CN1028231C - 具有新治疗活性的取代的苯并咪唑的制备方法 - Google Patents
具有新治疗活性的取代的苯并咪唑的制备方法 Download PDFInfo
- Publication number
- CN1028231C CN1028231C CN89109587A CN89109587A CN1028231C CN 1028231 C CN1028231 C CN 1028231C CN 89109587 A CN89109587 A CN 89109587A CN 89109587 A CN89109587 A CN 89109587A CN 1028231 C CN1028231 C CN 1028231C
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- compounds
- bioavailability
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 14
- 230000008569 process Effects 0.000 title claims description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- -1 4-cyclo propyl methoxy-2-pyridyl Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 9
- 239000000543 intermediate Substances 0.000 abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- DIUOJMLXZJHNDR-UHFFFAOYSA-N 2-[[4-(cyclopropylmethoxy)pyridin-2-yl]methylsulfinyl]-6-fluoro-1h-benzimidazole Chemical compound N=1C2=CC(F)=CC=C2NC=1S(=O)CC(N=CC=1)=CC=1OCC1CC1 DIUOJMLXZJHNDR-UHFFFAOYSA-N 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 238000012360 testing method Methods 0.000 description 19
- 239000000126 substance Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 241000700159 Rattus Species 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- 239000000829 suppository Substances 0.000 description 7
- 239000013543 active substance Substances 0.000 description 6
- 210000001198 duodenum Anatomy 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000002702 enteric coating Substances 0.000 description 5
- 238000009505 enteric coating Methods 0.000 description 5
- 210000004211 gastric acid Anatomy 0.000 description 5
- 230000027119 gastric acid secretion Effects 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 210000004051 gastric juice Anatomy 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000004278 EU approved seasoning Substances 0.000 description 3
- 206010016717 Fistula Diseases 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000009858 acid secretion Effects 0.000 description 3
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000003890 fistula Effects 0.000 description 3
- 235000011194 food seasoning agent Nutrition 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000003248 secreting effect Effects 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 2
- OKHRKOHJIIGRLO-UHFFFAOYSA-N 2-(chloromethyl)-4-(cyclopropylmethoxy)pyridine;hydrochloride Chemical compound Cl.C1=NC(CCl)=CC(OCC2CC2)=C1 OKHRKOHJIIGRLO-UHFFFAOYSA-N 0.000 description 2
- RYSGNEDNKANTCQ-UHFFFAOYSA-N 4-(cyclopropylmethoxy)-2-methyl-1-oxidopyridin-1-ium Chemical compound C1=[N+]([O-])C(C)=CC(OCC2CC2)=C1 RYSGNEDNKANTCQ-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- FQZAWZFOBLDFJY-UHFFFAOYSA-N O(C(=O)C)C1=NC=C(C(=C1OC)C1CC1)C Chemical compound O(C(=O)C)C1=NC=C(C(=C1OC)C1CC1)C FQZAWZFOBLDFJY-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229950010118 cellacefate Drugs 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- CDVMXMZPDJHSCC-UHFFFAOYSA-N chembl1684662 Chemical compound C=1C=C2C=C(C=3C4=NC=CC=C4NN=3)NC2=CC=1CC(=O)C1=CC=CC=C1 CDVMXMZPDJHSCC-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- WFPZPJSADLPSON-UHFFFAOYSA-N dinitrogen tetraoxide Chemical compound [O-][N+](=O)[N+]([O-])=O WFPZPJSADLPSON-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000002183 duodenal effect Effects 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940095399 enema Drugs 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- INOGLHRUEYDAHX-UHFFFAOYSA-N 1-chlorobenzotriazole Chemical compound C1=CC=C2N(Cl)N=NC2=C1 