CN102239167A - 抑制胃酸分泌的咪唑并吡啶衍生物 - Google Patents
抑制胃酸分泌的咪唑并吡啶衍生物 Download PDFInfo
- Publication number
- CN102239167A CN102239167A CN2009801484447A CN200980148444A CN102239167A CN 102239167 A CN102239167 A CN 102239167A CN 2009801484447 A CN2009801484447 A CN 2009801484447A CN 200980148444 A CN200980148444 A CN 200980148444A CN 102239167 A CN102239167 A CN 102239167A
- Authority
- CN
- China
- Prior art keywords
- imidazo
- pyridine
- acid
- dimethyl
- compound
- 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.)
- Granted
Links
- 210000004211 gastric acid Anatomy 0.000 title abstract description 4
- 230000028327 secretion Effects 0.000 title description 5
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
- 230000002265 prevention Effects 0.000 claims abstract description 3
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 19
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 208000005577 Gastroenteritis Diseases 0.000 claims description 7
- -1 alicyclic ketone Chemical class 0.000 claims description 7
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 6
- 210000004051 gastric juice Anatomy 0.000 claims description 6
- 208000011906 peptic ulcer disease Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 208000012895 Gastric disease Diseases 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 206010028813 Nausea Diseases 0.000 claims description 3
- 201000006549 dyspepsia Diseases 0.000 claims description 3
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 3
- 208000024798 heartburn Diseases 0.000 claims description 3
- 230000008693 nausea Effects 0.000 claims description 3
- 208000024981 pyrosis Diseases 0.000 claims description 3
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- VBKPPDYGFUZOAJ-UHFFFAOYSA-N 5-oxopentanoic acid Chemical compound OC(=O)CCCC=O VBKPPDYGFUZOAJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010063655 Erosive oesophagitis Diseases 0.000 claims description 2
- 150000003997 cyclic ketones Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims 1
- 230000027119 gastric acid secretion Effects 0.000 abstract description 4
- 208000017189 Gastrointestinal inflammatory disease Diseases 0.000 abstract 1
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 59
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- GHVIMBCFLRTFHI-UHFFFAOYSA-N 8-[(2,6-dimethylphenyl)methylamino]-n-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide Chemical compound C=1C(C(=O)NCCO)=CN2C(C)=C(C)N=C2C=1NCC1=C(C)C=CC=C1C GHVIMBCFLRTFHI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229950010119 linaprazan Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 0 Cc1c(C)nc(c(NCc2c(C)cccc2C)c2)[n]1cc2C(NCCOC(CC*)=O)=[U] Chemical compound Cc1c(C)nc(c(NCc2c(C)cccc2C)c2)[n]1cc2C(NCCOC(CC*)=O)=[U] 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108010079943 Pentagastrin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000009858 acid secretion Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 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
