6.73 5H, Ar-H), 3.47 6H, 2 x CH 3 3.24-3.19 4H, 2 x CH2), 3.04 (bs, 4H, 2 x

CH

2 HRMS: 391.2051 (391.2048 calcd. for C 27

H

25

N

3 WO 95/14467 PCT/US94/1354 I 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 0 C; 'H NMR (CD 3 OD): 5 8.65-7.25 14H, Ar-H), 3.33- 3.20 4H, 2 x CH 2 2.25 3H, -CH 3 Anal. Calcd. for

C

28

H

2 5

N

3

*CH

3

SO

3 H: 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

(CH

2

CI

2

:CH

3 OH; 1 H NMR (CD 3 OD): 5 7.65-7.20 (m, 9H, Ar-H), 3.30 4H 2 x CH 2 1.22 9H, 3 x CH 3

HRMS:

343.2043 (343.2048 calcd, for C 23

H

25

N

3 Example 6: N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)guanidine*HCI Preparation: As per Method A of Example 1, except that 4cyclohexylphenyl cyanamide was reacted with 5-acenaphthyl-1amine hydrochloride. White solid; mp: 232-34°C; 'H NMR (DMSO).

6 7.8-8.2 13H, Ar-H), 3.4-3.3 5H, 2 x CH 2 and CH), 1.8- 1.15 10H, 5 x CH 2 Anal. Calcd. for C 25

H

28

CIN

3 (405.95): C, 73.96; H, 6.95; N, 10.35; Cl, 8.73; Found: C, 73.91; H, 6.96; N, 10.12; CI, 8.56.

WO 95/14467 PuT/1JS94/J 3541 51 Example 7: N-(5-acenaphthyl)-N'-(4-secbutylphenyl)guanidineHCI Preparation: As per Method A of Example 1. White solid; TLC

(CH

2 0'1:CH 3 OH; Rf=O.

7 1 H NMR (CD 2 00): 6 7.60-7.15 (in, 9H, Ar-H), 3.30 (in, 4H, 2 x CH- 2 2.52 1H, 1.50 (in, 2H,

OH

2 1.1 1 3H, CH 3 0.71 3H, CH 3 HIRMS: 343.2051 (343.2049 calcd. for C 23

H-

2 ,1\ 3 Example 8: N-(5-acenaphthyl)-N'-(4-methoxyphenyl)guanidineoHBr Preparation: As per Method A of Example 1. Fluffy cream solid; mp: 187-200IC; TLC (CHCI 3

:CH

3 OH; 10:1); Rf =0.31; 'H NMR

(CDCI

3 J67.45-7.10 (in, 7H, Ar-H), 6.80 2H, J =8Hz, Ar-H4), 3.68 3H, OCH- 3 3.38-3.22 (in, 4H, 2 x OH 2 HRMS: 317.1509 (317.1528 calcd. for 0 20

H-

19 1\ 3 Anal. Calod. for C 20

H

2 (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)guanidineeHCl Preparation: As per Method A of Example 1. White (yellow tint) solid; mp: 124-30IC; TLC (CHCI 3

:CH

3 OH; 10:1): Rf=O.lS; 'H NMR (CDCI 3 6 7.59 1 H, J =8Hz, Ar-H), 7.47 1 H, J =8Hz, Ar- 7.36-7.14 (in, 6H, Ar-H), 3.40-3.25 (in, 4H, 2 x OH 2

HRMS:

355.0647 (355.0643 calcd. for CjqHjC 12 Example 10: N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)guanidinle Preparation: As per Method A of Example 1. Light yellow solid; mp: 191-92IC; TLC (CH 2

CI

2

:CH

3 OH; Rf=0.51; 'H NMR

(CD,

3 OD CDCI 3 6 8.17 1 H, J =8Hz, Ar-H), 7.73 1 H, J=8Hz, Ar-H), 7.66 1H, J=8Hz, Ar-H), 7.57-7.26 (in, 7H, Ar-H), WO 95/1,1467 ICIUS94/1354 I 52 7.09 1H, J=8Hz, Ar-H), 3.96 3H, OCH 3 3.43-3.35 4H, 2 x CH 2 HRMS: 367.1680 (367.1685 calcd. for C 24

H-

21 0N.), Example 11: N-(5-acenaphthyl)-N'-(3,4-dichlorophenyl)guanidine*HCI Preparation: As per Method A of Example 1. White solid; mp: 300WC; TLC (CHCI 3

:CH

3 OH; 10:1): Rf =0.27; 1H NMR (CDCI 3 7.55 1 H, J =8Hz Ar-H), 7.48 1 H, J =8Hz, Ar-H), 7.37 2H, J =8Hz, Ar-H), 7.30 2H, J =8Hz, Ar-H), 7.19 Cd, 1 H, J =7Hz, Ar- 7.13 (bd, 1 H, Ar-HI), 3.66-3.30 Cm, 4H, 2 x OH 2

HRMS:

355.0651 (355.0643 calcd. for Cl 9 HlCl 2

N

3 Example 12: N-(5-acenaphthyl)-N'-(4-chlorophenyl)guanidine*HBr 1 5 Preparation: As per Method A of Example 1, except N-4chlorophenyl cyanamide was reacted with 5-acenaphthyl-1 -amine hydrobromide. White solid; mp: 216-17CC; 1 H NMR (CDCI 3 6 7.65- 7.23 Cm, 9H, Ar-H), 3.42-3.35 Cm, 4H, 2 x CH 2 1-C NMR (CDCI 3 147.81, 146.47, 140.09, 133.35, 132.11, 131.98, 129.90, 129.40, 127.48, 126.83, 126.70, 126.66 124.65, 124.51, 120.52, 118.95, 30.49, 29.94; HRMS: 321.1039 (321.1033 calcd. for

C,

9

H

16 NCl).

Example 13: N-(5-acenaphthyl)-N'-(2-naphthyl)guanidineoHC Preparation: As per Method A of Example 1. Light yellow solid; mp: 20000; TLC (CHCI, 3

:CH

3 OH; 10:1): R 1 =0.14; 'H NMR

CCDCI

3

CD

3 OD): 65 7.78-7.14 Cm, 12H, Ar-H), 3.33-3.25 Cm, 4H, 2 x CH 2 HRMS: 337.1500 (337.1579 calcd. for C 23

H,

9

N

3 WO 95/14467 I1CIlUS94l135-1I 53 Example 14: N-(5-acenaphthyI)-N'(6-quinolinyl)guanidineeHCI Preparation: As per Method A of Example 1. White solid; mp: 242-441C; TLC (CHCI 3 :MeOH 10:1): R 1 0.2; 'H NMR (DMSO): 6~ 9.1 3 (in, 11 H, A r- 3. 5 2 (mn, 4H, 2 x COH- 2 Example 15: N-(5-acenaphthyl)-N'-(4-nitrophenyl)guanidine*HCI Preparation: As per Method A of Example 1. 0ff white solid; mp: 85-86OC; 'H NMR (CD 3 OD): 6 7.57-7.05 (mn, 9H, Ar-H), 3.49- 3.43 (mn, 4H, 2 x OH 2 MS(Cl): in/e 333 (M 1 for the free base).

Example 16: N-(5-acenaphthyl-N'-(3-bi-phenyl)guanidineoHCI Preparation: As per Method A of Example 1. White cream solid; mp: 128-361C; TLC (0H01 3

:CH

3 OH; 10:1): Rf=O.56; 1 H NMR

(CD

3 OD): 6 7.68-7.35 (in, 14H, Ar-H), 3.45-3.3 1 (in, 4H, 2 x OH 2 HRMS: 363.1726 (363.1735 calcd. for C 25

H

21 Example 17: N-(5-acenaphthyl)-N'-(2,3-dimethylphenyl)guanidine-,HCI Preparation: As per Method A of Example 1. Light yellow solid; inp: 199-20OoC; TLC (CHCI 3

:CH

3 OH; 10:1): Rf=O.

3 8; 'H NMR

(CD

3 OD): 6 7.68-7.58 (in, 2H, Ar-H), 7.48 1 H, J =8Hz, Ar-H), 7.41-7.36 (in, 2H, Ar-H), 7.23-7.16 (in, 3H, Ar-H), 3.45-3.39 (in, 4H, 2 x CO 2 2.34 3H, OH 3 2.28 3H, OH 3

HRMS:

315.1717 (315.1735 calcd. for C 21

H-

21 1\ 3 Example 18: N-(5-aceniaphthyl)-N'-(2-bi-phenyl)guanidine HBr Preparation: As per Method A of Example 1. White solid; mp: 141-43IO; iH NMR (CD 3 OD): 6 7,56-7.05 (in, 14H, Ar-H), 3.43- WO) 95/14467 PCIAS94II 35411 54 3.31 (in, 4H, 2 x OH 2 MS m/e 364 (M 1 for the free base); HRMS: 363.1737 (363.1735 calcd. for C 25

H

2

,N

3 Example 19: N-(5-acenaphthyl)-N'-(2,5-dibromophenyl)guanidine.HCI Preparation: As per Method A of Example 1. Yellow tint solid; mp: 194-96IC; TLC (CHCI 3

:CH

3 OH; RI=0.33; 'H NMR

(CD

3 00): 65 7.74-7.34 (in, 8H, Ar-H), 3.50-3.42 (mn, 4H, 2 x OH 2 HRMS: 442.9678 (442.9633 calcd. for C 18

H

15 Br 2

N

3 Example 20: N-(5-acenaphthyl)-N'-(3,4-dimethoxyphenyl) guanidine H Cl Preparation: As per Method A of Example 1. Brown solid; mp: 152-55oC; TLC (CHCI 3

:CH

3 OH; 10:1): RI=0.27; 1H NMR

(CD

3 OD): 6 7.70-7.58 (in, 2H, Ar-H), 7.47 I1H, J =Hz, Ar,H), 7.41-7.35 (mn, 2H, Ar-H), 7.04-6.92 (in, 3H, Ar-H), 3.85 3H,

CH

3 3.84 3H, OH 3 3.47-3.44 (mn, 2H, 2 x OH 2

HRMS:

347.1637 (347.1634 calcd. for C 21

H

21 0 2 Example 21: N-(5-acenaphthyl)-N'-(4-methoxy-1 -naphthyl)-Nmethylguanidine* HCi Preparation: As per Method B of Example 2. Light yellow solid; inp: 158-59IC; TLC (CHCI 3

:CH

3 OH; 10:1): Rf=O.

2 5; 'H NMR

(CD

3 OD): 65 8.30-6.90 (mn, 11 H, Ar-H), 4.03 3H, 00H 3 3.64 (bs, 3H, N-CH 3 3.50-3.41 (in, 4H, 2 x OH 2 HRMS: 381.1850 (381.1841 calcd. for C 25

H

23 0N 3 Example 22: N..(5-acenaphthyl)-N'-(4-methoxy-1-naphthyl)-N'-methyI guanidine*,HCI Preparation: As per Method B of Example 2, except that Nmethyl-N- (4-metho.:.y- 1-nap hthyl) cyanainide was reacted with WO( 9)5/1-4'167 PCFI.S94/1354 I 55 acenaphthyl-1-aminle hydrochloride. White solid; mp: 195-97oO; TLC (CHCIa:CH3OH; 10:1): Rf=O.1O; 1H IR (OD 3 OD): S68.37 1H, J=8.4Hz, Ar-H), 7.95-7.28 (in, 9H, F I, 7.05 1IH, J=8.3Hz, Ar-H), 4.07 3H, 00H 3 3.60 (bs, 3H, N-OH 3 3.47-3.31 (in, 4H, 2 x CH 2 HRMS: 381.1840 (381.1841 calod. for C 2

,H

23 0ON,).

Example 23: N-(5-acenaphthyl)-N'-(4-methoxy-1 -naphthyl)- N,N'-dimethyl guanidineoHCl Preparation: As per Method C of Example 3. White solid; mp: 210-12IO; TLC (CHCI 3

:CH

3 OH; 10:1): Rf=O.

3 4; 'H NMR (OD 3 OD): 7.95 1H, Ar-H), 7.38-6.65 (in, 10H, Ar-H), 3.82 3H, 00H 3 3.48 3H, N-CO 3 3.42 3H, N-OH 3 3.25-3.18 (in, 2H, OH 2 3.04-2.65 (in, 2H, OH 2 HRMS: 395.2005 (395.1998 calcd. for

C

26

H

25 0N 3 Example 24: N-(5-acenaphthyl)-N'-(4-chloro-1 -naphthiyl)guanidine.HCI Preparation:, As per Method A of Example 1. White solid; mp: 258-601C; 'H NMIR (CD 3 OD); 6 8.38-8.35 (in, 1 H, Ar-H), 8.15-8.11 (in, 1H, Ar-H1), 7.81-7.34 (mn, 9H, Ar-H), 3.44-3.41 (in, 4H, 2 x OH 2 MS mn/e 372 (M 1 for free base); Anal. Oalcd. for 0 23 H,,01 2

N

3 (408.31): 0, 57.65; H, 4.69; N, 10.29; Ff-iund: 0, 67.58; H. 4.60; N, 10.28; HPLO (OH 3

ON:H

2 0 50:50 with 0.1%9, TFA): 99.9% pure.

Example 25: N-(5-acenaphthyl)-N'-(3,4,5-trichlorophenyl) g uan idine0 H Cl Preparation: As per Method A of Example 1 White solid; inp: 234-361C; TLC: Rf 0.28 (0H 2 01 2

/OH

2 OH: 'H NMIR (OD 3

ODI:

7.68-7.35 (in, 7H, Ar-H), 3.53-3,40 (in, 4H, 2 X OH 2

HRMS:

381.0251 (389.0253 calod. for O, 9

H,

4 01 3

N

3 HPLO (OH 3

ON:H

2 0 50:50 with 0. 1% TFA): 95.5 pure.

%N 95/14467 PCIIS94/1354 I 56 Example 26: N-(5-acenaphthyl)-N'-(4-bi-phenyl)guanidine*CH 3

SO

3

H

Preparation: As per Method A of Example 1. White solid; mp: 196-981C; TLC (CHCI 3

:CH

3 OH; 10:1): Rf= 0.29, 'H NMR (CD3OD) c6 7.75-7.36 (in, 14H, Ar-H), 3.45 (bs, 4H, 2 X CO 2 2.69 3H,

OH

3 HRMS: 363.1737 (363.1735 cailcd. for C 2 51H 21 Example 27: N-(5-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl) guanidinee HCI Preparation: As per Method A of Example 1. White solid; mp: 223-25IC; TLC (CH 2 01 2

/CH

2 OH; Rf=O.51; jH NMR (CDOD): J 7.74-7.33 (mn, 6H, Ar-H), 3.47-3.40 (in, 4H, 2 X OH 2 Anal Calcd.

for C 19

H,

3 Cl 4

N

3 (461.59): C, 49.44; H, 3.06; N, 9.1; Found: C, 50.89; H, 3.15; N, 8.84; HRMS found: 422.9875 (422.9864 Calcd.

for r' H, 3 Cl 4

N

3 HPLC (CH 3

CN:,H

2 0 45:55 with 0 1 TFA): 95.5% p Lre.

Example 28: N-(5-acenaphthyl)-N'-(3-isopropylphenyl)guanidine-HCI Preparation: As per Method A of Example 1. White solid; mp: 149-51'C; TLC (CH01, 3

:CH

3 OH; 10:1): Rj=0.28; 1H NMR (CD 3 OD): 7.66-7.19 (in, 9H, Ar-H), 3,44 (bs, 4H, 2 X CO 2 3.00-2.89 (in, 1 H, 1.26 bH, J=7Hz, 2 X OH 3 HRMS: 329.1873 (329.1892 calcd. for C 23

H-

25 1\ 3 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 (OHCI 3

:OH

3 OH; 10:1): Rf=O.

2 6 'H NMR (OD 3 OD): 6 7.68-7.28 (in, 9H, Ar-H), 3.45-3.44 (in, 4H, 2 X OH 2 1.33 3H,

OH

3 HRMS: 343.2055 (343.2048 calcd. for O 22

H

23

N

3 WO 95/14467 1'cT/US94j/ 135411 57 Example 30: N-(5-acenaphthyl)-N'-(2,3,5,6tetra chlorophenyl)guanidinee CH 3

SO

3

H

Preparation: As per Method A of Example 1. White solid; mp: 248-50IC; H N MR (CD 3 OD): 6 8.12-7.33 (in, 6H, Ar-H), 3.44-3.40 (in, 4H, 2 X CH 2 2.69 3H, CH 3 MS 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: 203-04IC; TLC (CHCI 3

:CH

3 0H; 10:1): R 1 =0.19; 'H NMR 6 7.76-7.58 (in, 4H, Ar-H), 7.47 1H, J=7.33Hz, Ar-H), 7.42-7,34 (mn, 3H, Ar-H), 7.22 1 H, J =8Hz, Ar-H), 3.45-3.44 (in, 4H, 2 X

CH

2 HRMS: 413.0395 (413.0389 calcd. for C,,H 16

IN

3 Example 32: N-(5-acenaphthyl)-N'-(3-nitrophenyl)guanidine-HCI Preparation: As per Method A of Example 1. Yellow solid; mp: 244-48IC; TLC (CHCI 3

:CH

3 OH; 10:1): R 1 =0.16; 1 H NMR (CD 3 00): 6 8.25-8.16 (mn, 2H, Ar-H), 7.80-7.58 (mn, 4H, Ar-H), 7.51 1H, J =7.24Hz, Ar-H), 7.41 1 H, J =6.9Hz, Ar-H), 7.37 1 H, J =7.4Hz, Ar-H); HRMS: 332.1276 (332.1273 calcd. for

C

19

H

16

N

4 0 2 Example 33: Preparation: As per Method A of Example 1. Yellow-white solid; mp: 147-48IC; TLC (CHCII:CH 3 OH; 10:1): Rf=0.27; 1 H NMR

(CD

3 OD): J67.65-7.57 (mn, 2H, Ar-H), 7.46 1 H, J =7.3Hz, Ar-H), 7.41-7.29 (in, 3H, Ar-H), 7.22 (bs, 1 H, Ar-H), 7.12 (dd, 1 H, J =7.9 and 2.1 Hz, Ar-H), 3.47-3.43 (in, 4H, 2 X CH 2 2.92 (dd, 4H, WO 95/14467 PC'TI/IJS94/ 135,11 58 J =14.8 and 7.4Hz, 2 X Ar-OH 2 2.10 (in, 2H, OH 2

HRMS:

327.1742 (327.1735 calod for C 22

H

21 Example 34: N-(5-acenaphthyl)-N'-(3-acenaphthyl) guanidine*CH 3

SO

3

H

Preparation: As per Method A of Example 1. White solid; mp: 245 0 C, 'H NMR (300 MHz, CD 3 00): 65 7.69-7.73 (in, 2H, Ar-H), 7.60-7.65 (in, 2H, Ar-H); 7,49-7.53 (in; 2H, Ar-H); 7.35-7.48 (in, 4H, Ar-H); 3.41-3.49 (in, 4H, 2 X OH 2 2.68 3H, OH 3 MS (El): m/e 363 for free base); Elemental analysis for 0 25

H

2

,N

3

.CH

3

SO

3 H*2H 2 0: t-alcd: 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; HPLO (AcON: H 2 0 99.3% pure.

Example 35: N-(5-acenaphthy)-N'-(2-fluoreflyl)guanidine&HCI Preparation: As per Method A of Example 1. Buff white solid: mp: 239-240IO; 'H NMR (300 MHz, OD 3 OD): 6 7.90-7.92 (d, J =8Hz, 1 H, Ar-H), 7.82-7.84 J =7Hz, 1 H, Ar-H) 7.69-7.72 (d, 1 H, J =8Hz, Ar-H); 7.62-7.64 (in, 3H, Ar-H); 7.48-7.51 (d, 1H, Ar-H); 7.29-7.41 (in, 5H, Ar-H); 3.95 2H, OH 2 3.40-3.47 (in, 4H, 2-OH 2 MS in/e 375 (M for free base): Elemental analysis for 0 26

