CA2177084A1 - Therapeutic guanidines - Google Patents

Abstract

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

Description

wo 95/1446~ 2 1 7 7 0 8 4 Pr.~/usg4/l3541 THERAPEUTIC GUANIDINES
BAr~KGROUND OF THE INYENTION
1. Field of the l1vention The present nvention pertains to certain substituted ~uanidines, and methods of treatment and pharmaceutical 5 corl~,o:.;Lions that utilize or comprise one or more such guanidines.

2. R~rknrollnd Neurons of the mature central nervous system ("CNS"I are hi~hly crec~ d and in ~eneral do not replace themselves.
10 Consequently, death or deyeneration of cells in the nervous system can have far more serious consequences than cell death or de~eneld~ioll in other orcJans. Abnormal neuronal death can be rapid and widespread as in traumatic brain injury, or can occur over many years amon~ very s ~ecific populations of neurons as in chronic 15 neulode~e,~ eciseases.
Substantial evidence now points to pernicious overactivity of normal neulu~ s~ L~e~ systems as a contributory II~echd~ in many instances of patholosical neuronal de~eneration. In particular, 20 overstimulation of neuronal receptors for L-~qlutamate, the brain's most prevalent excitatory amino acid ("EAA") neu-uL~dnsllliLL~r, has been ~co~ æd as a causal or ~x~cerualillJ factor in several acute neurolo~qical disorders, and has been proposed to underlie a number of chronic neurodegenerative diseases as well. Choi, D.W., Neuron., 25 1:623 ~1988); Choi, D.W., Cerebrov. and Brain Metab. Rev., 2:105 (1990); Albers, G.W., et al., Ann. Ne~Jrol., 25:398 (1989). Indeed, it is believed that glutamate neurotoxicity is involved in acute injury to the nervous system as observed with seizure, hypoxia, hypoJlycemia, and trauma, as well as in chronic degenerative 30 diseases such as HuntinJton's disease, olivopontocerebellar atrophy , . , .. . _ _ _ ~ . !
woss/l4467 2 1 7~4 Pcr/Us~4/l3s4l r1~soc~ d with glutamate dehydrogenase deficiency and decreased ~lutamate ~r~tr'-' ", amyotrophic lateral sclerosis/Parkinsonium-dementia, Parkinson's disease, and Al~heimer's disease. Choi, D.W, Neuron, 1:623-634 (1988); Choi, D.W., Cereb. Brain Met., Rev.
5 2:105-147 (1990); Courtier et al., Lancet, 341:265-268 (1993);
Appel, S.H., TrendsNeurosci., 16:3-5 (1993).
In the ",~"""a~ brain, glutamate interacts with three major classes or receptors, i.e., N-methyl-D-aspartate ("NMDA") receptors, 10 non-NMDA receptors and metabotropic receptors (Watkins, J.D., et al., TrendsNeurosci., 10:265 (1987); and Seeburg, TIPS, 141:297 (1993)). While triggering distinctive postsynaptic ~D~.onses, all three classes of glutamate receptors can act to increase the intracellular concentration of free Ca2+ in nerYe cells (A.B. MacDermott, Nature 15 321:519 (1986)). Thus, binding of glutamate to the NMDA receptor opens a cation-selective channel that is markedly permeable to Ca2+, leadin~ to a large and rapid increase in intracellular Ca2+. Although non-NMDA receptors are in most instances linked to cation channels that largely exclude calcium, they can indirectly promote Ca2+ entry 20 into neurons by de~ol~ i"g the cell membrane, which in turn opens voltage-activated Ca2+-channels. The so-called "metabotropic receptor", on the other hand, is not associated with an ion channel but can promote the release of Ca2+ from jl ~ " l'^r stores via the second-messenger inositol 1, iyl1oDphal~.
Irrespective of the triggering mechanism, prolonged elevation of cytosolic Ca2+ is believed to be a key event in the initiation of neuronal destruction. Adverse consequences of elevated intracellu~ar Ca2+ include derangement of mitochondrial respiration, activation of 30 Ca2+- ;lepende"L proteases, lipases and endonucleases, free radical formation and lipid peroxidation of the cell membrane.

WO95/14467 2 ~ 77084 Pcrlus94ll3s4l

- 3 -The NMDA subtype of excitatory amino acid receptors is strongly involved in nerve cell death which occurs followin~q brain or spinal chord ischemia. Upon the occurrence of ischemic brain insults such as stroke, heart attack or traumatic brain injury, an excessive 5 release of endogenous glutamate occurs, resulting in the over-stimulation of NMDA receptors. Associated with the NMDA receptor is an ion channel. The recognition site, i.e., the NMDA receptor, is external to the ion channel. When glutamate interacts with the NMDA receptor, it causes the ion channel to open, thereby permittin~
10 a flow of cations across the cell ",e,llLlalle, e.g., Câ2t and Na1 into the cell and K~ out of the cell. it is believed that this flux of ions, especially the influx of Ca2~ ions, caused by the interaction of glutamate with the NMDA receptor, plays an important role in nerve cell death. See, e.g., Rothman, S.M. and Olney, J.W., Trends in 15 Neurosci., 10(7):299-302 (1987). Additionally, excessive excitation of neurons occurs in epileptic seizures and it has been shown that over-activation of NMDA receptors contributes to the pathophysiology of epilepsy (Porter, R.J., Epilepsia, 30(Suppl.
1):S29-S34 (1989~; and Rogawski, M.A., et al., Pharmacol. Rev., 20 42:224-286 (19901).
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 25 receptor sites are physically part of specific ion channel proteins.
Non-NMDA receptors have been broadly characterized into two major sllhclSlcses based on compounds selective therefor: kainate receptors and AMPA/quisqualate receptors. See J.C. Watkins et al., Trends Neuroscl., 10:265 (1987). AMPA is an abbreviation for a-amino-3-30 hydroxyl-5-methyl-~isoazole propionic acid. These s~lhcl~cs~s may be categorized as "non-NMDA" receptors.

WO 95/14467 2 ~ 7 7 ~ 8 4 PCT/US94/13541 .

- 4 -Compared to NMDA receptors, non-NMDA receptors have received less pha""acolo~ical scrutiny -- the existing antagonists are all competitive -- and in vivo research in this area has been hampered by the lack of druys that cross the blood-brain barrier. Nonetheless,

5 in vivo studies have clearly de"lon:,lldl~ that non-NMDA receptor a~onists can be as excitotoxic as NMDA agonists, although longer exposures can be required. In addition, evidence from animal studies and from human ~p;de",iological studies suygests that excitotoxicity mediated by non-NMDA receptors may be clinically important in 10 certain pathologies. See M.D. Ginsbery et al., Stroke, 20:1627 ( 1989) .
One such disorder is global cerebral ischemia, as occurs following cardiac arrest, drowning, and carbon monoxide poisoning.
15 Transient, severe interruption of the cerebral blood supply in animal causes a syndrome of selective neuronal necrosis, in which de~e".:,dliol~ occurs among special populations of vulnerable neurons (including neoco, li~,dl layers 3, 5 and 6, pyramidal cells in hippocampal zones CA1 and CA3, and small and medium sized 20 striatal neurons). The time course of this degeneration is also regionally variable, and can range from a few hours (striatum) to several days (I,, ,c r. ~ llplJS).
NMDA a"ld~o~ generally have not proven highly effective 25 in animal models of global ischemia; indeed, it has been suggested that positive results obtained usiny 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 dldl~ldl ~~"y effective in preventing delayed neuronal 30 d~ ne,d~ion followin~q transient forebrain ischemia in both gerbils WO95/14467 2 ~ 770~4 PCT/US94~13541 and rats. See, M.J. Sheardown et al., Sc~ence, 247:571-574 ~1990).
At present, there is a critical need for effective l~alrllellL~
5 which limit the extent of nerve cell death following a stroke or traumatic brain injury. Recent advances in the understanding of the ",eclla,.is",s underlying this nerve cell death have led to the hope that a drug treatment cân be developed. Research and development efforts in this area have focussed on blockin~q the actions of 10 glutamate that are mediated by the NMDA receptor-channel complex.
Two approaches have been developed: competitive NMDA receptor anta~onists (Choi D.W., Cerebrov. Brain Metab., Rev. 1:165-211 ~1990); Wâtkins~ J.C. and Olverman, H.J., TrendsNeurosci., 10:265-272 (1987)) and blockers of the ion channel of the NMDA
15 receptor-channel complex (Meldrum, B., CerebrovascularBrain Metab., Rev. 2:27-57 (1987); Choi, D.W., CerebrovascularBrain Metab., Rev. 2:105-147 (1987); and Kemp, J.A. eral., Trends Neurosci., 10:265-272 (1987)). However, some toxicity with certain ion-channel-blockets such as MK-801 (see Merck Index, mono~qraph 20 3392, 11th ed., 1989) has been reported. Olney, J.W. et al., Science, 244:1360-1362 (1989); Koek, W. and Colpaert, J., J.
Pharmacol. Exp. Ther., 252:349-357 (1990). NMDA antagonists also have been shown to inhibit memory acquisition. Morris, R.G.M., in Excitat. A.A. 's in Health and Disease, D. Lod~qe (ed.), Wiley, 297-25 320 (1988).
Blockers of neulol,dns"liller release have received someattention as potential neulop,~ .live agents. See Meldrum, B., Cerebrovascularand Brain Metab., Rev. 2: 27-57 (1990); Dolphin, 30 A.C. Nature, 316:148-150 ~1985)); Evans, M.C. et al., Neurosci.
Lett., 83:287-292 (1987); Ault, B. and Wang, C.M., Br. J.

woss/t4467 2 1 ~84 Pcr/uss4/l3s4l

- 6 -Fhar".acol., 87:695-703 11986); Kaneko, T., et al., Arzneim-Forsch./Drug Res., 39:445-450 ~1989); Malgouris, C., et al., J.
Neurosci., 9:3720-3727 (1989~; Jimonet, P. et al. BioOrgan. and Med. Chem. Lett., 983-988 (19931; Wahl, F. et al., Eur. J.
5 Pharmacol., 230:209-214 (1993); Koek, J.W. and Colpaert, F.C., J.
Pharmacol. Exp. Ther., 252:349-357 (1990); Kaneko, T. et al., Arznefm. -Forsch./Drug Res., 39:445-450 ( 1989) . Certain compounds said to inhibit glutamate release also have been reported to show anticonvulsant activity. Malgouris, C., et al., J. Neurosci., 10 9: 3720-3727 (1989); Milier, et al., New Anticonvulsant Drugs, Meldrum, B.S. and Porter R.J. (eds), London:John Libbey, 165-177 (1 986).
Calcium dllldgO~ S such as nimodipine have been reported to 15 act both as cerebral vaso,iildLo~ (Wong, M.C.W. and Haley, E.C. Jr., Stroke, 24:31-36 (1989)), and to block calcium entry into neurons (Scriabine, A., Adv. Neurosurg. (1990)). Modest improvement in the outcome of strqke has been observed in clinical trials. Gelmers, H.J.
et al., N. Eng. J. Med., 318:203-207 (1988). While there are 20 si~C~"iti..d.,l cardiovascular side effects, nimodipine appears less taxic than certain NMDA an~d~oni~
A.)Ldgùnk.~ of voltage-~ated Na channels can exhibit ne~.up,u~ ive properties. Graham, S.H., J. Chen, F.H. Sharp, and 25 R.P. Simon, J. Cereb. Blood Flowand Metab., ~3:88-97 (1993), Meldrum, B.S., et al., Brain Res., 593:1-6 and Stys, P.K., S.G.
Waxman, and B.R. Ransom, J. Neurosci., 12:430-439 (1992). In stroke, sustained hypoxia in the "core reyion" results from occlusion of the blood supply by a clot. As hypoxia develops, ATP depletion 30 leads to an inability of the Na, K-ATPase to maintain the ion gradients wh~ch generate the normal membrane potential of resting nerve cells.

W095/14167 2 ~ ~7Q84 PCT/US94/13541 As the cell depola~ i~as and reaches the threshold for action potentialfiring, Na channels are activated. Stys et al. ~Stys, P.K., S.G.
Waxman, and ~.R. Ransom, J. Neurosci., 12:430-439 (1992)) recently reported the development of Na channel hyperactivity in 5 anoxia of central white matter and demonstrate in vitro the nel~.u~ uL~ ive 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 l:
Arl - N(R) - ~ - N(R') - Ar NH
(I) 1 5 wherein:
R and Rl are each independently selected from the group co~ i"g 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 20 unsubstituted alkynyl having from 2 to about 20 carbon atoms, cl~hstit~lt-~d 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 25 unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, s"h$tit"t~d 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 havins at least about 5 ring atoms, or a substituted or unsubstituted 30 l~ loalullldtiu 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 9~114467 2 ~ 7 7 Q ~ ~ PCTIUS94/13~41 Ar and Ar' are each independently selected from the group consi~i"g of s~lhstitlltpd or ur~s~hstitl~tPd carbocyclic aryl having at least 5 carbon atoms, and substituted or unsubstituted he~e,oaro",a~ic group having 1 to 3 rings, 3 to 8 ring members in 5 each ring and from 1 to 3 hetero atoms; and pha~ aceutically dcc~ abl~ salts thereof.
Preferred compounds of the Formula I include those lapl~a.l~t:d by Formula IA:
~ R Rl <~,N~N~A, (IA) 1 5 wherein:
R and Rl are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or urlcllhstitlltpd alkenyl having from 2 to about 20 carbon atoms, substituted or uns~hstitl~tPd alkynyl having from 2 to 20 about 20 carbon atoms, s~lhstitllt~Pd or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or urlcllhstitlltPd aminoalkyl having from 1 to about 20 carbon atoms, substituted or ur~s~lhstitlltPd alkylthio having from 1 to about 20 carbon atoms, substituted or ur~s~hstitlltpd alkylsulfinyl having from 1 to about 20 25 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, s~lhstitlltPd 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 he~ ua~u~la~ic or heteroalicyclic group having from 1 30 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;

WO 9S/14467 2 i 7 7 0 8 ~ PCTlllS94113541 _ 9 _ Ar is selected from the ~roup consistin~ of substituted or unsubstituted carbocyclic aryl having at least 5 carbon atoms, and s~lh5titlltrd or unsubstituted h~ lOdlL)llldLi1 group having 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero 5 atoms; and pl~a""dceutically acceptable salts thereof.
Another group of preferred compounds of the present invention include those represented by Formula IB:
& NH (IB) wherein R, Rl and Ar are the same as defined above for Formula IA, and plla"llaceutically accepldblr, salts thereof.
In another aspect, preferred compounds of Formula i include those guanidines having an N- andlor N'-acenaphtyi substituent that 20 comprise one or more ring substituents. In particular, preferred compounds include those of the following Formula IIA:
(x2) ~R R
NH
wherein R, RI and Ar are the same as defined above for Formula IA, each R2 substituent is independentiy halogen, hydroxyl, cyano, isocyanato, nitro, amino, azido, substituted or unsubstituted alkyl 30 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 _ _ _ _ _ _ _ _ _ _ _ .. . .. . ..

7 2 ~ ~ 7 0 8 ~ PCT/US94/13541 carbon atoms, substituted or uns~lhstit~ltPd alkoxy having 1 to about 20 carbon atoms, substituted or ur~s~hstitllted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms, substituted or unsubstituted 5 alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or urlsllhstitlltPd 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 pharn~ce~l- "y acceptable 10 salts thereof.
Also preferred are guanidines having a substituted 3-acenapthyl moiety, particularly compounds of the following Formula IIB:
(R~,R Rl (IIB~
wherein R, R' and Ar are the same as defined above for Formula IA, each R2 substituent is independently halogen, hydroxyl, cyano, isocyanato, nitro, amino, azido, substituted or urlc~lhstitlltpd 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 25 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or 30 unsubstituted aminoalkyl having from 1 to about 20 carbon atom, or ~ WO 95114467 2 1 77 Q 8 ~ Pr~/us94~l3~4l sllhstitl~t~d 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 preferab~y substituted at the 3, 4, 5, 6, 7 and/or 8 positions of the acenap~,~l,yl group by one or more R2 1 0 groups.
Preferred compounds of Formula 1, IA, IB, IIA or IIB include ~icllhstitlltpd guanidines, i.e., where R and R' are each hydrogen, particularly where the group Ar and/or Ar1 j5 a heterocyclic group or a 15 sllhstitlltpd 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 li.e., where only one of R and R' are hydrogen) and tetra-20 substituted guanidines (i.e., where both R and R' are other thanhydrogen), particularly where the group Ar and/or Ar1 is a heterocyclic ~roup or a substituted or unsubstituted carbocyclic aryl group such as ur~s~lhstitlltPd and s~lhstitlltPd biphenyl and unsubstituted and sllhctitllJpd phenyl including mono-substituted 25 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 1, IA, IB, IIA and IIB include 30 the tautomeric isomers of the specified guanidines.
.. ..

WO 95114467 2 ~ ~ 7 0 ~ 4 PCTNS94/13~41 Preferred compounds of the invention modulate, particularly inhibit, the release of a neu~uL~al,~",i~L~r, preferably glutamate. More plt:rt:rdUIy the preferred substituted guanidines modulate, particularly inhibit, neulul~d~"~ r ~e.g., glutamate) release from ischemic 5 neuronâ~ cells, especially Illallllll " I 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 ~lutamate release 10 assay and veratridine induced glutamate release assay, as discussed more fully infra. As described above, these especially preferred compounds include a 3-acenaphthyl or 5-acenaphthyl group on one guanidine nitrogen and either a substituted or ur~ hstitlltr~d 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 lt~F' Lions, including ll~al~ l of those diseases that result from modulation of a particular neulul~d~ l system and that can be counteracted by 20 one or more of the substituted guanidines of the invention which act either on the same or another class of neuluL~dns"~
The present invention includes methods for treatment and/or prophylaxis of neurological conditions such as epilepsy, 25 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 30 Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, Korsakoff's ~ wo 95/14467 2 1 7 7 0 ~ 4 rcrlusg4/l354l disease, olivc~pontocerebellar atrophy, HlV-induced dementia and blindness or multi-infarct dementia. Compounds of the invention also may be used to treat anxiety, e.g. by ad~ llk>Llalion to subjects .
susceptible to generalized anxiety disorder. Compounds of the 5 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 10 a~,,li,,i~l,dlion of a theri~re~tic "y effective amount of one or more compounds of Formula 1, IA, IB, IIA or IIB to an animal, including a mammal, particularly a human.
The invention also provides pl~a~ aceutical compositions that 15 comprise one or more compounds of Formula I and a suitable carrier.
DET~" Fn ~ESC:RIPTI~N OF TH~ INYENTION
It has been found that compounds of the invention have the ability to modulate, i.e. inhibit or pulel~lia~ the release of 20 neulullallsll~ s~l or decrease or preferably iengthen the time course of action of neu,ulldlli~llliLL~r(s)l 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 neuluL~d~,~"~iLL~rs. It is thought 25 that s~lhstitlltr~d guanidines of the invention mediate the inhibition of neu,ulldllslllillrr 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 Illdllllll-' I cells such 30 as human neuronal cells, comprising the adllli"; ,L~dLion to the cells an effective amount of a compound(s) of Formula 1, IA, IB, IIA or IIB
.. .. . . _ _ _ _ , .