INOGLHRUEYDAHX-UHFFFAOYSA-N 0.000 description 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000272470 Circus Species 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018873 Haemoconcentration Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 108010064696 N,O-diacetylmuramidase Proteins 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 108010079943 Pentagastrin Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004642 Polyimide Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000013220 male mouse model Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 1
- 229960000444 pentagastrin Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000008400 supply water Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 150000003682 vanadium compounds Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了新的化合物5-氟-2-[[(4-环丙基甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑及其生理上可接受的盐及其制备方法,并公开了该化合物的中间体、以所述化合物为活性成分的药用组合物以及它在医学上的应用。所说化合物的制备方法包括将5-氟-2-[[(4-环丙基甲氧基-2-吡啶基)甲基]硫代]-1H-苯并咪唑氧化,必要时,将生成的化合物转化为盐或拆分为纯旋光异构体。
Description
本发明的目的在于提供一种新的化合物及其治疗上可接受的盐。这种化合物及其盐可抑制外原或内原刺激的胃酸分泌作用,因此可用于预防和治疗消化性溃疡。
本发明还涉及采用上述化合物、特别是其治疗上可接受的盐抑制哺乳动物和人的胃酸分泌。更广义地说,本发明化合物可用来预防和治疗哺乳动物和人的胃肠炎性疾病和与胃酸有关的疾病,例如:胃炎、胃溃疡、十二指肠溃疡和回流食管炎。此外,该化合物可用于需利用抑制胃分泌作用进行治疗的其它胃肠疾病,例如,用于治疗胃坏疽(gastrinomas)和急性上部胃肠出血。它还可用于需特殊照顾的病人,以及用于术前和术后的防止酸吸收和应激性溃疡形成。本发明化合物也可用来治疗或预防包括人在内的哺乳动物的炎症,特别是与溶菌酶有关的病。可具体列举的病症是类风湿性关节炎和痛风。本发明还涉及以本发明化合物或其药物上可接受的盐为活性成分的药用组合物。另一方面,本发明涉及这类新化合物的制备方法,用于制备本发明化合物的新中间体,以及利用活性化合物制备供上述医学目的之用的药用组合物。
本发明的一个主要具体目的是提供具高水平生物利用度的化合物。本发明化合物在中性pH下显示出高度的稳定性,并具有很高的抑制胃酸分泌的效力。
用于抑制胃酸分泌的苯并咪唑衍生物已在众多专利文献中得到公开,其中可列举的有GB1,500,043、GB1,525,958、US4,182,766、EP5129、BE890,024、EP0134,400、EP0175,464、EP014726、EP208,342和德温特文摘294449/42。EP-A-0,045,200中公开了可用于治疗或预防特殊胃肠炎性病症的苯并咪唑衍生物。
上述先有技术中公开的化合物是有效的酸分泌抑制剂,因而可用作抗溃疡化合物。为进一步扩大这类药的用途,应提高其生物利用度,同时仍应使其具有高度的抑制胃酸分泌效力,以及在中性pH下的高度化学稳定性。
已经认识到,试验化合物2-[(2-吡啶基甲基)亚硫酰基]-1H-苯并咪唑在生物利用度以及药效和稳定性方面显示出很大的差异性,并且很难找到具有全部三个优点的化合物。先有技术中没有指出如何获得兼有这三种性质的化合物的方法。
已发现,本发明化合物具极高的生物利用度,同时仍是有效的胃酸分泌制剂,在中性pH溶液中显示高度的化学稳定性。因此,本发明化合物可用于上述哺乳动物和人的病症。
本发明化合物是5-氟-2-[[(4-环丙基甲氧基-2-吡啶基)-甲基]亚硫酰基]-1H-苯并咪唑(式Ⅰ)及其生理上可接受的盐。本发明化合物在硫原子上具有一个不对称中心,即:存在两个旋光异构体(对映体)。无论是纯对映体、还是外消旋混合物(每个对映体自占50%)和它们的不平衡的混合物均包含在本发明的范围内。本发明还包括五种中间体及其制备方法。
制备
可按下述方法制备本发明化合物:
将5-氟-2[[(4-环丙基甲氧基-2-吡啶基)甲基]-硫代-1H-苯并咪唑(式Ⅱ)氧化,得到本发明化合物。这一氧化反应可采用以下氧化剂进行,它们包括硝酸、过氧化氢、(任意地在钒化合物的存在下)、过酸、过酯、臭氧、四氧化二氮、亚碘酰苯、N-卤代酰亚胺、1-氯苯并***、次氯酸叔丁酯、二氮杂二环[2,2,2]-辛烷溴复合物、偏高碘酸钠、二氧化硒、二氧化锰、铬酸、硝酸高铈铵、溴、氯和硫酰氯。该氧化反应通常在诸如卤代烃、醇、醚、酮之类的溶剂中进行。
采用氧化酶,通过酶催法,或采用适宜的微生物,通过微生物法,也可实施氧化。
根据操作条件和起始原料,所得的本发明化合
物可呈中性或盐形。中性化合物和化合物的盐均包括在本发明范围内。因此,可获得碱式、中性或混合盐以及半、单、倍半或多水合物。
本发明化合物的碱性盐的例子是该化合物的Li+、Na+、K+、Mg2+、Ca2+和N+(R)4等盐,其中R为C1-4烷基。优选的是Na+、Ca2+和Mg2+盐。尤其优选的是Na+和Mg2+盐。使化合物与能够释放所需阳离子的碱反应,可制得这类盐。
下面给出能够释放这类阳离子的碱的实例以及有关反应条件的实例。
a)在含水或非水介质中,用LiOH、NaOH或KOH处理本发明化合物,或在非水介质中,用LiOR、LiNH2、LiNR2、NaOR、NaNH2、NaNR2、KOR、KNH2或KNR2(式中R为含1-4个碳原子的烷基)处理化合物,均可制得其中阳离子为Li+、Na+或K+的盐。
b)在非水溶剂(例如仅用于制备醇盐的醇,如ROH)中,或者,在诸如四氢呋喃的醚中,用Mg(OR)2、Ca(OR)2或CaH2(其中R为C1-4烷基)处理本发明化合物,可制得其中阳离子为Mg2+或Ca2+的盐。
可将所得外消旋物拆分为纯对映体。可按已知方法,例如,采用层析或梯度结晶,由外消旋非对映盐完成所述的拆分。
可按已知的方法获得中间体实施例中所述的起始原料。
就临床应用而言,可将本发明化合物配制成药物组合物,供口服、直肠或其它方式给药之用。该药物组合物包含本发明化合物以及通常与之结合的药物上可接受的载体。所述载体可呈固体、半固体或液体稀释剂的形式,或者是胶囊。本发明的进一步的目的在于提供药物制剂。通常,活性化合物的量占制剂的0.1-95%(重量)肠道外使用时,占制剂的0.2-20%(重量),口服使用时,占制剂的1-50%。
在制备供口服给药的呈剂量单位形式的含本发明化合物的药用组合物时,将所选的化合物与固体、粉状载体或其它适宜载体、稳定物质以及润滑剂混合。所述粉状载体包括乳糖、蔗糖、山梨醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶;稳定物质包括碱性化合物,例如:钠、钾、钙、镁等的碳酸盐、氢氧化物和氧化物;润滑剂包括硬脂酸镁、硬酯酸钙、十八烷基富马酸钠和聚乙二醇蜡。然后,将混合物加工成颗粒或压成片剂。可对颗粒或片剂包上肠溶包衣,这样,只要药剂残留在胃中,就能保护活性化合物免受酸催化降解。肠溶包衣选自药物上可接受的肠溶包衣物质,例如:白蜂蜡、虫胶或阴离子成膜聚合物,例如:乙酸邻苯二甲酸纤维、羟丙基-甲基纤维素邻苯二甲酸酯、部分甲基酯化的甲基丙烯酸聚合物等。较理想的是,这类包衣物质与适宜的增塑剂配合应用。可将各种染料加到包衣成分中,以便区别含有不同活性化合物或不等量本发明活性化合物的片剂或颗粒剂。
