MXPA00007585A - Substituted semicarbazides and the use thereof. - Google Patents

Abstract

This invention is related to substituted semicarbazides represented by Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1 and R2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R3, R4, R5 and R6 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R3 and R4 is defined as above, and R5 and R6 together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; A1 and A2 are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or satured or partially unsaturated heterocycle, any of which is optionally substituted; X is one of O, S, NR7, CH2, C(O), NR7C(O), C(O)NR7, SO, SO2 or a covalent bond; where R7 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3. m is 0, 1, 2 or 3. The invention also is directed to the use of substituted semicarbazides for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), and for the treatment, prevention or amelioration of both acute or chronic pain, as anticonvulsants, and as antimanic depressants, as anti-migraine agents, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.

Description

SEMICABAZIDAS SUBSTITUIDAS AND THE USE OF THE SAME / Background of the Invention Field of the Invention This invention relates to the field of medicinal chemistry. In particular, the invention relates to novel substituted semicarbazides and to the discovery that these compounds are anticonvulsants and act as blockers of the sodium (Na +) channels.

Related Background Technique Various 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 the activity of the Na + channel (Catterall, WA, Trends Pharmacol, Sci. 8: 57-65 (1987)). Each of these agents is believed to act by interference from the rapid influx of Na + ions.

REF .: 122005 Recently, other Na + channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are currently in clinical trials (Graham et al., J. Pharmacol Exo. 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 + channel blockers is due to its effectiveness in reducing the concentration of extracellular glutamate during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na + channel blockers prevent hypoxic damage to the white matter of mammals (Stys et al., J. Neurosci, 12: 430-439 (1992 ' )). Therefore, they offer the advantages of treating certain types of attacks or neuronal trauma where damage to the tracts of the white substance is prominent. Another example of the 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 subsequently has been approved by the FDA for the treatment of ALS. In addition to the clinical uses mentioned above, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as that of trigeminal neurology, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trens Pharmacol. Sci. 16: 309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76 (1994)). It has been established that there are at least five to six sites on voltage-sensitive Na + channels, which bind to neurotoxins specifically (Catterall, W.A., Science 242: 50-61 (1988)). Studies have also 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 + channel and allosterically inhibit the interaction with site 2 of the Na + channel. neurotoxin receptor (Catterall, WA Ann. Rev. Pharmacol, Toxicol.10: 15-43 (1980)). The PCT International Published Request WO96 / 40628 describes the semicarbazones represented by the following Formula: wherein R? -R are independently hydrogen, halogen, alkyl with Ci-g, cycloalkyl with C3-9, -cycloalkyl, cyano, alkoxy with C1-9, or aryloxy with C6-? or, 5 is hydrogen, alkyl with C ? -9, cycloalkyl with C3-9, or aryl with Ce-io / and X is oxygen or sulfur. The compounds are described as going to be useful as anticonvulsants. However, it is not suggested or implied that semicarbazides, which can be prepared by the reduction of semicarbazones, will also act as anticonvulsants. Dimmock et al., J. Med. Chem. 39-3984-3997 (1996) describes (aryloxy) aryl semicarbazones which exhibited anticonvulsant activities when administered intraperitoneally to mice or orally to rats. However, it is not suggested or implied that semicarbazides, which can be prepared by the reduction of semicarbazones, will also act as anticonvulsants.

Brief Description of the Invention The present invention relates to the surprising discovery that the novel substituted semicarbazides represented by Formula I are anticonvulsants and act as blockers of the sodium (Na +) channels. Although the semicarbazides of Formula I can be prepared by the reduction of semicarbazones, the corresponding semicarbazides and semicarbazones are two different classes of compounds. Semicarbazide is a base due to the presence of the basic nitrogen N-l. Semicarbazone is not a base but the NH group on nitrogen N-2 is slightly acidic. The C = N double bond in semicarbazone makes it a relatively rigid molecule. The simple C-N bond in semicarbazide makes it a relatively non-rigid molecule. It is therefore a surprising discovery that the semicarbazides of this invention such as those represented by Formula I are anticonvulsants and act as sodium channel blockers (Na +), similarly to semicarbazones. The invention is also related to the treatment of a disorder in response to blockage of sodium channels in a mammal suffering from excessive activity of said channels by the administration of an effective amount of a compound of Formula I as indicated. described here. The present invention is also directed to the use of a compound of Formula I 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 antimaniac depressants, as local anesthetics, as antiarrhythmics, as anticonvulsants and for the treatment or prevention of diabetic neuropathy and for the treatment of pain including both acute and chronic pain and migraine headache. A first aspect of the present invention is directed to the novel substituted semicarbazides of the formula I. A second aspect of the present invention is directed to the novel compounds of Formula I as sodium channel blockers. A third aspect of the present invention is to provide a method for the treatment, prevention or amelioration of neuronal loss following global and focal ischemia; the treatment, prevention or improvement of pain including acute and chronic pain, and neuropathic pain; the treatment, prevention or improvement of neurodegenerative conditions; the treatment, prevention or improvement of manic depression; the treatment of local anesthesia, arrhythmias, and seizure by administration of a compound of Formula I to a mammal in need of such treatment. A fourth aspect of the present invention is to provide a pharmaceutical composition useful for the treatment of the responsible disorders of the blockade of the sodium ion channels, which contains an effective amount of a compound of the Formula I in a mixture with one or more carriers. or pharmaceutically acceptable diluents. A fifth aspect of the present invention is directed to the methods of preparation of the novel compounds of Formula I.