- 238000009472 formulation Methods 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 150000005232 imidazopyridines Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 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
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 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 2
- 229960000444 pentagastrin Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IPYWNMVPZOAFOQ-NABDTECSSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(carboxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;trihydrate Chemical compound O.O.O.S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 IPYWNMVPZOAFOQ-NABDTECSSA-N 0.000 description 1
- BNBOUFHCTIFWHN-UHFFFAOYSA-N 3-bromobutan-2-one Chemical compound CC(Br)C(C)=O BNBOUFHCTIFWHN-UHFFFAOYSA-N 0.000 description 1
- OIMRLHCSLQUXLL-UHFFFAOYSA-N 3-chlorobutan-2-one Chemical compound CC(Cl)C(C)=O OIMRLHCSLQUXLL-UHFFFAOYSA-N 0.000 description 1
- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 description 1
- ZBFDAUIVDSSISP-UHFFFAOYSA-N 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- CZDMAPPDNNZHMH-UHFFFAOYSA-N 6-chloro-5-nitropyridine-3-carbonyl chloride Chemical compound [O-][N+](=O)C1=CC(C(Cl)=O)=CN=C1Cl CZDMAPPDNNZHMH-UHFFFAOYSA-N 0.000 description 1
- 229940121819 ATPase inhibitor Drugs 0.000 description 1
- 229910000014 Bismuth subcarbonate Inorganic materials 0.000 description 1
- HWSISDHAHRVNMT-UHFFFAOYSA-N Bismuth subnitrate Chemical compound O[NH+]([O-])O[Bi](O[N+]([O-])=O)O[N+]([O-])=O HWSISDHAHRVNMT-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- BKUKMOXOORPSPN-UHFFFAOYSA-N Cc1c(C)nc(c(NCc2c(C)cccc2C)c2)[n]1cc2C(NCCOC(CCC(O)=O)=O)=O Chemical compound Cc1c(C)nc(c(NCc2c(C)cccc2C)c2)[n]1cc2C(NCCOC(CCC(O)=O)=O)=O BKUKMOXOORPSPN-UHFFFAOYSA-N 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 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
- 241000282326 Felis catus Species 0.000 description 1
- 102100021022 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- RXDALBZNGVATNY-CWLIKTDRSA-N ampicillin trihydrate Chemical compound O.O.O.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 RXDALBZNGVATNY-CWLIKTDRSA-N 0.000 description 1
- 229960003311 ampicillin trihydrate Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- MGLUJXPJRXTKJM-UHFFFAOYSA-L bismuth subcarbonate Chemical compound O=[Bi]OC(=O)O[Bi]=O MGLUJXPJRXTKJM-UHFFFAOYSA-L 0.000 description 1
- 229940036358 bismuth subcarbonate Drugs 0.000 description 1
- 229960004645 bismuth subcitrate Drugs 0.000 description 1
- JAONZGLTYYUPCT-UHFFFAOYSA-K bismuth subgallate Chemical compound OC(=O)C1=CC(O)=C2O[Bi](O)OC2=C1 JAONZGLTYYUPCT-UHFFFAOYSA-K 0.000 description 1
