FR2690160A1 - Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives to the preparation of medicaments, new products, their preparation and the medicaments containing them. - Google Patents
Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives to the preparation of medicaments, new products, their preparation and the medicaments containing them. Download PDFInfo
- Publication number
- FR2690160A1 FR2690160A1 FR9204614A FR9204614A FR2690160A1 FR 2690160 A1 FR2690160 A1 FR 2690160A1 FR 9204614 A FR9204614 A FR 9204614A FR 9204614 A FR9204614 A FR 9204614A FR 2690160 A1 FR2690160 A1 FR 2690160A1
- Authority
- FR
- France
- Prior art keywords
- alk
- radical
- formula
- alkyl
- cooalk
- 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.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- AIARBUCVYFXSIS-UHFFFAOYSA-N 1,1-dioxo-4h-1$l^{6},2,4-benzothiadiazine-3-carboxylic acid Chemical class C1=CC=C2NC(C(=O)O)=NS(=O)(=O)C2=C1 AIARBUCVYFXSIS-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 9
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- -1 piperidino, morpholino Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 239000005557 antagonist Substances 0.000 claims description 6
- 102000003678 AMPA Receptors Human genes 0.000 claims description 5
- 108090000078 AMPA Receptors Proteins 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 150000003254 radicals Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims 1
- 241000220259 Raphanus Species 0.000 claims 1
- 235000006140 Raphanus sativus var sativus Nutrition 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 abstract description 3
- 239000002243 precursor Substances 0.000 abstract description 3
- 239000000775 AMPA receptor antagonist Substances 0.000 abstract description 2
- 229940098747 AMPA receptor antagonist Drugs 0.000 abstract description 2
- 229940099433 NMDA receptor antagonist Drugs 0.000 abstract description 2
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012429 reaction media Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QRKDOAWSBBGNLE-UHFFFAOYSA-N 2h-1,2,4-benzothiadiazine Chemical compound C1=CC=C2N=CNSC2=C1 QRKDOAWSBBGNLE-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- CEIMELGOEGZARD-UHFFFAOYSA-N 2-amino-4,6-dichlorobenzenesulfonamide Chemical compound NC1=CC(Cl)=CC(Cl)=C1S(N)(=O)=O CEIMELGOEGZARD-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010002660 Anoxia Diseases 0.000 description 2
- 241000976983 Anoxia Species 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 201000005505 Measles Diseases 0.000 description 2
- 208000001089 Multiple system atrophy Diseases 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- 208000005374 Poisoning Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010037742 Rabies Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 206010043376 Tetanus Diseases 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 230000007953 anoxia Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000001398 anti-anorexic effect Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002397 epileptogenic effect Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000003706 n methyl dextro aspartic acid receptor stimulating agent Substances 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000002581 neurotoxin Substances 0.000 description 2
- 231100000618 neurotoxin Toxicity 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940072033 potash Drugs 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 0 *c(cc1NC(*)=N2)c(*)c(*)c1[S+]2(O)=O Chemical compound *c(cc1NC(*)=N2)c(*)c(*)c1[S+]2(O)=O 0.000 description 1
- AOIYTIDHFMNVOO-UHFFFAOYSA-N 2,3,3a,4,5,6-hexahydro-1h-indene Chemical compound C1CCC=C2CCCC21 AOIYTIDHFMNVOO-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- YAZSBRQTAHVVGE-UHFFFAOYSA-N 2-aminobenzenesulfonamide Chemical compound NC1=CC=CC=C1S(N)(=O)=O YAZSBRQTAHVVGE-UHFFFAOYSA-N 0.000 description 1
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000212384 Bifora Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 241000566113 Branta sandvicensis Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010013647 Drowning Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100030852 Run domain Beclin-1-interacting and cysteine-rich domain-containing protein Human genes 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 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
- 230000002920 convulsive effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- LBKJNHPKYFYCLL-UHFFFAOYSA-N potassium;trimethyl(oxido)silane Chemical compound [K+].C[Si](C)(C)[O-] LBKJNHPKYFYCLL-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001749 primary amide group Chemical group 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011012 sanitization Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 201000000371 schizophrenia 5 Diseases 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- KEAYESYHFKHZAL-BJUDXGSMSA-N sodium-22 Chemical compound [22Na] KEAYESYHFKHZAL-BJUDXGSMSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure 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
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
APPLICATION DE DERIVES D'ACIDE 2H-1,2,4-BENZOTHIADIAZINE-1,1-
DIOXYDE-3- CARBOXYLIQUE A LA PREPARATION DE MEDICAMENTS,
LES PRODUITS NOUVEAUX, LEUR PREPARATION ET LES
MEDICAMENTS LES CONTENANT
La présente invention concerne l'application de dérivés d'acide 2H1 ,2,4-benzothiadiazine-1 ,1-dioxyde-3-carboxylique de formule:
un sel d'un tel composé ou un précurseur d'un tel composé à la préparation de médicaments antagonistes du récepteur NMDA et/ou du récepteur AMPA, les nouveaux composés de formule (I), leur préparation et les médicaments les contenant.APPLICATION OF 2H-1,2,4-BENZOTHIADIAZINE-1,1- ACID DERIVATIVES
DIOXIDE-3- CARBOXYLIC IN THE PREPARATION OF MEDICINES,
NEW PRODUCTS, THEIR PREPARATION AND THE
DRUGS CONTAINING THEM
The present invention relates to the application of 2H1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid derivatives of formula:
a salt of such a compound or a precursor of such a compound for the preparation of medicaments antagonists of the NMDA receptor and / or of the AMPA receptor, the new compounds of formula (I), their preparation and the medicaments containing them.
Certains dérivés de formule (I) ont déjà été décrits comme diurétiques (Russian Pharmacol. and Toxicol., 40, 19-23 (1977); Chem. Certain derivatives of formula (I) have already been described as diuretics (Russian Pharmacol. And Toxicol., 40, 19-23 (1977); Chem.
Abst., 99, 384399 (1983)).Abst., 99, 384399 (1983)).
Dans la formule (I), - R1 représente un radical carboxy, alcoxycarbonyle, tétrazolyle, -CO-NHOH, -CO-N(alk)OH, -CO-NH-O-alk, -CO-N(alk)-ORs ou un groupe convertible en radical carboxy in vivo, - R2, R3 et R4, identiques ou différents, représentent un atome d'hydrogène
ou d'halogène ou un radical alkyle,
- R5 représente un radical alkyle ou phénylalkyle et
- alk représente un radical alkylène ou alkyle.In formula (I), - R1 represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N (alk) -ORs radical or a group convertible into carboxy radical in vivo, - R2, R3 and R4, identical or different, represent a hydrogen atom
or halogen or an alkyl radical,
- R5 represents an alkyl or phenylalkyl radical and
- alk represents an alkylene or alkyl radical.
II est entendu que les composés de formule (I) peuvent également se
trouver sous leur forme tautomère:
find in their tautomeric form:
Comme groupes convertibles en radical carboxy in vivo, on peut citer les radicaux-CO-R8 dans lequel R6 représente un radical amino, alkylamino, dialkylam ino, -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R7, -O-aI k-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7 -O-alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-NR8R9, -NH-alk-O-CO-alk, -N H-alk-O-COOalk, -N H-alk-O-CO-R7, -N H-alk-OH, -NH-alk-O-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -N H-alk-COOalk, -WH-alk-NR8R9. As groups convertible into a carboxy radical in vivo, mention may be made of the radicals -CO-R8 in which R6 represents an amino, alkylamino, dialkylam ino radical, -O-alk-O-CO-alk, -O-alk-O-COOalk , -O-alk-O-CO-R7, -O-aI k-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O- alk-S-R7 -O-alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-NR8R9, -NH-alk-O-CO-alk, -N H-alk- O-COOalk, -N H-alk-O-CO-R7, -N H-alk-OH, -NH-alk-O-alk, -NH-alk-O-R7, -NH-alk-S-R7 , -NH-alk-COOH, -N H-alk-COOalk, -WH-alk-NR8R9.
Dans ces définitiOns, alk représente un radical alkylène ou alkyle, R7 est un radical phényle, R8 et Rg, identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle, phényle ou phénylalkyle ou bien forment avec l'atome d'azote auquel ils sont rattachés un cycle pipéridino, morpholino ou pyrrolidino. In these definitions, alk represents an alkylene or alkyl radical, R7 is a phenyl radical, R8 and Rg, identical or different, represent a hydrogen atom or an alkyl, phenyl or phenylalkyl radical or else form with the nitrogen atom to which they are attached a piperidino, morpholino or pyrrolidino cycle.
Les atomes d'halogène sont les atomes de chlore, brome, fluor et iode. The halogen atoms are the chlorine, bromine, fluorine and iodine atoms.
Dans les définitions qui précédent et celles qui seront citées ciaprès,sauf mention contraire, les radicaux alkyle, alcoxy et alkylène et les portions alkyle, alcoxy et alkylène contiennent 1 à 6 atomes de carbone en chaîne droite ou ramifiée et de préférence 1 à 4 atomes de carbone. In the above definitions and those which will be cited below, unless otherwise stated, the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and alkylene portions contain 1 to 6 carbon atoms in a straight or branched chain and preferably 1 to 4 atoms of carbon.
Certains composés de formule (I), les sels de ces composés ou les prodrugs de ces composés sont nouveaux et en tant que tels font partie de l'invention. Ce sont les composés de formule (I) pour lesquels: - R1 représente un radical carboxy, alcoxycarbonyle, tétrazolyle, -CO-NHOH, -CO-N(alk)OH, -CO-NH-O-alk, -CO-N(alk)-ORs ou -CO-R6 dans lequel R6 représente un radical, amino, alkylamino, dialkylamino, -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7, -O-alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-N RgRg, -N H-alk-O-CO-alk, -N H-alk-O-COOalk, -NH-alk-O-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -N H-alk-COOH, -N H-alk-COOalk, -N H-alk-N RgRg, - R2, R3 et R4, identiques ou différents, représentent chacun un atome d'hydrogène ou d'halogène ou un radical alkyle, - R5 représente un radical alkyle ou phénylalkyle, - R7 représente un radical phényle, - R8 et Rg, identiques ou- différents, représentent chacun un atome d'hydrogène ou un radical aIkyle5 phényle ou phénylalkyle ou bien forment avec l'atome d'azote auquel ils sont rattachés un cycle pipéridino, morpholino ou pyrrolidino, - alk représente un radical alkylène ou alkyle, à l'exception des composés pour lesquels soit R2, R3 et R4 représentent un atome d'hydrogène et R1 représente un radical carboxy, alcoxycarbonyle ou -CO-R6 dans lequel R6 représente un radical amino ou alkylamino; soit R4 représente un atome de chlore ou de brome, R2 et R3 représentent un atome d'hydrogène et R1 représente un radical carboxy, alcoxycarbonyle ou -CO-R6 dans lequel R6 représente un radical amino ou alkylamino; soit R3 représente un atome de chlore ou de brome, R2 et R4 représentent un atome d'hydrogène et R1 représente un radical carboxy, alcoxycarbonyle ou -CO-R6 dans lequel R6 représente un radical amino ou alkylamino. Certain compounds of formula (I), the salts of these compounds or the prodrugs of these compounds are new and as such are part of the invention. These are the compounds of formula (I) for which: - R1 represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N radical (alk) -ORs or -CO-R6 in which R6 represents a radical, amino, alkylamino, dialkylamino, -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O- CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7, -O- alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-N RgRg, -N H-alk-O-CO-alk, -N H-alk-O-COOalk, -NH -alk-O-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-R7, -NH-alk-S- R7, -N H-alk-COOH, -N H-alk-COOalk, -N H-alk-N RgRg, - R2, R3 and R4, identical or different, each represent a hydrogen or halogen atom or an alkyl radical, - R5 represents an alkyl or phenylalkyl radical, - R7 represents a phenyl radical, - R8 and Rg, identical or different, each represents a hydrogen atom or a phenyl or phenylalkyl alkyl radical or else form with nitrogen atom to which they are attached a piperidino, morpholino or pyrrolidino ring, - alk represents an alkylene or alkyl radical, with the exception of the compounds for which either R2, R3 and R4 represent a hydrogen atom and R1 represents a carboxy, alkoxycarbonyl or -CO- radical R6 in which R6 represents an amino or alkylamino radical; either R4 represents a chlorine or bromine atom, R2 and R3 represent a hydrogen atom and R1 represents a carboxy, alkoxycarbonyl or -CO-R6 radical in which R6 represents an amino or alkylamino radical; either R3 represents a chlorine or bromine atom, R2 and R4 represent a hydrogen atom and R1 represents a carboxy, alkoxycarbonyl or -CO-R6 radical in which R6 represents an amino or alkylamino radical.
Les nouveaux médicaments contenant au moins un composé nouveau de formule (I), un sel d'un tel composé ou un précurseur d'un tel composé font également partie de l'invention. New drugs containing at least one new compound of formula (I), a salt of such a compound or a precursor of such a compound also form part of the invention.
Les composés de formule (I) nouveaux pour lesquels R1 représente un radical carboxy peuvent être préparés par hydrolyse des composés de formule (I) correspondants pour lesquels R1 représente un radical alcoxycarbonyle. The novel compounds of formula (I) for which R1 represents a carboxy radical can be prepared by hydrolysis of the corresponding compounds of formula (I) for which R1 represents an alkoxycarbonyl radical.
Cette hydrolyse s'effectue généralement au moyen d'un base telle qu'un hydroxyde de métal alcalin (soude, potasse, hydroxyde de lithium par exemple), au sein d'un solvant nene tel qu'un aNcool ou un mélange eaualcool, à autre température comprise entre 20 et 100 C ou au moyen de triméthylsilanolate de potassium, au sein d'un solvant inerte tel que le tétrahydrofuranne, le dioxanne, le dichlorométhane, à une température voisine de 20 C. This hydrolysis is generally carried out by means of a base such as an alkali metal hydroxide (soda, potash, lithium hydroxide for example), within a nene solvent such as an alcohol or a water-alcohol mixture, other temperature between 20 and 100 C or by means of potassium trimethylsilanolate, in an inert solvent such as tetrahydrofuran, dioxane, dichloromethane, at a temperature close to 20 C.
Les composés de formule (I) nouveaux pour lesquels R1 représente un radical alcoxycarbonyle peuvent être préparés par cyclisation d'un dérivé de formule:
dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I) et R10 représente un radical alkyle.The new compounds of formula (I) for which R1 represents an alkoxycarbonyl radical can be prepared by cyclization of a derivative of formula:
in which R2, R3 and R4 have the same meanings as in formula (I) and R10 represents an alkyl radical.
Cette cyclisation s'effectue de préférence au moyen d'une base telle qu'un alcoolate de métal alcalin, au sein de l'alcool correspondant, à une température Comprise entre 15 et 70 C. This cyclization is preferably carried out using a base such as an alkali metal alcoholate, within the corresponding alcohol, at a temperature between 15 and 70 C.
Les dérivés de formule (II) peuvent être préparés par action d'un dérivé de formule:
Cl-CO-COOR1 o (111) dans laquelle R10 a la même signification que dans la formule (II) sur un dérivé de formule:
dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I).The derivatives of formula (II) can be prepared by the action of a derivative of formula:
Cl-CO-COOR1 o (111) in which R10 has the same meaning as in formula (II) on a derivative of formula:
in which R2, R3 and R4 have the same meanings as in formula (I).
Cette réaction s'effectue au sein d'un solvant inerte tel que le tétrahydrofuranne. en présence d'une base telle qu'une amine tertiaire (triéthylamine par exemple), à une température voisine de 20 C. This reaction is carried out in an inert solvent such as tetrahydrofuran. in the presence of a base such as a tertiary amine (triethylamine for example), at a temperature in the region of 20 C.
Les composés de formule (I) pour lesquels R1 représente un radical alcoxycarbonyle peuvent également être préparés par action d'un dérivé de formule (IV) sur un oxalate de dialkyle. The compounds of formula (I) for which R1 represents an alkoxycarbonyl radical can also be prepared by the action of a derivative of formula (IV) on a dialkyl oxalate.
Cette réaction s'effectue de préférence au sein d'un solvant inerte tel qu'un alcool, à une température voisine de 20 C. This reaction is preferably carried out in an inert solvent such as an alcohol, at a temperature in the region of 20 C.
Les dérivés de formule (IV) peuvent être préparés par action d'ammoniac sur un dérivé de formule:
dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I)
Cette réaction s'effectue généralement à une température voisine de 20 C.The derivatives of formula (IV) can be prepared by the action of ammonia on a derivative of formula:
in which R2, R3 and R4 have the same meanings as in formula (I)
This reaction is generally carried out at a temperature in the region of 20 C.
Les composés de formule (V) peuvent être préparés par action de ClSO3H sur une aniline de formule:
dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I). The compounds of formula (V) can be prepared by the action of ClSO3H on an aniline of formula:
in which R2, R3 and R4 have the same meanings as in formula (I).
Cette réaction s'effectue à une température voisine de 1 00 C. This reaction is carried out at a temperature in the region of 1 00 C.
Les composés de formule (I) pour lesquels RI représente un radical tétrazolyle peuvent être préparés par réaction d'azoture de sodium sur un dérivé de formule:
dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I) et R11 représente un atome d'hydrogène ou un radical alkyle.The compounds of formula (I) for which RI represents a tetrazolyl radical can be prepared by reaction of sodium azide on a derivative of formula:
in which R2, R3 and R4 have the same meanings as in formula (I) and R11 represents a hydrogen atom or an alkyl radical.
Geste réaction s'effectue de préférence au sein d'un solvant inerte tel que le diméthylformamide, à une température comprise entre 20 et 300C. This reaction is preferably carried out in an inert solvent such as dimethylformamide, at a temperature between 20 and 300C.
Les dérivés de formule (VII) peuvent être obtenus par action de pentachlorure de phosphore sur un amide de formule:
dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I) et R11 représente un atome d'hydrogène ou un radical alkyle.The derivatives of formula (VII) can be obtained by the action of phosphorus pentachloride on an amide of formula:
in which R2, R3 and R4 have the same meanings as in formula (I) and R11 represents a hydrogen atom or an alkyl radical.
Cette réaction s'effectue généralement à une température comprise entre 110 et 1 60 C. This reaction is generally carried out at a temperature between 110 and 1 60 C.
Les amides de formule (vil) peuvent être préparés à partir des composés de formule (I) pour lesquels R1 représente un radical carboxy ou alcoxycarbonyle par toute méthode connue permettant de passer d'un acide ou d'un ester à un amide primaire ou secondaire et notamment par adaptation des méthodes décrites par Q. E. KENT et coll., Organic
Syntheses, III, 490; W. S. BISHOP, Organic Synthesis, III, 613. The amides of formula (vi) can be prepared from the compounds of formula (I) for which R1 represents a carboxy or alkoxycarbonyl radical by any known method making it possible to pass from an acid or an ester to a primary or secondary amide and in particular by adapting the methods described by QE KENT et al., Organic
Syntheses, III, 490; WS BISHOP, Organic Synthesis, III, 613.
Les composés de formule (I) pour lesquels R1 représente un radical -CO-NHOH, -CO-N(alk)OH, -CO-NH-O-alk, -CO-N(alk)-ORs peuvent être préparés par réaction d'un composé de formule (l) pour lequel R1 représente un radical carboxy ou alcoxycarbonyle sur un dérivé de formule:
HN(R12)-R13 (IX) dans laquelle R12 représente un atome d'hydrogène ou un radical alkyle et
R13 représente un radical hydroxy, -O-alk ou -ORs dans lequel R5 représente un radical alkyle ou phénylalkyle.The compounds of formula (I) for which R1 represents a radical -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N (alk) -ORs can be prepared by reaction of a compound of formula (I) for which R1 represents a carboxy or alkoxycarbonyl radical on a derivative of formula:
HN (R12) -R13 (IX) in which R12 represents a hydrogen atom or an alkyl radical and
R13 represents a hydroxy radical, -O-alk or -ORs in which R5 represents an alkyl or phenylalkyl radical.
Lorsque l'on met en oeuvre l'acide, on opère en présence d'un agent de condensation peptidique tel qu'un carbodiimide (par exemple le dicyclohexylcarbodiimide) ou le N,N'-diimidazolecarbonyle, dans un solvant inerte tel qu'un éther (tétrahydrnfuranne, dioxanne par exemple), un amide (diméthylformamide par exemple) ou un solvant chloré (chlorure de méthyle ne, chloroforme par exemple), à une température comprise entre 00C et la température de reflux du milieu réactionnel. When the acid is used, it is carried out in the presence of a peptide condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide) or N, N'-diimidazolecarbonyl, in an inert solvent such as ether (tetrahydrnfuran, dioxane for example), an amide (dimethylformamide for example) or a chlorinated solvent (methyl chloride ne, chloroform for example), at a temperature between 00C and the reflux temperature of the reaction medium.
Lorsque l'on met en oeuvre un ester, on opère soit en milieu organique éventuellement en présence d'un accepteur d'acide tel que le butylithlum. le lithium de la diisopropylamine ou une base organique azotée (trialkylamine, pyridine, diaza-1,8 bicyclo[5.4.0] undécène-7 ou diaza-1,5 bicyclo[4.3.0] nonène par exemple), dans un solvant tel que cité ci-dessus ou un mélange de ces solvants, à une température comprise entre 00C et la température de reflux du milieu réactionnel, soit en milieu hydroorganique biphasique en présence d'une base alcaline ou alcalinoterreuse (soude, potasse par exemple) ou d'un carbonate ou bicarbonate d'un métal alcalin ou alcalinoterreux, à une température comprise entre 0 et 40 C. When an ester is used, the operation is carried out either in an organic medium, optionally in the presence of an acid acceptor such as butylithlum. diisopropylamine lithium or an organic nitrogenous base (trialkylamine, pyridine, diaza-1,8 bicyclo [5.4.0] undecene-7 or diaza-1,5 bicyclo [4.3.0] nonene for example), in a solvent such as mentioned above or a mixture of these solvents, at a temperature between 00C and the reflux temperature of the reaction medium, either in a two-phase hydroorganic medium in the presence of an alkaline or alkaline earth base (soda, potash for example) or d '' an alkali or alkaline earth metal carbonate or bicarbonate, at a temperature between 0 and 40 C.
Les composés de formule (I) pour lesquels R1 représente un radical 6 dans lequel R6 représente un radical amino, alkylamino, dialkylam ino, -O-alk-O-CO-alk, -O-alk-0-COOalk, -O-alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R1 2, -O-alk-S-R7, -O-alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-NRgRg, -NH-alk-O-CO-alk, -N H-alk-0-COOalk, -N H-alk-O-CO-R7, -N H-alk-OH, -N H-alk-O-alk, -N H-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR8RS, peuvent être préparés par réaction d'un composé de formule (I) pour lequel R1 représente un radical carboxy ou alcoxycarbonyle sur un dérivé de formule:
R6-H (X) dans laquelle R6 a les mêmes significations que ci-dessus.The compounds of formula (I) for which R1 represents a radical 6 in which R6 represents an amino, alkylamino, dialkylam ino, -O-alk-O-CO-alk, -O-alk-0-COOalk, -O- radical alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R1 2, -O-alk-S- R7, -O-alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-NRgRg, -NH-alk-O-CO-alk, -N H-alk-0-COOalk , -N H-alk-O-CO-R7, -N H-alk-OH, -N H-alk-O-alk, -N H-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR8RS, can be prepared by reaction of a compound of formula (I) for which R1 represents a radical carboxy or alkoxycarbonyl on a derivative of formula:
R6-H (X) in which R6 has the same meanings as above.
Cette réaction s'effectue dans les conditions décrites précédemment pour la réaction des acides ou des esters avec les dérivés de formule (IX). This reaction is carried out under the conditions described above for the reaction of acids or esters with the derivatives of formula (IX).
Les composés de formule (I) peuvent être purifiés par les méthodes connues habituelles, par exemple par cristallisation, chromatographie ou extractions. The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extractions.
Les composés de formule (I) peuvent être éventuellement transformés en sels métalliques ou en sels d'addition avec les bases azotées selon des méthodes connues en soi. Ces sels peuvent être obtenus par action d'une base métallique (alcaline ou alcalinoterreuse par exemple), de l'ammoniac, d'un tétraalkylammonium, d'une amine ou d'un sel d'un acide organique sur un composé de formule (I), dans un solvant. Le sel formé est séparé par les méthodes habituelles. The compounds of formula (I) can optionally be converted into metal salts or into addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline earth for example), ammonia, a tetraalkylammonium, an amine or a salt of an organic acid on a compound of formula ( I), in a solvent. The salt formed is separated by the usual methods.
Ces sels font également partie de l'invention. These salts are also part of the invention.
Comme exemples de sels pharmaceutiquement acceptables, peuvent être cités les sels avec les métaux alcalins (sodium, potassium, lithium) ou avec les métaux alcalinoterreux (calcium, magnésium), le sel d'ammonium, les sels de tétraalkylammonium (tétrabutylammonium par exemple), les sels de bases azotées (éthanolamine, triméthylamine, méthgylarnine, benzylamine, N-benzyl-(3-phénéthylamine, choline, arginine, leucine, lysine, N-méthyl glucamine). Examples of pharmaceutically acceptable salts which may be mentioned are the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), the ammonium salt, the tetraalkylammonium salts (tetrabutylammonium for example), salts of nitrogenous bases (ethanolamine, trimethylamine, methgylarnine, benzylamine, N-benzyl- (3-phenethylamine, choline, arginine, leucine, lysine, N-methyl glucamine).
Les composés de formule (I) présentent des propriétés pharmacologiques intéressantes. Ces composés sont des antagonistes non compétitifs du récepteur N-méthyl-D-aspartate (NMDA) et, plus particulièrement, ce sont des ligands pour les sites modulateurs de la glycine du récepteur NMDA. The compounds of formula (I) have interesting pharmacological properties. These compounds are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulator sites of the NMDA receptor.
Par ailleurs, certains composés de formule (I) sont des antagonistes du récepteur acide a-amino-3-hydroxy-5-méthyl-4-isoxazolepropion que (AMPA), connu aussi sous le nom de récepteur du quisqualate. Furthermore, certain compounds of formula (I) are antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropion acid receptor as (AMPA), also known as the quisqualate receptor.
Ces composés sont donc utiles pour traiter ou prévenir toutes les ischèmies (telles l'ischémie focale ou globale) consécutives à des accidents vasculaires cérébraux, un arrêt cardiaque, une hypotension artérielle, une intervention chirurgicale cardiaque ou pulmonaire ou une hypoglycémie sévére. Ils sont également utiles dans le traitement des effets dus à une anoxie, qu'elle soit périnatale ou consécutive à une noyade ou à des lésions cérébro-spinales. Ces composés peuvent également être utilisés pour traiter ou prévenir l'évolution de maladies neurodégénératives, de la chorée d'HUNTINGTON, de la maladie d'ALZHEIMER, de la sclérose latérale amyotrophique, de l'atrophie olivo-pontocérébelleuse et de la maladie de
PARKINSON. Ces composés peuvent aussi être utilisés vis-à-vis des manifestations épileptogènes et/ou convulsives, pour le traitement de l'anxiété (KEHNE et coll., Eur. J.Pharmacol., 193, 283 (1991), de la dépression (TRULLAS et coll.,Eur. J. Pharmacol., 185, 1 (1990), de la schizophrénie (REYNOLDS, TIPS, 13, 116 (1992), en tant qu'analgésiques (DICKENSON et coll., Neurosc. Letters, 121, 263 (1991), antianorexiques (SORRELS et coll., Brain Res., 572, 265 (1992) et pour traiter les empoisonnements par des neurotoxines ou d'autres substances agonistes du récepteur NMDA, ainsi que les troubles neurologiques associés aux maladies virales telles que le sida (LIPTON et coll., Neuron, 7, 111 (1991), la rage, la rougeole et le tétanos (BAGETTA et coll., Br. J. Pharmacol., 101, 776 (1990).These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents, cardiac arrest, arterial hypotension, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or following drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and
PARKINSON. These compounds can also be used with respect to epileptogenic and / or convulsive manifestations, for the treatment of anxiety (KEHNE et al., Eur. J. Pharmacol., 193, 283 (1991), of depression ( TRULLAS et al., Eur. J. Pharmacol., 185, 1 (1990), of schizophrenia (REYNOLDS, TIPS, 13, 116 (1992), as analgesics (DICKENSON et al., Neurosc. Letters, 121 , 263 (1991), antianorexics (SORRELS et al., Brain Res., 572, 265 (1992) and to treat poisonings by neurotoxins or other NMDA receptor agonist substances, as well as neurological disorders associated with viral diseases such as AIDS (LIPTON et al., Neuron, 7, 111 (1991), rabies, measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776 (1990).
L'affinité des composés de formule (I) pour le site glycine lié au récepteur NMDA a été déterminée en étudiant l'antagonisme de la fixation spécifique du [3H]-DCKA sur des membranes de cortex cérébral de rat selon une méthode dérivée de celle décrite par BARON et coll., Eur. J. Pharm., 206, 149 (1991). Le [3H]-DCKA (20nM) est mis à incuber en présence de 0,1 mg de protéines à 4"C pendant 10 minutes dans du tampon HEPES 50 mM, pH7,5. La fixation non spécifique est déterminée en présence de glycine 1 mM. La radioactivité liée est séparée par filtration sur filtres Whatman GF/B. The affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor was determined by studying the antagonism of the specific binding of [3H] -DCKA on membranes of rat cerebral cortex according to a method derived from that described by BARON et al., Eur. J. Pharm., 206, 149 (1991). The [3H] -DCKA (20nM) is incubated in the presence of 0.1 mg of proteins at 4 "C for 10 minutes in 50 mM HEPES buffer, pH 7.5. The non-specific binding is determined in the presence of glycine 1 mM The bound radioactivity is separated by filtration on Whatman GF / B filters.
L'activité inhibitrice de ces produits est généralement inférieure à 100 FM. The inhibitory activity of these products is generally less than 100 FM.
L'affinité des composés de formule (I) vis-à-vis du récepteur AMPA a été déterminée en étudiant l'antagonisme de la fixation spécifique du [3H]-
AMPA sur des membranes de cortex cérébral de rat (HONORE et coll.,
Neuroscience letters, 54, 27 (1985)). Le [3H]-AMPA est mis à incuber en présence de 0,2 mg de protéines à 4"C pendant 30 minutes dans du tampon
KH2PO4 1 OmM, KSCN 100mM, pH7,5. La fixation non spécifique est déterminée en présence de L-glutamate 1 mu. La radioactivité liée est séparée par filtration sur filtres PHARMACIA (Printed Filtermate A). L'activité inhibitrice de ces produits est généralement inférieure à 100 CLAM. The affinity of the compounds of formula (I) with respect to the AMPA receptor was determined by studying the antagonism of the specific binding of [3H] -
AMPA on membranes of rat cerebral cortex (HONORE et al.,
Neuroscience letters, 54, 27 (1985)). [3H] -AMPA is incubated in the presence of 0.2 mg of protein at 4 "C for 30 minutes in buffer
KH2PO4 1 OmM, KSCN 100mM, pH7.5. Non-specific binding is determined in the presence of L-glutamate 1 mu. The bound radioactivity is separated by filtration on PHARMACIA filters (Printed Filtermate A). The inhibitory activity of these products is generally less than 100 CLAM.
Les composés de formule (I) présentent une toxicité faible. Leur
DL50 est supérieure à 50 mg/kg par voie IP.The compounds of formula (I) have a low toxicity. Their
LD50 is greater than 50 mg / kg by IP route.
Sont particulièrement intéressants comme antagonistes du récepteur
NMDA les composés de formule (I) pour lesquels R1 représente un radical carboxy ou alcoxycarbonyle et R2, R3 et R4 sont des atomes d'hydrogène ou bien R2 et R4 sont des atomes d'hydrogène et R3 représente un atome d'halogène ou bien R2 et R3 représentent des atomes d'hydrogène et R4 représente un atome d'halogène ou bien R3 représente un atome d'hydrogène et R2 et R4 représentent des atomes d'halogène
Sont particulièrement intéressants comme antagonistes du récepteur
AMPA les composés de formule (I) pour lesquels R1 représente un radical carboxy, R2 et R4 représentent un atome d'halogène et R3 représente un atome d'hydrogène ou bien R2 et R4 représentent un atome d'hydrogène et
R3 représente un atome d'halogène.Are particularly interesting as receptor antagonists
NMDA the compounds of formula (I) for which R1 represents a carboxy or alkoxycarbonyl radical and R2, R3 and R4 are hydrogen atoms or else R2 and R4 are hydrogen atoms and R3 represents a halogen atom or else R2 and R3 represent hydrogen atoms and R4 represents a halogen atom or R3 represents a hydrogen atom and R2 and R4 represent halogen atoms
Are particularly interesting as receptor antagonists
AMPA the compounds of formula (I) for which R1 represents a carboxy radical, R2 and R4 represent a halogen atom and R3 represents a hydrogen atom or else R2 and R4 represent a hydrogen atom and
R3 represents a halogen atom.
D'un intérêt particulier sont les composés suivants: - 2H-1 ,2,4-benzothiadiazine-l ,1 -dioxyde-3-carboxylate d'éthyle, - acide 1 ,2,4-benzothiadiazine 1,1 -dioxyde-3-carboxylique, - 6,8-dichloro-2H-l ,2,4-benzothiadiazine 1,1 -dioxyde-3-carboxylate de méthyle, - acide 6,8-dichloro-2H-1 52,4-benzothiadiazine-1 51 -dioxyde-3-carboxylique. Of particular interest are the following compounds: - 2H-1, 2,4-benzothiadiazine-1, 1-ethyl-3-dioxide-carboxylate, - acid 1, 2,4-benzothiadiazine 1,1-3-dioxide -carboxylic, - 6,8-dichloro-2H-1,2,4-benzothiadiazine 1,1-methyl dioxide-3-carboxylate, - 6,8-dichloro-2H-1 acid 52,4-benzothiadiazine-1 51 -dioxide-3-carboxylic.
Les exemples suivants illustrent l'invention sans la limiter. The following examples illustrate the invention without limiting it.
Exemple 1
A 100 cm3 d'une solution 1 N de méthylate de sodium dans le méthanol agitée sous azote à une température voisine de 20"C, on coule lentement une solution de 17,2 g de 2-aminobenzènesulfonamide et de 14,6 g d'oxalate de diéthyle dans 40 cm3 de méthanol. Après 24 heures d'agitation à cette température, le milieu réactionnel est versé dans 2 litres d'eau distillée et acidifié à l'aide d'acide chlorhydrique 1 N. Le précipité formé est filtré et lavé à l'eau jusqu'à pH neutre, puis solubilisé dans 50 cm3 de diméthylformamide chauffés à 100 C. La solution obtenue est refroidie et diluée avec 150 cm3 de méthanol.Les cristaux formés sont filtrés et lavés avec du méthanol. 5,3 g de produit ainsi obtenu sont solubilisés dans 70 cm3 de diméthylformamide puis ajoutés à 40 sm3 d'une solution de 1,4 g de potasse dans l'éthanol absolu. Le milieu réactionnel est agité à une température voisine de 20"C pendant 15 heures puis concentré à sec sous pression réduite. Après addition d'éther éthylique et filtration de l'insoluble, on obtient 6,4 g de sel de potassium de 2H-1 ,2,4-benzothiadiazine-1, 1 -dioxyde-3-carboxylate d'éthyle sous forme de poudre fondant à 235"C. Example 1
At 100 cm 3 of a 1 N solution of sodium methylate in methanol stirred under nitrogen at a temperature in the region of 20 ° C., a solution of 17.2 g of 2-aminobenzenesulfonamide and 14.6 g of diethyl oxalate in 40 cm3 of methanol After 24 hours of stirring at this temperature, the reaction medium is poured into 2 liters of distilled water and acidified using 1N hydrochloric acid. The precipitate formed is filtered and washed with water until neutral pH, then dissolved in 50 cm3 of dimethylformamide heated to 100 C. The solution obtained is cooled and diluted with 150 cm3 of methanol. The crystals formed are filtered and washed with methanol. g of product thus obtained are dissolved in 70 cm3 of dimethylformamide and then added to 40 sm3 of a solution of 1.4 g of potassium hydroxide in absolute ethanol. The reaction medium is stirred at a temperature in the region of 20 "C for 15 hours then concentrated to dryness under reduced pressure next. After addition of ethyl ether and filtration of the insoluble material, 6.4 g of potassium salt of 2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-3-carboxylate in powder form are obtained. melting at 235 "C.
Exemple 2 5,4 g de sel de potassium de 2H-1 ,2,4-benzothiadiazine 1 ,1-dioxyde-3-carboxylate d'éthyle sont solubilisés dans un mélange de 200 cm3 d'éthanol et de 50 cm3 d'eau distillée chauffé à 50"C. On ajoute alors 1,1 g de potasse et on laisse la réaction se poursuivre pendant 1 heure.Example 2 5.4 g of potassium salt of 2H-1, 2,4-benzothiadiazine 1, 1-ethyl dioxide-3-carboxylate are dissolved in a mixture of 200 cm3 of ethanol and 50 cm3 of water distilled heated to 50 "C. 1.1 g of potassium hydroxide are then added and the reaction is allowed to continue for 1 hour.
Le précipité formé est filtré, lavé avec de l'éthanol puis séché pour conduire à 4,7 g de disel de potassium de l'acide 1 ,2,4-benzothiadiazine 1,1-dioxyde-3-carboxylique sous forme d'une poudre dont le point de fusion est supérieur à 270"C. The precipitate formed is filtered, washed with ethanol and then dried to yield 4.7 g of potassium disel of 1,2,4-benzothiadiazine 1,1-3-dioxide-3-carboxylic acid in the form of a powder with a melting point above 270 "C.
Exemple 3
A une solution méthanolique de méthylate de sodium, préparée par addition de 0,75 g de sodium dans 50 cm3 de méthanol, on ajoute sous azote 1 1 g de 4,6-dichloro-2-éthyloxalylamino-benzènesulfonamide en solution dans le méthanol à 40 C. La réaction est poursuivie 2 heures à cette température, puis le milieu réactionnel est concentré à sec sous pression réduite. Le solide ainsi obtenu est repris dans 1 litre d'eau distillée puis acidifié à l'aide d'acide chlorhydrique 1N pour conduire à un précipité blanc. Après filtration, lavage et séchage, on obtient 8,6 g de 6,8-dichloro-2H-1 ,2,4-benzothiadiazine 1,1 -dioxyde-3-carboxylate de méthyle fondant vers 270"C. Example 3
To a methanolic solution of sodium methoxide, prepared by adding 0.75 g of sodium in 50 cm 3 of methanol, 1 1 g of 4,6-dichloro-2-ethyloxalylamino-benzenesulfonamide dissolved in methanol is added under nitrogen. 40 C. The reaction is continued for 2 hours at this temperature, then the reaction medium is concentrated to dryness under reduced pressure. The solid thus obtained is taken up in 1 liter of distilled water and then acidified with 1N hydrochloric acid to yield a white precipitate. After filtration, washing and drying, 8.6 g of methyl 6,8-dichloro-2H-1,2,4-benzothiadiazine 1,1-dioxide-3-carboxylate, melting at around 270 ° C., are obtained.
Le 4,6-dichloro-2-éthyloxalylamino-benzènesu Ifonamide peut être préparé de la manière suivante: à une solution de 12 g de 2-amino-4,6-dichlorobenzènesulfonamide et de 7,1 cm3 de triéthylamine dans 40 cm3 de tétrahydrofurane anhydre refroidis à 5 C, on ajoute goutte à goutte, en environ 30 minutes, une solution de 5,8 cm3 de chlorure d'éthyloxalyle dans 5 cm3 de tétrahydrofurane. Après une nuit d'agitation à une température voisine de 20 (: le milieu réactionnel est concentré à sec sous pression réduit. Le résidu solide est lavé à l'eau puis solubilisé à chaud dans 120 cm3 dèthanol aqueux à 10% d'eau.Après refroidissement, filtration et séchage des cristaux formés, on obtient 11 g de 4,6-dichloro-2-éthyloxalylamino-benzènesulfonamide fondant à 200"C. 4,6-dichloro-2-ethyloxalylamino-benzenesu Ifonamide can be prepared as follows: to a solution of 12 g of 2-amino-4,6-dichlorobenzenesulfonamide and 7.1 cm3 of triethylamine in 40 cm3 of tetrahydrofuran anhydrous cooled to 5 ° C., a solution of 5.8 cm3 of ethyloxalyl chloride in 5 cm3 of tetrahydrofuran is added dropwise over approximately 30 minutes. After stirring overnight at a temperature in the region of 20 (: the reaction medium is concentrated to dryness under reduced pressure. The solid residue is washed with water and then dissolved hot in 120 cm3 of aqueous ethanol at 10% water. After cooling, filtering and drying the crystals formed, 11 g of 4,6-dichloro-2-ethyloxalylamino-benzenesulfonamide are obtained, melting at 200 ° C.
Le 2-amino-4,6-dichlorobenzènesulfonamide peut être préparé selon la méthode décrite par J.H. SHORT et U. BIERMACHER, J. Am. Chem. Soc., 82, 1135-1137(1960 > Exemple 4 3,1 g de 8,8-dichloro-2H-1,2,4-benzothiadiazine-1,1-dioxyde-3-carboxylate de méthyle en solution dans 400 cm3 d'éthanol absolu sont traités à 50"C par 120 cm3 d'une solution aqueuse de potasse à 1%. Après 1 heure de réaction à cette température, le précipité formé est filtré, lavé à l'éthanol puis à l'eau et séché pour conduire à 3,2 g d'hydrate du disel de potassium de l'acide 6,8-dichloro-2H-1,2,4-benzothiadiazine-1,1-dioxyde-3-carboxylique sous forme de poudre fondant à une température supérieure à 300"C. 2-Amino-4,6-dichlorobenzenesulfonamide can be prepared according to the method described by J.H. SHORT and U. BIERMACHER, J. Am. Chem. Soc., 82, 1135-1137 (1960> Example 4 3.1 g of methyl 8,8-dichloro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 400 cm3 of absolute ethanol are treated at 50 ° C. with 120 cm 3 of a 1% aqueous potassium solution. After 1 hour of reaction at this temperature, the precipitate formed is filtered, washed with ethanol and then with water and dried to yield 3.2 g of potassium disel hydrate of 6,8-dichloro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid in the form of a powder melting at a temperature higher than 300 "C.
Les médicaments selon l'invention sont constitués par un composé de formule (I) sous forme libre ou sous forme d'un sel, à l'état pur ou sous forme d'une composition dans laquelle il est associé à tout autre produit pharmaceutiquement compatible, pouvant être inerte ou physiologiquement actif. Les médicaments selon l'invention peuvent être employés par voie orale, parentérale, rectale ou topique. The medicaments according to the invention consist of a compound of formula (I) in free form or in the form of a salt, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product. , which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.
Comme compositions solides pour administration orale, peuvent être utilisés des comprimés, des pilules, des poudres (capsules de gélatine, cachets) ou des granulés. Dans ces compositions, le principe actif selon l'invention est mélangé à un ou plusieurs diluants inertes, tels que amidon, cellulose, saccharose, lactose ou silice, sous courant d'argon. Ces compositions peuvent également comprendre des substances autres que les diluants, par exemple un ou plusieurs lubrifiants tels que le stéarate de magnésium ou le talc, un colorant, un enrobage (dragées) ou un vernis. As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.