WO9S114467 2 ~ 77~ Pcrluss4/13s41 ~

particularly such ad~ L~d~ion to a mammal in need of such treatment. By such blockage of calcium channels of neuronal cells, conditions ~ssQci~tr~d 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 neu,u~ldlls",i~e,~
10 such as ~amma-aminobutyric acid. Further and without wishing to be bound by theory, inhibiting the release of an excitatory neu~ulld~ls"~ i such as glutamate by ad",i"i;",d~ion of a compound of the invention may indirectly pu~r,lial~ the release or s~lhseq~ t actions of an inhibitory lla~ls~ r such as gamma-aminobutyric acid, 15 and thus the compound of the invention may treat disorders known to be alleviated by more direct pOlt:lllidlion of inhibitory neu,ulld~s~ ion~ e.~., anxiety or insomnia.
Compounds of the invention may be considered effective 20 inhibitors of neululla~ release if the compound causes at least about a 50% inhibition of neu,ul~a,,,,,liller~ such as glutamate, at a concenl~dlion of about 100 I~M accordin~ to the protocol disclosed in Example 64 below. More preferably the compound will cause at least about a 50% inhibition of neU~ullar,~"li~r, such as glutamate, 25 at a cùnce,llldlion of about 30 ~M according to the protocol disclosed in Example 64 below.
Compounds of the invention may modulate release of neu~ulldi~sr"ill~ that include glutamate, dopamine, norepinephrine, 30 glycine, aspartate and serotonin, particularly glutamate.

I W095114467 2 ~ 77D84 PCT/U594/13541 It has also been found that compounds of the invention, while effective modulators of neurotransmitter release as dei~on~L~d~d e.~.
in Example 64 which follows, exhibit reiatively low affinitv to the PCP and/or sigma receptors in typical PCP and sigma receptor binding 5 assavs. This su~gests that compounds of the invention have a clearly distinct therapeutic Ill~cl~dl,is,,, of action relative to neu,vplule~ ve ayents that exhibit high affinity for the PCP or sigma receptors.
Suitable halogen groups of compounds of the invention (including compounds of Formulas 1, IA, IB, IIA or IIB) are F, Cl, Br and 1. Preferred alkyl groups include having 1 to about 12 carbon atoms, more pl~r~:labl~ 1 to about 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, pentyl 15 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 pr~r~ldl l~ 2 to about 6 carbon atoms, still more preferably 2 to about 3 or 4 carbon atoms. Each of the terms alkyl, alkenyl and 20 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 25 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, 30 secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more . .

WO 9~/14467 2 1 7 7 0 8 ~ PCT/US94/13541 p,er~,d~ly 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 IS0) groups, more typically one 5 sulfinyl group, and from 1 to about 12 carbon atoms, more prefefably 1 to about 6 carbons, and even more preferably 1-3 carbon atoms.
Preferred alkylsulfonyl groups have one or more sulfono (S02~ groups, more typically one sulfono group, and from 1 to about 12 carbon atoms, more preferably 1 to about 6 carbons, and even more 10 p,~rt:r~bl~ 1-3 carbon atoms. Suitable heteroaromatic or heteroaryl and hr L~,o~ yclic groups of compounds of the invention contain 1-3 separate or fused rings and one or more N, 0 or S atoms and include, e.g., quinolinyl including 8-quinolinyl, indolinyl including 5-indolinyl, furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, 15 oxazolyl and pll~ ' "ir~o groups all of which may be optionally independently s~hstitlltPd at one or more available positions including fused to a further cyclic group le.g. fused to a benzene ring); and s~lhstitlltPd or uns~hstit~tPd tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl groups, pyrazinyl, 20 coumarinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, be,~ l,ia~olyl, ben~ullia~ùlyl, and bell~;,,,i,ld~ulyl~ Preferred aryl groups, including carbocyclic aryl groups, include those having about 5 to about 20 carbons, more preferably about 1 to 3 separate or fused rings and from 6 to about 18 carbon atoms, such as phenyl, 25 naphthyl, acenapf,ll"rl, phelldlllllryl, anthracyl and fluorene groups.
Said s~lhstitlltpd moieties of compounds of the invention may be substituted at one or more available positions by one or more suitable groups such as, e.g., halogen such as F, Cl, Br, or l; cyano;
30 hydroxyl; nitro; azido; carboxy; carbocyclic aryl; alkyl groups including alkyl groups having from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; slkenyl and alkynyl groups includin~
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 thûse groups having one or more oxygen linkages and from 1 5 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;
10 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 15 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 25 preferred substituted moieties are alkaryl groups which include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups, e.g., above-mentioned aryl - groups substituted by one or more Cl-C12, Cl-C6 or C1-C, alkyl groups such as phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl and 30 phenylhexyl groups as well as the branched chain isomers thereof.
Haloalkyl are also preferred, particularly fluoroalkyl such as , . ... . . . .. ~

WO 95/14467 ~ ~ 7 7 ~ ~ 4 Pr~/us94/l3s41 trifluoromethyl. Aroyl groups are also preferred substituted groups such as carbonyl s~hstit-lt~d by phenyl, naphthyl, acenaphthyl, phe"a"~ yl, and anthracyl groups and carboxylic acyl groups substituted by one or more aryl groups, e.g., diphenylacetoxy and 5 fluo~ er,a,l,oxy groups. Aralkanoyl groups are also preferred and include carbonyl substituted by the aralkyl groups described above.
Aralkoxy groups are also preferred substituted groups and include alkoxy groups substituted by phenyl, naphthyl, acenaphthyl, phenanthyl, and anthracyl groups. Preferred s~hstitllted aryl groups 10 include the above described aryl groups, particularly phenyl, substituted by halo, hydroxy, alkoxy, amino, and the like.
Particu~arly preferred substituent groups of compounds of the invention include halogen, hydroxy, CF3, C1-C~ acyl, Cl-Cs alkyl, C2-15 Cu alkenyl, C2-C~ alkynyl, C1-C~, alkoxy, C~l-Cl8 aryl, C2-C~ dialkoxy-methyl, cyano, C3-C~, cycloalkyl, C3-Cs heterocycloalkyl, C3-C1s dialkylaminoalkyl, carboxy, C2-C~, carboxylic acid, carboxamido, C1-C6 haloalkyl, C1-C~ haloalkylthio, allyl, C7-C20 aralkyl, a C3-C,~
heterocycloalkyl ring fused to a benzene ring, C1-C~ alkylthio, 20 arylthio, Cl-C~ ha'- " y, amino, C~-C~ alkylamino, C2-C1s dialkyl-amino, carbamoyl, C1-Cs N-alkylcarbamoyl, C2-C1s N,N-dialkyl-carbamoyl, nitro, C2-C1s dialkylsulfamoyl, and the like.
Particularly preferred R and R1 groups of compounds of the 25 invention include hydrogen and substituted and unsubstituted alkyl, particularly methyl, ethyl, propyl and butyl. Hydrogen and methyl and ethyl are especially preferred R and R1 groups.
Preferred R2 groups of compounds of the invention include 30 halo, substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsub-WO 9S/14467 2 ~ 7 7 ~ 8 4 PCTlUS94/13!i41 stituted alkylthio, and substituted or unsubstituted alkylsulfinyl.
Preferred substituted alkyl R2 groups include haloalkyl including fluoroalkyl such as fluoromethyl or fluoroethyl, particularly trifluoromethyl.

Typically preferred Ar substituents of compounds of Formula 1, 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 10 including phenyl groups having a single ring substituent e.g. at the 3 or 4 position; ~lisllhstit~lt~d phenyl groups including a 2,3-substituted phenyl group, 2,~substituted phenyl group, 2,5-substituted phenyl ~roup, 2,6-substituted phenyl group, a 3,4-substituted phenyl group or a 3~5-s~lhstitlltr~d phenyl group; and tric~hstitlltQd phenyl groups 15 including a 2,3,4-substituted phenyl group, a 2,3,5-substituted phenyl group, a 2,3,6-substituted phenyl group and a 3,4,5-substituted phenyl group; and tetr~cllhstitlltpd 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 20 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, 25 haloalkyl such as fluoroalkyl including trifluromethyl, chloroalkyl and bromoalkyl, haloalkoxy including fluoroalkoxy such as trifluoromethoxy, and carobocylic aryl, particularly substituted or unsubstituted phenyl.
Spe.,irically preferred Ar and/or Arl groups for Formula 1, IA, IB, IIA, or IIB include the following: halophenyl such as fluorophenyl, WO 95/144~7 PCTIUS94/13~;41 lulu,uhe~lyl, bru",ophe"yl and iodophenyl including 2,5-di~u~ophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 3,4,5-trichlorophenyl, 2,3,4,5-tetrachlorophenyl, 2,3,5,6-l~l,dcl~lo,uphenyl, 3-iodophenyl, and the 5 like; alkylphenyl such as 2,3-dimethylphenyl, 3-isopropylphenyl, tert-butylphenyl including 3-tert-butylphenyl, 4-tert-butylphenyl, cyclohexylphenyl including 4-cyclohexylphenyl, sec-butylphenyl including 4-sec-butylphenyl, adamantylphenyl including 3-adamantylphenyl and 4-adamantylphenyl, and the like;
10 haloalkylphenyl including fluoro, bromo, and chloroalkylphenyl such as trifluoromethylphenyl, particularly 4-trifluoromethylphenyl;
alkoxyphenyl including 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-n-butoxyphenyl and the like; nitrophenyl such as 3-nitrophenyl, 4-nitrophenyl and the like; s~lhstitllt~d and unsubstituted bi-phenyl such 15 as 2-bi-phenyl, 3-bi-phenyl, 4-bi-phenyl and the like; substituted and unsubstituted aralkylphenyl including aralkylphenyl having 1 to abûut 10 about carbon atoms and ple:rtllably an aryl substituent of phenyl such as e.g. (1~-methyl-2l-phel)~ Lllyl)phenyl ~i.e., C~H5-CH2CH(CH3)CI,H5-) such as 3-11 '-methyl-2'-phenylethyl)phenyl and 4-20 (1'-methyl-2'-phenylethyl)phenyl, phenethylphenyl (i.e.
C3H5CH2CH2C6H5-1 such as 3-phenethylphenyl and 4-phenethylphenyl and the like; sllhstitllt~d and unsubstituted aralk~ld",i"opl,e"yl such as e.g. (mono-phenylC1 ~alkylene)aminoPhenYl or (di-phenylCl.
"alkylene)aminophenyl such as (N,N-dibenzyl)aminophenyl, (N,N-25 di,uht~ ylene)aminophenyl, N-methyl-N-benzylaminophenyl, and the like; s~lhstitllt~d and unsubstituted arylûxyphenyl and aralkyloxyphenyl including substituted and unsubstituted phenoxyphenyl and benzyloxyphenyl such as e.g. 4-benzyloxyphenyl, 3-benzyloxyphenyl, dibenzyloxyphenyl such as 3-dibenzyloxyphenyl 30 and 4-dibenzyloxyphenyl, and the like; sllhstit~lt~d and unsubstituted WO 95/1446? 2 1 ~ 7 0 ~ ~ PCT/US94113541 (alkyleneoxyaryl)phenyl such as (C1 ~alkyleneoxyaryl)phenyl, particularly substituted and unsubstituted (C1 6alkyleneoxyphenyl)phenyl such as s~lhstitllt~d or unsubstituted benzyloxymethylenephenyl inciuding such groups having one or more 5 C1.~alkyl, halo-CI ~alkylhalo, alkoxy, alkylthio or nitro benzyl ring substituents; substituted and unsubstituted heterocyclic-subslituted phenyl, particularly heteroaromatic-substituted phenyl such as e.g.
phenyl substituted by indole such as 3-~2'-indole)phenyl and 4-(2'-indole)phenyl, phenyi substituted by benzothiazole such as 3-(2'-10 be"~u~ ule~phenyl, 4-~2-bell~o~l '-)phenyl, 3-(2'-bt:~zull~ia~ule-6'-methyl~phenyl, 4-12-benzothiazole-6'-methyl)phenyl, and phenyl substituted by one or more indolinyl including 5-indolinyl, furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl and ~.I,LI ' "i~o groups (all of which may be optionally independently 15 s~lhstitlltpd at one or more available positions including fused to a further cyclic group (e.~q. fused to a benzene rin~)), as well as phenyl substituted by one or more substituted or unsubstituted tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl groups, pyrazinyl, cûumarinyl, 20 tetrahydroquinolinyl, tetrahydroisoquinolinyl, be~ Li ~ia~olyl, and be"~i",idazGlyl. Typically preferred ht:Ld(ualullldlic-substituted phenyl substituents include those phenyl substituents independently substituted at one or more ring positions, more typically one or two phenyl ring positions, by h~l~larullldlic group(s) that each contains 1-25 3 rin~s, 3 to 8 ring members in each ring and 1-3 N, 0 or S atoms.
Suitable Ar and/or Ar1 groups of Formula 1, IA, IB, IIA, or IIB
- also include substituted and unsubstituted naphthyl; and substituted snd unsubstituted acenaphthyl including 3-acenaphthyl and 5-30 acenaphlllyl.

WO 9S/14467 2 ~ 7 I Q 8 ~ PCT/US94/13541 Specifically preferred compounds of the invention include:
N-(5-acenaphthyll-N'-12 3 4-trichlorophenyl~guanidine;
N-(5-acenaphll,yl)-N'-(2,3,4-~1iLl,lL~,uphellyl)-N-methylguanidine:
5 N-(5-acehapl l~l ,yl)-N'-(2,3 4-trichlorophenyl)-N'-methylguanidine;
N-(5-ace~laph~l,yl)-N'-(2,3,4-~ .l,lolophenyl)-N,N'-bis-methylguanidine;
N,N'-bis(5-acend~ l,yl)-N-methylguanidine;
N~N~-bis(5-acel~a~ 11"tl)-N N'-bis-methylguanidine;
10 N-(5-acenaphthyl)-N'-(1-anthracenyl)guanidine;
N-(5-acenaphthyl)-N'-(1 -anthracenyl)-N-methylguanidine;
N-(5-ace,,a,ul,~l,yl)-N'-(1-a"~l,ra. enyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(1-a"~lllace,~yl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-tert-butylphenyl)guanidine;
1 5 N-(5-~cenapl,~l,yl)-N'-(4-tert-butylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-tert-butylphenyl)-N'-methyl~uanidine;
N-(5-ace,~ap~,ll,yl)-N'-(4-tert-butylphenyi)-N N'-bis-methylguanidine;
N-(5-acendpl,~l,yl)-N'-(4-cyclohexylphenyl)guanidine;
N-(5-acena~,l,ll,yl)-N'-(4-cyclohexylphenyl)-N-methylguanidine;
20 N-(5-acella~ yl)-N'-(4-cyclohexylphenyl)-N'-methylguanidine;
N-(5-acend,u~,~l,yl)-N'-(4cyclohexylphenyl)-N,N'-bis-methylguanidine;
N-(5-aLenaph~l ,yl)-N'-(4-sec-butylphenyl)guanidine;
N-(5-ace,ldp~,~l ,yl)-N'-(4-sec-butylphenyl)-N-methylguanidine;
N-(5-acena~ l,yl)-N'-(4-sec-butylphenyl)-N'-methylguanidine;
25 N-(5-ac~,la~,h ll lyl)-N'-(4-sec-butylphenyl)-N N'-bis-methylguanidine;
N-(5-ace,lapl Ill ,yl)-N'-(4-methoxyphenyl)guanidine;
N-(5 a~ella,u~,~l,yl)-N'-(4-methoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)-N N'-bis-methylguanidine;
30 N-(5-acetlaphthyl)-N'-(2 3-dichlorophenyl)~uanidine;

~ W095/14467 2 1 ~ 7 ~ 8 ~ PCT/US94/13!i41 N-(5 acena~iil,yl)-N'-~2,3- i;~l,lorophe"yl)-N-methylguanidine;
N-~5-acenaphthyl)-N'-~2,3-dichlorophenyl)-N'-methylguanidine;
N-~5-acenaphthyl)-N'-~2,3-dichlorophenyl)-N N'-bis-methylguanidine;
N-~5-ace,,a,ul,ll,yl~-N'-~4-methoxy-2-naphthyl~guanidine;
5 N-~5-acel,ap~,ll,yl)-N'-~4-methoxy-2-naphthyl)-N-methylguanidine;
N-~5-ace,~apl,ll,yl)-N'-~4-methoxy-2-naphthyl)-N'-methylguanidine;
N-~5-ac~naph~l,yl)-N'-~4-methoxy-2-naphthyl)-N N'-bis-methylguanidine;
N-~5-acenaphthyl)-N'-~3 4-dichlorophenyl)guanidine;
10 N-~5-ace"aphll Iyl)-N'-(3 4~ 10, uphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4-dichlorophenyl)-N'-methylguanidine;
N-(5-acel~a,u~,Ll~yl)-N'-~3,4-dichlorophenyl)-N,N'-bis-methylguanidine;N-~5-acenaphll Iyl)-N'-(4-chlorophenyl)guanidine;
N-(5-acend~uhll ~yl)-N'-(4-chlorophenyl~-N-methylguanidine;
15 N- (5-acel1apl , ~I , yl)-N '-~4-chlorophenyl )-N'-methylg uanid ine;
N-~5-acellap~,ll,yl)-N'-~4-~,l,lo,op~l~"yl)-N,N'-bis-methylguanidine;
N-~5-acenaphthyl)-N'-~2-naphthyl)guanidine;
N-~5-ace"aphLI ~yl)-N'-~2-naphthyl)-N-methylguanidine;
N-~5-acellapl,ll,yl)-N'-~2-naphthyl)-N'-methylguanidine;
20 N-~5-acena~hl~"/l)-N'-~2-naphthyl)-N N'-bis-methylguanidine;
N-~5-acenaphthyl)-N'-~6-quinolinyl)guanidine;
N-~5-acella~ l 1l1 ,yl)-N'-~6-quinolinyl)-N-methylguanidine;
N-(5-ac~,)a~ yl)-N'-(6-quinolinyl)-N'-methylguanidine;
N-~5-acenaphll,yl)-N'-(6-quinolinyl)-N N'-bis-methylguanidine;
25 N-(5-acr, Idp~lll ,yl)-N'-(4-nitrophenyl)guanidine;
N-~5-acenaphthyl)-N'-~4-nitrophenyl)-N-methylguanidine;
N-(5-acenaphll Iyl)-N'-~4-,~iL, L phel~yl)-N'-methylguanidine;
- N-~5-dc~"d~ l,yl)-N'-~4-nitrophenyl)-N,N'-bis-methylguanidine;
N-~5-acendp~Lllyl-Nl-~3-bi-phenyl)guanidine;
30 N-~5-dce~d,~ yl-N'-~3-bi-phenyl)-N-methylguanidine;
.

_ _ _ _ . . .. .. .

