HRP960077A2 - Substituted benzenesulfonylureas and -thioureas, process for their preparation, their use as medicinal or diagnostic agent as well as medicaments containing them - Google Patents
Substituted benzenesulfonylureas and -thioureas, process for their preparation, their use as medicinal or diagnostic agent as well as medicaments containing them Download PDFInfo
- Publication number
- HRP960077A2 HRP960077A2 HR19505397.4A HRP960077A HRP960077A2 HR P960077 A2 HRP960077 A2 HR P960077A2 HR P960077 A HRP960077 A HR P960077A HR P960077 A2 HRP960077 A2 HR P960077A2
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- Croatia
- Prior art keywords
- formula
- carbon atoms
- substituted
- hydrogen
- alkyl
- Prior art date
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- 239000003814 drug Substances 0.000 title claims description 16
- 238000000034 method Methods 0.000 title claims description 15
- 230000008569 process Effects 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 6
- 239000000032 diagnostic agent Substances 0.000 title 1
- 229940039227 diagnostic agent Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims description 36
- -1 methoxyethoxy Chemical group 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000000126 substance Substances 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical class NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Chemical group 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 239000011737 fluorine Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 239000011593 sulfur Chemical group 0.000 claims description 9
- PVMBGVAQRSHDBB-UHFFFAOYSA-N benzenesulfonylthiourea Chemical compound NC(=S)NS(=O)(=O)C1=CC=CC=C1 PVMBGVAQRSHDBB-UHFFFAOYSA-N 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- 229940124530 sulfonamide Drugs 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 6
- 230000033764 rhythmic process Effects 0.000 claims description 6
- 206010049418 Sudden Cardiac Death Diseases 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000012948 isocyanate Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 102000016924 KATP Channels Human genes 0.000 claims description 3
- 108010053914 KATP Channels Proteins 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- 150000003672 ureas Chemical class 0.000 claims description 3
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical class OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 claims description 2
- 150000002540 isothiocyanates Chemical class 0.000 claims description 2
- UJYAZVSPFMJCLW-UHFFFAOYSA-N n-(oxomethylidene)benzenesulfonamide Chemical compound O=C=NS(=O)(=O)C1=CC=CC=C1 UJYAZVSPFMJCLW-UHFFFAOYSA-N 0.000 claims description 2
- ZACBJJDJJBGIDC-UHFFFAOYSA-N n-(sulfanylidenemethylidene)benzenesulfonamide Chemical compound S=C=NS(=O)(=O)C1=CC=CC=C1 ZACBJJDJJBGIDC-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- UVVUGWBBCDFNSD-UHFFFAOYSA-N tetraisocyanatosilane Chemical compound O=C=N[Si](N=C=O)(N=C=O)N=C=O UVVUGWBBCDFNSD-UHFFFAOYSA-N 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 229940125904 compound 1 Drugs 0.000 claims 4
- 230000004217 heart function Effects 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 230000000302 ischemic effect Effects 0.000 claims 1
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims 1
- RISUTSCZAANJJQ-UHFFFAOYSA-N sulfinylurea Chemical compound NC(=O)N=S=O RISUTSCZAANJJQ-UHFFFAOYSA-N 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000002253 acid Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 150000007513 acids Chemical class 0.000 description 11
- 239000012442 inert solvent Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000036982 action potential Effects 0.000 description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 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
- 239000002585 base Substances 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 206010003119 arrhythmia Diseases 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Substances [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 150000003456 sulfonamides Chemical class 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 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
- 206010019280 Heart failures Diseases 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 230000006793 arrhythmia Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229960004580 glibenclamide Drugs 0.000 description 4
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical group COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 241000700198 Cavia Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 150000004679 hydroxides Chemical class 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 238000004904 shortening Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 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
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910001507 metal halide Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 210000003540 papillary muscle Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
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- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- NOGBKWXHNPDHFA-UHFFFAOYSA-N tetraisothiocyanatosilane Chemical compound S=C=N[Si](N=C=S)(N=C=S)N=C=S NOGBKWXHNPDHFA-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 150000005311 thiohalides Chemical class 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical class NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/52—Y being a hetero atom
- C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
- C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
- C07C311/58—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- 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
- A61P9/06—Antiarrhythmics
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/40—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of thiourea or isothiourea groups further bound to other hetero atoms
- C07C335/42—Sulfonylthioureas; Sulfonylisothioureas
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Description
Izum se odnosi na supstituirane benzolsulfoniluree i tiouree formule 1
[image]
u kojoj
R(l) je vodik, metil ili trifluormetil;
R(2) je alkoksi sa 4, 5, 6, 7, 8, 9 ili 10 C-atoma, pri čemu 1 do 6 ugljikovih atoma su zamijenjeni s heteroatomima
O, S ili NH;
E je kisik ili sumpor;
Y je -[CR(3)2]1-4;
R(3) je vodik ili alkil s 1 ili 2 C-atoma;
X je vodik, halogen ili alkil s 1, 2, 3, 4, 5 ili 6 C-atoma ;
Z je halogen, alkoksi s 1, 2, 3 ili 4 C-atoma ili alkil s 1, 2, 3 ili 4 C-atoma;
te njihove farmaceutski podnošljive soli.
Sulfoniluree poznate su iz njemačkog priopćenja 2413514, njemačkog patentnog spisa 1 518 874. Tamo se opisuje njlhov učinak smanjenja šećera u krvi. Prototip takovih sulfonilurea koje smanjuju šećer u krvi je Glibenclamid, koji se terapeutski upotrebljava kao sredstvo za liječenje diabetesa mellitusa, a u istraživanju služi kao vrlo cijenjeno sredstvo za istraživanje takozvanih ATP senzitivnih kanala kalija. Pored učinka smanjenja šećera u krvi Glibenclamid ima i druge učinke koji se do sada još nisu mogli koristiti terapeutski, a koji se svi skupa mogu svesti na blokadu tih ATP-senzitivnih kanala kalija. Tu spada naročito antifibrilacijski učinak na srcu. Međutim, kod liječenja treperenja komore, ili njegovog predstupnja, nepoželjno je istovremeno smanjenje šećera u krvi ili je čak opasno, jer to može dalje pogoršati stanje pacijenta.
U europskom priopćenju 0 612 724 (HOE 93/F 056) već su opisani spojevi ograničenog učinka smanjenje šećera u krvi, all koji još nisu dostatni za mnoge svrhe. Tamo nema spojeva s drugim heteroatomom u supstituentu R(2), niti su predočeni.
Zadatak predloženog izuma bio je stoga sintetizirati spojeve koji pokazuju jednako dobar učinak na srce kao Glibenclamid, ali ne utječu ili utječu uočljivo manje na šećer u krvi u dozama ili koncentracijama koje utječu na srce kao Glineclamid.