H

2 1

N

3 *H01025H 2 0: Oalcd: 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-butoxypheflyl)guanidine*HC Preparation: As per Method A of Example 1. Brownish solid; inp: 9000; 1 H NMR (300 MHz, CD 3 OD): 65 7.57-7.67 (in, 2H, Ar-H), 7.45-7.47 J=7.5Hz, 1H, Ar-H); 7.34-7.40 (in, 2Hm Ar-H); 7.27- 7.30 (in, 2H, Ar-H); 6.99-7.02 (in, 2H, Ar-H); 3.97-4.02 2H, 0-

M

WO 95/1167 PCT/IS94II354 I 59

OH

2 3.41-3.47 (in, 4H, 2-CH 2 1.71-1.78 (dt, 2H, OH 2 1.46-1.54 (in, 2H, OH 2 0.95-1.00 3H, OH 3 MS mle 359 for free base); Elemental analysis for C 23

H

2

,N

3 0*HCI*0*75H 2 0: Oalcd: 0, 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) guanidinesHCI Preparation: As per Method A of Example 1. White solid; mp: 23000; 'H NMR (300 MHz, OD 3 OD): J68.06-8.09 (dd, J1 J2 =1.5Hz, 1 H, Ar-H), 7.80 1 H, Ar-H), 7.73-7.76 J 1H, Ar-H), 7.60-7.65 (in, 3H, Ar-H), 7.46-7.56 (in, 2H, Ar-H), 7.34- 7.40 (in, 3H, Ar-H), 4.10 3H, 0-OH 3 3.40-3.43 (in, 4H, 2-OH 2 MS m/e 407 for free base); Elemental analysis for 0 26

H

2 jN 3 0 2 *HCI*0925H 2 0: Oalcd: 0, 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-2fluorenyl)guanidineoHCI Prepairation: As per Method A of Example 1. White solid; mp: 26510; 1 H NMR (300 MHz, OD 3 OD): 65 7.80-7,83 J=8Hz, 1 H, Ar-H), 7.69-7.74 2H, Ar-H), 7.60-7.64 (in, 3H, Ar-H), 7.49-7.52 J =7.5Hz, 1 H, Ar-H), 7.34-7.42 (in, 5H, Ar-H), 5.58 1 H, -OH), 3.45 (brs, 4H, 2-OH 2 MS m/e 391 (M for free base); Elemental analysis for C 2

,H

2

N

3 0HI0025H 2 0: Oalcd: 0, 72.22; H, 5.24; N, 9.7; Found: 0, 72.35; H, 5.35; N, 9.58.

Example 39: N cena phthyl)-N'-(4-trif lu oroflethylp hen yl) guanidine*HCI Preparation: As per Method A of Example 1. White solid; mp: 234-2361C; TLC (0H 2 01 2

:OH

3 OH 9: Rf 1 H NMR (0D01 3 WO 95/14467 1CT1S415 60 7.70-7.25 (in, 9H, Ar-H), 3.46-3.38 (in, 4H, 2 X -OH 2 MS(CI): m/e 356 (M Anal Calcd, for C 2 0HlN 3

F

3 oHCI (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) guanidinesHCI Preparation: As per Method A of Example 1. White solid; mp: 168-170aC; TLC (CH 2

CI

2

:CH

3 OH Rf=O.

38 1H NMR (CD, 3

OD):

7.76-7.38 (mn, 9H, Ar-H), 3.53-3.37 (in, 4H, 2 X -OH 2 2.57 3H, MS(Ci): in/e 334 (M Anal. Calcd. for C 20 Hl 9

N

3

S*HCI

(369.91): C, 64.94; H, 5,45; N, 11.36; Found: C, 64.38; H, 5.73; N, 11.05.

1 5 Example 41: N-(5-Acenaphthyl)-N'-(4-benzyloxyphenyl) guanidine*HCl Light green foam; mp: 1 17-127OC; TLC (CH 2

CI

2

:CH

3

OH;

15:1): Rf=0.50; 1 H NMR (CD 3 OD): 7.646-7.094 (in, Ar-H, 14H), 5.127 CH 2 2H), 3.454-3.449 (in, CH 2

CH

2 4H); Anal. Calcd for

C

26

H

23

N

3 0*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 (CH 2

CI

2

:CH

3 OH; 15:1):

R

1 =0.50; 'H NMR (CD 3 OD): 7.639-6.981 (in, Ar-H, 14H), 5.117 (s,

CH

2 2H), 3.451-3.344 (in, CH 2

CH

2 4H); Anal. Calcd. for

C

2

,H

23

N

3 0*-HCI*0.5H 2 0 (438.95): C, 71.07; H, 5.70; N, 9.57; Found: C, 71.44; H, 5.60; N, 9.83.

WO 95/141467 TICr/uS94/I354 I 61 Example 43: N-(5-Acenaphthyl)-N'-(3-benzyloxypheny) guanidinee Mesylate Light yellow foam; mp: 90-98IC; TLC (AcOEt:CH 3 OH; 10:1): Rf=O.30; 1H NMVR (CDCI 3 7.647-7.268 (in, Ar-H, 11H), 6,956- 6.923 (in, Ar-H, 3H), 5.086 OH_-- 2 2H), 3.458-3.410 (mn, CH 2

CH

2 4H), 2.857 CH 3 3H); Anal. Calcd. for C 27

H

27

N

3 04S (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: 136-138IC; TLC (CH 2

CI

2 MeOH; 19:1): Rf=0.31; 'H NMR (CD 3 7.668-7.164 (mn, 9H, Ar-H), 3.483- 3.411 (mn, CH 2

CH

2 4H), 2.655-2.627 (mn, CH, 1.656-1.589 (mn,

CH

2 2H), 1.257-1.234 J=6.87Hz, CH 3 3H), 0.860-0.813 (in,

CH

3 3H); Anal. Calcd. for C 23

H

2

,N

3 C1 (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; inp: 260-262IC; TLC (CH 2

CI

2 MeOH; 15:1):

R

1 =0.31; 'H NMR (CD 3 OD): 8.527-8.502 Ar-H, J-=7.63Hz, 2H), 8.183-8.153 Ar-H, J=9.28Hz, 1H), 8.044 br, Ar-H, 3H), 7.771-7.617 (in, Ar-H, 2H), 7.542-7.368 (in, 6H, Ar-H), 3.449- 3.418 (mn, C H 2

CH

2 4H); Anal, Calod. for C 27

H

2

,N

3 C1 (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-phenethylpheny)guanidine*HCI White solid; inp: 116-118IC; TLC (CH 2

CI

2 :MeOH; 15,1): Rf=O.3l; 'H NMVR (CD 3 OD): 7.645-7.156 (in, Ar-H, 14H), 4,233- 4.161 CH, J=7.l4Hz, 1H), 3.478-3.414 (mn, CH 2

CH

2 4 H), WO 95/14467 1ICT/US')4/1354 I 62 1.650-1,626 J =7.2OHz, OH 3 3H); Anal. Calod. for C 27

H

26 N.C1 (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)guaflidileGHCI White solid; mo: 2401C; TLC (CH 2 C1 2 :MeOH; 15:1): RI=.31; 'H NMR (CD 3 OD): 7.639-7.289 (in, Ar-H, 9H), 3.443-3.403 (in,

CH

2

CH

2 4H), 2.086-1.756 (in, CH's, 13H); Anal. Calcd, for

C

2 9H, 2

N

3 C1 (458.08): C, 76.04; H, 7.04; N, 9.17; Found: C, 75.97; H, 6.88; N, 9.06.

Example 48: N-(5-Acenaphthyl)-N'-(3-benzyloxyphenyl)-N'methylguanidinesHCl White solid; inp: 102-105'C; TLC (CH 2

CI

2 MeOH; 15:1); Rf=O.3O; 'H NMR (CD 3 OD): 7.605-7.134 (mn, 14H, Ar-H), 5.149 (s,

OH

2 2H), 3.636 OH 3 3H), 3.532-3.444 (in, CH 2

CH

2 4H); Anal.

Calod. for C 27

H

2

,N

3 C10 (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'methylguanidine9HCl White solid; inp: 108-110C'C; TLC (CH 2

CI

2 :MeOH; 15: 1);

R

1 =0.30; 'H NMVR (CD 3 OD): 7.605-7.134 (in, 14H, Ar-H), 5.149 (s,

OH

2 2H), 3.536 OH 3 3H), 3.532-3.444 (in, CH 2

CH

2 4H); Anal.