WO 95114467 PCINS94/13~41 21 ~ 4 24-N-~5-acenaphthyl-N'-~3-bi-phenyl)-N'-methylguanidine;
N-~5-ac~.~a~ yl-N'-~3-bi-phenyl1-N,N'-bis-methylguanidine;
N-~5-acenaphthyl)-N'-~2,3-dimethvlphenyl)guanidine;
N-~5-acel~aphll ,yl)-N'-~2,3-dimethylphenyl)-N-methylguanidine;
5 N-~5-acenap~,lllyl)-N'-~2,3-dimethylphenyl)-N'-methylguanidine;
N-~5-acella~,hLllyl)-N'-~2,3-dimethylphenyl)-N,N'-bis-methylg~anidine;
N-~5-abenaph~l ,yl)-N'-(2-bi-phenyl)guanidine;
N-(5-a"ellaphll ,yl)-N'-(2-bi-phenyl)-N-methylguanidine;
N-(5-a~,e,ldpl ,~l ,yl)-N'-(2-bi-phenyl)-N'-methylguanidine;
10 N-(5-a.,e~ l,yll-N'-(2-bi-phenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-~2,5-dibromophenyl)guanidine;
N-~5-acenaphthyl)-N'-~2,5-dibromophenyl)-N-methylguanidine;
N-~5-acel~apl,l~lyl)-N'-~2,5-dibromophenyl)-N'-methylguanidine;
N-~5-acenaphthyl)-N'-~2,5-dibromophenyl)-N,N'-bis-methylguanidine;
1 5 N-(5-acenaphthyl)-N'-(3,4-dimethoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N-methylguanidine;
N-~5-ace,laph~l ,yl)-N'-~3,4-dimethoxyphenyl)-N'-methyl~uanidine;
N-~5-acena,uhll ,yl)-N'-~3,4-dimethoxyphenyl~-N,N'-bis-methvlguanidine;
20 N-~5-acen~.hll,yl)-N'-~4-methoxy-1-naphthyl)-N-methylguanidine;
N-~5-acellaplllllyl)-N'-14-methoxy-1-naphthyl)-N'-methylguanidine;
N-~5-acena,cl,lllyl)-N'-~4-methoxy-1-naphthyl)-N,N'-dimethylguanidine;
N-~5-acenaphthyl)-N'-~4-chloro-1 -naphthyl)guanidine;
N-~5-acel,al,hll ,yl~-N'-~4-chloro-1 -naphthyl)-N-methylguanidine;
25 N-~5-ace,laplllllyl)-N'-~4-chloro-1-naphthyl)-N'-methylguanidine;
N-~5-acenaphthyl)-N'-(4-chloro-1 -naphthyl)-N,N'-bis-methylguanidine;
N-(5-acenap~ll ,yl)-N'-(3,4,5-trichlorophenyl)guanidine;
N-(5-acenaphthyl)-N'-(3,4,5-trichlorophenyl)-N-methylguanidine;
N-(5-acenapl,lllyl)-N'-(3,4,5-trichlorophenyl)-N'-methylguanidine;

~ WO 95/14467 2 1 7 7 0 8 4 PCT/US94/13541 N-(5-fice~ hl~,yl)-N'-13,4,5-l,icl,lo,uphenyll-N,N'-bis-methylguanidine;
N-(5-acenapl lll ,yl~-N'-~4-bi-phenyl)~uanidine;
N-(5-~ce,ldu~,Ll ,yl)-N'-~4-bi-phenyl)-N-methylguanidine;
5 N-(5-acellap~lLllyl)-N'-(4-bi-phenyl)-N'-methylguanidine;
N-(5-acenapl,ll,yl)-N'-(4-bi-phenyl)-N N'-bis-methyl~uanidine;
N-~5-dcellaphll,yl)-N'-(2,3,4,5-tetrachlorophenyl)guanidine;
N-(5-acel~ap~ yl)-N'-(2,3,4,5-tetrachlorophenyl)-N-methylguanidine;
N-(5-acelldap~llllyl)-N'-(2,3,4,5-1~1c,chh~luphenyll-N'-methyl~uanidine;
10 N-(5-acenaphthyl)-N'-(2 3 4 5-tetrachlorophenyl)-N N'-bis-methyl~uanidine;
N-(5-acenaphthyl)-N'-(3-isopropylphenyl)guanidine;
N-(5-scenaphthyl)-N'-(3-isopropylphenyl)-N-methylguanidine;
N-(5-acenaplllllyl)-N'-(3-isopropylphenyl)-N'-methylguanidine;
15 N-(5-ace,laul ,ll ,yl~-N'-(3-isopropylphenyl)-N N'-bis-methylguanidine;
N-(5-acelld~.~,ll ,yl)-N'-(3-tert-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-tert-butylphenyl)-N-methylguanidine;
N-(5-acenaphll,yl)-N'-(3-tert-butylphenyl)-N'-methylguanidine;
N-(5-acelld~Jhlllyl)-N'-(3-tert-butylphenyl)-N,N'-bis-methylguanidine;
20 N-(5-acelld~ l,yl)-N'-(2,3 5 6-l~ cl~lolophenyl)guanidine;
N-(5-acc,~dphlllyl)-N'-(2 3 5 6-tetrachlorophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3,5,6-1~ clllulopll~"yl)-N'-methylguanidine;
N-(5-acend~,hlllyl)-N'-(2,3,5,6-tetrachlorophenyl)-N,N'-bis-methylguanidine;
25 N-(5-acendplllllyl)-N'-(3-iodophenyl)~uanidine;
N-(5-a~,cndp~,lllyl)-N'-(3-iodophenyl)-N-methylguanidine;
N-(5-acelldpl lll ,yl)-N'-(3-iodophenyl)-N'-methylguanidine;
N-(5-a. e,~ap~,ll ,yl)-N'-(3-iodophenyl)-N N'-bis-methyl~uanidine;
N-(5-acenaphthyl)-N'-(3-nitrophenyl)guanidine;
30 N-(5-acenaphthyl)-N'-(3-nitrophenyl)-N-methyl~uanidine;
, .. . .. . .. .. .. . . . .. . .

W09S/14467 ~ ~ 7 7 0 8 ~ PCI/[~S94/13~41 N-(5-scenaphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-nitrophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl j-N'-(5-indolinyl)guanidine;
N-(5-&cel~apl,l~,yl)-N'-(5-indolinyl)-N-methylguanidine;
5 N- (5-acel~apl ,11 Iyl )-N'- ( 5-indolinyl)-N '-methylguanid ine;
N-(5-&cenapt,ll,yl)-N'-(5-indolinyl)-N,N'-bis-methylguanidine;
N-(5-a~,enapl,lllyl)-N'-(3-acenaphthyl)guanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N-methylguanidine;
N-(5-acel ,apt,ll Iyl)-N'-(3-acenaphthyl)-N'-methylguanidine;
10 N-(5-acellaplllllyl)-N'-(3-acenaphthyl)-N,N'-bis-methylguanidine;
N-(5-acel~aplll~ly)-N'-(2-fluorenyl)guanidine;
N-(5-acellapilllly)-N'-(2-fluorenyl)-N-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N'-methyiguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N,N'-bis-methylguanidine;
1 5 N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N'-methylguanidine;
N-(5-acena~ l,yl)-N'-(4-n-butoxyphenyl)-N,N'-bis-methylguanidine;
N-(5-acella~ 1,yl)-N'-(3-(2-methoxy)dibenzofuranyl)guanidine;
20 N-(5-ace,~a~ yl)-N'-(3-(2-methoxy)dibenzofuranyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N,N'-bis-25 methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)guanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N,N'-bis-30 methylguanidine;
_ _ _ _ _ _ .

wo 95/14467 PC r/uss4n3s4~
2 1 ~8~

N-(5-a~el~dp~ yl)-N~-(4-trifluoromethylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-trifluotomethylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N'-methylguanidine;
N- (5-dGel la~ 1 ,yl)-N '-(4-trifluoromethylphenyl)-N, N' -bis-5 methyl~uanidine; N-15-acenaphthyl)-N'-(4-meth~lLl,;ophe"yl)guanidine;
N-(5-acend,u~,Ll,yl)-N'-(4-methylthiophenyl)-N-methylguanidine;
N-(5-a~ellap~"l ,yl)-N'-(4-methylthiophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N,N'-bis-methylguanidine;
10 N-(5-accnapl,ll~yl)-N'-(3-sec-butylphenyl)guanidine;
N-(5-âcel la,ul 1ll ~yl)-N'-(3-sec-butylphenyl)-N-methylguanidine;
N-(5-ace,~dphLI ,yl)-N'-(3-sec-butylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphll,yl)-N'-(2,3,4-trichlorophenyl)guanidine;
15 N-(3-ace"dphLl,yl)-N'-(2,3,4-trichlorophenyl)-N-methylguanidine;
N-(3-acend~h~l~yl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N,N'-bis-methylguanidine;
N,N'-bis(3-acenaphthyll-N-methylguanidine, 20 N,N'-bis(3-acenaphll,~l)-N,N'-bis-methylguanidine;
N-(3-ace,ldphll,yl)-N'-(1 -a"~ll,d.,e,~yl)guanidine;
N-(3-âcenaphLllyl)-N~-(1-anthracenyl)-N-methylguanidine;
N-(3-ac~ ~aphLl lyl)-N~-( 1 -al ~ d~el lyl)-N~-methylguanidine;
N-(3-ace,lapl,Lllyl)-N~-(1-al~lllldl~ellyl)-N~N~-bis-methylguanidine;
25 N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)-N-methylguanidine;
N-(3-ac~ndpl ,LI ,yl)-N'-(4-tert-butylphenyl)-N'-methylguanidine;
N-(3-ac~lapl~Ll lyl)-N~-(4-tert-butylphenyl)-N~N ~-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-cyclohexylphenyl)guanidine;
30 N-(3-ac~ndpl,L~yl)-N'-(4-cyclohexylphenyl)-N-methylguanidine;
_ _ _ _ _ _ _ .. .. . . . . . . ..

WO 9S/14467 2 1 7 7 ~ 8 ~ PCI/US94/13541 N-(3-acenaphthyl)-N'-(4-cyclohexylphenyll-N'-methylguanidine;
N-(3-acenaphthyl~-N'-(4-cyclohexylphenyl)-N N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-sec-butylphenyl)guanidine;
N-(3-ace,laplllllyl)-N'-(4-sec-butylphenyl)-N-methylguanidine;
5 N-(3-aCe~lapl~lllyl)-N~-~4-sec-butylphellyl)-N~-methyl9uallidirie;
N-(3-acenaplllllyl)-N'-~4-sec-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-ace"apl,ll,yl)-N'-14-methoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-methoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxyphenyl)-N'-methylguanidine;
10 N-(3-ace"aplllllyl)-N'-(4-methoxYphenyl)-N N'-bis-methylguanidine;
N-(3-ac~,~aplllllyl)-N'-(2,3-dichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,3-dichlorophenyl)-N-methylguanidine;
N-(3-ace,~aphlllyl)-N'-(2,3-dichloruphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2 3-dichlorophenyl)-N,N'-bis-methylguanidine;
1 5 N-(3-ace"aphl~,yl)-N'-(4-methoxy-2-naphthyl)guanidine;
N-(3-ace"ap~,ll ,yl)-N'-(4-methoxy-2-naphthyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N'-methylguanidine;
N-(3-acella~ yl)-N'-(4-methoxy-2-naphthyl)-N,N'-bis-methylguanidine;
20 N-(3-ace, lap~,lllyl)-N'-(3 4-dichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3,4-diul)loruphellyl)-N-methylguanidine;
N-(3-ace, lap~,ll ,yl)-N'-(3 4-dichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3 4-dichlorophenyl)-N N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-chlorophenyl)guanidine;
25 N-(3-acenaphthyl)-N'-(4-chlorophenyl)-N-methylguanidine;
N-(3-ac~naphlllyl)-N'-(4-chlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-chlorophenyl)-N N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2-naphthyl)guanidine;
N-(3-acr,~aphll,yl)-N'-(2-naphthyl)-N-methylguanidine;
30 N-(3-ace,~apl,Ll,yl)-N'-(2-naphthyl)-N'-methylguanidine;

~ WO 95/14467 2 1 ~ 84 PCT/US94/13541 N-(3-acenaphthyl)-N'-12-naphthyl)-N N'-bis-methylguanidine;
N-(3-acenaphthyl~-N'-16-quinolinyl)guanidine;
N-~3-acel~apl Ill ,yl)-N'-~6-quinolinyl)-N-methylguanidine;
N-~3-acelldpllLllyl)-N~-~6-quinolinyl)-N~-methylguanidine;
5 N-~3-acelld~J~llllyl)-N~-l6-quinolinyl)-N~N~-bis-methylyuanidine;
N-(3-acenaphthyl)-N'-(4-nitrophenyl)guanidine;
N-~3-a~ ellapl Ill ,yl)-N'-~4-nitrophenyl)-N-methylguanidine;
N-~3-a~ella~Jh~llyl)-N~-(4-nitrophenyl)-N~-methylguanidine;
N-(3-acellap~,~l,yl)-N'-(1 nitrophenyl)-N N'-bis-methylguanidine;
10 N-(3-acena,~ l,yl-N'-(3-bi-phenyl)guanidine;
N-~3-acelldp~"llyl-N'-~3-bi-phenyl)-N-methylguanidine;
N-~3-acellapll~llyl-N'-~3-bi-phenyl)-N'-methylguanidine;
N-~3-acenaphthyl-N'-(3-bi-phenyl)-N N'-bis-methylguanidine;
N-~3-acellap~"l,yl)-N'-~2 3-dimethylphenyl)guanidine;
1 5 N-~3-scenaphthyl)-N'-(2,3-dimethylphenyl)-N-methylguanidine;
N-(3-acellap~"l,yl)-N'-(2,3-dimethylphenyl)-N'-methylguanidine;
N-(3-acenapl"l,yl)-N'-~2 3-dimethylphenyl)-N N'-bis-methylguanidine;
N-~3-ace,)ap~"l Iyl)-N'-~2-bi-phenyl)guanidine;
N-~3-acellaph~l ,yl)-N'-~2-bi-phenyl)-N-methylguanidine;
20 N-~3-ace,lapl 1~l ,yl)-N'-~2-bi-phenyl)-N'-methylguanidine;
N-~3-ac~naph~llyl)-N'-~2-bi-phenyl)-N,N'-bis-methylguanidine;
N-~3-ac~l,apl"llyl)-N'-~2,5-dibromophenyl)guanidine;
N-~3-acenapl,~l,yl)-N'-~2,5-dibromophenyl)-N-methylguanidine;
N-~3-ac~llaph~l,yl)-N'-~2,5-dibromophenyl)-N'-methylguanidine;
25 N-~3-ac~l~ap~"l,yl)-N'-(2 5-dibromophenyl)-N N'-bis-methylguanidine;
N-(3-ace:nap~,Ll lyl)-N~-~3~4-dimethoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3 4-dimethoxyphenyl)-N-methylguanidine;
- N-(3-acenaphthyl)-N'-(3 4-dimethoxyphenyl)-N'-methylguanidine;
N-(3-âcenaphthyl)-N'-(3,~dimethoxyphenyl)-N,N'-bis-30 methylguanidine;
_, _ _ _ _ W0 95/14467 2 ~ 7 7 0 8 ~, PCTNS94/13541 ~

N-(3-acenaphthyl)-N'-~4-methoxy-1 -naphthyl)-N-methylguanidine;
N-~3-acenaptllllyl)-N'-(4-methoxy-1 -naphthyl)-N'-methylguanidine;
N-13-acenaphthyl)-N'-14-methoxy-1 -naphthyl)-N,N'-dimethylguanidine;
N-13 2cenaptll1,yl)-N'-(4-chloro-1-naphthyl)guanidine;
5 N-(3-acenaphthyl)-N'-(4-chloro-1-naphthyl)-N-methylguanidine;
N-13-acenapt,ll,yl)-N'-(4-chloro-1 -naphthyl)-N'-methylguanidine, N-(3-acenaphthyl)-N'-(4-chloro-1 -naphthyl)-N,N'-bis-methyiguanidine;
N-(3-acenaphl~lyl)-N'-(3,4,5-trichlorophenyl)guanidine;
N-(3-acenap~llllyl)-N'-(3,4,5-lli~ rophenyl)-N-methylguanidine;
10 N-(3-acenaphthyl)-N'-(3,4,5-trichlorophenyl)-N'-methylguanidine;
N-(3-,3cena~J11lllyl)-N~-(3~4~5-trichlorophenyl)-N~N~-b methylguanidine;
N-(3-acenaphthyl)-N'-(4-bi-phenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-bi-phenyl)-N-methylguanidine;
15 N-(3-dcelld;.~hLl,yl)-N'-(4-bi-phenyl)-N'-methylguanidine;
N-(3-2cenaphthyl)-N'-(4-bi-phenyl)-N,N'-bis-methylguanidine;
N-(3-acenaplllllyl)-N'-(2,3,4,5-tetrachlorophenyl)guanidine;
N-(3-acenaphllly~)-N'-(2,3,4,5-tetrachlorophenyl)-N-methylguanidine;
N-(3-acenapl,ll,yl)-N'-(2,3,4,5-tetrachlorophenyl)-N'-methylguanidine;
20 N-(3-6cenapt,11,yl)-N'-(2,3,4,5-tetrachlorophenyl)-N,N'-bis-methylguanidine;
N-(3 ~c~naphll,yl)-N'-(3-isopropylphenyl)guanidine;
N-(3-acen2phll,yl)-N'-(3-~sopropylphenyl)-N-methylguanidine;
N-(3-acenaptlll,yl)-N'-(3-isopropylphenyl)-N'-methylguanidine;
25 N-(3-acel~api,ll,yl)-N'-(3-isopropylphenyl)-N,N'-bis-methy)guanidine;
N-(3-acenaphthyl)-N'-(3-tert-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-rert-butylphenyl)-N-methylguanidine;
N-(3-acena,ut,~l,yl)-N'-(3-tert-butylphenyl)-N'-methylguanidine;
N-(3-dcenaphthyl)-N~-(3-tert-butylphenyl)-N~N~-bis-methylguanidine;
30 N-(3-âcenaphthyl)-N'-(2,3,5,6-tetrachlOrOphenyl)9uanidine;
.. . _ _ . . . .. _ .. _ _ _ _ _ WO95/14467 2~ ~7D84 PCT/US!94/13~41 N-(3-ace.~au~llllyl)-N'-12,3,5,6-tclla.,l-lo,uphellyl)-N-methylguanidine;
N-(3-acenâphthyl)-N'-(2,3,5,6-tetrachlorûphenyl)-N'-methylguanidine;
N-(3-acel,au)llllyl)-N'-~2,3,5,6-lclldulll~lùplle,lyl)-N~N~-bis-methylguanidine;
5 N-13-acena,ul lll ,yl)-N'-(3-iûdophenyl)guanidine;
N-(3-ac6,1d,uhlllyl)-N'-(3-iodophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-iodophenyl)-N'-methylguanidine;
N-13-accnd~,llLllyl)-1~1'-(3-iodophenyl)-N,N'-bis-methylguânidine;
N-(3-âcclla~J~lll ,yl)-N'-(3-nitrophenyl)guanidine;
10 N-(3-acella~,ll,yl)-N'-(3-nitrophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine;
N-(3-acenaphlllyl)-N'-(3-nitrophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaul,Ll,yl)-N'-(5-indolinyl)guanidine;
N-(3-acc,~du~lll ,yl)-N'-(5-indolinyl)-N-methylguanidine;
15 N-(3-ac~llapllll,yl)-N'-(5-indolinyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indûlinyl)-N N'-bis-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)guanidine;
N-(3-acdllapllllly)-N'-(2-fluorenyl)-N-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N'-methylguanidine;
20 N-(3-âcenâphthy)-N'-(2-fluorenyl)-N N'-bis-methylguanidine;
N-(3-accllap~,Ll ,yl)-N'-(4-n-butoxyphenyl)guanidine;
N-(3-âcenaphthyl)-N'-(4-n-butoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N'-methylguanidine;
N-(3-accl-aphll,yl)-N'-(4-n-butoxyphenyl)-N N'-bis-methylguanidine;
25 N-(3-accl-apl I Ll Iyl )-N'- (3-( 2-methoxy)d ibenzofuranyl)guanidine;
N-(3-acc;l~a,c l,Ll ,yl)-N'-(3-(2-methoxy)dibenzofurânyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N'-methylguanidine;

