EP1434777A1 - Benzisothiazolyl-substituierte aminomethylchromane zur behandlung von erkrankungen des zentralen nervensystems - Google Patents
Benzisothiazolyl-substituierte aminomethylchromane zur behandlung von erkrankungen des zentralen nervensystemsInfo
- Publication number
- EP1434777A1 EP1434777A1 EP02767489A EP02767489A EP1434777A1 EP 1434777 A1 EP1434777 A1 EP 1434777A1 EP 02767489 A EP02767489 A EP 02767489A EP 02767489 A EP02767489 A EP 02767489A EP 1434777 A1 EP1434777 A1 EP 1434777A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mmol
- dihydro
- chromen
- acid
- compounds
- 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- Withdrawn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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 10
- 201000010099 disease Diseases 0.000 title abstract description 8
- 210000003169 central nervous system Anatomy 0.000 title abstract description 7
- -1 Benzisothiazolyl-substituted aminomethyl chromanes Chemical class 0.000 title description 18
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 10
- 208000006011 Stroke Diseases 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 3
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical group C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 150000001843 chromanes Chemical class 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 21
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
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- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
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- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
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- GRPGDBKIWXIPHM-UHFFFAOYSA-N ethyl 6-methoxy-7-phenylmethoxy-3,4-dihydro-2h-chromene-2-carboxylate Chemical compound C1=C2OC(C(=O)OCC)CCC2=CC(OC)=C1OCC1=CC=CC=C1 GRPGDBKIWXIPHM-UHFFFAOYSA-N 0.000 description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- BITUJTOHCYCQDX-OAHLLOKOSA-N [(2r)-6-methoxy-7-phenylmethoxy-3,4-dihydro-2h-chromen-2-yl]methanol Chemical compound O([C@@H](CO)CCC=1C=C2OC)C=1C=C2OCC1=CC=CC=C1 BITUJTOHCYCQDX-OAHLLOKOSA-N 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- RXQGJGVDTAXBQZ-UHFFFAOYSA-N ethyl 6-methoxy-4-oxo-7-phenylmethoxychromene-2-carboxylate Chemical compound C1=C2OC(C(=O)OCC)=CC(=O)C2=CC(OC)=C1OCC1=CC=CC=C1 RXQGJGVDTAXBQZ-UHFFFAOYSA-N 0.000 description 3
- ROKVTBVTGYCEDT-UHFFFAOYSA-N ethyl 7-hydroxy-6-methoxy-3,4-dihydro-2h-chromene-2-carboxylate Chemical compound COC1=C(O)C=C2OC(C(=O)OCC)CCC2=C1 ROKVTBVTGYCEDT-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- MGIYRDNGCNKGJU-UHFFFAOYSA-N isothiazolinone Chemical compound O=C1C=CSN1 MGIYRDNGCNKGJU-UHFFFAOYSA-N 0.000 description 3
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- 239000002287 radioligand Substances 0.000 description 3
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
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- 206010061216 Infarction Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
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- 230000036506 anxiety Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- DUPIUWHQWBDPCP-XMMPIXPASA-N benzyl n-[[(2r)-3,4-dihydro-2h-chromen-2-yl]methyl]-n-[4-(1,1,3-trioxo-1,2-benzothiazol-2-yl)butyl]carbamate Chemical compound O=C1C2=CC=CC=C2S(=O)(=O)N1CCCCN(C[C@@H]1OC2=CC=CC=C2CC1)C(=O)OCC1=CC=CC=C1 DUPIUWHQWBDPCP-XMMPIXPASA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 229960002069 diamorphine Drugs 0.000 description 1
- ZAYMRPIJNLRXJH-UHFFFAOYSA-N dichloromethane methanesulfonyl chloride Chemical compound CS(=O)(=O)Cl.ClCCl ZAYMRPIJNLRXJH-UHFFFAOYSA-N 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009297 electrocoagulation Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- GRPGDBKIWXIPHM-MRXNPFEDSA-N ethyl (2r)-6-methoxy-7-phenylmethoxy-3,4-dihydro-2h-chromene-2-carboxylate Chemical compound C([C@@H](OC1=C2)C(=O)OCC)CC1=CC(OC)=C2OCC1=CC=CC=C1 GRPGDBKIWXIPHM-MRXNPFEDSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GJJUEEGRVKSEEU-UHFFFAOYSA-N methyl 4-[tert-butyl(dimethyl)silyl]oxy-3,4-dihydro-2h-chromene-2-carboxylate Chemical compound C1=CC=C2OC(C(=O)OC)CC(O[Si](C)(C)C(C)(C)C)C2=C1 GJJUEEGRVKSEEU-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 210000003657 middle cerebral artery Anatomy 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- GWWZKXQHXCOMEH-UHFFFAOYSA-N n-benzyl-4-hydroxy-3,4-dihydro-2h-chromene-2-carboxamide Chemical compound O1C2=CC=CC=C2C(O)CC1C(=O)NCC1=CC=CC=C1 GWWZKXQHXCOMEH-UHFFFAOYSA-N 0.000 description 1
- 210000005157 neural retina Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- YGYBFMRFXNDIPO-QGZVFWFLSA-N repinotan Chemical class O=S1(=O)C2=CC=CC=C2C(=O)N1CCCCNC[C@@H]1OC2=CC=CC=C2CC1 YGYBFMRFXNDIPO-QGZVFWFLSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000002295 serotoninergic effect Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000000825 ultraviolet detection Methods 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to chromans, processes for their preparation and their use in medicaments, in particular as agents for combating diseases of the central nervous system.