Taj cilj postignut je s uvodno opisanim spojevima.
Spojevi 1 su ponajprije oni u kojima
R(l) je vodik, metil ili trifluormetil;
R(2) je alkoksi sa 4, 5, 6, 7, 8, 9 ili 10 C-atoma, u kojem jedan do šest ugljikovih atoma su zamijenjeni s heteroatomima O, NH ili S;
E je kisik ili sumpor;
Y je ravan sups'tituirani ili nesupstituirani ugljikovodični ostatak formule: -[CR(3)2]1-4;
R(3) je vodik ili alkil s 1 ili 2 C-atoma;
X je vodlk, klor, fluor ili alkil s 1, 2, 3 ili 4 C-atoma;
Z je nitro, fluor, klor, alkil s 1, 2, 3 ili 4 C-atoma ili alkoksi s 1, 2, 3 ili 4 C-atoma;
te njihove farmaceutskl podnošljive soli.
Posve osobitu prednost imaju spojevl 1 u kojima
R(l) je vodik ili metil;
R(2) je alkoksi sa 4, 5, 6, 7, 8, 9 ili 10 C-atoma, kod kojeg 1 do 6 ugljikovih atoma su zamijenjeni s heteroatomima O, S ili NH;
E je kisik ili sumpor;
Y je -[CR(2)3]1-4;
R(3) je vodik ili alkll s 1 ili 2 C-atoma;
X je vodik, fluor, klor ili alkll s 1, 2, 3 ili 4 C-atoma;
Z je fluor, klor, alkil s 1, 2, 3 ili 4 C-atoma ili alkoksi s 1, 2, 3 ili 4 C-atoma;
te njihove farmaceutski podnošljive soli.
Od naročite prednosti su spojevi formule 1 u kojima
R(1) je vodik ili metil;
R(2) je metoksietoksl ili metoksietoksietoksi;
E je kisik ili sumpor;
Y je [CR(3)]2-3;
R(3) je vodik ili metil;
X je vodik, fluor, klor ili alkil s 1, 2 ili 3 6 C-atoma;
Z je fluor, klor, alkil s 1, 2 ili 3 C-atoma ili alkoksi s 1, 2 ili 3 C-atoma;
te njihove farmaceutski podnošljive soli.
Ako nije izričito navedeno drugačije alkil znači ravan, razgranati ili ciklički zasićeni ugljikovodični ostatak s jednim do šest ugljikovih ostataka. Pojam alkoksi predstavlja eterski supstituent s ravnim, razgranatim ili cikličkim zasićenim ugljikovodičnim ostatkom od jedanog do deset ugljikovih atoma. Kao halogeni supstituenti upotrebljivi su elementi fluor, klor, brom i jod. Ugljikovi atomi alkilnog bočnog lanca Y i alkoksilnog lanca mogu biti supstituirani asimetrično.
Pri tome izum se odnosi na spojeve jednog ili drugog enantioniera te racemične smjese ili mješavine obaju antipoda u različitim omjerima. Nadalje spojevi se mogu pojaviti s dva središta kiralnosti u alkilnom bočnom lancu Y i alkoksilnom lancu. U tom slučaju izum također obuhvaća pojedinačne antipode same za sebe, kao također i smjesu obaju enantiomera u različitim omjerima, te pripadne mezospojeve.
Spojevi sukladni izumu su dragocjeni lijekovi za liječenje poremećaja ritma srca različitih geneza i za sprečavanje iznenadne srčane smrti uvjetovane aritmijom, i stoga se mogu upotrijebiti kao antiaritmici. Primjeri aritmičkih poremećaja srca su supraventrikularni poremećaji ritma kao slučajna tahikardija pretklijetke, treperenje pretklijetke ili paroksizmalni supraventrikularni poremećaji ritma ili ventrikularni poremećaji ritma kao ventirikularne ekstrasistole, osobito međutim životno opasne ventrikularne tahikardije ili osobito opasna treperenja komore. Oni su osobito prikladni za takove slučajeve gdje su aritmije posljedica suženja koronarne posude, kao što se primjerice pojavljuju kod angine pectoris ili tijekom akutnog srčanog infarkta ili kao kronična posljedica srčanog infarkta. Oni su stoga osobito prikladni kod pacijenata nakon infarkta za sprečavanje nagle srčane smrti. Daljnje slike bolesti kod kojih imaju ulogu takovi poremećaji ritma i/ili iznenadne srčane smrti uvjetovane aritmijom jesu primjerice srčana insuficijencija ili srčana hipertrofija kao posljedica kronično povišenog krvnog tlaka.
Zbog toga spojevi mogu pozitivno utjecati na smanjenu kontraktilnost srca. Tu se može raditi o popuštanju kontraktilnosti srca uvjetovanom bolešću, kao primjerice kod srčane insuficijencije ali također i o akutnim slučajeviina kao otkazivanju srca kod djelovanja šoka. Kod transplantaclje srca nakon uspješne operacije srce također može brže i pouzdanije ponovno preuzeti svoju radnu sposobnost. Isto vrijedi za operacije na srcu kod kojih je potrebno učiniti privrenieno smirenje aktivnosti srca pomoću kardioplegijskih otopina.
Kao pokusne životinje za dokazivanje takovih učinaka prikladni su na primjer miševi, štakori, zamorci, kunići, psi majmuni ili svinje. Spojevi se stoga mogu upotrijebiti kao aktivne tvari za lijekove u humanoj medicini ili veterini. Mogu se, nadalje, upotrijebiti kao meduproizvodi za proizvodnju daljnjih aktivnih tvari za lijekove.
Izum se nadalje odnosi na postupak za proizvodnju spojeva I, koji je naznačen time da se
(a) aromatski sulfonamid formule II
[image]
ili njegova sol formule III
[image]
s R(1)-supstituiranim izocijanatom formule IV
R(1)-N=C=O IV
kemijski pretvara u supstituiranu benzolsulfonilureu I.
Kao kationi M u solima formule III u obzir dolaze alkalni i zemno alkalni, amonijevi te tetraalkilamonijevi ioni. Ekvivalentno R(1)-supstituiranim izocijanatima IV može se upotrijebiti R(1)-supstituirani ester karbamidne kiseline, R(1)-supstituirani halogenid karbamidne kiseline ili R(1)-supstituirana urea.
(b) Nesupstituiranu benzolsulfonilureu Ia [R(1) = H] može se proizvesti kemijskom pretvorbom aromatskog benzol-sulfonamida formule II ili njegove soli ili s trialkil-sililizocijanatom ili silicijevim tetraizocijanatom i hidrolizom primarne benzolsulfoniluree supstituirane sa silicijem. Moguće je, nadalje, benzolsulfonamid II ili njegovu sol III pripremiti kemijskom pretvorbom s halogencijanom i hidrolizom primarno nastalog N-cijano-sulfonamida s mineralnim kiselinama pri temperaturama od 0°C do 100°C.