Detailed description of the invention The present invention arises from the discovery that the novel substituted semicarbazides of Formula I are anticonvulsive and act as the blocker of the Na + channel. In view of this discovery, the compounds of Formula I are useful for the treatment of disorders in response to blockage of sodium ion channels. The compounds useful in this aspect of the present invention are the novel substituted semicarbazides represented by Formula I: or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ri and R2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R3, R4, R5 and R6 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R3 and R4 are as defined above, and R5 and R6 together with the nitrogen to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; Ai and A2 are independently aryl, heteroaryl, partially saturated or unsaturated carbocycle or partially saturated or unsaturated heterocycle, any of which is optionally substituted; X is one of 0, S, NR7, CH2, C (0), NR7C (0), C (0) NR7, SO, S02 or a covalent bond; wherein R7 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3; m is 0, 1, 2, or 3. Preferred compounds that are considered within the scope of Formula I include the compounds wherein Ai and A2 are both aryl portions, preferably both phenyl portions, which are each independently substituted optionally by one to four substituents independently selected from the group consisting of halogen, nitro, amino, alkyl with C? _6, haloalkyl with C? _6, cycloalkyl with C3_8, cyano, alkoxy with C? _6, or aryloxy with? iOf Ri and R2 are independently hydrogen, alkyl with C? _6, cycloalkyl with C3_8, or aryl with Ce-1; R3, R4, Rs and Re are independently hydrogen or alkyl with C? _6, X is 0; ynym are 0. Preferred compounds within Formula I also include those compounds wherein i is a substituted aryl group optionally selected from the group consisting of phenyl and naphthyl, and A2 is an optionally substituted aryl or heteroaryl group, selected from the group consisting of it consists of pyridyl, pyrimidinyl, 1,3,5-triazinyl, furanyl, thiophenyl, naphthyl, quinolyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and quinoxalinyl. Also included are biphenylmethyl and triphenylmethyl. Additional preferred compounds within Formula I also include those compounds wherein Ax is an optionally substituted aryl group, selected from the group consisting of phenyl or naphthyl, and A2 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 compounds within Formula I include those compounds wherein Ai is an aryl or substituted heteroaryl group optionally selected from the group consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl, and thiophenyl, and A2 is a substituted aryl or heteroaryl group optionally selected from the group consisting of phenyl, furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and naphthyl. Additional preferred compounds within Formula I include those compounds wherein Ai is a partially saturated, saturated or unsaturated carbocycle or heterocycle, optionally selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl, and A2 is an aryl or substituted heteroaryl group optionally selected from the group consisting of phenyl, furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl, or naphthyl. Preferred exemplary compounds that can be employed in this method of the invention include, without limitation: 1- (4-phenoxybenzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chlorophenoxy) benzyl) semicarbazide; 1- (4- (4-bromophenoxy) benzyl) semicarbazide; 1- (4- (4-methoxyphenoxy) benzyl) semicarbazide; 1- (4- (4-trifluoromethylphenoxy) benzyl) -semicarbazide; 1- (4- (4-methylphenoxy) benzyl) semicarbazide; 1- (4- (3,4-difluorophenoxy) benzyl) semicarbazide;andRa. 1- (4- (4-chloro-2-fluorophenoxy) benzyl) -semicarbazide; 1- (4- (-nitrophenoxy) benzyl) semicarbazide; 1- (4- (3-methylphenoxy) encyl) semicarbazide; 1- (4- (4-t-butylphenoxy) benzyl) semicarbazide; 1- (4- (4-propylphenoxy) benzyl) semicarbazide; 1- (4- (4-s-butylphenoxy) benzyl) semicarbazide; 1- (4- (3, 4-methylenedioxyphenoxy) benzyl) -semicarbazide; 1- (4-cyclohexyloxybenzyl) semicarbazide; 1- (4-cycloheptyloxybenzyl) semicarbazide; 1- (4- (5-indanyloxy) benzyl) semicarbazide; 1- (4- (6-quinolinyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) -3-fluorobenzyl) -semicarbazide; 1- (4- (tetrahydropyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl-4-methylsemicarbazide; and 1- (4- (4-fluorophenoxy) benzyl) -2-methyl-semicarbazide.

Since the compounds of Formula I are sodium channel blockers (Na +), a number of diseases and conditions mediated by the influx of sodium ion can be treated using these compounds. Therefore, the invention is related to a method of treatment, prevention or improvement of neuronal loss associated with attacks or attacks, global or focal ischemia, CNS trauma, hypoglycemia and surgery, marrow trauma. spinal; as well as the treatment or improvement of neurodegenerative diseases that include Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, the treatment or improvement of anxiety, seizures, glaucoma, migraine headache, and muscle spasms. The compounds of Formula I are also useful as antimalarial depressants, as local anesthetics, and as antiarrhythmics; as well as for the treatment, prevention or improvement of pain including surgical, chronic and neuropathic pain. In each case, the methods of the present invention require administration to an animal in need of such treatment of an effective amount of a sodium channel blocker of the present invention, or a pharmaceutically acceptable salt or prodrug thereof. Specifically, the preferred substituted semicarbazides are represented by Formulas II-VI. In particular, a preferred embodiment is represented by Formulas II: or a pharmaceutically acceptable salt or prodrug thereof, wherein: i R2? R3? R4r s, Rß / X, n and m are as previously defined with respect to Formula I; and R9, Rio, Rii, and R12 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, partially saturated or 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 Rio or Rn and Ri2 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle. Examples of the bridges formed by Rg and R10 or Ru and R? 2 taken together are -0CH20-, -0CF20-, - (CH2) 3-, - (CH2) -, -0CH2CH20-, -CH2N (R? 8 ) CH2-, -CH2CH2N (Rlß) CH2-, -CH2N (R? 8) CH2CH2-, and -CH = CH-CH = CH-; wherein R18 is hydrogen, alkyl or cycloalkyl; R3 and R2 are independently hydrogen, halo, haloalkyl, aryl, cycloalkyl, partially saturated or unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylaryl, heterocycloalkyl , hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or one of RX3 and R4, or R14 and Rx5, or R15 and R16, or R16 and Ri7 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle. Examples of bridges formed by R13 and Ri4, or R? 4 and R15, or R? 5 and R? 6, or R? 6 and R? taken together are -0CH20-, -0CF20-, - (CH2) 3-, - (CH2) 4-, -0CH2CH20-, -CH2N (R18) CH2-, -CH2CH2N (R? 8) CH2-, -CH2N ( R18) CH2CH2-, and -CH = CH-CH = CH-; wherein Ri8 is hydrogen, alkyl or cycloalkyl. Another preferred embodiment of the invention includes the substituted semicarbazides represented by Formula III and Formula IV: or a pharmaceutically acceptable salt or prodrug thereof, wherein: R? -R6, R9-R12? R13-R17 n, m, Ai, A2 and X are as previously defined with respect to formulas I and II. Preferred compounds within Formula III include those compounds' wherein A2 is an aryl or substituted heteroaryl group optionally selected from the group consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl, and thiophenyl. Compounds within Formula IV include those compounds wherein Ai is an aryl or substituted heteroaryl group optionally selected from the group consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl, and thiophenyl.