Oalcd. for C 27

H

2

,N

3 CO0 (443.98): C, 73.04; H, 5.98; N, 9.46; Found: C, 72.93; H, 6.00; N, 9.919.

WO 95/14467 PcTr/US94/13S4 I 63 Example 50: N-(5-Acenaphthyl)-N'-(3-biphenyl)-N'methylguanidine* HCI White solid; mp: 2170C; TLC (CH 2

CI

2 :MeOH; 10:1): Rf= 0.30; 1H NMVR (CDCI 3 7.513-7,022 (in, 14H, Ar-H), 3.668 OH 3 3H-), 3.322-3.203 (in, CH 2

CH

2 4H); Anal. Calcd, for C 26

H

24 N.C1*2H 2 0 (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-(l1'-methiyl-2'phenyl)ethyl)guanidineo HCI White solid; mp: 106-108'C; TLC (CH 2 01 2 :MeOH; 15:1) Rf= 0.36; 'H NMR (CD 3 00): 7.698-7.070 (mn, 14H, Ar-H), 3.467- 3.312 (mn, CH 2

CH

2 3.105-3.033 (in, OH, 2.928-2.810 (in,

OH

2 1.267-1.244 J=6.87Hz, CH, Anal. Oalcd. for

C

28

H

28

N

3 C1 (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) guanidinee HCI White solid; inp: 158-160OC; TLC (CH 2 01 2 :MeOH; 15:1):

R

1 =0.36;'H NMR (0D01 3 7.631-6.985 (in, 8H, Ar-H), 3.484-3.373 (in, OH 2 t s, 4H), 2.747 (in, OH 2 2H), 1.793-1.784 (in, CH 2 ,2H); Anal. Oalcd. for 0 23

H

24 01 (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*HC White solid; inp: 161-1 6200; TLC (AcOEt:MeOH; 10:1) Rf =0.44; 'H NMR; 7.647-7.118 (in, Ar-H, 13H); Anal. Oalcd. for

C

30

H

3

ON

3 C1v1/2H 2 0 (477.04): C, 75.47; H, 6.50; N, 8.81; Found: 0, 75.23; H, 6.28; N, 8.82.

WO 95/14467 1PC'ruS94/1354 I 64 Example 54: N-(5-Acenaphthyl)-N'-(3,4-dibenzyloxyphenyl) guanidinee Mesylate White solid; mp: 185-187'C; TLC (AcOEt:MeOH; 10:1) Rf=0.44; 1H NMR; 7.647-7.118 (in, Ar-H, 13H); Anal. Calcd. for

C

30

H

3

ON

3 05S-,H 2 0 (613.73): 0, 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)guanidineeMesylate White solid; mnp: 93-95oO; TLC 10:1): Rf=0.0.

4 9 1H NMR; 7.636-7.575 (mn, Ar-H, ,7.41 6-7.128 (in, Ar-H, 11 6.922 Ar-H, 1 6.871-6.842 Ar-H, J =8.72Hz, 2H), 6.639-6.610 Ar-H, J=8.66Hz, 2H), 3.782-3.748 00H 2 J=7.4OHz, 2H), 3.498-3,417 (Mn, CH 2

CH

2 4H), 3.006-2.980 (in, OH, 1H), 2.848 OH 3 3H), 2.835-2.706 (in, OH 2 2H), 1.317- 1.193 (in, OH 3

OH

3 6H); Anal. Calcd, for 0 3

,H

35

N

3 0 4 S (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; inp: 150-1 5200; TLC (AcOEt:MeOH; 10:1) Rf =0.44; 1 H NMR; 7.568-7.174 (in, Ar-H, 17H), 6.745-6.530 (in, Ar-H, 2H), 4.697 OH 2 2H), 3.497-3.413 (in, OH 2

OH

2 4H), 2.825

OH

3 3H); HRMS: 482.2446 (482.628 calcd. for O 33

H,,N

4 Example 57: N-(5-Acenaphthyl)-N'-(3-(l1'-benzylbutyl)phenyl) guanidine*Mesylate White solid; inp: 90-92IO; TLC (AcOEr:MeOH; 10:1); Rf=0.48; 1H NMR (ODOI 3 7.655-7.558 (mn, Ar-H, 2H), 7.411-7.269 (in, Ar-H, 5H), 7.169-6.800 (in, Ar-H, 7H), 3.492-3.414 (in,

I

WVO 9)5/14467 1I(TUS94/1354 I

CH

2

CH

2 4H), 3.022-2.662 (in, OH 2 CH, 3H), 2.842 OH 3 3H), 1.733-1.695 (mn, CH 2 2H), 1.252-1.176 (rn, OH 2 2H), 0.895-0.847

OH

3 J =7.28Hz); HRMS: 433.2516 (433.5962 calcd. for

O

30

H

3 lN 3 Example 58: N-(5-Acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl) phenylguanidine* Mesylate White solid; mp: 113-115IC; TLC (AcOEt:MeOH; 10:1); Rf=O0.

3 9 'H NMR (ODCI 3 7.681-7.267 (in, Ar-H, I1IH), P.904- 6.875 Ar-H, J =8.92Hz, 2H), 5.067 OH 2 2H), 3,498-3.434 (in, CH 2

CH

2 4H), 2.856 OH 3 3H), 1 .278 tert-butyl, 9H); HRMS: 449.2452 (449.5956 calcd. for C 30

H-

31 01\ 3 1 5 Example 59: N-(5-Acenaphthyl)-N'-2(2-indolyl)phenylguanidine

HCI

inp: 174-176IC; TLC: Rr=O.

3 2 (SiO 2

CHCI

3 /MeOH 10:1); 1H NMR (CD 3 OD): 9 ppm 6.86-7.83 (in, ARH, 14H), 3.30-3.40 (in,

CH

2 4H); MS(EI): in/e 402.2 C 27

H-

22 1\ 4 Anal. (C,H,N;

C

2 7

H

22

N

4 .HCI): Calcd.(%): C, 70.33; H, 5.58; N, 12.16; Found C, 70.01; H, 5.65; N, 11.56.

Example 60: N-(5-Acenaphthyl)-N'-(phenyl-3-broino)guanidine

HCI

inp: 204-205IC; TLC: Rf=O.

2 O (SiO 2

CHCI

3 /MeOH =10:1); 'H NMR (CD 3 OD): J ppm: 7.35-7.68 (in, ArH), 3.4-3.5 (mn, OH 2 4H); MS(El): in/e 365.0 C, 9 H-1 6 1\ 3 1r0; Anal. (C,H,N; Cl 9 HlN 3 BR*HCI): Calcd. C, 56.67; H, 4.25; N, 10.43; Found C, 56.49; H, 4,43; N, 10.18.

W0)95/1-467 ffT/11S94/1354 I 66 Example 61: N-(5-Acenaphyl)-N'-(2,3,4-trichlorophenyl)-N,N'dimethyI guanidine HCI TLC: Rf=0.14 (SO 2

CHCI

3 /MeOH 1H NMR (00300D): J ppm: 6.72-7.44 (in, AriA, 7H), 3.5-3.6 OH 3 6H), 3.4-3.5 (mn,

OH

2 4H); MS(EI): m/e 418.0 C 2

,H,,N

3 0l 3 Anal. (C,H,N;

C

2 lHl 8

N

3

CI

3 eHCl): Calcd. C, 55.41; H, 4.21; N, 9.23; Found C, 55.26; H, 4.11; N, 9.03.

Example 62: N-(5-Acenaphyl)-N'-(2,3,4-trichlorophenyl)-N'methylguanidine H~l mp: 229-231 00C; TLC: Rf 19 (SiO 2

CHCI

3 /MeOH 10:1); 'H NMR (CD 3 OD): J ppm: 7.54-7.70 (in, ArH, 4H), 7.33-7.40 ArH, 3H); MS m/e 403.1 C 20

H

16

N

3 C1 3 Anal. (C,H,N; C 20

H

16

N

3 Cl 3 HCI): 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)guanidineoHCI mp: 244.5-2461C; TLC: R1=0.23 (SiC 2

CHCI

3 /MeOH 10:1); 1 H NMR (CD 3 OD): J ppm 8.15-8.17 (in, ArH, 2H), 7.36-7.91 (in, ArH, 10H), 3.40-3.50 (in, OH 2 4 2. 50 C1 1 1H); M S(EI1): m/e 434.1 C 27

H

22

N

4 Anal, C 27

H

22

N

4 S*HCI): Calcd.

C, 68.85; H, 4.92; N, 11.89; Found C, 68.66; H, 4.91; N, 11 .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.

~Bb;s~ WO ')5/14467 C("I11S94/135,41 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, 10 pM or 3 pm. All solutions including the controls are made to have the same concentration of methanol. Methanol concentration never exceeded 0.3% 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 1A 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 R 2 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 1A 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 WO 9514467 cI'1LJs,4/1354 I WO 95/14467 68 Cmpd. %Block of Glu Rel of Ex.

No. R R R 2 10puM 3puM 1 2,3,4-trichlorophenyl H H NT 97 2 5-acenaphthyl H CH, 62 NT 3 5-acenaphthyl CH, CH, NT 53 4 1 -anthracenyl H H 95 4-tertbutylphenyl H H 1 00 49 6 4-cyclohexylphenyl H H NT 7 4-secbutylphenyl H H NT 84 8 4-methoxyphenyl H H 50 3 9 2,3-dichlorophenyl H Hl 86 47 4-OCH,-2-naphthyl H H 84 11 3,4-dichlorophenyl H H 82 NT 12 4-chlorophenyl H H 69 NT 13 2-naphthyl H H 81 NT 4-nitrophenyl H H 35 78 16 3-bi-phenyl H H NT 98 17 2,3-dimethylphenyl H H NT 46 1 8 2-bi-phenyl H H NT 54 19 2,5-dibromophenyl Hl H NT 46 3,4-dimethoxyphenyl H H NT 46 21 4-methoxy-1 -naphthyl CH 3 H NT 54 22 4-methoxy-1-naphthyl H CH, NT 43 23 4-methoxy-1 -naphthyl CH, CH, NT 24 4-chloro-l-naphthyl H H NT 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-tertbutylphenyi H H NT 71 WO 95/14467 WO 9514467PCTIUS94'1354 1 -39 Cmpd. %Block of C31u Rel of Ex.

No. R R' 10,M 3pM 34 3-acenaphthyl H H NT 77 2-fluorenyl H H NT 81 39 4-trif luorom ethyl H H NT 52 4-methylthio H H NT 46, TABLE 1A: INHIBITION OF GLUTAMATE RELEASE Cmnpd. %Block of Glu Rel of Ex.