(c) Benzolsulfonilurea Ia može se pripremiti iz aromatskog benzolsulfonamida II ili njegove soli III s
R(1)-supstituiranim trikloracetamidom formule V
Cl3C-C(CO) -NHR(1) V
u prisutnosti baze u inertnom otapali prema Synthesis 1987 y 734-735 pri temperaturama od 25°C do 150°C.
Kao baze prikladni su na primjer hidroksidi alkalnlh metala ili zemno alkalnih metala, hidridi, aznidi ili također alkoholati, kao natrijev hidroksid, kalijev hidroksid, kalcijev hidroksid, natrijev hidrid, kalijev hidrid, kalcijev hidrid, natrijev amid, kalijev amid natrijev metilat, natrijev metanolat, kalijev metilat ili kalijev metanolat. Kao inertna otapala prikladni su eteri kao tetrahidrofuran, dioksan, etileglikoldimetileter (diglim), ketoni kao aceton ili butanon, nitrili kao acetonitril, nitrospojevi kao nitrometan, ester kao etilacetat, amidi kao dimetilformamid (DMF) ili N-metil-pirolidon (NMP), heksametiltriamid fosforne kiseline, sulfoksidi kao DMSO, sulfoni kao sulfolan, ugljikovodici kao benzol, toluol, ksilol. Prikladne su nadalje također i medusobne mješavine tih otapala.
(d) Benzolsulfoniltioura Ib
[image]
priprema se iz benzolsulfonamida II ili njegove soli III i R(1)-supstituiranog izotiocijanata VI
R(1) –N=C=S VI
Nesupstituirana benzolsulfoniltiourea Ib [R(1)=H] može se proizvesti kemijskom pretvorbom aromatskog benzolsulfon-amida II ili njegove soli III s trimetilsililizotio-cijanatom ili silicijevim tetraizotiocijanatom i hidrolizom primarno nastale benzolsulfoniluree supstituirane sa silicijem. Aromatski benzolsulfonamid II ili njegova sol II može se nadalje kemijski pretvoriti s benzoilizotio-cijanatom, a intermedijarnu benzolsulfoniltioureu, supstituirane s benzoilom, može se kemijski pretvoriti u Ib [R(1) = H] s vodenoni mineralnom kiselinom. Slični postupci opisani su u J. Med. Chem, 1992, 35, 1137-1144.
e) Supstituirana benzolsulfonilurea formule la može se pripremiti reakcijom pretvorbe iz benzolsulfoniltiouree strukture Ib. Zamjena atoma sumpora s kisikovim atomom u odgovarajuće supstituiranini benzolsulfoniltioureama može se provesti primjerice pomoću oksida ili soli teških metala ili također primjenom oksidacijskih sredstava kao vodikovog peroksida, natrijevog peroksida ili dušičaste kiseline.
Tiouree se mogu osloboditi sumpora obradom s fozgenom ili fosfornim pentakloridom. Kao međuspojevi dobiju se amidi klor mravlje kiseline odnosno karbodinimidi, koji se na primjer saponifikacijom lli adicijom vode prevode u odgovarajuće supstituirane benzolsulfoniluree. Pri desumporiranju izotiouree se ponašaju kao tiouree i stoga također mogu poslužiti kao polazne tvari za ove reakcije.
(f) Benzolsulfonilurea Ia može se proizvesti iz benzolsulfonilhalogenida formule VII
[image]
s R(1)-supstituiranom ureom ili R(1) -supstituiranom bis-(trialkilsilil)ureom. Trialkilsililna zaštitna skupina može se odstraniti iz dobivene (trialkilsilil)benzolsulfoniluree standardnim metodama. Nadalje, kloridi sulfonske kiseline VII mogu se kemijski pretvoriti s parabanskim kiselinama u benzolsulfonilparabanske kiseline, čija hidroliza s mineralnim kiselinama daje odgovarajuće benzolsulfoniluree la.
(g) Benzolsulfonilurea la može se proizvest-i kemijskom pretvorbom amina formule R(1)-NH2 s benzolsulfonil-izocijanatom formule VIII
[image]
Amini R(1)-NH2 također se mogu kemijski pretvoriti u spojeve 1a s esterima benzolsulfonilkarbamidne kiseline, halogenidima benzolsulfonilkarbamidne kiseline ili s benzolsulfonilureama la [s R(1) = H] .
(h) Benzolsulfoniltiourea Ib može se proizvesti kemijskozn pretvorbom amina formule R(1)-NH2 s benzolsulfonilizotio-cijanatom formule IX
[image]
Amini R(1)-NH2 također se mogu kemijski pretvoriti u spojeve Ib s tioesterom benzolsulfonilkarbamidne kiseline ili tiohalogenidom benzolsulfonilkarbamidne kiseline.
(i) Odgovarajuće supstituirane benzosulfeniluree ili benzolsulfiniluree moqu se oksidirati u benzolsulfoniliree Ia s oksidacijskim sredstvima kao vodikovim peroksidom, natrijevim peroksidom ili dušičastom kiselinom.
Spojevi I te njihove fiziološk.i nedvojbene soli dragocjeni su terapeutici koji su prikladni ne samo kao antiaritmici već također i za profilaksu kod poremećaja kardiovaskularnog sistema, kod srčane insuficijencije, kod transplantacije srca ili oboljenja cerebralnih krvnih žila na Ijudima ili sisavcima (na primjer majmunima, psima, miševima, štakorima, kunićima zamorcima ili mačkama).
Pod fiziološki nedvojbenim solima spojeva I prema Rernmington s Pharmaceut.ical Science, 17. izdanje, 1985, strane 14-18, podrazumijevaju se spojevi formule XI
[image]
koji se mogu pripremiti iz netoksičnih organskih i anorganskig baza i supstituiranih benzolsulfonilurea I. To ponajprije mogu biti soli u kojima M u formuli XI je natrijev, kalijev, rubidijev, kalcijev, magnezijev, amonijev ion, te proizvodi kiselinske adicije bazičnih aminokiselina, kao lizina ili arginina.
Polazni spojevi za spomenute postupke sinteze benzolsulfoniluree I proizvode se po poznatim metodama, kao onima poznatim u literaturi (na primjer u standardnim djelima kao Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Willey & Sons, Inc., New York; te onim opisanim u gore navedenim patentnim priopćenjima), i to pod reakcijskim uvjetima koji su poznati i prikladni za navedene kemijske pretvorbe. Pri tome se također mogu primijeniti i poznate varijante koje nisu pobliže spomenute. Po želji polazne tvari mogu se proizvesti također i in situ, tako da ih se ne izolira iz reakcijske smjese, već ih se odmah dalje kemijski pretvara.
