Related Background Art Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine, have been shown to share a common mechanism of action by blocking or modulating Na'channe activity (Catterall, W. A., Trends Pharmacol. Sci. 8: 57-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Na+ ions.

Recently, otherNa+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham et al., J. Pharmacol. Exp.

Ther. 269: 854-859 (1994); Brown et al., British J. Pharmacol. 115: 1425-1432 (1995); SCRIP 1870: 8 (1993); SCRIP 1773: 14 (1992)).

The neuroprotective activity of Na'channe blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na channe blockers prevent hypoxic damage to mammalian white matter (Stys et al., J. Neurosci. 12: 430-439 (1992)). Thus, they may offer avantages for-treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.

Another example of clinical use of a Na+ channel blocker is riluzole.

This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al., New Engl. J. Med. 330: 585-591 (1994)) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16: 309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et Clin.Psychiatry55:70-76(1994)).al.,J.

It has been established that there are at least five to six sites on the voltage-sensitive Na'channels which bind neurotoxins specifically (Catterall, W. A., Science 242: 50-61 (1988)). Studies have further revealed that therapeutic antiarrhythmics, anticonvulsants and local anesthetics whose actions are mediated by Na+ channels, exert their action by interacting with the intracellular side of the Na'channe and allosterically inhibiting interaction with neurotoxin receptor site 2 (Catterall, W. A., Ann. Rev. Pharmacol.

Toxicol. 10: 15-43 (1980)).

PCT International Published Application WO 90/14334 and WO 97/05102 disclose 2-(4-substituted)-benzylamino-2-methyl-propanamide derivatives represented by Formula I : where n is 0-3; X is O, S, CH2 or NH; each of R and R, independently is hydrogen, C1-6 alkyl, halogen, hydroxy, C, 4 alkoxy, or trifluoromethyl; each of R2, R3 and R4 independently is hydrogen, C, 6 alkyl or C37 cycloalkyl ; The

compound are disclosed to be useful as antiepileptics, in the treatment of Parkinson's disease and as neuroprotective agents, e. g. preventing or treating neuronal loss associated with stroke, hypoxia, ischemia, CNS trauma, hypoglycemia or surgery, and in treating and preventing neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, Huntington's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), infarctual dementia and infections or inflammations in the brain; they can also be used as antidepressants, hypnotics, and antispastic agents and in treating ocular damage and retinopathy. However, their mechanism of action was not disclosed.

Summary of the Invention The present invention is related to treating a disorder responsive to the blockade of sodium channels in a mammal suffering from excess activity of said channels by administering an effective amount of a compound of Formula I. The present invention is also related to treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom by administering an effective amount of a compound of Formula 11 as described herein.

The present invention is also directe to the use of a compound of Formulae I or 11 for the treatment of neuronal damage following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy and for the treatment of pain including chronic pain.

The present invention also is directe to the process for preparing novel substituted 2-aminoacetamide of Formula II.

A first aspect of the present invention is directe to the use of compound of Formulae I or 11 as blockers of sodium channels.

A second aspect of the present invention is to provide a method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating pain including chronic pain; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing or ameliorating manic depression; inducing local anesthesia; and treating arrhythmias by administering a compound of Formulae I or Il to a mammal in need of such treatment.

A number of compound within the scope of the present invention are novel compound. Therefore, a third aspect of the present invention is to provide novel compound of Formula II, and to also provide for the use of these novel compound for treating, preventing or ameliorating convulsions.

A fourth aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the blockade of sodium ion channels, containing an effective amount of a compound of Formulae I or 11 in a mixture with one or more pharmaceutically acceptable carriers or diluent.

A fifth aspect of the present invention is directe to methods for preparing novel compound of Formulae II.

Detailed Description of the Invention The present invention arises out of the discovery that compound of Formulae I and 11 act as blocker of the Na+ channel. In view of this discovery, compound of Formulae I and 11 are useful for treating disorders responsive to the blockade of sodium ion channes.

The compound useful in this aspect of the present invention are substituted 2-aminoacetamides represented by Formula 11:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R, R2, R3 and R4 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R5, R6 and R, are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R5, is defined as above, and R6 and R, together with the nitrogen atom to which they are attache form a heterocycle; A, and A, are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; X is one or O, S, NR8, CH2, C (O), NR8C (O), C (O) NR8, SO, SOU or a covalent bond; where R8 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; nisO, 1, 2Or3.

Preferred compound falling within the scope of Formula 11 include compound wherein A, and A, are both aryl moities, preferably both phenyl moities, that are each optionally independently substituted by one or two substituents independently selected from the group consisting of halogen, nitro, amino, C1-6 alkyl, C38 cycloalkyl, cyano, C,. 6 alkoxy or C6, 0 aryloxy; R, is hydrogen, C, 6 alkyl, C3-8 cycloalkyl or C6_, o aryl; O or S.

Preferred compound within Formula 11 also include those compound where A, is an optionally substituted aryl group selected from the group consisting of phenyl and naphthyl, and A, is an optionally substituted heteroaryl or aryl group selected from the group consisting of pyridyl, pyrimidinyl, 1,3, 5-triazinyl, furanyl, thiophenyl, naphthyl, quinolyl, 3,4- methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl, biphenylmethyl, triphenylmethyl and quinoxalinyl.