- the invention therefore relates to new compounds of the general formula (I)
- the Neritatien according to the invention can exist in stereoisomeric forms that either behave like image and mirror image (enantiomers), or that do not behave like image and mirror image (diastereomers).
- the invention relates to both
- Enantiomers or diastereomers or their respective mixtures These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
- inventive compounds can also be in the form of their salts, hydrates and / or solvates.
- preferred salts are physiologically acceptable salts of the Neritatien according to the invention.
- Physiologically acceptable salts of the Neritatien invention can be acid addition salts of the Neritatien with mineral acids, carboxylic acids or sulfonic acids.
- salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, eansulfonic acid, toluenesulfonic acid, benzenesulfonic acid, ⁇ aphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid are particularly preferred. Hydrates of the compounds according to the invention are stoichiometric compositions of the compounds or its salts with water.
- Solvates of the compounds according to the invention are stoichiometric compositions of the compounds or its salts with solvent, optionally in an isomeric form, and their salts.
- Preferred compounds of the general formula (I) are those which have the R configuration in the 2-position of the chroman radical.
- inventive compounds of the general formula (I) can be prepared as illustrated in the following formula schemes and as described in the exemplary embodiments:
- the compounds according to the invention can be used as active ingredients in pharmaceuticals.
- the substances according to the invention have a particularly high affinity for cerebral 5-hydroxy-tryptamine receptors of the 5-HTi A type.
- Active substances for combating diseases which are characterized by disorders of the serotoninergic system, in particular when receptors of the 5-HT ⁇ type are involved. They are therefore suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for
- the compounds of the general formula (I) and the pharmaceutical compositions derived from these compounds, as for other 5HT]! A ligands shown in WO 99/26621 are used for the post-acute therapeutic treatment of various neurological conditions in which various cell types of the nervous system have been degenerated and / or damaged as a result of neurodegenerative diseases or interventions or exposures.
- compounds of the general formula (T) can be used for the treatment of secondary conditions in which damage to cells of the nervous system due to surgical interventions, infections, exposure to toxic agents, tumors, nutritional deficits or metabolic diseases has occurred.
- compounds of the general Formula (I) are used to treat the consequences of neurodegenerative diseases, such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, substance abuse or drug addiction (alcohol, cocaine, heroin, amphetamine or the like), spinal cord diseases and / or - Injuries, dystrophy or degeneration of the neural retina (retinopathies) and peripheral neuropathies, such as diabetic neuropathy and / or peripheral neuropathies induced by toxins.
- compounds of general formula (I) can be used in conjunction with surgical implantation of tissues and / or prostheses for the treatment of Alzheimer's disease or other neurological diseases and / or malfunctions in which an implantation is indicated.
- Rat hippocampal membranes measured. It was found that the Neritatien compete with the radioligand for the binding and inhibit it.
- the left cerebral artery in rats is occluded by electrocoagulation.
- the resulting infarct volume in cortical (subcortical) regions that are supplied by the middle cerebral artery is used as a measure of the size of the stroke-induced neuronal damage.
- Substance application After occlusion as a continuous IV. Infusion (4 hours) of the test substance, starting immediately after the operation. The animals are sacrificed for evaluation 7 days after the operation.