- 229960000199 bismuth subgallate Drugs 0.000 description 1
- 229960001482 bismuth subnitrate Drugs 0.000 description 1
- ZREIPSZUJIFJNP-UHFFFAOYSA-K bismuth subsalicylate Chemical compound C1=CC=C2O[Bi](O)OC(=O)C2=C1 ZREIPSZUJIFJNP-UHFFFAOYSA-K 0.000 description 1
- 229960000782 bismuth subsalicylate Drugs 0.000 description 1
- ZQUAVILLCXTKTF-UHFFFAOYSA-H bismuth;tripotassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[K+].[K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O ZQUAVILLCXTKTF-UHFFFAOYSA-H 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 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
- 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
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000003743 cholecystokinin B receptor antagonist Substances 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 1
- 229960005132 cisapride Drugs 0.000 description 1
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 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
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000001330 gastroprokinetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229940031958 magnesium carbonate hydroxide Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960004085 mosapride Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 229940049547 paraxin Drugs 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229950008375 tenatoprazole Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
-
- 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
-
- 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
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及式I的取代的咪唑并[1，2-a]吡啶，其中R是-CH2COOH或-COOH，其抑制外源性或内源性刺激的胃酸分泌，并可以被用于与胃酸有关的疾病和胃肠炎性疾病的预防和治疗。
Description
技术领域
本发明涉及抑制外源性或内源性刺激的胃酸分泌的新的咪唑并吡啶衍生物和其药学上可接受的盐。所述化合物可用于预防和治疗胃肠炎性疾病。在进一步的方面，本发明具体涉及取代的咪唑并[1，2-a]吡啶和其药学上可接受的盐，涉及用于制备其的方法，涉及包含所述化合物作为活性成分的药物组合物，以及涉及所述化合物在制备用于上面指出的医学用途的药物中的用途。
背景技术
可用于消化性溃疡疾病的治疗的取代的咪唑并[1，2-a]吡啶，从EP0033094、US4450164、EP0204285、US4725601、WO99/55706、WO99/55705、WO03/018582和WO2006/100119和从J.J.Kaminski等人于Journal of Medicinal Chemistry第28卷，876-892，1985和第34卷，533-541，1991的出版物中获知。
胃酸泵(H+、K+-ATP酶)的药理学综述由Sachs等人在Ann.Rev.Pharmacol.Toxicol，第35卷，277-305，1995中提出。
发明概述
现在已经发现可用于治疗胃肠炎性疾病，特别是可用于治疗消化性溃疡疾病的新的取代的咪唑并[1，2-a]吡啶。所述取代的咪唑并[1，2-a]吡啶显示了几种有利的性质，如快速起效，高体内效力和/或长的作用持续时间，高溶解度和高溶解速率。由于它们的两性离子特性，这些化合物在酸性和碱性溶液中都形成可溶的盐。
本发明的公开内容
已经令人惊奇地发现新的通式I的取代的咪唑并[1，2-a]吡啶作为胃酸分泌的抑制剂是特别地有效的。特别地，本发明涉及通式I的取代的咪唑并[1，2-a]吡啶及其药学上可接受的盐，其中取代基R是-CH2COOH或-COOH。
取决于过程条件，获得中性形式或盐形式的根据式I的取代的咪唑并[1，2-a]吡啶。这些化合物的中性形式和盐形式都属于本发明的范围。
方法
本发明还提供了用于制备式I的取代的咪唑并[1，2-a]吡啶的方法。
用于制备式I的取代的咪唑并[1，2-a]吡啶的方法在下文被详细描述。
使用本领域已知的任何适合的方法，例如根据WO02/20523中公开的方法，可获得式II的起始材料2，3-二甲基-8-(2，6-二甲基苄基氨基)-N-羟基乙基-咪唑并[1，2-a]吡啶-6-甲酰胺，其中
a)使商业上可获得的式III的6-氯-5-硝基烟酰氯
与式R1-OH的醇(其中R1是烷基，如甲基、乙基、异丙基等)反应以得到下式IV的相应的酯。
反应通常在标准条件下进行。
b)使式IV的化合物与氨反应以得到以下式V的化合物