W095/14467 21 77~8~ PCT/US94/13541 ~

N-(3-ace,la~,l,Ll,yl)-N'-(3:~2-methoxy)dibenzofuranyl)-N,N'-bis-methylguanidine;
N-(3-scenaphthyl~-N'-(9-hydroxy-2-fluorenyl)guanidine;
N-(3-acenaphLI ,yl)-N'-(9-hydroxy-2-fluorenyl)-N-methylguanidine;
5 N-(3-acellapl ,11 ,yl)-N'-(9-hydroxy-2-fluorenyl)-N'-methylguanidine;
N-(3-ace,lapl,ll,yl)-N'-I9-hydroxy-2-fluorenyl)-N,N'-bis-methyl~uanidine;
N-13-acellap~,LI ,yl)-N'-14-trifluoromethylphenyl)guanidine;
N-13-ace~la~.~,Ll,yl)-N'-(4-trifluoromethylphenyl)-N-methylguanidine;
10 N-(3-acel Id~J~lLl ,yl)-N'-(4-trifluoromethylphenyl)-N'-methylguanidine;
N-(3-acella~ l,yl)-N'-(4-trifluoromethylphenyl)-N,N'-bis-methylguanidine; N-(3-acenapl 1~l Iyl)-N'-(4-methylthiophenyl)guanidine;
N-(3-ac~napl ,~1 ,yl)-N'-(4-methylthiophenyl)-N-methylguanidine;
1 5 N-(3-acena,u~l~llyl)-N~-(4-methylthiophenyl)-N~-methylguanidine;
N-(3-acenap~,1l,yl)-N'-(4-methylthiophenyl)-N N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(3-ac~:"a~ l,yl)-N'-(3-sec-butylphenyl)-N-methylguanidine;
N-(3-acelldph~l ,yl)-N'-(3-sec-butylphenyl)-N'-rnethylguanidine;
20 N-13-ace~lapl ,~1 ,yl)-N'-(3-sec-butylphenyl)-N N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-benzyloxyphenyl)guanidine;
N-(5-acenap~,11,yl)-N'-13-benzyloxyphenyl)guanidine;
N-15-acenap~,~l,yl)-N'-13-sec-butylphenyl)guanidine;
N-(5-acenapl,~l,yl)-N'-(2-anthracenyl)guanidine;
25 N-(5-acenap~,~l,yl)-N'-13-phenethylphenyi)guanidine;
N-15-~c~ aphlllyl)-N'-(4-adamantylphenyl)guanidine;
N-(5-ace,~ap~,11 ,yl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-14-benzyloxyphenyl)-N'-methylguanidine;
N-(5-ace~laph11 ~yl)-N'-(3-biphenyl)-N'-methylguanidine;
30 N-(5-acenaphthyl)-N'-(3-11 '-methyl-2'-phenylethyl)phenyl)guanidine;

~ WO 95/14467 2 1 77 084 PCT/US94/13541 N-(5-dce,~ ,LI,yl)-N'-~3,4-tetralinylphenyl)guanidine;
N-(5 i~e,e"dp~,Ll,yll-N'-(7-benzyltetralinylphenyl)guanidine;
N-15-scel1dpl,l~,yl)-N'-~3,4-dibenzyl oxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-13-1 -(4-5 ethoxy)phenyl~propanyl)phenyl)guanidine;
N-~5-acel~a~ lyl)-N~-~3-~N~N~-dibenzyl)aminophenyl)guanidine;
N-~5-ace,lap~,ll,yl)-N'-~3-~1 '-benzylbutyl)phenyl)guanidine;
N-15-dcenaplll~lyl)-N'-3-(4-tert-butylbenzoxymethyl)phenylguanidine;
N-(5-dce,lapl,Ll,yl)-N'-(2-(2-indolyl)phenyl)guanidine;
10 N-(5-acel1apl ILI ,yl-N'-(3-bromophenyl)guanidine;
N-(5-acenaphyl)-N'-(2,3,4-trichlorophenyl)-N,N'-dimethylguanidine;
N-(5-acenapill~,yl)-N'-(2,3,4-trichloro-phenyl)-N'-methylguanidine;
N-(5-dcellap~,Lllyl)-N~-(4-(2~-bell~rJL~ cl 6'-methyl)phenyl)guanidine;
N-(3-acendpl ILI ,yl)-N'-(4-benzoyloxyphenyl)guanidine;
15 N-(3-acenap~lLl,yl)-N'-(3-benzoyloxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(3-scenaphthyl)-N'-(2-a"Lll~a~e~)yl)guanidine;
N-(3-acehdp~ lyt)-N'-(3-phenethy~phenyl)guanidine;
N-(3-acel1apl ILI ,yl)-N'-(4-adamantylphenyl)guanidine;
20 N-(3-acel-aphLllyl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-benzyloxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-biphenyl)-N'-methylguanidine;
N-(3-a~ c,pllL~lyl)-N'-(3-(1'-methyl-2'-phenylethyl)phenyl)guanidine;
N-(3-dcel1ap~1Ll ,yl)-N'-(3,4-tetralinylphenyl)guanidine;
25 N-(3-ac~,1dphLllyl)-N'-(7-benzyltetralinylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-1 -(4-ethoxy)phenyl)propanyl)phenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-(N",N"-dibenzyl)aminophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-(1 '-benzylbutyl)phenyl)guanidine;
30 N-(3-acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl)phenylguanidine;
_ _ _ _ _ _ .. . . .. . . . .. ..

N-(3-a~t,nspl,ll,yl)-N'-(2-(2-lndolyl)phenvl)~uanidine;
N-(3-acenaphthyl-N'-(3-b,u,,,oph~,,yl)guanidine;
N-(3-a~,enapl~ yl)-N'-(3,4-dibenzyl oxyphenyl)guanidine;
N-(3-acenapthyl)-N'-(2,3,4-trichlorophenyl)-N,N'-dimethyl guanidine;
5 N-(3-acellapl,ll,yl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine;
N-(3-scenap~lll ,yl)-N'-(4-(2'-bell~ull 1ia~ole-6'-methyl)phenyl)guanidine;
and pharm~ce~l "y ~cepl~h'~ salts of said compounds.
Additional preferred compounds include those named above 10 with one or more riny substituents on the dce~lap~,Ll~yl group thereof, particularly those R2 ~roups defined above for Formulas IIA and IIB.
Specific~lly preferred phar",~c~ltic~lly acce,uldble salts of said compounds include those compounds identified in the examples 15 which follow, and 3-acenaphthyl derivatives of those exemplified compounds, i.e. compounds that contain 3-dcellapllLllyl group~s) in place of 5-act:llaphll,yl group(s).
Compounds of the invention can be prepared by reaction of an 20 amine, typically an amine salt such as an amine hydrochloride, with a ur~ed 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 25 (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);
tZlllaliOrlal ~Pt " lions W0 91/12797 and PCTIUS92/01050.
More particularly, the synthesis of the diaryl substituted 30 guanidines of the invention is typically achieved by condensin~ a salt ~ WO 95/14467 2 1 ~ 7 ~ 8 4 PCT/US94/~3541 :
of an arylamine with a substituted aryl cyanamide such as 3-acenaphthyl or 5-acenaphthyl cyanamide in a suitable solvent, e.g.
refluxin~q chlorobenzene or toluene, as shown in the Scheme-1 where Ar is as defined aboYe. The cydl1al"ide can be suitably prepared by 5 reduction of the corresponding nitro-substituted aryl to an amine, followed by treatment with cyano~en bromide as shown in the following Scheme.
SCHEME-1: PREPARATION OF N,N'-DI-ARYLGUANIDINES
0 1. <~--NO2 ELOAC & NH2 +
Mi~tu~e of 5 ~3 NH2 ~a,NI12 ~n~ ~a,NHCN ~3~NH2 Hr~r Ar--NH2~HX
r~30. c~a ~eflux NlN~rHl1`Ar In step 1 of the above Scheme, a mixture of 5- and 3-nitro-acenaphthene is reduced with Pd/C in suitable solvent such as ethyl acetate under H2 and suitable pressure such as 40 psi and the resulting amines are separated such as by recry~ldlli~d~iun. In step 2, 25 the desired amino ace,,d,uhll,ene is treated with cyano~en bromide in suitable solvent such as ethyl acetate to give N-a1e"dphll,yl cyanamide and acend,u~,Lllyl amine hydrobromide salt. This cyanamide is subsequently reacted with substituted arylamine salts in a suitable solvent with heat such as refluxin~q chlorobenzene or 30 toluene to ~qive the final product.

wo ss/14467 ~ 8 ~ Pcr/uss4/l3s SCHEME-2: PREPARATION OF N-ALKYL AND N N -DIALKYL N N -Dl-ARYL GUANIDINES
& R-X ~ `CN
k ~ NH HX
C6E~iCI/AlC13 ~, ~eflux f q F~l R
0~ 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-3-ace,-api,Ll,yl-N-alkyl cyanamide (suitably prepared as discussed 20 above) is treated with a salt of an aryl amine ~for synthesis of tri-sllhstitlltpd ~uanidine) or salt of N-alkyl aryl amine (for synthesis of tetra-s~lhstitllt~d guanidine) in a suitable solvent such as chlorobenzene in the presence of AICI3 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 30 above to provide compounds of the invention havin~ a substituted acellapllLllyl moiety, including compounds of Formula IIA or IIB.

~ W095/14467 21770~ PCT/US94113541 Such substituted cyanamide reagents can be readily prepared. For example a substituted acenapl,Lllyl derivative can be nitrated (e.g.
treatment with HN03/H2SO4) to provide a 3-nitroacephthyl or 5-,uacepl,ll,yl having one or more additional ring substituents. See5 the procedure of M.D. Vareny et al., J. Med. Chem., 35: 671 (1992). The reaction products can be separated by recry:,i r 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 10 bromide and then an arylamine salt as described above to provide a compound of Formula IIA or IIB. Suitable substituted acenaphthyl derivatives that can be nitrated and further reacted in such manner include, e.g., haloacenaur,~l,ddlene such as 3-fluon~ace~lauh~l,alene 3-chlo,uaGena~ ll ,e, 3-bromoacelldph~llalène~ 4-15 fluu~oac~llau~ dlel~e~ 4-chlo(oacenapl,ll,alene 4-blul,,~acenapl,~ ne~ 4-fluc.,uacenàp~ le 4-~I,Ioruacenaul,ll, ,e and 4-b,u",oace"dphthalene;
alkanoylacenaphthalene such as 4-acetylace"ap~Ll.slcne;
alkoxynaphthalene such as 4-methoxyacenaphthalene;
20 acenaphthalene 3-acid; 5-acendu~l~l,alene ethanol; 5-acellauhll,al~ne methanol;alkenyldc~na,cIlI~ nesuchas3-(1-llleL~ upe~yl)ace~âuhll~alelle; 5-acenapl,~l,a!~necarboxanilide; and the like.
If the ring substitutent of the acenaul,ll,yl derivative includes a puLelli 'y reactive functionality (e.g. an unsaturated carbon-carbon bond that could be reduced during hydrogenation of the nitro group) a suitable protectin~ group can be employed that is later removed as will be known to those skilled in the synthesis art.

, W09~/14467 ~'1 77~84 Pr~/usg41l3541 ~

In addition to nitration of a substituted acephthyl deriva~ive, compounds of the invention having a sllhstitllted acenaphthyl moiety, including compounds of Formulas IIA or IIB, can be prepared by a number of other routes. Specifically, for preparation of other 5 ace~la~ yl derivatives having an amine or amine-precursor ~roup 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. Fu~lla~hii, Isobret. Prom.
Obraztsy, Tovarnye Znaki, 13), 96-7 ~1982); J. P. Li, et al., US 78-10 890736 11978); N. S. Vorozhtsov, Zh. Org. Khim., 8(2): 353-7 (1972~; J. Wolinski et al., Rocz. Chem., 44(9): 1721-31 (1970); A.
P. Karishin, et al., Zh. Obshch. Khim., 39(9): 2098-101 ~1969); and V.V. Mezheritskii, et al., Zh. Org. Khim., 27(10), 2198-204 ~19911.
Compounds prepared by such methods can be converted to an 15 amine, if necessary, and then reacted with CNBr and an aryl amine as described above tû provide guanidine derivatives having a substituted ace,la~ l ,yl moiety.
As discussed above, the N,N'-diaryl substituted guanidines of 20 the invention are useful for a number of therapeutic applications, includinrd ~ d~ r~l of those diseases that result from modulation of a particular neurotransmitter system that can be counteracted by one or more of the s~lhstitlltPd guanidines of the invention. As mentioned above, modulation of neulul~ dl, .",ill~r release involves either the 25 inhibition of neu,u~ldlls"li~r~r release, the potentiation of neu~u~dll~"~ l release, or the increase or decrease of the time course of action of ne~rùl,d,,~,,,ill~r release from neuronal tissue.
Neu,ul,dns,,,ill~l~ which may be modulated by compounds of the invention include, but are not limited to, glutamate, dopamine, 30 norepinephrine, glycine, aspartate and serotonin. One of ordinary WO 95/14467 PCI/US94/1354]
~ 1 ~J39~1 8~
skiiled in the art can select those compounds which are effective or particularly effective modulators of neu~ul~dn~ release using the procedures disclosed herein or in PCT/US92/01050 with no more than routine eA,u~lilllt:nldliull~ For example, compounds for the 5 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 consicle,ed to be particularly predictive of neuruplul~Llive efficacy in stroke. See Ginsburg, et al., Stroke, 20:1 627-1642 (1989). Efficacy of lead compounds also may be 10 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, 15 neurodegenerative concliLions 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 cdndiddl~s for treatment include heart attack, stroke, brain or spinal cord injury patients, patients 20 ul,de(i ,9 major surgery where brain ischemia is a potential cv.,, " n and patients such as divers suffering from deco,,,u,~;un sickness due to gas emboli in the blood stream.
The invention also provides methods to treat and/or preYent 25 various neurodegenerative diseases of a subject such as an animal, particularly a human, by ad~"i"i~le,i"g 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 30 Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, _ _ _ , . . .

W095/14467 2 ~ ~ 7 Q 8 4 PCT/US94/13541 Korsakoff's disease, olivopontocerebellar atrophy, HlV-induced dementia and blindness or multi-infarct dementia. As disclosed by Dreyer et al., Science, 248:364-367 (1990), gp120 neurotoxicity is rd with increased levels of Ca2+ which are apparently 5 mediated by excitatory amino acids bindiny at the NMDA receptor site. Though again not wishing to be bound by theory, compounds of the invention should have utility in treating HlV-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 adi"i"i~le(i,1g to a subject including a mammal, particularly a human, one or more compounds of the invention in an 15 amount effective to treat the disease. ~ aal~,le,l~ of animals with the NMDA antagonist MK-801 IMerck 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. Absrr., 14:774 (19881.
20 Therefore, compounds of the invention have utility for the attenuation of cell loss, h~",orlllag~s and amino acid changes AeC~CiAtPcl with Korsâkoff's disease.
At least some compounds of the invention will have utility in 25 treating or preventing conditions treatable by the blockage of voltage-2ctivated 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 Illdllllllalidll cells such as human neuronal 30 cells, comprisin~ the âdlll;~ ld~ion to the cells of an effective ~ W095/14467 2 1 770~ Pr~/usg4/l3541 amount of a compound of the invention, particularly by such ~111 lialldliOn 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 5 sodium channels in addition to presynaptic calcium channels. This dual action pole~ lly may be particularly desirable for neu,uprulc:cLive therapies.
It has been reported that NMDA antagonists which do not 10 cross the blood/brain barrier may be used to alleviate certain u"de;,i, ' ' side effects of cancer clle~uLlleld~Jyl e.g. nausea and emesis IA. Fink-Jensen et al., Neurosci. Lett., 137(2):173 ~1992)~.
See also Price, M.T., et al., Soc. Neurosci. Abstr., 16:377, 15 abstr. 161.16 (1990). Compounds of the invention, particularly those compounds that are charged such as in the form of a pl~a",~e~ "y accep~dL!~, salt, and those compounds that otherwise are hydrophilic such as compounds that comprise one or more polar fu"LIion ' ~ e.g. carboxy, amino, hydroxy and the like, 20 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 p~ . ' ' Iy, will be clinically useful to ameliorate the side effects ~csoci~ted with 25 LlldlllO~leldpy, particularly cancer thelllloL~leld~Jy~ that may be experienced by a mammal, particularly a human receiving such chemotherapy. The compound of the invention would be typically a.l",;"k.t~.~d to the subject in coordination with the chemotherapy regime.

W0 95/14467 .,~ Q 8 ~ PCT/US94/13541 Compounds of the invention may be used in therapy in conjunction with other "~e~ ,a"ler~l~. For example, for treatment of a stroke victim, one or more compounds of the invention may be suitably ad",i"i~ d together with a pharmaceutical targeted for 5 ill~dla~lion in the blood clotting "~eclla,l;."ll such as ~ ,L~,ki~lase, TPA and urokinase.
The compounds of this invention can be administered illlldll~ '~y, orally or by injection, e.g., intramuscular, intraperitoneal, 10 subcutaneous or intravenous injection, or by Lldllsdellllal, intraocular or enteral means. The optimal dose can be d~:L~ e~ by conventional means including the assays of Exampies 64-65 which follow. Guanidines of the present invention are suitably administered to a subject in the protonated and water-soluble form, e.g., as a 15 pha",.~e~ltir~lly aCCe~J~dLlL salt of an organic or inorganic acid, e.g., hydrochloride, hydrobromide, sulfate, hemi-sulfate, rnesylate, 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 pharl"aceutical co"lpo~ilion in mixture with conventional excipient, i.e., pha,lllaceutically accepldblr, organic or 25 inorganic carrier substances suitable for pdlt:llL~Idl, enteral or intranasal a~F' ~ion which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof. Suitable pha",.~ceut "lr acceptable carriers include but are not limited to water, sa~t solutions, alcohol, vegetable oils, polyethylene glycols, 30 gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, ~ W095/14467 2177Q84 PCT/US94/13541 Yiscous paraffin, perfume oil, fatty acid monoglycerides and ce~id~, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The phar~ac~utical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, 5 preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances snd the like which do not deleteriously react with the active compounds.
For pdll~ ldl . ~7, '' an, particularly suitable are solutions, p,~e,dbly oily or aqueous solutions as well as suspensions, emulsions, or implants, includin~ sllrpos;tnries. Ampoules are convenient unit dosages.
For enteral application, particularly suitable are tablets, dra~ees or capsules havin~ talc and/or carbohydrate carrier binder or the like, the carrier p,er~,d11~ 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 co,,,po~iliuns can be 20 formulated including those wherein the active co~ponenl is protected with dirr~,- "l:~l'y degradable coatings, e.g., by ;~"ue~ ti~n, multiple coatin~s, etc.
Intravenous or pa,~rllerdl ad~i";~l~dlion, e.d., sub-cutaneous, 25 i"l,du~,ilolleal or intramuscular ad",i";..l,dliun are generally preferrcd.
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 30 formulated, the mode of application, the particular site of WO 95114467 2 ~ 7 ~ q 8 ~ PCI/US94/13541 e ' ,,I~ ,t.Llon, the subJect's wei~ht, age and ~eneral health, etc.
Optimal ad",i";~llaliol- rates for a given protocol of ad~ dLiun can be readily asc~, la;lled by those skilled in the art using conventional dosage d~le,lllillaliûn tests conducted with regard to 5 the foregoing guidelines. In general, a suitable effective dose ûf one or more compounds of Formula 1, Formula IA, Formula IB, Formula IIA
or Formula IIB, particularly when using the more potent compound(s) of Formula 1, Formula IA, Formula IB, Formula IIA or Formula IIB will be in the range of from 0.5 to 50111 '~i,, alll~ per kilogram bodyweight 10 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 ad",;";~l~rt:d once daily, or several sub-doses, e.g., 2 to 4 sub-doses, are ad", I;~ d at app~up~ialt: intervals through the day, or other appropriate schedule. Such sub-doses may be administered 15 as unit dosage forms, e.g., containing from 0.25 to 25111 ", alll~ of compound(s) of Formula 1, Formula IA, Formula IB, Formula IIA or Formula IIB per unit dosage, pn:~dlab~ly from 0.5 to 5 " "'i, alllS 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 acc~l~rdlu~.
All documents mentioned herein are incorporated herein by 25 reference in their entirety.
The present invention will be further illustrated with reference to the following examples which aid in the ul~de~ldi1dillg of the present invention, but which are not to be construed as limitations 30 thereof.