Additional preferred compound within Formula 11 also include those compound where A, is an optionally substituted aryl group selected from the

group consisting of phenyl or naphthyl, and A. is an optionally substituted carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl, adamantyl, exo-norbornyl and cyclopentenyl.

Additional preferred compound within Formula 11 include those compound where A, is an optionally substituted heteroaryl or aryl group selected from the group consisting of pyridyl, pyrimidinyl, 1,3, 5-triazinyl, naphthyl, quinolyl, furanyl, and thiophenyl, and A, is an optionally substituted heteroaryl or aryl group selected from the group consisting of phenyl, furanyl, thiophenyl, quinolinyl, 3, 4-methylenedixoyphenyl, 3, 4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and naphthyl.

Additional preferred compound within Formula 11 include those compound where A, is an optionally substituted, saturated or partially unsaturated carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl, and A, is an optionally substituted aryl or heteroaryl group selected from the group consisting of phenyl, furanyl, thiophenyl, quinolinyl, 3, 4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl, or naphthyl.

Exemplary preferred compound that may be employed in this method of invention inclue, without limitation: 2-(4-(2-fluorobenzyloxy) benzylamino)-2-methyl-propanamide(4-(2-fluorobenzyloxy) benzylamino)-2-methyl-propanamide ; 2- (4- (4-fluorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (3,4-methylenedioxyphenoxy) benzylamino)-2-methyl-propanamide ; 2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-prop anamide; 2-(4-cyclohexyloxybenzylamino)-2-methyl-propanamide; 2- (4- (5,6,7,8-tetrahydro-2-naphthoxy) benzylamino)-2-methyl-propanamide; 2- (4- (2-adamantanoxy) benzylamino)-2-methyl-propanamide; 2- (4- (4-Chloro-2-fluorophenoxy) benzylamino)-2-methyl-propanamide;

2- (4- (2,4-difluorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- ('), 4-difluorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (6-bromo-4-fluorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (4-nitrophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (4-tetrahydropyranoxy) benzylamino)-2-methyl-propanamide; 2- (4- (3,5-difluorophenoxy)benzylamino)-2-methyl-propanamide; 2- (4- (4-chlorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (4-methylphenoxy) benzylamino)-2-methyl-propanamide; 2-(4-(2-chloro-4-fluorophenoxy) benzylamino)-2-methyl-propanamide(4-(2-chloro-4-fluorophenox y) benzylamino)-2-methyl-propanamide ; 2- (4- (5-indanoxy) benzylamino)-2-methyl-propanamide; 2- (4-cycloheptoxybenzylamino)-2-methyl-propanamide ; 2-(4-(1-methyl-4-piperidinoxy) benzylamino)-2-methyl-propanamide(4-(1-methyl-4-piperidinoxy ) benzylamino)-2-methyl-propanamide ; 2- (4- (exo-2-norbornoxy) benzylamino)-2-methyl-propanamide; 2- (3- (4-fluorophenoxy)-5-pyridylmethylamino)-2-methyl-propanamide ; 2- (4- (4-pyridinoxy) benzylamino)-2-methyl-propanamide; 2- (3-fluoro-4- (4-fluorophenyl) benzylamino)-2-methyl-propanamide; 2- (4- (2-pyrimidinoxy) benzylamino)-2-methyl-propanamide; 2-(4-(6-quinolinoxy)benzylamino)-2-methyl-propanamide; 2- (4- (N, N-diphenylamino) benzylamino)-2-methyl-propanamide ; 2- (4-diphenylmethoxy) benzylamino-2-methyl-propanamide; and 2- (4-triphenylmethoxy)benzylamino-2-methyl-propanamide.

Since the compound of Formula I and 11 are blockers of sodium (Nat) channels, a number of diseases and conditions mediated by sodium ion influx can be treated employing these compound. Therefore, the invention is related to a method of treating, preventing or ameliorating neuronal loss associated with stroke, global and focal ischemia, CNS trauma, hypoglycemia and surgery, spinal cord trauma ; as well as treating or ameliorating

neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, treating or ameliorating anxiety, convulsions, glaucoma, migraine headache, and muscle spasm. The compound of Formula I and 11 are also useful as antimanic depressants, as local anesthetics, and as antiarrhythmics; as well as for treating, preventing or ameliorating pain including surgical, chronic and neuropathic pain. In each instance, the methods of the present invention require administering to an animal in need of such treatment an effective amount of a sodium channel blocker of the present invention, or a pharmaceutically acceptable salt or prodrug thereof.

The present invention is also directe to novel compound within the scope of Formula II. These compound include those compound of Formula 11 where: RI, R,, R3 and R4 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R5, R6 and R7 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or RsX is defined as above, and R6 and R, together with the nitrogen atom to which they are attache form a heterocycle, including piperidine, piperazine, morpholine; A, and A2 are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; X is one or 0, S, NR8, CH2, C (O), NR8C (O), C (O) NR8, SO, SO2 or a covalent bond; where R8 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; 0,1,2or3.nis provided that:

when X is 0, S, CH2 or NH; R, and R, are hydrogen, R3 and R4 are methyl, then A, and A2 are not both phenyl, with A, optionally substituted by one or two non-hydrogen substituents.

