CN1019577B - 6-氯-4-羟基-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1,1-二氧化物烯醇醚类化合物制备方法 - Google Patents
6-氯-4-羟基-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1,1-二氧化物烯醇醚类化合物制备方法Info
- Publication number
- CN1019577B CN1019577B CN88107381A CN88107381A CN1019577B CN 1019577 B CN1019577 B CN 1019577B CN 88107381 A CN88107381 A CN 88107381A CN 88107381 A CN88107381 A CN 88107381A CN 1019577 B CN1019577 B CN 1019577B
- Authority
- CN
- China
- Prior art keywords
- methyl
- pyridyl
- dioxide
- chlortenoxicam
- thieno
- 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
- 238000000034 method Methods 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000002084 enol ethers Chemical class 0.000 title abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical class O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 claims description 21
- 229960002202 lornoxicam Drugs 0.000 claims description 21
- -1 alkali metal cation Chemical class 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- WLHQHAUOOXYABV-UHFFFAOYSA-N lornoxicam Chemical compound OC=1C=2SC(Cl)=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 WLHQHAUOOXYABV-UHFFFAOYSA-N 0.000 abstract description 2
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 abstract 1
- 229960002702 piroxicam Drugs 0.000 description 12
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 235000010418 carrageenan Nutrition 0.000 description 9
- 229920001525 carrageenan Polymers 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000001939 inductive effect Effects 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
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture 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
- 238000010992 reflux Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YVRGKFXJZCTTRB-UHFFFAOYSA-N 1-chloroethyl ethyl carbonate Chemical compound CCOC(=O)OC(C)Cl YVRGKFXJZCTTRB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 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 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 238000009835 boiling Methods 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 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
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000019580 granularity Nutrition 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 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