~ WO 95114467 2 ~ 7 7 ~ ~ 4 PCIIUS94/13541 UER~l CC'`"~'-A'TS
In the following examples, all percentages reported herein, un~ess otherwise specified, are percent by weight. All temperatures are ~Ap,~:,sed in degrees Celsius.

Melting points were determined in open capillary tubes on a Thomas-Hoover apparatus and are u~co~e-,led. Thin-layer chromatography was performed on Merck silica gel 60 F264 (0.2 mm) or Baker-flex 1 B2-F silica gel plates. Guanidines were visualized on 10 TLC with 254-nM UV light or as a blue spot with blulllcl~ol spray reagent (Sigma Chemical Co.~. Preparative TLC was pe,lullll6d on Analtech GF precoated silica gel (1000 ~m) glass-backed plates (20 x 20 cm). The IR, 1H and '3C NMR spectra of all compounds were consistent with their assigned structures. NMR spectra were 15 recorded on a General Electric ~E-300 or Varian Gemini 300 and the chemical shifts were reported in ppm (0 relative to the residual signal of the deuterated solvent (CHCI3, ~ 7.26; CHD20D, ~ 3.30). Infrared spectra were recorded in CHCI3 lunless otherwise noted) on a Nicolet 5DXB FT-IR or Perkin-Elmer model 1420. All new compounds were 20 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 (IH) for their purity. Elemental analyses were performed by Desert Analytics (Tucson, AZ) or Galbraith Laboratories (Knoxville, TN). High Resolution Mass spectra 25 (HRMS) were recorded on a Finnegan MAT 90. HPLC were perru",led on a C18 reverse phase column using 50:50 vvc,~r;ac~lùnitrile 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 30 purified by standard procedures before use, or they were prepared, W095114467 2 1 77~84 PCTII~S94/13541 where noted, by published procedures. Chlorobenzene was freshly distilled from CaH2 or anhydrous quality solvent (Sure Seal) supplied by Aldrich wa used. Ether IEtzO) and tetrahydrofuran (THF) were refluxed over sodiumlbenzophenone ketyl and freshly distilled under 5 N2 before their use or anhydrous quality solvents ISure Seal) supplied by Aldrich were used. All other solvents were reagent grade. Alkyl-and arylcyanamides were prepared as described above and according to published procedures (e.g., PCT/US92101050) by reaction of the amines with BrCN in ether.
Example 1: P~ r ali~ln of N-~5-~c~ l)-N'-(2,3,4-llh,ll1t.uuh~ l - Ir~llCl IMETHOD-A
IScheme-1 ~) Ster~ 1. 5-AcenAr~llthvl cvanamide 5-Aminoacelldp~llllene (7.0 9, ~1.4 mmol) was dissolved in a mixture of ether (100 Ml) and ethyl acetate (Z5 Ml). To this solution was added 5.2 mL of a 5M solution of cyanogen bromide in acelunil,il~ (25.6 mmol of cyanogen bromide). The solution was stirred overnight, with the gradual appea'allce of gray pl~ui~ dL~.
20 The solid was removed by filtration (the hydrobromide of 5-_."i,~odcel~apl~ ,e) and the resulting filtrate conce,lI,dlt:d in vacuo to afford a semi-solid residue. Ether (60 mL) was added to the residue and the mixture was stirred overni~ht. The solid was removed (more hydrobromide of 5-aminoacenaphthene) and the 25 filtrate col-c~:,lllal~d to approximately 20 mL and then diluted with warm cy.,loll~dlle (15 mL). Upon standing at room temperature, off white crystals were deposited. They were collected, washed with cyclohexane-ether (1:1) and dried in vacuo to give 1.5 9 of pure product, mp 163-65C.

~W095/14467 2~77D~ PCT/US`i4/13541 ~iteD 2. p,~n~.dlion of N-(5-acen~t~l"llvll-N'-(2.3.4-trichloroDhenvl)ql ~nidine-HCI
A mixture of 5-acenaphthyl cyanamide (0.194 9, 1 mmol~ and 5 2,3,~trichloroaniline hydrochloride (0.221 9, 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 20C and allowed 10 to stand for 24 hours. The solid was collected by filtration and washed with excess of methylene chloride and dried in vacuo at 40C to give product (0.293 9, 68%) as an off white solid, mp: 208-10C; 'H NMR (CD30D): ~ 7.70-7.58 (m, 3H, Ar-H), 7.48 (d, 2H, J=7.5Hz, Ar-H), 3.47-3.41 (m, 4H, 2 x CH2); HRMS 389.0220 15 (389.0253 calcd. for C,9H14N3CI3); Anal Calcd. for Cl9H,sN3CI4 (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: r~t:pa..~ of N,N'-bis(5 a ~ r~ N;
y~ld~ -IICI lMETHOD B (Scheme-2J) Part 1. PreParation Qf N-methvl-N-5-acer~nhthvl cvarLamide A solution of 5-acenaphthyl cyanamide (1.5 9, 7.73 mmol) in 25 THF (22 mL) was slowly added to a stirred suspension of sodium hydride (0.6 9, 15.1 mmol) in THF (8 mL) at room temperature.
After 3 hour reflux, the reaction mixture was cooled to 20C, methyl iodide ~2.64 9, 18.6 mmol) wa added and stirred the contents at 20C. After 16 hours, the reaction was quenched by careful 30 addition of methanol (15 mL) followed by water (35 mL). Extracted by methylene chloridc (3 x 30 mL), dried over MgSO4 and the solvent was evaporated. The residue was purified on flash chromato~raphy WO 95/14467 f~ t 7 7 0 8 ~ PCT/USi94113541 to yield the product (0.8 9, 50%) as a tan solid. TLC (CHCI3:CH30H;
1 0: 1 ) : R~ = 0.72.
e~ Prepa~aLion of N.N -bis(5-acenaDi~ yll-N-methyl guanidine-HCI
Aluminum chloride 10.28 9, 2.11 mmol) was added to a stiFred solution of N-5-acenaphthyl-N-methyl cyanamide (0.4 9, 1.92 mmol~
in cl io.uDe,l e,~e (5.8 mL) at 145C. After 10 minutes 5-10 acellapi-"llene amine hydrochloride (0.39 9, 1.29 mmol, prepared from 5-a.,ella~ l lel-e and 1 .0M HCI-ether~ was added and continued reflux. After 20 hours, the reaction mixture was evaporated and the product was purified by flash chromatography to afford the title compound (0.41 f~, 55%) as orange tint white solid; mp: 236C;
15 TLC (CH2CI2:CH3OH; 9:1); R,=0.19; 1H NMR (CDCI3 + CD30D~: ,5 7.61-7.04 (m, 10H, Ar-H), 3.84-3.81 (m, 2H, CH2), 3.43-3.27 (m, 9H, 3 x CH2 and CH3); HRMS: 377.1897 (377.1892 calcd. for C2eH23N3) .
20 Exsmple 3: r f3p ~a~iùi~ of N,N -bis(5 ~-~e~ ,rl)-N,N -bis-methyl ~ .e~llCI ~METHOD C ~Scheme-2)) Part 1. PreDaration of N-methvl-N-5-acenaohthvl cvanamide Prepared as per part 1 in Method B of Example 2.
P~rt 2. PltDa,~liùn of N-methvl-N-5-al,ena~Fllllyl amine 5-Acenaphthene amine (5.8 9, 34.3 mmol) was dissolved in warm formic acid (97%, 25 mL~ and refluxed. After 7 hours, the 30 reaction mixture was cooled to 25C and then let is stand in ~tli~e,~lor for 12 hours. The solid was filtered and washed with ~ W095t14467 2 ~ 7 7 ~ ~ PCT/US94/13541 act:luniL,il~ and then air-dried to afford the formamide (6.65 ~), which was used in the next step without further purification.
BH3-THF solution (50 mL~ was added dropwise to a stirred 5 suspension of above formamide (6.07 9, 30.4 mmol) in THF (100 mLI at ice-bath temperature. After stirring the contents at 25C for 18 hours, the reaction mixture was concentrated to a volume of ca.
35 mL and the ethyl acetate (10 mL) was added at 10C. The mixture was quenched with 3N HCI solution and then basified with 10 NaOH solution. It was extracted with methylene chloride (2 x 75 mL), dried (Na25O4) and evaporated to ~ive a tan colored solid (5.45 9). It was recrystallized from methanol to afford the title compound (2.85 a) as tan colored crystals; mp 102-03C.
15 Part 3. r~ alalion of N.N'-bis~5-acenaohthYI~-N,N'-bis-methyl aud"iJi"r~l iCI
Aluminum chloride (0.21 ~, 1.58 mmol) was added to a stirred solution of N-5-acenap~"l,yl-N-methyl cyanamide (0.3 y, 1.44 mmol) 20 in chlorobenzene (7 mL) at 145C. After 10 minutes 5-ace,~ap~,~l,ene-N-methyl amine hydrochloride (0.29 ~, 1.3 mmol;
prepared from 5-acenaphthene-N-methyl amine and 1.0M HCI-ether) was added and continued reflux. After 4 hours, the reaction mixture was evaporated on rotavap and the product was purified by flash 25 chromatography to afford the title compound (0.25 ~, 45/O) as yellowsolid; mp: 272C; TLC (CHCI3:CH30H; 10:1): R~=0.17; 'H
NMR (CD30D): ~ 7.18 (bs, 5H, Ar-H), 6.78-6.73 (m, 5H, Ar-H), 3.47 (s, 6H, 2 x CH3), 3.24-3,19 (m, 4H, 2 x CH2), 3.04 (bs, 4H, 2 x CH2); HRMS: 391,2051 (391.2048 calcd. for C27H25N3).

WO 95114467 ~ 7 Q 8 ~ PCTIUS94113541 Exsm~les 4-63 By methods indicated above, including by the specified Methods A-C of Examples 1-3 respectively and using appropriately 5llh5tjtllt~d rea~ents, the following named compounds were prepared 5 having the indicated physical cl,d,d-l~ri~lics.
i-xample 4: N-15-~1c~.~a~Jl,lilyl)-N'-(1-ânthrâcenyl~gua" ' ,~~",e.ylâlt7 P,~:pa,dlic.n: As per Method A of Example 1, White solid; mp:
10 243-45C; 1H NMR (CD30D~: ~ 8.65-7.25 ~m, 14H, Ar-H~, 3.33-3.20 (m, 4H, 2 x CH2), 2.25 (s, 3H, -CH3); Anal. Calcd. for C28H2sN3-CH3SO3H: C, 69.54; H, 5.21; N, 8.69; Found: C, 69.33; H, 5.23; N, 8.55.
15 Exampl~ 5: N-(5 r. , ' (~.t~l-N'-(4-t~rtbuty~pheny~)guanidine-HC~
P,~pa,dliu~: As per Method A of Example 1. White solid; TLC
(CH2CI2:CH30H; 9:1): R~=0.5; 1H NMR (CD30D): ~ 7.65-7.20 (m, 9H, Ar-H), 3.30 (m, 4H 2 x CH2), 1.22 (s, 9H, 3 x CH3); HRMS:
20 343.2043 (343.2048 calcd. for C23H26N3).
Example 6: N-(5 n.~ 1)-N'-(4-cy~ ,e~ y~,uh~r,t~)a~ " ,r~llCI
Preparation: As per Method A of Example 1, except that 4-25 cyclohexylphenyl cyanamide was reacted with 5-acenaphthyl-1-amine hydrochloride. White solid; mp: 232-34C; 'H NMR (DMS0) 7.8-8.2 (m, 13H, Ar-H), 3.4-3.3 (m, 5H, 2 x CH2 and CH), 1.8-1.15 lm, 10H, 5 x CH2); Anal. Calcd. for C25H2aClN3 (405.95): C, 73.96; H, 6.95; N, 10.35; Cl, 8.73; Found: C, 73.91; H, 6.96; N, 30 10.12; Cl, 8.56.
.

~i,'7708~ ~
WO 95114467 ' PCT~lsS94113541 Example 7: N-(5 ~c~ ,yl)-N'-(4-secbutylphenyl)guanidine-HCI
~l~pdldlion: As per Method A of Example 1, White solid; TLC
(CH2CI2:CH3OH; 9:1): R~=0.7; 1H NMR (CD30D): ~ 7.60-7.15 (m, 5 9H, Ar-H), 3.30 (m, 4H, 2 x CH2), 2.52 (q, 1H, -CH), 1.50 (m, 2H, -CH2), 1.11 (d, 3H, CH3), 0.71 (t, 3H, CH3); HRMS: 343.2051 (343.2049 calcd. for C23H25N3).
Example 8: N-(5 e- ~c.pl,~l,yl)-N'-(4-methoxyphenyl)9~l- " --~IBi rl~:pald~iUIl: As per Method A of Example 1. Fluffy cream solid; mp: 187-200C; TLC (CHCI3:CH30H; 10:1); R~=0.31; 1H NMR
(CDCI3): ~ 7.45-7.10 (m, 7H, Ar-H), 6.80 (d, 2H, J=8Hz, Ar-H), 3.68 (s, 3H, OCH3), 3.38-3.22 (m, 4H, 2 x CH2); HRMS: 317.1509 15 (317.1528 calcd. for C20H,DN30); Anal. Calcd. for C20H20N3BrO
(398.30): C, 60.44; H, 5.08; N, 10.58; Found: C, 60.28; H, 5.14;
N, 10.41.
Example 9: N-15 ~c~nd,Jhll,~l)-N'(2,3-~" '1 opl,el,yl)~,uanidine-HCI
rlbsldld~ion: As per Method A of Example 1. White (yellow tint) solid; mp: 124-30C; TLC (CHCI3:CH30H; 10:1): R,=0.18; 1H
NMR (CDCI3): ~ 7.59 (d, lH, J=8Hz, Ar-H), 7.47 (t, lH, J =8Hz, Ar-H), 7.36-7.14 (m, 6H, Ar-H), 3.40-3.25 (m, 4H, 2 x CH2); HRMS:
25 355.0647 (355.0643 calcd. for C1DH15C12N3).
Example 10: N-~5 ~c~ , ~,II,yl)-N'-(4-methoxy-2-naphthyl)guanidine r,epard~iul1: As per Method A of Example 1. Li~ht yellow 30 solid; mp: 191-92C; TLC (CH2CI2:CH30H; 9:1): R,=0.51; 1H NMR
(CD30D + CDCi3): ~ 8.17 (d, 1H, J=8Hz, Ar-H), 7.73 (d, 1H, J=8Hz, Ar-H), 7.66 (d, 1H, Jz8Hz, Ar-H), 7.57-7.26 (m, 7H, Ar-H), W095/14467 2 ~ 7 ~Q ~ ~ PCTIUS94/13541 7.09 (d, 1H, J=8Hz, Ar-H), 3.96 (s, 3H, OCH3), 3.43-3.35 (m, 4H, 2 x CH2); HRMS: 367.1680 (367.1685 calcd. for Cz4H21ON3).
Exr~mple 11: N-(5 ~ ~dpl~ l)-N'-13,4-~ opil~ guanidinr~-HCI
~ pa~dLion As per Method A of Example 1. White solid; mp:
> 300C; TLC (CHCI3:CH30H; 10:1): R,=0.27; 1H NMR (CDCI3): ~
7.55 (d, 1H, J=8Hz Ar-H), 7.48 (t, 1H, J=8Hz, Ar-H), 7.37 (d, 2H, J=8Hz, Ar-H), 7.30 (t, 2H, J=8Hz, Ar-H), 7.19 (d, 1H, J=7Hz, Ar-10 H), 7.13 (bd, 1H, Ar-H), 3.66-3.30 (m, 4H, 2 x CH2); HRMS:
355.0651 (355.0643 calcd. for C1gH15CI2N3).
Example 12: N-(5 ac~,~dpl~ yl)-N'-~4-Ll~ upl~e,~l)9~ HBr Preparation: As per Method A of Example 1, except N-4-chlorophenyl cyanamide was reacted with 5-acenapr,Ll,yl-1-amine hyd,ubrur";de. White solid; mp: 216-17C; 1H NMR (CDCI3): d 7.65-7.23 (m, 9H, Ar-H), 3.42-3.35 (m, 4H, 2 x CH2): 13C NMR (CDCI3):
147.81, 146.47, 140.09, 133.35, 132.11, 131.98, 129.90, 20 129.40, 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~aH1,~N3CI) ~
Example 13: N-(5-8G~ l,ll.tl)-N'-(2-naphthyl)~ -IICI
Pl~pa,d~ion: As per Method A of Example 1. LiFht yellow solid; mp: 200C; TLC (CHCI3:CH30H; 10:1): R,=0.14; lH NMR
(CDCI3+ CD30D): ~ 7.78-7.14 (m, 12H, Ar-H), 3.33-3.25 (m, 4H, 2 x CH2); HRMS: 337.1500 (337.1579 calcd. for C23H19N3).