Specifically, preferred substituted 2-aminoacetamides are represented by Formulae III-VIII. In particular, a preferred embodiment is represented by Formulae III and IV: or a pharmaceutically acceptable salt or prodrug thereof, wherein R,, R2, R3, R4, R5, R6, R7, X, n, A, and A, are as defined previously with respect to Formula 11; and R9, R10, R11 and R12 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or R9 and R, o or R"and R,, are taken together with the carbon atoms to which they are attache to form a carbocycle or heterocycle. Examples of bridges formed by R9 and R, o or R"and R, 2 taken together are -OCH2O-, -(CH2)4-,-OCH2CH2O-,-CH2N(R18)CH2-,-OCF2O-,-(CH2)3-,

and-CH=CH-CH=CH-;-CH2CH2N(R18)CH2-,-CH2N(R18)CH2CH2- where R, 8 is hydrogen, alkyl or cycloalkyl; provided that when A, in Formula III is an optionally substituted phenyl, then Rg and R10 or R"and R, 2 are taken together with the carbon atoms to which they are attache to form a carbocycle or heterocycle.

R, 3, R, 4, R, 5, R, 6 and R17 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or one of R13 and R14andR15,orR15andR16,orR16andR17areor taken together with the carbon atoms to which they are attache to form a carbocycle or heterocycle. Examples of bridges formed by R, 3 and R14, or R, 4 and R, 51 or R15 and R16, or R, 6 and R, 7 taken together are-OCH, O-, -OCF,O-,-(CHZ)3,-(CH,)4,-OCHCH,O--CH,N(R,g)CH;, -CH2CH2N(R18)CH2-, -CH2N (R, 8) CH, CH ; and-CH=CH-CH=CH- ; where R, 8 is hydrogen, alkyl or cycloalkyl. provided that when A, in Formula IV is an optionally substituted phenyl, then R, 3 and R14, or R14 and R, 51 or R, 5 and R, 6, or R16 and R17 are taken together with the carbon atoms to which they are attache to form a carbocycle or heterocycle.

Preferred values of A2 in Formula III include furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3, 4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl, and naphthyl.

Preferred values of A, in Formula IV include furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3.4-ethylenedioxyphenyl, indanyl, naphthyl.tetrahydronaphthyland Another preferred embodiment of the invention inclues substituted 2- aminoacetamides represented by Formula V and Formula VI:

or a pharmaceutically acceptable salt or prodrug thereof, wherein R1-R7, R9-R12, R, 3-R, 7, n and X are as defined previously with respect to Formulae II, III and IV; and A, B, C, D and E are independently nitrogen or carbon, provided that no more than three of A, B, C, D and E are nitrogen, and there is no substituent. except for oxygen (when the nitrogen is present as a N-oxide), present on A, B, C, D or E when said A, B, C, D or E represents nitrogen.

Preferred compound of Formula V are those where one, two or three of A through E are nitrogens. Preferred compound of Formula VI are those where one or two of A through D are nitrogens.

Another preferred embodiment of the invention inclues substituted 2- aminoacetamide represented by Formula VII and Formula VIII:

or a pharmaceutically acceptable salt or prodrug thereof, wherein R1-R7, R9-R12, R, 3-R17, n and X are as defined previously with respect to Formulae II, III and IV; and B, is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle; and B, is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle.

Preferred B, and B2 independently include cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl.

Generally, preferred compound of Formulae II-VIII are those compound where R, and R, is hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, and where R3 and R4 are independently hydrogen or C1-4 alkyl.

Preferred values of X in Formulae II-VIII are O and S.

Preferred values of R5-R7 with respect to Formulae II-VIII are hydrogen alkyl.C1-4 Preferred values of R9-R, 2, and R, 3-R17, with respect to Formulae II- VIII include hydrogen, halo, Cl-C6 haloalkyl, C6-C10 aryl, C4-C7 cycloalkyl, C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl (CI-C,) alkyl, C6-C, O aryl (C2-C6) alkenyl, C6-C10 aryl(C2-C6) alkynyl, Cl-C6 hydroxyalkyl, nitro,

amino, ureido, cyano, C1-C6 acylamido, hydroxy, thiol, C,-C, acyloxy. azido, C1-C6 alkoxy, and carboxy. Alternatively, R9 and R, o or R,, and R, 21 or two adjacent R, 3 through R, 7 can form a bridge selected from the group consisting -(CH2)3-,-(CH2)4-,-OCH2CH2O-,-CH2N(R18)CH2-,of-OCH2O-, and-CH=CH-CH=CH-,-CH2CH2N(R18)CH2-,-CH2N(R18)CH2CH2-, where R, 8 is hydrogen or C,-C6 alkyl. Most preferably, at least one, two or three of Rg, RIO, RII, R, 2 are hydrogen. Most preferably, at least one, two or three of R, 3 through R17 are hydrogen.