其中R1是烷基，如甲基、乙基、异丙基等。反应通常在标准条件下进行。
c)式V的化合物例如通过使用氢气和氢化催化剂如Pd/C来氢化，以得到式VI的化合物
其中R1是烷基，如甲基、乙基、异丙基等。反应通常在标准条件下在惰性溶剂中进行。
d)通过使式VI的化合物与3-氯-2-丁酮或3-溴-2-丁酮在标准条件下在惰性溶剂(如丙酮、乙腈、环己酮和二甲基甲酰胺等)中任选地在碱的存在下反应来制备式VII的咪唑并[1，2]吡啶化合物，其中R1是烷基，如甲基、乙基、异丙基等。
e)然后使式VII的咪唑并[1，2]吡啶化合物与式VIII的化合物反应
其中X是溴(Br)或氯(Cl)，以得到式IX的化合物，其中R1是烷基，如甲基、乙基、异丙基等。这一反应通常在惰性溶剂(如丙酮、乙腈、二甲氧基乙烷、乙醇或二甲基甲酰胺)中任选地在碱(如碳酸钾、碳酸钠或有机胺，如三乙胺)的存在下进行。
f)使式IX的化合物与乙醇胺反应以得到式II的起始材料2，3-二甲基-8-(2，6-甲基苄基氨基)-N-羟基乙基-咪唑并[1，2-a]吡啶-6-甲酰胺。通常通过在纯乙醇胺中或在溶剂(如甲醇或乙醇)中在升高的温度(如从40℃至80℃)下加热反应物进行反应。该反应通过氰化物盐和强碱(如甲醇钠、乙醇钾和1，8-二氮杂双环(5.4.0)十一碳-7-烯(DBU))催化。
用于制备式I的取代的咪唑并[1，2-a]吡啶(其中R是-CH2COOH或-COOH)的根据本发明的方法包括以下步骤，其中使起始材料2，3-二甲基-8-(2，6-二甲基苄基氨基)-N-羟基乙基-咪唑并[1，2-a]吡啶-6-甲酰胺与1-4当量的选自戊二酸酐和琥珀酸酐的酐反应以得到期望的式I的化合物。在升高的温度下通过在惰性溶剂或其混合物中加热反应物进行反应。适合的惰性溶剂是例如DMF(二甲基甲酰胺)、DMA(二甲基乙酰胺)、NMP(N-甲基吡咯烷酮)、THF(四氢呋喃)、环酮(如环己酮)和脂环酮(如丙酮和甲基乙基酮)。适合的反应温度范围在40℃与130℃之间，优选地在60℃至120℃之间。压力范围可以在从大气压至5×102KPa。反应之后，例如使用从反应混合物中结晶来分离产物，或使用适合的溶剂如丙酮来沉淀产物。
取决于过程条件，获得中性形式或盐形式的根据式I的取代的咪唑并[1，2-a]吡啶。由于两性离子性质，式I的化合物在pH≤4呈带正电荷的阳离子的形式，如盐酸盐，在pH≥8其呈带负电荷的阴离子的形式，如羧酸阴离子，而在pH在约5与7之间的范围时，化合物的中性形式可以存在，因为可发现化合物的电介质点(dielectric point)在5-7的pH范围附近。
在式I的取代的咪唑并[1，2-a]吡啶的盐，特别地酸加成盐的制备中，优选地使用能够形成药学上可接受的盐的酸。适合的酸的实例是盐酸、硫酸、磷酸、硝酸和磺酸，如甲磺酸、乙磺酸、羟基乙磺酸、甲苯磺酸和萘磺酸。
在碱性盐如钠盐、钾盐、钙盐和镁盐的制备中，优选地使用能够形成药学上可接受的盐的碱。这些盐可通过使用诸如以下的碱制备：氢氧化钠、碳酸钠、碳酸氢钠、氢氧化钾、碳酸钾、碳酸氢钾、氢氧化钙、乙酸钙、氢氧化镁和乙酸镁。
医学用途
在进一步的方面，本发明涉及式I的取代的咪唑并[1，2-a]吡啶在治疗中的用途。特别地，本发明提供了式I的取代的咪唑并[1，2-a]吡啶在制备用于抑制胃酸分泌和用于治疗胃肠炎性疾病，特别是消化性溃疡疾病的药物中的用途。
已显示，根据本发明的取代的咪唑并[1，2-a]吡啶具有显著的治疗效果。在大鼠研究中，如果向大鼠施用1μmol/kg的根据本发明的化合物，对于实施例1，观察到100％的酸分泌的最大抑制，且对于实施例2为70％。因此，这些化合物可以被用于预防和治疗包括人的哺乳动物中的胃肠炎性疾病和与胃酸有关的疾病，如胃炎、反流性食管炎、佐-埃综合征和消化性溃疡疾病，包括胃溃疡和十二指肠溃疡。此外，化合物可以被用于例如在患有胃泌素瘤的患者中和在患有急性上消化道出血的患者中治疗其中期望胃的抑制分泌作用的其它胃肠道病症。化合物也可以被用于有效控制和治疗胃灼热和其它胃食管返流疾病(GERD)症状、反胃、酸返流疾病的短期和长期管理以及恶心。它们还可以在处于重症监护状态的患者中使用，并在手术前和手术后使用，以预防酸吸入(acid aspiration)和应激性溃疡。
两性离子特性给予本发明的化合物特别有利的物理性质。这些性质使得该化合物适合不同的药物组合物。根据本发明的化合物在酸性介质中(例如，在胃中)具有好的溶解性，其有利于速释(instant release)(IR)制剂。在中性pH时，根据本发明的化合物例如两性离子具有低的溶解性，其可以被用于缓释(ER)制剂。在碱性pH时，根据本发明的化合物呈阴离子形式，其具有好的溶解性且尤其适合静脉内制剂。
体内施用之后，根据本发明的化合物产生linaprazan作为主要的代谢物。linaprazan是已知胃酸分泌抑制剂。因此，本发明的化合物也作为用于linaprazan的前药。
根据本发明的化合物作为药学活性物质的典型的日剂量在宽的范围内变化，且将取决于各种因素，如例如每位患者的个体需要、施用途径和待治疗的疾病。一般，口服和肠胃外剂量将在每天5mg至500mg的活性物质的范围，优选地在10mg至60mg的范围，例如40mg。
取决于个体需要和疾病，可以将本发明的化合物以连续的治疗以及按需要治疗施用到患者。给出了通过本发明的化合物提高遭受与胃酸相关的疾病和/或胃肠炎性疾病的个体的生活质量的可能性。
取决于个体需要和疾病，可以将本发明的化合物以连续治疗以及按需要治疗施用到人患者或施用到非人哺乳动物患者，如马、狗、猫等。
药物组合物
在又进一步的方面，本发明涉及包含本发明的取代的咪唑并[1，2-a]吡啶或其药学上可接受的盐作为活性成分的药物组合物。
为了治疗用途，本发明的化合物被配制成用于口服、直肠、肠胃外或其它施用模式的药物组合物。该药物组合物包含与一种或多种药学上可接受的成分/赋形剂结合的本发明的物质。药物组合物可以包括处于固体、半固体或液体稀释剂形式的载体，或药物组合物可以被包含在胶囊中。
这些药物制品是本发明进一步的目的。通常在用于口服施用的制品中，药物组合物中本发明的化合物的量在按重量计0.1％与90％之间，优选地在按重量计0.1％与20％之间。
呈用于口服施用的剂量单位形式的根据本发明的药物组合物的制备包括以下步骤：其中将根据本发明的化合物与本领域已知的固体、粉末状成分如乳糖、蔗糖、山梨糖醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶或其它适合的成分混合，以及与崩解剂和润滑剂如硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠和聚乙二醇蜡混合。然后，使用本领域中已知的任何适合的方法，将混合物加工成颗粒或压成片剂。