Another preferred embodiment of the invention includes the substituted semicarbazides represented by Formula V and Formula VI: or a pharmaceutically acceptable salt or prodrug thereof, wherein: R? -R6, R9-R? 2, Ri3-Ri? n, m and 'X are as previously defined with respect to Formulas I and II; and Bi is a partially saturated, unsaturated, optionally substituted carbocycle or partially saturated or unsaturated heterocycle, optionally substituted; and B2 is a partially saturated, or unsaturated carbocycle, optionally substituted or partially saturated or unsaturated heterocycle, optionally substituted.

Preferred bi and B2 independently include cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl. Generally, the preferred compounds of the Formulas I-VI are those compounds wherein Ri and R2 are hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, and wherein R3 and R4 are independently hydrogen or alkyl with C? _4. Preferred values of X in Formulas I-VI are 0. Preferred values of R 5 -R 6 with respect to Formulas I-VI are hydrogen or C 1-4 alkyl. Preferred values of Rg-R 2, and R 3 -R 2, with respect to Formulas II-VI include hydrogen, halo, haloalkyl with Ci-Ce, aryl with C 6 -C 0, cycloalkyl with C 4 -C 7, alkyl with C? _C6, alkenyl with C2_C6, alkynyl with C2-C6, C2-C6 aryl (Ci-Cd) alkyl, C6-C? aryl (C2-C6) alkenyl, e-Cio aryl (C2-Cg) alkynyl, hydroxyalkyl with C? _C6, nitro, amino, ureido, cyano, acylamido with Ci-Cß, hydroxy, thiol, acyloxy with Ci-Ce, azido, alkoxy with C-β, or carboxy. Alternatively, Rg and Ri0 or Rn and Ri2, or two of adjacent R13 to Ri7 can form a bridge selected from the group consisting of -0CH20-, - (CH2) 3-, - (CH2) 4-, -0CH2CH20-, - CH2N (R18) CH2-, -CH2CH2N (R? 8) CH2-, -CH2N (R18) CH2CH2-, and -CH = CH-CH = CH-; wherein Ri8 is hydrogen or alkyl with C? _C6. With respect to the novel methods of treatment of the present invention, a further preferred subset of substituted semicarbazides includes the compounds of Formula I, wherein Ai and A2 are phenyl portions, which are each independently substituted by one or two selected substituents independently of the group consisting of hydrogen, halogen, alkyl with C? _6, cycloalkyl with C3_8, cyano, alkoxy with Ci-e or aryloxy with Ce-1; Ri and R2 is hydrogen, alkyl with C? -6, or cycloalkyl with C3_8; R3 and R4 are hydrogen, or alkyl with C? -6, * X is 0; n and m are 0. Compounds useful in this aspect of the present invention include: 1- (4-phenoxybenzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chlorophenoxy) benzyl) semicarbazide; 1- (4- (4-bromophenoxy) benzyl) semicarbazide; 1- (4- (4-methoxyphenoxy) benzyl) semicarbazide; 1- (4- (4-trifluoromethylphenoxy) benzyl) -semicarbazide; 1- (4- (4-methylphenoxy) benzyl) semicarbazide; 1- (4- (3,4-difluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chloro-2-fluorophenoxy) benzyl) -semicarbazide; 1- (4- (4-nitrophenoxy) benzyl) semicarbazide; 1- (4- (3-methylphenoxy) benzyl) semicarbazide; 1- (4- (4-t-butylphenoxy) benzyl) semicarbazide; 1- (4- (4-propylphenoxy) benzyl) semicarbazide; 1- (4- (4-s-butylphenoxy) benzyl) semicarbazide; 1- (4- (3, 4-methylenedioxyphenoxy) benzyl) -semicarbazide; 1- (4-cyclohexyloxybenzyl) semicarbazide; 1- (4-cycloheptyloxybenzyl) semicarbazide; 1- (4- (5-indanyloxy) benzyl) semicarbazide; 1- (4- (6-quinolinyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) -3-fluorobenzyl) -semicarbazide; 1- (4- (tetrahydropyranyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl-4-methylsemicarbazide and 1- (4- (4-fluorophenoxy) benzyl) -2-methyl-semicarbazide.

Useful aryl groups are aryl with C6-? 4, especially aryl with Ce-io- Typical aryl groups with Ce-? 4 include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl.

Useful cycloalkyl groups are cycloalkyl with C3-8. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and cycloheptyl. The saturated or partially saturated carbocyclic groups, useful, are the cycloalkyl groups as defined above, the cycloalkenyl groups, such as the cyclopentenyl, cycloheptenyl and cyclooctenyl groups, the bicycloalkyl groups such as the norbornyl groups, as well as the Tetrahydronaphthyl and indanyl groups. Useful halo or halogen groups include fluorine, chlorine, bromine and iodine. Useful alkyl groups include C? _??, Branched and straight-chain C grupos _ alquilo alkyl groups, more preferably alkyl groups with Ci-β- Typical C C1-10 alquilo alkyl groups include methyl, ethyl groups , propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl. A group of trimethylene substituted on two adjacent positions in the benzene ring of the compounds of the invention is also contemplated. Useful alkenyl groups are the alkenyl groups with C2_6, preferably the alkenyl with C2_4.

Typical C2_4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl. Useful alkynyl groups are the alkynyl groups with C2_6, preferably alkynyl with C2_4. Typical C2_ alkynyl groups include the ethynyl, propynyl, butynyl, and 2-butynyl groups. Useful arylalkyl groups include any of the abovementioned C grupos _? Alkyl groups substituted by any of the above-mentioned C6 ~ ?4 aryl groups. Useful values include benzyl, phenethyl and naphthylmethyl. Useful arylalkenyl groups include any of the aforementioned C2-4 alkenyl groups, substituted by any of the aforementioned C6-? 4 aryl groups. Useful arylalkynyl groups include any of the aforementioned C 2-4 alkynyl groups, substituted by any of the aforementioned C 1 -C 14 aryl groups. Useful values include phenylethynyl and phenylpropynyl. Useful cycloalkylalkyl groups include any of the above-mentioned C?-Α or alkyl groups, substituted by any of the aforementioned cycloalkyl groups.