~ WO 95114467 2 1 7 7 P 8 ~ PCTIUS94/13541 Example 14: N-(5 a~e , ' ' ,I)-N'(6-quinolinyl)~ " .r,-llCI
r~pd,~Iion: As per Method A of Example 1. White solid; mp:
242-44C; TLC ~CHCla:MeOH 10:1~: R~=0.2; 1H NMR (DMS0):
5 9.1-7.3 ~m, 11H, Ar-H), 3.5-3.2 ~m, 4H, 2 x CH2~.
Example 15: N-(5-acr,l)dphIl,tl)-N'-(4-l,iL(r,pl~nyl~gua" " ~IICI
Plt:pdldLioll As per Method A of Example 1. Off white solid;
10 mp: 85-86C; 1H NMR ~CD30D): ~ 7.57-7.05 ~m, 9H, Ar-H), 3.49-3.43 Im, 4H, 2 x CH2~; MS(CI): mle 333 (M + 1 for the free base).
Example 16: N-15-acenaphthyl-N'-13-bi-phenyl)~quanidine-HCI

~pa,dIion: As per Method A of Example 1. White cream solid; mp: 128-36C; TLC (CHCI3:CH30H; 10:1): R,=0.56; 'H NMR
(CD30D): ~ 7.68-7.35 (m, 14H, Ar-H), 3.45-3.31 (m, 4H, 2 x CH2);
HRMS: 363.1726 (363.1735 calcd. for C25H21N3).
Example 17: N-(5 e na~Jl.Lh~l)-N'-12~3- ::,yl~ enyl)S, " ~HCI
Pl~,a,dLiol1: As per Method A of Example 1. Light yellow solid; mp: 199-207C; TLC (CHCI3:CH30H; 10:1): R,=0.38; lH NMR
25 (CD30D): ~ 7.68-7.58 (m, 2H, Ar-H), 7.48 (d, 1H, J=8Hz, Ar-H), 7.41-7.36 (m, 2H, Ar-H), 7.23-7.16 (m, 3H, Ar-H), 3.45-3.39 (m, 4H, 2 x CH2), 2.34 (s, 3H, CH3), 2.28 (s, 3H, CH3); HRMS:
315.1717 (315.1735 calcd. for C2,H21N3).
30 Example 18: N-15 . r,a~,l,Ll,yl)-N'-12-bi-phenyl)~l " ,c~llBr P,~.a,dLion. As per Method A of Example 1. White solid; mp:
141-43C; lH NMR (CD30D): ~ 7.56-7.05 (m, 14H, Ar-H), 3.43-WO g5/14467 ~ ~ ~ 7 Q 8 ~ PCT/US 4/13541 3.31 Im, 4H, 2 x CH2); MS (El): m/e 364 (M + 1 for the free base);
HRMS: 363.1737 (363.1735 calcd. for C2sH21N3).
Example 19: N-~5-ac~.~a~Jl.Il.~ll-N'-(2,5-"' ~r..~ l)guanidine-HCI
Frt:palalion; As per Method A of Example 1. Yellow tint solid;
mp: 194-96C; TLC (CHCI3:CH30H; 9:1): R,=0.33; 'H NMR
(CD30D): ~ 7.74-7.34 (m, 8H, Ar-H~, 3-50-3-42 (m, 4H, 2 x CH2);
HRMS: 442.9678 (442.9633 calcd. for C1aHI5Br2N3).
Example 20: N-(5 F~ N -(3,4- i;.~-allloA~"l)ell~l) ~ual '' ' ~ ~ i ICI
P,~paldIion: As per Method A of Example 1. Brown solid;
15 mp: 152-55C; TLC (CHCI3:CH30H; 10:1): R,=0.27; 1H NMR
(CD30D): ~ 7.70-7.58 (m, 2H, Ar-H), 7.47 (d, 1H, J=Hz, Ar,H), 7.41-7.35 (m, 2H, Ar-H), 7.04-6.92 (m, 3H, Ar-H), 3.85 (s, 3H, CH3), 3.84 (s, 3H, CH3~, 3.47-3.44 (m, 2H, 2 x CH2); HRMS:
347.1637 (347.1634 calcd. for C21H21O2N3).
i_xample 21: N-(5 ~ )âpl-Ill,~l)-N'-(4-methoxy-1-naphthyl)-N-methyl~-- ! '- IC~IIcl P.t:pal~lliun: As per Method B of Example 2. Light yellow 25 solid; mp: 158-59C; TLC (CHCI3:CH30H; 10:1): R,=0.25; 1H NMR
(CD30D): ~ 8.30-6.90 (m, 11H, Ar-H), 4.03 (s, 3H, OCH3), 3.64 (bs, 3H, N-CH3), 3.50-3.41 (m, 4H, 2 x CH2); HRMS: 381.1850 1381.1841 calcd. for C25H23ON3).
30 Example 22: N-(5 ac~.l..,,~lIll~l)-N'-14-methoxy-1-naphthyl)-N'-methyl I ICI
Prepâration: As per Method B of ~xample 2, except that N-methyl-N-(4-methoxy-1-naphthyl) cyanamide was reacted with 5-W0951~4467 2 1 7 7~ ~ PCTIUS94/13541 ac~.,à~,hll,yl-l-amine hydrochloride. White solid; mp: 195-97C; TLC
(CHCI3:CH30H; 10:1): R,=0.10; 1H NMR ~CD30D): ~ 8.37 (d, 1H, J=8.4Hz, Ar-H~, 7.95-7.28 (m, 9H, Ar-H), 7.05 (d, 1H, J=8.3Hz, Ar-H), 4.07 (s, 3H, OCH3), 3.60 (bs, 3H, N-CH3), 3.47-3.31 (m, 4H, 5 2 x CH2); HRMS: 381.1840 (381.1841 calcd. for C2sH23ON3).
Exampl~ 23: N-(5-ac~ndpl,ll"~l)-N'-~4-methoxy-1-naphthyl)-N,N'-dimethyl D~ " e~l ICI
PltpalaliOIl: As per Mcthod C of Example 3. White solid; mp:
210-12C; TLC (CHCI3:CH30H; 10:1): R,=0.34; IH NMR (CD30D):
7.95 (d, 1H, Ar-H), 7.38-6.65 (m, 10H, Ar-H), 3.82 (s, 3H, OCH3), 3.48 (s, 3H, N-CH3), 3.42 (s, 3H, N-CH3), 3.25-3.18 (m, 2H, CH2), 3.04-2.65 (m, 2H, CH2); HRMS: 395.2005 (395.1998 calcd. for 1 5 C2~H2sON3).
Example 24: N-(5-ace,~ap~,ll,~i)-N'-(4-chloro-1-naphthyl)guânidine-HCI
Preparâtion: As per Method A of Example 1. White solid; mp:
20 258-60C; 'H NMR (CD30D); ~ 8.38-8.35 (m, 1H, Ar-H), 8.15-8.11 (m, 1H, Ar-H), 7.81-7.34 (m, 9H, Ar-H), 3.44-3.41 (m, 4H, 2 x CH2);
MS (El): mle 372 (M + 1 for free base); Anal. Calcd. for C23H~gCI2N3 (408.31): C, 57.65; H, 4.69; N, 10.29; Found: C, 67.58; H, 4.60;
N, 10.28; HPLC (CH3CN:H20 50:50 with 0.1% TFA): 99.9% pure.
Example 25: N-(5-ac2na~ l)-N'-(3,4,5-l, ' l( ~,p~,e,~
- ~I ICI
Preparation: As per Method A of Example 1. White solid; mp:
30 234-36C; TLC: R, = 0.28 (CH2CI2/CH3OH: 9:1); lH NMR (CD30D):
7.68-7.35 (m, 7H, Ar-H), 3.53-3,40 (m, 4H, 2 X CH2); HRMS:
381.0251 (389.0253 calcd. for C,gHl4C13N3); HPLC (CH3CN:H2O
50:50 with 0.1% TFA): 95.5% pure.

2 ~ 71Q8~ --Example 26: N-15 rr~ -N -(4-bi-phenyl~ --CH3503H
~ pa,aliùn: As per Method A of Exâmple 1. White solid; mp:
196-98C; TLC ~CHCI3:CH30H; 10:1): R,=0.29, 1H NMR (CD30D) 5 7.75-7.36 (m, 14H, Ar-H), 3.45 lbs, 4H, 2 X CH2), 2.6g (s, 3H, CH3~; HRMS: 363.1737 ~363.1735 câlcd. for C2sH21N3).
Example 27: N-(C ~ -N -12,3,4,5-~ àcl.l~.uphen ~ ~ ~ I ICl Prepârâtion: As per Method A of Example 1. White solid; mp:
223-25C; TLC (CH2CI21CH20H; 9:1): R~=0.51; 1H NMR (CDlOD):
7.74-7.33 (m, 6H, Ar-H), 3.47-3.40 (m, 4H, 2 X CH2); Anal Calcd.
for Cl9H,3CI4N3 (461.59): C, 49.44; H, 3.06; N, 9.1; Found: C, 15 50.89; H, 3.15; N, 8.84; HRMS found: 422.9875 (422.9864 Calcd.
for C1~H13CI4N3~; HPLC (CH3CN:H20 45:55 with 0.1% TFA~: 95.5%
pure.
Example 28: N-(5 ~ "I,~I~-N -(3 :-~op~op~ h~ guanidine-HCI
r.t:pa.dLion: As per Method A of Exâmple 1. White solid; mp:
149-51C; TLC (CHCI3:CH30H; 10:1): R,=0.28; 1H NMR (CD30D):
7.66-7.19 (m, 9H, Ar-H), 3.44 (bs, 4H, 2 X CH2), 3.00-2.89 (m, 1H, -CH-), 1.26 (d, 6H, J=7H~, 2 X CH3); HRMS: 329.1873 (329.1892 25 calcd. for C23H2GN3).
Example 29: N-15-a~e~,a~.l.ll.yl~-N -(3-tert-butylphenyl~yuanidine-HCI
P~pa,a~ion: As per Method A of Exâmple 1. White solid; mp:
30 176-78C; TLC (CHCI3:CH30H; 10:1): R,=0.26; 1H NMR (CD30D):
7.68-7.28 (m, 9H, Ar-H), 3.45-3.44 (m, 4H, 2 X CH2), 1.33 (s, 3H, CH3); HRMS: 343.2055 (343.2048 câlcd. for C22H23N3).

WO 95/14467 2 1 ~ ~ Q ~ ~ PCT/US94113541 Exsmple 30: N-(5-acenaphthyl)-N -(2,3,5,6-upl-e~ ~ y l)~ - CH3S03H
Preparation: As per Method A of Example 1. White solid; mp:
5 248-50C; lH NMR (CD30D): ~ 8.12-7.33 (m, 6H, Ar-H), 3.44-3.40 (m, 4H, 2 X CH2), 2.69 (s, 3H, CH3); MS (Ell: m/e 426 (M + 1 for the free base).
Example 31: N-(5-acenaphthyl)-N -(3-iodopl1e..~1)9~l .r,~HCI
Preparation: As per Method A of Example 1. White solid; mp:
203-04C; TLC (CHCI3:CH30H; 10:1): R,=0.19; H NMR (CD30D):
7.76-7.58 (m, 4H, Ar-H), 7.47 (d, lH, J=7.33Hz, Ar-H), 7.42-7.34 (m, 3H, Ar-H), 7.22 (t, 1H, J=8Hz, Ar-H), 3.45-3.44 ~m, 4H, 2 X
15 CH2); HRMS: 413.0395 (413.0389 calcd. for C19Hl,jlN3).
Example 32: N-(5-~cr.)~ .ll.yl)-N -(3-~ -u,~l.r,.)~l)gua . .~IICI
Preparation: As per Method A of Example 1. Yellow solid; mp:
20 244-48C; TLC (CHCI3:CH30H; 10:1): R,=0.16; lH NMR ~CD30D):

8.25-8.16 (m, 2H, Ar-H), 7.80-7.58 (m, 4H, Ar-H), 7.51 (d, 1H, J=7.24Hz, Ar-H), 7.41 (d, 1H, J=6.9Hz, Ar-H), 7.37 (d, 1H, J=7.4Hz, Ar-H); HRMS: 332.1276 (332.1273 calcd. for Cl3Hl,~N402) Example 33: N-(5-ac~naphll.~l)-N -(5-indolinyl)guanidine-HCI
P.~,~,a,dlion: As per Method A of Example 1. Yellow-white solid; mp: 147-48C; TLC ICHCI3:CH30H; 10:1~: R,=0.27; lH NMR
30 (CD30D~: ,5 7.65-7.57 (m, 2H, Ar-H~, 7.46 (d, 1H, J=7.3Hz, Ar-H~, 7.41-7.29 (m, 3H, Ar-H), 7.22 (bs, 1H, Ar-Hi, 7.12 (dd, 1H, J=7.9 and 2.1Hz, Ar-H), 3.47-3.43 (m, 4H, 2 X CH2), 2.92 (dd, 4H, Woss/~4467 2 1 7 7 ~ 8 4 Pcr/USs41l3s41 J=14.8 and 7.4Hz, 2 X Ar-CH2), 2.10 ~m, 2H, CH2); HRMS:
327.1742 (327.1735 calcd. for C22H2lN3).
, Example 34: N-~5-ac , '~ N'-(3-acenaphthyl) ~ CHISO3H
P,.:pa,dliDn: As pet Method A of Example 1. White solid, mp:
245C, 1H NMR (300 MHz, CD30D): d 7.69-7.73 (m, 2H, Ar-H), 7.60-7.65 (m, 2H, Ar-H); 7.49-7.53 (m; 2H, Ar-H); 7.35-7.48 (m, 10 4H, Ar-H); 3.41-3.49 (m, 4H, 2 X CH2); 2.68 (s, 3H, CH3); MS (El):
mle 363 (M + for free base): Elemental analysis for C25H2lN3-CH3S03H-2H20: Calcd: C, 61.62; H, 5.76; N, 8.28; S, 6.32; Found: C, 61.77; H, 5.43; N, 8.22; S, 5.47; HPLC (AcCN: H20 1:1): 99.3% pure.
Example 35: N-(5 F~ )-N'-12-fluorenyl)gl.~ -HCI
r~pdlaliull: As per Method A of Example 1. Buff white solid:
mp: 239-240C; lH NMR (300 MHz, CD30D): ~ 7.90-7.92 (d, 20 J=8Hz, 1H, Ar-H), 7.82-7.84 (d, J=7Hz, 1H, Ar-H) 7.69-7.72 (d, 1H, J=8Hz, Ar-H); 7.62-7.64 (m, 3H, Ar-H); 7.48-7.51 (d, J=7.5Hz, 1H, Ar-H); 7.29-7.41 (m, 5H, Ar-HI; 3.95 (s, 2H, CH2);
3.40-3.47 (m, 4H, 2-CH2); MS (El): m/e 375 (M+ for free base):
Elemental analysis for C2~H2lN3-HCI-0-25H20: Calcd: C, 74.99; H, 25 5.44; N, 10.08; Found: C, 75.25; H, 5.44; N, 10.14.
Example 36: N-(5-acell~pl~ l)-N'-(4-n-butoxyphenyl)~ IICI
Plt:pa,a~iDn: As per Method A of Example 1. Brownish solid;
30 mp: 90C; lH NMR (300 MHz, CD30D): ~ 7.57-7.67 (m, 2H, Ar-H), 7.45-7.47 (d, J=7.5Hz, 1H, Ar-H); 7.34-7.40 (m, 2Hm Ar-H); 7.27-7.30 (m, 2H, Ar-H); 6.99-7.02 (m, 2H, Ar-H); 3.97-4.02 (t, 2H, 0-Woss/l4467 2 1 77~84 Pcr~l-fss4/l3s4~

CH2); 3.41-3.47 (m, 4H, 2-CH2); 1.71-1.78 (dt, 2H, CH2): 1.46-1.54 (m, 2H, CH2); 0.95-1.00 (t, 3H, CH3); MS (El): m/e 359 (M+ for free base); Elemental analysis for C23H2sN30-HCI-0-75H20: Calcd: C, 67,47; H, 6.77; N, 10,26; Found: C, 67.66; H, 6.67; N, 10.26.

Example 37: N-(5-ac~.ld,ulltl,~ N'-(3-(2-methoxy)dibenzofuranyl) ~f"d"~ ICI
ffa,dLio~: As per Method A of Example 1. White solid; mp:
10 230C; 'H NMR (300 MHz, CD30D): ~ 8.06-8.09 (dd, J1 =7.5Hz, J2=1.5Hz, lH, Ar-H), 7.80 (s, 1H, Ar-H), 7.73-7.76 (d, J=7.5Hz, 1H, Ar-H), 7.60-7.65 (m, 3H, Ar-H), 7.46-7.56 (m, 2H, Ar-H), 7.34-7.40 (m, 3H, Ar-H), 4.10 (s, 3H, O-CH3), 3.40-3.43 (m, 4H, 2-CH2);
MS (El): m/e 407 (M+ for free base); Elemental analysis for 15 C26H21N302-HCI-0-25H20: Calcd: C, 69,64; H, 5.06; N, 9.36;
Found: C, 69.68; H, 4.98; N, 9.40.
Example 38: N-(5 a~ apl,~llrl)-N'-(9-hydroxy-2-fluorenyl)guanidine-HCI
Pl~?dld~ion: As per Method A of Example 1. White solid; mp:
265C; 'H NMR (300 MHz, CD30D): f~7.80-7.83 (d, J=8Hz, 1H, Ar-H), 7.69-7.74 (t, 2H, Ar-H), 7.60-7.64 (m, 3H, Ar-H), 7.49-7.52 (d, J=7.5Hz, 1H, Ar-H), 7.34-7.42 (m, 5H, Ar-H), 5.58 (s, 1H, -OH), 25 3.45 (brs, 4H, 2-CH2); MS (El): m/e 391 (M+ for free base);
Elemental analysis for C26H2,N30-HCI-0-25H20: Calcd: C, 72.22; H, 5.24; N, 9.7; Found: C, 72.35; H, 5.35; N, 9.58.
Example 39: N-~5-ace,~dpllLl,~l)-N'-(4-trifluo(u,l.~ n~l) g~al l . - I I CI
?~f~a,dlion: As per Method A of Example 1. White solid; mp:
234-236C; TLC (CH2C12:CH30H 9:1): Rf=0.4; 1H NMR (CDCI31:

WO95/14467 2 1 7~ PCTNS94/13541 7.70-7.25 Im, 9H, Ar-H), 3.46-3.38 ~m, 4H, 2 X -CH2); MS(CI): m/e 356 (M+1); Anal Calcd. for C2OH1,N3F3-HCI 1391.82): C, 61.31; H, 4.37; N, 10.72; Found: C, 62.14; H, 4.34; N, 10.80.
5 Exampl~ 40: N-15 ~ -N (~ opl,6..~1) ~, ' .c~llCI
P,~pa"~ion: As per Method A of Example 1. White solid; mp:
168-170C; TLC ~CH2CI2:CH30H 9:1): R,=0.38; 1H NMR ICD30D):
10 7.76-7.38 (m, 9H, Ar-H), 3.53-3.37 (m, 4H, 2 X-CH2), 2.57 (s, 3H, -SCH3); MS(CI): m/e 334 (M+1); Anal. Calcd. for C20H19N3S-HCI
(369.91): C, 64.94; H, 5.45; N, 11.36; Found: C, 64.38; H, 5.73;
N, 1 1.05 .
15 Exsmple 41: N-~5-Ac~n . ~I~-N -14-benzyloxyphenyll 9U6~, IG'IICI
Light green foam; mp: 117-127C; TLC (CH2CI2:CH30H;
15:1): R,=0.50; 1H NMR (CD30D): 7.646-7.094 (m, Ar-H, 14H), 20 5.127 (s, CH2 2H), 3.454-3.449 (m, CH2CH2, 4H); Anal. Calcd. for C20H23N30-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-Ac~l~dpl,II,~I)-N -(3-benzyloxyphenyl)gud" I~-HCI
Light green foam; mp: 94-98C; TLC (CH2CI2:CH30H; 15:1):
R~=0.50; H NMR (CD30D): 7.639-6.981 ~m, Ar-H, 14H), 5.117 (s, CH2, 2H), 3.451-3.344 (m, CH2CH2, 4H); Anal. Calcd. for C2~H23N30-HCI-0.5H20 (438.95): C, 71.07; H, 5.70; N, 9.57;
30 Found: C, 71.44; H, 5.60; N, 9.83.

.
WO 95114467 2 t 7 7 ~ 8 4 PCT/US94/13541 Example 43: N-(5 Ar~n~ l,yl)-N'-(3-benzyloxyphenyl~

9~ 9 _ r ~
Light yellow foam; mp: 90-98C; TLC (AcOEt:CH30H; 10:1~:
5 R~=0.30; IH NMR ICDCI3): 7.647-7.268 (m, Ar-H, 11H), 6.956-6.923 (m, Ar-H, 3H), 5.086 (s, CH2, 2H), 3-458-3-410 (m, CH2CH2, 4H), 2.857 (s, CH3, 3H); Anal. Calcd. for C27H27N3O4S (489.59~: C, 66.24; H, 5.56; N, 8.58; Found: C, 66.99; H, 5.35; N, 8.74.