用包含本发明的化合物、植物油、脂肪或用于软明胶胶囊的其它适合的媒介物的胶囊可以制备软明胶胶囊。硬明胶胶囊可以包含本发明的化合物的颗粒。硬明胶胶囊还可以包含与固体粉末状成分如乳糖、蔗糖、山梨糖醇、甘露糖、马铃薯淀粉、玉米淀粉、支链淀粉、纤维素衍生物或明胶结合的本发明的化合物。
可以制备用于直肠施用的剂型单位呈如下形式：(i)呈栓剂的形式，其包含与中性的脂肪碱(fat base)混合的本发明的化合物；(ii)呈明胶直肠胶囊形式，其包含本发明的化合物与植物油、石蜡油或用于明胶直肠胶囊的其它适合的媒介物的混合物；(iii)呈预制的微型灌肠剂的形式；或(iv)呈干的微型灌肠制剂的形式以恰恰在施用之前在适合的溶剂中被重新构成。
可以制备用于口服施用的液体制品呈糖浆剂或悬浮剂的形式，例如，包含按重量计0.1％至20％的本发明的化合物且剩余物由糖或糖醇和乙醇、水、甘油、丙二醇和聚乙二醇的混合物组成的溶液或悬浮液。若需要，这些液体制品可以包含着色剂、调味剂、糖精和羧甲基纤维素或其它增稠剂。用于口服施用的液体制品也可以制备呈干粉末的形式，以在使用前用适合的溶剂重新构成。
可以将用于肠胃外施用的溶液制备为本发明的化合物在药学上可接受的溶剂中的溶液，优选地以按重量计0.1％至10％的浓度。这些溶液还可以包含稳定成分和/或缓冲成分，且被分配到安瓿或小瓶的形式的单位剂量。用于肠胃外施用的溶液也可以被制备成干的制品，以在使用之前临时用适合的溶剂重新构成。
根据本发明的化合物还可以与其它活性成分一起被用于制剂，例如用于治疗或预防涉及由人胃粘膜的幽门螺旋杆菌(helicobacter pylori)感染的病况。这些其它活性成分可以是抗微生物剂且特别地是：
·B-内酰胺抗生素，如阿莫西林、氨苄西林、头孢噻吩、头孢克洛或头孢克肟；
·大环内酯类，如红霉素或克拉霉素；
·氨基糖苷类，如正大霉素、卡那霉素或阿米卡星；
·喹诺酮类，如诺氟沙星、环丙沙星或依诺沙星；
·其它，如甲硝哒唑、硝基呋喃妥英或氯霉素；或
·包含铋盐如次柠檬酸铋、碱式水杨酸铋、碱式碳酸铋、次硝酸铋或次没食子酸铋的制品。
根据本发明的化合物还可以与抗酸剂如氢氧化铝、碳酸镁和氢氧化镁或海藻酸一起或结合用于同时、单独或顺序使用；或与抑制酸分泌的药物如H2-阻断剂(例如，西咪替丁、雷尼替丁)，H+K+-ATP酶抑制剂(例如，奥美拉唑、泮托拉唑、兰索拉唑、雷贝拉唑或替那拉唑)一起或结合用于同时、单独或顺序使用；或与促胃运动剂(gastroprokinetics)(例如，西沙必利或莫沙必利)一起或结合用于同时、单独或顺序使用。
根据本发明的化合物还可以与其它活性成分一起或结合用于同时、单独或顺序使用，例如用于治疗或预防涉及药物诱导的胃溃疡的病况。这些其它活性成分可以是NSAID、NO-释放的NSAID、COX-2-抑制剂或二磷酸盐。
根据本发明的化合物还可以与胃泌素拮抗剂如CCK2拮抗剂一起或结合用于同时、单独或顺序使用。
根据本发明的化合物被适宜地用于治疗和/或预防人或非人哺乳动物中与胃酸有关的疾病、胃肠炎性疾病、胃灼热、症状性GERD、腐蚀性食管炎、消化性溃疡疾病、反胃、酸返流疾病或恶心的方法，其包括向需要其的人或非人哺乳动物施用有效量的根据本发明的化合物。
用以下实施例更详细地说明本发明，然而对于本领域技术人员明显的是本发明的范围无意仅限于实施例。
实施例
实施例1
5-{2-[({8-[(2，6-二甲基苄基)氨基]-2，3-二甲基咪唑并[1，2-a]吡啶-6-基}羰基)氨基]乙氧基}-5-氧代戊酸的制备
向DMF(10ml)中加入2，3-二甲基-8-(2，6-二甲基苄基氨基)-N-羟基乙基-咪唑并[1，2-a]吡啶-6-甲酰胺(使用根据WO02/20523的方法获得)(2.0g，5.46mmol)和戊二酸酐(0.95g，8.33mmol)。将混合物加热至80℃并在这一温度搅拌16h。将丙酮(20ml)加到反应混合物中，借此产物开始结晶。将混合物冷却至室温。4h之后将产物滤出并用丙酮(20ml)洗涤。获得2.25g(86％)的标题化合物。用1H-NMR图谱确认该化合物的结构。
1H-NMR(300MHz，DMSO)：δ1.73(m，2H)，2.2-2.4(m，16H)，3.52(m，2H)，4.18(t，2H)，4.36(d，2H)，4.99(t，1H)，6.67(s，1H)，7.0-7.2(m，3H)，8.04(s，1H)，8.56(t，1H)，12.10(bs，1H).
实施例2
4-{2-[({8-[(2，6-二甲基苄基)氨基]-2，3-二甲基咪唑并[1，2-a]吡啶-6-基}羰基)氨基]乙氧基}-4-氧代丁酸的制备
向DMF(2ml)中加入2，3-二甲基-8-(2，6-二甲基苄基氨基)-N-羟基乙基-咪唑并[1，2-a]吡啶-6-甲酰胺(使用根据WO2/20523的方法获得)(250mg，0.680mmol)和琥珀酸酐(150mg，1.50mmol)。将混合物在70℃搅拌16小时。加入丙酮(7ml)，并将混合物冷却至室温。在室温搅拌几小时之后，将形成的沉淀滤出，并用丙酮(10ml)洗涤。获得280mg(88％)的标题化合物。用1H-NMR图谱确认该化合物的结构。
1H-NMR(300MHz，DMSO)：δ2.22(s，3H)，2.33(s，6H)，2，37(s，3H)，2.45-2.50(m，4H)，3.51(m，2H)，4.16(t，2H)，4.36(d，2H)，4.99(t，1H)，6.67(s，1H)，7.0-7.2(m，3H)，8.04(s，1H)，3.55(t，1H)，12.21(s，1H).
实施例3
起始材料2，3-二甲基-8-(2，6-二甲基苄基氨基)-N-羟基乙基-咪唑并[1，2-a]吡啶-6-甲酰胺的制备
将8-[(2，6-二甲基苄基)氨基]-2.3-二甲基咪唑并[1，2-a]吡啶-6-羧酸异丙酯(按照WO2/20523中描述的获得)(5g，14mmol)、乙醇胺(2.0g 33mmol)和1，8-二氮杂双环(5.4.0)十一碳-7-烯(DBU)(1.5g，10mmol)溶解在甲醇(25ml)中。将混合物回流过夜。将反应混合物冷却至5℃。将固体产物滤出并用甲醇(15ml)洗涤。获得4.2g(84％)的白色固体状标题化合物。用1H-NMR图谱确认该化合物的结构。
1H NMR(300MHz，d6-DMSO)：δ2.23(s，3H)，2.34(s，6H)，2.37(s，2H)，3.3-3.4(m，2H)，3.5-3.6(m，2H)，4.37(d，2H)，4.77(t，1H)，4.97(t，1H)，6.71(s，1H)，7.0-7.2(m，3H)，8.08(s，1H)，8.44(t，1H).