[image]
Prikladno supstituirani amini opće formule XII prema shemi 1 mogu se tako acilirati i podvrgnuti halogen-sulfoniranju. Kao sredstvo za aciliranje amino skupina prikladni su svrhovito alkilesteri, halogenidi (na primjer kloridi ili bromidi) ili anhidridi karbonskih kielina formule R(4)-COB. R(4) predstavlja ovdje trihalogen-metilni ostatak, (C1-C4)-alkilni ostatak ili derivat benzojeve kiseline, Derivat benzojeve kiseline može tako biti nesupstituiran ili supstituiran s jednim ili dva jednaka ili različita ostatka Y, Z. Mogući supstituent X predstavlja vodik, (C1-C4)-alkil ili halogen, supstituent Z predstavlja vodik, halogen, (C1-C4)-alkil, (C1-C4) -alkoksi ili nitro. B je zaštitna skupina kao na primjer halogend, (C1-C4) -alkoksi trihalogenacetat, (C1-C4) -karboksilat.
To su primjerice acetanhidrid, trihalogenacet-anhidrid, acetilhalogenid, trihalogenacetilhalogenid, propionilklorid, izobutirilbromid i -klorid, mravlja kiselina, anhidrid octene kiseline, benzoilklorid, anhidrid ili klorid 5-klor-2-metoksibenzojeve kiseline, te -( C1-C4) -alkilester ili klorid 2,5-difluor-benzojeve kiseline. Sinteze spoja XIII provode se uz dodatak tercijarne baze kao na primjer piridina ili trialkilamina u prisutnosti ili odsutnosti inertnog otapala, pri čemu se također može dodati katalizator, kao na primjer dimetilaminopiridin. Kemijska pretvorba se može postići pri temperaturama od otprilike (0°C do 160°C, ponajprije od 20 do 150°C. Acilna skupina amina XII također može biti zaštitna skupina, kao također, u slučaju derivata benzojeve kiseline, može biti dio spoja I. Kao inertna otapala prikladni su eteri kao tetrahidrofuran, dioksan, glikoeter kao etilenglikolmono-metil- ili -monoetileter (metilglikol ili etilglikol), etilenglikoldimetileter (diglim), ketoni kao aceton ili butanon, nitrili kao acetonitril, nitrospojevi kao nitrometan, ester kao etilacetat, amidi kao dimetilformamid (DMF) ili N-metilpirolidon (NMP), heksametiltriamid fosforne kiseline, sulfoksidi kao DMSO, klorirani ugljikovodici kao diklormetan, klorofonn, trikloretilen, 1,2-dikloretan ili tetraklorugljik, ugljikovodici kao benzol, tolul, ksilol.
Prikladne su, nadalje, također i medusobne mješavine tih otapala.
[image]
Amini XIII, acilirani prema shemi 1, mogu se prevesti u sulfonamide XIV na poznati način prema shemi 2.
Sulfonamidi XIV proizvode se po poznatim metodama i to pod uvjetima reakcije koji su poznati i prikladni za navedene kemijske pretvorbe. Pri tome se mogu također primijeniti i poznate varijante ali koje nisu pobliže spomenute. Po želji, sinteze se mogu privesti kraju u jednom, dva ili više stupnjeva. Osobitu prednost imaju postupci u kojima se acilirani amin XII prevodi u aromatske sulfonske kiseline kao i njihove derivate, kao u halogenide sulfonske kiseline, pomoću elektrofilnih reagenata u prisutnosti ili odsutnosti inertnih otapala pri temperaturama od -10°C do 120°C, ponajprije od 0°C do 100°C.
Sulfoniranja se mogu provesti prlmjerice sa sumpornom kiselinom ili oleumom, halogensulfoniranja s halogensulfonskim kiselinama, reakcijama sa sulfurilhalogenidima u prisutnosti bezvodnih metalnih halogenida ili tiohalogenida u prisutnosti benzvodnih metalnih halogenida sa završnim, a na poznat način, oksidacijama u aromatske kloride sulfonske kiseline. Ako su sulfonske kiseline primarni reakcijski proizvodi tada se one ili izravno ili obradom s tercijarnim aminima, kao na primjer s piridinom ili trialkilaminima, ili s alkalnim ili zemnoalkalnim hidroksidima ili reagensima koji in situ tvore te bazične spojeve, na poznat način mogu prevesti u halogenide sulfonske kiseline pomoću kiselinskih halogenida, kao na primjer fosfornog trihalogenida, fosfornog pentahalogenida, fosfornog oksiklorida, tionil-halogenida, oksalilhalogenida.
Prevodenje derivata sulfonske kiseline u sulfonamide odvija se na način poznat iz literature, ponajprije kloridi sulfonske kiseline kemijski se pretvaraju s vodenim amonijakom u inertnim otapalima pri temperaturama od 0°C do 100°C. Nadalje, aromatski sulfonamidi mogu se sintetizirati po postupcima poznatlm iz literature iz aciliranih amina formule XIII, proizvedenih po shemi 1, kemijskom pretvorbom s alkalnim ili zemno alkalnim metaloorganskim spojevima u inertnim otapalima i u atmosferi inertnog plina pri temperaturama od -100°C do 50°C, ponajprije od -100°C do 30°C, sa sumpornim dioksidoin i konačno toplinskom obradozn s amidosulfonskom kiselinoni.
Ako acilna skupina djeluje kao zaštitna skupina za amin XIII ona se može odcijepiti nakon pripremanja sulfonamida XIV s kiselinaina ili bazama. Odcjepljenjem s vodenim kiselinama ili kiselinama u inertnim otapalima može nastati pripadna kiselinska adicijska sol. Za tu kemijsku pretvorbu u obzir dolaze primjerice sumporna kiselina, dušična kiselina, halogenovodične kiseline, kao klorovodična kiselina ili bromovodična kiselina, fosforna kiseline kao ortofosforna kiselina, sulfaminska kiselina, nadalje organske kiseline, naročito alifatske, alicikličke, aralifatske, aromatske ili heterocikličke jedno- ili višebazne karbonske, sulfonske ili sumporne kiseline, na primjer octena kiselina, propionska kiselina, pivalinska kiselina, dietiloctena kiselina, malonska kiselina, jantarna kiselina, pimelinska kiselina, fumarna kiselina, maleinska kiselina, mliječna kiselina, vinska kiselina, jabučna kiselina, benzojeva kiselina, salicilna kiselina 2-ili 3-fenilpropionska kiselina, feniloctena kiselina, liminska kiselina, glukonska kiselina, askorbinska kiselina, nikotlnska kiselina, izonikotinska kiselina, metan- ili etansulfonska kiselina, et.andisulfonska kiselina, 2-hidroksietansulfonska kiselina, benzolsulfonska kiselina, p-toluolsulfonska kiselina, naftalin-mono- i disulfonska kiselina, laurilsumporna kiselina. Cijepanje aciliranog amina formule XIII s bazama može se provesti u vodenim ili inertnim otapalima. Kao baze prikladni su na primjer hidroksidi alkalnih i zemno alkalnih metala, hidridi, amidi ili također i alkoholati, kao natrijev hidroksid, kalijev hidroksid, kalcijev hidroksid, natrijev hidrid, kalijev hidrid, kalcijev hidridy natrijev amid, kalijev amid, natrijev metilatr natrijev metanolat, kalijev metilat ili kalijev metanolat.
