[go: up one dir, main page]

WO1999039712A9 - Semicarbazides substitues et leur utilisation - Google Patents

Semicarbazides substitues et leur utilisation

Info

Publication number
WO1999039712A9
WO1999039712A9 PCT/US1999/002419 US9902419W WO9939712A9 WO 1999039712 A9 WO1999039712 A9 WO 1999039712A9 US 9902419 W US9902419 W US 9902419W WO 9939712 A9 WO9939712 A9 WO 9939712A9
Authority
WO
WIPO (PCT)
Prior art keywords
benzyl
semicarbazide
alkyl
hydrogen
aryl
Prior art date
Application number
PCT/US1999/002419
Other languages
English (en)
Other versions
WO1999039712A1 (fr
Inventor
Sui X Cai
Nancy C Lan
Soo Hong-Bae
Original Assignee
Cocensys Inc
Sui X Cai
Nancy C Lan
Hong Bae Soo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cocensys Inc, Sui X Cai, Nancy C Lan, Hong Bae Soo filed Critical Cocensys Inc
Priority to EP99905734A priority Critical patent/EP1058550A4/fr
Priority to US09/601,698 priority patent/US6281211B1/en
Priority to MXPA00007585A priority patent/MXPA00007585A/es
Priority to AU25831/99A priority patent/AU754681B2/en
Priority to IL13767199A priority patent/IL137671A0/xx
Priority to CA002319484A priority patent/CA2319484A1/fr
Priority to JP2000530210A priority patent/JP2002511387A/ja
Publication of WO1999039712A1 publication Critical patent/WO1999039712A1/fr
Publication of WO1999039712A9 publication Critical patent/WO1999039712A9/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention is in the field of medicinal chemistry.
  • the invention relates to novel substituted semicarbazides and the discovery that these compounds are anticonvulsants and act as blockers of sodium (Na + ) channels.
  • 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 + channel activity (Catterall, W.A., Trends Pharmacol. Sci. 8:51-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Na ⁇ ions.
  • Na + channel blockers such as B W619C89 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 775:1425-1432 (1995); SCRIP 1870:8 (1993); SCRIP 1773:14 (1992)).
  • Na + channel blockers prevent hypoxic damage to mammalian white matter (Stys et al, J. Neurosci. 72:430-439 (1992)). Thus, they may offer advantages 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.
  • 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. 7(5:309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al, J. Clin. Psychiatry 55: 70-76 (1994)).
  • R,-R 4 are independently hydrogen, halogen, C,. 9 alkyl, C 3 . 9 cycloalkyl, cyano, C,_ 9 alkoxy, or C 6 . 10 aryloxy;
  • R 5 is hydrogen, C,. 9 alkyl, C 3 . 9 cycloalkyl, or C 6 . 10 aryl;
  • X is oxygen or sulfur.
  • the present invention is related to the surprising discovery that novel substituted semicarbazides represented by Formula I are anticonvulsants and act as blockers of sodium (Na + ) channels.
  • the semicarbazides of Formula I can be prepared by reduction of the corresponding semicarbazones, semicarbazides and semicarbazones are two different classes of compounds.
  • Semicarbazide is a base due to the presence of the basic N-1 nitrogen.
  • Semicarbazone is not a base but the NH group on N-2 nitrogen is slightly acidic.
  • the C-N single bond in semicarbazide make it a relatively non-rigid molecule.
  • semicarbazides of this invention as represented by Formula I are anticonvulsants and act as blockers of sodium (Na 1 channels, similar to semicarbazones.
  • the invention is also related with 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 as described herein.
  • 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 antimanic 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.
  • ALS amyotrophic lateral sclerosis
  • a first aspect of the present invention is directed to the novel substituted semicarbazides of Formula I.
  • a second aspect of the present invention is directed to the novel compounds of Formula I as blockers of sodium channels.
  • a third 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 acute and chronic pain, and neuropathic pain; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing or ameliorating manic depression; treating local anesthesia, arrhythmias, and convulsion by administering 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 treating disorders responsive to the blockade of sodium ion channels, containing an effective amount of a compound of Formula I in a mixture with one or more pharmaceutically acceptable carriers or diluents.
  • a fifth aspect of the present invention is directed to methods for preparing novel compounds of Formula I.
  • the present invention arises out of the discovery that novel substituted semicarbazides of Formula I are anticonvulsants and act as blocker of the Na + channel.
  • compounds of Formula I are useful for treating disorders responsive to the blockade of sodium ion channels.
  • the compounds useful in this aspect of the present invention are novel substituted semicarbazides represented by Formula I:
  • R, and R 2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
  • R 3 , R 4 , R 5 and R « are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R 3 and R 4 is defined as above, and R 5 and R ⁇ , together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine;
  • A, and A 2 are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted;
  • X is one of O, S, NR 7 , CH 2 , C(O), NR 7 C(O), C(O)NR 7 , SO, SO 2 or a covalent bond;
  • R 7 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 falling within the scope of Formula I include compounds wherein A, and A 2 are both aryl moieties, preferably both phenyl moieties, that are each optionally independently substituted by one to four substituents independently selected from the group consisting of halogen, nitro, amino, C,. 6 alkyl, C,. 6 haloalkyl, C 3 . 8 cycloalkyl, cyano, C,.
  • R, and R 2 is independently hydrogen, C,_ 6 alkyl, C 3 . 8 cycloalkyl or C 6 . 10 aryl; R 3 , R 4 , R 5 and R ⁇ are independently hydrogen or C,. 6 alkyl; X is O; and n and m are 0.
  • Preferred compounds within Formula I also include those compounds where A, is an optionally substituted aryl group selected from the group consisting of phenyl and naphthyl, and A 2 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 and quinoxalinyl. Also including are biphenylmethyl and triphenylmethyl.
  • Additional preferred compounds within Formula I also include those compounds where A, is an optionally substituted aryl group selected from the group consisting of phenyl or naphthyl, and A 2 is an optionally substituted carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl, adamantyl, ex ⁇ -norbornyl and cyclopentenyl.
  • A is an optionally substituted aryl group selected from the group consisting of phenyl or naphthyl
  • a 2 is an optionally substituted carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl, pyrrolidinyl,
  • Additional preferred compounds within Formula I include those compounds 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 2 is an optionally substituted heteroaryl or aryl group 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 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 2 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.
  • A is an optionally substituted, saturated or partially unsaturated carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, pipe
  • Exemplary preferred compounds that may be employed in this method of invention include, without limitation: 1 -(4-phenoxybenzyl)semicarbazide; l-(4-(4-fluorophenoxy)benzyl)semicarbazide; l-(4-(4-chlorophenoxy)benzyl)semicarbazide; l-(4-(4-bromophenoxy)benzy)lsemicarbazide; l-(4-(4-methoxyphenoxy)benzyl)semicarbazide; 1 -(4-(4-trifluoromethy lphenoxy )benzy l)semicarbazide ; l-(4-(4-methylphenoxy)benzyl)semicarbazide; l-(4-(3,4-difluorophenoxy)benzyl)semicarbazide; l-(4-(4-chloro-2-fluorophenoxy)benzyl)se
  • 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 compounds of Formula I 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.
  • 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.
  • preferred substituted semicarbazides are represented by Formulae II- VI.
  • a preferred embodiment is represented by Formulae II:
  • Rute R 2 , R 3 , R 4 , R 5 , Ro, X, n and m are as defined previously with respect to Formula I; and Kg, R, 0 , R, i and R 12 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, hetroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkyl
  • R-, and R 10 or R ⁇ and R I2 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle.
  • Examples of bridges formed by R, and R 10 or R, , and R 12 taken together are — OCH 2 O— , — OCF 2 O— , — (CH 2 ) 3 — , — (CH 2 ) 4 — , — OCH 2 CH 2 O— , — CH 2 N(R 18 )CH — , — CH 2 CH 2 N(R 18 )CH 2 — ,
  • R 18 is hydrogen, alkyl or cycloalkyl
  • R 13 , R 14 , R 15 , R 16 and R 17 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, hetroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or one of R 13 and R 14 , or R 14 and R 15 , or R I5 and R, 6 , or R, 6 and R
  • R R ⁇ , R 9 -R 12 , R 13 -R 17 , n, m, A,, A 2 and X are as defined previously with respect to Formulae I and II;
  • Preferred compounds within Formula III include those compounds where A 2 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.
  • Preferred compounds within Formula IV include those compounds 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.
  • R,-R 6 , R 13 -R 17 , n, m and X are as defined previously with respect to Formulae I and II;
  • B is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle
  • B 2 is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle.
  • Preferred B, and B 2 independently include cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl.
  • preferred compounds of Formulae I- VI are those compounds where R, and R 2 is hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, and where
  • R 3 and R 4 are independently hydrogen or C,. 4 alkyl.
  • Preferred values of X in Formulae I- VI are O.
  • R j -Rg with respect to Formulae I- VI are hydrogen or C M alkyl.
  • R 13 -R 17 , with respect to Formulae II- VI include hydrogen, halo, C,-C 6 haloalkyl, C 6 -C 10 aryl, C 4 -C 7 cycloalkyl, C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl(C r C 6 )alkyl, C 6 -C 10 aryl(C 2 -C 6 )alkenyl, C 6 -C I0 aryl(C 2 -C 6 )alkynyl, C,-C 6 hydroxyalkyl, nitro, amino, ureido, cyano, C,-C 6 acylamido, hydroxy, thiol, C,-C 6 acyloxy, azido, C,-C 6 alkoxy
  • an additional preferred subset of substituted semicarbazides includes compounds of
  • A, and A 2 are phenyl moieties, that are each independently substituted by one or two substituents independently selected from the group consisting of hydrogen, halogen, C,. 6 alkyl, C 3 . 8 cycloalkyl, cyano, C,. 6 alkoxy or C 6.I0 aryloxy;
  • R, and R 2 is hydrogen, C,_ 6 alkyl, or C 3 . 8 cycloalkyl;
  • R 3 and R 4 is hydrogen, or C,. 6 alkyl;
  • X is O; n and m is 0.
  • Useful compounds in this aspect of the present invention include: 1 -(4-phenoxybenzyl)semicarbazide; l-(4-(4-fluorophenoxy)benzyl)semicarbazide; l-(4-(4-chlorophenoxy)benzyl)semicarbazide; l-(4-(4-bromophenoxy)benzyl)semicarbazide; l-(4-(4-methoxyphenoxy)benzyl)semicarbazide; 1 -(4-(4-trifluoromethylphenoxy)benzyl)semicarbazide; l-(4-(4-methylphenoxy)benzyl)semicarbazide;
  • Useful aryl groups are C 6 . 14 aryl, especially C 6 . 10 aryl.
  • Typical C 6.14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • Useful cycloalkyl groups are C 3 . 8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and cycloheptyl. Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as defined above, cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl, bicycloalkyl groups such as norbornyl groups, as well as tetrahydronaphthyl and indanyl groups. Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
  • Useful alkyl groups include straight-chained and branched C 0 alkyl groups, more preferably C ] . 6 alkyl groups.
  • Typical C 0 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, .see-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 compounds of the invention.
  • Useful alkenyl groups are C 2 . 6 alkenyl groups, preferably C 2 ⁇ alkenyl.
  • Typical C 2 . 4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.
  • Useful alkynyl groups are C 2 . 6 alkynyl groups, preferably C 2 ⁇ alkynyl.
  • Typical C2.4 alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups.
  • Useful arylalkyl groups include any of the above-mentioned C M0 alkyl groups substituted by any of the above-mentioned C 6 ., 4 aryl groups. Useful values include benzyl, phenethyl and naphthylmethyl.
  • Useful arylalkenyl groups include any of the above-mentioned C 2 . 4 alkenyl groups substituted by any of the above-mentioned C 6 . 14 aryl groups.
  • Useful arylalkynyl groups include any of the above-mentioned C 2 . 4 alkynyl groups substituted by any of the above-mentioned C 6 ., 4 aryl groups. Useful values include phenylethynyl and phenylpropynyl.
  • Useful cycloalkylalkyl groups include any of the above-mentioned C,. 10 alkyl groups substituted by any of the above-mentioned cycloalkyl groups.
  • Useful haloalkyl groups include C,. 10 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 C,. 10 alkyl groups substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.
  • Useful alkoxy groups include oxygen substituted by one of the C 0 alkyl groups mentioned above.
  • Useful alkylthio groups include sulphur substituted by one of the C, . , 0 alkyl groups mentioned above.
  • Useful acylamino groups are any C,. 6 acyl (alkanoyl) attached to an amino nitrogen, e.g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as aryl-substituted C2-6 substituted acyl groups.
  • Useful acyloxy groups are any C,_ 6 acyl (alkanoyl) attached to an oxy (-O-) 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 0 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
  • heteroaryl group contains a nitrogen atom in a ring
  • 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 C I _JQ alkyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Useful heteroarylalkenyl groups include any of the above-mentioned C2.4 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Useful heteroarylalkynyl groups include any of the above-mentioned C2.4 alkynyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Useful amino groups include -NH2, -NHR 14 , and -NR I4 R 15 , wherein R 14 and
  • R 15 are Cj_10 alkyl or cycloalkyl groups as defined above.
  • Useful aminocarbonyl groups are carbonyl groups substituted by — NH 2 , — NHR, 4 , and — NR 14 R 15 , wherein R 14 and R 15 are C, .10 alkyl groups.
  • Optional substituents on any of the aryl, heterocyclic, heteroaryl, and cycloalkyl rings in Formulae I-VI 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,
  • Certain of the compounds of Formula I may exist as optical isomers and the invention includes both the racemic mixtures of such optical isomers as well as the individual entantiomers that may be separated according to methods that are well know 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.
  • prodrugs include esters or amides of Formula I with as hydroxyalkyl or aminoalkyl, and these may be prepared by reacting such compounds with anhydrides such as succinic anhydride.
  • the invention is also directed to a method for treating disorders responsive to the blockade of sodium channels in animals suffering thereof.
  • Particular preferred embodiments of the substituted semicarbazides for use in method of this invention are represented by previously defined Formula I.
  • the compounds of this invention may be prepared using methods known to those skilled in the art, or by the novel methods of this invention.
  • Compounds with Formulae I-VI can be prepared as illustrated by exemplary reaction in Scheme 1 from reduction of the corresponding semicarbazones.
  • the compounds of the present invention were assessed by electrophysiological assays in dissociated hippocampal neurons for sodium channel blocker activity. These compounds also could be assayed for binding to the neuronal voltage- dependent sodium channel using rat forebrain membranes and [ 3 H]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 compounds herein described as specific Na + channel blockers. Based upon the discovery of this mechanism, these compounds 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 compounds are also expected to be useful as antiarrhythmics, anesthetics and antimanic depressants.
  • the present invention is directed to compounds of Formulae I that are blockers of voltage-sensitive sodium channels.
  • those compounds having preferred sodium channel blocking properties exhibit an IC50 of about 100 ⁇ M or less in the electrophysiological assay described herein.
  • the compounds of the present invention exhibit an IC50 of 10 ⁇ M or less.
  • the compounds of the present invention exhibit an IC50 of about 1.0 ⁇ M or less.
  • Substituted semicarbazides of the present invention may be tested for their Na + channel blocking activity by the following electrophysiological and binding assays.
  • HEK-293 cells stably expressing the hSkMl isoform of Na + channels were cultured using standard techniques, as described previously (Verdoorn, T.A, et al, Neuron 4:919-928 (1990)).
  • cells were plated onto 35 mm Petri dishes (pre-coated with poly-D-lysine) at a density of 1 :40 on the day of re-seeding from confluent cultures. Cells are suitable for recordings for 2-3 days after plating.
  • Patch-clamp recordings of voltage-sensitive Na + currents were made using conventional patch-clamp techniques (Hamill et al, Pfluegers Arch. 5 7:85-100 (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 the external solution (150 mM NaCl, 5.4 mM KC1, 1.8 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 10 mM glucose, pH 7.4 (NaOH)) at a speed of about 1 ml/min.
  • the external solution 150 mM NaCl, 5.4 mM KC1, 1.8 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 10 mM glucose, pH 7.4 (NaOH)
  • DMSO dimethylsulfoxide
  • I co ⁇ tro ⁇ is the maximal Na " current in the absence of antagonist
  • [compound] is the drug concentration
  • IC 50 is the concentration of compound that produces half maximal inhibition.
  • the binding assays were conducted in 130 ⁇ M choline chloride at 37°C for 60-minute incubation with [ 3 H] saxitoxin and [ 3 H] batrachotoxin as radioligands for site 1 and site 2, respectively.
  • the compounds of the present invention may be tested for in vivo anticonvulsant activity after iv. po 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 compounds may be tested for their neuroprotective activity after focal and global ischemia produced in rats or gerbils according to the procedures described in
  • the compounds may be tested for their neuroprotective activity after traumatic spinal cord injury according to the procedures described in Wrathall et. al. (Exp.
  • 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 its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the compounds 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, anesthetic, arrhythmia, manic depression, and pain.
  • the dose is generally about one-half of the oral dose.
  • the compound 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, 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.
  • the compounds 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 compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.
  • 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 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.
  • non-toxic pharmaceutically acceptable salts of the compounds of the present invention are also included within the scope 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 compounds of the invention. Foremost among such animals are mammals, e.g., humans, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes.
  • 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.
  • compositions 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.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds 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, hydroxy- propylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • 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,
  • 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.
  • 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.
  • cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate
  • 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 push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds 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.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may 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.
  • gelatin rectal 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.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active compounds 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 compounds are soluble in PEG-400).
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • MES electroshock-induced seizures
  • 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 observed for a period of up to 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.
  • l-[4-(4-Fluorophenoxy)benzyl] semicarbazide was administered iv to mice 10 min before the test procedure. The compound exhibited protection against MES with an ED 50 (the dose protecting 50% of animals) of 4.2 mg/kg.
  • l-[3-Fluoro-4-(4- fluorophenoxy)benzyl] semicarbazide was tested po in mice and was found to have an ED 50 of 3.2 mg/kg.
  • l-[4-(4-Fluorophenoxy)benzyl]semicarbazide was tested in the electrophysiological and binding assays described above and produced dose-dependent inhibition of voltage-gated sodium currents recorded HEK-293 cells stably expressing hSkMl sodium channels.
  • the blocking effect of this compound on Na * currents was highly sensitive to the holding voltage, indicating that l-[4-(4- fluorophenoxy)benzyl] semicarbazide 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. 40:156-165 (1991); Kuo and Bean, Mol.
  • the apparent antagonist dissociation constant (K d ) of this compound for inactivated sodium channels is -7.5 ⁇ M.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Anesthesiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Quinoline Compounds (AREA)
  • Furan Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

L'invention concerne des semicarbazides substitués représentés par la formule (I), un sel pharmaceutiquement acceptable ou un promédicament de ceux-ci. Dans cette formule, R1 et R2 représentent chacun indépendamment hydrogène, alkyle, cycloalkyle, alcényle, alcynyle, haloalkyle, aryle, aminoalkyle, hydroxyalkyle, alcoxyalkyle ou carboxyalkyle; R3, R4, R5 et R6 sont indépendamment hydrogène, alkyle, cycloalkyle, alcényle, alcynyle, haloalkyle, aryle, aminoalkyle, hydroxyalkyle, alcoxyalkyle ou carboxyalkyle; ou R3 et R4 sont définis comme susmentionnés, et R5 et R6 forment ensemble avec l'atome d'azote auquel ils sont attachés un hétérocycle comprenant pipéridine, pipérazine, morpholine; A1 et A2 représentent indépendamment aryle, hétéroaryle, cyclocarbone saturé ou partiellement non saturé ou hétérocycle saturé ou partiellement non saturé, l'un quelconque étant éventuellement substitué. X représente l'un de O, S, NR7, CH2, C(O), NR7C(O), C(O)NR7, SO, SO2 ou une liaison covalente; où R7 est hydrogène, alkyle, cycloalkyle, alcényle, alcynyle, haloalkyle, aryle, aminoalkyle, hydroxyalkyle, alcoxyalkyle ou carboxyalkyle; n est 0, 1, 2 ou 3. m est 0, 1, 2 ou 3. L'invention concerne également l'utilisation des semicarbazides substitués pour traiter les lésions neuronales consécutives à une ischémie globale ou focale, pour traiter ou prévenir des états neurodégénératifs tels que la sclérose latérale amyotrophique (ALS), pour traiter, prévenir ou améliorer une douleur chronique ou aiguë et pour traiter ou prévenir la neuropathie diabétique. Ces semicarbazides sont notamment des anesthésiques locaux, des dépresseurs anti-maniaco-dépressifs, des médicaments antimigraineux, des anesthésiques locaux, des antiarythmiques.
PCT/US1999/002419 1998-02-04 1999-02-04 Semicarbazides substitues et leur utilisation WO1999039712A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP99905734A EP1058550A4 (fr) 1998-02-04 1999-02-04 Semicarbazides substitues et leur utilisation
US09/601,698 US6281211B1 (en) 1999-02-04 1999-02-04 Substituted semicarbazides and the use thereof
MXPA00007585A MXPA00007585A (es) 1998-02-04 1999-02-04 Semicarbazidas substituidas y el uso de las mismas.
AU25831/99A AU754681B2 (en) 1998-02-04 1999-02-04 Substituted semicarbazides and the use thereof
IL13767199A IL137671A0 (en) 1998-02-04 1999-02-04 Semicarbazide derivatives and pharmaceutical compositions containing the same
CA002319484A CA2319484A1 (fr) 1998-02-04 1999-02-04 Semicarbazides substitues et leur utilisation
JP2000530210A JP2002511387A (ja) 1998-02-04 1999-02-04 置換セミカルバジドおよびその使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7371098P 1998-02-04 1998-02-04
US60/073,710 1998-02-04

Publications (2)

Publication Number Publication Date
WO1999039712A1 WO1999039712A1 (fr) 1999-08-12
WO1999039712A9 true WO1999039712A9 (fr) 1999-10-21

Family

ID=22115328

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/002419 WO1999039712A1 (fr) 1998-02-04 1999-02-04 Semicarbazides substitues et leur utilisation

Country Status (7)

Country Link
EP (1) EP1058550A4 (fr)
JP (1) JP2002511387A (fr)
AU (1) AU754681B2 (fr)
CA (1) CA2319484A1 (fr)
IL (1) IL137671A0 (fr)
MX (1) MXPA00007585A (fr)
WO (1) WO1999039712A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA00004919A (es) 1997-11-21 2002-10-17 Euro Celtique Sa 2-aminoacetamidas sustituidas y uso de las mismas.
GB9727523D0 (en) 1997-12-31 1998-02-25 Pharmacia & Upjohn Spa Alpha-aminoamide derivatives useful as analgesic agents
EP1115389B1 (fr) 1998-09-25 2014-03-12 PhilERA New Zealand Limited Fructosamine-oxydase: antagonistes et inhibiteurs
WO2000018891A1 (fr) 1998-09-25 2000-04-06 Glycox Corporation Limited Dosage de fructosamine-oxydase: procedes et substances
US6281211B1 (en) 1999-02-04 2001-08-28 Euro-Celtique S.A. Substituted semicarbazides and the use thereof
JP2002541215A (ja) 1999-04-09 2002-12-03 ユーロ−セルティック エス． ア． ナトリウムチャネル遮断薬組成物およびその使用
GB0002666D0 (en) 2000-02-04 2000-03-29 Univ London Blockade of voltage dependent sodium channels
EP1423168B1 (fr) 2001-09-03 2006-02-08 Newron Pharmaceuticals S.p.A. Composition pharmaceutique comprenant de la gabapentine ou un analogue de celle-ci et un alpha-aminoamide, et utilisation analgesique de ladite composition
CN1649577A (zh) 2002-03-08 2005-08-03 普罗特米克斯公司 预防和/或治疗心血管疾病和/或相关的心衰
CA2496411A1 (fr) 2002-08-20 2004-03-04 Protemix Corporation Limited Formes posologiques et traitements s'y rapportant
EP1438956A1 (fr) 2003-01-16 2004-07-21 Newron Pharmaceuticals S.p.A. Dérivés alpha-aminoamides en tant qu'agents antimigraine
EP1778618B1 (fr) 2004-07-19 2013-12-25 PhilERA New Zealand Limited Synthese de triethylenetetramines
PH12013501258A1 (en) 2010-12-22 2013-08-28 Purdue Pharma Lp Substituted pyridines as sodium channel blockers
AU2012324010A1 (en) 2011-10-31 2013-05-16 Purdue Pharma L.P. Heteroaryl compounds as sodium channel blockers

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH480308A (de) * 1966-08-11 1969-10-31 Ciba Geigy Verfahren zur Herstellung von Thiosemicarbazid-Verbindungen
BE706907A (fr) * 1966-11-24 1968-04-01
US4866173A (en) * 1982-09-22 1989-09-12 Rorer Pharmaceutical Corporation Therapeutic substituted semicarbazides
EP0144853B1 (fr) * 1983-11-21 1990-09-26 Fujisawa Pharmaceutical Co., Ltd. Dérivés semicarbazides, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4694004A (en) * 1984-07-09 1987-09-15 Fujisawa Pharmaceutical Co., Ltd. Semicarbazide derivatives, processes for preparation thereof and pharmaceutical composition comprising the same
US5741818A (en) * 1995-06-07 1998-04-21 University Of Saskatchewan Semicarbazones having CNS activity and pharmaceutical preparations containing same

Also Published As

Publication number Publication date
EP1058550A1 (fr) 2000-12-13
AU2583199A (en) 1999-08-23
MXPA00007585A (es) 2002-10-17
CA2319484A1 (fr) 1999-08-12
JP2002511387A (ja) 2002-04-16
WO1999039712A1 (fr) 1999-08-12
AU754681B2 (en) 2002-11-21
IL137671A0 (en) 2001-10-31
EP1058550A4 (fr) 2002-12-18

Similar Documents

Publication Publication Date Title
US6281211B1 (en) Substituted semicarbazides and the use thereof
US6479484B1 (en) Substituted 2-aminoacetamides and the use thereof
EP0986540B1 (fr) L'utilisation des semicarbazones et thiosemicarbazones carbocycliques et heterocycliques substitues comme agents bloquants du canal sodique
AU754681B2 (en) Substituted semicarbazides and the use thereof
EP1568690A1 (fr) Semicarbazones et thiosemicarbazones carbocycliques et heterocycliques substitues utiles comme agents bloquants du canal sodique
MXPA99009660A (en) Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: C2

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: C2

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

COP Corrected version of pamphlet

Free format text: PAGES 1-24, DESCRIPTION, REPLACED BY NEW PAGES 1-24; PAGES 25-34, CLAIMS, REPLACED BY NEW PAGES 25-34; DUE TO LATE TRANSMITTAL BY THE RECEIVING OFFICE

ENP Entry into the national phase

Ref document number: 2319484

Country of ref document: CA

Ref country code: CA

Ref document number: 2319484

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 25831/99

Country of ref document: AU

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 530210

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/007585

Country of ref document: MX

Ref document number: 137671

Country of ref document: IL

NENP Non-entry into the national phase

Ref country code: KR

WWE Wipo information: entry into national phase

Ref document number: 1999905734

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 09601698

Country of ref document: US

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1999905734

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 25831/99

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 1999905734

Country of ref document: EP