生物学效应
为了确认根据本发明的化合物的生物学效应，按照体内实验进行化合物的生物学测试。
在雌性大鼠中对酸分泌的抑制效果
使用Sprague-Dawley品系的雌性大鼠。它们在胃(内腔)中和在十二指肠的上部分别被装有插入的漏管，用于收集胃分泌物和施用测试物质。手术之后在开始测试之前提供14天的恢复期。
在分泌试验之前，将动物剥夺食物，但不剥夺水，持续20h。用自来水(+37℃)通过胃导管重复洗涤胃，并皮下给予6ml Ringer葡萄糖。采用在2.5-4h期间注入(1.2ml/h，皮下地)五肽胃泌素和卡巴胆碱(分别20nmol/kg·h和110nmol/kg·h)来刺激酸分泌，期间胃分泌物以30-min级份被收集。在开始刺激之后60min(静脉内和十二指肠内给药，1ml/kg)或开始刺激之前2h(口服给药，5ml/kg，胃插管闭合)给予测试物质或媒介物。可以增加给药和刺激之间的时间间隔以研究作用持续时间。用NaOH，0.1M将胃液样品滴定至pH 7.0，并根据滴定剂体积和浓度的乘积计算酸排出。
进一步的计算基于来自4-6只大鼠的组平均应答。在刺激过程中施用的情况下，在施用测试物质或媒介物之后的期间，酸排出被表达为百分比应答，将施用前30-min期间的酸排出设置至1.0。从由测试的化合物和媒介物引起的百分比应答计算百分比抑制。在刺激之前施用的情况下，百分比抑制从测试的化合物和媒介物之后记录的酸排出直接计算。用本发明的两种化合物每次口服施用1μmol/kg之后，五肽胃泌素刺激的酸分泌在大鼠中被抑制大于70％。
Claims (8)
1.式I的取代的咪唑并[1，2-a]吡啶或其药学上可接受的盐
其中R是-CH2COOH或-COOH。
2.5-{2-[({8-[(2，6-二甲基苄基)氨基]-2，3-二甲基咪唑并[1，2-a]吡啶-6-基}羰基)-氨基]乙氧基}-5-氧代戊酸。
3.4-{2-[({8-[(2，6-二甲基苄基)氨基]-2，3-二甲基咪唑并[1，2-a]吡啶-6-基}羰基)-氨基]乙氧基}-4-氧代丁酸。
4.一种用于制备根据权利要求1所述的取代的咪唑并[1，2-a]吡啶的方法，其特征在于使式II的2，3-二甲基-8-(2，6-二甲基苄基氨基)-N-羟基乙基-咪唑并[1，2-a]吡啶-6-甲酰胺
与选自戊二酸酐和琥珀酸酐的酐在溶剂中在40℃与130℃之间的温度范围内反应。
5.根据权利要求4所述的方法，其特征在于所述溶剂选自二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮、四氢呋喃、环酮和脂环酮。
6.根据权利要求4或5所述的方法，其特征在于所述方法在大气压至5×102Kpa的压力范围内进行。
7.一种药物组合物，其包含与药学上可接受的稀释剂或载体结合的根据权利要求1所述的取代的咪唑并[1，2-a]吡啶。
8.根据权利要求1所述的取代的咪唑并[1，2-a]吡啶用于制备用于治疗或预防与胃酸有关的疾病、胃肠炎性疾病、症状性GERD、腐蚀性食管炎、消化性溃疡疾病、胃灼热、反胃、酸返流疾病和恶心的药物的用途。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI20086158A FI20086158A0 (fi) | 2008-12-03 | 2008-12-03 | Imidatsopyridiinijohdannaiset |
| FI20086158 | 2008-12-03 | ||
| PCT/FI2009/050861 WO2010063876A1 (en) | 2008-12-03 | 2009-10-27 | Imidazopyridine derivatives which inhibit the secretion of gastric acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102239167A true CN102239167A (zh) | 2011-11-09 |
| CN102239167B CN102239167B (zh) | 2015-06-17 |
Family
ID=40240558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200980148444.7A Active CN102239167B (zh) | 2008-12-03 | 2009-10-27 | 抑制胃酸分泌的咪唑并吡啶衍生物 |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US8669269B2 (zh) |
| EP (1) | EP2365975B1 (zh) |
| JP (2) | JP5702295B2 (zh) |
| KR (1) | KR101742328B1 (zh) |
| CN (1) | CN102239167B (zh) |
| AU (1) | AU2009324007B2 (zh) |
| BR (1) | BRPI0916475A2 (zh) |
| CA (1) | CA2744647C (zh) |
| CY (1) | CY1114038T1 (zh) |
| DK (1) | DK2365975T3 (zh) |
| ES (1) | ES2415894T3 (zh) |
| FI (1) | FI20086158A0 (zh) |
| HK (1) | HK1164277A1 (zh) |
| HR (1) | HRP20130476T1 (zh) |
| IL (1) | IL213242A (zh) |
| MX (1) | MX2011005769A (zh) |
| PL (1) | PL2365975T3 (zh) |
| PT (1) | PT2365975E (zh) |
| RU (1) | RU2509771C2 (zh) |
| SI (1) | SI2365975T1 (zh) |
| SM (1) | SMT201300066B (zh) |
| WO (1) | WO2010063876A1 (zh) |
| ZA (1) | ZA201104838B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279151A (zh) * | 2015-06-26 | 2017-01-04 | 江苏太瑞生诺生物医药科技有限公司 | 5-(2-(8-((2,6-二甲基苄基)氨基)-2,3-二甲基咪唑并[1,2-a]吡啶-6-甲酰胺基)乙氧基)-5-氧代戊酸的固体形式及其制备方法 |
| CN114901262A (zh) * | 2019-11-04 | 2022-08-12 | 辛克鲁斯制药控股有限公司 | X842的口服制剂 |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI20086158A0 (fi) * | 2008-12-03 | 2008-12-03 | Mikael Dahlstroem | Imidatsopyridiinijohdannaiset |
| KR101777971B1 (ko) * | 2016-07-05 | 2017-09-12 | 제일약품주식회사 | 이미다조[1,2-a]피리딘 유도체, 이의 제조방법 및 이의 용도 |
| WO2023079093A1 (en) | 2021-11-05 | 2023-05-11 | Cinclus Pharma Holding AB (publ) | Polymorphs of the mesylate salt of linaprazan glurate |
| AU2022381536A1 (en) | 2021-11-05 | 2024-05-02 | Cinclus Pharma Holding AB (publ) | Polymorphs of the hydrochloride salt of linaprazan glurate |
