ZA200104037B - Use of anticonvulsant derivatives for treating alcohol dependency. - Google Patents
Use of anticonvulsant derivatives for treating alcohol dependency. Download PDFInfo
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- ZA200104037B ZA200104037B ZA200104037A ZA200104037A ZA200104037B ZA 200104037 B ZA200104037 B ZA 200104037B ZA 200104037 A ZA200104037 A ZA 200104037A ZA 200104037 A ZA200104037 A ZA 200104037A ZA 200104037 B ZA200104037 B ZA 200104037B
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims description 25
- 230000001773 anti-convulsant effect Effects 0.000 title description 3
- 239000001961 anticonvulsive agent Substances 0.000 title description 3
- 229960003965 antiepileptics Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 claims description 9
- -1 methylenedioxy group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 229960004394 topiramate Drugs 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 206010012335 Dependence Diseases 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000002009 alkene group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 206010010904 Convulsion Diseases 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 5
- 208000007848 Alcoholism Diseases 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 206010015037 epilepsy Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-M chlorosulfate Chemical compound [O-]S(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-M 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 201000009032 substance abuse Diseases 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000033001 Complex partial seizures Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010040703 Simple partial seizures Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 206010001584 alcohol abuse Diseases 0.000 description 2
- 208000025746 alcohol use disease Diseases 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960002737 fructose Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 2
- WJXREUZUPGMAII-UHFFFAOYSA-N sulfurazidic acid Chemical compound OS(=O)(=O)N=[N+]=[N-] WJXREUZUPGMAII-UHFFFAOYSA-N 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 206010001488 Aggression Diseases 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010063659 Aversion Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 101000687448 Homo sapiens REST corepressor 1 Proteins 0.000 description 1
- 101000703464 Homo sapiens SH3 and multiple ankyrin repeat domains protein 2 Proteins 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000037158 Partial Epilepsies Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100024864 REST corepressor 1 Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102100030680 SH3 and multiple ankyrin repeat domains protein 2 Human genes 0.000 description 1
- 229910006024 SO2Cl2 Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000011360 adjunctive therapy Methods 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 208000012761 aggressive behavior Diseases 0.000 description 1
- 208000029650 alcohol withdrawal Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- YUMNNMSNSLHINV-UHFFFAOYSA-N chloro sulfamate Chemical compound NS(=O)(=O)OCl YUMNNMSNSLHINV-UHFFFAOYSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000035863 hyperlocomotion Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000013759 synthetic iron oxide Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
Landscapes
- Health & Medical Sciences (AREA)
- Addiction (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
ANTICONVULSANT DERIVATIVES USEFUL IN TREATING ALCOHOL
DEPENDENCY, ADDICTION AND ABUSE
Compounds of Formula I:
X CH,0SO,NHR ~K
R2
Rs Rs are structurally novel antiepileptic compounds that are highly effective : anticonvulsants in animal tests (Maryanoff, B.E, Nortey, S.0,, Gardocki, J.F., Shank,
R.P. and Dodgson, S.P. J. Med. Chem. 30, 880-887, 1987; Maryanoff, B.E., Costanzo,
M.J.,, Shank, R.P., Schupsky, J.J., Ortegon, M.E., and Vaught J.L. Bioorganic &
Medicinal Chemistry Letters 3, 2653-2656, 1993). These compouhds are covered by
US Patent No.4,513,006. One of these compounds 2,3:4,5-bis-O-(1- ) methylethylidene)--D-fructopyranose sulfamate known as topiramate has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy . or as monotherapy in treating simple and complex partial seizures and secondarily generalized seizures (E. FAUGHT, B.J. WILDER, R.E. RAMSEY, R.A. REIFE, L D.
KRAMER, G.W. PLEDGER, R.M. KARIM et. al., Epilepsia 36 (S4) 33, 1995; S.K.
SACHDEOQ, R.C. SACHDEO, R.A. REIFE, P. LIM and G. PLEDGER, Epilepsia 36 (S84) 33, 1995), and is currently marketed for the treatment of simple and complex partial seizure epilepsy with or without secondary generalized seizures in approximately twenty countries including the United States, and applications for regulatory approval are presently pending in several additional countries throughout the world.
Compounds of Formula I were initially found to possess anticonvulsant activity in the traditional maximal electroshock seizure (MES) test in mice (SHANK, R.P.,
GARDOCKI, J.F.,, VAUGHT, J.L., DAVIS, C.B., SCHUPSKY, J.J., RAFFA, RB,
DODGSON, S.J, NORTEY, S.O., and MARYANOFF, B.E., Epilepsia 35 450-460, 1994). Subsequent studies revealed that Compounds of Formula I were also highly effective in the MES test in rats. More recently topiramate was found to effectively block seizures in several rodent models of epilepsy (J. NAKAMURA, S. TAMURA,
T. KANDA, A. ISHII, K. ISHIHARA, T. SERIKAWA, J. YAMADA, and M. SASA,
Eur. J. Pharmacol. 254 83-89, 1994), and in an animal model of kindled epilepsy (A.
WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77, 1996).
Preclinical studies on topiramate have revealed previously unrecognized pharmacological properties which suggest that topiramate will be effective in treating alcohol addiction and abuse. :
Accordingly, it has been found that compounds of the following formula I:
X. CH,0SO,NHR 20S0;
Ry
R;
Ra R3 ) wherein X is O or CH2, and R1, R2, R3, R4 and RS are as defined hereinafter are useful in treating alcohol addiction and abuse. ’
The sulfamates of the invention are of the following formula (I):
X CH,0SO,NHR
Ri—
Ra
Rj Rs wherein
X is CH2 or oxygen;
R] is hydrogen or alkyl; and
R2, R3, Rg and Rs are independently hydrogen or lower alkyl and, when X is CH),
R4 and R5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R2 and R3 and/or R4 and Rs together may be a methylenedioxy group of the following formula (II): \ ~~
C
/ - R7 \ o— wherein
Rg and R7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.
R1 in particular is hydrogen or alkyl of about 1 to 4 carbons, such as methyl, ethyl and iso-propyl. Alkyl throughout this specification includes straight and branched chain alkyl. Alkyl groups for R2, R3, R4, R35, Rg and R7 are of about 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl. When X is CH2, R4 and R5 may combine to form a benzene ring fused to the 6-membered X-containing ring, i.c., R4 and Rs are defined by the alkatrienyl group =C-CH=CH-CH=.
A particular group of compounds of formula (I) is that wherein X is oxygen and both
R2 and R3 and R4 and R$ together are methylenedioxy groups of the formula (II), wherein Rg and R7 are both hydrogen both alkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, in particular where Rg and R7 are both alkyl such as methyl. A second group of compounds is that wherein X is CH? and R4 and Rj are joined to form a benzene ring. A third group of compounds of formula (I) is that wherein both R2 and R3 are hydrogen.
The compounds of formula (I) may be synthesized by the following methods: (a) Reaction of an alcohol of the formula RCH72OH with a chlorosulfamate of the formula CISO2NH? or CISO2NHR] in the presence of a base such as potassium a- butoxide or sodium hydride at a temperature of about -20° to 25° C and in a solvent such as toluene, THF or dimethylformamide wherein R is a moiety of the following - formula (III):
X CH,0SO,NHR
Ry
R2
R; Rs; (b) Reaction of an alcohol of the formula RCH20H with sulfurylchloride of the formula SO2Cl2 in the presence of a base such as triethylamine or pyridine at a temperature of about -40° to 25° C in a solvent such as diethyl! ether or methylene chloride to produce a chlorosulfate of the formula RCH20S02Cl.
The chlorosulfate of the formula RCH20S0O2 Cl may then be reacted with an amine of the formula R]NH) at a temperature of abut 40° to 25° C in a solvent such as methylene chloride or acetonitrile to produce a compound of formula (I). The reaction conditions for (b) are also described by T. Tsuchiya et al. in Tet. Letters, No. 36, p. 3365 to 3368 (1978). (c) Reaction of the chlorosulfate RCH2OSO2Cl with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile yields an . azidosulfate of the formula RCH2OSO2N3 as described by M. Hedayatullah in Tet.
Lett. p. 2455-2458 (1975). The azidosulfate is then reduced to a compound of formula (I) wherein R] is hydrogen by catalytic hydrogenation, e.g. with a noble metal and H) or by heating with copper metal in a solvent such as methanol.
The starting materials of the formula RCH72OH may be obtained commercially or as known in the art. For example, starting materials of the formula RCH2OH wherein both R72 and R3 and R4 and Rs are identical and are of the formula (II) may be obtained by the method of R. F. Brady in Carbohydrate Research, Vol. 14, p. 35 to 40 (1970) or by reaction of the trimethylsilyl enol ether of a RCOR?7 ketone or aldehyde with fructose at a temperature of about 25° C, in a solvent such a halocarbon, e.g. methylene chloride in the presence of a protic acid such as hydrochloric acid or a
Lewis Acid such as zinc chloride. The trimethylsilyl enol ether reaction is described by G. L. Larson et al in J. Org. Chem. Volaa 38, No. 22, p. 3935 (1973). " Further, carboxylic acids and aldehydes of the formulae RCOOH and RCHO may be reduced to compounds of the formula RCH20H by standard reduction techniques, e.g. ‘reaction with lithium aluminum hydride, sodium borohydride or borane-THF complex in an inert solvent such a diglyme, THF or toluene at a temperature of about 0° to 100° C, e.g. as described by H.O. House in "Modem Synthetic Reactions”, 2nd Ed., pages 45 to 144 (1972).
The compounds of formula I: may also be made by the process disclosed in 5,387,700, which is incorporated by reference herein.
The compounds of formula I include the various individual isomers as well as the racemates thereof, e.g., the various alpha and beta attachments, i.e., below and above the plane of the drawing, of R2, R3, R4.and R5 on the 6-membered ring. Preferably, the oxygene of the methylenedioxy group (II) are attached on the same side of the 6- membered ring.
The activity of the compounds of formula I in treating alcohol dependency, addiction and abuse was evidenced in experimental research studies using a rat model of chronic intermittent ethanol (CIE) ingéstion to induce alcohol withdrawal signs. Withdrawal from abused substances like ethanol is typified experimentally in rodents by anxiety, aggressive behavior, hyperlocomotion, vocalization, aversion to handling, and seizure . susceptibility (E. Majchrowicz E, Psychopharmacologia 43, 245-254,1975). Chronic ethanol with repeated withdrawal in rats leads to a kindling-like condition with : } + persistently heightened withdrawal severity (N. Kokka, D. W. Sapp, A.M. Taylor and
R. W. Olsen, Alcohol: Clin Exp Res 17, 525-531, 1993). This experimentally induced condition has been termed the chronic intermittent ethanol (CIE) model of drug dependence. In CIE animals, the hippocampus is in a state of hypoinhibition due to a decrease in the functional properties of GABA, receptors (M. Kang, I. Spigelman, D.
W. Sapp and R. W. Olsen, Brain Res 709, 221-228, 1996). These observations suggest a connection between the effects of chronic intermittent ethanol, a reduced threshold to seizures induced by pentylenetetrazol (PTZ), and the inhibitory neurotransmitter GABA. In humans, alcohol dependency is due, in part, to alcohol- induced changes in the state of the brain that result in withdrawal signs and symptoms similar to those observed in CIE rats (REF). Therefore CIE in rats appears to be an appropriate model of alcohol dependency in humans. Consequently, compounds that reduce or prevent withdrawal signs in CIE rats would be expected to exert similar effects on withdrawal signs in humans with alcohol dependency. In the study on topiramate using CIE rats, the degree of ethanol-induced withdrawal was measured quantitatively by the degree to which the threshold for PTZ-induced seizures was reduced. When topiramate was administered to CIE rats (40 mg/kg, i.p.) 1 hr prior to tail vein injection of PTZ, the threshold for seizures was significantly higher than for
CIE rats treated with vehicle (P<0.05) and was essentially the same as for control rats chronically treated with saline rather than ethanol (The R.W. Johnson Pharmaceutical
Research Institute Document ID EDMS-USRA-2321301:3.0). Therefore, based on the threshold for PTZ-induced seizures as representative of ethanol withdrawal signs, topiramate essentially prevented this specific withdrawal sign in CIE rats. :
For treating alcohol dependency, addiction and abuse, a compound of formula (I) may : be employed at a daily dosage in the range of about 32 to 512 mg, usually in two divided doses, for an average adult human. A unit dose would contain about 16 to 128 mg of the active ingredient.
To prepare the pharmaceutical compositions of this invention, one or more sulfamate compounds of formula (I) are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for . administration, e.g., oral, by suppository, or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. Suppositories may be prepared, in which case cocoa butter could be used as the carrier. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed. Topiramate is currently available for oral administration in round tablets containing 25 mg, 100 mg or 200 mg
© WO 00/23059 SE PCT/US99/23769 ©) of active agent. The tablets contain the following inactive ingredients: lactose hydrous, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.
The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, . capsule, powder injection, teaspoonful, suppository and the like from about 25 to about 200 mg of the active ingredient. :
Claims (11)
1. Use of a compound of the formula I: X CH,0SO,NHR 2030; R, Raz wherein: X is CH, or oxygen; R; is hydrogen or alkyl; and Ry, R3, R4 and R4 are independently hydrogen or lower alkyl and, when X is CH», R4, and Rg may be alkene groups joined to form a benzene ring and, when X is oxygen, R, and R3 and/or Ry and R4 together may be a methylenedioxy group of the following formula (II): Re O = NN 7 Cc / CR No — wherein: Rg and Ry are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cylcopentyl or cyclohexyl ring, in the manufacture of a preparation for treating alcohol dependency, addiction and abuse by administering an effective amount of said preparation to a mammal.
