CN1370172A - 光学活性的吡咯并哒嗪化合物 - Google Patents
光学活性的吡咯并哒嗪化合物 Download PDFInfo
- Publication number
- CN1370172A CN1370172A CN00811599A CN00811599A CN1370172A CN 1370172 A CN1370172 A CN 1370172A CN 00811599 A CN00811599 A CN 00811599A CN 00811599 A CN00811599 A CN 00811599A CN 1370172 A CN1370172 A CN 1370172A
- Authority
- CN
- China
- Prior art keywords
- optically active
- alkyl
- acceptable salt
- pharmacologically acceptable
- 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.)
- Granted
Links
- -1 pyrrolopyridazine compound Chemical class 0.000 title claims description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- YTJAMOLQXDNLJC-UHFFFAOYSA-N N1N=CC=C2N=CC=C21 Chemical class N1N=CC=C2N=CC=C21 YTJAMOLQXDNLJC-UHFFFAOYSA-N 0.000 claims abstract description 32
- 208000025865 Ulcer Diseases 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 85
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 125000005843 halogen group Chemical group 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 239000011737 fluorine Substances 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 230000002265 prevention Effects 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 238000012986 modification Methods 0.000 claims description 12
- 230000004048 modification Effects 0.000 claims description 12
- PCRSIUOCDHDRMN-UHFFFAOYSA-N 1h-pyrrolo[2,3-d]pyridazine Chemical compound N1=NC=C2NC=CC2=C1 PCRSIUOCDHDRMN-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- PXLAFWIVWICIRK-UHFFFAOYSA-N [difluoro(trifluoromethoxy)methyl] hypofluorite Chemical compound FOC(F)(F)OC(F)(F)F PXLAFWIVWICIRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 150000004892 pyridazines Chemical class 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims 3
- 150000003233 pyrroles Chemical class 0.000 claims 2
- HNORUNBXDVOQJC-XHDPSFHLSA-N 7-[(2,4-difluorophenyl)methoxy]-2,3-dimethyl-1-[[(1s,2s)-2-methylcyclopropyl]methyl]pyrrolo[2,3-d]pyridazine Chemical compound C[C@H]1C[C@@H]1CN1C2=C(OCC=3C(=CC(F)=CC=3)F)N=NC=C2C(C)=C1C HNORUNBXDVOQJC-XHDPSFHLSA-N 0.000 claims 1
- 241000590002 Helicobacter pylori Species 0.000 abstract description 15
- 229940037467 helicobacter pylori Drugs 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 abstract description 9
- 210000004400 mucous membrane Anatomy 0.000 abstract description 5
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 230000002496 gastric effect Effects 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 210000004211 gastric acid Anatomy 0.000 abstract description 2
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 abstract 1
- 230000003248 secreting effect Effects 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 235000002639 sodium chloride Nutrition 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000012442 inert solvent Substances 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 210000004051 gastric juice Anatomy 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical class [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000027119 gastric acid secretion Effects 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000000845 anti-microbial effect Effects 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 150000008282 halocarbons Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 230000000452 restraining effect Effects 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 231100000397 ulcer Toxicity 0.000 description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 3