- the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more Neritatien of the general formula (I), or which consist of a or several active ingredients of the formula (I), and processes for the preparation of these preparations.
- the active compounds of the formula (I) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture.
- the pharmaceutical preparations can also contain other pharmaceutical active ingredients.
- the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
- the residue is purified by chromatography (silica gel, mobile phase dichloromethane / ethanol, gradient 1: 0 to 5: 1).
- the product fractions thus obtained are freed from the solvent by concentration, taken up in ethanol and carefully mixed with 10 ml of a 4 N solution of HCl gas in ethanol. After cooling in ice, the solid obtained is suction filtered, dissolved in 550 ml of hot heat and treated with activated carbon. After filtration, the mixture is concentrated to about 100 ml. The crystals which precipitate are filtered off with suction and dried in vacuo.
- the raw product is purified by HPLC chromatography under the following conditions: Nucleosil ® 100 C-18 column, 125 x 16 mm (particle size 7 ⁇ m), column temperature room temperature, eluent 85% acetonitrile / 15% water (v / v), Flow 6 ml / min., UV detection at 230 nm.
- the product-containing fractions are combined and evaporated to dryness.
- the residue is dissolved in 2.5 ml of ethanol and 6 ml of acetone and again evaporated to dryness.
- the product is dried in a desiccator over blue gel.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10148425 | 2001-10-01 | ||
| DE10148425A DE10148425A1 (de) | 2001-10-01 | 2001-10-01 | Chromane |
| PCT/EP2002/010447 WO2003029250A1 (de) | 2001-10-01 | 2002-09-18 | Benzisothiazolyl-substituerte aminomethylcromane zur behandlung von erkrankungen des zentralen nervensystems |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1434777A1 true EP1434777A1 (de) | 2004-07-07 |
Family
ID=7700998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02767489A Withdrawn EP1434777A1 (de) | 2001-10-01 | 2002-09-18 | Benzisothiazolyl-substituierte aminomethylchromane zur behandlung von erkrankungen des zentralen nervensystems |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6919360B2 (https=) |
| EP (1) | EP1434777A1 (https=) |
| JP (1) | JP2005507901A (https=) |
| CA (1) | CA2462142A1 (https=) |
| DE (1) | DE10148425A1 (https=) |
| WO (1) | WO2003029250A1 (https=) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2199086B1 (es) | 2002-07-31 | 2005-06-01 | Cepa Schwarz Pharma Sl | Nuevos derivados de cicloalcanodionas, procedimiento para su preparacion y sus aplicaciones farmacologicas. |
| ES2238015B1 (es) * | 2004-01-30 | 2006-11-01 | Cepa Schwarz Pharma, S.L. | Derivados de cicloalcanodionas con actividad neuroprotectora. |
| EP1856126A2 (en) * | 2005-02-17 | 2007-11-21 | Wyeth a Corporation of the State of Delaware | Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3901814A1 (de) | 1988-07-28 | 1990-02-01 | Bayer Ag | Substituierte aminomethylzetraline sowie ihre heterocyclischen analoga |
| DE19522088A1 (de) * | 1995-06-19 | 1997-01-02 | Bayer Ag | Benzisothiazolyl-substituierte Aminomethylchromane |
| DE19543476A1 (de) * | 1995-11-22 | 1997-05-28 | Troponwerke Gmbh & Co Kg | Verwendung von substituierten Aminomethyl-chromanen zur Behandlung von Schädel-Hirn-Trauma |
-
2001
- 2001-10-01 DE DE10148425A patent/DE10148425A1/de not_active Withdrawn
-
2002
- 2002-09-18 EP EP02767489A patent/EP1434777A1/de not_active Withdrawn
- 2002-09-18 JP JP2003532498A patent/JP2005507901A/ja not_active Withdrawn
- 2002-09-18 WO PCT/EP2002/010447 patent/WO2003029250A1/de not_active Ceased
- 2002-09-18 US US10/490,315 patent/US6919360B2/en not_active Expired - Fee Related
- 2002-09-18 CA CA002462142A patent/CA2462142A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO03029250A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE10148425A1 (de) | 2003-04-17 |
| US6919360B2 (en) | 2005-07-19 |
| JP2005507901A (ja) | 2005-03-24 |
| US20040259924A1 (en) | 2004-12-23 |
| WO2003029250A1 (de) | 2003-04-10 |
| CA2462142A1 (en) | 2003-04-10 |
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