With respect to the novel methods of treatment of the present invention, an additional preferred subset of substituted 2-aminoacetamide compound inclues compound of Formula II, wherein A, and A, are phenyl moities, that A, is substituted by one or two substituents independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, hydroxy, C1-4 alkoxy, or trifluoromethyl; each of R, and R2 are hydrogen; R3 and R4 are methyl; and R ;-R, are independently C1-6 alkyl or C3-1 cycloalkyl.

Useful compound in this aspect of the present invention include: 2- (4- (2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide; 2- (4- (4-fluorophenoxy)benzylamino)-2-methyl-propanamide; 2-(4-(3, 4-methylenedioxyphenoxy) benzylamino)-2-methyl-propanamide; 2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-prop anamide; 2- (4-cyclohexyloxybenzylamino)-2-methyl-propanamide; 2- (4- (5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methyl-propan amide; 2- (4- (2-adamantanoxy)benzylamino)-2-methyl-propanamide; 2- (4- (4-Chloro-2-fluorophenoxy)benzylamino)-2-methyl-propanamide; 2- (4- (2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide; 2-(4-(3, 4-difluorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (6-bromo-4-fluorophenoxy)benzylamino)-2-methyl-propanamide; 2- (4- (4-nitrophenoxy)benzylamino)-2-methyl-propanamide; 2- (4- (4-tetrahydropyranoxy)benzylamino)-2-methyl-propanamide;

2- (4- (3,5-difluorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (4-chlorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (4-methylphenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (2-chloro-4-fluorophenoxy) benzylamino)-2-methyl-propanamide; 2- (4- (5-indanoxy) benzylamino)-2-methyl-propanamide; 2- (4-cycloheptoxybenzylamino)-2-methyl-propanamide; 2-(4-(1-methyl-4-piperidinoxy)(4-(1-methyl-4-piperidinoxy) benzylamino)-2-methyl-propanamide; 2- (4- (exo-2-norbornoxy) benzylamino)-2-methyl-propanamide; 2- (3- (4-fluorophenoxy)-5-pyridylmethylamino)-2-methyl-propanamide ; 2- (4- (4-pyridinoxy) benzylamino)-2-methyl-propanamide; 2- (3-fluoro-4- (4-fluorophenyl) benzylamino)-2-methyl-propanamide; 2- (4- (2-pyrimidinoxy) benzylamino)-2-methyl-propanamide; 2- (4- (6-quinolinoxy) benzylamino)-2-methyl-propanamide; 2- (4- (N, N-diphenylamino) benzylamino)-2-methyl-propanamide; 2-(4-diphenylmethoxy)benzylamino-2-methyl-propanamide;and 2-(4-triphenylmethoxy)benzylamino-2-methyl-propanamide.

Useful aryl groups are C6, 4 aryl, especially C6, 0 aryl. Typical C6, 4 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

Useful cycloalkyl groups include C38 cycloalkyl groups. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and cycloheptyl.

Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as defined above, as well as cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.

Useful halo or halogen groups include fluorine. chlorine, bromine and iodine.

Useful alkyl groups include straight-chained and branche C,, O alkyl groups, more preferably C1-6 alkyl groups. Typical C, _, o alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylene group substituted on two adjoining positions on the benzene ring of the compound of the invention.

Useful alkenyl groups include C, _6 alkenyl groups, preferably C24 alkenyl. Typical C2-4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec.-butenyl.

Useful alkynyl groups include C26 alkynyl groups, preferably C24 alkynyl. Typical C2-4 alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups.

Useful arylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned C6_, 4 aryl groups. Typical groups include benzyl, phenethyl and naphthylmethyl.

Useful arylalkenyl groups include any of the above-mentioned C24 alkenyl groups substituted by any of the above-mentioned C6_, 4 aryl groups.

Useful arylalkynyl groups include any of the above-mentioned C,--4 alkynyl groups substituted by any of the above-mentioned C6, 4 aryl groups.

Typical groups include phenylethynyl and phenylpropynyl.

Useful cycloalkylalkyl groups include any of the above-mentioned C,, O alkyl groups substituted by any of the above-mentioned cycloalkyl groups.

Useful haloalkyl groups include C, _, o alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e. g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups.

Useful hydroxyalkyl groups include Cl, O alkyl groups substituted by hydroxy, e. g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.

Useful alkoxy groups include oxygen substituted by one of the C,, O alkyl groups mentioned above.

Useful alkylthio groups include sulphur substituted by one of the C, _, o alkyl groups mentioned above.

Useful acylamino groups are any C1-6 acyl (alkanoyl) attache to an amino nitrogen, e. g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as aryl-substituted substituted acyl groups.

Useful acyloxy groups are any C, 6 acyl (alkanoyl) attache to an oxy group, e. g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.

Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperizinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl and pyrazolinyl groups.

Useful heterocycloalkyl groups include any of the above-mentioned C, lO alkyl groups substituted by any of the above-mentioned heterocyclic groups.