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
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- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
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- 239000012153 distilled water Substances 0.000 description 2
- XLZCIXFPTHCUFB-UHFFFAOYSA-N dmf pocl3 Chemical compound CN(C)C=O.ClP(Cl)(Cl)=O XLZCIXFPTHCUFB-UHFFFAOYSA-N 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- HJOVHMDZYOCNQW-UHFFFAOYSA-N isophorone Chemical compound CC1=CC(=O)CC(C)(C)C1 HJOVHMDZYOCNQW-UHFFFAOYSA-N 0.000 description 2
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
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- 239000012044 organic layer Substances 0.000 description 2
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- 229960003415 propylparaben Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000012177 spermaceti Chemical class 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical class O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000004360 trifluorophenyl group Chemical group 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
- 239000001993 wax Chemical class 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
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Abstract
本发明提供一种具有通式(I)的光学活性的吡咯并哒嗪化合物或其可药用盐。本发明的吡咯并哒嗪化合物或其可药用盐具有优良的胃酸分泌抑制作用、胃粘膜保护作用以及对幽门螺杆菌(Helicobacter pylori)具有优良的抗菌作用,作为医药、特别是作为溃疡性疾病的预防或治疗剂是有用的(式中,R1表示烷基,R2和R3相同或不同,表示烷基;R4表示可以被取代的芳基;A表示亚氨基、氧原子或硫原子。)。
Description
技术领域
本发明涉及一种光学活性的吡咯并哒嗪化合物或其可药用盐、含有以光学活性的吡咯并哒嗪化合物或其可药用盐作为有效成分的医药组合物(特别是用于溃疡性疾病的预防或治疗的组合物)、用于制备医药组合物(特别是用于溃疡性疾病的预防或治疗的组合物)的光学活性的吡咯并哒嗪化合物或其可药用盐的使用、将有效量的光学活性的吡咯并哒嗪化合物或其可药用盐向温血动物(特别是人)给药的疾病(特别是溃疡性疾病)的预防或治疗方法或者光学活性的吡咯并哒嗪化合物或其可药用盐的制备方法。
背景技术
消化性溃疡是胃粘膜的攻击因子和防御因子的平衡失调而产生的,通过抑制作为攻击因子的胃酸的分泌,对溃疡的预防和治疗是有用的。迄今为止,作为可有效抑制胃酸分泌的药剂,临床上广泛地使用抗胆碱剂、西米替丁等的组胺H2受体拮抗剂、奥美拉唑等的质子泵抑制剂。但是,上述药剂虽然具有优良的溃疡治疗效果,但停止使用后溃疡复发已成为一大问题。最近,有人指出溃疡复发与幽门螺杆菌(Helicobacter pylori)的关系,实际上,目前正尝试着将胃酸分泌抑制剂与抗生素合并使用来进行治疗。
因此,人们期待着一种能够强力抑制作为攻击因子的胃酸的分泌、同时具有保护胃粘膜的作用,而且对于幽门螺杆菌具有抗菌作用的化合物作为优良的溃疡疾病的预防剂或治疗剂。
作为具有胃酸分泌抑制作用和胃粘膜保护作用的化合物,已知有几种吡咯并哒嗪衍生物(例如WO 91/17164、WO 92/06979、WO 93/08190等),另外,还已知兼有对幽门螺杆菌的抗菌作用的吡咯并哒嗪衍生物(例如,特开平7-247285号等)。
发明的公开
本发明人等以开发一种能够强力抑制作为攻击因子的胃酸的分泌,保护胃粘膜,并且对幽门螺杆菌具有优良的抗菌作用的抗溃疡剂为目标,对于吡咯并哒嗪衍生物的合成及其药理活性进行了长期的深入研究,结果发现,某种光学活性的具有反式-烷基环丙基甲基的吡咯并哒嗪衍生物,在具有强力的胃酸分泌抑制作用和胃粘膜保护作用的同时,还具有对幽门螺杆菌的优良的抗菌作用,进一步地,与对应的外消旋体相比,具有作为医药品的优良的性质,至此完成本发明。
本发明提供一种光学活性的吡咯并哒嗪化合物或其可药用盐、含有光学活性的吡咯并哒嗪化合物或其可药用盐作为有效成分的医药组合物(特别是用于溃疡性疾病的预防或治疗的组合物)、用于制备医药组合物(特别是用于溃疡性疾病的预防或治疗的组合物)的光学活性的吡咯并哒嗪化合物或其可药用盐的使用、将有效量的光学活性的吡咯并哒嗪化合物或其可药用盐向温血动物(特别是人)给药的疾病(特别是溃疡性疾病)的预防或治疗方法或者光学活性的吡咯并哒嗪化合物或其可药用盐的制备方法。
本发明的光学活性的吡咯并哒嗪化合物,具有如下通式。
上述式中,R1表示C1~C6烷基,R2和R3相同或不同,表示C1~C6烷基;R4表示可以被选自C1~C6烷基、卤代C1~C6烷基、C1~C6烷氧基、卤代C1~C6烷氧基以及卤素中的取代基取代的C6~C10芳基;A表示亚氨基、氧原子或硫原子。
上述通式(I)中,R1、R2和R3的C1~C6烷基、R4中包含的C1~C6烷基或R4中包含的卤代C1~C6烷基、C1~C6烷氧基或卤代C1~C6烷氧基的C1~C6烷基部分,例如可以为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基或己基,优选为C1~C4烷基,更优选为甲基或乙基,最优选为甲基。
R4中包含的卤原子,例如可以是氟、氯、溴或碘原子,优选为氟、氯或溴原子,更优选为氟或氯原子。
R4的C6~C10芳基例如可以为苯基或萘基,优选为苯基。
被取代的芳基的取代基的数目,例如为1~5个,优选为1~3个,更优选为1~2个,特别优选为1个。
可以被选自C1~C6烷基、卤代C1~C6烷基、C1~C6烷氧基、卤代C1~C6烷氧基以及卤素中的取代基取代的C6~C10芳基,优选为苯基、甲基苯基、三氟甲基苯基、甲氧基苯基、三氟甲氧基苯基、二氟甲氧基苯基、氟苯基、氯苯基、溴苯基、二氟苯基、氯氟苯基、二氯苯基、三氟苯基、三氯苯基、萘基、甲基萘基、甲氧基萘基、氟萘基、氯萘基或溴萘基,更优选为苯基、4-甲基苯基、4-三氟甲基苯基、4-甲氧基苯基、4-三氟甲氧基苯基、4-二氟甲氧基苯基、2-、3-或4-氟苯基、2-、3-或4-氯苯基、4-溴苯基、2,4-或2,6-二氟苯基、4-氯-2-氟苯基、2-氯-4-氟苯基、2,4-或2,6-二氯苯基、2,4,6-三氟苯基或2,4,6-三氯苯基,进一步优选为4-氟苯基、4-氯苯基、2,4-二氟苯基、4-氯-2-氟苯基、2-氯-4-氟苯基或2,4-二氯苯基,最优选为4-氟苯基或4-氯苯基。
A优选为氧或硫原子,更优选为氧原子。
本发明化合物(I)的可药用盐为酸附加盐,例如可以是氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等氢卤酸盐;硝酸盐、高氯酸盐;硫酸盐;磷酸盐;碳酸盐;甲磺酸盐、三氟甲磺酸盐、乙磺酸盐、五氟乙磺酸盐、丙磺酸盐、丁磺酸盐、戊磺酸盐、己磺酸盐等的可被氟原子取代的C1~C6烷基磺酸盐;苯磺酸盐、对甲苯磺酸盐等C6~C10芳基磺酸盐;醋酸盐、丙酸盐、丁酸盐、苯甲酸盐、富马酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、丙二酸盐等羧酸盐;或者谷氨酸盐、天门冬氨酸盐等氨基酸盐等的酸附加盐,优选为盐酸盐、硫酸盐或羧酸盐,更优选为盐酸盐。
另外,本发明的化合物(I)或其盐可以以水合物的形式存在,本发明中也包含它们的水合物。
具有通式(I)的化合物中,例如优选:
(1)R1为C1~C4烷基的化合物、
(2)R1为甲基的化合物、
(3)R2和R3相同或不同,为C1~C4烷基的化合物、
(4)R2和R3相同,为甲基的化合物、
(5)R4为被选自C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代C1~C4烷氧基、氟、氯和溴中的1~3个取代基取代的苯基的化合物、
(6)R4为被选自甲基、三氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、氟、氯和溴中的1~3个取代基取代的苯基的化合物、
(7)R4为被选自氟和氯中的1~2个取代基在选自2位、4位和6位中1~2个取代位置取代的苯基的化合物、
(8)R4为被选自氟和氯中的1~2个取代基在4位或2,4-位取代位置取代的苯基的化合物、
(9)A为氧原子或硫原子的化合物、
(10)A为氧原子的化合物。
另外,上述(1)~(2)、(3)~(4)、(5)~(8)或(9)~(10)的组中,随着序号增加,表示更优选的化合物[以下(11)~(14)组中也是同样。],分别从组(1)~(2)中选择R1、从组(3)~(4)中选择R2和R3、从组(5)~(8)中选择R4、从组(9)~(10)中选择A,并将它们任意组合而获得的化合物也是优选的,例如可以举出以下的化合物。
(11)R1为C1~C4烷基、
R2和R3相同或不同,为C1~C4烷基、
R4为被选自C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代C1~C4烷氧基、氟、氯和溴中的1~3个取代基取代的苯基、
A为氧原子或硫原子的化合物、
(12)R1为甲基、
R2和R3相同,为甲基、
R4为被选自甲基、三氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、氟、氯和溴中的1~3个取代基取代的苯基、
A为氧原子或硫原子的化合物、
(13)R1为甲基、
R2和R3相同,为甲基、
R4为被选自氟和氯中的1~2个取代基在选自2位、4位和6位中1~2个取代位置取代的苯基、
A为氧原子的化合物、
(14)R1为甲基、
R2和R3相同,为甲基、
R4为被选自氟和氯中的1~2个取代基在4位或2,4-位取代位置取代的苯基、
A为氧原子的化合物。
表1 示例化合物示例化合物序号No. A R4
1 O Ph
2 O 2-FPh
3 O 3-FPh
4 O 4-FPh
5 O 2,4-diFPh
6 O 2,6-diFPh
7 O 2,4,6-triFPh
8 O 2-ClPh
9 O 4-ClPh
10 O 2,4-diClPh
11 O 2,4,6-triClPh
12 O 4-MePh
13 O 4-CF3Ph
14 O 4-OMePh
15 O 4-OCHF2Ph
16 O 2-Cl-6-FPh17 O 2-Cl-4-FPh18 O 4-Cl-2-FPh19 S Ph20 S 2-FPh21 S 4-FPh22 S 2,4-diFPh23 S 2,4,6-triFPh24 S 4-ClPh25 S 2,4-diClPh26 S 2,4,6-triClPh27 S 4-CF3Ph28 S 2-Cl-4-FPh29 S 4-Cl-2-FPh30 NH Ph31 NH 4-FPh32 NH 2,4-diFPh33 NH 2,4,6-triFPh34 NH 4-ClPh35 NH 2,4-diClPh36 NH 4-CF3Ph37 NH 2-Cl-4-FPh38 NH 4-Cl-2-FPh39 O 4-OCF3Ph40 O 3-ClPh41 O 4-BrPh42 O 2,6-diClPh43 S 4-OCF3Ph44 S 4-OCHF2Ph45 S 3-FPh46 S 2-ClPh47 S 4-BrPh48 S 2,6-diFPh
49 S 2,6-diClPh
50 NH 4-OCF3Ph
51 NH 2-FPh
52 NH 2-ClPh
53 NH 2,6-diFPh
54 NH 2,6-diClPh
55 NH 2,4,6-triClPh
上述表中,省略号表示以下基团。
Me ...甲基
Ph ...苯基。
上述表1中,优选为:
示例化合物序号1、2、4、5、7、9、10、11、13、17、18、19、21、22、23、24、25、28、29、30、31、32、34、37或38的化合物,更优选为:
示例化合物序号1、4、5、7、9、10、17、18、21、22、24、25、31、32或34的化合物,进一步优选为:
示例化合物序号4、5、9、10、21、22或24的化合物,特别优选为以下化合物:
化合物序号4:7-(4-氟苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪、
化合物序号5:7-(2,4-二氟苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪、或
化合物序号9:7-(4-氯苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪。
R1、R2、R3、R4和A与上述定义相同,R5表示C1~C6烷基,R6表示氢原子或甲酰基,X表示卤素原子(优选为氯、溴或碘原子)或甲磺酰氧基、乙磺酰氧基、丁磺酰氧基、苯磺酰氧基、甲苯磺酰氧基、萘磺酰氧基等C1~C6链烷基或C6~C10芳基磺酰氧基(优选甲磺酰氧基、乙磺酰氧基、苯磺酰氧基或对甲苯磺酰氧基),Y表示卤素原子(优选氯、溴或碘原子)。
步骤1为具有通式(IV)的化合物的制备步骤,可通过在惰性溶剂中,在碱的存在下,使具有通式(II)的化合物与具有通式(III)的化合物反应,在R6为氢原子的场合,可通过使获得的化合物进一步甲酰化来达到。
化合物(II)与化合物(III)的反应中所使用的碱,例如可以是氢化锂、氢化钠、氢化钾等碱金属氢化物;氨基锂、氨基钠、氨基钾等氨基碱金属;碳酸锂、碳酸钠、碳酸钾等碱金属碳酸盐;甲醇锂、甲醇钠、乙醇钠、叔丁醇钾等碱金属醇盐;或者三乙胺、三丁胺、二异丙基乙基胺、N-乙基吗啉、吡啶、甲基吡啶、4-(N,N-二甲基氨基)吡啶、喹啉、N,N-二甲基苯胺、N,N-二乙基苯胺、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)等有机胺,优选为碱金属氢化物(特别是氢化钠)或碱金属醇盐(特别是叔丁醇钾)。
所使用的惰性溶剂,只要不阻碍反应,并可在一定程度上溶解起始物质,就没有特别的限定,例如可以举出己烷、庚烷、轻汽油、石油醚等脂肪族烃类;苯、甲苯、二甲苯等芳香族烃类;二氯甲烷、氯仿、四氯化碳、二氯乙烷、氯苯、二氯苯等卤代烃类;乙醚、异丙醚、四氢呋喃、二噁烷、二甲氧基乙烷、二甘醇二甲基醚等醚类;丙酮、丁酮、甲基异丁基酮、异佛尔酮、环己酮等酮类;甲酰胺、二甲基甲酰胺、二甲基乙酰胺、N-甲基-2-吡咯烷酮、六甲基磷酰三胺等酰胺类;二甲基亚砜、环丁砜等亚砜类;或者它们的混合溶剂,优选为醚类(特别是四氢呋喃或二噁烷)。
反应温度通常为0℃~250℃(优选为室温~150℃),反应所需要的时间根据反应温度等而有所不同,为1分钟~50小时(优选为10分钟~30小时)。
另外,为了使本反应有效地进行,也可以添加苄基三甲基铵氯化物、四丁基铵氯化物、四丁基铵溴化物等季铵盐类;或者18-冠-6、二苯并-18-冠-6等冠醚类。
R6为氢原子的场合,对化合物(II)与化合物(III)反应而获得的化合物进行甲酰化的反应,可在惰性溶剂的存在或不存在下,使相应的化合物与Vilsmeier试剂反应来进行。
所使用的Vilsmeier试剂是公知的,例如为氯氧化磷-二甲基甲酰胺、溴氧化磷-二甲基甲酰胺、草酰氯-二甲基甲酰胺等卤化剂-二甲基甲酰胺类,优选为氯氧化磷-二甲基甲酰胺。
所使用的惰性溶剂,只要不阻碍反应,并可以在一定程度上溶解起始物质,就没有特别的限定,例如可以是苯、甲苯、二甲苯等芳香族烃类;二氯甲烷、氯仿、四氯化碳、二氯乙烷、氯苯、二氯苯等卤代烃类;乙醚、异丙醚、四氢呋喃、二噁烷、二甲氧基乙烷、二甘醇二甲基醚等醚类;或者二甲基甲酰胺等酰胺类,优选为卤代烃类(特别是二氯甲烷、氯仿或二氯乙烷)。
反应温度通常为-20℃~150℃(优选为0℃~100℃),反应所需要的时间根据反应温度等而有所不同,为15分钟~12小时(优选为30分钟~5小时)。
步骤2是具有通式(V)的化合物的制备步骤,可通过在惰性溶剂中使化合物(IV)与肼或其水合物反应来达到。
所使用的惰性溶剂,只要不阻碍反应,并可在一定程度上溶解起始物质,就没有特别的限定,例如可以为乙醚、异丙醚、四氢呋喃、二噁烷、二甲氧基乙烷、二甘醇二甲基醚等醚类;甲醇、乙醇、丙醇、异丙醇等醇类;苯、甲苯、二甲苯等芳香族烃类;醋酸、丙酸等羧酸类;甲酰胺、二甲基甲酰胺、二甲基乙酰胺、N-甲基-2-吡咯烷酮、六甲基磷酰三胺等酰胺类;三乙胺、吡啶等胺类;水;或它们的混合溶剂,优选为醇类(特别是乙醇)或羧酸类(特别是醋酸)。
反应温度通常为-50℃~150℃(优选为-10℃~120℃),反应所需要的时间根据反应温度等而有所不同,为10分钟~12小时(优选30分钟~5小时)。
步骤3为具有通式(VI)的化合物的制备步骤,可通过在惰性溶剂的存在或不存在下,使化合物(V)与卤化剂反应来达到。
所使用的卤化剂,例如可以是氯氧化磷、溴氧化磷、亚硫酰氯、亚硫酰溴、草酰氯、五氯化磷或五溴化磷,优选为氯氧化磷或亚硫酰氯,也可以兼作溶剂而过量使用。
所使用的惰性溶剂,只要不阻碍反应,并可在一定程度上溶解起始物质,就没有特别的限定,例如可以是苯、甲苯、二甲苯等芳香族烃类;二氯甲烷、氯仿、四氯化碳、二氯乙烷、氯苯、二氯苯等卤代烃类;乙醚;异丙醚、四氢呋喃;二噁烷、二甲氧基乙烷、二甘醇二甲基醚等醚类;二甲基甲酰胺、二甲基乙酰胺、N-甲基-2-吡咯烷酮等酰胺类;或二甲基亚砜等亚砜类,优选为卤代烃类(特别是二氯甲烷或二氯乙烷)。
反应温度通常为0℃~150℃(优选为室温~120℃),反应所需要的时间根据反应温度等而有所不同,为30分钟~12小时(优选为1小时~6小时)。
另外,为了使本反应有效地进行,也可以添加三乙胺、三丁胺、二异丙基乙基胺、N-乙基吗啉、吡啶、甲基吡啶、4-(N,N-二甲基氨基)吡啶等有机胺类。
步骤4为目的化合物(I)的制备步骤,可通过在惰性溶剂中、在碱的存在下,使化合物(VI)与具有通式(VII)的化合物反应来达到,本步骤可以与上述步骤1同样地进行。
上述记载的各步骤中,各反应的目的化合物采用常规方法从反应混合物中提取。例如,在存在不溶物的场合,可通过适宜过滤并蒸馏除去溶剂,或者通过在蒸馏出溶剂后向残留物中加入水,用适当的非水溶性溶剂萃取,再用无水硫酸镁等干燥后蒸馏出溶剂,由此分离出目的化合物。另外,如果需要,可以按照常规方法,采用例如重结晶、柱色谱等方法进行精制。
另外,上述步骤1中,使用对应的外消旋体(IIIa,1S,2S-体与1R,2R-体的混合物)代替光学活性的原料化合物(III)(1S,2S-体),进行同样的反应,将所获得的相应的外消旋体化合物(与化合物(I)、(IV)、(V)或(VI)相对应的外消旋体的任一个)进行光学拆分,由此也可以制备所希望的光学活性体(1S,2S-体)。作为光学拆分的方法,可以适宜地选择通常的方法,例如使用光学拆分柱的柱色谱法、优先晶析法、用非对映异构体盐拆分的方法等来进行。
进一步地,可按照常规方法,用酸对化合物(I)进行处理,由此可将其转变成可药用盐。例如,通过在惰性溶剂(优选乙醚、四氢呋喃、二噁烷等醚类;甲醇、乙醇、丙醇等醇类;或者二氯甲烷、氯仿等卤代烃类)中,使其与相应的酸在室温下反应5分钟~1小时,蒸馏出溶剂,由此可以获得目的的盐。
原料化合物(II)、(III)和(IIIa)是公知的,或者可以采用公知的方法(例如特开平7-247285号,Monatschefte fur Chemie(1973),104,925,J.Chem.Soc.Perkin.Trans.II(1979)287等)来制备。
发明的效果
本发明的具有上述通式(I)的化合物或其可药用盐,具有优良的胃酸分泌抑制作用以及胃粘膜保护作用,同时,对于幽门螺杆菌具有优良的抗菌作用,进一步地,还具有作为医药品的优良的性质,因此,作为医药、特别是消化性溃疡、急性或慢性胃溃疡、胃炎、逆流性食道炎、胃食道反射疾病、消化不良、胃酸过多、Zollinger-Ellison综合症等溃疡性疾病的预防或治疗剂(特别是治疗剂)或作为幽门螺杆菌的感染症的预防或治疗剂(特别是治疗剂)是有用的。
产业上的实用性
将本发明的化合物(I)及其可药用盐类用作医药、特别是用作上述疾病的预防或治疗剂的场合,可以将其本身或使其与适宜的可药用赋形剂、稀释剂等混合,以片剂、胶囊剂、颗粒剂、散剂或糖浆剂等形式口服给药或者以注射剂等形式非口服给药(优选口服给药)。这些制剂使用下述添加剂,采用公知的方法来制备。所说添加剂包括:赋形剂(例如乳糖、白糖、葡萄糖、甘露糖醇、山梨糖醇等的糖衍生物;玉米淀粉、马铃薯淀粉、α-淀粉、糊精、羧甲基淀粉等淀粉衍生物;结晶纤维素、低取代度羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧甲基纤维素钙、内部交联羧甲基纤维素钠等纤维素衍生物;阿拉伯树胶;葡聚糖;支链淀粉;轻质硅酸酐、合成硅酸铝、偏硅酸铝酸镁等硅酸盐衍生物;磷酸钙等磷酸盐衍生物;碳酸钙等碳酸盐衍生物;硫酸钙等硫酸盐衍生物等)、粘合剂(例如上述的赋形剂;明胶、聚乙烯吡咯烷酮;聚乙二醇等)、崩解剂(例如上述的赋形剂;交联羧甲醚纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮等经化学改性的淀粉、纤维素衍生物等)、润滑剂(例如滑石;硬脂酸;硬脂酸钙、硬脂酸镁等硬脂酸金属盐;胶态氧化硅;蜂胶、鲸蜡等蜡类;硼酸;乙二醇、富马酸、己二酸等羧酸类;苯甲酸钠等的羧酸钠盐;硫酸钠等的硫酸类盐;亮氨酸;月桂基硫酸钠、月桂基硫酸镁等月桂基硫酸盐;硅酸酐、硅酸水合物等硅酸类;上述的赋形剂中的淀粉衍生物等)、稳定剂(例如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等的对羟基苯甲酸酯类;氯丁醇、苄醇、苯基乙基醇等醇类;苯扎氯铵;苯酚、甲酚等酚类;硫汞撒;醋酸酐;山梨酸等)、矫味矫臭剂(例如通常使用的甜味料、酸味料、香料等)、稀释剂、注射剂用溶剂(例如水、乙醇、甘油等)。其用量根据症状、年龄等而有所不同,对于成人来说,在口服给药的场合,每次每天下限1mg(优选5mg)、上限1000mg(优选500mg),在静脉内给药的场合,每次每天下限0.1mg(优选1mg),上限500mg(优选300mg),根据症状,希望每天给药1~6次。
实施发明的最佳方案
以下结合实施例、试验例和制剂例,更详细地说明本发明,但本发明不受这些例子的限定。
实施例1
7-(4-氟苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪
(a)3-甲酰基-4,5-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯-2-羧酸甲酯
向3-甲酰基-4,5-二甲基吡咯-2-羧酸甲酯5.79g(31.9mmol)和18-冠-60.41g(1.55mmol)的四氢呋喃(130ml)溶液中添加叔丁醇钾3.94g(35.1mmol),在室温下搅拌1小时。接着,在50℃下,花30分钟滴入(1S,2S)-2-甲基环丙基甲基溴化物5.71g(38.3mmol),然后加热回流3小时。然后,追加叔丁醇钾0.36g(3.22mmol)和(1S,2S)-2-甲基环丙基甲基溴化物0.48g(3.21mmol),再加热1小时。将反应液注入冰水中,用醋酸乙酯萃取,萃取液用水和饱和食盐水依次洗涤后,用无水硫酸镁干燥。减压下蒸馏出溶剂,获得淡茶色油状物的标题化合物8.26g(100%)。
质谱(CI,m/z):250(M++1)。
NMR谱(CDCl3,δppm):0.25(dt;J=8Hz,5Hz,1H),0.48(dt;J=8Hz,5Hz,1H),0.71-0.80(m,1H),0.82-0.89(m,1H),1.00(d;J=6Hz,3H),2.20(s,3H),2.26(s,3H),3.89(s,3H),4.25(d;J=7Hz,2H),10.43(s,1H)。
旋光度:[α]D 20=+17.6°(C=1.02,EtOH)
(b)2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]-6,7-二氢吡咯并[2,3-d]哒嗪-7-酮
在室温下,向3-甲酰基-4,5-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯-2-羧酸甲酯7.96g(31.9mmol)的醋酸(38ml)溶液中加入肼一水合物1.92g(38.4mmol),在90℃下搅拌1小时。反应结束后,将反应液冷却至室温,注入冰水中。过滤收集生成的粗结晶,水洗后,溶解于氯仿/甲醇(=9/1)溶液中。分离有机层,用饱和食盐水洗涤,用无水硫酸镁干燥后减压浓缩。向浓缩液中加入甲苯/己烷,过滤收集析出的结晶,获得浅乳白色粉末结晶的标题化合物7.02g(95.0%)。
质谱(CI,m/z):232(M++1)。
NMR谱(CDCl3,δppm):0.22(dt;J=8Hz,5Hz,1H),0.64(dt;J=8Hz,5Hz,1H),0.86-0.95(m,2H),0.98(d;J=5Hz,3H),2.21(s,3H),2.35(s,3H),4.44(d;J=7Hz,2H),8.05(s,1H),9.97(s,1H)。
旋光度:[α]D 20=+11.2°(C=0.50,EtOH)
(c)7-氯-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪
向2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]-6,7-二氢吡咯并[2,3-d]哒嗪-7-酮6.95g(30.1mmol)中添加氯氧化磷55ml(590mmol),在90℃下加热搅拌3.5小时。反应结束后,将反应液冷却至室温,滴入冰水中。将该水溶液用5当量氢氧化钠水溶液中和,用二氯甲烷萃取。萃取液用水洗涤,用无水硫酸镁干燥后减压浓缩。向浓缩液中加入己烷,过滤收集析出的结晶,获得浅黄色粉末结晶的标题化合物6.90g(92.0%)。
质谱(CI,m/z):250(M++1)。
NMR谱(CDCl3,δppm):0.29(dt;J=8Hz,5Hz,1H),0.54(dt;J=8Hz,5Hz,1H),0.73-1.02(m,5H),2.30(s,3H),2.43(s,3H),4.44(d;J=6Hz,2H),9.15(s,1H)。
旋光度:[α]D 20=+12.3°(C=1.01,EtOH)
(d)7-(4-氟苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪
向氢氧化钠0.26g(10.8mmol)的四氢呋喃(6ml)溶液中滴入对氟苄醇1.45g(11.5mmol)的四氢呋喃(2ml)溶液,在室温下搅拌30分钟。接着,在室温下滴入7-氯-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪2.50g(10.0mmol)的四氢呋喃(13ml)溶液,加热回流3小时。反应结束后,将反应液注入冰水中,用醋酸乙酯萃取。萃取液用饱和食盐水洗涤后,用无水硫酸镁干燥。减压浓缩后,向获得的浓缩液中注入己烷,过滤收集析出的结晶,获得粗结晶。将该粗结晶用醋酸乙酯/己烷重结晶,获得淡褐色结晶的标题化合物2.25g(66.4%)。
熔点:114~115℃。
质谱(CI,m/z):340(M++1)。
NMR谱(CDCl3,δppm):0.14(dt;J=8Hz,5Hz,1H),0.39(dt;J=8Hz,5Hz,1H),0.59-0.65(m,1H),0.76-0.85(m,1H),0.89(d;J=6Hz,3H),2.26(s,3H),2.36(s,3H),4.13(dd;J=15Hz,7Hz,1H),4.27(dd;J=15Hz,6Hz,1H),5.63(d;J=12Hz,1H),5.68(d;J=12Hz,1H),7.05-7.12(m,2H),7.47-7.52(m,2H),8.96(s,1H)。
旋光度:[α]D 20=+17.9(C=0.50,EtOH)。实施例2
3-甲酰基-4,5-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯-2-羧酸甲酯
(a)4,5-二甲基-1-[(E)-2-甲基环丙基甲基]吡咯-2-羧酸甲酯
向4,5-二甲基吡咯-2-羧酸甲酯25.02g(163mmol)和18-冠-6 3.19g(12.1mmol)的四氢呋喃(150ml)溶液中添加叔丁醇钾18.33g(164mmol),在室温下搅拌1小时。接着,加入(E)-2-甲基环丙基甲基溴化物(外消旋体)12.70g(85.2mmol),加热回流7小时。反应结束后,将反应液注入冰水中,用醋酸乙酯萃取。萃取液用水和饱和食盐水洗涤,用无水硫酸镁干燥。减压蒸馏出溶剂后,残留物用柱色谱(溶剂:甲苯)精制,获得茶色油状物的标题化合物(外消旋体)13.50g(71.6%)。
质谱(CI,m/z):222(M++1)。
NMR谱(CDCl3,δppm):0.20(dt;J=8Hz,5Hz,1H),0.48(dt;J=8Hz,5Hz,1H),0.67-0.93(m,2H),0.98(d;J=6Hz,3H),2.01(s,3H),2.18(s,3H),3.76(s,3H),4.21(d;J=7Hz,2H),6.76(s,1H)。
(b)4,5-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯-2-羧酸甲酯
采用下述条件,用高速液相色谱精制(E)-4,5-二甲基-1-(2-甲基环丙基甲基)吡咯-2-羧酸甲酯10.00g,分别获得标题化合物[(S,S)体]3.33g及其对映体[(R,R)体]3.97g。分离条件
柱子:CHIRALCEL OJ(50Φ*500mm,Daicel化学制)
溶剂:己烷/2-丙醇(1000/1)
流速:25ml/min标题化合物[(S,S)体]
质谱(CI,m/z):222(M++1)。
NMR谱(CDCl3,δppm):0.20(dt;J=8Hz,5Hz,1H),0.48(dt;J=8Hz,5Hz,1H),0.66-0.80(m,1H),0.82-0.91(m,1H),0.98(d;J=6Hz,3H),2.01(s,3H),2.18(s,3H),3.76(s,3H),4.21(d;J=7Hz,2H),6.76(s,1H)。
旋光度:[α]D 20=+17.6°(C=1.00,EtOH)。对映体[(R,R)体]
质谱(CI,m/z):222(M++1)。
NMR谱(CDCl3,δppm):0.20(dt;J=8Hz,5Hz,1H),0.48(dt;J=8Hz,5Hz,1H),0.66-0.80(m,1H),0.82-0.91(m,1H),0.98(d;J=6Hz,3H),2.01(s,3H),2.18(s,3H),3.77(s,3H),4.21(d;J=7Hz,2H),6.76(s,1H)。
旋光度:[α]D 20=-17.0°(C=1.01,EtOH)。
(c)3-甲酰基-4,5-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯-2-羧酸甲酯
向二甲基甲酰胺1.10g(15.0mmol)的甲苯(2ml)溶液中添加氯氧化磷2.15g(14.0mmol),在室温下搅拌30分钟。接着,添加4,5-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯-2-羧酸甲酯2.21g(10.0mmol)的甲苯(6ml)溶液,在80℃下加热10小时。反应结束后,将反应液注入水中,用饱和碳酸氢钠水溶液中和后,分液,用饱和食盐水洗涤有机层,用无水硫酸镁干燥。减压蒸馏出溶剂,残留物用柱色谱(溶剂:醋酸乙酯/己烷=10/1)精制,获得淡黄色油状物的标题化合物1.95g(78.2%)。
实施例3
7-(4-氟苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪
(a)7-(4-氟苄氧基)-1-[(E)-2-甲基环丙基甲基]-2,3-二甲基吡咯并[2,3-d]哒嗪(外消旋体)
用(E)-2-甲基环丙基甲基溴化物(外消旋体)代替(1S,2S)-2-甲基环丙基甲基溴化物,除此之外,与实施例1同样地进行反应,获得标题化合物,收率56%。
熔点:120~122℃。
质谱(CI,m/z):340(M++1)。
NMR谱(CDCl3,δppm):0.14(dt;J=8Hz,5Hz,1H),0.39(dt;J=8Hz,5Hz,1H),0.59-0.65(m,1H),0.76-0.85(m,1H),0.89(d;J=6Hz,3H),2.26(s,3H),2.36(s,3H),4.13(dd;J=15Hz,7Hz,1H),4.27(dd;J=15Hz,6Hz,1H),5.63(d;J=12Hz,1H),5.68(d;J=12Hz,1H),7.05-7.12(m,2H),7.47-7.52(m,2H),8.96(s,1H)。
(b)7-(4-氟苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪
采用下述条件,用高速液相色谱精制7-(4-氟苄氧基)-1-[(E)-2-甲基环丙基甲基]-2,3-二甲基吡咯并[2,3-d]哒嗪(外消旋体)25.00g,用醋酸乙酯重结晶,获得标题化合物[(S,S)体]8.54g和其对映体[(R,R)体]7.60g。分离条件
柱子:CHIRALCEL OJ(50Φ*500mm,Daicel制)
溶剂:己烷/乙醇(90/10)
流速:25ml/min标题化合物[(S,S)体]
熔点:114~115℃。
质谱(CI,m/z):340(M++1)。
NMR谱(CDCl3,δppm):0.14(dt;J=8Hz,5Hz,1H),0.39(dt;J=8Hz,5Hz,1H),0.59-0.65(m,1H),0.76-0.85(m,1H),0.89(d;J=6Hz,3H),2.26(s,3H),2.36(s,3H),4.13(dd;J=15Hz,7Hz,1H),4.27(dd;J=15Hz,6Hz,1H),5.63(d;J=12Hz,1H),5.68(d;J=12Hz,1H),7.05-7.12(m,2H),7.47-7.52(m,2H),8.96(s,1H)。
旋光度:[α]D 20=+19.0°(C=0.99,MeOH)。对映体[(R,R)体]
熔点:114~115℃。
质谱(CI,m/z):340(M++1)。
NMR谱(CDCl3,δppm):0.15(dt;J=8Hz,5Hz,1H),0.39(dt;J=8Hz,5Hz,1H),0.58-0.66(m,1H),0.78-0.85(m,1H),0.89(d;J=6Hz,3H),2.26(s,3H),2.37(s,3H),4.13(dd;J=15Hz,7Hz,1H),4.27(dd;J=15Hz,6Hz,1H),5.63(d;J=12Hz,1H),5.68(d;J=12Hz,1H),7.06-7.11(m,2H),7.49-7.52(m,2H),8.97(s,1H)。
旋光度:[α]D 20=-18.8°(C=0.98,MeOH)。试验例1质子·钾-三磷酸腺苷酶(H+·K+-ATPase)活性试验
按照Sachs等人的方法[J.Bio.,Chem.,251,7690(1976)],将新鲜的猪胃粘膜层均质化并用密度梯度超速离心法配制的微粒体组分用作H+·K+-ATPase标样。向含有换算为蛋白质浓度30~80μg/ml的酶标样的70mM Tris-盐酸缓冲液(氯化镁5mM,氯化钾20mM,pH=6.85)0.75ml中,加入溶解在二甲基亚砜中的被检测化合物溶液10μl,在37℃下,以200次/分钟的振荡次数温育45分钟。加入8mM的三磷酸腺苷2钠盐溶液0.25ml,开始酶反应。进行20分钟的酶反应,加入10%三氯醋酸-活性炭(100mg)溶液1ml,停止反应。将反应液离心分离(4℃,3000rpm,15分钟)后,采用Yoda等人的方法[Biochem.Biophys.Res.Commun.,40,880(1970)]对上清液中的三磷酸腺苷水解生成的无机磷酸进行比色定量。另外,同样地测定不存在氯化钾时反应溶液中的无机磷酸的量,从存在氯化钾时的无机磷酸量中扣除,由此测定H+·K+-ATPase活性。由对比活性值与被检测化合物各浓度时的活性值求出抑制率(%),从而求出对于H+·K+-ATPase的50%抑制浓度(IC50μg/ml)。其结果,实施例1的化合物显示出IC50<0.1μg/ml的优良活性。试验例2对幽门螺杆菌的抗菌作用
抗菌能力的评价,使用幽门螺杆菌9470、9472以及9474菌株,求出本发明化合物对幽门螺杆菌的MIC(Minimum InhibitoryConcentration:最小生长抑制浓度)值。
将幽门螺杆菌在平板培养基上培养4天。所使用的培养基是将脑心浸液琼脂培养基(Difco公司制)溶解于规定量的蒸馏水中,高压灭菌后,注入马血(日本生物材料公司制)至7%后,使其固化的培养基。
将在微好氧条件下、在37℃下培养4天的幽门螺杆菌悬浮在生理食盐水中,使菌量为约108CFU/ml。将悬浮液稀释100倍,将其约10μl接种到MIC测定用培养基上。MIC测定用培养基使用与上述培养用培养基组成相同的培养基。其制法是:将本发明化合物溶解于二甲基亚砜(DMSO)中,制成用灭菌蒸馏水2倍稀释系列的溶液,将系列稀释物与培养基按1∶99的比例混合,在培养皿上固化后,作为MIC测定用培养基。与上述培养同样,在微好氧条件下,在37℃下将幽门螺杆菌培养3天。培养结束后,用肉眼观察接种部分的菌的生长情况,将观察不到细菌生长的本发明化合物的最小浓度作为MIC(μg/ml)。其结果,实施例1的化合物显示出MIC<12.5μg/ml的优良抗菌活性。试验例3胃酸分泌抑制作用
使一组3~5只大鼠绝食一夜后,在乙醚麻醉下,切开腹部正中,结扎幽门。将胃和十二指肠复原到体内原先位置上后,将腹部切开部缝合。使一定量的试验化合物悬浮于羧甲基纤维素钠盐0.5%和吐温80(聚山梨醇酯80)0.4%水溶液中,将该悬浮液向大鼠口服给药。另外,作为对照,将羧甲基纤维素钠盐0.5%和吐温80(聚山梨醇酯80)0.4%水溶液(悬浮溶剂)向大鼠口服给药。从试验化合物或悬浮溶剂的给药开始4小时后,使大鼠吸入二氧化碳气,使其安乐死,切开腹部,将胃摘出。将胃中的内容物收集到玻璃制带刻度的离心管中后,进行离心分离,测定上清液的体积(ml)和沉渣的体积(ml)。沉渣体积在0.5ml以上的作为饮食过量而从数据中除去。将上清液100μl采集到试管中,加入4ml蒸馏水,用0.01当量的氢氧化钠滴定至pH7.0。同时滴定作为标准酸浓度溶液的在0.1当量盐酸100μl中加入4ml蒸馏水而成的盐酸水溶液。按照下述公式计算胃液酸浓度(mEq/l)、胃酸排出量(AO,μEq/hr)和抑制率(%)。胃液酸浓度(mEq/l)=A/B×100
A:上清液100μl的滴定所需要的氢氧化钠量(ml)
B:0.1当量盐酸100μl的滴定所需要的氢氧化钠量(ml)胃酸排出量(AO,μEq/hr)=胃液上清液量(ml)×胃液酸浓度(mEq/l)/4抑制率(%)=(C-D)/C×100
C:悬浮溶剂给药组的AO(μEq/hr)
D:试验化合物给药组的AO(μEq/hr)
将各给药量(0.3mg/kg、1mg/kg、3mg/kg和10mg/kg)时的抑制率与对数用量的最小二乘法划出用量-抑制率直线,由该直线求出50%抑制用量(ID50mg/kg),示于下表2。
表2 胃酸分泌抑制效果
试验化合物 | 胃酸分泌50%抑制用量(ID50mg/kg) |
实施例1的化合物 | 0.52 |
化合物A | 1.64 |
化合物A:实施例1的化合物及其对映体的1∶1混合物(外消旋体:特开平7-247285号的实施例57的化合物)
从表2的结果看出,就胃酸分泌抑制作用而言,实施例1的化合物显示出比其外消旋体约强3倍的效果。制剂例1片剂
实施例1的化合物 30.0mg
乳糖 144.0
玉米淀粉 25.0
硬脂酸镁 1.0
200.0mg
将上述处方的粉末混合,用制片机制片,制成每片200mg的片剂。
该片剂可根据需要包糖衣或涂层。
Claims (21)
1.一种光学活性的吡咯并哒嗪化合物或其可药用盐,它具有如下通式,
(式中,R1表示C1~C6烷基,R2和R3相同或不同,表示C1~C6烷基;R4表示可以被选自C1~C6烷基、卤代C1~C6烷基、C1~C6烷氧基、卤代C1~C6烷氧基以及卤素中的取代基取代的C6~C10芳基;A表示亚氨基、氧原子或硫原子)。
2.权利要求1中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,R1为C1~C4烷基。
3.权利要求1中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,R1为甲基。
4.权利要求1~3任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,R2和R3相同或不同,为C1~C4烷基。
5.权利要求1~3任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,R2和R3相同,为甲基。
6.权利要求1~5任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,R4为被选自C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代C1~C4烷氧基、氟、氯和溴中的1~3个取代基取代的苯基。
7.权利要求1~5任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,R4为被选自甲基、三氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、氟、氯和溴中的1~3个取代基取代的苯基。
8.权利要求1~5任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,R4为被选自氟和氯中的1~2个取代基在选自2位、4位和6位中的1~2个取代位置取代的苯基。
9.权利要求1~5任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,R4为被选自氟和氯中的1~2个取代基在4位或2,4-位取代位置取代的苯基。
10.权利要求1~9任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,A为氧原子或硫原子。
11.权利要求1~9任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐,其中,A为氧原子。
12.一种光学活性的吡咯并哒嗪化合物或其可药用盐,它选自:
7-(4-氟苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪、
7-(2,4-二氟苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪、以及
7-(4-氯苄氧基)-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基甲基]吡咯并[2,3-d]哒嗪。
13.一种医药组合物,其中,含有权利要求1~12中所述的光学活性的吡咯并哒嗪化合物或其可药用盐作为有效成分。
14.权利要求13中所述的医药组合物,其中,医药组合物是用于溃疡性疾病的预防或治疗的组合物。
15.权利要求1~12任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐在制备医药组合物中的应用。
16.权利要求15中所述的应用,其中,医药组合物是用于溃疡性疾病的预防或治疗的组合物。
17.一种疾病的预防或治疗方法,该方法是将有效量的权利要求1~12任一项中所述的光学活性的吡咯并哒嗪化合物或其可药用盐向温血动物给药。
18.权利要求17中所述的方法,其中,疾病是溃疡性疾病。
19.权利要求17~18中所述的方法,其中,温血动物是人。
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HUP0204579A3 (en) * | 2000-02-10 | 2006-01-30 | Ube Industries | Pyrrolopyridazine derivatives, pharmaceutical compositions containing them and their use |
WO2004029057A1 (ja) * | 2002-09-25 | 2004-04-08 | Sankyo Company, Limited | 内臓痛の治療または予防のための医薬組成物 |
WO2004029058A1 (ja) * | 2002-09-25 | 2004-04-08 | Sankyo Company, Limited | 血中ガストリン濃度上昇の抑制のための医薬組成物 |
EP1974730A1 (en) | 2003-11-03 | 2008-10-01 | AstraZeneca AB | Imidazo[1,2-a]pyridine derivatives for use in the treatment of sleep disturbance due to silent gastro-esophageal reflux |
CN101010321B (zh) | 2004-09-03 | 2011-10-26 | 株式会社柳韩洋行 | 吡咯并[3,2-b]吡啶衍生物及其制备方法 |
CN105919998B (zh) | 2009-07-09 | 2021-08-24 | 拉夸里亚创药株式会社 | 用于治疗与异常肠胃运动有关的疾病的酸泵拮抗剂 |
CN105367550A (zh) * | 2014-08-11 | 2016-03-02 | 江苏柯菲平医药股份有限公司 | 四氢环戊二烯并[c]吡咯类衍生物、其制备方法及其在医药上的应用 |
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WO1991017164A1 (de) | 1990-04-27 | 1991-11-14 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Neue pyridazine |
AU8712191A (en) | 1990-10-15 | 1992-05-20 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New diazines |
JPH07500329A (ja) | 1991-10-25 | 1995-01-12 | ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | ピロロ−ピリダジン |
ES2185693T3 (es) | 1994-01-19 | 2003-05-01 | Sankyo Co | Derivado de pirrolopiridacina. |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007082470A1 (fr) * | 2006-01-17 | 2007-07-26 | Shanghai Hengrui Pharmaceutical Co.Ltd. | Dérivés de pyrrolo-pyridazine, leurs procédés de préparation et leurs utilisations |
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