Useful haloalkyl groups include alkyl groups with Ci-1 substituted by one or more fluorine, chlorine, bromine or iodine atoms, for example the fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups. Useful hydroxyalkyl groups include alkyl groups with C? -? Or substituted by hydroxy, for example hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl. Useful alkoxy groups include oxygen substituted by one of the abovementioned C grupos _? Alkyl groups. Useful alkylthio groups include sulfur substituted by one of the abovementioned C? _? Alkyl groups. Useful acylairium groups are any acyl with Ci-e (alkanoyl) attached or bonded to an amino nitrogen, for example acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as acyl groups substituted with C2_e and substituted with aryl. Useful acyloxy groups are any acyl with C? -6 (alkanoyl) attached to an oxy (-0-) group, for example acetoxy, propionyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.

Saturated or partially saturated, useful heterocyclic groups include the tetrahydrofuranyl, pyranyl, piperidinyl groups, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl and pyrazolinyl. Useful heterocycloalkyl groups include any of the aforementioned Ci-io alkyl groups, substituted by any of the heterocyclic groups mentioned above. Useful heteroaryl groups include any of the following: thienyl, benzo [b] thienyl, naphtho [2, 3-b] thienyl, thiantrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxantiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl , pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4-quinolizinyl, isoquinolyl, quinolyl, ftalzinyl, naphthyridinyl, quinozalinyl, cinolinyl, pteridinyl, 5aH-carbazolyl, carbazolyl, β -carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxalin-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 a nitrogen atom may be in the form of an N-oxide, for example a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and similar. Useful heteroarylalkyl groups include any of the aforementioned C? _? Alkyl groups, substituted by any of the aforementioned heteroaryl groups. Useful heteroarylalkenyl groups include any of the C2_ alkenyl groups mentioned above, substituted by any of the aforementioned heteroaryl groups. Useful heteroarylalkynyl groups include any of the C2_ alkynyl groups mentioned above, substituted by any of the heteroaryl groups mentioned above. Useful amino groups include -NH2, -NHR14, and -NR? 4Ri5, wherein R? 4 and R? 5 are alkyl or cycloalkyl groups with C? _? 0 as defined above. Useful aminocarbonyl groups are the carbonyl groups substituted by -NH2, -NHR? 4, and -NR? 4R? 5, where Ri4 and R? 5 are the alkyl groups with Ci-io- The optional substituents on either of the aryl, heterocyclic, heteroaryl, and cycloalkyl rings in Formulas I-VI include any of the halo, haloalkyl, aryl, heterocycle, cycloalkyl, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl groups, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, aminocarbonyl, and alkylthiol mentioned above. Preferred optional substituents include: halo, haloalkyl, hydroxyalkyl, aminoalkyl, nitro, alkyl, alkoxy and amino. Certain of the compounds of Formula I may exist as optical isomers and the invention includes both the racemic mixtures of such optical isomers and the individual enantiomers which may be separated according to methods that are well known to those of ordinary skill in the art. technique. Examples of pharmaceutically acceptable addition salts include organic and inorganic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, acetic acid, dichloracetic acid and oxalate. Examples of prodrugs include esters or amides of Formula I with Ri-Rβ as hydroxyalkyl or aminoalkyl, and these can be prepared by reacting such compounds with anhydrides such as succinic anhydride. The invention is also directed to a method for the treatment of disorders in response to blockage of sodium channels in animals suffering from this. Particular preferred embodiments of substituted semicarbazides for use in the method of this invention are represented by Formula I previously defined. The compounds of this invention can be prepared using methods known to those skilled in the art., or by the novel methods of this invention. Compounds with Formulas I-VI can be prepared as illustrated by the exemplary reaction in Scheme I from the reduction of the corresponding semicarbazones.

Scheme 1 The compounds of the present invention were evaluated by electrophysiological assays in hippocampal neurons dissociated for sodium channel blocking activity. These compounds could also be tested by binding to the voltage-dependent sodium channel, neuron, using membranes from the prosencephalon of the rat 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 in Na + permeability in response to the depolarization associated with the potential action 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 compounds herein, described as the blockers of the specific Na + channel. Based on the discovery of this mechanism, these compounds are contemplated to be useful in the treatment or prevention of neuronal loss due to focal or global ischemia, and to the treatment or prevention of neurodegenerative disorders including ALS, anxiety, and epilepsy. They are also expected to be effective in the treatment, prevention or improvement of neuropathic pain, surgical pain and chronic pain. The compounds are also expected to be useful as antiarrhythmics, anesthetics and antimalarial depressants. The present invention is directed to the compounds of Formulas I which are blockers of voltage-sensitive sodium channels. In accordance with the present invention, those compounds which have preferred sodium channel blocking properties exhibit an IC 50 of about 100 μM or less in the electrophysiological assay described herein. Preferably, the compounds of the present invention exhibit an IC50 of 10 μM or less. More preferably, the compounds of the present invention exhibit an IC50 of about 1.0 μM or less. The substituted semicarbazides of the present invention can be tested to verify their blocking activity of the Na + channel by the following binding and electrophysiological assays.