- 229940099259 vaseline Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- 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]
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)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及新类型的6-氯-4-羟基-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羰基酰胺1,1-二氧化物烯醇醚类化合物,其通式为:
其中R表示(C1-C6)-烷基,(C5-C7)-环状烷基或苄基;以及它们的制备方法。该类新化合物具有抗炎活性并适用于风湿病的治疗。
Description
本发明涉及新类型6-氯-4-羟在-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1.1-二氧化物烯醇醚类化合物,它们的制备方法及作为抗炎药物的应用。
在美国专利说明书4,180,662中叙述了抗炎止痛药,该美国专利说明书中所描述的物质,6-氯-4-羟基-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1.1-二氧化物(chlortenoxicam)已经被证实有特效。然而,由于该化合物的极性及酸性结构,在极少数病例中,可能会引起胃肠道刺激。该物质的局部应用的配方有缺点,它们的皮肤穿透作用不理想,并且强烈的黄色会沾污覆盖的布料。
欧洲专利说明书0,147,177中叙述了喜康(oxicam)的烯醇醚类化合物,该欧洲专利说明书中描述的烯醇醚类化合物有缺点,然而,这些烯醇醚的药理活性低于未醚化的oxicam类化合物的活性。
本发明中的烯醇醚类化合物意外地被证实具有比未醚化的chlortenoxicam更高的药理活性,该烯醇醚类化合物是无色的,因而适于局部应用。
因此,本发明涉及通式Ⅰ化合物
其中R表示(C1-C6)-烷基,(C5-C7)-环状烷基或苄基。
在此处,术语(C1-C6)-烷基指带有1~6个碳原子的直链的或支链的饱和烃基,例如,甲基,乙基,异丙基,叔丁基及戊基。下文中卤素可是氯,溴或碘。
一个更可取的个别化合物为:6-氯-4-(1-(乙氧羰基氧基)乙氧基)-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1.1-二氧化物。
通式Ⅰ化合物可用下列方法制备,在对该反应是惰性的,极性非质子性溶剂中,将通式Ⅱ化合物与通式Ⅲ化合物反应,得到通式Ⅰ化合物。
通式Ⅱ化合物为chlortenoxicam的盐
其中,M+表示一个碱金属阳离子或碱土金属阳离子或季铵离子。
在通式Ⅲ化合物中
R含义同上,而X表示卤素。
所需chlortenoxicam的盐最好用从反应液中分离出来的产品。然而,这些盐可通过向反应液中加入至少等当量的强碱而制成,所用强碱可以是碱金属氢化物或碱金属碳酸盐,反应在极性的、质子惰性的、对反应惰性的无水溶剂中进行。例如,二
甲基甲酰胺,二甲基亚砜,丙酮,2-丁酮等等。反应温度并不是关键,它可选在室温至所用溶剂沸点的范围内。
反应时间取决于反应温度和离去基团X;通常在2~30小时之间。可通过加入碘化钠使反应速度加快(Finckelstein反应),碘化钠用量取决于烷化剂,可选在0.5~3倍过量的范围内。最佳的反应条件是:以丙酮为溶剂、过量的碳酸钠或碳酸钾为碱、在回流温度下,用chlortenoxicam同通式Ⅲ化合物反应,并加入大约1.5倍过量(相对烷化剂而言)的碘化钠。
可依照美国专利说明书4,180,662中的方法,制备chlortenoxicam。通式Ⅲ化合物可以从市场上购买,也可以依照H.Muller,J,Liebigs Ann.Chem 258,50(1890)的方法或依照欧洲专利说明书0,147,177中的方法制备。
在体外模型中,新类型的通式Ⅰ化合物具有显著的抗炎活性。
基于此药理学性质,该类新化合物可单独或混同其他活性物质,配制成常规的药物制剂,用于消除风湿病之类疾病引起的炎症和疼痛。
可用熟知的标准方法测定抗炎活性,例如用角叉菜胶透导的鼠爪肿胀试验。
在该实验中(实例2),将chlortenoxicam,chlortenoxicam的烯醇醚、即6-氯-4-(1-(乙氧羰基氧基)乙氧基)-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1.1-二氧化物,炎痛喜康(2-甲基-N-(2-吡啶基)-4-羟基-2H-1,2-苯并噻嗪-3-羧基酰胺1,2-二氧化物)及炎痛喜康的烯醇醚、即4-(1-乙氧羰基氧基)乙氧基)-2-甲基-N-(2-吡啶基)-2H-1,2-苯并噻嗪-3-羧基酰胺1.1-二氧化物的抗炎活性加以比较,可发现在给定的实验条件下,只有chlortenoxicam的烯醇醚的炎症抑制率达80%。以炎症抑制率达50%时的用药量而言,可推断出chlortenoxicam的烯醇醚的活性,几乎是chlortenoxicam活性的2倍,而炎痛喜康的烯醇醚的活性远远低于炎痛喜康。按抗炎效力依次递减排列如下:
chlortenoxicam的烯醇醚/chlortenoxicam/炎痛喜康/炎痛喜康的烯醇醚