| WO2023184282A1 (en) | 2022-03-30 | 2023-10-05 | Guizhou Sinorda Biomedicine Co., Ltd | X842 formulation |
| KR102496869B1 (ko) * | 2022-07-29 | 2023-02-07 | 제일약품주식회사 | 이미다조[1,2-a]피리딘 화합물의 신규 염, 이의 결정형 및 제조방법 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA81219B (en) | 1980-01-23 | 1982-01-27 | Schering Corp | Imidazo (1,2-a) pyridines ,process for their preparation and pharmaceutical compositions containing them |
| EP0068378B1 (en) | 1981-06-26 | 1986-03-05 | Schering Corporation | Novel imidazo(1,2-a)pyridines and pyrazines, processes for their preparation and pharmaceutical compositions containing them |
| US4725601A (en) * | 1985-06-04 | 1988-02-16 | Fujisawa Pharmaceutical Co., Ltd. | Certain imidazo[1,2-a]pyridines useful in the treatment of ulcers |
| SE9801526D0 (sv) | 1998-04-29 | 1998-04-29 | Astra Ab | New compounds |
| SE0003186D0 (sv) * | 2000-09-07 | 2000-09-07 | Astrazeneca Ab | New process |
| SE0102808D0 (sv) | 2001-08-22 | 2001-08-22 | Astrazeneca Ab | New compounds |
| SE0301905D0 (sv) | 2003-06-26 | 2003-06-26 | Astrazeneca Ab | Novel imidazopyridine compound I with therapeutic effect |
| SE0301903D0 (sv) | 2003-06-26 | 2003-06-26 | Astrazeneca Ab | Novel imidazopyridine compound III with therapeutic effect |
| CN1874772A (zh) | 2003-11-03 | 2006-12-06 | 阿斯利康(瑞典)有限公司 | 治疗隐匿性胃食管反流的咪唑并[1,2－a]吡啶衍生物 |
| SE0303451D0 (sv) * | 2003-12-18 | 2003-12-18 | Astrazeneca Ab | New compounds |
| AR055321A1 (es) | 2005-03-24 | 2007-08-15 | Glaxo Group Ltd | Compuestos de imidazopiridina uso para a fabricacion de un medicamento para el tratamiento o profilaxis de enfermedades o trastornos en los que se requiere un antagonista de una bomba de acido y composicion farmaceutica que lo comprende |
| EP1934215A1 (en) * | 2005-09-22 | 2008-06-25 | Nycomed GmbH | Isotopically substituted imidazopyridine derivatives for the treatment of gastrointestinal disorders |
| FI20086158A0 (fi) * | 2008-12-03 | 2008-12-03 | Mikael Dahlstroem | Imidatsopyridiinijohdannaiset |
-
2008
- 2008-12-03 FI FI20086158A patent/FI20086158A0/fi not_active Application Discontinuation
-
2009
- 2009-10-27 AU AU2009324007A patent/AU2009324007B2/en active Active
- 2009-10-27 SI SI200930616T patent/SI2365975T1/sl unknown
- 2009-10-27 PL PL09748823T patent/PL2365975T3/pl unknown
- 2009-10-27 RU RU2011124169/04A patent/RU2509771C2/ru active
- 2009-10-27 ES ES09748823T patent/ES2415894T3/es active Active
- 2009-10-27 BR BRPI0916475A patent/BRPI0916475A2/pt not_active Application Discontinuation
- 2009-10-27 US US13/132,564 patent/US8669269B2/en active Active
- 2009-10-27 KR KR1020117015341A patent/KR101742328B1/ko active IP Right Grant
- 2009-10-27 DK DK09748823.3T patent/DK2365975T3/da active
- 2009-10-27 JP JP2011539063A patent/JP5702295B2/ja active Active
- 2009-10-27 PT PT97488233T patent/PT2365975E/pt unknown
- 2009-10-27 EP EP09748823A patent/EP2365975B1/en active Active
- 2009-10-27 CA CA2744647A patent/CA2744647C/en active Active
- 2009-10-27 MX MX2011005769A patent/MX2011005769A/es active IP Right Grant
- 2009-10-27 CN CN200980148444.7A patent/CN102239167B/zh active Active
- 2009-10-27 WO PCT/FI2009/050861 patent/WO2010063876A1/en active Application Filing
-
2011
- 2011-05-31 IL IL213242A patent/IL213242A/en active IP Right Grant
- 2011-06-30 ZA ZA2011/04838A patent/ZA201104838B/en unknown
-
2012
- 2012-05-08 HK HK12104485.0A patent/HK1164277A1/zh unknown
-
2013