Electrof i sológico test: Cell preparation: HEK-293 cells stably expressing the hSkMl isoform of Na + channels (generous gift from Dr. AL George, Vanderbilt University Medical School) were cultured using standard techniques, as previously described (Verdoorn , TA, et al., Neuron 4: 919-928 (1990)). For electrophysiology, the cells were plated on 35 mm Petri dishes (pre-coated with poly-D-lysine) at a density of 1:40 on the day of re-sowing from confluent cultures. The cells are suitable for recording for 2-3 days after plating. Patch Registers for Voltage-Sensitive Na + Currents: Affinity recordings or whole-cell voltage fixations were made using patch fixation techniques (Hamill et al., Pfluegers Arch. 391: 85-100). (1981)) with an Axopatch 200A amplifier (Axon Instruments, Foster City, CA). The records were made within 2-3 hours after the dissociation of the neurons. The recording chamber was continuously superfused with the external solution (150 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl 2, 1 mM MgCl 2, 10 mM HEPES, 10 mM glucose, pH 7.4 (NaOH)) to a speed of approximately 1 ml / min. The recording pipettes were pulled from the thin-walled capillaries (WPI, Sarasota, Fl) and polished with fire. Pipette resistances ranged from i to 3 MO when the pipettes were filled with the internal solution containing (in mM): 110 CsF, 10 NaCl, 5 MgCl2, 11 EGTA, 10 HEPES, pH adjusted to 7.4 with CsOH. The osmolality was adjusted with a difference of 15-20 mmoles / kg between the internal and external solutions (lower inside the cell). Drugs and intermediate washes were applied through a linear network of flow pipes (Drummond Microcaps, 2-μl, 64-mm long). The compounds are dissimethyl in dimethylsulfoxide (DMSO) to make a 30 mM storage solution, which was subsequently diluted in the external solution to give the final concentrations of 0.1-100 μM. At the highest concentration (1%), DMSO inhibited the size of the Na + stream only slightly. The currents were recorded at room temperature (22-25 ° C), filtered at 5 Hz with an active 8-pole Bessel filter (Frequency Devices, Haverhill, MA), digitized at intervals of 10-50 μs, and was stored using the Digidata 1200 analog / digital interconnection with the Pclamp6 / Clampex program (Axon Instruments). The series resistance was typically canceled by ~ 75% when necessary. The inhibitory potency of the drugs was evaluated by measuring the reductions in the maximum amplitude of the Na + currents induced by the increasing concentrations of the compounds tested. The Na + currents were produced by grading the membrane voltage from the retention potentials over the range of -100 mV to -50 mV, up to an impulse potential of -10 mV. The duration of the test pulse was 5-10 msec, repeated at a frequency of < 1 Hz. The concentration-inhibition curves were adjusted with equation 1: I / Icontrol = 1 (1 + ([compound / IC50) Ec, where Icontroi is the maximum Na + current in the absence of the antagonist, [compound] is the concentration of the drug, and IC50 is the concentration of the compound that produces the highest intermediate inhibition.

Union Test: The ability of the compounds of the present invention to modulate either site 1 or site 2 of the Na + channel was determined following the procedures described fully in Yasushi, J. Biol. Chem. 261: 6149-6152 (1986) and Creveling , Mol. Pharmacol. 23: 350-358 (1983), respectively. The forebrain membranes of the rat were used as sources of the Na + channel proteins. Binding assays were carried out in 130 μM choline chloride at 37 ° C for 60 minutes of incubation with [3 H] saxitoxin and [3 H] batrachotoxin as the radioligands for site 1 and site 2, respectively. The compounds of the present invention can be tested to verify anticonvulsant activity in vivo after iv, po or ip injection using a number of anticonvulsant tests in the mice (audiogenic access model in DBA-2 mice, accessions induced by pentylenetetrazole in mice). mice, maximum electric shock test (MES)). The compounds can be tested to verify 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 compounds can be tested to verify their neuroprotective activity after traumatic spinal cord injury according to the procedures described in Wrathall et. to the. (Exp. Neurology 137: 119-126 (1996)) and Iwasaki et. to the. (J. Neuro Sci. 134: 21-25 (nineteen ninety five) ) . Compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve their intended purpose. Although the individual needs vary, the determination of the optimum intervals of the effective amounts of each component are within the experience of the technique. Typically, the compounds can be administered to mammals, for example 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 that It is treated against epilepsy, neurodegenerative diseases, as anesthetics, antiarrhythmic substances, against manic depression, and against pain. For intramuscular injection, the dose is generally approximately half 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, epilepsy status and surgery, the compound can be administered 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 the administration of the compound as a chemical raw material, the compounds of the invention can be administered as part of a pharmaceutical preparation containing the pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate the processing of the compounds 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 tablets, dragees, and capsules, and also the preparations which can be administered rectally , such as suppositories, as well as solutions suitable for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of the active compound (s), together with the excipient. Also included within the scope of the present invention are the pharmaceutically acceptable, non-toxic salts of the compounds of the present invention. The 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. The basic salts are formed by mixing a solution of the particular 2-aminoacetamide of the present invention with a non-toxic pharmaceutically acceptable base solution such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and similar.

The pharmaceutical compositions of the invention can be administered to any animal that experiences the beneficial effects of the compounds of the invention. The main ones among such animals are mammals, for example, humans, although the invention is not proposed to be so limited. The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration may be by the parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, the administration may be by the oral route. The dosage administered may be dependent on the age, health, and weight of the recipient or patient, the kind of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect. The pharmaceutical preparations of the present invention are manufactured in a manner which is known per se, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Accordingly, 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 the granules., after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. Suitable excipients, in particular, are fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose and / or calcium phosphate preparations, for example tricalcium phosphate and calcium phosphate and hydrogen, as well as binders such as starch paste, using, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, disintegrating agents such as the above-mentioned starches can be added 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 can 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. To produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate are used. The coloring matters or pigments can be added to the tablets or coating of the tablets, for example, for the identification or to characterize the combinations of the doses of the active compound. Other pharmaceutical preparations which can be used orally include soft-setting capsules made of gelatin, as well as sealed, soft, gelatin capsules, and a plasticizer such as glycerol or sorbitol. The soft-fit capsules can contain the active compounds in the form of granules which can 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 compounds are dissolved or suspended preferably in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers can be added.

Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds 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 rectal gelatin capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. Formulations suitable for parenteral administration include aqueous solutions of the active compounds in the water soluble form, for example, water soluble salts and alkaline solutions. In addition, suspensions of the active compounds such as the 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 compounds are soluble in PEG-400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension including, for example, 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 modifications and suitable 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 1- [4- (4-Fluoro-enoxy) benzyl] semicarbazide A mixture of the 4- (4-fluorophenoxy) benzaldehyde semicarbazone (100 mg, 0.37 mmol) and 5% Pd / C (45 mg) in 15 mL of MeOH was hydrogenated at 1 atm of hydrogen overnight. The catalyst was removed by vacuum filtration over celite and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash chromatography using 19: 1 ethyl acetate / MeOH with a few drops of TEA per 100 ml of the mixture. of the solvent to give 30 mg (38%) of the title compound as a white powder: X-NMR (DMSO-d6) 3.74 (S, 2H), 4.97 (sa, 1H), 5.79 (sa, 2H), 6.91 (d , 2H), 7.00-7.04 (m, 3H), 7.17-7.23 (m, 2H), 7.34 (d, 2H).