10 Example 44: N-(5 Ar~ l.tl)-N'-(3-sec-butylphenyl) 9~ t ' ~ la l~
White solid; mp: 136-138C; TLC (CH2CI2: MeOH; 15:1):
R,=0.31; lH NMR (CD30D): 7.668-7.164 (m, 9H, Ar-H), 3.483-15 3.411 (m, CH2CH2, 4H), 2.655-2.627 (m, CH, lH), 1.656-1.589 (m, CH2, 2H), 1.257-1.234 (d, J=6.87Hz, CH3, 3H~, 0.860-0.813 (m, CH3, 3H); Anal. Calcd. for C23H2,~N3CI (379.93): C, 72.71; H, 6.90;
N, 11.06; Found: C, 72.73; H, 6.75; N, 11.12.
20 Exâmple 45: N-(5 Ar~ -tl)-N'-(2-, II~ tl)~ IICI
Green solid; mp: 260-262C; TLC (CH2CI2: MeOH; 15:1):
R,=0.31; 'H NMR (CD30D): 8.527-8.502 (d, Ar-H, J=7.63Hz, 2H), 8.183-8.153 (d, Ar-H, J=9.28Hz, 1H), 8.044 (s, br, Ar-H, 3H), 25 7.771-7.617 (m, Ar-H, 2H), 7.542-7.368 (m, 6H, Ar-H), 3.449-3.418 (m, CH2CH2, 4H); Anal. Calcd. for C27H22N3CI (423.50): C, 76.50; H, 5.23; N, 9.91; Found: C, 76.33; H, 5.46; N, 9.70.
Example 46: N-(5 A~ tl)-N'-I3-pl1eneII,~ el,tl)~ll~ ' e-HCI
White solid; mp: 116-118C; TLC (CH2CI2:MeOH; 15:1):
R,=0.31; lH NMR (CD30D): 7.645-7.156 (m, Ar-H, 14H), 4.233-4.161 (q, CH, J=7.14Hz, 1H), 3.478-3.414 ~m, CH2CH2, 4H), .. . . , , _ . .

WO 95/14467 2 1 7 ~ ~) 8 ~ PCI'/US94/13541 1.650-1.626 (d, J=7.20H7!, CH3, 3H); Anal. Calcd. for C2,H2,jN3CI
(427.98): C, 75.77; H, 6.12; N, 9.82; Found: C, 75.63; H, 5.98; N, 9.69.
5 Example 47: N-15-Ac~lld~ l)-N' ~ don~~~tylphenyl)guanidine-HCI
White solid; mp: 240C; TLC (CH2CI2:MeOH; 15:1): R~=0.31;
1H NMR (CD30D): 7.639-7.289 lm, Ar-H, 9H), 3.443-3.403 (m, CH2CH2, 4H), 2.086-1.756 Im, CH's, 13H); Anal. Calcd. for 10 C29H32N3CI (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-Ac~.ldpl,Il,~l)-N'-~3-benzyloxyphenyl)-N'-methyl~ I ICI

White solid; mp: 102-105C; TLC (CH2CI2: MeOH; 15:1);
R,=0.30; 1H NMR (CD30D): 7.605-7.134 (m, 14H, Ar-H), 5.149 (s, CH2, 2H), 3.636 (s, CH3, 3H), 3.532-3.444 (m, CH2CH2, 4H); Anal.
Calcd. for C27H23N3CIO (443.98): C, 73.04; H, 5.98; N, 9.46; Found:
20 C, 72.98; H, 5.95; N, 9.42.
Example 49: N-~5-Acen~pl~II"/I~-N'-~4-benzyloxyphenyll-N'-White solid; mp: 108-110C; TLC (CH2CI2:MeOH; 15:1);
R,=0.30; lH NMR (CD30D): 7.605-7.134 (m, 14H, Ar-H), 5.149 (s, CH2, 2H), 3.536 (s, CH3, 3H), 3.532-3.444 (m, CH2CH2, 4H); Anal.
Calcd. for C27H2~N3CIO (443.981: C, 73.04; H, 5.98; N, 9.46; Found:
C, 72.93; H, 6.00; N, 9.919.

Wo 95/14467 2 ~ 7 7 Q 8 fi Pr~T/US9411354~

Example 50: N-~5-Acena~ l,yl)-N'-(3-biphenyl)-N'-methylguanidine-HCI
White solid; mp: 217C; TLC (CH2CI2:MeOH; 10:1): R,=0.30;
5 ~H NMR (CDCI3): 7.513-7.022 (m, 14H, Ar-H), 3.668 (s, CH3, 3H), 3.322-3.203 (m, CH2CH2, 4H~; Anal Calcd- for C26H24N3C1-2H20 (449.98): C, 69.40; H, 6.27; N, 9.34; Found: C, 69.25; H, 6.27; N, 9.48.
0 Exsmple 51: N-(5 A~n~ l.,/l)-N'-(3-(1'-methyl-2'-phenyl)ethyll~l~ ' " ,e~llCi White solid; mp: 106-108C; TLC (CH2CI2:MeOH; 15:1) R,=0.36; 'H NMR (CD30D): 7.698-7.070 (m, 14H, Ar-H), 3.467-15 3.312 (m, CH2CH2, 4H), 3.105-3.033 (m, CH, 1H), 2.928-2.810 (m, CH2, 2H), 1.267-1.244 (d, J=6.87Hz, CH3, 3H); Anal. Caicd. for C28H28N3CI (442.00): C, 76.09; H, 6.39; N, 9.51; Found: C, 76.11;
H, 6.55; N, 9.38.
20 Example 52: N-(5 Rr~ yl)-N'-(3,4-lel. " ~ hrd,.~l) .,- ~r ~I lCI
White solid; mp: 158-160C; TLC (CH2CI2:MeOH; 15:1~:
R~=0.36;lH NMR (CDCI3): 7.631-6.985 (m, 8H, Ar-H~, 3.484-3.373 25 (m, CH2's, 4H), 2.747 (m, CH2, 2H~, 1.793-1.784 (m, CH2,2H~;
Anal. Calcd. for C23H2"CI (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 Ac~ I,II,yl)-N'-(7-~e,.~yl~. " ,yl)guanidine-HCI
White solid; mp: 161-162C; TLC (AcOEt:MeOH; 10:1) Rf=0.44; lH NMR; 7.647-7.118 (m, Ar-H, 13H); Anal. Calcd. for C30H30N3C1-1/2H20 (477.04): C, 75.47; H, 6.50; N, 8.81; Found: C, 75.23; H, 6.28; N, 8.82.

WO 95114467 2 ~ 7 7 Q 8 ~ PCT/US94/13541 Example 54: N-(5 A~n~ l)-N'-(3,4-dibenzyloxyphenyl) ~l , " o ~Mesylate White solid: mp: 185-187CC; TLC (AcOEt:MeOH; 10:1) 5 Rf=0.44; lH NMR; 7.647-7.118 Im, Ar-H, 13H); Anal. Calcd. for C30H30N3O5S-H2O ~613.73): C, 66.54; H, 5.75; N, 6.85; Found: C, 66.86; H, 5.36; N, 6.92.
Example 55: N-(5-Acel,u~ l)-N'-(3-1-(4-othoxy)phenyl)propanyl) phenyl)~ll, " etr'~
White solid; mp: 93-95C; TLC (AcOet:MeOH; 10:1):
R,=0Ø49; 'H NMR; 7.636-7.575 (m, Ar-H, 2H), 7.416-7.128 (m, Ar-H, 11H), 6.922 (s, Ar-H, 1H), 6.871-6.842 (d, Ar-H, J=8.72Hz, 15 2H), 6.639-6.610 (d, Ar-H, J=8.66Hz, 2H), 3.782-3.748 (q, OCH2, J=7.40Hz, 2H), 3.498-3.417 (m, CH2CH2, 4H), 3.006-2.980 (m, CH, 1H), 2.848 (s, CH3, 3H), 2.835-2.706 (m, CH2, 2H), 1.317-1.193 (m, CH3, CH3, 6H); Anal. Calcd. for C3lH35N3O4S (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-Ac~,~.".l,ll.rl)-N'-~3-~N",N"-dibenzyl~a ,opllen11) ~1 7- ? ~'y la Id White solid; mp: 150-152C; TLC (AcOEt:MeOH; 10:1) 25 Rf=0.44; 1H NMR; 7.568-7.174 (m, Ar-H, 17H), 6.745-6.530 (m, Ar-H, 2H), 4.697 (s, CH2, 2H), 3.497-3.413 (m, CH2CHz, 4H), 2.825 (s, CH3, 3H); HRMS: 482.2446 ~482.628 calcd. for C33H30N~).
Example 57: N-(5-Acenapl,ll,tl)-N'-(3-(1'-benzylbutyl)phenyl) yu~ ~~e ,ylal~
White solid; mp: 90-92C; TLC (AcOEt:MeOH; 10:1);
Rf=0.48; lH NMR (CDCI3): 7.655-7.558 (m, Ar-H, 2H), 7.411-7.269 (m, Ar-H, 5H), 7.169-6.800 (m, Ar-H, 7H), 3.492-3.414 (m, WO 9S/14467 2 1 ~ 7 ~ 8 ~ PCT/US94113541 CH2CH2, 4H~, 3.022-2.662 (m, CH2, CH, 3H), 2.842 (s, CH3, 3H), 1.733-1.695 (m, CH2, 2H), 1.252-1.176 ~m, CH2, 2H), 0.895-0.847 It, CH3, J=7.28Hz~; HRMS: 433.2516 (433.5962 calcd. for C30H3lN3) .

Exampl~ 58: N-~5 A~A~ Il,tl~-N'-3-(4-tert-bllIyll,3.)~o,.y,.,~I1,~1) phenyl~ y: 1~
White solid; mp: 113-115C; TLC (AcOEt:MeOH; 10:1):
10 R,=0.39; lH NMR (CDCI3): 7.681-7.267 Im, Ar-H, 1 lH), 6.904-6.875 ~d, Ar-H, J=8.92Hz, 2H), 5.067 (s, CH2, 2H), 3.498-3.434 Im, CH2CH2, 4H), 2.856 ~s, CH3, 3H), 1.278 (s, tert-butyl, 9H);
HRMS: 449.2452 (449.5956 calcd. for C30H3l0N3).
15 Example 59: N-15 A~ tl,~l)-N'-2(2-indolyl)phenylgl~ ' " e HCI
mp: 174-176C; TLC: R~=0.32 (Si02, CHCI3/MeOH = 10:1);
1H NMR ~CD30D): ~ ppm 6.86-7.83 (m, ARH, 14H), 3.30-3.40 (m, CH2, 4H); MS(EI): m/e 402.2 (M+: C2,H22N4); Anal. (C,H,N;
20 C2,H22N4-HCI): Calcd.(%): C, 70.33; H, 5.58; N, 12.16; Found (fO):
C, 70.01; H, 5.65; N, 11.56.
Example 60: N-(5-Acel)~pl,~ l)-N'-lphenyl-3-bromo)~ " ~e HCI
mp: 204-205C; TLC: R,=0.20 (SiO2, CHCI3/MeOH = 10:1);
lH NMR (CD30D): ~ ppm: 7,35-7.68 (m, ArH), 3.4-3.5 (m, CH2, 4H);
MS(EI): m/e 365.0 (M+: C1~3H,~3N3Br); Anal. (C,H,N;
Cl3HI~,N3BR~HCI): Calcd. (%): C, 56.67; H, 4.25; N, 10.43; Found (%): C, 56.49; H, 4.43; N, 10.18.

~0 95/14467 2 ~ 7 7 Q 8 ~ PCT/US94/13541 Example 61: N-~5-Acenaphyl~-N'-(2,3,4~ ,l.lù~upl,el-yl)-N,N'dimethyl ~uan~dino HCI
TLC: R~=0.14 (SO2, CHCI3/MeOH = 10:1); 'H NMR (CD30D):
~ ppm: 6.72-7.44 (m, ArH, 7H), 3.5-3.6 (s, CH3, 6H), 3.4-3.5 (m, CH2, 4H); MS(EI): m/e 418.0 (M+: C2~H18N3CI3); Anal. (C,H,N;
C2~H18N3CI3-HCI): Cslcd. (%): C, 55.41; H, 4.21; N, 9.23; Found (%): C, 55.26; H, 4.11; N, 9.03.
Example 62: N-15 A~ r',~i~-N'-(2,3,4-~li.,l,lo.uphcllyl~-N'-methylguanidine HCI
mp: 229-231C; TLC: R,=0.19 (SiOzCHCl3/MeOH = 10:1);1H
NMR (CD30D): ~ ppm: 7.54-7.70 (m, ArH, 4H), 7.33-7.40 (m, ArH, 3H); MS (El): m/e 403.1 (M+: C20H1~N3CI3); Anal. (C,H,N;
C20H1~,N3CI3HCI): 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'-14-12'-ber,~ui' - -' 6'-methyi~phenyl~ i ' ' ?~HCI
mp: 244.5-246C; TLC: R~=0.23 (SiO2, CHCI3/MeOH = ~
10:1); 1H NMR (CD30D): ~ ppm 8.15-8.17 (m, Ar_, 2H), 7.36-7.91 (m, ArH, 10H), 3.40-3.50 (m, CH2, 4H), 2.50 (s, CH3, 1H); MS(EI):
25 m/e 434.1 (Mi: C27H22N4S); Anal. (C,H,N; C27H22N4S-HCI): Calcd.
(%): C, 68.85; H, 4.92; N, 11.89; Found (%): C, 68.66; H, 4.91; N, 1 1 .86.
Example 64: Inhibition of Glutarnate Release Compounds were tested for inhibition of ~lutamate 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.

W0 95/14467 2 ~ ~ 7 ~ ~ PCT/US94~ 41 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 conc~"I,dtion of the compound as specified in Table I below, i.e., 10 IIM or 3 ,~m. All solutions 5 including the r;ontrols are made to have the same ~;ul~cel~ ion of methanol. Methanol concer,L,dtio" never exceeded 0.30/D (V/V) of buffers. Synaptosomes we~e first exposed to the compound during the wash before superfusion and also during the entire superfusion protocol. The total time sylla~lso"les were exposed to the test 10 organic compounds before the glutamate re~ease 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 15 reference to corresponding Example No. and the following formula where the substituent groups R, R' and R2 are specified in the Tables.
The desiynation "NT" in the Tables indicates the compound was not tested in the specified assay.

A number of compounds identified in Table I and Table lA
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 25 described in Epileps/a, 27: 490-497 (1986).
TABLE 1: INHIBITION OF GLUTAMATE RELEASE
~RI RZ
_ _ _ _ WO9~114467 2 ~ 7708~ PCTIUS94/13541 .

Cmpd. % Block of Giu Rel of Ex.
No. R R' R' @ 10 I~M @ 3 2,3,4-l,i"l,lu,.,' Iyl H H NT 97 5 25-acenaphthyl H CH3 62 NT
35~ I CH3 CH3 NT 53 41-anthracenyl H H 95 85 54-tortbutylphenyl H H 100 49 64-c~,.lulle~yl~ l H H NT 90 10 74-secbutylphenyl H H NT 84 84 . ' yu~ l H H 50 3 92,3-di"l,lu",' ,l H H 86 47 104-OCHJ-2-naphthyl H H 84 80 113,4-~liullluluph~ l H H 82 NT
15124 ulllu,u~ I H H 69 NT
132-naphthyl H H 81 NT
154. uuI,~n,~l H H 35 78 163-bi-phcnyl H H NT 98 172,3-l' ' 1'~ ' .fl H H NT 46 20182-bi-phenyl H H NT 54 192,5 dib., , ' ,~l H H NT 46 203,4- ' ' ~, ' "~l H H NT 46 214-methoxy-1-naphthyl CHJ H NT 54 224-methoxy-1-naphthyl H CH3 NT 43 25234-methoxy-1-naphthyl CH3 CH3 NT 40 244-chloro-1-naphthyl H H NT 75 253,4,5-l,i"l.lu,u~Jl.~.. )jl H H NT 49 264-bi-phenyl H H NT 38 272,3,4,5-~e~ lllulup~_.l;l H H NT 37 30283 _uu~uu~ lcllrl H H NT 64 293-tertbutylphenyl H H NT 71 WO95/14467 ~ l 7 7 ~ 8 ~ PCT/US94113541 Cmpd. % Block of Glu Rel oNOEx. R R' RZ @ 10 IIM @ 3 ~M
34 3- ', jl H H NT 77 35 2-fiuorenyl H H NT 81 39 4 tiirluull : ;I H H NT 52 40 4 ~ H H NT 46 TABLE lA: INHIBITION OF GLUTAMATE RELEASE

Cmpd. % Block of Glu Rel of Ex.
No. R Rl R2 @ 1 ~Im @ 0.3 /Im 41 4-t~ lu~yull_.lyl H H -- 38 42 3-benzy'u~y~ ."~l H H -- 24 2-anthracenyl H H 44 --46 3 pl~ ilul,_....... ,l H H 79 31 47 4-a~ llljl,ull.... jl H H 20 --48 3 tic"~ x~r~JI,. .. jl H CH3 83 46 49 4-benz~lux-yuh_.,~I H CHa 44 11 50 3-(1-methyl-2'-~-l,_.. ,!~;'.~') h_.. ~l~ H H 72 --51 3-biphenyl H CH3 47 --53 7-t~ l H H 100 --56 3-(Nn N--di~_.l,~!` ,;.,uuI,_.-jl H H -- 7 57 3-(1'-t~ :tuLyl~ l._.ljl H H -- 23 58 3-(4-t-butylbenzoxy~.,_.h,lc.~ ;l H H -- 19 62 2,3,4-L~ lulu~Jlicll~l H CH3 -- 15 Example 65: Ca-Flux Assay Compounds were also tested to determine where the Ca2~
dependent and i~depende~ c~ uollellL~ of glutamate release are related to the blocka~e of 45Ca uptake. Calcium uptake is one step in WO 95114467 2 1 7 ~7 Q ~ ~ PCIII~S94/13541 the cascade of events which occur in neuronal cell death from Ischem~a. See RPsc~clou~ll 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 ll below. Rat brain synaptosomes were 5 prepared according to Hajos, 8rain 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 conce,,l,dlion of 10,uM and incubated for 5 minutes at room temperature. 45Ca uptake was then 10 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 15 block) of control potassium-stimulated 45Ca 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 ll below. in Table ll, the tested compounds are identified bv reference to corresponding Example No. and the depicted structural 20 formula where the substituent groups R, R1 and R2 are specified in Table ll.
TABLE ll: ACTIVITY IN THE Ca FLUX ASSAY

3~ ~ NH

wo 95/14467 2 1 7 7 ~ 8 4 PCT/I~S94/13541 Block of Cmpd. '~sCa @ 101JM
r-x R R1 R2 % Block ICso JIM
5 5 4-tertbutylphenyl H H 50 6 4cyclohexylphenyl H H 63 7 4-sec-butylphenyl H H 53 10 4-methoxy-2-naphthyl H H 43 6.35 16 3-bi-phenyl H H 7.18 10 39 4-trifluoromethyl H H 52 40 4-methylthio H H 46 Example 66: Sodium Channel 810ckade Assay The ability of compounds of the invention to block sodium 15 channels of Illdllllll '' ~ cells is ~x~",,ul;ried by the data summarized in Table lll beiow. The data de",on~L~dl~s that at least some compounds of the invention block the saxitoxin binding site on voltage-activated Na channels which are believed to control glutamate release in vivo. The assay protocol was as described by F.
20 Gusvosky, et al., Brain Research, 518: 101-106 11990~. The following solutions were prepared:
1 ) Slock Solution of the following composition lamounts of col",uone"~ expressed as grams/liter~:
ComrJonent ~ms~
30 mM KCI 2.23 8 mM MgS04 0.96 250 mM Hepes/Tris 59.57 (pH to 7.4 with Tris Base) 1 M Choline Chloride 139.60 18 mM CaCI2 1 99 The Stock Solution is made in ddH20, filtered and stored at room temperature for 4-6 weeks. The Hepes stock is kept le:rl i~e, d~d.