No. R R' R ~pm 0.3pjm 41 4-benzyloxyphenyl H H -38 1 5 42 3-benzyloxyphenyl H H 24 2-anthracenyl H H 44 46 3-phenethylphenyl H H 79 31 47 4-adamantylphenyl H H 48 3-benzyloxyphenyl H CH 3 83 46 49 4-benzyloxyphenyl H CH, 44 11 3-(1 -methyl-2'-ph enyl ethyl) phe nyl) H H 72 51 3-biphenyl H C H 47 b3 7-benzyltetralinyl H H 100 56 3-(N",N"-dibenzyl)amninophenyl H H 7 57 3-(1'-benzylbutyl)phenyl H H *-23 58 3- t-b Utyl benzo xym ethylene)ph enyI H H -1 9 1 62 2,3,4-trichlorophenyl H C Example 6 b: 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 15 Ca uptake. Calcium uptake is one step in WO 95/14467 PCTIUS94/13541 70 the cascade of events which occur in neuronal cell death from ischemia, See Bassaclough and Leach, Current Patents Ltd., 2-27.

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 KCI) at 2 mg/ml. Test compounds in LK were added to synaptosomes to a final concentration of 10 pM and incubated for 5 minutes at room temperature. 4 "Ca uptake was then measured by adding isotope in either LK or high potassium (150 mM KCI) 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 15 mL of quench buffer. The effect of drug is expressed as inhibition (or block) of control potassium-stimulated 45 Ca influx. This method is an adaptation of the method disclosed by Nachsen and Blaustein, J.

Physiol., 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, R' and R 2 are specified in Table II.

TABLE II: ACTIVITY IN THE Ca FLUX ASSAY 1 R

R

NH

I

P(It'S94/13541l WO 95/14467 -71 Block of Cmpd. 4 bCa Ex.

No. R R 1

R

2 Block ICou pM 5 4-tertbutylphenyl H H 6 4-cyclohexylphenyl H H 63 7 4-sec-butylphenyl H H 53 4-methoxy-2-naphthyl H H 43 6.35 16 3-bi-phenyl H H 7.18 39 4-trifluoromethyl H H 52 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 Ill below. The data demonstrates that at least some compounds of the invention block the saxitoxin binding site on voltag--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 30 mM KCI 2.23 8 mM MgSO 4 0.96 250 mM Hepes/Tris 59.57 (pH to 7.4 with Tris Base) 1 M Choline Chloride 139.60 18 mM CaCI 2 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.

I

WO 95/14467 PCT/US94/13541 72 2) Toxin: 1 mg of 1 mM Tetrodotoxin dissolved in 3.1 mis ddH 2 0 (stored at 4 0

C).

3) Incubation Buffer of the following composition (amounts of components expressed as mis): Component Amount 5.4 mM KCI 0.8 mM MgSO 4 mM Hepes 10.0 130 mM Choline Chloride 19.5 mis of ddHO 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 MgSO 4 100 1.8 mM CaCI, 100 mM Hepes 617 mls of ddHO and are added to the admixture to provide the Wash Buffer.

Synaptosome preparation Synapturomes were prepared as described in Example 8 of PCT/US92/01050. The prepared synaptosomes are frozen in 1 ml aliquots DMSO) at -80 0 C. Preparation is thawed on ice immediately before assay and diluted to get approximately 1000 cpm for totals per filter (10-15 pg protein/filter to avoid any potential problems testing relatively lipophilic compounds that could be absorbed out of solution by the membranes).

I

WO 95/14467 PCT/US94/13541 73 Assay A test Assay is prepared of the following composition and having 200A final volume: 3 H]Saxitoxin: 5.9 nM (Amersham TRK.877) approximately a 1:300 dilution of stock (the 3 H]Saxitoxin is stored according to Amersham recommendations) Compound of interest (diluted [10x] in ddHO due to low solubility) Incubation buffer 50A protein: 10-15 pg rat synaptosomes This mixture is incubated for 30 minutes at 37 0 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. 3 H]STX is very unstable and can lose "H when H 2 0 evaporates while filters dry. 5 mis scintillation fluid (CytoScint ICN #882465) are added and the samples counted for minutes each. Nonspecific binding is determined by 10 pM 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, R 1 and R 2 specified in Table III. The tested compounds were in salt form, as indicated in the Table.

TABLE III WO 9/1447 C'US94/13541 WO 95/14467 74 Sodium Channel Cmpd. Block vs. 'HSTX No. R R I pm Salt 1 1 -anthracene H Hi 1 .4 HCI 2 4-methoxy-l-naphthyl H H 4 mesylate.

3 6-benzodioxolyl H H 100 HCl 4 4-tertbutylphenyl H H 25.2 HG! 5 4-sec-butylphenyl H H 34 HO! 6 5-acenaphthyl CH, H 1 00 HCI 7 4-methoxyphenyl H H 100 HBr 8 2,3-dichlorophenyl H H 57,5 HiCI 9 4-methoxy-2-naphthyl H H >30 HO! 10 3,4-dichloropheny! H H 19.9 HO! 11 4-chlorophenyl H H >30 HBr 13 2-naphthyl H H 57.8 HO! 14 4-nitrophenyl H H 100 HG! 3-biphenyl H H 7.8 HG! 16 4-fluorophenyl H H 100 HO! 17 2,3-dimethylphenyl H H 21 HO! 1 8 2,3,4-trichlorophenyl H H 10 HG! 19 3,4,5-trimethoxyphenyl H H 100 HO! 2-biphenyl H H 71.1 HBr 21 2,3-difluorophenyl H H 100 HG! 22 2,5-dibromophenyl H H 40.5 HO! 23 2,3,4-trifluorophenyl H H 100 HG! 24 4-methoxy- 1-naphthyl H H 23.3 HG! 4-methoxy-l-naphthyl H OH, 63 HG! 26 5-acenaphthyl H H 8.4 mesylate 27 4-methoxy-1 -naphthy! OH, CH, 100 HG! 28 5-acenaphthyl OH, OH 3 100 HO! S4/3541 PC'TVIS94/13541 WO 95/14467 Sodium Channel Cmpd. Block vs. 'HSTX No. R R' R' ICEso m Salt 29 2,4-dichlorophenyl H H 66 HCI 2,3,4,5-tetrachlorophenyl H H >3 HCI 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 (6)