利用含本发明活性化合物,植物油、脂肪或其它适用于软胶囊的载体,可制得软胶囊剂。软胶囊剂也可呈上述肠溶包衣的形式。硬胶囊剂可包含活性化合物的颗粒剂或肠溶包衣颗粒剂。硬胶囊剂还可包含在活性化合物结合的固体粉状载体,例如:乳糖、蔗糖、山梨醇、甘露醇、土豆淀粉、支链淀粉、纤维素衍生物或明胶。硬胶囊剂可呈上述肠溶包衣形式。
可制成供直肠给药的栓剂剂量单位,所述栓剂含有与中性脂肪碱混合的活性物质;或可制成供直肠给药的胶囊,它包含活性物质以及与之混合的植物油、石蜡油或其它适宜于直肠给药胶囊的载体;或可制成易于制备的微型灌肠剂,或可制成无水灌肠剂组合物,给药前用适宜的溶剂重新配制。
可按糖浆或混悬液的形式制备供口服给药的液态制剂,例如溶液或混悬液,它们含有0.2%至20%(重量)活性成分,其余部分由糖或糖醇和乙醇、水、甘油、聚丙二醇和/或聚乙二醇组成。必要时,这类液体制剂可包含着色剂、调味剂、糖精、羧甲基纤维素或其它增稠剂。还可将用于口服给药的液态制剂制成无水粉末,使用前,用适宜溶剂重新配制。
最好以0.1%至10%(重量)的浓度,使本发明化合物溶于药物上可接受的溶剂中,由此制成供胃肠道外给药的溶液。这类溶液还可含稳定剂和/或缓冲剂,并可以不同单位剂量安瓿或药瓶制剂制备之。也可制成干性制剂,使用前用适宜溶剂临时重新配制成供胃肠道外给药的溶液。
活性物质的一般日剂量取决于多种因素,例如:每个病人的个体需要、给药途径和症状。一般
而言,口服和注射剂量为每天用5至500mg活性物质。
通过以下实施例说明本发明。
实施例1
5-氟-2-[[(4-环丙基甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑
将5-氟-2-[[(4-环丙基甲氧基-2-吡咯基)甲基]硫代]-1H-苯并咪唑(1.25g,0.0036mol)溶解于CH2Cl2(40ml)中。将NaHCO3(0.6g,0.0072mol)水(20ml)溶液加到上述混合物中,冷却至+2℃。搅拌下,加84%的间氯过苯甲酸(0.73g,0.0036mol)的CH2Cl2(5ml)溶液,于室温下继续搅拌15分钟。使两相分离,将NaOH(0.29g,0.0072mol)水(25ml)溶液加到有机相中,搅拌,分离两相,用苏长岩处理H2O相,过滤。搅拌下滴加甲酸甲酯(0.45ml,0.0073mol)的水(5ml)溶液。用CH2Cl2提取后,用Na2SO4干燥,蒸发溶剂。由此得到标题化合物(0.93g,69%)。最终产物的NMR数据如下表所示。
实施例2
5-氟-2-[[(4-环丙基甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑,钠盐的制备
将5-氟-2-[[(4-环丙基甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑(5g;14.5mmol)的二氯甲烷(100ml)液和氢氧化钠(0.56g;14mol)的水(100ml)溶液移至一分液漏斗中。将混合物摇振至平衡,此后,分离溶剂相。用二氯甲烷(2×25ml)洗涤水溶液,然后冻干。用二氯甲烷/***对残余物重结晶,得到3.7g(71%)标题化合物。下面给出NMR数据。
(表1见文后)
中间体的制备
实施例Ⅰ
1)4-环丙基甲氧基-2-甲基吡啶-N-氧化物的制备
将环丙基-甲醇(50ml)加到氢化钠(55%纯)(4.4g,0.1mol)(经石油醚洗涤)中。接着,在大约1小时内,加2-甲基-4-硝基吡啶-N-氧化物(6.5g,0.042mol)的环丙基甲醇(30ml)溶液。将暗褐色的混合物加热至90℃,并在此温度下搅拌1小时。此后,减压蒸馏出环丙基甲醇,将二氯甲烷(100ml)加到残余物中,搅拌约30分钟,然后过滤,浓缩,得到9.5g粗制物。
经硅胶闪层析,对该粗制物进行纯化,以二氯甲烷-甲醇(90-10)为洗脱剂,得到4.0g(53%)纯标题化合物。NMR数据如表2所示。
2)2-乙酸基甲基-4-环丙基甲氧基吡啶的制备
将4-环丙基甲氧基-2-甲基吡啶-N-氧化物(3.8g,0.021mol)溶于乙酸酐(10ml)中,并将该混合物滴入乙酸酐中(20ml)(温热至90℃)。此后,使温度升至110℃,在此温度下搅拌1小时,然后蒸馏掉溶剂,所得粗制产物无需纯化便可使用。NMR数据如下表2所示。
3)4-环丙基甲氧基-2-羟甲基吡啶
将NaOH(100ml,2M)加到粗制的2-乙酸基甲基-4-环丙基甲氧基吡啶中,并将混合物回流2小时。用二氯甲烷提取混合物,分离两相。用Na2SO4干燥有机层,过滤,蒸去溶剂,产生2.7g粗制的标题化合物。NMR数据如以下表2所示。该粗制产物无需进一步纯化便可使用。
4)4-环丙基甲氧基-2-氯甲基吡啶盐酸盐的制备
将4-环丙基甲氧基-2-羟甲基吡啶(93%纯)(0.9g,0.0046mol)溶解于二氯甲烷(10mol)中,并冷却至0℃,在此温度下,滴加SOCl2(0.5ml,0.0069mol)的二氯甲烷(5ml)溶液,于室温下搅拌15分钟。加异丙醇(0.5ml),蒸发混合物,产生所需产物(0.68g,78%)。
5)用作起始原料的5-氟-2-[[(4-环丙基甲氧基-2-吡啶基)甲基]硫代]-1H-苯并咪唑的制备
依次将NaOH(0.2g,0.0051mol)的H2O(1ml)水溶液和4-环丙基甲氧基-2-氯甲基-吡啶盐酸盐(0.91g,0.0046mol)的甲醇液(10ml)加到5-氟-2-巯基-1H-苯并咪唑(0.88g,0.0051mol)的甲醇(25ml)液中。将混合物加热至沸腾,加NaOH(0.2g,0.005mol)的水(1ml)溶液,将混合物回流1小时。蒸发甲醇,加CH2Cl2(75ml)和H2O(50ml),将pH调至10。剧烈搅拌混合物,分离两相,用Na2SO4干燥有机相,蒸发,得到所需产物(1.25g,72%)。该产物的NMR数据如表2所示。
表2
例 溶剂 NMR 数据 δppm
Ⅰ1.CDCl30.36(m,2H);0.68(m,2H);
(500MHz)1.26(m,1H);2.52(s,3H);
3.83(d,2H);6.70(dd,1H);
6.77(d,1H);8.16(d,1H)
Ⅰ2.CDCl30.37(m,2H);0.69(m,2H);
(500MHz)1.26(s,3H);3.87(d,2H);
6.75(dd,1H);6.87(d,1H);
8.42(d,1H)
Ⅰ3.CDCl30.36(m,2H);0.67(m,2H);
(500MHz)1.27(m,1H);3.86(d,2H);
4.69(s,2H);6.72(dd,1H),
6.78(d,1H);8.33(d,1H)
Ⅰ4.DMSO-d60.40(m,2H);0.60(m,2H);
(300MHz)1.30(m,1H);4.20(d,2H);
5.00(s,2H);7.45(dd,1H),
7.65(d,1H);8.70(d,1H)
Ⅰ5.CDCl30.36-0.39(m,2H);0.67-0.71
(500MHz)(m,2H);1.27(m,1H);3.89(d,2H),
4.29(s,2H);6.81(dd,1H);
6.89(d,1H);6.94(m,1H);
7.24(dd,1H);7.46(dd,1H),
8.43(d,1H)
实施本发明的最佳方式是采用式Ⅰ化合物的钠盐,例如实施例2所述的化合物。
以下组合物说明以本发明化合物为活性成分的药剂。
糖浆剂
利用以下成分制备含1%(重量/体积)活性物质的糖浆剂:
实施例1的化合物 1.0g
糖,粉状 30.0g
甘油 5.0g
糖精 0.6g
调味剂 0.05g
乙醇96% 5.0g
蒸馏水加至最终体积为 100ml
将糖和糖精溶于60克温水中。冷却后,将活性化合物加到糖溶液中,加甘油和调味剂乙醇液。用水将混合物稀释成100ml的最终体积。
肠溶包衣片剂
由以下成分制备含50mg活性化合物的肠溶包衣片剂:
Ⅰ实施例Ⅰ化合物的镁盐 500g
乳糖 700g
甲基纤维素 6g
交联聚乙烯吡咯烷酮 50g
硬脂酸镁 15g
碳酸钠 6g
蒸馏水 适量
Ⅱ乙酸邻苯二甲酸纤维素 200g
鲸蜡醇 15g
