EP1472219A1 - Nouveaux derives de benzothiazine et benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent - Google Patents
Nouveaux derives de benzothiazine et benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennentInfo
- Publication number
- EP1472219A1 EP1472219A1 EP02805406A EP02805406A EP1472219A1 EP 1472219 A1 EP1472219 A1 EP 1472219A1 EP 02805406 A EP02805406 A EP 02805406A EP 02805406 A EP02805406 A EP 02805406A EP 1472219 A1 EP1472219 A1 EP 1472219A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- group
- compound
- linear
- branched
- 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.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- 238000000034 method Methods 0.000 title description 13
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 title description 4
- 150000007658 benzothiadiazines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 39
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- 239000001301 oxygen Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims abstract description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical group 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 230000009471 action Effects 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000004434 sulfur atom Chemical group 0.000 claims description 9
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- -1 cyano, nitro, amino Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 150000001409 amidines Chemical class 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 125000002734 organomagnesium group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 230000008707 rearrangement Effects 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 2
- 150000002431 hydrogen Chemical group 0.000 abstract description 3
- 239000005864 Sulphur Chemical group 0.000 abstract 2
- 229940079593 drug Drugs 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 230000008018 melting Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 238000004452 microanalysis Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- KOSYAAIZOGNATQ-UHFFFAOYSA-N o-phenyl chloromethanethioate Chemical compound ClC(=S)OC1=CC=CC=C1 KOSYAAIZOGNATQ-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000012429 reaction media Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000003678 AMPA Receptors Human genes 0.000 description 3
- 108090000078 AMPA Receptors Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- DSUQOTGCKDGCEZ-UHFFFAOYSA-N 2-amino-5-methoxybenzenesulfonamide Chemical compound COC1=CC=C(N)C(S(N)(=O)=O)=C1 DSUQOTGCKDGCEZ-UHFFFAOYSA-N 0.000 description 2
- WLOKSNLRCIKYSN-UHFFFAOYSA-N 2h-1,2,3-benzothiadiazin-7-yl phenyl carbonate Chemical compound C=1C=C2C=NNSC2=CC=1OC(=O)OC1=CC=CC=C1 WLOKSNLRCIKYSN-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HAVZTGSQJIEKPI-UHFFFAOYSA-N benzothiadiazine Chemical compound C1=CC=C2C=NNSC2=C1 HAVZTGSQJIEKPI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002461 excitatory amino acid Effects 0.000 description 2
- 239000003257 excitatory amino acid Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000287 oocyte Anatomy 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical class CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- JXAGXXIWINHQJQ-UHFFFAOYSA-N (4-chlorophenoxy)methanethioic s-acid Chemical compound SC(=O)OC1=CC=C(Cl)C=C1 JXAGXXIWINHQJQ-UHFFFAOYSA-N 0.000 description 1
- BGPJLYIFDLICMR-UHFFFAOYSA-N 1,4,2,3-dioxadithiolan-5-one Chemical compound O=C1OSSO1 BGPJLYIFDLICMR-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- JSXOLUYPSRUBHR-UHFFFAOYSA-N 4-ethyl-7-methoxy-2,3-dihydro-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound COC1=CC=C2N(CC)CNS(=O)(=O)C2=C1 JSXOLUYPSRUBHR-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical group NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 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 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 241000269370 Xenopus <genus> Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 1
- ZXNRTKGTQJPIJK-UHFFFAOYSA-N aniracetam Chemical compound C1=CC(OC)=CC=C1C(=O)N1C(=O)CCC1 ZXNRTKGTQJPIJK-UHFFFAOYSA-N 0.000 description 1
- 229960000793 aniracetam Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
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- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
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- 239000006071 cream Substances 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
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- 206010015037 epilepsy Diseases 0.000 description 1
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- 230000005284 excitation Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000007334 memory performance Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000008587 neuronal excitability Effects 0.000 description 1
- 230000007996 neuronal plasticity Effects 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LUCZGTXVPODASE-UHFFFAOYSA-N phenylsulfanylmethanethioic s-acid Chemical compound SC(=O)SC1=CC=CC=C1 LUCZGTXVPODASE-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
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- 201000000980 schizophrenia Diseases 0.000 description 1
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- 230000024587 synaptic transmission, glutamatergic Effects 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
Definitions
- the present invention relates to new benzothiazine and benzothiadiazine derivatives, their preparation process and the pharmaceutical compositions containing them.