1. 5-acenaphthyl)-N'-(3,4-dichilorophenyl) gu an idine; aph thyl)-N-(3,4-dichlorophe nyl) -N-m ethylguaniin e; '-(3,4-dichloroplheny)-N'-methylguanidine; 5-acenaphthyl)-N'-(3,4-dichlorophenyl)-N, N'-bls-r-nethiylguanidine; N-(S-acenaphthyl)-N'-(4-chlorophenyl)guanidine; N-(5-aceriaphthyl)-N'-(4-chloropheny)-N-methylguanidine; .:N-(5-acenaphthyl)-N'-(4-clhloroplheryl) -N'-r-nethylguanidine; N- (5 -acenaphthyl) lorop le nyl) N'-b is-m ethyig ua nidine; N-(5-acenaphthyl)-N'-(2-naphthyl)guanidine; N-(5-acenaphthyl)-N'-(2-naphthyl)-N-methiylguanidine; N-(5-acenaphthyl)-N'-(2-naphthyl)-N'-mothylguanldlne; N-(5-acenaphthyl)-N'-(2-naphthiyl)-N,N'-bis-methylguanidine; t -(6-quinollniyl)-N-methylguanldlne; '-(6-quinoiniyl) -N'-metlhylguanidine; 2* N-(5-acenaphthyl)-N'-(6-quinoinyl)-N, N-bls-methylguanidine; Ni 5-aconaphthyl)-N'-(4-nitrophenyl) guanidine; N-(5-acenaphthyl)-N'-(4-nltrophenyl)-N-methiyiguanidine; S N-(5-acenaphthyl)-N'-(4-nitroplhenyl)-N'-methylguanlne; 5-acenaphthyl)-N '-(4-nitrophenyl)-N, N'-bis-mathiylguanldlne; N-(5-acenaplhthyl-N'-(3-bi-phenyl)guanidlne; 5-acenaphthyl-N '-(3-bi-plhenyl)-N-methylguanidlne; Ni 5-acenaphthyl-N '-(3-bi-phenyI)-N'-methylguanidine; Ni 5-acenaphthyl-N'-(3-bi-pheny)-N, N-bis-methylguanldlne; N- (5-acana phthyl)- 3-dimeithylphenyl) gu ani dine; N-(5-acenaphthyl)-N'-(2, 3-dimethylphenyl)-N-methyrguanidine; WJWY972A.SPR.Tl 1 114 1k 11, 11~' 'HLIfn t 'j 4fill 4,11 Vj i 78 N- (5-acenaphthyl) 3-dimethylpheriyl) ethylg u anidin e N- (5-acena phthyl) 3-dlmethylphe nyl) N, N'-b is-methylg uanidin e; N- (5-acenaphthyl)- bi-pheny1) guan id ine; N-(5-acenaphthyl)-N'-(2-bi-plienyl) -N-methylguanidine; S N- (5-aconaphthyl) -N'-(2-bi-plienyl)-N'-methylguanldine; N-(5-acenaphthyf)-N'-(2-bi-phenyl) N'-bis-methylguanldlne; N (5-acenaphthyl)-N'-(2, N-(5-acenaphthyl)-N'-(2, N-(5-acenaphthyl)-N'-(2 1 0 N- (5-acenaphthyI)-N'-(2,5-dibromopheny)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(3,4-dlmethoxyphenyl) guanidine; Ni(5-acenaphthy-N'-(3,4-dimetlioxyphenyl)-N-methyiguanidine; 1 N-(5-acenaphthy)-~N'-(4-methoxy-.1 -naphthyi)-N-methylguanidine; 5aeahh eloy1 npty)N- Etyg a jie N-(5-acenaphthyl)-N'-(4-metlhoxy-1 -naphthyl)-N,'-methylguanidine; 5-acenaphthyi)-N '-(4-meto-1 -iaphhy)-,Nmtyguanidine; N-(5-acenaphthyl)-N'-(4-chloro- I-naphthvflauaN-de:luniie N-(5-acenaphthyl)-N'-(4-chrloro-l1-naphthyl)-N-methylguanidine; 2: acenaphthyfl-N'-(4-ch loro- 1 naphthyl) -NN'-ethyetguaniu nWi e '-(34-rchloronphhyl)un, N-ls-ethlunii 5-acenaphthyl)-N 5-trichlorophenyl)guN-tldlne; ine hthyl)-N (3,4,5-trich Iorophenyl) -N-me hylg uan ine; 5-aceriaphthyi)-N'-(3,4, 5-trichlorophenyl)-N,'-erh-guidygine; e N-(5-acenaphthyl)-N'-(34bi-tlchnlorphNyl-,-isethylguanidine; 5-acenaphthyl)-N'-(4-bi-phenyl) gunidins;uaidne S-acenaphthyl)-N'-(4-bi-phenyl)-NNi-merhylguaniine; e 5-acenaphthyl)-N'-(2, 3,4,5-tetrachlorophenyl)guanidine; J/fl)'FM2.PL.1 141 II II HIL 114FI1 1114P I I ti ,411 444 dIt I I -79 5-acenaphthyl)-N N (5-acen p hthyl)-N'- 3,4, 5-tetrachloroph enyl) -N-m ethylg uan Wine; N-(5-acenaphthyl)-N'-(2,3,4, 5-tetrachlIorophenyl)-N, N -bls-methylguani dinie; N- (5-ace naphthy1) -N'-(3-isopropy lpheny) g uanId Ine, N- (5-sce nap hthyl) (3-isop ro pylph enyl)-N-riioEthylg ualldin e; N-(5-acenaphthyI)-N'-(3-isopropylphenyI)-N'-rethylguanidine; N-(5-aceriaphthyI)-N'-(3-isopropypheny)-N, W-bis-methylguaniflne; N-(5-acenaphthyl)-N'-(3-tert-butylphenyl)guanidine; N- (5-ace ia ph thyl) -N -te rt-b utyl ph enyl -N-rnet hy g uan idine; N-(5-acenaphthyl)-N'-(3-tert-butylphenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(3-tert-butylphenyl)-N,N'-bis-methyguanidine; N-(5-acenaphthyl)-N'-(2,3,5,6-tetraclhlorophenyl)guanidine; N-(5-acenaphthyl)-N'-(2,3,5,6-terachlorophenyl)-N-methylguanidile; N-(5-acenaphthyl)-N'-(2,3, 5,6-tetrachlorophenyl)-N'-rnethylguanidine; 1 N-(5-acenaphthyl)-N-(2,3, 5,6-tetrachlorophenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(3-Iodophenyl)guanldine; -N '-(3-iodoplhenyl)-N-merhylguanldine; N-(5-acenaphthyl)-N'-(3-odophenyl)-N'-nethygualdlfe; N-(5-acenaphthyl)-N'-(3-iodophienyl-N,N'-bls-rnethylguanidine; 2D- N-(E5-acenaphthyl)-N'-(3-nltrophenyl)guanidine; N-5aeahty)N-3-irp eyl*5ehlg aiie N-C 5-acenaphthyl)-N -(3-nitrophienyl)-N'-mehylguanidine; 5-acenaphthyl)-N'-(3-nitroplhenyl)-N,'-ethvhlguaniine;e ldsmtygaile 5-acenaphthyl)-N'-(5-indolinyl) guaniine; idne 25N-(5-acenaphthyI)-N'-(5-indolinyI)-N'-methylguanidine; 5-Indolinyl)-N, N'-bis-rnethylguanldine; N-C 5-acenaphthyl)-N'-(3-acenaphthyl)guanidine; 5-acenaphthyl)-N'-( 3-acenaphthyl)-N-methylguanidine; N-(5-acenaphtlhyl)-N'-(3-acenaphthyl)-N'-methylguanidlne; 1j2Jpcpgw2.SPn,79 11 11 VAJ I, I il I lwl I. 1111 1 1 A-1 I [it-it I I Hldfo I I ft I 41 il I 1 .LIH N- (5-acenaphthyl) -N -(3-acenaphthyl)-N, N '-bis-methyiguaniclin a; N- (5 -acena phthyl) luore nyl) guani dine; N-f 5-acen a phthyl)-N'-(2-f luorenyl) -N-methyl guanidine; N- (5-acen aphthyl) luorenyi) N'-methylg ua ndne; N-f 5-acen aphthyl)-N'-(2-f luorenyl)-N, N-bis-methylguanid ine; N- acen aphthyi) (4-n-bu toxyphenyl) gua nid ine; N- (5-acen aphthyI) (4-n-butoxypheny) -N-me thylg u anid Ine; N-f 5-acen ap hthyI) butoxyph eny) N-rnethylg ua nId ine; N-f 5-acenaphthyi)-N'-(4-n-butoxyphenyl)-N, N'-bis-methylguanldine; N-f 5-acenaphthyl)-N'-(3-f 2-methoxy) dibenzof uranyl)g uanidine; N-f 5-acenaphthyl)-N'-(3-(2-methioxy)dibenzofuranyl)-N-methylguanldlne; ~N-(5-acenaphthyl)-N-(3-(2-methoxy)dibenzofuranyl)-N Nretslmehyiuniine N- (5-cna lbezfuay)-N 0bsm ty anWn N-(5-acenaphthyt)-N'-(9-hydroxy-2-fluorenyl)guanidine; lb N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N-methyiguanidine; N-f 5-acenaphthy)-N'-(9-hydroxy-2-fluoreny)-N'-methyiguanidine; N-f 5-acenaphthyl)-N'-(9-hydroxy-2-fluornyl)-N, N-bis-metliyiguanline; N-(5-acenaphthyl)-N'-(4-trifluoroinethiylphieryl)guanidine; N-f 5-acenaphthyl)-N'-(4-trlfluoromethylplhenyl)-N-methylguanidine; 20 N-(5-acenaphthyi)-N'-(4-trifluoroinethiylphenyl)-N'-methylguanldlne; N-f 5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N, N'-bls-methylguanldlne; N-f 5-acenaphthyl)-N'-(4-methytlioplhenyl) guanidine; 5ae a hh l- eh lho h n l- eh lu iiie *N-(5-acenaphthyl)-N'-(4-methiylthilophienyl)-N-methyguanidn; N-f 5-acenaphthyl)-N'-(4-methylthloplienyl)-NNi-methylguanid; N-(5-acenaphthyl)-N'-(4-mecbthylipenyl)gunNi-ethlunll N-f 5-acenaphthyl)-N'-( 3-sec-butylphienyf)Ntlguanidine; N-f 5-acenaphthyl)-N '-(3-sec-butylphenyl)-N'-methylguanidine; N-(5-acenaphthyl)-N'-(3-sec-butylphienyl)-N, N'-bis-methylguanillne; N-f 5-acenaphthyl)-N'-(4-benzyloxyphenyl) guanldlne; I WK9PV72A.5P!,W3t -81- 5-acenaphthyl)-N *-(3-benzyloxyphenyl) guanidine; N- 5-acenaphthyl) -N '-(3-secbuTylphenyl) g uanidline; 5-acenaphthyl)- N'-(2-anthracenyl) guanidine; N-i 5-ac enaphthyl) phenethylphenyl g uan Idine; N-(5-acenaphthyl)-N'-(4-adamantylphenyl) gu a ndine; N- (5-ac ena phthyl) be nzy loxyp henyl) -N -m ethyl g uanidin e; N- (5-acenaphthyl)-N'-(4-beizyloxyphenyl)-N -methylguanidine; 5-acenaphthyl)-N'-( 3-biplhenyl)-N -methylguanidine; N-(5-aconaphthyl)-N'-(3-(1 '-methyl-2'-phenylethyl)pheny)guanidine; N-(5-acenaphthyl)-N'-(3,4-teTralinyiphenyl)guanidine; N-(5-acenaphthyl)-N'-(7-benzyTetralinylpheny) guanidine; N-(5-acenaphthyl)-N'-(3-1 -(4-ethoxy)phenyl)propanylphenylguanidine; Seahhl)N-3("N -dbny~mnphnlgaiie N-( 5 -acenaphthyl)-N'-(3-(N",N"-dlbenzyl)amphenyl)guanidine; N-(5-acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl) phenylguanidine; N-5-acenaphthyl)-N-(2-(2-indolyl)phenyl)guanidine; NI 5-acenaphthyl-N'-(3-bromophenyl)guanidine; N-(5-acenaphthyl)-N'-(2,3,4-trlchlorophenyl)-NN'-dimethyguanidine; N-(5-acenaphthyl)-N'-(2, 3,4-Trlchlorophenyl)-N'-methylguanidinB; N-(5-acenaphthyl)-N'-(3,4-dibenzyloxyphenyl)guanidine; and N-(5-acenaphthyl)-N'-(4-(2'-benzothiazole-6'-methyl)phenyl)guanidine; and pharmaceutically acceptable salts of said compounds. 2. A compound of claim 1, substantially as herein described with reference to any one of the Examples. 3. A method for treating a disorder of the nervous system in which the pathophysiology of the disorder Involves excessive release of endogenous glutamate 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 or claim 2. 4 The method of claimn 3, wherein the disorder is 1 nausea resulting 1tI~nWr2h -ruj'i i''V i1 1J :ll'i H I Ni #4 1Hi -i hIl I 41tn ll] f. In -82- from chemotherapy, 2) epilepsy, 3) convulsions, 4) carbon monoxide poisoning, 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. A method for treating 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 or claim 2.