Useful heteroaryl groups include any one of the following: thienyl, benzo [b]thienyl, naphtho [2,3-b] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, 5aH-carbazolyl, carbazolyl, ß-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido [1,2- a] pyrimidin-4-one, 1,2-benzoisoxazol-3-yl, 4-nitrobenzofurazan, benzimidazolyl, 2-oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the

form of an N-oxide, e. g. a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and the like.

Useful heteroarylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned heteroaryl groups.

Useful heteroarylalkenyl groups include any of the above-mentioned C24 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.

Useful heteroarylalkynyl groups include any of the above-mentioned C24 alkynyl groups substituted by any of the above-mentioned heteroaryl groups.

Useful amino groups include-NH,),-NHR, g, and-NRl9R20, wherein R, 9 and R20 are C1-10 alkyl or cycloalkyl groups as defined above.

Useful aminocarbonyl groups are carbonyl groups substituted by-NH2, NHR, 9, andNRI9R20, wherein R, 4 and R2 () are C,, O alkyl groups.

Optional substituents on any of the aryl, heterocyclic, heteroaryl and cycloalkyl rings in Formulae II-VIII include any one of halo, haloalkyl, aryl, heterocycle, cycloalkyl, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro. amino, ureido, cyano, acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, aminocarbonyl, and alkylthiol groups mentioned above. Preferred optional substituents include: halo, haloalkyl, hydroxyalkyl, aminoalkyl, nitro, alkyl, alkoxy and amino.

Certain of the compound of Formula 11 may exist as optical isomers and the invention inclues both the racemic mixtures of such optical isomers as well as the individual entantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.

Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, acetic acid, dichloroacetic acid and oxalate.

Examples of prodrugs include esters or amides of Formula 11 with R,-R, as hydroxyalkyl or aminoalkyl, and these may be prepared by reacting such compound with anhydrides such as succinic anhydride.

The invention is also directe to a method for treating disorders responsive to the blockade of sodium channels in animals suffering thereof.

Particular preferred embodiments of the substituted 2-aminoacetamide for use in method of this invention are represented by previously defined Formula II.

The compound of this invention may be prepared using methods known to those skilled in the art, or by the novel methods of this invention. The methods described in PCT published application W097/05102, can be employed to synthesize compound within the scope of the invention.

Compound with Formulae II-VIII can be prepared as illustrated by exemplary rections in Schemes 1-5.

Scheme 1

Scheme 2 Scheme 3 Scheme 4 Scheme 5

The compound of the present invention were assessed by electrophysiological assays in dissociated hippocampal neurons for sodium channel blocker activity. These compound also could be assayed for binding to the neuronal voltage-dependent sodium channel using rat forebrain membranes and [3H]BTX-B.

Sodium channels are large transmembrane proteins that are expressed in various tissues. They are voltage sensitive channels and are responsible for the rapid increase of Na+ permeability in response to depolarization associated with the action potential in many excitable cells including muscle, nerve and cardiac cells.

One aspect of the present invention is the discovery of the mechanism of action of the compound herein described as specific Na'channe blockers.

In one aspect of the present invention it has been discovered that compound disclosed in international published application WO 97/05102 are specific Na+ channel blockers. Based upon the discovery of this mechanism, these compound, as well as novel compound described herein, are contemplated to be useful in treating or preventing neuronal loss due to focal or global ischemia, and in treating or preventing neurodegenerative disorders including ALS, anxiety, and epilepsy. They are also expected to be effective in treating, preventing or ameliorating neuropathic pain, surgical pain and chronic pain.

The compound are also expected to be useful as antiarrhythmics, anesthetics and antimanic depressants.

The present invention is directe to compound of Formulae 11 that are blockers of voltage-sensitive sodium channes. According to the present invention, those compound having preferred sodium channel blocking properties exhibit an lC51 of about 100 FM or less in the electrophysiological assay described herein. Preferably, the compound of the present invention exhibit an IC50 of 10 tM or less. Most preferably, the compound of the present invention exhibit an IC50 of about 1.0 FM or less. Substituted 2-aminoacetamide disclosed in WO 97/05102, as well as novel compound of the present invention, may be tested for their Na channe blocking activity by the following electrophysiological and binding assays.

ElectropltysiologicalAssay: Cell preparation. Acute cultures of rat hippocampal neurons were prepared daily using a modification of procedures described previously (Kuo and Bean, Mol. Pharm. 4 (6: 716-725 (1994)). Briefly, hippocampi were isolated from 3-11 day old rat pup brains (Sprague-Dawley; Charles River) and were sectioned, by hand, into 0.5-1 mm thick transverse slices (Whittemore and Koerner, Eur. J. Pharm. 192: 435-438 (1991)). Slices were incubated for at least-30 min at room temperature (20-24°C) in an oxygenated medium (124 mM NaCl, 3.3 mM KCl, 2.4 mM MgSO4, 2.5 mM Cal,, 1.2

mM KH2PO4, 26 mM NaHC03, pH = 7.4) continuously bubbled with 5% C02<BR> <BR> /95 % °2 Prior to recording, 4-5 slices were transferred to an oxygenated dissociation medium (82 mM NaS04,30 mM K2SO4,3 mM MgCl2,2 mM HEPES, 26 mM NaHC03,0.001% phenol red, pH = 7.4) containing 3 mg/ mL protase XXIII (Sigma, St. Louis, MO) and incubated for 10-15 min at continuouslybubblingwith5%CO2/95%O2.Enzymatic37°C,while digestion was terminated by transferring the slices to dissociation medium without bicarbonate, supplemented with 1 mg/mL bovine serum albumin and 1 mg/mL trypsin inhibitor (Sigma, St. Louis, MO). Slices were then transferred to a 35 mm culture dish containing dissociation medium without bicarbonate, and triturized with a fire-polished glass Pasteur pipette to release single cells. Cells were allowed to settle in this dish for-30 minutes and were then used for making electrical recordings.