Example 2 1- [4- (4-Fluorophenoxy) benzyl] -2-methylsemicarbazide A mixture of 4- (4-fluorophenoxy) benzaldehyde-2'-methyl semicarbazone (103 mg, 0.36 mmol) and 5% Pd / C (45 mg) in 15 mL of MeOH is hydrogenated at 1 atm of hydrogen throughout the night. The catalyst was removed by vacuum filtration over Celite and the filtrate was concentrated under reduced pressure to give 101 mg (97%) of the title compound as a white solid: R1 NMR (DMSO-d6) 2.91 (s, 3H), 3.79 (d, 2H), 4.50 (t, 1H), 5.94 (sa, 2H), 6.90 (d, 2H), 6.99-7.04 (m, 2H), 7.20 (t, 2H), 7.37 (d, 2H).

The following semicarbazides were prepared from the corresponding semicarbazones using a similar procedure: 1- [4- (cycloheptyloxy) benzyl] semicarbazide; 1- [4- (cyclohexylmethoxy) benzyl] semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) benzyl] semicarbazide; 1- [4- (5-indanoxy) benzyl] semicarbazide; 1- [4- (3, 4-methylenedioxyphenoxy) benzyl] semicarbazide; 1- [3- (3-methylphenoxy) benzyl] semicarbazide; 1- [4- (trifluoromethyl) benzyl] -2-semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) benzyl] -2-methyl-semicarbazide; 1- [4- (5, 6, 7, 8-tetrahydro-2-naphthoxy) benzyl] -semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) -1-phenylethyl] -semicarbazide; 1- [4- (3, -difluorophenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (3, 5-difluorophenoxy) encyl] semicarbazide; 1- [4- (benzyl) benzyl] semicarbazide; 1- [4- (3,4-methylenedioxyphenoxy) benzyl] -2- methy1semicarbazide; 1- [4- (5, 6, 7, 8-tetrahydro-2-naphthoxy) benzyl] -2-methylsemicarbazide; 1- [3-fluoro-4- (5-indanoxy) benzyl] semicarbazide; 1- [4- (Exo-2-norbromoxy) benzyl] semicarbazide; 1- [4- (Exo-2-norbrom benzyl] -2-methylsemicarbazide; 1- [3-chloro-4- (4-fluorophen benzyl] semicarbazide; 1- [3-chloro-4- (4-fluorophen -cyclic] -2-methylsemicarbazide; 1- [4- (phen benzyl] semicarbazide; 1- [4- (phen benzyl] -2'-ethylsemicarbazide; 1- [3- [4- (2-Butyl) phen benzyl] semicarbazide; The following semicarbazides can be prepared from the corresponding semicarbazones using a similar procedure: 1- [4- (cyclohexyl benzyl] semicarbazide; 1- [3- (4-methylphen benzyl] semicarbazide; 1- [4- (3, 4-difluorophen benzyl] semicarbazide; 1- [4- (2, 4-difluorophen benzyl] semicarbazide; 1- [4- (2, 4-difluorophen benzyl] -2-methylsemicarbazide; 1- [4- (2-fuorobenzyl benzyl] semicarbazide.

Example 3 1- [4- (4-Fluorophen benzyl] semicarbazide as anticonvulsant The ability of 1- [4- (4-fluorophen benzyl] -semicarbazide to block maximal electro-shock induced (MES) access was determined by the following procedure. The accesses were induced by the application of a current (50 mA, 60 pulses / sec, 0.8 msec pulse width, 1 sec duration, D.C.) using a Ugo Basile ECT device (model 7801). The mice were limited in their movement by holding the skin loosely on their dorsal surface and corneal electrodes coated with a saline solution were held or held lightly against the two corneas. Current was applied and the mice were observed for a period of up to 30 seconds to verify the presentation of an extensor response of the hind leg, tonic. A tonic access was defined as an extension of the hind paw or claw in excess of 90 degrees from the body plane. The 1- [4- (fluorophen benzyl] semicarbazide was administered iv to the mice 10 minutes before the test procedure. The compound exhibited protection against MES with an ED50 (the protective dose at 50% of the animals) of 4.2 mg / kg. 1- [3-Fluoro-4- (4-fluorophen benzyl] semicarbazide was tested by po and was found to have an ED50 of 3.2 mg / kg.

Example 4 Activity of 1- [4- (4-fluorophen benzyl] -semicarbazide as a Sodium Channel Blocker 1- [4- (4-fluorophen benzyl] semicarbazide was tested in the electrophysiological and binding assays described above and produced the dose-dependent inhibition of HEK-293 cells with registered sodium currents with voltage gates that express Stably the sodium channels hSkMl. The blocking effect of this compound on the Na + currents was highly sensitive to the clamping voltage, indicating that 1- [4- (4-fluorophen benzyl] -semicarbazide binds to the voltage-sensitive Na + channels in their inactive state and has a weak potency towards the Na + channels in their resting state (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 the inactivated sodium channels is ~ 7.5 μM. Having now fully described this invention, it will be understood by those skilled in the art that it may be effected within a range of conditions, formulations and other parameters, broad and 'equivalent, without affecting the scope of the invention or any other embodiment of the invention. same All patents, patent applications and publications cited herein are fully incorporated for reference in their entirety.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following

Claims (21)

1. A compound having the formula I: or a pharmaceutically acceptable salt or prodrug thereof, characterized in that: Ri and 2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R3, R4, R5 and Re are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R3 and R are as defined above, and R5 and R6 together with the nitrogen to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; Ai and A2 are independently aryl, heteroaryl, partially saturated or unsaturated carbocycle or partially saturated or unsaturated heterocycle, any of which is optionally substituted; X is one of O, S, NR7, CH2, C (0), NR7C (0), C (0) NR7, SO, S02 or a covalent bond; wherein R is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3; m is 0, 1, 2, or 3.

2. A compound according to claim 1, characterized in that: Ai and A2 is phenyl optionally substituted with hydrogen, alkyl, haloalkyl, or halogen; and X is 0.

3. A compound according to claim 1, characterized in that: Ai is phenyl optionally substituted with hydrogen, alkyl, haloalkyl, or halogen; and A2 is 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen.