异丙醇 2000g
二氯甲烷 2000g
Ⅰ 将实施例1的粉状化合物同乳糖混合,与甲基纤维素和碳酸钠的水溶液一起粒化。使该湿性物质通过筛子,于烘箱内将颗粒烘干。之后,将颗粒同聚乙烯吡咯酮和硬脂酸镁混合。采用具7mm直径冲的压片机,将干燥的混合物压成片芯(10000片),每片含50mg活性物质。
Ⅱ 利用Accela CotaRManesty包衣设备,将乙酸邻苯二甲酸纤维素和鲸蜡醇的异丙醇/二氯甲烷溶液包覆在片剂Ⅰ上。得到重为110mg的最终片剂。
静脉注射液
由以下成分制备每毫升含4毫克活性化合物的静脉注射用组合物:
实施例2的化合物 4g
无菌水加至最终体积为 1000ml
将活性化合物溶解于水中,至最终体积为1000ml。使溶液滤过0.22μm的滤片,立即配入10ml无菌安瓿。将安瓿密封。
胶囊剂
由以下成分制备含30mg活性化合物的胶囊剂:
实施例1的化合物 300g
乳糖 700g
微晶纤维素 40g
低取代的羟丙基纤维素 62g
磷酸氢二钠 2g
净化水 q.s.
将活性化合物同干的成分混合,与磷酸氢二钠溶液一起粒化。使该湿性物质通过挤压机,团成球状,于流化床内干燥。
采用流态化床包衣机,用羟丙基甲基纤维素(30g)的水(750g)溶液对500g上述小丸进行包衣。干燥后,用以下成分对小丸进行第二次包衣。
包衣溶液:
羟丙基甲基纤维素 70g
鲸蜡醇 4g
丙酮 200g
乙醇 600g
将小丸填入胶囊中。
栓剂
采用熔接步骤,由以下成分制备栓剂。每个栓剂含40mg活性化合物。
实施例1的化合物 4g
Witepsol H-15 180g
在41℃下,将活性化合物与Witepsol H-15均匀混合。将熔融物质注入预制栓剂盒至净重为1.84g。冷却后,将盒加热密封。每个栓剂含40mg活性化合物。
使用前,将活性化合物溶解于10ml无菌水中,将溶液移至100ml供输注的标准生理盐水液中,得到约110ml的总体积。该溶液于大约30分钟内以静脉输注的形式给出。
生物作用
生物利用度
试验动物的选择
就生物利用度而言,从两种不同动物大鼠和狗上所得的试验结果表明:同一种化合物的生物利用度水平随动物种属而异。根据我们的认识,肝代谢是影响生物利用度的最主要的因素,就这一类型的化合物而言,这类化合物在人体内的代谢方式与雄性大鼠十分相象(在代谢方式上,比雌鼠和狗更类似于人类),因此,从生物利用度考虑,我们选择雄性大鼠作为最相关的试验动物。此外,与狗的试验结果相比,在雄性大鼠上获得的生物利用度的试验结果往往具有更宽的“差距”,因此,雄鼠模型在不同化合物之间带来更明显的生物利用度差异。换言之,可以认为,在雄鼠上测试的生物利用度可用来更好地评价不同试验化合物在人体上的相对差异,尤其用于比较采用狗作试验时所得的试验结果。
生物利用度测定
为测定生物利用度(即本发明化合物的最卓越的特性),计算十二指肠内(id)给药和静脉内(iv)给药后的大鼠或狗的血浆浓度(AUC)曲线下形成的面积商数。采用低治疗相关剂量。将这一方法用于测定生物利用度是科学的(例如参见:M.Rowland and T.N.Tozer,Clinical Pharmacokinetics,Znded,Lea & Febiger,London 1989,P42)。表3中提供了从大鼠和狗身上获得的数据。
粗筛模型
由于上述生物利用度模型费时、费工,且需要进行大量血浆分析,因此,采用以抑制酸分泌的相对效力为基准的粗筛模型[例如参见:A.Goth,Medical Pharmacology,7th ed.,C.V.Mosby Company,Saint Louis 1974,P19)。由此计算静脉内给药下的ED50和十二指肠内给药下的ED50之比。表3中同样提供了这些数据。
效力
在雄性大鼠和狗身上同时静脉内和十二指肠内给药,测定抑制酸分泌的效力。当本发明化合物的动物试验数据与在人体内的某一给定化合物产生的药效相关时,可以认为,人体内的药效水平约在雄鼠测定水平和狗测定水平之间的某处。表3中给出了从两种动物上获得的数据。
生物试验
在清醒雄性大鼠体内抑制胃酸分泌
采用Sprague-Dawley种雄性大鼠。在这些动物的胃腔和十二指肠上部装上瘘管,分别用来收集胃分泌物和提供试验物质。在试验开始前,使动物在手术后恢复十四天。
在进行分泌试验前,对动物禁食20天,但在这期间自由供水。通过胃套管反复洗胃,S.C.注射6ml林格葡萄糖液。用五肽促胃酸激素和卡巴可(分别为20和110nmol/kg h)的灌注液,刺激酸分泌3.5小时(1.2ml/h,s.c.),期间,以每30分钟为一批,收集胃分泌物。在开始刺激后,于90分钟时,以1ml/kg的体积,经
静脉或十二指肠施用试验物质或载体。用NaOH(0.1mol/L)将胃液试样滴定至pH7.0,并根据滴定剂产物体积和浓度计算酸排出量。以4-5只大鼠的集体平均应答为基础作进一步计算。用分数应答(fractional responses)表示给予试验物质或载体后的一段时间内的酸排出量,将给药前30分钟内的酸排出量计为1.0。通过由试验化合物和载体得出的分数应答计算抑制百分比。根据10g剂量-应答曲线,通过图解内推法得到ED50值,或者,假定所有剂量应答曲线的斜率均相同,由单剂量实验估计ED50值。通过计算ED50(iv)/ED50(id)比,测得生物利用度。所报道的结果基于使用药物/载体后第二个小时内的胃酸分泌。
雄鼠上产生的生物利用度
采用Sprague-Dawley种成年雄鼠。
实验前一天,将所有大鼠麻醉,在左颈动脉上插套管。在用于静脉实验的大鼠的颈静脉上插套管。(参见Vpopovic and Popovic,J Appl Physiol1960;15,727-728)。在用于十二指肠内实验的大鼠的十二指肠上部抽套管。使套管于动物颈背处伸出体外。手术后,单独关养动物,对其禁食,但提供水,然后给予试验物质。在大约一分钟内,经静脉内和十二指肠内提供相同剂量(4μmol/kg)的呈大丸剂(bolus)的试验物质(2ml/kg)。
给予所述剂量后,以4小时为间隔,反复从颈动脉抽取血样。尽快冷冻试样,直到分析试验化合物为止。
通过线性梯形规则确定血液浓度一时间曲线下的面积ACU,并用终相消除速率常数除以最后测定的血浓度将其外推至无穷大。可按下式计算十二指肠内给药后的体内生物利用度(F%):
F(%)= (AUCid)/(AUCiv) ×100
在清醒狗体内抑制胃酸分泌和生物利用度
采用任何性别的Harrier狗。给动物装上用以施用试验化合物或载体的十二指肠瘘管和用来收集胃分泌物的胃腔瘘管。
在进行分泌试验前,对动物禁食约18小时,但随意提供水。在产生大约80%个体最高分泌应答的剂量下,用4小时时间灌输二盐酸组胺(12ml/h),以刺激胃酸分泌,并以30分钟为一批连续收集胃液。在开始灌输组胺一小时后,按0.5ml/kg体重的体积id或iv施用试验物质或载体。滴定至pH7.0,确定胃液试样的酸度,并计算出排酸量。将用药前分离的排酸量定为1.0,用分数应答表示施用试验物质或载体后收集期间的排酸量。通过由试验化合物载体得出的分数应答来计算抑制百分比。根据10g剂量-应答曲线,由图解内推法获得ED50值,或者假定所有试验化合物的剂量应答曲线的斜率相同,从单剂量实验测定ED50值。所报道的所有结果均基于用药后2小时的排酸量。以用药后3小时为间隔抽取血样,用以分析血浆中试验化合物的浓度。分离血浆,并在收集后的30分钟内冷冻之。利用线性绨形规则计算AUC(血浆-时间曲线下的面积),并外推至无限大。按100×(AUCid/AUCiv)计算经十二指肠内用药后的体内生物利用度(F%)。必要时,先将各AUC归一为相同剂量。
化学稳定性
在不同pH值的缓冲水溶液中,在37℃低浓度下,根据动力学观察本发明各个化合物的化学稳定性。表3中的结果表示在pH7时的半衰期t1/2,即:在这段时间后,原始化合物的一半仍未改变。
生物及稳定性试验的结果
表3归纳了本发明化合物以及先有技术中结构上与之十分相关的化合物的试验数据。表3中的这些相关化合物称为对照化合物,即EP175,464中所述的5-氟-2-[[(4-异丙氧基-2-吡啶基)-甲基]亚硫酰基]-1H-苯并咪唑。从表3可以看出,本发明的化合物具有很高的生物利用度(在大鼠上的F=82%)、药效(在大鼠上产生的ED50iv=1.2μmol/kg,ED50id=2.2μmol/kg)和化学稳定性(t1/2=23小时)。此外,就本发明化合物最卓越的性质-生物利用度而言,本发明化合物的值比对照化合物的值更高(82%对31%),其它性质也较优(对照化合物的ED50iv=1.8μmol/kg,ED50id=4.0μmol/kg和t1/2=14小时)。