- the AMPA receptor (“-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid”) appears to be the most involved in the phenomena of physiological neuronal excitability and in particular in those involved in memorization processes. For example, learning has been shown to be associated with increased binding of AMPA to its receptor in the hippocampus, one of the brain areas essential for mnemocognitive processes. Likewise, nootropic agents such as aniracetam have been described very recently as positively modulating the AMPA receptors of neuronal cells (Journal of Neurochemistry, 1992, 58, 1199-1204).
- patent EP 692 484 describes a benzothiadiazme derivative having a facilitating activity on the AMPA current and patent application WO 99/42456 describes inter alia certain benzothiadiazme derivatives as modulators of AMPA receptors.
- Prior. They are useful as AMPA modulators for the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depressive syndromes, progressive neurogenerative diseases, Alzheimer's disease, Pick's disease, chorea. Huntington's, schizophrenia, sequelae of acute neurodegenerative diseases, sequelae of ischemia and sequelae of epilepsy.
- Ri represents an aryl or heteroaryl group
- R 2 represents a hydrogen atom, a halogen atom or a hydroxy group
- X represents an oxygen or sulfur atom
- Y represents an oxygen or sulfur atom or a group NR in which R represents a hydrogen atom or an alkyl group (C ⁇ -C 6 ) linear or branched, A represents a group CR_jR 5 or a group NR4, R 3 represents a hydrogen atom, a linear or branched alkyl group (C ⁇ -C 6 ) or a cycloalkyl group (C 3 -C), Rj represents a hydrogen atom or a linear or branched alkyl group (C ⁇ -C 6 ) , or A represents a nitrogen atom and forms with the group -CHR 3 - adjacent the ring in which m represents 1, 2 or 3,
- R 5 represents a hydrogen or halogen atom
- alkyl groups C ⁇ -C 6 linear or branched
- alkyl (C ⁇ -C 6 ) sulfonylamino optionally substituted by one or more alkyl groups (C ⁇ -C 6 ) linear or branched
- alkyl (C ⁇ -C 6 ) sulfonylamino optionally substituted by one or more alkyl groups (C ⁇ -C 6 ) linear or branched
- hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane sulfonic, camphoric acids, etc.
- the preferred aryl group is the phenyl group.
- the preferred group R is the hydrogen atom.
- A preferably represents an NR group or else a nitrogen atom and forms with the group -CHR 3 - adjacent the —N - ring, m preferably representing
- Y preferably represents an oxygen or sulfur atom.
- the invention also extends to the process for the preparation of the compounds of formula (I).
- R'i represents a linear or branched alkoxy group (C ⁇ -C 6 ),
- R ′ 2 represents a hydrogen or halogen atom or a linear or branched alkoxy group (C ⁇ -C 6 ), who is :
- R 3 is such a defined in formula (I),
- R'i represents a linear or branched alkoxy group (C ⁇ -C 6 ),
- R ' 2 represents a hydrogen, halogen atom or an alkoxy group (C ⁇ -C 6 ) linear or branched, which undergoes the action of chloroacetone in the presence of a mineral base in dimethylformamide medium, to lead to the compound of formula (XVI):
- R'i and R ' 2 have the same meaning as above, including, possibly, in the particular case where R 3 is different from the hydrogen atom, we protects the nitrogen atom with a protective group, then, after treatment with a strong base, which is treated with a compound of formula R ' 3 -P, in which R' represents an alkyl group (-C 6 ) linear or branched or a cycloalkyl group (C 3 -C) and P represents a leaving group, to lead after deprotection of the nitrogen atom, to the compound of formula (XlX'a):
- R'i, R ' 2 and R' have the same meaning as above, composed of formula (XIXa) and (XlX'a) represented by the formula (XIX):
- R'i and R ' 2 have the same meaning and R 3 is as defined in formula (I), which:
- R'i and R ' 2 have the same meaning as above, R' 5 represents a halogen atom,
- R 'MgBr represents a linear or branched alkyl group (C ⁇ -C 6 )
- R'i, R ' 2 and R' 4 have the same meaning as above and R ' 5 represents a halogen atom
- Ri in which Ri, X have the same meaning as in formula (I), and Y 'represents an oxygen or sulfur atom or a group ⁇ in which R represents a linear or branched (C ⁇ -C 6 ) alkyl group ,
- the invention also extends to pharmaceutical compositions containing as a principle active a compound of formula (I) with one or more inert, non-toxic and suitable excipients.