Patch-clamp recordings of voltage-sensitive Na+ currents: Whole-cell voltage-clamp recordings were made using conventional patch-clamp technique (Hamill et al., Pfluegers Arch. 391: 85-100 (1981)) with an Axopatch 200A amplifier (Axon Instruments, Foster City, CA). Recordings were made within 2-3 hours after neuron dissociation. The recording chamber was continuously superfused with Tyrode's solution (156 mM NaCl. 3.5 mM KCl, 2 mM CaCl2, 5 mM NaHCO3, 10 mM HEPES, 10 mM glucose, pH 7.4) at a speed of about 1 ml/min. Thin-walled pipettes were pulled from 100-p1 Clay Adams Accu-Fill 90 Micropet disposable pipettes (Becton, Dickenson and Company, Parsipanny, NJ), fire-polished and sylgarded (Dow-Corning, Midland, MI). The pipette resistances ranged from 1 to 3 MQ when the pipettes were filled with internal solution containing (in mM): 130 CsF, 20 NaCl, 1 CaCl2,2 MgCl2,10 EGTA, 10 HEPES, pH adjusted to 7.4 with CsOH. Drugs and intervening wash-outs were applied through a linear array of flow pipes (Drummond Microcaps, 2-µl, 64-mm length). Compound are dissolve in dimethylsulfoxide (DMSO) to make a 10 mM stock solution, which was subsequently diluted into Tyrode's solution to give final concentrations of 0.1-20 pM.-At the highest (1%) concentration DMSO

inhibited the size of Na+ current only slightly. Currents were recorde at room temperature (22-25°C), filtered at 5 kHz with 4-pole Bessel filter, digitized at 20-50-Ls intervals, and stored using Digidata 1200 analog/digital interface with Pclamp6/Clampex software (Axon Instruments). Residual series resistance ranged from 0.4 to 0.8 MQ after partial compensation (typically #90%). The inhibitory potency of drugs was assessed by measuring reductions in the peak amplitude of Na+ currents induced by increasing concentrations of compound tested. Na+ currents were elicited by stepping membrane voltage from holding potentials over the range-100 mV to-50 mV, to a pulse potential of-10 mV. The test pulse duration was 5-10 msec, repeated at a frequency < 1 Hz. Concentration-inhibition curves were fitted with equation 1: ([compound]/IC50))Eq.1I/Icontrol=1/(1+ where IColltrol is the maximal Na+ current in the absence of antagonist, [compound] is the drug concentration, and ICso is the concentration of compound that produces half maximal inhibition.

Binding Assay: The ability of compound of the present invention to modulate either site 1 or site 2 of the Na'channe was determined following the procedures fully described in Yasushi. J. Biol. Chem. 261: 6149-6152 (1986) and Creveling, Mol. Pharmacol. 23: 350-358 (1983), respectively. Rat forebrain membranes were used as sources of Na'channe proteins. The binding assays were conducted in 130 µM choline chloride at 37°C for 60-minute incubation with [3H] saxitoxin and [3H] batrachotoxin as radioligands for site 1 and site 2, respectively.

The compound of the present invention may be tested for in vivo anticonvulsant activity after iv or ip injection using a number of anticonvulsant

tests in mice (audiogenic seizure model in DBA-2 mice, pentylenetetrazol- induced seizures in mice, maximum electroshock seizure test (MES)).

The compound may be tested for their neuroprotective activity after focal and global ischemia produced in rats or gerbils according to the procedures described in Buchan et al. (Stroke, Suppl. 148-152 (1993)) and Sheardown et al. (Eur. J. Pharmacol. 236: 347-353 (1993)) and Graham et al.

(J. Pharmacol. Exp. Therap. 276: 1-4 (1996)).

The compound may be tested for their neuroprotective activity after traumatic spinal cord injury according to the procedures described in Wrathall et. al. (Exp. Neurology 137: 119-126 (1996)) and Iwasaki et. al. (J. Neuro Sci.

134: 21-25 (1995)).

Compositions within the scope of this invention include all compositions wherein the compound of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compound may be administered to mammals, e. g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof. per day of the body weight of the mammal being treated for epilepsy, neurodegenerative diseases, anesthesia, arrhythmia, manic depression, and pain. For intramuscular injection, the dose is generally about one-half of the oral dose.

In the method of treatment or prevention of neuronal loss in global and focal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia, status epilepsy and surgery, the compound can be administrated by intravenous injection at a dose of about 0.025 to about 10 mg/kg.

The unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.

In addition to administering the compound as a raw chemical, the compound of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compound into preparations which can be used pharmaceutically. Preferably, the preparations, particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tables, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound (s), together with the excipient.

Also included within the scope of the present invention are the non- toxic pharmaceutically acceptable salts of the compound of the present invention. Acid addition salts are formed by mixing a solution of the particular 2-aminoacetamide of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like. Basic salts are formed by mixing a solution of the particular 2-aminoacetamide of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.

The pharmaceutical compositions of the invention may be administered to any animal which may experience the beneficial effects of the compound of the invention. Foremost among such animals are mammals, e. g., humans, although the invention is not intended to be so limite.

The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration-may be by the oral route. The dosage

administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetyl- cellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example,

for identification or in order to characterize combinations of active compound doses.

Other pharmaceutical preparations which can be used orally include pus-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The pus-fit capsules can contain the active compound in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compound are preferably dissolve or suspende in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations which can be used rectally inclue, for example, suppositories, which consist of a combination of one or more of the active compound with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compound with a base. Possible base materials inclue, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form, for example, water- soluble salts and alkaline solutions. In addition, suspensions of the active compound as appropriate oily injection suspensions may be administered.

Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compound are soluble in PEG-400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension inclue, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.

The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and

adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.

Example 1 2- (4- (2-Fluorobenzyloxy) benzylamino)-2-methyl propanamide as Na'channe blocker 2- (4- (2-Fluorobenzyloxy) benzylamino)-2-methyl-propanamide was tested in the electrophysiological and binding assays described above and produced dose-dependent inhibition of voltage-gated Na+ currents recorde in acutely dissociated rat hippocampal neurons. The blocking effect of this compound on Na currents was highly sensitive to the holding voltage. For example, at concentrations between 0.1-10 AM, 2-(4-(2- fluorobenzyloxy) benzylamino)-2-methyl-propanamide had very little effect on Na+ currents activated from a holding membrane voltage of-100 mV, but inhibited currents with increasing potency as the holding potential was progressively depolarized. The most potent block in these studies was seen at a membrane holding voltage of-65 mV. The decrease in current was due to steady-state inactivation of the Na'channels.

This data indicates that 2- (4- (2-fluorobenzyloxy) benzylamino)-2- methyl-propanamide binds to voltage-sensitive Na+ channels in their inactivated states and has weak potency towards Na channels in their resting states (Ragsdale et al., Mol. Pharmacol. 40: 756-765 (1991); Kuo and Bean, Mol. Pharmacol. 46: 716-725 (1994)). The apparent antagonist dissociation constant (Kd) of this compound for inactivated Na+ channels is # 1. 2 AM.

Example 2 2- (4- (3,4-Methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide a) 4- (3,4-Methylenedioxyphenoxy) benzaldehyde: A mixture of sesamol (5.13 g, 37.1 mmol), 4-fluorobenzaldehyde (4.0 mL, 37.3 mmol), potassium carbonate (6.21 g, 44.9 mmol) in N, N dimethylacetamide (SO mL) was refluxed for 23 h. The mixture was added to water and extracted with an ethyl acetate/hexane solution. The organic layer was washed with aqueous sodium hydroxide (2 N), dried over sodium sulfate, and evaporated under reduced pressure to give crude product. The crude product was purifie by flash chrmoatography to give a pink solid, which was decolorized by refluxing with activated charcoal in chloroform for 1 h.

Filtration through Celite and removal of the chloroform in vacuo gave the desired aldehyde. lH NMR (CDC13) 6 9. 91 (s, 1H), 7.83 (d, J = 9. 0 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7Hz, 1H), 6.62 (d, J = 2. 4 Hz, 1H), 6.58-6.54 (m, 1H), 6.02 (s, 2H). b) 2-Amino-2,2-dimethylethanamide: A solution of HUI in dioxane (4.0 M), methanol (54 ml) and aminoisobutyric acid (11.7 g, 0.114 mol) was refluxed for 6 h. Once at rt, the solution was concentrated to a white solid.

NMR of the solid showed that the solid was a mixture of aminoisobutyric acid and methyl 2-amino-2,2-dimethylacetate. This crude intermediate was heated to 50 degree Celsius in aqueous ammonium hydroxide (29%, 140 ml) in a sealed tube for 24 hours. The solution was cooled to room temperature, then evaporated under reduced pressure to give a white solid.

'H NMR of the solid showed that the white solid contained 40% of the title product.'H NMR (CDC13) 6 807. (s, 2H), 7.48 (s, 2H), 1.27 (s, 6H). c) 2- (4- (3,4-Methylenedioxyphenoxy) benzylamino)-2-methylpropanamide: To a solution of 4- (3,4-methylenedioxyphenoxy) benzaldehyde (0.51 g, 0.21 mmol) in 30 mL of anhydrous ethanol was added 3A molecular sieves (1 g), and 2-amino-2,2-dimethylethanamide (1.67 g, 40% by weight by'H

NMR, 0.49 mmol). After stirring for 24 h, the resulting mixture was treated with sodium cyanoborohydride (95%; 1.0 g, 16 mmol). After stirring for an additional 8 h, the rection was quenched with water. The aqueous layer was extracted three times with an ethyl acetate/hexane mixture. The combine organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude product was purifie by column chromatography to give 77 mg (11%) of the title product, mp = 123-124 °C.'H NMR (CDCl3) 6 257. (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 6.47 (d, J = 8.1 Hz, 1H), 5.96 (s, 2H), 5.47 (bs, 2H), 3.66 (s, 2H), 1.42 (s, 6H).