(表3见文后)
表1
实施例 溶剂 NMR 数据 δppm(500MHz)
1. CDCl30.22(m,2H);0.60(m,2H);1.10(m,1H);
3.45(m,1H);3.60(m,1H);4.52(d,1H);
4.70(d,1H);6.65(d,1H);6.70(dd,1H);
7.08(m,1H);7.30-7.90(b,2H);8.28(d,1H)
2.D2Oδ(D2O,4.82) 0.09(m,2H);0.49(m,2H);0.88(m,1H);
2.92(m,1H);3.34(m,1H);4.62(d,1H);
4.71(d,1H);6.05(d,1H);6.75(m,1H);
7.05(m,1H);7.33(m,1H);7.58(m,1H);
8.23(d,1H)
表3 生物试验数据和化学稳定性数据
抑制酸分泌
生物利用度 pH7下的
试验化合物 狗ED50鼠,ED50“生物利用度” F% 化学稳定性
实施例编号 (μmol/kg) (μmol/kg) 鼠ED50iv/ED50id(%)
给药途径 给药途径 t1/2(h)
iv id iv id 狗 鼠
1 1) 1.0 1.2 2.2 55 80 82 23
对照例 n.t. n.t. 1.8 4.0 45 n.t. 31 14
n.t.=未试验
1)狗11μmol/kg 产生35%的抑制率
狗21μmol/kg 未产生抑制作用
狗32μmol/kg 产生98%抑制率
因此未测得ED50值。
Claims (3)
1、一种制备5-氟-2[[(4-环丙基甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑及其生理上可接受的盐以及它的旋光异构体的方法,该方法包括将5-氟-2-[[(4-环丙基甲氧基-2-吡啶基)甲基]-硫代]-1H-苯并咪唑氧化,必要时,将生成的化合物转化为盐或拆分为纯旋光异构体。
2、按照权利要求1的方法,其中产物是该化合物的钠盐。
3、按照权利要求1的方法,其中产物是该化合物的镁盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE19888804629A SE8804629D0 (sv) | 1988-12-22 | 1988-12-22 | New therapeutically active compounds |
SE8804629 | 1988-12-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1043713A CN1043713A (zh) | 1990-07-11 |
CN1028231C true CN1028231C (zh) | 1995-04-19 |
Family
ID=20374310
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN89109587A Expired - Fee Related CN1028231C (zh) | 1988-12-22 | 1989-12-21 | 具有新治疗活性的取代的苯并咪唑的制备方法 |
Country Status (32)
Country | Link |
---|---|
US (2) | US5008278A (zh) |
EP (1) | EP0449940B1 (zh) |
JP (1) | JP2793906B2 (zh) |
KR (1) | KR910700249A (zh) |
CN (1) | CN1028231C (zh) |
AR (1) | AR248136A1 (zh) |
AT (1) | ATE127799T1 (zh) |
AU (1) | AU634741B2 (zh) |
BG (1) | BG60102B2 (zh) |
CA (1) | CA2005986C (zh) |
DD (2) | DD296079A5 (zh) |
DE (1) | DE68924273T2 (zh) |
DK (1) | DK170800B1 (zh) |
EG (1) | EG19303A (zh) |
FI (2) | FI913035A0 (zh) |
GR (1) | GR1002252B (zh) |
HR (1) | HRP920831A2 (zh) |
HU (2) | HU205927B (zh) |
IE (1) | IE894048L (zh) |
IL (1) | IL92798A0 (zh) |
LT (2) | LT3914B (zh) |
LV (1) | LV10187B (zh) |
NZ (1) | NZ231872A (zh) |
PH (1) | PH27400A (zh) |
PL (1) | PL161150B1 (zh) |
PT (1) | PT92648B (zh) |
RO (1) | RO110494B1 (zh) |
RU (2) | RU2073676C1 (zh) |
SE (1) | SE8804629D0 (zh) |
WO (1) | WO1990006925A1 (zh) |
YU (1) | YU46806B (zh) |
ZA (2) | ZA899795B (zh) |
Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ244301A (en) * | 1991-09-20 | 1994-08-26 | Merck & Co Inc | Preparation of 2-pyridylmethylsulphinylbenzimidazole and pyridoimidazole derivatives from the corresponding sulphenyl compounds |
TNSN95063A1 (fr) * | 1994-05-27 | 1996-02-06 | Astra Ab | Nouveaux benzimidazoles substitues |
UA41946C2 (uk) * | 1994-07-08 | 2001-10-15 | Астра Актієболаг | Оральна фармацевтична складова одинична дозована форма у вигляді таблетки, спосіб її одержання, упаковка у вигляді блістера та спосіб інгібування секреції шлункової кислоти і/або лікування шлунково-кишкових запальних захворювань |
SE9402431D0 (sv) * | 1994-07-08 | 1994-07-08 | Astra Ab | New tablet formulation |
SE9500422D0 (sv) * | 1995-02-06 | 1995-02-06 | Astra Ab | New oral pharmaceutical dosage forms |
SE9500478D0 (sv) * | 1995-02-09 | 1995-02-09 | Astra Ab | New pharmaceutical formulation and process |
US6489346B1 (en) * | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
US6645988B2 (en) | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
US6699885B2 (en) * | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