Iz tako proizvedenih amina supstituiranih sa sulfonamidom ill njlhovih kiselinskih adlcijskih spojeva proizvode se kao Što je gore sponienuto aromatski benzolsulfonamidi formule III. Ovisno o prirodi članova R(l), R(2), R(3), X, Y i Z u pojedinačnim slučajevima za proizvodnju spojeva I može biti neprikladan jedan ili drugi od navedenih postupaka ili može biti potrebno učiniti barem privremene mjere za zaštitu aktivnih skupina. Takove relativno rijetke slučajeve stručnjak će lako prepoznati i u takovim slučajevima neće predstavljati teškoću uspješno primijeniti drugi opisani put sinteze.
Spojevi I mogu imati jedan ili više kiralnih centara. Oni se stoga pri njihovoj proizvodnji mogu dobiti kao racemati ili, ako se upotreljavaju optički aktivne polazne tvari također u optički aktivnom obliku- Ako spojevi imaju dva ili više kiralnih centara tada se sintezom mogu dobiti kao smjesa racemata iz koje se pojedinačni izomeri mogu izolirati u čistom obliku, primjerice prekristalizacijom iz inertnih otapala. Dobiveni racemati, ako je poželjno, mogu se rastaviti na svoje enantiomere mehanički ili kemijski samim po sebi poznatim metodama. Tako se kemijskom pretvorbom s optički aktivnim sredstvom za rastavljanje iz racemata mogu dobitl diastereomeri.
Kao sredstvo za rastavljanje za bazične spojeve prikladne su na primjer optički aktivne kiseline, kao R- odnosno R, R- i S- odnosno S,S-oblici vinske kiselina, dibenzoilvinske kiseline, diacetilvinske kiseline, kamforsulfonske kiseline, bademove kiseline, jabučne kiseline ili mliječne kiseline. Karbinoli se mogu nadalje amidirati pomoću kiralnih reagenata za aciliranje, na primjer R- ili S-a-metilbenzilizocijanata i zatim rastaviti. Različiti oblici diastereomera mogu se rastaviti poznatim metodama npr. frakcijskom kristalizacijom, a enantiomeri formule 1 mogu se osloboditi iz diastereomera na poznat način.
Rastavljanje enantiomera moguće je nadalje i kromatografijom na optički aktivnim tvarima nosiocima.
Spojevi I sukladni izumu i njihove fiziološki nedvojbene soli mogu se upotrijebiti za proizvodnju farmakoloških pripremaka, osobito nekemijskim načinom. Tako se oni mogu dovesti u oblike prikladne za doziranje zajedno s najmanje jednim čvrstim ili tekućim nosiocem ili pomoćnom tvari sami ili u kombinaciji s drugim lijekovima koji djeluju na srčani optok, kao eventualno antagonistima kalcija, NO-donatorima ili sredstvima za suzbijanje ACE-a. Ti pripremci mogu se upotrijebit:i kao lijekovi u humanoj medicini ili veterini. Kao noseće tvari u obzir dolaze organske ili anorganske tvari koje su prikladne za enteralnu (npr. oralnu), parenteralnu, kao npr. intravenoznu aplikaciju, ili topičku primjenu, i sa spojevima 1 ne reagiraju, primjerice voda, biljna ulja, benzilalkoholi, polietilenglikoli, glicerintriacetat, želatina, ugljikohidrati kao laktoza ili škrob, magnezijev stearat, talk, lanolin, vazelin.
Za oralnu primjenu služe osobito tablete, dražeje, kapsule, sirupi, sokovi ili kapljice za rektalnu primjenu otopine, ponajprije uljne ili vodene otopine, nadalje čepići, emulzije ili implantati, za topičku primjenu masti, kreme, paste, losioni, želei, sprejevi, pjene, aerosoli, otopine (na primjer u alkoholima kao etanolu ili izopropanolu, acetonitrilu, DMF-u, dimetilacetamidu, 1,2-propandiolu ili njihovlm medusobnim ili mješavinama s vodom) ili puder. Spojevi 1 mogu se upotrijebiti također liofilizirani, a doblveni lioflllzati mogu se upotrijebiti, na primjer, za proizvodnju injekcijskih preparata. Za topičku primjenu naročito dolaze u obzir također i liposomalni pripremci, koji sadrže stabilizatore i/ili kvasila, emulgatore, soli i/ili pomoćne tvari kao klizna sredstva, konzervanse za utjecanje na osmotski tlak, pufere, bojila i sredstva za okus ili aromu. Po želji također mogu sadržavati jednu ili više drugih aktivnih tvari, na primjer jedan ili više vitamina *
Doziranja, koja su potrebna za liječenje poremećaja ritma srca sa spojevima I, ovise o tome da li se daje akutna ili profllaktička tarapija. Profilaktički normalno se daju doze otprilike od najmanje 0,1 mg, ponajprije najmanje 1 mg do najviše 100, ponajprije do najviše 10 mg po kg i danu. Raspon doza je ponajprije od 1 do 10 mg po kg i danu u odnosu na odraslu osobu težine 75 kg. Pri tome doza može biti podijeljena na oralne ili parenteralne pojedinačne doze ili podijeljena na do ćetiri pojedinačne doze. Ako se liječe akutni poreinećaji ritma srca, primjerice na stanici intenzivne njege, parenteralno davanje može biti od prednosti. Raspon doze kojoj se daje prednost u kritičnim situacijama tada može iznositi 10 do 100 mg i daje se primjerice kao intravenozna trajna infuzija.