The following compound were prepared similiarly: =103-1062-(4-(4-Fluorophenoxy)benzylamino)-2-methylpropanami de:mp <BR> <BR> <BR> <BR> °C;'H NMR (CDCl3) 8 277. (d, J = 8.4 Hz, 2H), 7.02-6.92 (ion, 6H), 5.6 (bs, 2H), 3.68 (s, 2H), 1.43 (s, 6H).

2- (4- (2,4-Difluorophenoxy) benzylamino)-2-methylpropanamide: TLC solvent: 60: 40 hexane/ethylacetate; TLC Rf 0.5;'H NMR (CDCl3) # 7.27-6. 85 (ion, 7H), 5.5 (bs, 2H), 3.67 (s, 2H), 1.42 (s, 6H).

2- (4- (5-Indanoxy) benzylamino)-2-methylpropanamide: mp = 81-83 °C ;'H <BR> <BR> <BR> <BR> NMR (CDCl3) 6 257. (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.87 (s, 1H), 6.78 (d, J = 6.0 Hz, 1H), 5.5 (bs, 2H), 3.66 (s, 2H), 2.88 (t, J = 6.9 Hz, 4H), 2.19-2.0 (ion, 2H), 1.41 (s, 6H).

The following compound can be similarly prepared by allowing the appropriate aldehyde precursor to react with 2-methylpropanamide as described above: 2- (4- (3,4-Methylenedioxyphenoxy)benzylamino)-2-methylpropanamide

2- (4-Cyclohexyloxybenzylamino)-2-methylpropanamide 2- (4- (5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methylpropana mide 2- (4- (2-Adamantanoxy) benzylamino)-2-methylpropanamide 2- (4- (4-Chloro-2-fluorophenoxy) benzylamino)-2-methylpropanamide 2- (4- (2-Chloro-4-fluorophenoxy) benzylamino)-2-methylpropanamide 2- (4- (3,4-Difluorophenoxy) benzylamino)-2-methylpropanamide 2- (4- (3,5-Difluorophenoxy) benzylamino)-2-methylpropanamide 2-(4-(6-Bromo-4-fluorophenoxy)benzylamino)-2-methylpropanami de 2- (4- (4-Nitrophenoxy) benzylamino)-2-methylpropanamide 2-(4-(4-Tetrahydropyranoxy)benzylamino)-2-methylpropanamide 2- (4- (4-Chlorophenoxy) benzylamino)-2-methylpropanamide 2- (4- (4-Methylphenoxy) benzylamino)-2-methylpropanamide 2- (4-Cycloheptoxybenzylamino)-2-methylpropanamide 2-(4-(1-Methyl-4-piperidinoxy)(4-(1-Methyl-4-piperidinoxy) benzylamino)-2-methylpropanamide 2- (4- (exo-2-norbornoxy) benzylamino)-2-methylpropanamide 2-(3-(4-Fluorophenoxy)-5-pyridylmethylamino)-2-methylpropana mide 2- (4- (4-Pyridinoxy)benzylamino)-2-methylpropanamide 2- (3-Fluoro-4- (4-fluorophenyl) benzylamino)-2-methylpropanamide 2- (4- (2-Pyrimidinoxy)benzylamino)-2-methylpropanamide 2- (4- (6-Quinolinoxy)benzylamino)-2-methylpropanamide 2- (4- (N, N-diphenviamino) benzylamino)-2-methylpropanamide 2- (4-Diphenylmethoxy) benzylamino)-2-methylpropanamide 2- (4-Triphenylmethoxy) benzylamino)-2-methylpropanamide

2- (4- (3,4-Methylenedioxybenzyloxy)benzylamino)-2-methylpropanamid e The ability of selected 2-methylpropanamide derivatives to block maximal electroshock-induced seizures (MES) was determined by the following procedure.

Seizures were induced by application of current (50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D. C.) using a Ugo Basile ECT device (model 7801). Mice were restrained by gripping the loose skin on their dorsal surface and saline-coated corneal electrodes were held lightly against the two cornea. Current was applied and mice were observe for a period of up tao 30 sec for the occurrence of a tonic hindlimb extensor response. A tonic seizure was defined as a hindlimb extension in excess of 90 degrees from plane of the body. The 2-methylpropanamides tested were administered iv to mice 10 min before the test procedure.

Table 1. Activity of Substituted Benzylamino 2-methylpropanamide in MES iv in mouse Substituent Example iv MES activity (number No. protected/number screened) 4-fluorophenoxy 2 8/8 3,4-methylenedioxvphenoxy 2 8/8 2,4-difluorophenoxy 2 8/8 5-indanoxy 2 1/8 Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.