SE9600070D0 (sv) | 1996-01-08 | 1996-01-08 | Astra Ab | New oral pharmaceutical dosage forms |
DE19758573C2 (de) * | 1997-11-26 | 2001-03-01 | Implex Hear Tech Ag | Fixationselement für ein implantierbares Mikrofon |
US20020039597A1 (en) * | 1998-04-20 | 2002-04-04 | Koji Ukai | Stabilized compositions containing benzimidazole-type compounds |
TWI243672B (en) | 1999-06-01 | 2005-11-21 | Astrazeneca Ab | New use of compounds as antibacterial agents |
KR20020038759A (ko) | 1999-10-20 | 2002-05-23 | 다니구치 미즈오 | 벤즈이미다졸계 화합물 안정화 방법 |
SE0000774D0 (sv) | 2000-03-08 | 2000-03-08 | Astrazeneca Ab | New formulation |
SE0101379D0 (sv) | 2001-04-18 | 2001-04-18 | Diabact Ab | Komposition som hämmar utsöndring av magsyra |
US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
SE0102993D0 (sv) | 2001-09-07 | 2001-09-07 | Astrazeneca Ab | New self emulsifying drug delivery system |
MXPA04007169A (es) * | 2002-01-25 | 2004-10-29 | Santarus Inc | Suministro transmucosal de inhibidores de bomba de protones. |
WO2003082858A1 (en) * | 2002-03-26 | 2003-10-09 | Dr. Reddy's Laboratories Limited | Crystalline forms of rabeprazole sodium |
SE0203065D0 (sv) | 2002-10-16 | 2002-10-16 | Diabact Ab | Gastric acid secretion inhibiting composition |
TWI367759B (en) * | 2003-02-20 | 2012-07-11 | Santarus Inc | A novel formulation, omeprazole antacid complex-immediate release, for rapid and sustained suppression of gastric acid |
CA2531564C (en) * | 2003-07-18 | 2016-01-19 | Santarus, Inc. | Pharmaceutical composition for inhibiting acid secretion |
AU2004257864A1 (en) * | 2003-07-18 | 2005-01-27 | Santarus, Inc. | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders |
US8993599B2 (en) * | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
MXPA06003450A (es) | 2003-09-26 | 2006-08-31 | Johnson & Johnson | Recubrimiento de farmaco que proporciona alta carga del farmaco y metodos para proporcionar el mismo. |
US20070292498A1 (en) * | 2003-11-05 | 2007-12-20 | Warren Hall | Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers |
US8906940B2 (en) * | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
US8815916B2 (en) * | 2004-05-25 | 2014-08-26 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
US8541026B2 (en) | 2004-09-24 | 2013-09-24 | Abbvie Inc. | Sustained release formulations of opioid and nonopioid analgesics |
US7981908B2 (en) | 2005-05-11 | 2011-07-19 | Vecta, Ltd. | Compositions and methods for inhibiting gastric acid secretion |
US7803817B2 (en) | 2005-05-11 | 2010-09-28 | Vecta, Ltd. | Composition and methods for inhibiting gastric acid secretion |
EP2046334B1 (en) | 2006-07-25 | 2014-05-21 | Vecta Ltd. | Compositions and meth0ds for inhibiting gastric acide secretion using derivatives of small dicarboxylic acids in combination with ppi |
US20090092658A1 (en) * | 2007-10-05 | 2009-04-09 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
AU2009290712A1 (en) | 2008-09-09 | 2010-03-18 | Astrazeneca Ab | Method for delivering a pharmaceutical composition to patient in need thereof |
AU2010263304A1 (en) | 2009-06-25 | 2012-02-02 | Astrazeneca Ab | Method for treating a patient at risk for developing an NSAID-associated ulcer |
WO2011080501A2 (en) | 2009-12-29 | 2011-07-07 | Orexo Ab | New pharmaceutical dosage form for the treatment of gastric acid-related disorders |
WO2011080500A2 (en) | 2009-12-29 | 2011-07-07 | Orexo Ab | New pharmaceutical dosage form for the treatment of gastric acid-related disorders |
WO2011080502A2 (en) | 2009-12-29 | 2011-07-07 | Orexo Ab | New pharmaceutical dosage form for the treatment of gastric acid-related disorders |