将通式Ⅰ化合物用于哺乳动物,特别是人类,它们可按常规的方式服用,例如,口服或不经肠道服用。最好采用口服和局部用药,口服的每日剂量大约0.5~100mg,最好为1.0~10mg。然而,根据病人的身体状况和年龄,所用通式Ⅰ合适的化合物,病情以及配方的性质,但任治疗的医生也可开出剂量超过或低于此范围的处方。在局部应用时,通式Ⅰ化合物的浓度在0.01~3%之间。
通式Ⅰ化合物可以单独服用,或与其他药用活性物质一起服用,通式Ⅰ化合物的含量在0.1~99%之间。通常提供的是,该药用活性化合物与适当的惰性辅助剂和/或赋形剂或稀释剂组成的混合物。所用赋形剂或稀释剂可以是,如药剂学允许用的溶剂,动物胶,阿拉伯胶,乳糖淀粉、硬脂酸镁,滑石,植物油,聚(亚烷基)二醇,凡士林等。
该药剂制品可以是固态的,例如,片剂、包衣片剂、栓剂、胶囊等等;可以是半固态的,例如,软膏,凝胶;也可以是液态的,例如,溶液,悬浮液或乳浊液。如果适用的话,可将其灭菌并加入辅助剂,如防腐剂,稳定剂,乳化剂,调节渗透压用的盐等等。
尤其是药物制剂可以含有与其它治疗上有用物质相结合的本发明中的化合物。本发明中这些化合物能与上述辅助剂和/或赋形剂或稀释剂配制成复方。
实例1
6-氯-4-(1-(乙氧羰基氧基)乙氧基)-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1.1-二氧化物
将10g(26.9mmol)的6-氯-4-羧基-2-甲基-N-(2-吡啶基)-2H-噻吩并-(2,3-e)-1,2-噻嗪-3-羧基酰胺1.1-二氧化物,9.29g(99.5mmol)的碳酸钾及15.1g(99.5mmol)的碳酸1-氯乙基乙酯,在150ml丙酮中加热回流20小时。然后,加入24.5g(163.3mmol)的碘化钠,该混合物再加热回流5小时。之后,滤除沉淀出来的氯化钠,将滤液蒸干,使残余物分布于100ml二氯甲烷和100ml饱和碳酸氢钠溶液中,分出有机相并用100ml水及20ml3%浓度的亚硫酸氢钠溶液洗涤。有机相用硫酸钠干燥,过滤,蒸发。所得油状粗品(17.5g)用硅胶过滤(100g硅胶60粒度0.04~0.063mm,洗脱剂:二氯甲烷∶乙酸乙酯=9∶1),得到10.1g淡橙色结晶。将该结晶溶于17ml
沸腾的二氧六环中,向该溶液中加入0.6g活性炭,然后将溶液热过滤。冷却滤液,加入40ml乙醚。滤集沉淀出的无色结晶,经乙醚洗涤,干燥(50℃/1mbar),产率:6.3g无色结晶(理论值的48%)。
熔点:148℃(分解)
1H-NMR(CDCl3):
数据(ppm):8.9(s broad;1H,-NH-);8.3(m;2H;py-H);7.8(m;1H;py-H);7.2(s;1H;Th-H);7.1(m;1H;py-H);6.5(q;1H;O-CH-O);4.1(q;2H;-CH2-);3.2(s;3H;N-CH3);1.7(d;3H;-CH-CH3);1.2(t;3H;-CH2-CH3)。
13C-NMR(CDCl3):
数据(ppm):157.9;153.1;150.5;147.9;142.1;137.9;135.9;135.5;134.9;126.6;121.1;120.1;113.9;100.1;64.4;36.7;19.9;13.7。
实例2
角叉菜胶诱导的鼠爪肿胀试验
通过测试被试物对经角叉菜胶诱导的鼠爪肿胀的抑制作用,来测定它们的抗炎作用。
所用被测物质为:
chlortenoxicam(6-氯-4-羟基-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1,1-二氧化物)
chlortenoxicam的烯醇醚(6-氯-4-(1-(乙氧羰基氧基)乙氧基)-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1.1-二氧化物)
炎痛喜康(2-甲基-N-(2-吡啶基)-4-羟基-2H-1,2-苯并噻嗪-3-羧基酰胺1.1-二氧化物)
炎痛喜康的烯醇醚(4-(1-乙氧羰基氧基)乙氧基)-2-甲基-N-(2-吡啶基)-2H-1,2-苯并噻嗪-3-羧基酰胺1.1-二氧化物)
在实验前,用器官充满度测量法测定大鼠右后爪的体积,并记录下所显示的水毫升数。
将被测物质悬浮于0.5%浓度的羧甲基纤维素中,用胃管经口服给药。剂量为0.3/1.0/3.0和10毫克/每公斤体重。每种被测物质的剂量级及对照组动物数均为8只。给药一小时后,向实验动物的右后爪注射0.05ml角叉菜胶(Lambda carrageenan)浓度为2%、NaCl浓度为0.9%的溶液,以诱发炎症。3至4小时后炎症形成,再用器管充满度测量法测定大鼠右后爪的体积。炎症抑制程度以百分数值表示,从该数值算出80%及50%的IHD(抑制剂量)。(80% IHD表示以毫克/每公斤体重为单位的剂量,该剂量下的炎症抑制率可达到80%。)
实例3:
批量制备chlortenoxicam烯醇醚的凝胶
在一台FRYMA加工设备中,将8g的6-氯-4-(1-(乙氧羰基氧基)乙氧基)-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1.1-二氧化物溶于4,717g乙醇及2,082g水中。在搅拌下分批加入167g卡波醇(carbopob),在加入139g Luvitol EHO之后,用由83g二异丙基胺,833g乙醇及833g水组成的溶液中和该批产品,再用含有28g二异丙基胺,555g乙醇及555g水的溶液将该产品pH值调至7.5。将该凝胶装填到管子中。