Prema izumu, osim spojeva opisanih u izvedbenim primjerima, mogu također sadržavati i spojeve I navedene i u slijedećoj tablici:
[image]
Primjer 1
2-metoksi-5-klor-{N-2-[3-sulfonilamino-N- (metilaminotio-karbonil) -4-metoksietoksifenil]-etil}-benzamid;
[image]
670 mg 2-metoksi-5-klor-{N-2-[3-sulfonilainino-4-metoksietoksifenil]-etil}-benzamida otopi se u 10 ml apsolutnog DMF-a i pomiješa sa 70 mg 60%-tnog NaH. Miješa se 20 minuta pri sobnoj temperaturi i dokaplje se 1, 6 ml 1-molarne otopine metilizotiocijanata u DMF-u.
Grije se 1,5 sata pri 80°C i nakon hlađenja reakcijsku otopinu doda se kap po kap na 100 ml 1 N solne kiseline. Ekstrahira se s octenim esterom, osuši i otapalo se odstrani u vakuumu. Dobivenu čvrstu tvar otopi se vruće u malo etanola i istaloži s vodom. Iskorištenje: 720 mg; talište 134°C.
Primjer 2
2-metoksi-5-klor-(N-2-[3-sulfonilamino-N- (metilaniinotio-karbonil) -4-metoksietoksietoksifenil]-etil}-benzamid
[image]
390 mg 2-metoksi-5-klor-{N-2-[3-sulfonilamino-4-metoksietoksietoksifenil]-etil}-benzamida otopi se u 6 ml DMF-a i pomiješa s 35 mg 60%-tnog NaH. Miješa se 20 minuta pri sobnoj temperaturi i dokaplje se 0,8 ml 1-molarne otopine metilizotiocijanata u DMF-u. Grije se 1,5 sata pri 80°C i nakon hladenja reakcijsku otopinu doda se kap po kap na 50 ml 1 N solne kiseline. Ekstrahira se s octenim esterom, osuši i otapalo se odstrani u vakuumu. Talište 108°C.
Farmakološki podaci
Terapeutska svojstva spojeva I mogu se predočiti sa slijedećim modelima:
(1) Trajanje akcijskog potencijala na papilarnom mišiću zamorca:
(a) Uvod
ATP-nedostatna stanja, kako se opažaju tijekom ishemije u stanicama srčanog mišića, vodit će do skraćenja trajanja akcijskog potencijala. Ona vrijede kao jedan od uzroka za takozvane Reentryjeve aritmije koje mogu uzrokovati iznenadnu srčanu smrt. Uzrokom toga smatra se otvaranje ATP-senzitivnih K-kanala zbog smanjenja ATP-a.
(b) Metoda
Za mjerenje akcijskog potencijala koristi se tehnika standardnih mikroelektroda. Udarcem u glavu usmrte se zamorci obje vrste, uzmu se srca, izvade se i odvoje papilarni mišići i objese u kupelj za organe. Kupelj za organe propere se s Ringerovom otopinom (0,9% NaCl, 0,048% KCl, 0,024% CaClar 0,02% NaHCO3 i 0,1% glukoze) i oplini se sa smjesom od 95% kisika i 5% ugljičnog dioksida pri temperaturi od 36°C. Mišić se pobudi preko elektrode s pravokutnim impulsima od 1 V, trajanja 1 ms i frekvencije od 2 Hz. Akcijski potencijal odvodi se i registrira pomoću intracelularno utaknute staklene mikroelektrode koja je napunjena s 3 inmolnom otopinom KCl-a. Ispitne tvari dodaju se Ringerovoj otopini u koncentraciji od 2,2-10-5 mola po litri. Akcijski potencijal pojačava se s pojačalom Hugo Sachs i prikazuje na osciloskopu.
Trajanje akcijskog potencijala odreduje se kod stupnja repolarizacije od 95% (APD95). Skraćenja akcijskog potencijala izazivaju se ili dodatkom otopine otvarača kalijevog kanala Hoe 234 koncentracije 1 pM [(J- Kaiser, H. Gogelein, Naunyn-Schmiedebergs Arch. Phann. 1991, 343, R(59)] ili dodatkom 2-dezoksiglukoze. Efekat skraćenja akcijskog potencijala te tvari sprečava se ili ograničava istovremenim dodavanjem ispitnih tvari. Ispitne tvari dodaju se otopini kupelji kao osnovne otopine u propandiolu. Navedene vrijednosti odnose se na mjerenja 30 minuta nakon dodavanja. U ovim mjerenjima Glibenclamid je služio kao standard. Ispitna koncentracija u svim slučajevima iznosi 2 x 10-6 M.
[image]
Claims (12)
1. Supstituirane benzoensulfoniluree i -tiouree, naznačene time, da su predstavljene formulom 1
[image]
u kojoj
R(1) je vodik, metil ili trifluormetil;
R(2) je alkoksi sa 4, 5, 6, 7, 8, 9 ili 10 C-atoma, pri čemu 1 do 6 ugljikovih atoma su zamijenjeni s heteroatomima O, S ili NH;
E je kisik ili sumpor;
Y je -[CR(3)2]1-4;
R(3) je vodik ili alkil s 1 ili 2 C-atoma;
X je vodik, halogen ili alkil s 1, 2, 3, 4, 5 ili 6 C-atoma;
Z je halogen, alkoksi s 1, 2, 3 ili 4 C-atoma ili alkil s 1, 2, 3 ili 4 C-atoma;
te njihove farmaceutski podnošljive soli-
2. Spojevi formule I prema zahtjevu 1, naznačeni time, da u njima
R(1) je vodik, metil ili trifluormetil;
R(2) je alkoksi sa 4, 5, 6, 7, 8, 9 ili 10 C-atoma, pri čemu jedan do šest ugljikovih atoma su zamijenjeni s heteroatomima O, S ili NH;
E je kisik ili sumpor;
Y je ravan supstituirani ili nesupstituirani ugljkovodični ostatak formule: -[CR(3)2]1-4;
R(3) je vodik ili alkil s 1 ili 2 C-atoma;
X je vodik, klor, fluor ili alkil s 1, 1, 3 ili 4 C-atoma;
Z je nitro, fluor, klor, alkil s 1, 2, 3 ili 4 C-atoma
ili alkoksi s 1, 2, 3 ili 4 C-atoma.
3. Spojevi formule 1 prema najmanje jednom od zahtjeva 1 ili 2, naznačeni time, da u njima
R(1) je vodik ili metil;
R(2) je alkoksi sa 4, 5, 6, 7, 8, 9 ili 10 C-atoma, pri čemu 1 do 6 ugljikovih atoma su zamijenjeni s heteroatomima O, S ili NH;
E je kisik ili sumpor;
Y je -[CR(2)3]1-4;
R(3) je vodik ili alkil s 1 ili 2 C-atoma;
X je vodik, fluor, klor ili alkil s 1, 2, 3 ili 4 C-atoma;
Z je klor, fluor, alkil s 1, 2, 3 ili 4 C-atoma ili alkoksi s 1, 2, 3 ili 4 C-atoma.