4. A compound according to claim 1, characterized in that it has the Formula II: or a pharmaceutically acceptable salt or prodrug thereof, wherein: RIA R2R R3 R4f Rs Re, X, n and m are as previously defined with respect to Formula I; and R9, Rio, Rn, and Ri2 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, partially saturated or 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 Rio or R11 and R12 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle. Examples of the bridges formed by R9 and Rio or Rn and R12 taken together are -OCH20-, -OCF20-, - (CH2) 3-, ~ (CH2) 4-, -OCH2CH20-, -CH2N (R? 8) CH2-, -CH2CH2N (R18) CH2-, -CH2N (R? 8) CH2CH2-, and -CH = CH-CH = CH-; wherein Ris is hydrogen, alkyl or cycloalkyl; Ri3r R? 4 / is, Ri6 and R17 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, partially saturated or 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 RH, or R14 and R15, or Ri5 and Rie, or R16 and R7 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle. Examples of the bridges formed by Ri3 and R? 4, or Ri4 and R? 5, or Ri5 and R? 6, or Ri6 and R7 taken together are -0CH20-, -OCF20-, ~ (CH2) 3-, - (CH2) 4-, -0CH2CH20-, -CH2N (R? 8) CH2-, -CH2CH2N (R18) CH2-, -CH2N (R18) CH2CH2-, and -CH = CH-CH = CH-; wherein R 8 is hydrogen, alkyl or cycloalkyl.

5. A compound according to claim 1, having the Formula III or Formula IV: or a pharmaceutically acceptable salt or drug thereof, characterized in that: R? -R6, R9-R12, Ri3-Ri7r n, m, Ai, A2 and X are as previously defined with respect to Formulas I and II.

6. A compound according to claim 5, characterized in that: A2 is an optionally substituted aryl or heteroaryl group including pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl, and thiophenyl.

7. A compound according to claim 5, characterized in that: Ai is an optionally substituted aryl or heteroaryl group including pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl, and thiophenyl.

8. A compound according to claim 1, having the Formula V or the Formula VI: or a pharmaceutically acceptable salt or prodrug thereof, characterized in that: Ri-Re, RT-RI, Ri3-Ri7 n, m and X are as previously defined with respect to Formulas I and II; and Bi is a partially saturated, unsaturated, optionally substituted carbocycle or partially saturated or unsaturated heterocycle, optionally substituted; and B2 is a partially saturated, or unsaturated carbocycle, optionally substituted or partially saturated or unsaturated heterocycle, optionally substituted.

9. A compound according to claim 8, characterized in that Bi is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl.

10. A compound according to claim 8, characterized in that B2 is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl tetrahydropyranyl, pyrrolidinyl or piperidinyl.

11. A compound according to claim 1, characterized in that the compound is: 1- (4-phenoxybenzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chlorophenoxy) benzyl) semicarbazide; 1- (4- (4-bromophenoxy) benzyl) semicarbazide; 1- (4- (4-methoxyphenoxy) benzyl) semicarbazide; 1- (4- (4-trifluoromethylphenoxy) benzyl) -semicarbazide; 1- 4- (4-methylphenoxy) benzyl) semicarbazide; 1- 4- (3,4-difluorophenoxy) benzyl) semicarbazide; 1-4- (4-chloro-2-fluorophenoxy) benzyl) -semicarbazide; 1-4- (4-nitrophenoxy) benzyl) semicarbazide; 1- 4- (3-methylphenoxy) benzyl) semicarbazide; 1- 4- (4-t-butylphenoxy) benzyl) semicarbazide; 1- 4- (4-propylphenoxy) benzyl) semicarbazide; 1- 4- (4-s-butylphenoxy) benzyl) semicarbazide; 1-4- (3,4-methylenedioxyphenoxy) benzyl) -semicarbazide; 1-4-cyclohexyloxybenzyl) semicarbazide; 1-4-cycloheptyloxybenzyl) semicarbazide; 1- 4- (5-indanyloxy) benzyl) semicarbazide; 1- (6- (6-quinolinyloxy) benzyl) semicarbazide; 1- 4- (4-fluorophenoxy) -3-fluorobenzyl) -semicarbazide; 1- 4- (tetrahydropyranyloxy) benzyl) semicarbazide; 1-4- (4-fluorophenoxy) benzyl-4-methylsemicarbazide; 1- 4- (4-fluorophenoxy) benzyl) -2-methyl-semicarbazide; 1- (4-trifluoromethyl) benzyl] -2'-methyl-semicarbazide; 1- 3- (4-methylphenoxy) encyl) semicarbazide; 1- [(4-cyclohexylmethoxy) benzyl] semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) benzyl] -semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) benzyl] -2'-methyl-semicarbazide; 1- [4- (5,6,7,8-tetrahydro-2-naphthoxy) benzyl] -semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) -1-phenylethyl] -semicarbazide; 10 1- [4- (3, 4-difluorophenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (3, 5-difluorophenoxy) benzyl] semicarbazide; 1- [4- (benzyl) benzyl] semicarbazide; 1- [4- (3,4-methylenedioxyphenoxy) encyl] -2- 15 methylsemicarbazide; 1- [4- (5,6,7,8-tetrahydro-2-naphthoxy) benzyl] -2-methylsemicarbazide; 1- [3-fluoro-4- (5-indanoxy) benzyl] semicarbazide; 1- [4- (Exo-2-norbromoxy) benzyl] semicarbazide; 20 1- [4- (Exo-2-norbromoxy) benzyl] -2-methylsemicarbazide; 1- [3-chloro-4- (4-fluorophenoxy) benzyl] -semicarbazide; 1- [3-chloro-4- (4-fluorophenoxy) benzyl] -2- 25 methylsemicarbazide; 1- [4- (phenoxy) benzyl] -2-methylsemicarbazide; and 1- [3- [4- (2-butyl) phenoxy) benzyl] semicarbazide;

12. A pharmaceutical composition, characterized in that it comprises the compound of any of claims 1-11, and a pharmaceutically acceptable carrier or diluent.

13. A method of treating a disorder in response to blockage of sodium channels in a mammal suffering from it, characterized in that it comprises administering to a mammal in need of such treatment an effective amount of a compound having the formula I : or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ri and R2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R3, R4, Rs and Rβ are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R3 and R4 are as defined above, and R5 and R6 together with the nitrogen to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; Ai and A2 are independently aryl, heteroaryl, partially saturated or unsaturated carbocycle or partially saturated or unsaturated heterocycle, any of which is optionally substituted; X is one of 0, S, NR7, CH2, C (0), NR7C (0), C (0) NR7, SO, S02 or a covalent bond; wherein R7 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3; m is 0, 1, 2, or 3.