- pharmaceutical compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injections, oral suspensions, etc.
- the useful dosage is adaptable according to the nature and severity of the disease, the route of administration as well as the age and weight of the patient. This dosage varies from 1 to 500 mg per day in one or more doses.
- the starting materials used are known products or prepared according to known procedures.
- the product obtained in the preceding stage is stirred overnight, at room temperature, in 320 ml of an aqueous solution of IN sodium hydroxide. After adding 50 ml of ethyl acetate and vigorous stirring, the expected product which precipitates is filtered, rinsed and dried.
- the expected product is obtained by replacing, in Stage E, phenyl chloroformate with phenyl thionochloroformate. Melting point: 252-254 ° C Elemental microanalysis: C H N S
- the expected product is obtained by replacing, in stage E, phenyl chloroformate with 4-chlorophenyl thionochloroformate, Melting point: 189-194 ° C. Elemental microanalysis:
- a suspension of 3.0 g of 2-amino-5-methoxybenzenesulfonamide is stirred for 1 night at 80 ° C. in the presence of 1.31 g of formamidine hydrochloride and 2.27 ml of triethylamine in 50 ml of toluene.
- the toluene is evaporated under vacuum, the residue is taken up in water and the precipitate is filtered.
- Stage E O- (4-Ethyl-l, l-dioxido-3,4-dihydro-2-H-l, 2,4-benzothiadiazin-7-ylVO- phenyl thiocarbonate
- the expected product is obtained according to the process described in Stage E of Example 1, replacing the phenyl chloroformate with the phenyl thionochloroformate.
- the expected product is obtained according to the process described in Example 5 by replacing, in Stage E, phenyl thionochloroformate with 4-chlorophenyl thionochloroformate. Melting point: 155-156 ° C
- MRNAs are prepared from the cerebral cortex of a male Wistar rat by the guanidium thiocyanate / phenol / chloroform method.
- Poly (A + ) mRNAs are isolated by chromatography on oligo-dT cellulose and injected at a rate of 50 ng per oocyte. The oocytes are left for 2 to 3 days in incubation at 18 ° C to allow the expression of receptors and then stored at 8-10 ° C.
- the electrophysiological recording is carried out in a plexiglass® chamber at 20-24 ° C in OR2 medium (J. Exp. Zool., 1973, 184, 321-334) by the "voltage clamp" method with 2 electrodes, a third electrode placed in the bath serving as a reference.
- the compounds of the invention very strongly potentiate the excitatory effects of AMPA and their activity is very clearly superior to that of the reference compounds.
- the compound of Example 2 has in particular an EC2X equal to 1.8 ⁇ M and an EC5X equal to 9.6 ⁇ M.
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0116620A FR2833955B1 (fr) | 2001-12-21 | 2001-12-21 | Nouveaux derives de benzothiazine et de benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR0116620 | 2001-12-21 | ||
| PCT/FR2002/004483 WO2003053978A1 (fr) | 2001-12-21 | 2002-12-20 | Nouveaux derives de benzothiazine et benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1472219A1 true EP1472219A1 (fr) | 2004-11-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02805406A Withdrawn EP1472219A1 (fr) | 2001-12-21 | 2002-12-20 | Nouveaux derives de benzothiazine et benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US7262189B2 (zh) |
| EP (1) | EP1472219A1 (zh) |
| JP (1) | JP2005518385A (zh) |
| KR (1) | KR100586684B1 (zh) |
| CN (1) | CN1289508C (zh) |
| AR (1) | AR038260A1 (zh) |
| AU (1) | AU2002364673B2 (zh) |
| BR (1) | BR0214926A (zh) |
| CA (1) | CA2471120A1 (zh) |
| EA (1) | EA007492B1 (zh) |
| FR (1) | FR2833955B1 (zh) |
| GE (1) | GEP20063757B (zh) |
| HK (1) | HK1071746A1 (zh) |
| HU (1) | HUP0402583A3 (zh) |
| MA (1) | MA27088A1 (zh) |
| MX (1) | MXPA04005839A (zh) |
| NO (1) | NO20042708L (zh) |
| NZ (1) | NZ533329A (zh) |
| PL (1) | PL370166A1 (zh) |
| UA (1) | UA78742C2 (zh) |
| WO (1) | WO2003053978A1 (zh) |
| ZA (1) | ZA200404295B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2877342B1 (fr) * | 2004-11-03 | 2007-01-26 | Servier Lab | Nouveaux derives de benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| EA022078B1 (ru) * | 2010-08-10 | 2015-10-30 | Такеда Фармасьютикал Компани Лимитед | Гетероциклическое соединение и его применение |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2722502B1 (fr) * | 1994-07-12 | 1996-08-23 | Adir | Nouveau derive de benzothiadiazine, son procede depreparation et les compositions pharmaceutiques qui le contiennent |
| PL342843A1 (en) * | 1998-02-18 | 2001-07-16 | Neurosearch As | Novel compounds and their use as positive ampa receptor modulators |
| FR2812291B1 (fr) * | 2000-07-28 | 2002-12-13 | Adir | Nouveaux derives de benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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- 2002-12-20 WO PCT/FR2002/004483 patent/WO2003053978A1/fr active Application Filing
- 2002-12-20 CA CA002471120A patent/CA2471120A1/fr not_active Abandoned
- 2002-12-20 BR BR0214926-5A patent/BR0214926A/pt not_active IP Right Cessation
- 2002-12-20 JP JP2003554694A patent/JP2005518385A/ja active Pending
- 2002-12-20 UA UA20040706009A patent/UA78742C2/uk unknown
- 2002-12-20 US US10/499,164 patent/US7262189B2/en not_active Expired - Fee Related
- 2002-12-20 PL PL02370166A patent/PL370166A1/xx not_active Application Discontinuation
- 2002-12-20 KR KR1020047009200A patent/KR100586684B1/ko not_active IP Right Cessation
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- 2002-12-20 EA EA200400757A patent/EA007492B1/ru not_active IP Right Cessation
- 2002-12-20 EP EP02805406A patent/EP1472219A1/fr not_active Withdrawn
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Non-Patent Citations (1)
| Title |
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| See references of WO03053978A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA04005839A (es) | 2004-09-10 |
| HUP0402583A2 (hu) | 2005-03-29 |
| NO20042708L (no) | 2004-06-28 |
| AR038260A1 (es) | 2005-01-12 |
| FR2833955B1 (fr) | 2004-01-30 |
| HK1071746A1 (en) | 2005-07-29 |
| UA78742C2 (en) | 2007-04-25 |
| AU2002364673B2 (en) | 2007-11-22 |
| ZA200404295B (en) | 2005-06-01 |
| NZ533329A (en) | 2006-10-27 |
| EA007492B1 (ru) | 2006-10-27 |
| EA200400757A1 (ru) | 2004-10-28 |
| US20050065146A1 (en) | 2005-03-24 |
| CA2471120A1 (fr) | 2003-07-03 |
| FR2833955A1 (fr) | 2003-06-27 |
| PL370166A1 (en) | 2005-05-16 |
| US7262189B2 (en) | 2007-08-28 |
| JP2005518385A (ja) | 2005-06-23 |
| GEP20063757B (en) | 2006-02-27 |
| KR100586684B1 (ko) | 2006-06-08 |
| BR0214926A (pt) | 2004-11-30 |
| CN1606559A (zh) | 2005-04-13 |
| WO2003053978A1 (fr) | 2003-07-03 |
| KR20040073479A (ko) | 2004-08-19 |
| AU2002364673A1 (en) | 2003-07-09 |
| HUP0402583A3 (en) | 2009-01-28 |
| CN1289508C (zh) | 2006-12-13 |
| MA27088A1 (fr) | 2004-12-20 |
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