4. Spojevi formule 1 prema najmanje jednom od zahtjeva 1 do 3, naznačeni time, da u njima
R(1) je vodik ili metil;
R(2) je metoksietoksi ili metoksietoksietoksi;
E je kisik ili sumpor;
Y je [CR(3)]2-3;
R(3) je vodik ili metil;
X je vodik, fluor, klor ili alkil s 1, 2 ili 3 C-atoma;
Z je fluor, klor, alkil s 1, 2 ili 3 C-atoma ili alkoksi s 1, 2 ili 3 C-atoma.
5. Postupak za proizvodnju spojeva 1 prema zahtjevu 1, naznačen time, da se
a) aromatski sulfonamid formule II
[image]
ili njegova sol formule III
[image]
kemijski pretvara s R(1)-supstituiranim izocijanatom formule IV
R(1)-N=C=O IV
u supstituiranu benzolsulfonilureu I,
pri čemu R(1), R(2), X, Y i Z imaju značenja navedena u zahtjevu 1, a M je alkalni, zemno alkalni, amonijev ili tetraalkilamonijev ion;
ili
b) proizvede nesupstituiranu benzolsulfonilureu la [R(1) = H] kemijskom pretvorbom aromatskog benzolsulfonamida formule II ili njegove soli III s trialkilsilil-izocijanatom ili silicijevim tetraizocijanatom i hidrolizom primarne benzolsulfoniluree supstituirane sa silicijem;
ili
c) da se proizvede benzolsulfonilureu Ia iz aromatskog benzolsulfonamida II ili njegove soli III s R(1)-supstituiranim trikloracetamidom formule V
Cl3C-C(CO) -NH(R1) V
u prisutnosti baze;
ili
d) da se proizvede benzolsulfoniltioureu Ib
[image]
iz benzolsulfonamida II te njegove soli III i R(1)-supstituiranog izotiocijanata VI
R(1)-N=C=S VI
ili
(e) da se proizvede supstituiranu benzolsulfoniltioureu formule Ia reakcijom pretvorbe iz benzolsulfoniltiouree strukture Ib;
ili
(f) da se proizvede benzolsulfonilureu Ia iz benzol-sulfonilhalogenida formule VII
[image]
s R(1)-supstituiranom ureom ili R(1)-supstituiranom bis(trialkilsilil)ureom;
ili
(g) da se proizvede benzolsulfonilureu Ia kemijskom pretvorbom amina formule R(1)-NH2 s benzolsulfonil-izocijanatom formule VIII
[image]
ili
h) da se proizvede benzolsulfoniltioureu Ib kemijskom pretvorbom amina formule R(1)-NH2 s benzolsulfonil-izotiocijanatom formule IX
[image]
ili
i) da se supstituiranu benzosulfenil- ili sulfinilureu oksidira u benzolsulfonilireu Ia, i da se po potrebi prevede u farmaceutski podnošljivu sol.
6. Upotreba spoja 1 prema zahtjevu 1, naznačena time, da se koristi za proizvodnju lijeka za liječenje poremećaja ritma srca.
7. Upotreba spoja 1 prema zahtjevu 1, naznačena time, da se koristi za proizvodnju lijeka za sprečavanje iznenadne srčane smrti.
8. Upotreba spoja 1 prema zahtjevu 1, naznačena time, da se koristi za proizvodnju lijeka za liječenje ishemijskih stanja srca-
9. Upotreba spoja 1 prema zahtjevu 1, naznačena time, da se koristi za proizvodnju znanstvenog sredstva za inhibiciju ATP-senzitivnih kalijevih kanala.
10. Upotreba spoja I, naznačena time, da se koristi za proizvodnju lijeka za liječenje oslabljene snage srca.
11. Upotreba spoja I, naznačena time, da se koristi za proizvodnju lijeka za poboljšanje funkcije srca nakon transplantacije srca.
12. Lijek, naznačen time, da sadrži učinkovitu količinu spoja formule 1 prema zahtjevu 1.
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| Application Number | Priority Date | Filing Date | Title |
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| DE19505397A DE19505397A1 (de) | 1995-02-17 | 1995-02-17 | Substituierte Benzolsulfonylharnstoffe und -thioharnstoffe, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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| Publication Number | Publication Date |
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| HRP960077A2 true HRP960077A2 (en) | 1997-12-31 |
| HRP960077B1 HRP960077B1 (en) | 2001-06-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR960077A HRP960077B1 (en) | 1995-02-17 | 1996-02-15 | Substituted benzenesulfonylureas and -thioureas, process for their preparation, their use as medicinal or diagnostic agent as well as medicaments containing them |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US5652268A (hr) |
| EP (1) | EP0727416B1 (hr) |
| JP (1) | JP3905568B2 (hr) |
| KR (1) | KR100450914B1 (hr) |
| CN (1) | CN1058705C (hr) |
| AR (1) | AR003924A1 (hr) |
| AT (1) | ATE189213T1 (hr) |
| AU (1) | AU700793B2 (hr) |
| BR (1) | BR9600778A (hr) |
| CA (1) | CA2169694C (hr) |
| CY (1) | CY2220B1 (hr) |
| CZ (1) | CZ291271B6 (hr) |
| DE (2) | DE19505397A1 (hr) |
| DK (1) | DK0727416T3 (hr) |
| ES (1) | ES2143675T3 (hr) |
| FI (1) | FI120393B (hr) |
| GR (1) | GR3033049T3 (hr) |
| HR (1) | HRP960077B1 (hr) |
| HU (1) | HU226463B1 (hr) |
| IL (1) | IL117150A (hr) |
| MY (1) | MY113431A (hr) |
| NO (1) | NO305751B1 (hr) |
| NZ (1) | NZ280991A (hr) |
| PL (1) | PL181950B1 (hr) |
| PT (1) | PT727416E (hr) |
| RU (1) | RU2198163C2 (hr) |
| SI (1) | SI9600049B (hr) |
| SK (1) | SK281605B6 (hr) |
| TR (1) | TR199600118A2 (hr) |
| TW (1) | TW355183B (hr) |
| ZA (1) | ZA961231B (hr) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19546736A1 (de) * | 1995-12-14 | 1997-06-19 | Hoechst Ag | Substituierte Chromanylsulfonyl(thio)harnstoffe, Verfahren zu ihrer Herstellung und ihre Verwendung zur Herstellung pharmazeutischer Präparate |
| DE19647000A1 (de) * | 1996-11-14 | 1998-05-20 | Hoechst Ag | 3-Amido-chromanylsulfonyl(thio)harnstoffe, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