Comme compositions liquides pour administration orale, on peut utiliser des solutions, des suspensions, des émulsions, des sirops et des élixirs pharmaceutiquement acceptables contenant des diluants inertes tels que l'eau, I'éthanol, le glycérol, les huiles végétales ou l'huile de paraffine. As liquid compositions for oral administration, use may be made of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
Ces compositions peuvent comprendre des substances autres que les diluants, par exemple des produits mouillants, édulcorants, épaississants, aromatisants ou stabilisants.These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
Les compositions stériles pour administration parentérale, peuvent être de préférence des solutions aqueuses ou non aqueuses, des suspensions ou des émulsions. Comme solvant ou véhicule, on peut employer l'eau, le propylèneglycol, un polyéthylèneglycol, des huiles végétales, en particulier l'huile d'olive, des esters organiques injectables, par exemple l'oléate d'éthyle ou d'autres solvants organiques convenables. Ces compositions peuvent également contenir des adjuvants, en particulier des agents mouillants, isotonisants, émulsifiants, dispersants et stabilisants. La stérilisation peut se faire de plusieurs façons, par exemple par filtration aseptisante, en incorporant à la composition des agents stérilisants, par irradiation ou par chauffage.Elles peuvent également être préparées sous forme de compositions solides stériles qui peuvent être dissoutes au moment de l'emploi dans de l'eau stérile ou tout autre milieu stérile injectable. The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example by sanitizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Les compositions pour administration rectale sont les suppositoires ou les capsules rectales qui contiennent, outre le produit actif, des excipients tels que le beurre de cacao, des glycérides semi-synthétiques ou des polyéthylèneglycols. The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
Les compositions pour administration topique peuvent être par exemple des crèmes, lotions, collyres, collutoires, gouttes nasales ou aérosols
En thérapeutique humaine, les composés selon l'invention sont particulièrement utiles pour le traitement et/ou la prévention des conditions qui requièrent l'administration d'un antagoniste du récepteur NMDA ou d'un antagoniste du récepteur AMPA.Ces composés sont notamment utiles pour traiter ou prévenir toutes les ischémies et en particulier l'ischémie cérébrale, les effets dus à une anoxie, l'évolution de maladies neurodégénératives, de la chorée d'HUNTINGTON, de la maladie d'ALZHEIMER, de la sclérose latérale amyotrophique, de l'atrophie olivo-pontocérébelleuse et de la maladie de PARKINSQGil, vis-à-vis des manifestations épileptogènes et/ou convuisixres, pour le traitement de l'anxiété, de la dépression, de la schizophrénie5 en tant qu'analgésiques, antianorexiques et pour traiter les empoisonnements par des neurotoxines ou d'autres substances agonistes du récepteur NMDA, ainsi que les troubles neurologiques associés aux maladies virales telles que le sida, la rage, la rougeole et le tétanos.The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
In human therapy, the compounds according to the invention are particularly useful for the treatment and / or prevention of conditions which require the administration of an NMDA receptor antagonist or an AMPA receptor antagonist. These compounds are especially useful for treat or prevent all ischemia and in particular cerebral ischemia, the effects due to anoxia, the evolution of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PARKINSQGil disease, vis-à-vis epileptogenic and / or convective manifestations, for the treatment of anxiety, depression, schizophrenia5 as analgesics, antianorexics and to treat poisoning by neurotoxins or other NMDA receptor agonist substances, as well as neurological disorders associated with viral diseases such as e AIDS, rabies, measles and tetanus.
Les doses dépendent de l'effet recherché, de la durée du traitement et de la voie d'administration utilisée; elles sont généralement comprises entre 10 mg et 100 mg par jour par voie orale pour un adulte avec des doses unitaires allant de 5 mg à 50 mg de substance active. The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance.
D'une façon générale, le médecin déterminera la posologie appropirée en fonction de l'âge, du poids et de tous les autres facteurs propres au sujet à traiter. In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
Les exemples suivants illustrent des compositions selon l'invention:
EXEMPLE A
On prépare, selon la technique habituelle, des gélules dosées à 50 mg de produit actif ayant la composition suivante:
- Acide 6,8-dichioro-2H-l ,2,4-benzoth iadiazine-l,l
-dioxyde-3-carboxylique 50 mg
- Cellulose...................................... 18 mg
- Lactose........................................ 55 mg
- Silice colloïdale 1 mg
- Carboxyméthylamidon sodique 10 mg
- Talc........................................... 10 mg
- Stéarate de magnésium.......................... 1 mg
EXEMPLE B
On prépare selon la technique habituelle de comprimés dosés à 50 mg de produit actif ayant la composition suivante:: - 6,8-dichloro-2H-1,2,4-benzothiadiazine-1,1#
- dioxyde-3-carboxylate de méthyle............... 50 mg
- Lactose........................................ 104 mg
- Cellulose...................................... 40 mg
- Polyvidone 10 mg
- Carboxyméthylamidon sodique 22 mg
- Talc........................................... 10 mg
- Stéarate de magnésium.......................... 2 mg
- Silice colloïdale 2 mg
- Mélange d'hydroxyméthylcellulose, glycérine, oxyde de
titane (72-3,5-24,5) q.s.p. 1 comprimé pelliculé terminé à 245 mg
EXEMPLE C
On prépare une solution injectable contenant 10 mg de produit actif ayant la composition suivante: :
- Acide 2H-1,2,4-benzothiadiazine-1,1
-dioxyde-3-carboxylique 10 mg
- Acide benzoique............................... 80 mg
- Alcool benzylique 0,06 cm3
- Benzoate de sodium............................. 80 mg
- Ethanol à 95 %................................. 0,4 cm - Hydroxyde de sodium........................... 24 mg - Propylène glycol 1,6 cm3 - Eau......................................q.s.p. 4 cm The following examples illustrate compositions according to the invention:
EXAMPLE A
Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:
- Acid 6,8-dichioro-2H-l, 2,4-benzoth iadiazine-l, l
-dioxide-3-carboxylic 50 mg
- Cellulose ...................................... 18 mg
- Lactose ........................................ 55 mg
- Colloidal silica 1 mg
- Carboxymethyl starch sodium 10 mg
- Talc ........................................... 10 mg
- Magnesium stearate .......................... 1 mg
EXAMPLE B
Prepared according to the usual technique of tablets dosed with 50 mg of active product having the following composition: - 6,8-dichloro-2H-1,2,4-benzothiadiazine-1,1 #
- methyl dioxide-3-carboxylate ............... 50 mg
- Lactose ........................................ 104 mg
- Cellulose ...................................... 40 mg
- Polyvidone 10 mg
- Carboxymethyl starch sodium 22 mg
- Talc ........................................... 10 mg
- Magnesium stearate .......................... 2 mg
- Colloidal silica 2 mg
- Mixture of hydroxymethylcellulose, glycerin, oxide of
titanium (72-3.5-24.5) qs 1 film-coated tablet finished at 245 mg
EXAMPLE C
A solution for injection containing 10 mg of active product having the following composition is prepared:
- 2H-1,2,4-Benzothiadiazine-1,1 acid
-dioxide-3-carboxylic 10 mg
- Benzoic acid ............................... 80 mg
- Benzyl alcohol 0.06 cm3
- Sodium benzoate ............................. 80 mg