EP2601947A1 (en) | 2011-12-05 | 2013-06-12 | Abo Bakr Mohammed Ali Al-Mehdar | Fixed-dose combination for treatment of helicobacter pylori associated diseases |
CA2860231A1 (en) | 2011-12-28 | 2013-07-04 | Pozen Inc. | Improved compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US428098A (en) | 1890-05-20 | Electric railway | ||
US727150A (en) | 1902-06-18 | 1903-05-05 | Peter Paul Keller | Adjustable hanger for incandescent lamps. |
SE418966B (sv) * | 1974-02-18 | 1981-07-06 | Haessle Ab | Analogiforfarande for framstellning av foreningar med magsyrasekretionsinhiberande verkan |
SE416649B (sv) * | 1974-05-16 | 1981-01-26 | Haessle Ab | Forfarande for framstellning av foreningar som paverkar magsyrasekretionen |
IN148930B (zh) * | 1977-09-19 | 1981-07-25 | Hoffmann La Roche | |
SE7804231L (sv) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Magsyrasekretionsmedel |
US4359465A (en) * | 1980-07-28 | 1982-11-16 | The Upjohn Company | Methods for treating gastrointestinal inflammation |
CH644116A5 (de) * | 1980-08-21 | 1984-07-13 | Hoffmann La Roche | Imidazolderivate. |
DE3215503A1 (de) | 1982-04-26 | 1983-11-03 | Zängl GmbH, 8000 München | Elektrisch beheiztes schneidgeraet |
SE8301182D0 (sv) * | 1983-03-04 | 1983-03-04 | Haessle Ab | Novel compounds |
HU195220B (en) * | 1983-05-03 | 1988-04-28 | Byk Gulden Lomberg Chem Fqb | Process for production of new fluor-alkoxi-benzimidasole-derivatives and medical compositions containig them |
JPS6150979A (ja) * | 1984-08-16 | 1986-03-13 | Takeda Chem Ind Ltd | ピリジン誘導体およびその製造法 |
JPS6150978A (ja) * | 1984-08-16 | 1986-03-13 | Takeda Chem Ind Ltd | ピリジン誘導体およびその製造法 |
AU568441B2 (en) * | 1984-09-24 | 1987-12-24 | Upjohn Company, The | 2-(pyridylalkenesulfinyl) benzimidazole derivatives |
US4738975A (en) * | 1985-07-02 | 1988-04-19 | Takeda Chemical Industries, Ltd. | Pyridine derivatives, and use as anti-ulcer agents |
JPS6261978A (ja) * | 1985-09-12 | 1987-03-18 | Otsuka Pharmaceut Co Ltd | 5−フルオロ−1h−ベンズイミダゾ−ル誘導体 |
SE8505112D0 (sv) * | 1985-10-29 | 1985-10-29 | Haessle Ab | Novel pharmacological compounds |
JPS62201884A (ja) * | 1986-02-28 | 1987-09-05 | Tokyo Tanabe Co Ltd | ベンズイミダゾール誘導体及びその製造法 |
FI90544C (fi) * | 1986-11-13 | 1994-02-25 | Eisai Co Ltd | Menetelmä lääkeaineina käyttökelpoisten 2-pyridin-2-yyli-metyylitio- ja sulfinyyli-1H-bensimidatsolijohdannaisten valmistamiseksi |
NZ234564A (en) * | 1986-11-21 | 1991-04-26 | Haessle Ab | 1-substituted benzimidazoles and pharmaceutical compositions |
FI96860C (fi) * | 1987-06-17 | 1996-09-10 | Eisai Co Ltd | Analogiamenetelmä lääkeaineena käytettävän pyridiinijohdannaisen valmistamiseksi |
DE3722810A1 (de) * | 1987-07-10 | 1989-01-19 | Hoechst Ag | Substituierte benzimidazole, verfahren zu deren herstellung, diese enthaltende pharmazeutische zubereitungen und deren verwendung |
DK171989B1 (da) * | 1987-08-04 | 1997-09-08 | Takeda Chemical Industries Ltd | Fremgangsmåde til fremstilling af 2-(2-pyridylmethylsulfinyl)-benzimidazoler |
JPH0676323B2 (ja) * | 1987-08-28 | 1994-09-28 | 東京田辺製薬株式会社 | 抗潰瘍剤 |
-
1988
- 1988-12-22 SE SE19888804629A patent/SE8804629D0/xx unknown
-
1989
- 1989-12-18 EG EG62189A patent/EG19303A/xx active
- 1989-12-18 IE IE894048A patent/IE894048L/xx unknown
- 1989-12-18 AR AR89315705A patent/AR248136A1/es active
- 1989-12-19 NZ NZ231872A patent/NZ231872A/en unknown
- 1989-12-19 CA CA002005986A patent/CA2005986C/en not_active Expired - Lifetime
- 1989-12-19 PH PH39732A patent/PH27400A/en unknown
- 1989-12-19 IL IL92798A patent/IL92798A0/xx not_active IP Right Cessation