2) Toxin: 1 mg of 1 mM Tetrodotoxin dissolved in 3.1 mls ddH20 (stored at 4C).
3) Incubation Buffer of the following composition (amounts of co""~ol~e"ls expressed as mls):
Col"~)one~l Amount 5.4 mM KCI 9.0 0.8 mM MgS04 5,0 50 mM Hepes 10.0 130 mM Choline Chloride 6.5 19.5 mls of ddH20 and are added to the admixture followed by the addition of 0.049 ~rams of 5.5 mM ~lucose 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 ~,uressed as mls).
ComDonent ~m 20 163 mM Choline Chloride 163 0.8 mM M~S04 100 1.8 mM CaCI2 100 5.0 mM Hepes 20 617 mls of ddH20 and are added to the admixture to provide the Wash Buffer.
S~ aulusollle preparation Synaptosomes were prepared as described in Example 8 of PCT/US92/01050. The prepared synaptosomes are frozen in 1 ml 30 aliquots (5% DMS0) at -80C. Pl~pald~ion is thawed on ice i"~"~edi~l~ly before assay and diluted to ~et approximately 1000 cpm for totals per filter (10-15 ~/9 protein/filter to avoid any potential problems testing relatively lipophilic compounds that could be absorbed out of solution by the membranes).

WO 95114467 2 ~ ~7 0 8 4 PcrNs94/l3541 A test Assay is prepared of the followin~ ~,o~ JGS;LiOII and having 200,1 final volume:
5ozll3H]saxitoxin: 5.9 nM (Amersham TRK.877) approximately 5 a 1:300 dilution of stock (the [~H]Saxitoxin is stored according to Amersham l~co,,lll,enddlions) 20,i Compound of interest (diluted 110x] in ddH20 due to low solubility) 80,1 Incubation buffer 50,i protein: 10-15 ~9 rat synaptosomes This mixture is incubated for 30 minutes at 37C, then filtered over Whatmann GF/C ~lass fiber filters, and washed 3X with 4 mls of Wash Buffer, and the filters punched filters to vials immediately 15 upon co"".i~i.", of assay. l~H]STX is very unstable and can lose :~H
when H20 evaporates while fiiters dry. 5 mls scintillation fluid (CytoScint ICN #882465) are added and the samples counted for 5 minutes each. Nonspecific binding is d~ ll"illed by 10IIM TTX and is about 5% of total bindin~ at the above [protein].
In Table lll, the tested compounds are identified by reference to the formula depicted below with the substituent ~roups of the tested compounds R, Rl and RZ specified in Table lll. The tested compounds were in salt form, as indicated in the Table.
TABLE lll ~ ,RI R2 ~ ~ R

WO 95/14467 2 1 7 7 ~ ~ ~ . PCTIUS94/13541 Sodium Channel Cmpd. Block vs. 3HsTX
5 No. R Rl R' ICbo l~m Sslt 1-anthracene H H 1.4 HCI
24-mothoxy-1-naphthyl H H 4 mesylate 3ô-l,_.-Lùd;uxul~l H H >100 HCI
44-tertbutylphenyl H H 25.2 HCI
10 54-sec-butylphenyl H H 34 HCI
65-a~G--au~ l CH, H > 100 HCI
74 '.u,.~uI._.. yl H H > 100 HBr 82,3-di~ lul~, ' ,I H H 57.5 HCI
94-methoxy-2-naphthyl H H >3û HCI
15103,4-J;ul.;u-u,ul,_.-~l H H 19.9 HCI
114-chlorophenyl H H > 30 HBr 132-naphthyl H H 57.8 HCI
144-nitrûphenyl H H > 100 HCI
153-biphenyl H H 7.8 HCI
20164-fluorophcnyl H H > 100 HCI
172,3-dimethylphenyi H H 21 HCI
182,3,4-l-i.,l-lu-~,' fl H H >10 HCI
193,4,5-l-i.. _.l-oxy~ l H H > 100 HCI
202-biphenyl H H 71.1 HBr 25212,3-difluûrûphenyl H H > 100 HCI
222,5 LliL... , ' .,l H H 40.5 HCI
232,3,4-trifluorophGnyl H H > 100 HCI
244-methoxy-1-naphthyl H H 23.3 HCI
254-methoxy-1-naphthyl H CHa 63 HCI
30265-àcG.lc-u~LII~l H H 8.4 mesylate 274-methoxy-1-naphthyl CH3 CH3 >100 HCI
285-d~6.-a,ul, ~.il CH, CH3 >100 HCI

WO 95/14467 2 1 7 7 ~ 8 4 PCT/US94/13541 Sodium Channel Cmpd. Block vs. YHSTX
No. R R~ R2 ICb},vm Salt 29 2~4-d;~I~IU~U~ I H H 66 HCI
30 2,3,4,5 t~ a~ lu~u~Jh~,.)yl H H >3 HCI
The present invention has been described in detail, including 5 the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of the present disclosure, may make m~diri-.~liolls 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 (16)

What is claimed is:

1. A compound having the formula:

wherein:
R and R1 are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
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.

2. A compound having the formula:

wherein:
R and R1 are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;

Ar is selected from the group consisting of substituted or unsubstituted carbocyclic aryl having at least 5 carbon atoms, and substituted or unsubstituted heteroaromatic group having 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; and pharmaceutically acceptable salts thereof.

3. A compound of claim 1 or 2 wherein Ar is phenyl independently substituted at one or more positions by halo, haloalkyl substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkoxy, nitro and substituted or unsubstituted carbocyclic aryl.

4. A compound of claim 1 or 2 where Ar is phenyl substituted by substituted or unsubstituted aralkyl, substituted or unsubstituted aralkylamino, substituted or unsubstituted aryloxy, substituted or unsubstituted alkyleneoxyaryl, or a substituted or unsubstituted heterocyclic group.

5. A compound of claim 1 or 2 wherein Ar is substituted or unsubstituted anthracenyl, substituted or unsubstituted indolinyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted bi-phenyl, substituted or unsubstituted dibenzofuranyl or substituted or unsubstituted tetralinyl.

6. A compound of claim 1 or 2 selected from the group of N-(5-acenaphthyl)-N'-(2,3,4-trichlorophenyl)guanidine;
N-(5-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine;

N-(5-acenaphthyl)-N'-(2,3 4-trichlorophenyl)-N,N'-bis-methylguanidine;
N,N'-bis(5-acenaphthyl)-N-methylguanidine;
N,N'-bis(5-acenaphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(1-anthracenyl)guanidine;
N-(5-acenaphthyl)-N'-(1-anthracenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(1-anthracenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(1-anthracenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-tert-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-tert-butylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-tert-butylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-tert-butylphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-cyclohexylphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-sec-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-sec-butylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-sec-butylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-sec-butylphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxyphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3-dichlophenyl)guanidine;
N-(5-acenaphthyl)-N'-(2,3-dichlorophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3-dichlorophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3-dichlorophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)guanidine;
N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N-methylguanidine;

N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4-dichlorophenyl)guanidine;
N-(5-acenaphthyl)-N'-(3,4-dichlorophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4-dichlorophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4-dichlorophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-chlorophenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-chlorophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-chlorophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-chlorophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(2-naphthyl)guanidine;
N-(5-acenaphthyl)-N'-(2-naphthyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(2-naphthyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(2-naphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(6-quinolinyl)guanidine;
N-(5-acenaphthyl)-N'-(6-quinolinyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(6-quinolinyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(6-quinolinyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-nitrophenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-nitrophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-nitrophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-nitrophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl-N'-(3-bi-phenyl)guanidine;
N-(5-acenaphthyl-N'-(3-bi-phenyl)-N-methylguanidine;
N-(5-acenaphthyl-N'-(3-bi-phenyl)-N'-methylguanidine;
N-(5-acenaphthyl-N'-(3-bi-phenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3-dimethylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(2,3-dimethylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3-dimethylphenyl)-N'-methylguanidine;

N-(5-acenaphthyl)-N'-(2,3-dimethylphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(2-bi-phenyl)guanidine;
N-(5-acenaphthyl)-N'-(2-bi-phenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(2-bi-phenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(2-bi-phenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(2,5-dibromophenyl)guanidine;
N-(5-acenaphthyl)-N'-(2,5-dibromophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(2,5-dibromophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(2,5-dibromophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4-dimethoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxy-1-naphthyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxy-1-naphthyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methoxy-1-naphthyl)-N,N'-dimethylguanidine;
N-(5-acenaphthyl)-N'-(4-chloro-1-naphthyl)guanidine;
N-(5-acenaphthyl)-N'-(4-chloro-1-naphthyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-chloro-1-naphthyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-chloro-1-naphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4,5-trichlorophenyl)guanidine;
N-(5-acenaphthyl)-N'-(3,4,5-trichlorophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4,5-trichlorophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4,5-trichlorophenyl)-N,N'-bis-methylguanidine;
N-(5-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-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-isopropylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-isopropylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-isopropylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-isopropylphenyl)-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,N'-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'-methylguanidine;
N-(5-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-iodophenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-iodophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-iodophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-iodophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-nitrophenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-nitrophenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-nitrophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(5-indolinyl)guanidine;
N-(5-acenaphthyl)-N'-(5-indolinyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(5-indolinyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(5-indolinyl)-N,N'-bis-methylguanidine;

N-(5-acenaphthyl)-N'-(3-acenaphthyl)guanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-acenaphthyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)guanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N'-methylguanidine;
N-(5-acenaphthy)-N'-(2-fluorenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-n-butoxyphenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)guanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)guanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N,N'-bis-methylguanidine; N-(5-acenaphthyl)-N'-(4-methylthiophenyl)guanidine;

N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N-methylguanidine;
N-15-acenaphthyl)-N'-(4-methylthiophenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-methylthiophenyl)-N,N'-bis-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N,N'-bis-methylguanidine;
N,N'-bis(3-acenaphthyl)-N-methylguanidine;
N,N'-bis(3-acenaphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(1-anthracenyl)guanidine;
N-(3-acenaphthyl)-N'-(1-anthracenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(1-anthracenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(1-anthracenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-tert-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-cyclohexylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-cyclohexylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-cyclohexylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-cyclohexylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-sec-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-sec-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-sec-butylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-sec-butylphenyl)-N,N'-bis-methylguanidine;

N-(3-acenaphthyl)-N'-(4-methoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-methoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxyphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,3-dichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dichlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxy-2-naphthyl)guanidine;
N-(3-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxy-2-naphthyl)-N,N-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3,4-dichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dichlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-chlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-chlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-chlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-chlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2-naphthyl)guanidine;
N-(3-acenaphthyl)-N'-(2-naphthyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2-naphthyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2-naphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(6-quinolinyl)guanidine;
N-(3-acenaphthyl)-N'-(6-quinolinyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(6-quinolinyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(6-quinolinyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-nitrophenyl)guanidine;

N-(3-acenaphthyl)-N'-(4-nitrophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-nitrophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-nitrophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl-N'-(3-bi-phenyl)guanidine;
N-(3-acenaphthyl-N'-(3-bi-phenyl)-N-methylguanidine;
N-(3-acenaphthyl-N'-(3-bi-phenyl)-N'-methylguanidine;
N-(3-acenaphthyl-N'-(3-bi-phenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dimethylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,3-dimethylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dimethylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3-dimethylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2-bi-phenyl)guanidine;
N-(3-acenaphthyl)-N'-(2-bi-phenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2-bi-phenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2-bi-phenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,5-dibromophenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,5-dibromophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,5-dibromophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,5-dibromophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4-dimethoxyphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxy-1-naphthyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxy-1-naphthyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methoxy-1-naphthyl)-N,N'-dimethylguanidine;
N-(3-acenaphthyl)-N'-(4-chloro-1-naphthyl)guanidine;
N-(3-acenaphthyl)-N'-(4-chloro-1-naphthyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-chloro-1-naphthyl)-N'-methylguanidine;

N-(3-acenaphthyl)-N'-(4-chloro-1-naphthyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4, 5-trichlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3,4, 5-trichlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4, 5-trichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3,4, 5-trichlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-bi-phenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-bi-phenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-bi-phenyl)-N'-methylguanidine;
N-(3-scenaphthyl)-N'-(4-bi-phenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,4,5-tetrachlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-isopropylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-isopropylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-isopropylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-isopropylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-tert-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-tert-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-tert-butylphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-tert-butylphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)guanidine;
N-(3-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(2,3,5,6-tetrachlorophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-iodophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-iodophenyl)-N-methylguanidine;

N-(3-acenaphthyl)-N'-(3-iodophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-iodophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-nitrophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)guanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(5-indolinyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)guanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N'-methylguanidine;
N-(3-acenaphthy)-N'-(2-fluorenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-n-butoxyphenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)guanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-(2-methoxy)dibenzofuranyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)guanidine;
N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(9-hydroxy-2-fluorenyl)-N,N'-bis-methylguanidine;

N-(3-acenaphthyl)-N'-(4-trifluoromethylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-trifluoromethylphenyl)-N'-methylguanidine;
N-(3-scenaphthyl)-N'-(4-trifluoromethylphenyl)-N,N'-bis-methylguanidine; N-(3-acenaphthyl)-N'-(4-methylthiophenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-methylthiophenyl)-N,N'-bis-methylguanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N-methylguanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N'-methylguanidine; and N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)-N,N'-bis-methylguanidine;
and pharmaceutically acceptable salts of said compounds.

7. A compound of claim 1 or 2 selected from the group consisting of:
N-(5-acenaphthyl)-N'-(4-benzyloxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-benzyloxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(2-anthracenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-phenethylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-adamantylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(4-benzyloxyphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-biphenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3-(1'-methyl-2'-phenylethyl)phenyl)guanidine;
N-(5-acenaphthyl)-N'-(3,4-tetralinylphenyl)guanidine;
N-(5-acenaphthyl)-N'-(7-benzyltetralinylphenyl)guanidine;

N-(5-acenaphthyl)-N'-(3-1-(4-ethoxy)phenyl)propanyl)phenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-(N",N"-dibenzyl)aminophenyl)guanidine;
N-(5-acenaphthyl)-N'-(3-(1'-benzylbutyl)phenyl)guanidine;
N-(5-acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl)phenylguanidine;
N-(5-acenaphthyl)-N'-(2-(2-indolyl)phenyl)guanidine;
N-(5-acenaphthyl-N'-(3-bromophenyl)guanidine;
N-(5-acenaphyl)-N'-(2,3 4-trichlorophenyl)-N,N'-dimethylguanidine;
N-(5-acenaphthyl)-N'-(2,3,4-trichloro-phenyl)-N'-methylguanidine;
N-(5-acenaphthyl)-N'-(3,4-dibenzyloxyphenyl)guanidine;
N-(5-acenaphthyl)-N'-(4-(2'-benzothiazole-6'-methyl)phenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-benzoyloxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-benzoyloxyphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-sec-butylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(2-anthracenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-phenethylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(4-adamantylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-benzyloxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-benzyloxyphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-biphenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(3-(1'-methyl-2'-phenylethyl)phenyl)guanidine;
N-(3-acenaphthyl)-N'-(3,4-tetralinylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(7-benzyltetralinylphenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-1-(4 ethoxy)phenyl)propanyl)phenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-(N",N"-dibenzyl)aminophenyl)guanidine;
N-(3-acenaphthyl)-N'-(3-(1'-benzylbutyl)phenyl)guanidine;
N-(3-acenaphthyl)-N'-3-(4-tert-butylbenzoxymethyl)phenylguanidine;
N-(3-acenaphthyl)-N'-(2-(2-indolyl)phenyl)guanidine;
N-(3-acenaphhthyl-N'-(3-bromophenyl)guanidine;

N-(3-acenaphthyl)-N'-(3,4-dibenzyloxyphenyl)guanidine;
N-(3-acenapthyl)-N'-(2,3,4-trichlorophenyl)-N,N'-dimethyl guanidine;
N-(3-acenaphthyl)-N'-(2,3,4-trichlorophenyl)-N'-methylguanidine;
N-(3-acenaphthyl)-N'-(4-(2'-benzothiazole-6'-methyl)phenyl)guanidine;
and pharmaceutically acceptable salts of said compounds.

8. A compound having the formula:
wherein:
R and R1 are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;

each R substituent is independently halogen, hydroxyl, cyano, isocyanato, nitro, amino, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted 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, 2, 3, 4, 5, 7, 8 or 9;
Ar is selected from the group consisting of substituted or unsubstituted carbocyclic aryl having at least 5 carbon atoms, and substituted or unsubstituted heteroaromatic group having 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; and pharmaceutically acceptable salts thereof.

9. A compound having the formula:
wherein:
R and R1 are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heterocyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
each R substituent is independently halogen, hydroxyl, cyano, isocyanato, nitro, amino, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted 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, 2, 3, 4, 5, 6, 7, 8 or 9;

Ar is selected from the group consisting of substituted or unsubstituted carbocyclic aryl having at least 5 carbon atoms, and substituted or unsubstituted heteroaromatic group having 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; and pharmaceutically acceptable salts thereof.

10. A method for treating or preventing a disorder of the nervous system in which the pathophysiology of the disorder involves excessive release of a neurotransmitter from neuronal cells comprising administering to a mammal exhibiting symptoms of said disorder or susceptible to said disorder an effective amount of a compound of claim 1, 2, 8 or 9.

11. The method of claim 10 wherein the disorder is 1) nausea resulting from chemotherapy, 2) epilepsy, 3) convulsions, 4) carbon monoxide poisoning, 5) cyanide poisoning, 6) toxic brain damage caused by tetrodotoxin or shell fish toxins, 7) amnesia, 8) migraine or river blindness, or 8) nerve cell death resulting from hypoxia, hypoglycemia, brain or spinal cord ischemia, brain or spinal cord trauma, stroke, heart attack, or drowning.

12. A method for treating or preventing nerve cell death comprising administering to a subject exhibiting symptoms of nerve cell death or susceptible to nerve cell death an effective amount of a compound of claim 1, 2, 8 or 9.

13. A method for modulating the release of excess endogenous neurotransmitters from a subject comprising administering to the subject an effective amount of a compound of claim 1, 2, 8 or 9.

14. A method of blocking voltage sensitive calcium channels of mammalian neuronal cells comprising administering to the cells an effective amount of a compound of claim 1, 2, 8 or 9.

15. A method of blocking voltage sensitive sodium channels of mammalian neuronal cells comprising administering to the cells an effective amount of a compound of claim 1, 2, 8 or 9.

16. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 1, 2, 8 or 9 and a pharmaceutically acceptable carrier.