2. 6. A met:.-,d of treating brain or spinal cord trauma, stroke or heart attack comprising administering to a mammal exhibiting symptoms of or susceptible to brain or spinal cord trauma, stroke or heart attack an effective amount of a compounds of claim 1 or claim 2, S 7. A method of treating a disease selected from the group consisting of Huntington's disease, Amyotrophic Lateral Sclerosis, Alzhelmer's disease, 1 Down's Syndrome, Korsakoff's disease, olivopontocerebellar atrophy, HIV-lnduced dementia, HIV-lnduced blindness, multi-infarct dementia, or epilepsy, the method comprising administering to a mammal exhibiting symptoms of the disease or susceptible to said disease an effective amount of a S. compound of claim 1 or claim 2.
3. 8. A method for modulating the release of excess endogenous glutamate from a subject comprising administering to the subject an effective amount of a compound of claim 1 or claim 2,
4. 9. A method of blocking voltage sensitive calcium channels or voltage sensitive sodium channels of mammalian neuronal cells comprising administering to the cells an effective amount of a compound of claim 1 or claim 2. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 1 or claim 2 and a pharmaceutically acceptable carrier.
5. 11. A compound selected from the group of: IJnuCXi'w12.SPR,t I flit 1141111 1111.11011 a ill 1i41 ii I iaI.1l~[I ii liii I ii -83 N (3 acenaphthyl)-N'-(2, 3,4-trichiorophenyl)guanidile; N-(3 aceriap h, byN'(2,3,4trichoropel)-N-methylgualidile; N (3.-ac,-naplhthyt) 3,4-tricliloropheniyi)-N'-metlylguafidile; N (3 dLelaphlttlyl)-N 3,4-trichlorophenyl)-N,N'-bis-r11ethiylguafidile; N,N'-bis(3-acenaphthyl)-N-methygLiof'idifle; N, N' bis(3-acenaphthyl)-N,N'-bis-methylguanlife; N-(3-acenaphthyl)-N'-( 1 -anthracenyl)guanidine; N (3 acenaphthyl)-N'-(l1-anthracenyl)=N-methylguariidifle; N (3 ac e naphthyl) -N (1 -anthracenyl) -N'-rethylguaninfe; 1 0 N-(3-acenaphthyl)-N'-( 1 anthracenyI)-N,N'-bis-methylguanidine; N (3 iiceniaphtlhyl)-N'-(4-tert-butylpleyl)gualidile; N (3 acenaphthyl).N-(4tert-butylpel)-N-methylguaflidile; N (3 ac hh ypey)-N-ehlun'ie 3-acenaplhthyl)-N'-(4-ter.-butylplelyl)-N1 N'-bis-rnlethiylguanldinie; 15: N (3 acenaphthyI)-N'-(4-cyclolhexyipheniyI)guanidile; N (3 aconiaphthyl)-N'-(4-cycloohexylpphenyl)-N-metlyguaidile; N- (3-acenaphthy() -N '-(4-cyclohexythenyi)-N'-methylguanidiie; N- (3 acen a phthy 1 (4-cycloh exylphenyl)N,'-bis-ethy g uaIdIn e; N (3 acernaphthy()-N'-(4-sec-butylplhenyl)guanidine;- N- 3-acenaphthyi)-N'-(4-sec-butylplheiyl)-N-metlylgualidiile; N-(3-acenaphthyl)-N'-(4-sec-butylphey)-N'-metiylguanidine; N (3 acenaphthyl) -N'-(4-sec-butylphenyl)-N,N'-bis-i-nethiylguanildinie; N- (3 -ace naphithyI) eth oxypheny) 9uanldin e; N (3 ace n aphthy) (4-m ethoxyphel-N-m ethylg ualid le; N (3-aceapthyl)-N'-(4-methoxypheny)-N'-mehylgualidle; 3-accnaphthyl) -N'-(4-methoxyphenyl)-N, N'-bis-metlhylguaniidinie; N (3 ace ca ph thyl) 3-dich lorophenyl) guaniWine; N (3 aceniaphthyl)-N-(2,3-dllorophenyl)-N-methylgualidile; N (3 -acenaphthyl) -N'-(e2.3-dichlorophenyl)-N'-r-netlhylguanidinie; N (3 acenaphthyl)-N'-(2, 3-dichlorophenyl)-N,N'-bls-merhylguanidlne; I fl9KDR72 9110,93 ILI it I 11, If it .1 1 1 Ildl 0 11 I 11 1.1141 1 LIL i.I.
6. 84- N- (3-acenaphthyl) (4-i-nethoxy-2-naphthyl) -N-methylg uarl N-(3-acenaphthyI) 4-unethoxy-2-na phthiyO- N'methylg uanidine; N-(3-acenaphthy)-N'-(4-methoxy-2-naphthy)-N, N'-bis-methyiguanidine; N-(3-acenaphthyl)-N'-(3,4-dichlorophenyl)guanidine; N-(3-acenaphthyl)-N'-(3,4-dichlorophenyl)-N-methylguanidine; N-(3-acenaphThyl)-N'-(3,4-dichioropheny)-N'-mEthylguan,,dine; N- (3-acenaphthyl)-N'-(3,4-dichlorophenyl)-N,N'-bis-mathylguanidine; N-(3-acenaphthyl)-N'-(4,-clhlorophanyl)guanlidne; N-(3-acenaphthyi)-N'-(4-chtlorophenyl)-N-methylguanidine; 1 0 N- (3-acenaphthyl) (4-c h orophenyl)-N'-methylgua n ine; N-(3-acenaphthyl)-N'-(4-chlorophenyl)-N, N'-bis-methylguanidine; N-(3-acenaphthyl)-N'-(2-riaphithyl)guanidine; N-13-acenaphthyl)-N'-(2-naphtliyl)-N-methylguanldine; N-(3-acenaphthyi)-N'-(2-naphthyl)-N'-methyiguanldine, 1, N-(3-acenaphthyl)-N'-(2-naphthyl)-N,N'-bis-methylguanidine; N-(3-ucenaphthyl)-N'-(6-quinoinyl)-N-methylguanldlne; N-(3-acenaphthyl)-N '-(6-quinolinyt)-N'-methylguanidine; N-(3-acenaphthyl)-N'-(6-quinolinyl)-N,N'-bis-methylguanidine; N-(3-acen aphthyl) -N'-(4-nitrop hanyl) 9uanidine; o0 N- (3-acenaphthyl) (4-nitrophenyl) -N-methylgu antd ne; N-(3-acenaphthyl)-N'-(4-nitrophenyl)-N'-methylguanidine; N-(3-acenaphthyl)-N '-(4-nitrophenyl)-N, N'-bis-methylguanidine; N-(3 -acenaphihyl-N'-(3-bi-pheniyl)guanidine; N-(3-acenaphthyl-N-(3-bI-phenyl)-N-merhylguanidine; N-(3-acenaphthyl-N'-(3-bi-phenyl)-N'-methylguanidine; N-(3-acenaphthyl-N'-(3-bi-phenyl)-N,N'-bis-methylguanidine; N-(3-acsnaphthyl)-N 3-dimethylphenyl)guaridirie; Ni 3-aoenaphthyl)-N'-(2, 3-dlmethylphenyl)-N-mathyiguanidine; N-C 3-acenaphthyt)-IP'-(2, 3-dlmethylphenyl)-N'-methylguanidine; N-(3-acenaphthiyl)-N'-(2, 3-dlmethytphenyl)-N,N'-bis-methylguanidine; InJ(XX'I"A SPU.U 1 I j, 1I i' 1.1: 11 1 111 1 1141114 1 11'I4 LI I~ I j ''H1,14lVil I 85 N- (3-acenaphthyl) -N'-(2-bi-phe nyl) guanidine; N- (3-acen aphthyl) -N'-(2-bl-phenyl) -N-merhylg uanidine; N-C 3-acenaphthyl) -N '-(2-bi-phenyfl)-N'-rniethylg ua n ldne; N-(3-acenaphthyl)-N'-(2-bi-phienyl)-N, N'-bis-methylguanidine; N- (3-ac enaphthyl1) (2,5-dibromophenyl) gu anidine; N- (3-acena phthyl) 5-dlbromop henyl)-N-methylguani!dine; 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-dime3thoxyphenyl)guanidine; 1 0 N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N-methylguanidine; N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N'-methylguanidine; .N-(3-acenaphthyl)-N'-(3,4-dimellhoxyphenyl)-N, N'-bis-mnethytguanidine; N-(3-acenaphthyl).N'-(4-methoxy-1 -naphthyl)-N-methylguanidine; N-3aeahhl*'(- ehx -npty)N- otyg aiie 14 N-(3-acenaphth-yl)-N'-(4-methioxy-1 -naphthyI)-N,'-metyguanidine; N-(3-acenaphthyl)-N'-(4-mehox--naphThyl)-N-mtyguanidine; *N-(3-acenaphthyl)-N'-(4-chloro-l1-naphthyl)guNide;~uniie N-(3-acenaphthyl)-N'-(4-chloro-l1-niaphithyfl-N'-methylguanidine; N-(3-acenaph thyi) -N'-(4-chloro-1I -n aphthyl)-N, '-ethylguanuicnid N-(3-acenaphthyl)-N'-(34-lr-1 -naphhy)-NN-bmethyiguanidine N-(3-acenaphthyl)-N'-(3,4,5-trichlorophenyl)gu'-anidine; iin N-(3-acenaphthyl)-N'-(3,4, N-(3-acenaphthyl)-N -trhenlorpeyNmtguanidine; N-(3-acenaphthyl)-N'-(34-rihnl)rphnyl,--methylguanidine; N-(3-acenaphthyl)-N'-(4-bi-phenyl)guNidmtln; idn 25N-(3-acenaphthyl)-N'-(4-bI-phenyl)-NNi-methylguanidine; N-(3-acenaphthyl)-N'-(2, 3,4, N-(3-acenaphthyI)-N'-(2, 3,4, N-(3-acenaphthyl)-N'-(2, 3,4,5-tetrachloropheny)-N'-methylguanidine; I 1710-CP72A.AP1,91 I 111,111 111, 111 1.1: 1 1 (fill 114 01 Ifil-11011 1 .1 I if I I 1 01 '1 It 1 1.1 86 N- (3-ace naphthyl) 3,4, 5-tetrachlorophe nyl) N'-bis-m ethylguani dine; N- ace naphthyl) (3-isopro pylp henyl) guanidine; N- acenaphthyl) -N (3-iso propyl pheny1) N-fnethylgu anidinea; N- (3-ace nap hthy1) (3 -is opro pylIph enyl) ethyl gu an idin e; N-3aeahhl-'(-spoypey)N N'-bis-m ethyl guanidlne; N- ace naphthyI)- N'-(3-tert-butylpheny) guanidine; N -(3-acenaplithyl)-N'-(3-tert-butylphenyl)- N-rnethylqu anidine; N- (3-acenap hthyl)- N' (3-tert-butylplieny1) N-methylg uani dine; N-(3-acenaphthyl) (3-teri.