| DE19832009A1 (de) | 1998-07-16 | 2000-01-20 | Hoechst Marion Roussel De Gmbh | 2,5-Substituierte Benzolsulfonylharnstoffe und -thioharnstoffe, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende pharamazeutische Präparate |
| NZ510424A (en) * | 1998-09-10 | 2003-06-30 | Aventis Pharma Gmbh | Use of benzenesulfonyl(thio)ureas for the treatment and prophylaxis of dysfunctions of the autonomous nervous system and use of benzenesulfonyl(thio)ureas in combination with beta-receptor blockers |
| DE19917233A1 (de) * | 1999-04-16 | 2000-10-19 | Aventis Pharma Gmbh | Kristalline Formen des Natriumsalzes des 5-Chlor-2-methoxy-N-(2-(4-methoxy-3-methylaminothiocarbonylaminosulfonyl-phenyl)-ethyl)- benzamids |
| DE19923086A1 (de) * | 1999-05-20 | 2000-11-23 | Aventis Pharma Gmbh | Cinnamoylaminoalkyl-substituierte Benzolsulfonamidderivate, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
| DE10054482A1 (de) | 2000-11-03 | 2002-05-08 | Aventis Pharma Gmbh | Heteroarylacryloylaminoalkyl-substituierte Benzolsulfonamidderivate, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
| DE10054481A1 (de) | 2000-11-03 | 2002-05-08 | Aventis Pharma Gmbh | Acylaminoalkyl-substituierte Benzolsulfonamidderivate, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
| DE10129704A1 (de) * | 2001-06-22 | 2003-01-02 | Aventis Pharma Gmbh | Verwendung von Benzolsulfonyl(thio)harnstoffen in der Behandlung des septischen Schocks |
| DE102004061017A1 (de) * | 2004-12-18 | 2006-06-22 | Sanofi-Aventis Deutschland Gmbh | Piperidinsulfonylharnstoffe und -thioharnstoffe, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
| CN101679191B (zh) * | 2007-06-05 | 2014-03-12 | 塞诺菲-安万特股份有限公司 | 二杂芳基环己烷衍生物、其制备方法、用途及含有它们的药用组合物 |
| US20250145564A1 (en) * | 2021-08-16 | 2025-05-08 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Sulfonylurea compound, preparation method therefor, and application thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1198354B (de) * | 1963-09-25 | 1965-08-12 | Hoechst Ag | Verfahren zur Herstellung von Benzol-sulfonylharnstoffen |
| DE1518874C3 (de) * | 1964-10-07 | 1975-03-13 | Farbwerke Hoechst Ag, Vormals Meister Lucius & Bruening, 6000 Frankfurt | Benzolsulfonylharnstoffe und Verfahren zu ihrer Herstellung |
| BE754454A (fr) * | 1969-08-06 | 1971-02-05 | Bayer Ag | Nouveaux composes hypoglycemiques du type d'arylsulfonylurees et d'arylsulfonylsemicarbazides contenant des groupes carbonamide |
| DE2413514C3 (de) * | 1974-03-21 | 1982-03-04 | Hoechst Ag, 6000 Frankfurt | N-Acylaminoathylbenzolsulfonyl-N'-methylharnstoffe, Verfahren zu ihrer Herstellung und deren Verwendung |
| US4927453A (en) * | 1986-10-17 | 1990-05-22 | E. I. Du Pont De Nemours And Company | Herbicidal sulfonamides |
| ATE146775T1 (de) * | 1993-02-23 | 1997-01-15 | Hoechst Ag | Substituierte benzolsulfonylharnstoffe und - thioharnstoffe- verfahren zu ihrer herstellung und ihre verwendung als pharmazeutika |
-
1995
- 1995-02-17 DE DE19505397A patent/DE19505397A1/de not_active Withdrawn
- 1995-12-28 HU HU9503879A patent/HU226463B1/hu not_active IP Right Cessation
-
1996
- 1996-01-29 PL PL96312528A patent/PL181950B1/pl not_active IP Right Cessation
- 1996-02-12 AT AT96101976T patent/ATE189213T1/de active
- 1996-02-12 DK DK96101976T patent/DK0727416T3/da active
- 1996-02-12 TW TW085101695A patent/TW355183B/zh not_active IP Right Cessation
- 1996-02-12 DE DE59604262T patent/DE59604262D1/de not_active Expired - Lifetime
- 1996-02-12 EP EP96101976A patent/EP0727416B1/de not_active Expired - Lifetime
- 1996-02-12 PT PT96101976T patent/PT727416E/pt unknown
- 1996-02-12 ES ES96101976T patent/ES2143675T3/es not_active Expired - Lifetime
- 1996-02-14 CZ CZ1996436A patent/CZ291271B6/cs not_active IP Right Cessation
- 1996-02-14 CN CN96102016A patent/CN1058705C/zh not_active Expired - Fee Related
- 1996-02-15 NZ NZ280991A patent/NZ280991A/en not_active IP Right Cessation
- 1996-02-15 HR HR960077A patent/HRP960077B1/xx not_active IP Right Cessation
- 1996-02-15 TR TR96/00118A patent/TR199600118A2/xx unknown
- 1996-02-15 AU AU45560/96A patent/AU700793B2/en not_active Ceased
- 1996-02-15 US US08/602,053 patent/US5652268A/en not_active Expired - Lifetime
- 1996-02-15 SK SK211-96A patent/SK281605B6/sk not_active IP Right Cessation
- 1996-02-15 FI FI960689A patent/FI120393B/fi not_active IP Right Cessation
- 1996-02-15 AR ARP960101392A patent/AR003924A1/es unknown
- 1996-02-15 IL IL11715096A patent/IL117150A/xx not_active IP Right Cessation
- 1996-02-16 JP JP02905396A patent/JP3905568B2/ja not_active Expired - Fee Related
- 1996-02-16 KR KR1019960003824A patent/KR100450914B1/ko not_active Expired - Fee Related
- 1996-02-16 CA CA002169694A patent/CA2169694C/en not_active Expired - Fee Related
- 1996-02-16 RU RU96102869/04A patent/RU2198163C2/ru not_active IP Right Cessation
- 1996-02-16 MY MYPI96000623A patent/MY113431A/en unknown
- 1996-02-16 ZA ZA961231A patent/ZA961231B/xx unknown
- 1996-02-16 NO NO960627A patent/NO305751B1/no not_active IP Right Cessation
- 1996-02-16 SI SI9600049A patent/SI9600049B/sl not_active IP Right Cessation
- 1996-02-16 BR BR9600778A patent/BR9600778A/pt not_active Application Discontinuation
-
2000
- 2000-03-24 GR GR20000400736T patent/GR3033049T3/el unknown
-
2001
- 2001-05-03 CY CY0100006A patent/CY2220B1/xx unknown
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