- 95% ethanol ................................. 0.4 cm - Sodium hydroxide .... ....................... 24 mg - Propylene glycol 1.6 cm3 - Water ................ ...................... qs 4 cm
Claims (11)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9204614A FR2690160A1 (en) | 1992-04-15 | 1992-04-15 | Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives to the preparation of medicaments, new products, their preparation and the medicaments containing them. |
| PCT/FR1993/000361 WO1993021171A1 (en) | 1992-04-15 | 1993-04-09 | Use of 2h-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives for preparing nmda/ampa receptor antagonist drugs, novel products, preparation thereof and drugs containing same |
| AU39571/93A AU3957193A (en) | 1992-04-15 | 1993-04-09 | Use of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives for preparing NMDA/AMPA receptor antagonist drugs, novel products, preparation thereof and drugs containing same |
| CA002130095A CA2130095A1 (en) | 1992-04-15 | 1993-04-09 | 2h-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives used for preparing therapeutic compounds; new products obtained; process for preparing them and therapeutic agents containing the same |
| ZA932576A ZA932576B (en) | 1992-04-15 | 1993-04-13 | 1,2,4-benzothiadiazine-3-carboxylic acid derivatives, their preparation and their use |
| IL105391A IL105391A0 (en) | 1992-04-15 | 1993-04-14 | 1,2,4-benzothiadiazine-3-carboxylic acid derivatives,their preparation and pharmaceutical compositions containing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9204614A FR2690160A1 (en) | 1992-04-15 | 1992-04-15 | Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives to the preparation of medicaments, new products, their preparation and the medicaments containing them. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| FR2690160A1 true FR2690160A1 (en) | 1993-10-22 |
Family
ID=9428891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9204614A Pending FR2690160A1 (en) | 1992-04-15 | 1992-04-15 | Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives to the preparation of medicaments, new products, their preparation and the medicaments containing them. |
Country Status (6)
| Country | Link |
|---|---|
| AU (1) | AU3957193A (en) |
| CA (1) | CA2130095A1 (en) |
| FR (1) | FR2690160A1 (en) |
| IL (1) | IL105391A0 (en) |
| WO (1) | WO1993021171A1 (en) |
| ZA (1) | ZA932576B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11492346B2 (en) | 2019-06-18 | 2022-11-08 | Pfizer Inc. | Benzisoxazole sulfonamide derivatives |
| US11911372B2 (en) | 2018-06-28 | 2024-02-27 | Ctxt Pty Ltd | Compounds |
| US12365655B2 (en) | 2018-06-20 | 2025-07-22 | Ctxt Pty Ltd | Compounds |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK162491D0 (en) * | 1991-09-20 | 1991-09-20 | Novo Nordisk As | Heterocyclic compounds, their preparation and pharmaceutical preparations containing the compounds |
| FR2702150B1 (en) * | 1993-03-03 | 1995-04-07 | Rhone Poulenc Rorer Sa | Application of 2H-1,2-4-benzothiadiazine-3 (4H) -one-1,1-dioxide derivatives as non-competitive NMDA receptor antagonists. |
| US6943159B1 (en) | 1998-02-18 | 2005-09-13 | Neurosearch A/S | Compounds and their use as positive AMPA receptor modulators |
| FR2801587B1 (en) * | 1999-11-30 | 2002-01-11 | Adir | NOVEL BENZOTHIADIAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| ES2342090T3 (en) | 2004-08-25 | 2010-07-01 | Essentialis, Inc. | PHARMACEUTICAL FORMULATIONS OF OPENING AGENTS OF POTASSIUM CHANNELS DEPENDENT ON ATP AND USES OF THE SAME. |
| CN103172592B (en) | 2006-01-05 | 2016-01-06 | 伊森舍丽斯有限公司 | Salt of potassium ATP channel opener and uses thereof |
-
1992
- 1992-04-15 FR FR9204614A patent/FR2690160A1/en active Pending
-
1993
- 1993-04-09 AU AU39571/93A patent/AU3957193A/en not_active Abandoned
- 1993-04-09 CA CA002130095A patent/CA2130095A1/en not_active Abandoned
- 1993-04-09 WO PCT/FR1993/000361 patent/WO1993021171A1/en not_active Ceased
- 1993-04-13 ZA ZA932576A patent/ZA932576B/en unknown
- 1993-04-14 IL IL105391A patent/IL105391A0/en unknown
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 86, no. 1, 3 Janvier 1977, Columbus, Ohio, US; abstract no. 5420x, P.A. PETYUNIN ET AL. 'Studies on the chemistry of heterocycles. LVIII. Synthesis of derivatives of 1,1-dioxo-2H-1 ,2,4-benzothiadiazine-3-carboxylic acid from 2-sulfamoyloxanilic acid esters' page 470 ; * |
| JOURNAL OF MEDICINAL CHEMISTRY vol. 34, no. 4, Avril 1991, WASHINGTON US pages 1243 - 1252 P.D. LEESON ET AL. 'Kynurenic Acid Derivatives. Structure-Activity Relationships for Excitatory Amino Acid Antagonism and Identification of Potent and Selective Antagonists at the Glycine Site on the N-Methyl-D-aspartate Receptor' * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12365655B2 (en) | 2018-06-20 | 2025-07-22 | Ctxt Pty Ltd | Compounds |
| US11911372B2 (en) | 2018-06-28 | 2024-02-27 | Ctxt Pty Ltd | Compounds |
| US11492346B2 (en) | 2019-06-18 | 2022-11-08 | Pfizer Inc. | Benzisoxazole sulfonamide derivatives |
| US12371425B2 (en) | 2019-06-18 | 2025-07-29 | Pfizer Inc. | Benzisoxazole sulfonamide derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| IL105391A0 (en) | 1993-08-18 |
| AU3957193A (en) | 1993-11-18 |
| ZA932576B (en) | 1993-10-28 |
| WO1993021171A1 (en) | 1993-10-28 |
| CA2130095A1 (en) | 1993-10-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0752988B1 (en) | 5H-INDENO[1,2-b]PYRAZINE-2,3-DIONE DERIVATIVES ANTAGONISTS OF AMPA AND NMDA RECEPTORS | |
| FR2711993A1 (en) | Medicaments containing 7H-imidazol [1,2-a] pyrazine-8-one derivatives, the novel compounds and their preparation. | |
| EP0708778B1 (en) | Imidazo[1,2-a]pyrazin-4-one derivatives for use as ampa and nmda receptor antagonists | |
| FR2707643A1 (en) | Derivatives of imidazo [1,2-a] pyrazine-4-one, their preparation and the medicaments containing them. | |
| EP0789699B1 (en) | SPIRO[HETEROCYCLE-IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZINE]-4'-ONES, PREPARATION THEREOF AND DRUGS CONTAINING SAME | |
| EP0662971B1 (en) | 5H,10H-IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZINE-4-ONE DERIVATIVES, PREPARATION THEREOF AND MEDICAMENTS CONTAINING THEM | |
| EP0752991B1 (en) | IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZIN-4-ONES ANTAGONISTS OF AMPA AND NMDA RECEPTORS | |
| WO1991013874A1 (en) | Derivatives of glycinamide, their preparation and medicaments containing them | |
| WO1997025329A1 (en) | 5H,10H-IMIDAZO[1,2-a]INDOLO[3,2-e]PYRAZINE-4-ONE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME | |
| FR2690160A1 (en) | Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives to the preparation of medicaments, new products, their preparation and the medicaments containing them. | |
| EP0752994A1 (en) | IMIDAZO[1,2-a]PYRAZIN-4-ONE DERIVATIVES, THEIR PREPARATION AND DRUGS CONTAINING THEM | |
| EP0533827A1 (en) | NEW OXAZOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. | |
| EP0772615B1 (en) | IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZINE-2-CARBOXYLIC ACID DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME | |
| EP0719262A1 (en) | 3,4-dihydro-2h-1,2,4-benzothiadiazine 1,1-dioxide-3-carboxylic acid derivatives, their preparation and drugs containing same | |
| FR2738821A1 (en) | INDENO [1,2-E] PYRAZIN-4-ONES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM | |
| EP0772612A1 (en) | 4-hydroxy-3-phenyl-indeno(1,2-b)pyridine-2(1h)-one derivatives as nmda antagonists | |
| FR2690159A1 (en) | New di:hydro-benzothiadiazine di:oxide carboxylic acid derivs. | |
| FR2743364A1 (en) | DERIVATIVES OF 5H, 10H-IMIDAZO (1,2-A) INDENO (1,2-E) PYRAZINE-4-ONE, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM | |
| FR2696457A1 (en) | New di:hydro-benzothiadiazine di:oxide carboxylic acid derivs. | |
| WO1997025326A1 (en) | 2-SUBSTITUTED 5H,10H-IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZINE-4-ONES, PREPARATION THEREOF AND DRUGS CONTAINING SAME |