-bu1.ypheny)-N, N-bis-meth~ylgu a iidine; N-(3-acenaphtlyi)-N'-(2, 3, 5,6-tetrachorophenyl)g uanidine; N-(3-acenaphthyI)-N'-(2,3,5,6-tetrachloroplheiy)-N-methylguanidine; N-(3-dcenaphthyl)-N'-(2,3, 5,6-tetraclIloropbernyl)-N'-methylguanidine; *N-(3-aceniaphtlhyl)-N'-(2, 3,5,6-tetrach~lorophenyI)-N,N'-bis-methylguanidlne; a: N-(3-acenaphthyl)-N'-(3-iodophenyl)guanidine; N-(3-acenaphthyl)-N'-(3-iodoplhenyl)-N-metliylguanidinea; N-(3-acenaphthiyl)-N '-(3-lodophenyl)-N'-rnethylguanidine; N-(3-acenaphthyl)-N'-(3-Iodophenyl)-N, N'-bis-methylguanidine; N-(3-acenaphthyl)-N'-(3-ritrophienyl)guanidlne; N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N-metlhylguanidine; ."2a N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N'-metlhylguanidline; N-3ae a hh l- '(-irpieil-, 'bsm tyg a iie guanidine; N-3ae a hhl* oln l--n tyg a iie N- (3-ac enaphthyl) -N'-(5-iridollinyl) '-ethylguanididine N-(3-acenaphthyl)-N'-(2-fldollnyl)guNidn- ~eth un~he N-(3-acenaphthyl)-N'-( 2-f Iuorenyl)guN-de;ygaiie Ni 3-acenaphthy)-N'-(2-fluoreny)-N'-metlylguanidinieI N- (3-acenaphthyl)-N'-( 2-f Iuorenyl)-N,'-ethylguanidinne N-(3-acenaphthyI)-N'-(4-n-butoxyphenyl)guanldlne; InINCOM4.6111,H6 i L'l 1" 11 iii l il i~ 114 [11idI'[I II I. I I I It 11 1-11 '1111 f I I I 87 N- (3-ace n aphthyl)- (4-n-butoxyphenyl) -N-m ethylg uanidine; N-( 3 -ace naph thyI) (4-n-butoxyphenyl) ethylgu an idine; N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N, N'-bls-methylgu an idine; N- (3-acen aphthyl) -N'-(3-(2-meth oxy) dibenzof uranyl) guanine; N- 3 -acen aphthyl) -N'-(3-(2-rrieth oxy) dl benzof uranyl) N-meothylguanidin 0; N-(3-acena ph thyi)-N'-(3-(2-methoxy) dibenzofuranyl) -N -methylguanidine; N-(3-acenaphthyl)-N '-3-(2-methioxy)dibenzof uranyl)-N, N'-bis-methylguanidine; N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl) guanidine; N- (3-acena phthyl) -N'-(9-hydroxy-2-f Iuore nyl)- N-methylg uan Wine; 1 0 N- (3 -ace n aph thyl) yd roxy- 2-f Iuore nyI1) -N-m ethyl g uan id ine; N-(3-acenaphthy)-N'-(9-hydroxy-2-fluoreny)-N, N-bis-methlguanidine; N-(3-acenaphthyl)-N'-(4-trifluoromethylphenyI)guanidine; N-(3-acenaphthyl)-N'-(4-trifluorornethylphenyl)-N-methylguanidine; Ni 3 -acenaphthyl)-N'-(4-trlfluoromethylphenyl)-N'-methyguanidine; 1 N-( 3 -aoenaphthyl)-N'-(4-trifluoromethylphienyi)-N,N'-bis-methylguanidine; N-(3-acenaphthyl)-N'-(4-methyithiophenyl) guanidine; N-(3-acenaphthyl)-N '-(4-metlhylthiophenyl)-N-methylguanidine; N-(3-acenaphthy)-N'-(4-methyltlhioplbenyl)-N,N'-bis-methylguanidine; N- (3-acenaphthyl)-N'-(3-sec-butylphenyl)guan !dine; N-3ae*p tyl -utlh n etyg a iie N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N'-methyguanidine;an SN-(3-acenaphthy)-N-(3-sec-butylplieriy)-N, N'-bis-methylguanidine; 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- acen aphthyl) (3-phanethylphenyl) gu an idine; N-(3-acenaphthyl)-N'-(4-adamantylphenyl)guanidine; N-(3-acenaphthyl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine; I t2.;99Cl?97U.SPHV7 I 1 11 11 1 11 1 111 1 0" I I I I I it t 1141 IH 1 11141" 11 1"I I 1111 44 41 .f ,tlI I. I1 88 N- (3-ace na phthyl) -Nr(4-bel~oxyph eflyl) N-methylg uan idin e; N- (3-acen aphihyl) (3-bi phenlyl)- N' -methylg uanidirle; N-(3-acenaphithyl)-N'-(3-(1'I-methyl-2'-phenylethyl) phenyl)guanid in e; N- (3-acenaphthyl) (7-belzyltetral inylpheflyl) g uafid ine; N- (3-acenaphthyI) -(4-ethoxy) phenyl) propanyl) phelylguaflidile, N-(3-acenaphthyl)-N N'-dlIbenzyl) aminopheriylguanidlne; N-(3-acenaphthyl)-N'-(3-( 1 '-benzylbutyl0 phe nyl) guanidine; N-C 3-acenaphthy) -N-3-(4-tert-butylbezoxymethyl) ph enylg uanlId Ine; N-(3-acenaphthyl) -N'-(2-(2-indolyl) phenyl) guanidinle; N-(3-acenaphthyl-N'-(3-bromophenyl)guanidifle; N-(3-acenaphthyl)-N'-(3,4-dibelzyloxyphelyl)gualidilS; N-(3-acen-apthiyl)-N'-(2,3,4-triclhlorophenyll-N,N'-dimethyl guanidine; N-(3-acenapthyl)-N'-(2, 3,4-trichlorophienyl)-N'-methylgualidlfle; and and pharmaceutically acceptable salts of said compounds, 1 2. A compound of claim 11, substantially as herein described with reference to any one of the Examples. 13. A method for treating a disorder of the nervous system in which the pahpyiooyo tedsrder 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 11 or claim 12. 14. The method of claim 13, wherein the disorder is 1) nausea resulting from chemotherapy, 2) epilepsy, 3) convulsions, 4) carbon monoxide poisoning, cyanide poisoning, 6) toxic brain damage caused by tetrodotoxln or shell fish toxins, 7) amnesia, 8) migraine or river blindness, or 8) nerve cell death resulting from hypoxia, hypoglycemia, brain or spinal cord Ischemla, brain or spinal cord trauma, stroke, heart attack, or drowning, 1 5. A method for treating nerve cell death comprising administering to a 1/3/W9Cpgt4.SPfl' pl'i'l 11 1.111 i "H,114, IIA I I 'I 141 1111 1% 11" -89- subject exhibiting symptoms of nerve cell death or susceptible to nerve cell death an effective amount of a compound of claim 11 or claim 12. 16. The method of claim 15, wherein the nerve call death results from hypoxia, hypoglycemia, brain or spinal cord trauma, stroke, heart attack, or drowning. 17. A method of treating brain or spinal cord trauma, stroke or heart attack comprising administering to a mammal exhibiting symptorms of or susceptible to brain or spinal cord trauma, stroke or heart attack an effective amount of a compound of claim 11 or claim 12. 18. A method of treating a disease selected from the group consisting of Huntington's disease. Amyotrophic Lateral Sclerosis, Alzhelmer's disease, Down's Syndrome, Korsakoff's disease, olivopontocerebellar atrophy, HIV-induced dementia, HIV-induced blindness, multi-infarct dementia, or epilepsy, the method comprising administering to a mammal exhibiting symptoms of the disease or susceptible to said disease an effective amount of a compound of claim 11 or claim 12. 19. A method for modulating the release of excess endogenous glutamate from a subject comprising administering to the subject an effective amount of a compound of claim 11 or claim 12, 20. A method of blocking voltage sensitive calcium channels or voltage sensitive sodium channels of mammalian neuronal cells comprising administering to the cells an effective amount of a compound of claim 11 or claim 12, 21. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 11 or claim 12 and a pharmaceutically acceptable carrier. 22. A method of any one of claims 3 to 9 or 13 to 20 which method is substantially as herein described with reference to any one of the Examples. 23. A pharmaceutical composition of claim 10 or claim 21, substantially as herein described with reference to any one of the Examples. \niuvfcMu.a3,s'9 l'I'N' 11;t ill l H I NuN IH[,]I fM ll. *inr ilm I.1ln 24, Use of a compound of any one of claims 1, 2, 11 or 12 in the preparation of a medicament for the treatment of a disorder of the nervous system; for the treatment of nerve cell death; for the treatment of brain or spinal cord trauma, stroke or heart attack; or for the treatment of a disease selected from the group consisting of Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, Korsakoff's disease, olivopontocerebellar atrophy, HIV-induced dementia, HIV-induced blindness, multi-infarct dementia, or epilepsy. S DATED this 1st day of February, 1999. S1 Q CAMBRIDGE NEUROSCIENCE, INC. S By their Patent Attorneys; CALLINAN LAWRIE K "wnXco^ S\ia.jY\lj~I l121 W2u