14. The method according to claim 13, characterized in that Ai and A2 are both optionally substituted aryl portions.

15. The method according to claim 13, characterized in that: Ai and A2 are phenyl portions which are optionally substituted by one or two substituents independently selected from the group consisting of hydrogen, C? -6 alkyl, halogen, hydroxy, C1-4 alkoxy or trifluoromethyl; Ri and R2 are hydrogen; R3 and R4 are hydrogen or methyl; R5 and R6 independently are hydrogen, C1-6alkyl, or cycloalkyl with C3-7; and X is 0, CH2, or NH.

16. The method according to claim 13, characterized in that the compound is selected from the group consisting of: 1- (4-phenoxybenzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chlorophenoxy) benzyl) semicarbazide; 1- (4- (4-bromophenoxy) benzyl) semicarbazide; 1- (4- (4-methoxyphenoxy) benzyl) semicarbazide; 1- (4- (4-trifluoromethylphenoxy) benzyl) -semicarbazide; 1- (4- (4-methylf-noxy) benzyl) semicarbazide; 1- (4- (3,4-difluorophenoxy) benzyl) semicarbazide; 1- (4- (-chloro-2-fluorophenoxy) benzyl) -semicarbazide; 1- (4- (4-nitrophenoxy) benzyl) semicarbazide; 1- (4- (3-methylphenoxy) benzyl) semicarbazide; 1- (4- (4-t-butylphenoxy) benzyl) semicarbazide; 1- (4- (4-propylphenoxy) benzyl) semicarbazide; 1- (4- (4-s-butylphenoxy) benzyl) semicarbazide; 1- (4- (3, 4-methylenedioxyphenoxy) benzyl) -semicarbazide; 1- (4-cyclohexyloxybenzyl) semicarbazide; 1- (4-cycloheptyloxybenzyl) semicarbazide; 1- (4- (5-indanyloxy) benzyl) semicarbazide; 1- (4- (6-quinolinyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) -3-fluprobenzyl) -semicarbazide; 1- (4- (tetrahydropyranyloxy) benzyl) semicarbazide; 15 1- (4- (4-fluorophenoxy) benzyl-4-methylsemicarbazide; 1- (4- (4-fluorophenoxy) benzyl) -2-methyl-semicarbazide; 1- (3-fluoro-4- (4-fluorophenoxy) benzyl) -semicarbazide; 1- (3- (4-methylphenoxy) benzyl) semicarbazide; 1- (4-trifluoromethyl) benzyl) -2'-methyl-semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) benzyl] -2-methyl-semicarbazide; 25 1- [4- (5, 6, 7, 8-tetrahydro-2-naphthoxy) benzyl] -semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) -1-phenylethyl] -semicarbazide; 1- [4- (3, 4-difluorophenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (3, 5-difluorophenoxy) benzyl] semicarbazide; 1- [4- (benzyl) benzyl] semicarbazide; 1- [4- (3, 4-methylenedioxyphenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (5, 6,7, 8-tetrahydro-2-naphthoxy) benzyl] -2-methylsemicarbazide; 1- [3-fluoro-4- (5-indanoxy) benzyl] semicarbazide; 1- [4- (Exo-2-norbromoxy) benzyl] semicarbazide; 1- [4- (Exo-2-norbromoxy) benzyl] -2-methylsemicarbazide; 1- [3-chloro-4- (4-fluorophoxy) benzyl] -semicarbazide; 1- [3-chloro-4- (4-fluorophenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (phenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (phenoxy) benzyl] -2 '-methylsemicarbazide; and 1- [3- [4- (2-butyl) phenoxy) benzyl] semicarbazide.

17. A method for the treatment, prevention or improvement of neuronal loss following global and focal ischemia; the treatment, prevention or improvement of neurodegenerative conditions; the treatment, prevention or improvement of pain; the treatment, prevention or improvement of manic depression; the provision of local anesthesia; or the treatment of arrhythmias, or the treatment of seizures, characterized in that it comprises administering to a mammal in need of such treatment, an effective amount of a compound having Formula I: or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ri and R2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R3, R4, R5 and R6 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R3 and R4 are as defined above, and R5 and R6 together with the nitrogen to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; Ai and A2 are independently aryl, heteroaryl, partially saturated or unsaturated carbocycle or partially saturated or unsaturated heterocycle, any of which is optionally substituted; X is one of 0, S, NR7, CH2, C (0), NR7C (0), C (0) NR7, SO, S02 or a covalent bond; wherein R is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3; m is 0, 1, 2, or 3.

18. The method according to claim 17, characterized in that the method is for the treatment, prevention or improvement of pain and pain is one of neuropathic pain, surgical pain or chronic pain.

19. The method according to claim 17, characterized in that: i and A2 are phenyl portions which are optionally substituted by one or two substituents independently selected from the group consisting of hydrogen, alkyl with C? _6, halogen, hydroxy, alkoxy with C ? 4 or trifluoromethyl; Ri and 2 are hydrogen; R3 and R4 are hydrogen or methyl; Rs and R6 independently are hydrogen, C1-6 alkyl, or cycloalkyl with C3-7; and X is 0, CH2, or NH.

20. The method according to claim 17, characterized in that: Ai is a substituted aryl group optionally selected from the group consisting of phenyl and naphthyl, and A2 is an optionally substituted aryl or heteroaryl 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 and quinoxalinyl.

21. The method according to claim 17, characterized in that: Ai is a substituted aryl group optionally selected from the group consisting of phenyl or naphthyl, and A2 is a substituted carbocycle or heterocycle optionally selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl, adamantyl, exo-norbornyl and cyclopentenyl. SUMMARY OF THE INVENTION This invention relates to the substituted semicarbazides represented by the formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ri and R2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl , alkoxyalkyl or carboxyalkyl; R3, R4, R5 and Re are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R3 and R4 are as defined above, and R5 and R6 together with the nitrogen to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; Ai and A2 are independently aryl, heteroaryl, partially saturated or unsaturated carbocycle or partially saturated or unsaturated heterocycle, any of which is optionally substituted; X is one of O, S, NR7, CH2, C (O), NR7C (0), C (0) NR7, SO, S02 or a covalent bond; wherein R7 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3; m is 0, 1, 2, or 3. The invention is also directed to the use of substituted semicarbazides for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), and for the treatment, prevention or improvement of both acute and chronic pain, as anticonvulsants, and as antimalarial depressants, as antimigraine agents, as local anesthetics, as antiarrhythmics and for the treatment or prevention of Diabetic neuropathy.