- 2013-05-29 HR HRP20130476AT patent/HRP20130476T1/hr unknown
- 2013-06-04 CY CY20131100442T patent/CY1114038T1/el unknown
- 2013-06-19 SM SM201300066T patent/SMT201300066B/xx unknown
-
2014
- 2014-02-19 US US14/183,852 patent/US8993589B2/en active Active
- 2014-12-05 JP JP2014246949A patent/JP2015063548A/ja active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279151A (zh) * | 2015-06-26 | 2017-01-04 | 江苏太瑞生诺生物医药科技有限公司 | 5-(2-(8-((2,6-二甲基苄基)氨基)-2,3-二甲基咪唑并[1,2-a]吡啶-6-甲酰胺基)乙氧基)-5-氧代戊酸的固体形式及其制备方法 |
| CN114901262A (zh) * | 2019-11-04 | 2022-08-12 | 辛克鲁斯制药控股有限公司 | X842的口服制剂 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102239167B (zh) | 抑制胃酸分泌的咪唑并吡啶衍生物 | |
| CN105143187A (zh) | 制备磺酰氯化合物的方法 | |
| JP2013129632A (ja) | Ｅｎｐｐ２阻害化合物 | |
| CA2339372A1 (en) | New compounds | |
| AU2014201644B2 (en) | Imidazopyridine derivatives which inhibit the secretion of gastric acid | |
| US7691875B2 (en) | Imidazopyridine compounds, processes for their preparation and therapeutic uses thereof | |
| EP1742946A1 (en) | Dialkoxy-imidazopyridines derivatives | |
| US20070244115A1 (en) | Amino-Halogen-Imidazopyridines as Proton Pump Inhibitors | |
| WO2004113340A1 (en) | Novel imidazopyridine compound iii with therapeutic effect | |
| WO2004113338A1 (en) | Novel imidazopyridine compound i with therapeutic effect |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1164277 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1164277 Country of ref document: HK |
|
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20111109 Assignee: Jiangsu Tairui Shengnuo Biomedical Technology Co.,Ltd. Assignor: Mikael Darstom Contract record no.: 2016990000196 Denomination of invention: Imidazo pyridine derivatives which inhibit gastric acid secretion Granted publication date: 20150617 License type: Exclusive License Record date: 20160512 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: Jiangsu Tairui Shengnuo Biomedical Technology Co.,Ltd. Assignor: Mikael Darstom Contract record no.: 2016990000196 Date of cancellation: 20230105 |
|
| EC01 | Cancellation of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20111109 Assignee: Jiangsu Tairui Shengnuo Biomedical Technology Co.,Ltd. Assignor: Cincruz Pharmaceutical Co.,Ltd. Contract record no.: X2023990000150 Denomination of invention: Imidazole pyridine derivatives that inhibit gastric acid secretion Granted publication date: 20150617 License type: Exclusive License Record date: 20230116 |
|
| EE01 | Entry into force of recordation of patent licensing contract | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Stockholm, SWE Patentee after: Sinkrus Pharmaceutical Holdings Public Ltd. Address before: Stockholm, SWE Patentee before: Sincrus Pharmaceuticals Holdings Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230329 Address after: Finland Blo Marv Patentee after: Mikael Darstom Patentee after: Kyle Anderson Patentee after: Peter Anger Address before: Finland Blo Marv Patentee before: Mikael Darstom Effective date of registration: 20230329 Address after: Basel, SUI Patentee after: Xinkruz Pharmaceutical Co.,Ltd. Address before: Finland Blo Marv Patentee before: Mikael Darstom Patentee before: Kyle Anderson Patentee before: Peter Anger Effective date of registration: 20230329 Address after: Stockholm, SWE Patentee after: Sincrus Pharmaceuticals Holdings Ltd. Address before: Basel, SUI Patentee before: Xinkruz Pharmaceutical Co.,Ltd. |
|
| TR01 | Transfer of patent right |