JPH07108881B2 - バルプロ酸または（ｅ）―２―バルプロ酸誘導体、それらの製造法ならびにそれらを含有する抗てんかん剤または抗けいれん剤 - Google Patents
バルプロ酸または（ｅ）―２―バルプロ酸誘導体、それらの製造法ならびにそれらを含有する抗てんかん剤または抗けいれん剤Info
- Publication number
- JPH07108881B2 JPH07108881B2 JP62153215A JP15321587A JPH07108881B2 JP H07108881 B2 JPH07108881 B2 JP H07108881B2 JP 62153215 A JP62153215 A JP 62153215A JP 15321587 A JP15321587 A JP 15321587A JP H07108881 B2 JPH07108881 B2 JP H07108881B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- general formula
- ethyl
- pivaloyloxyethyl
- formula
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
Links
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 229960000604 valproic acid Drugs 0.000 title claims abstract description 27
- 239000001961 anticonvulsive agent Substances 0.000 title claims description 15
- 229960003965 antiepileptics Drugs 0.000 title claims description 10
- 230000001773 anti-convulsant effect Effects 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 239000002253 acid Substances 0.000 claims abstract description 15
- -1 (2-propyl-pentanoyloxy) -methyl Chemical group 0.000 claims description 44
- 239000007858 starting material Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 8
- 125000005633 phthalidyl group Chemical group 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 239000007903 gelatin capsule Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical group OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims 2
- NFHXOQDPQIQPKT-XBWDGYHZSA-N (3'ar,4s,7's,7'as)-2,2,2',2'-tetramethylspiro[1,3-dioxolane-4,6'-3a,4,7,7a-tetrahydro-[1,3]dioxolo[4,5-c]pyran]-7'-ol Chemical compound C([C@H]1OC(O[C@H]1[C@@H]1O)(C)C)O[C@@]21COC(C)(C)O2 NFHXOQDPQIQPKT-XBWDGYHZSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 230000002082 anti-convulsion Effects 0.000 abstract description 6
- ZKNJEOBYOLUGKJ-FNORWQNLSA-N 2-n-Propyl-2-pentenoic acid Chemical compound CCC\C(C(O)=O)=C/CC ZKNJEOBYOLUGKJ-FNORWQNLSA-N 0.000 abstract description 5
- 150000002148 esters Chemical class 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 230000003556 anti-epileptic effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 36
- 230000000694 effects Effects 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 230000002920 convulsive effect Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910001619 alkaline earth metal iodide Inorganic materials 0.000 description 2
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- YIYBQIKDCADOSF-UHFFFAOYSA-N alpha-Butylen-alpha-carbonsaeure Natural products CCC=CC(O)=O YIYBQIKDCADOSF-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000001037 epileptic effect Effects 0.000 description 2
- 238000004508 fractional distillation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 235000014380 magnesium carbonate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- YIYBQIKDCADOSF-ONEGZZNKSA-N trans-pent-2-enoic acid Chemical compound CC\C=C\C(O)=O YIYBQIKDCADOSF-ONEGZZNKSA-N 0.000 description 2
- BVPDSBPYJMUZSF-FNORWQNLSA-N (e)-2-propylpent-2-enoyl chloride Chemical compound CCC\C(C(Cl)=O)=C/CC BVPDSBPYJMUZSF-FNORWQNLSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- TWYIPMITVXPNEM-UHFFFAOYSA-N 1-(2-hydroxyethyl)pyrrolidine-2,5-dione Chemical compound OCCN1C(=O)CCC1=O TWYIPMITVXPNEM-UHFFFAOYSA-N 0.000 description 1
- ZIJGGSZJPPURSY-UHFFFAOYSA-N 1-ethoxycarbonyloxyethyl 2-propylpentanoate Chemical compound CCCC(CCC)C(=O)OC(C)OC(=O)OCC ZIJGGSZJPPURSY-UHFFFAOYSA-N 0.000 description 1
- OXIWKZICMMWPTE-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-propylpent-2-enoate Chemical compound CCCC(=CCC)C(=O)OCOC(=O)C(C)(C)C OXIWKZICMMWPTE-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VIRWKAJWTKAIMA-UHFFFAOYSA-N 2-chloroethyl acetate Chemical compound CC(=O)OCCCl VIRWKAJWTKAIMA-UHFFFAOYSA-N 0.000 description 1
- HUWWTMMDDJPISS-UHFFFAOYSA-N 2-propan-2-ylpent-2-enoic acid Chemical compound CCC=C(C(C)C)C(O)=O HUWWTMMDDJPISS-UHFFFAOYSA-N 0.000 description 1
- ZKNJEOBYOLUGKJ-UHFFFAOYSA-N 2-propyl-2-pentenoic acid Chemical compound CCCC(C(O)=O)=CCC ZKNJEOBYOLUGKJ-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- WPRYUWYMOZQHIY-UHFFFAOYSA-N methyl 2-propylpentanoate Chemical compound CCCC(CCC)C(=O)OC WPRYUWYMOZQHIY-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- OTTYFDRFBJPGRW-UHFFFAOYSA-N pent-2-enoyl chloride Chemical compound CCC=CC(Cl)=O OTTYFDRFBJPGRW-UHFFFAOYSA-N 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- GNPDWINWHAJSCR-UHFFFAOYSA-L tetrabutylazanium sulfate hydrate Chemical compound S(=O)(=O)(O)[O-].[OH-].C(CCC)[N+](CCCC)(CCCC)CCCC.C(CCC)[N+](CCCC)(CCCC)CCCC GNPDWINWHAJSCR-UHFFFAOYSA-L 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- DJEFRLDEQKSNLM-UHFFFAOYSA-N valproate pivoxil Chemical compound CCCC(CCC)C(=O)OCOC(=O)C(C)(C)C DJEFRLDEQKSNLM-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D317/34—Oxygen atoms
- C07D317/40—Vinylene carbonate; Substituted vinylene carbonates
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (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)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20846A/86 | 1986-06-19 | ||
| IT20846/86A IT1190133B (it) | 1986-06-19 | 1986-06-19 | Derivati di acido valproico e di acido (e)-2-valproenoico,procedimento per la loro preparazione e relative composizioni farmaceutiche |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6366153A JPS6366153A (ja) | 1988-03-24 |
| JPH07108881B2 true JPH07108881B2 (ja) | 1995-11-22 |
Family
ID=11172940
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62153215A Expired - Lifetime JPH07108881B2 (ja) | 1986-06-19 | 1987-06-18 | バルプロ酸または（ｅ）―２―バルプロ酸誘導体、それらの製造法ならびにそれらを含有する抗てんかん剤または抗けいれん剤 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5162573A (enExample) |
| EP (1) | EP0250997B1 (enExample) |
| JP (1) | JPH07108881B2 (enExample) |
| AT (1) | ATE74900T1 (enExample) |
| CA (1) | CA1331186C (enExample) |
| DE (1) | DE3778219D1 (enExample) |
| ES (1) | ES2032405T3 (enExample) |
| GR (1) | GR3004712T3 (enExample) |
| IT (1) | IT1190133B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101864085B1 (ko) * | 2017-09-22 | 2018-06-01 | 동아대학교 산학협력단 | 발프로산 유도체, 이의 제조방법 및 이를 포함하는 항경련제 |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2627487B1 (fr) * | 1988-02-19 | 1991-03-29 | Martin Laboratoires | Nouveau derive de l'acide valproique, procede de preparation de ce compose ainsi que medicament antiepileptique le contenant |
| US5585358A (en) * | 1993-07-06 | 1996-12-17 | Yissum Research Development Corporation Of The Hebrew University Of Jerusalem | Derivatives of valproic acid amides and 2-valproenoic acid amides, method of making and use thereof as anticonvulsant agents |
| US5939455A (en) * | 1997-03-11 | 1999-08-17 | Beacon Laboratories, Inc. | Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives |
| US6110955A (en) * | 1997-03-11 | 2000-08-29 | Beacon Laboratories, Inc. | Metabolically stabilized oxyalkylene esters and uses thereof |
| JP2004520263A (ja) | 2000-07-21 | 2004-07-08 | テバ ファーマシューティカル インダストリーズ リミティド | 双極性障害における躁病を治療するためのバルプロ酸および２−バルプロエン酸アミド誘導体の使用 |
| US6720445B2 (en) * | 2000-12-21 | 2004-04-13 | Beacon Laboratories, Inc. | Acetyloxymethyl esters and methods for using the same |
| CA2478093A1 (en) | 2002-02-28 | 2003-09-12 | A & D Bioscience, Inc. | Glycuronamides, glycosides and orthoester glycosides of fluoxetine, analogs and uses thereof |
| US20050107310A1 (en) * | 2002-03-19 | 2005-05-19 | Holick Michael F. | Carboxylic acid glycuronides, glycosamides and glycosides of quinolones, penicillins, analogs, and uses thereof |
| US20050255038A1 (en) * | 2002-04-12 | 2005-11-17 | A And D Bioscience, Inc. | Conjugates comprising cancer cell specific ligands, a sugar and diagnostic agents and uses thereof |
| EP1549323A2 (en) * | 2002-05-07 | 2005-07-06 | A & D Bioscience, Inc. | Conjugates comprising central nervous system active drug |
| US20050215487A1 (en) * | 2002-06-27 | 2005-09-29 | Holick Michael F | Conjugates comprising an nsaid and a sugar and uses thereof |
| US20040191803A1 (en) | 2002-11-22 | 2004-09-30 | Michela Gallagher | Target for therapy of cognitive impairment |
| US7459280B2 (en) * | 2006-02-27 | 2008-12-02 | Picobella, Llc | Methods for diagnosing and treating kidney cancer |
| US20080267977A1 (en) * | 2007-04-26 | 2008-10-30 | Friedrich-Alexander University Of Erlangen-Nuremberg | Combined immunological agent and sensitizing agent for the treatment of cancer |
| ES2865504T3 (es) | 2008-10-16 | 2021-10-15 | Univ Johns Hopkins | Procedimientos y composiciones para la mejora de la función cognitiva |
| US8921533B2 (en) | 2011-07-25 | 2014-12-30 | Chromatin Technologies | Glycosylated valproic acid analogs and uses thereof |
| CA2872976A1 (en) * | 2012-05-08 | 2013-11-14 | Cellixbio Private Limited | Compositions and methods for the treatment of neurological disorders |
| US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
| US10806717B2 (en) | 2013-03-15 | 2020-10-20 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
| JP6433482B2 (ja) | 2013-03-15 | 2018-12-05 | エージンバイオ， インコーポレイテッド | 認知機能を改善するための方法および組成物 |
| AU2016268096B2 (en) | 2015-05-22 | 2021-04-01 | Agenebio, Inc. | Extended release pharmaceutical compositions of levetiracetam |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3953449A (en) | 1973-05-09 | 1976-04-27 | Synthelabo | 2-(4-M-CF3 or -SCF3 phenylpiperazino)-ethyl benzoates |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES403631A1 (es) * | 1972-06-08 | 1975-05-01 | Made Labor Sa | Un metodo de obtencion de dos esteres de n-(2-hidroxietil)-pirrolidina. |
| IT1061352B (it) * | 1973-03-27 | 1983-02-28 | Crinos Industria Farmaco | Sali misti di esteri polisolforici di glicopeptidi naturali con metalli e con basi organiche e procedimento per la loro preparazione |
| FI783743A7 (fi) * | 1977-12-14 | 1979-06-15 | Gerot Pharmazeutika | Foerfarande foer framstaellning av 3-di-n-propyl-acetoxi-benzodiazepin-2-oner |
| IL59407A (en) * | 1979-03-06 | 1983-12-30 | Sanofi Sa | Di-n-propylacetic acid diesters of glycerol,their preparation and pharmaceutical compositions containing them |
| US4654370A (en) * | 1979-03-12 | 1987-03-31 | Abbott Laboratories | Glyceryl valproates |
| IT1121282B (it) * | 1979-06-08 | 1986-04-02 | Medea Res Srl | Composto ad attivita'antiepilettica e anticonvulsivante,processo per la sua preparazione e composizioni farmaceutiche relative |
| AT365164B (de) * | 1980-06-04 | 1981-12-28 | Lagap S A Pharmaceuticals | Verfahren zur herstellung des neuen pivaloyloxymethyl-2-propylpentanoats |
| IL67623A (en) * | 1983-01-05 | 1984-09-30 | Teva Pharma | 1'-ethoxycarbonyloxyethyl ester of valproic acid,its preparation and pharmaceutical compositions containing it |
| IT1194343B (it) * | 1983-07-26 | 1988-09-14 | Valeas Spa | Sali di endo-8,8-dialchil-8-azoniabiciclo (3.2.1) ottan-6,7-esso-epossi-3-alchilcarbossilati,processo per la loro preparazione e composizioni terapeutiche che li contengono come principio attivo |
| JPH0713028B2 (ja) * | 1986-03-31 | 1995-02-15 | 日東電工株式会社 | 外皮投与用組成物 |
-
1986
- 1986-06-19 IT IT20846/86A patent/IT1190133B/it active
-
1987
- 1987-06-13 EP EP87108550A patent/EP0250997B1/en not_active Expired - Lifetime
- 1987-06-13 DE DE8787108550T patent/DE3778219D1/de not_active Expired - Lifetime
- 1987-06-13 ES ES198787108550T patent/ES2032405T3/es not_active Expired - Lifetime
- 1987-06-13 AT AT87108550T patent/ATE74900T1/de not_active IP Right Cessation
- 1987-06-17 US US07/063,643 patent/US5162573A/en not_active Expired - Lifetime
- 1987-06-18 CA CA000540031A patent/CA1331186C/en not_active Expired - Fee Related
- 1987-06-18 JP JP62153215A patent/JPH07108881B2/ja not_active Expired - Lifetime
-
1992
- 1992-05-26 GR GR920401052T patent/GR3004712T3/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3953449A (en) | 1973-05-09 | 1976-04-27 | Synthelabo | 2-(4-M-CF3 or -SCF3 phenylpiperazino)-ethyl benzoates |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101864085B1 (ko) * | 2017-09-22 | 2018-06-01 | 동아대학교 산학협력단 | 발프로산 유도체, 이의 제조방법 및 이를 포함하는 항경련제 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA1331186C (en) | 1994-08-02 |
| ES2032405T3 (es) | 1993-02-16 |
| IT8620846A0 (it) | 1986-06-19 |
| ATE74900T1 (de) | 1992-05-15 |
| EP0250997A3 (en) | 1988-12-14 |
| EP0250997B1 (en) | 1992-04-15 |
| IT8620846A1 (it) | 1987-12-19 |
| JPS6366153A (ja) | 1988-03-24 |
| DE3778219D1 (de) | 1992-05-21 |
| US5162573A (en) | 1992-11-10 |
| IT1190133B (it) | 1988-02-10 |
| GR3004712T3 (enExample) | 1993-04-28 |
| EP0250997A2 (en) | 1988-01-07 |
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