- 1989-12-19 GR GR890100838A patent/GR1002252B/el unknown
- 1989-12-20 HU HU901095A patent/HU205927B/hu not_active IP Right Cessation
- 1989-12-20 DE DE68924273T patent/DE68924273T2/de not_active Expired - Fee Related
- 1989-12-20 DD DD89335981A patent/DD296079A5/de not_active IP Right Cessation
- 1989-12-20 ZA ZA899795A patent/ZA899795B/xx unknown
- 1989-12-20 JP JP2501537A patent/JP2793906B2/ja not_active Expired - Fee Related
- 1989-12-20 ZA ZA899794A patent/ZA899794B/xx unknown
- 1989-12-20 US US07/454,047 patent/US5008278A/en not_active Expired - Lifetime
- 1989-12-20 HU HU901084A patent/HU205926B/hu not_active IP Right Cessation
- 1989-12-20 EP EP90901079A patent/EP0449940B1/en not_active Expired - Lifetime
- 1989-12-20 RO RO147866A patent/RO110494B1/ro unknown
- 1989-12-20 DD DD89335980A patent/DD296078A5/de not_active IP Right Cessation
- 1989-12-20 RU SU894895789A patent/RU2073676C1/ru active
- 1989-12-20 AT AT90901079T patent/ATE127799T1/de not_active IP Right Cessation
- 1989-12-20 AU AU48175/90A patent/AU634741B2/en not_active Ceased
- 1989-12-20 WO PCT/SE1989/000740 patent/WO1990006925A1/en active Application Filing
- 1989-12-21 PT PT92648A patent/PT92648B/pt not_active IP Right Cessation
- 1989-12-21 YU YU242689A patent/YU46806B/sh unknown
- 1989-12-21 CN CN89109587A patent/CN1028231C/zh not_active Expired - Fee Related
- 1989-12-22 PL PL1989282923A patent/PL161150B1/pl unknown
-
1990
- 1990-08-21 KR KR1019900701828A patent/KR910700249A/ko not_active Application Discontinuation
- 1990-12-20 US US07/633,007 patent/US5039808A/en not_active Expired - Lifetime
-
1991
- 1991-06-19 BG BG94659A patent/BG60102B2/bg unknown
- 1991-06-20 FI FI913035A patent/FI913035A0/fi not_active Application Discontinuation
- 1991-06-21 DK DK122291A patent/DK170800B1/da not_active IP Right Cessation
- 1991-06-21 RU SU914895805A patent/RU2042673C1/ru active
-
1992
- 1992-10-02 HR HR920831A patent/HRP920831A2/hr not_active Application Discontinuation
-
1993
- 1993-06-30 LV LVP-93-860A patent/LV10187B/en unknown
- 1993-12-30 LT LTIP1726A patent/LT3914B/lt not_active IP Right Cessation
- 1993-12-30 LT LTIP1721A patent/LT3980B/lt not_active IP Right Cessation
-
1995
- 1995-10-06 FI FI954768A patent/FI954768A0/fi not_active Application Discontinuation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1028231C (zh) | 具有新治疗活性的取代的苯并咪唑的制备方法 | |
CN1052671A (zh) | 具有治疗活性的氯取代的苯并咪唑及其制备方法和应用 | |
CN1048245C (zh) | 5-吡咯基-2-吡啶基甲基亚磺酰基苯并咪唑衍生物,其制备方法及含它们的抗溃疡组合物 | |
CN1028232C (zh) | 具有治疗活性的取代的苯并咪唑的制备方法 | |
JP5902029B2 (ja) | アミド化合物およびその医薬用途 | |
CN1026322C (zh) | 苯并哑唑衍生物的制备方法 | |
CN1155598C (zh) | 四氢吡啶醚化合物 | |
CN1255406C (zh) | 取代的2-芳基-3-(杂芳基)-咪唑并[1,2-a]嘧啶类化合物以及相关的药物组合物和方法 | |
CN1058212A (zh) | 取代的莱并咪唑、其制备方法和其在药物上的用途 | |
CN1110477A (zh) | 旋光纯的吡啶甲基亚磺酰基-1h-苯并咪唑类化合物的盐 | |
CN1306533A (zh) | 抑制胃酸分泌的咪唑并吡啶衍生物 | |
CN1187188A (zh) | 旋转异构酶活性的小分子抑制剂 | |
CN1028233C (zh) | 具有抑制胃酸作用的取代的苯并咪唑的制备方法 | |
JP4837722B2 (ja) | 置換スルホキシド化合物、その調製方法、およびその使用方法 | |
CN1161355C (zh) | 新的化合物 | |
CN1142227A (zh) | 新的噻唑烷-4-酮衍生物 | |
CN1048014C (zh) | 取代的吡咯类化合物及其制法、药物组合物和用途 | |
MX2007015269A (es) | Derivados de benzotiazol-2-ona como inhibidores de lipasas y fosfolipasas. | |
CN1031827C (zh) | 取代的苯并咪唑的制备方法 | |
CN86103227A (zh) | 制备2-吡咯烷酮衍生物的方法 | |
CA2509899C (fr) | Enantiomere (-) du tenatoprazole et son application en therapeutique | |
CN1052654A (zh) | 一种氨基酸肥及其制法 | |
CN1863799A (zh) | 治疗糖尿病和脂质紊乱的色原烷羧酸衍生物 | |
CN1610679A (zh) | 制备因子xa抑制剂的有效方法 | |
EP1098888A1 (fr) | Derives de piperazinones et leurs applications |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |