CN1019196B - 2-噻唑烷酮类衍生物的制备方法 - Google Patents
2-噻唑烷酮类衍生物的制备方法Info
- Publication number
- CN1019196B CN1019196B CN88108626A CN88108626A CN1019196B CN 1019196 B CN1019196 B CN 1019196B CN 88108626 A CN88108626 A CN 88108626A CN 88108626 A CN88108626 A CN 88108626A CN 1019196 B CN1019196 B CN 1019196B
- Authority
- CN
- China
- Prior art keywords
- compound
- logical formula
- halogen
- thiazolidone
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- SLYRGJDSFOCAAI-UHFFFAOYSA-N 1,3-thiazolidin-2-one Chemical class O=C1NCCS1 SLYRGJDSFOCAAI-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000000203 mixture Substances 0.000 title description 10
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- DSUKUFGNCZKNGB-UHFFFAOYSA-N 2H-1,3-thiazol-2-ide 1-oxide Chemical class S1([C-]=NC=C1)=O DSUKUFGNCZKNGB-UHFFFAOYSA-N 0.000 claims description 10
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical class NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 7
- ROORDVPLFPIABK-UHFFFAOYSA-N diphenyl carbonate Chemical compound C=1C=CC=CC=1OC(=O)OC1=CC=CC=C1 ROORDVPLFPIABK-UHFFFAOYSA-N 0.000 claims description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 238000001149 thermolysis Methods 0.000 claims description 2
- 125000005905 mesyloxy group Chemical group 0.000 claims 1
- 239000012454 non-polar solvent Substances 0.000 claims 1
- 125000000951 phenoxy group Chemical class [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims 1
- 208000007107 Stomach Ulcer Diseases 0.000 abstract description 5
- 230000001120 cytoprotective effect Effects 0.000 abstract description 2
- 208000000718 duodenal ulcer Diseases 0.000 abstract description 2
- 230000002496 gastric effect Effects 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 230000027119 gastric acid secretion Effects 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000002329 infrared spectrum Methods 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 229960003151 mercaptamine Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LEGPKNRMLKZMIH-UHFFFAOYSA-N [CH-]1C=[N+]([CH-]S1=O)CC2=CC=CC=C2 Chemical compound [CH-]1C=[N+]([CH-]S1=O)CC2=CC=CC=C2 LEGPKNRMLKZMIH-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- -1 amino, phenoxy group Chemical group 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 201000005917 gastric ulcer Diseases 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 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
- HXBMIQJOSHZCFX-UHFFFAOYSA-N 1-(bromomethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CBr HXBMIQJOSHZCFX-UHFFFAOYSA-N 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000002594 sorbent Substances 0.000 description 3
- UAATZBCHQVMMCU-UHFFFAOYSA-N 5-methyl-4H-1,3-thiazol-4-ide 1-oxide Chemical compound CC1=[C-]N=CS1=O UAATZBCHQVMMCU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-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
- 241001597008 Nomeidae Species 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012074 organic phase Substances 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
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000000935 solvent evaporation Methods 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
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GURNIKPBOPIBON-UHFFFAOYSA-N 2-[(2-chlorophenyl)methylamino]ethanethiol Chemical compound SCCNCC1=CC=CC=C1Cl GURNIKPBOPIBON-UHFFFAOYSA-N 0.000 description 1
- KHUKMCZFKMZLLL-UHFFFAOYSA-N 3-benzyl-4,5-dihydro-1,3-thiazol-3-ium-2-amine;bromide Chemical compound Br.N=C1SCCN1CC1=CC=CC=C1 KHUKMCZFKMZLLL-UHFFFAOYSA-N 0.000 description 1
- IWTYTFSSTWXZFU-UHFFFAOYSA-N 3-chloroprop-1-enylbenzene Chemical compound ClCC=CC1=CC=CC=C1 IWTYTFSSTWXZFU-UHFFFAOYSA-N 0.000 description 1
- REGFWZVTTFGQOJ-UHFFFAOYSA-N 4,5-dihydro-1,3-thiazol-2-amine Chemical class NC1=NCCS1 REGFWZVTTFGQOJ-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010022714 Intestinal ulcer Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 108010079943 Pentagastrin Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- YWRRQOZWAIHODP-UHFFFAOYSA-N [CH-]1C=[N+]([CH-]S1=O)CC=CC2=CC=CC=C2 Chemical compound [CH-]1C=[N+]([CH-]S1=O)CC=CC2=CC=CC=C2 YWRRQOZWAIHODP-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009635 nitrosylation Effects 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 1
- 229960000444 pentagastrin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D277/14—Oxygen atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
- Silver Salt Photography Or Processing Solution Therefor (AREA)
Abstract
本发明涉及一种新型的通式(I)为
(其中,A表示氢、卤素、C1-4烷基、C1-4烷氧基或不在4位(对位)的硝基:而n为0或1)的2-噻唑烷酮衍生物的制备方法。本发明的化合物显示了细胞保护和胃酸分泌的抑制作用,因而可以被使用于胃和十二指肠溃疡的治疗。
Description
本发明涉及具有以下通式的2-噻唑烷酮类的衍生物
(其中,A表示氢、卤素、或C1-4烷基、C1-4烷氧基或硝基;n为0或1)及其含有这类化合物的药学组合物。
通式(Ⅰ)的新化合物具有很高的治疗学上的重要性,因为患胃溃疡和十二指肠溃疡的病人的人数从绝对意义和相对意义上来说都在不断地增加。尽管可获得一些抗溃疡的药物,但仅仅是其结构显著地不同于通式(Ⅰ)的化合物的2-(3,4-二甲氧基苯基)-5-甲基-4-噻唑烷酮(KM-1146)的相似效果被描述在噻唑烷的一类物质中〔Arzneim.-Forsch./Drug Res.36/Ⅱ/8,1236(1986)〕。
在通式(Ⅰ)的化合物中,只有3-(4-硝苯基甲基)-2-噻唑烷酮已在文献中报导,它是2-(4-硝苯基甲基硫)3-(4-硝苯基甲基)-2-溴代噻唑啉鎓的碱水解之产物(J.Chem.soc.(1971,103)。然而,所引用的文献中所给出的熔点(137-138℃)显著地不同于我们用其它方法(见实施例6:即146-148℃)制备的产物。所给出的3-苯甲基-2-噻唑烷酮的结构是推测的,但把3-苯甲基-2-噻唑烷硫酮氧化成3-苯甲基-2-噻唑烷-1,1-二氧化物时并没有得到分离出来的中间体〔J.Org.Chem.25,5103(1961)〕。
根据本发明的一个方面,提供了制备通式(Ⅰ)的新化合物的
方法(其中A表示氢、卤素或C1-4烷基、C1-4烷氧基或硝基;而n为0或1),该方法包括:
a)使通式(Ⅱ)
(其中,A和n为如上所述)的半胱胺衍生物与通式(Ⅲ)
(其中,Y表示卤素、氨基、苯氧基或吡啶氧基)的碳酸衍生物进行反应;或
b)使通式(Ⅳ)
(其中,A和n为如上所述)的化合物经加热分解;或
c)使通式(Ⅴ)
(其中,A和n为如上所述,X表示卤素、甲磺酰氧基、甲苯磺酰氧
基)的化合物与2-噻唑烷酮进行反应。
本发明方法a)的反应是在溶剂存在下进行的。根据所使用的反应物的反应活性,合适的溶剂为C1-5醇类;C3-8酮类、腈类、芳香烃或氯化的烃。一般合适的是使反应在40-130℃的温度下完成,可选择的温度可以是所使用的溶剂之沸点。反应的副产物取决于离去基团的本质。反应中所生成的氯化氢或氨(当Y=NH2时)部分地是以气体形式从反应混合物中逸出,而在其他情况下,缩合反应中所产生的苯酚或羟基吡啶必须在对反应混合物进行蒸发之后通过碱萃取或蒸馏来加以除去。反应混合物经这样预处理之后可用蒸馏、柱层析色谱或结晶等方法,从反应混合物分离出产物。
作为本发明中方法b)的起始物质的通式(Ⅳ)的化合物可通过将相应的亚氨基化合物或它的盐进行亚硝基化来制备。如此制备的通式(Ⅳ)的化合物经分离、干燥,并在不加以净化的情况下通过使之在高沸溶剂(例如在C3-6醇、C6-10芳烃)中进行回流来使它接受热分解。把溶剂蒸发掉以后,用合适的溶剂研磨该残留物,产物即可经过滤而被分离出来。
本发明方法c)的反应是在溶剂的存在下进行的。C3-8酮类或含水酮、二甲基甲酰胺、二甲基亚砜、最好是甲基异丁酮能够在存在有酸接受体的情况下使用,较好的是使用碱金属碳酸盐或碳酸氢盐。把无机沉淀物滤去和把溶剂除去之后,就通过蒸馏、结晶或柱层析色谱法对产物进行提纯。用作起始物质的2-噻唑烷酮的制备可从文献中得知[J.Am.Chem.soc.73,5349(1956);J.Chem.Soc.1952,3094]。
用作起始化合物的通式(Ⅱ)的半胱胺衍生物可通过以金属氢化物复合体对2-芳基噻唑啉衍生物进行还原来制备,所说的2-芳基噻唑啉衍生物又是通过使半胱胺与适当的氧代化合物反应来得到的[Org.Chem.27,4712(1963)]。通过使相应的2-氨基-2-噻唑啉衍生物的烷基化可制得通式(Ⅳ)的2-氨基噻唑烷衍生物(见,例如,Zhurnal Obsch.Chim,1962,3215)。
根据药理学的研究,3-苯甲基-2-噻唑烷酮类(编码名称:RGH-6148)是通式(Ⅰ)的化合物中的杰出例子。
药理学
1)RGH6148对幽门结扎的(Shay-rat)大鼠具有抗分泌作用[Gastroenterology 5,43(1945)]。ED50:2.6mg/kg口服和3.7mg/kg腹腔注射。这种化合物没有在灌满了的鼠胃中抑制被刺激后的(被组胺、Charbachole,五肽促胃酸激素刺激)酸分泌。
2)用RGH-6148进行的预治疗显示了它对酸化乙醇所引起的胃损伤有细胞保护(胃保护)作用:ED50=6mg/kg口服[Gastroenterology77,(1979)]
3)RGH-6148预防了由以下物质所导致的胃溃疡
a)消炎痛:ED50=1.0mg/kg口服
b)阿司匹灵:ED50=1.3mg/kg口服
c)阿司匹灵′stress:ED50=22.0mg/kg口服
4)RGH-6148加速了由醋酸(3mg/kg天,38%)
所导致的鼠的慢性胃溃疡的愈合。
5)RGH-6148阻止了消炎痛引起的肠溃疡。
6)RGH-6148在大鼠中的急性毒性(半数致死量),LD50为700mg/kg(口服)
意义
结合一些文献上的发现,我们的现有结果为胃溃疡的病理和RGH-6148的作用机理提供了一些有价值的假设。
这些假设强调了粘膜的乳突细胞之作用。RGH-6148不抑制刺
激的酸分泌这一事实意味着作用的部位也处在粘膜的乳突细胞之水平,而不是处在壁细胞之水平。
RGH-6148代表了一类能被称为粘膜的乳突细胞保护体(MMCP)的新抗溃疡药。
3-(2-硝苯基甲基)-2噻唑烷酮按10mg/kg的剂量被口服时,在细胞保护试验(Rober试验)中导致了100%的抑制(与对照的比较)当它按25mg/kg的剂量被口服时,就在酸分泌的抑制试验(Shay test)中导致了60%的抑制(与对照的比较)。通过使用同样的方法进行试验时,3-(4-氯苯基甲基)-2噻唑烷酮分别显示了30%和60%的抑制。
以下,将通过非限制性的实施例来对本发明作详细的说明。
实施例1
3-苯甲基-2-噻唑烷酮的制备
a)将200ml乙醇中含有33.6g(0.2mol)N-苯甲基半胱胺和42.8g(0.2mol)二苯基碳酸酯的溶液在氮气氛下回流24小时,然后在减压下把乙醇蒸发掉。接着把残留物溶解在乙酸乙酯中,用2N的氢氧化钠溶液进行洗涤,直到它不含有苯酚为止,以后再用水洗涤,并进行干燥和蒸发。在减压下对残留物加以蒸馏后便获得了21.8g(56.4%)的标题化合物,沸点为140℃/1.5Hgmm,它在石油醚的存在下固化,熔点为50-51℃
分析:按C10H11OS的计算(分子量:193.26):
C62.15;H5.73;N7.25;S16.59%;
实测:C62.23;H5.98;N7.17;S16.45。
红外光谱(KBr):1660cm-1(C=0)
1445cm-1(N-CH2)
1230cm-1(S-CH2)
′H-核磁共振(CDCl3):3.0-3.7ppm(m,4H,2CH2)
4.5ppm(S,2H,CH2)
7.3ppm(S,5H,ArH)
b)用光气在10℃下对30ml的甲苯加以饱和后,滴入15ml在甲基中的10.02g(0.06mol)N-苯甲基半胱胺的溶液。过一会儿产生了稠厚的白色沉淀物。然后把该混合物慢慢地加热至沸点并进行回流直到获得清澈的溶液为止。将该热溶液再用氮通入鼓泡直到它不含有光气为止,此后在减压下加以蒸发。
接着,使该混合物在40ml乙醇中回流2小时,然后在减压条件下把乙醇蒸发掉,并又在减压下进行蒸馏。该蒸馏液会在石油醚的存在下固化。于是获得了6.65g(57.3%)标题化合物,熔点为50-51℃。
c)往10ml水中的2.73g(0.01ml)2-亚氨基-3-苯甲基噻唑烷溴化氢溶液中加入1.36g无水醋酸钠和0.62ml的冰醋酸,然后在搅拌的条件且5℃下向上述混合物中滴入溶解在3ml水中的0.75g亚硝酸钠,接着在5℃下再对该混合物搅拌3小时。在冰箱中静置一夜之后,又在室温下搅拌该溶液达3小时。经研磨后出现了沉淀物,以后,滤出沉淀物,再用水进行洗涤并进行干燥,然后用5份体积的正-丁醇对此作2小时的回流。把溶剂蒸发掉之后,再用二异丙醚对残留物进行研磨,并滤出产物。于是获得了0.81g(42.3%)的标题产物,熔点为49-50℃
d)含有3.09g(0.03mol)2-噻唑烷、11.2g碳酸钾、1.8g碳酸氢钾、0.5ml水、30ml甲基异丁酮和3.0ml(0.033mol)苄溴的混合物被回流达7小时。冷却之后,分别二次,每次用30ml水对反应混合物加以洗涤,再对有机相加以干燥和蒸发。通过柱层析色谱法(把230-400目的硅胶60作为吸附剂,而把氯仿作为洗脱剂)对黄色的油状产物(它一静置就会固化)加以提纯,从而获得了3.2g(55.2%)的标题化
合物,熔点为50-51℃。
实施例2
3-(4-甲氧基苯甲基)2-噻唑烷酮的制备
将25ml乙醇中含有4.53g(0.025mol)N-(4-甲氧基苯甲基)-半胱胺和5.35g(0.025mol)二苯基碳酸酯的溶液在氮气氛下回流24小时,然后蒸发。接着残留物溶解在乙酸乙酯中,再用2N的氢氧化钠溶液洗涤直到它不含苯酚为止,此后再用水洗涤,并加以干燥和蒸发。残留物在醚存在下会变为固体。于是获得了1.82g(32.6%)的标题化合物,熔点为84-86℃。
分析:按C11H13NO2S计算(分子量为223.29):
C59.17;H5.87;N6.27;S14.36;
实测:C59.35;H5.91;N6.03;S14.23
红外光谱(KBr):1640cm-1(C=0)
2850cm-1(O-CH3)
1247cm-1(Ar-O-C)
1H-核磁共振(CDCl3):3.3ppm(m,4H,2CH2)
3.8ppm(S,3H,CH2)
4.4ppm(S,2H,CH2)
7.0ppm(q,4H,ArH)
实施例3
3-(2-氯苯基甲基)-2-噻唑烷酮的制备
按照实施例2的操作程序,把5.05g(0.025mol)的N-(2-氯苯基甲基)半胱胺与5.35g(0.025mol)的二苯基碳酸酯进行反应,然后进行操作。通过柱层析色谱法(把230-400目的硅胶60作为吸附剂,把氯仿用作洗脱剂)提纯之后就获得了2.5g(43.9%)标题化合物,n30 D=1.600
分析:按C10H10ClNOS计算(分子量为227.71)
C52.75;H4.43;N6.15;S14.07;
实测:C52.98;H4.25;N6.28;S14.22
红外光谱(KBr):1670cm-1(C=0)
1055cm-1(Ar-Cl)
1H-核磁共振(CDCl3):3.3ppm(m,2H,CH2)
3.6ppm(m,2H,CH2)
4.7ppm(S,2H,CH2)
7.4ppm(S,5H,ArH)
实施例4
3-(4-甲苯基甲基)-2-噻唑烷酮的制备
按照实施例2的操作程序,把4.0g(0.022mol)的N-(4-甲苯基甲基)半胱胺与4.71g(0.022mol)的二苯基碳酸酯进行反应,然后对该反应混合物进行操作下去,从而得到1.36g(29.8%)的标题化合物,熔点:49-50℃
分析:按C11H13NOS计算(分子量为207.29)
C63.73;H6.32;N6.76;S15.47
实测:C63.78;H6.39;N6.67;S15.44
红外光谱(KBr):1660cm-1(C=0)
1H-核磁共振(CDCl3):2.2ppm(S,3H,CH3)
2.9-3.6ppm(m,4H,2CH2)
4.3ppm(S,2H,CH2)
7.0ppm(S,5H,ArH)
实施例5
3-(2-硝苯基甲基)-2-噻唑烷酮的制备
将含有3.09g(0.03mol)2-噻唑烷酮、11.2g碳酸钾、1.8g碳酸氢钾、0.5ml水、30ml甲基异丁酮和6.5g(0.03mol)2-硝基苄溴的混合物回流6小时,然后被冷却并与50ml水作充分混合。接着对该
混合物进行过滤并把澄清的滤液分离出来。用10ml水对有机相加以洗涤,并加以干燥和蒸发。用乙醇对油状残留物进行重结晶之后就获得了2.65g(37.0%)标题化合物,熔点为92-93℃。
分析:按C10H10N2O3S计算(分子量为238.26)
C50.41;H4.23;N11.76;S13.45
实测 C50.63;H4.10;N11.84;S13.63。
红外光谱(KBr)1670cm-1(O=0)1525,1345cm-1(NO2)
1H-核磁共振(CDCl3):3.1-3.8ppm(m,4H,2CH2)
4.9ppm(S,2H,CH2)
7.2-8.3ppm(m,4H,ArH)
实施例7
3-(4-氯苯基甲基)-2-噻唑烷酮的制备
按照实施例5的方法,所不同的是使用了5.0g(0.03mol)的4-氯苄氯而不是2-硝基苄溴。于是获得了3.95g(56%)标题化合物,熔点为68-69℃。
分析:按C10H10ClNOS计算(分子量为227.71)
C52.75;H4.43;N6.15;S14.07;
实测 C52.83;H4.67;N6.12;S14.24
红外光谱(KBr):1670cm-1(C=0)
1095cm-1(Ar-Cl)
1H-NMR(CDCl3):3.3ppm(q,2H,CH2)
3.5ppm(q,2H,CH2)
4.5ppm(S,2H,CH2)
7.3ppm(S,4H,ArH)
实施例8
3-肉桂基-2-噻唑烷酮的制备
按照实施例5的方法,所不同的是使用了4.58g(0.03mol)的肉桂基氯而不是使用2-硝基苄溴。用色谱法〔把230-400目的硅胶60用作吸附剂,把(醋酸乙酯∶石油醚=8∶2)的混合物作为洗脱剂〕提纯并且用二异丙醚重结晶后就获得了3.92g(59.6%)标题化合物,熔点为50-52℃。
分析:按C12H13NOS计算(分子量为219.30)
C65.72;H5.97;N6.39;S14.62;
实测 C65.93;H6.06;N6.26;S14.51
红外光谱(KBr):1670cm-1(C=0)
980cm-1(C=C)
1H-核磁共振(CDCl3)::3.2ppm(m,2H,CH2)
3.6ppm(m,2H,CH2)
4.0ppm(d,2H,CH2)
5.9-6.6ppm(m,2H,2CH)
7.3ppm(S,5H,ArH)
实施例9
药学组合物
含有50mg活性组分的片剂的制备
为制备1000片而使用了下列组分:
3-苯甲基-2-噻唑烷酮 50g
乳糖 200g
淀粉 32g
硬脂酸镁 3g
活性组分和辅助物料在混合设备中被混合,然后在制片机中被压制成片剂。
3.6ppm(m,2H,CH2)
4.0ppm(d,2H,CH2)
5.9-6.6ppm(m,2H,2CH)
7.3ppm(S,5H,ArH)
实施例9
药学组合物
含有50mg活性组分的片剂的制备
为制备1000片而使用了下列组分:
3-苯甲基-2-噻唑烷酮 50g
乳糖 200g
淀粉 32g
硬脂酸镁 3g
活性组分和辅助物料在混合设备中被混合,然后在制片机中被压制成片剂。
Claims (3)
2、根据权利要求1a所述的方法,其特征是把二苯基碳酸酯用作通式(Ⅲ)的化合物。
3、根据权利要求1a所述的方法,其特征是把光气用作溶解在非极性溶剂中的通式(Ⅲ)的化合物。
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CN103351358B (zh) * | 2013-07-03 | 2015-05-27 | 北京化工大学 | 一种5-取代2-噻唑烷酮的制备方法 |
RU2643669C1 (ru) * | 2017-04-03 | 2018-02-05 | Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) | 3-[3-(морфолин-4-ил)пропил]-2-[(2,2,3-триметилциклопент-3-ен-1-ил)метил]-1,3-тиазолидин-4-он, обладающий противоязвенной и противовоспалительной активностью |
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KR890009897A (ko) | 1989-08-04 |
HU198915B (en) | 1989-12-28 |
EP0320910B1 (en) | 1993-12-08 |
LV5491A3 (lv) | 1994-03-10 |
CA1332419C (en) | 1994-10-11 |
ES2049243T3 (es) | 1994-04-16 |
DE3886185T2 (de) | 1994-05-05 |
JPH02279A (ja) | 1990-01-05 |
SU1657062A3 (ru) | 1991-06-15 |
US4937252A (en) | 1990-06-26 |
HUT49125A (en) | 1989-08-28 |
ATE98235T1 (de) | 1993-12-15 |
DE3886185D1 (de) | 1994-01-20 |
KR920010179B1 (ko) | 1992-11-19 |
LT2199B (lt) | 1993-10-15 |
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