2. Use according to claim 1 wherein the compound of formula I is topiramate. AMENDED SHEET
} ¥ PCT/US99/30484
3. Use according to claim 1, wherein the effective amount is of from about 32 to 512 mg.
4. Use according to claim 1, wherein the amount is of from about 16 to 128 mg.
5. A substance or composition for use in a method for treating alcohol dependency, addiction and abuse, said substance or composition comprising a compound of the formula I: X CH,0SO,NHR Ri Raz R4 Ra wherein: : X is CH, or oxygen; R is hydrogen or alkyl; and Rs, Ry, Ry and Rq are independently hydrogen or lower alkyl and, when X is CH, Ry, and R5 may be alkene groups joined to form a benzene ring and, when X is oxygen, Ry and R4 and/or R,4 and Rs together may be a methylenedioxy group of the following formula (II): Rs o— AN Cc / A wherein: Rg and Ry are the same or different and are hydrogen, lower alkyl or are alkyl and AMENDED SHEET
PCT/US99/30484 are joined to form a cylcopentyl or cyclohexyl ring, and said method comprising administering to a mammal effective amounts of said substance or composition for treating such condition.
6. A substance or composition for use in a method of treatment according to claim 5, wherein the compound of formula I is topiramate.
7. A substance or composition for use in a method of treatment according to claim 5, wherein the effective amount is of from about 32 to 512 mg.
8. A substance or composition for use in a method of treatment according to claim 5, wherein the amount is of from about 16 to 128 mg.
9. A use according to claim 1, substantially as herein described and illustrated.
10. A substance or composition for use in a method of treatment according to claim 5, substantially as herein described and illustrated.
11. A new use of a compound as defined in claim 1, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
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US10488798P | 1998-10-20 | 1998-10-20 |
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ZA200104037A ZA200104037B (en) | 1998-10-20 | 2001-05-17 | Use of anticonvulsant derivatives for treating alcohol dependency. |
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JP (1) | JP2002527470A (en) |
AU (1) | AU759756B2 (en) |
BR (1) | BR9914722A (en) |
CA (1) | CA2348017C (en) |
MX (1) | MXPA01004015A (en) |
NO (1) | NO20011901D0 (en) |
NZ (1) | NZ511173A (en) |
WO (1) | WO2000023059A2 (en) |
ZA (1) | ZA200104037B (en) |
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US6890951B2 (en) | 1998-08-05 | 2005-05-10 | Brookhaven Science Associates Llc | Treatment of addiction and addiction-related behavior |
US6541520B1 (en) | 1998-08-05 | 2003-04-01 | Brookhaven Science Associates | Treatment of addiction and addiction-related behavior |
DE60019904T2 (en) * | 1999-02-24 | 2006-05-04 | University Of Cincinnati, Cincinnati | USE OF SULPHATE DERIVATIVES FOR THE TREATMENT OF IMPULSE CONTROL DISEASES |
CA2430010A1 (en) | 2000-11-30 | 2002-06-06 | University Of Florida | Treatments for neurogenetic disorders, impulse control disorders, and wound healing |
US6462084B1 (en) * | 2001-05-14 | 2002-10-08 | Brookhaven Science Associates, Llc | Treatment for obsessive-compulsive disorder (OCD) and OCD-related disorders using GVG |
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
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US4513006A (en) * | 1983-09-26 | 1985-04-23 | Mcneil Lab., Inc. | Anticonvulsant sulfamate derivatives |
US6541520B1 (en) * | 1998-08-05 | 2003-04-01 | Brookhaven Science Associates | Treatment of addiction and addiction-related behavior |
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1999
- 1999-10-18 MX MXPA01004015A patent/MXPA01004015A/en not_active Application Discontinuation
- 1999-10-18 WO PCT/US1999/023769 patent/WO2000023059A2/en active IP Right Grant
- 1999-10-18 BR BR9914722-0A patent/BR9914722A/en not_active Application Discontinuation
- 1999-10-18 CA CA002348017A patent/CA2348017C/en not_active Expired - Fee Related
- 1999-10-18 JP JP2000576834A patent/JP2002527470A/en active Pending
- 1999-10-18 AU AU13131/00A patent/AU759756B2/en not_active Ceased
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AU1313100A (en) | 2000-05-08 |
WO2000023059A2 (en) | 2000-04-27 |
BR9914722A (en) | 2001-07-10 |
NO20011901L (en) | 2001-04-18 |
MXPA01004015A (en) | 2003-03-10 |
JP2002527470A (en) | 2002-08-27 |
NZ511173A (en) | 2003-09-26 |
CA2348017A1 (en) | 2000-04-27 |
AU759756B2 (en) | 2003-05-01 |
WO2000023059A3 (en) | 2000-11-23 |
NO20011901D0 (en) | 2001-04-18 |
CA2348017C (en) | 2005-07-19 |
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