80% IHD值
被测物质 注射角叉菜胶 注射角叉菜胶 几何平均值
3小时后(mg/kg) 4小时后(mg/kg) (mg/kg)
chlortenoxicam 3.01 3.03 3.02
的烯醇醚
chlortenoxicam n.r n.r n.r
炎痛喜康 n.r n.r n.r
炎痛喜康 n.r n.r n.r
的烯醇醚
n.r:未能达到80%的抑制率。
50% IHD值
被测物质 注射角叉菜胶 注射角叉菜胶 几何平均值
3小时后(mg/kg) 4小时后(mg/kg) (mg/kg)
chlortenoxicam 0.23 0.36 0.29
的烯醇醚
chlortenoxicam 0.35 0.60 0.46
炎痛喜康 3.88 5.06 4.43
炎痛喜康 大于10 大于10 大于10
的烯醇醚
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT285587 | 1987-10-29 | ||
ATA2855/87 | 1987-10-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1033809A CN1033809A (zh) | 1989-07-12 |
CN1019577B true CN1019577B (zh) | 1992-12-23 |
Family
ID=3541372
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN88107381A Expired CN1019577B (zh) | 1987-10-29 | 1988-10-27 | 6-氯-4-羟基-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1,1-二氧化物烯醇醚类化合物制备方法 |
Country Status (25)
Country | Link |
---|---|
US (1) | US4927821A (zh) |
EP (1) | EP0313935B1 (zh) |
JP (1) | JP2588598B2 (zh) |
KR (1) | KR970011395B1 (zh) |
CN (1) | CN1019577B (zh) |
AT (1) | ATE109152T1 (zh) |
AU (1) | AU613416B2 (zh) |
CA (1) | CA1314883C (zh) |
CZ (1) | CZ278281B6 (zh) |
DD (1) | DD275689A5 (zh) |
DE (1) | DE3850845D1 (zh) |
DK (1) | DK168384B1 (zh) |
ES (1) | ES2056868T3 (zh) |
FI (1) | FI86855C (zh) |
HU (1) | HU201082B (zh) |
IL (1) | IL87951A (zh) |
MY (1) | MY103782A (zh) |
NO (1) | NO174928C (zh) |
NZ (1) | NZ226477A (zh) |
PL (1) | PL150950B1 (zh) |
SK (1) | SK695188A3 (zh) |
SU (1) | SU1591813A3 (zh) |
UA (1) | UA5916A1 (zh) |
YU (1) | YU48037B (zh) |
ZA (1) | ZA887731B (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT399880B (de) * | 1992-07-03 | 1995-08-25 | Chem Pharm Forsch Gmbh | Neue thienothiazinderivate, verfahren zu ihrer herstellung und ihre verwendung |
EP0658559A1 (de) * | 1993-12-14 | 1995-06-21 | Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. | Thienothiazinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als 5-dipoxygenase und Cyclooxygenaseinhibitoren |
DE4400867A1 (de) * | 1994-01-14 | 1995-07-20 | Nycomed Arzneimittel Gmbh | Neue Thienothiazinderivate, ein Verfahren zu ihrer Herstellung und ihre Verwendung |
US5538966A (en) * | 1994-01-21 | 1996-07-23 | Alcon Laboratories, Inc. | Carbonic anhydrase inhibitors |
US6254057B1 (en) * | 1998-10-22 | 2001-07-03 | Integra Dynamics Inc. | Valve control system |
AT413944B (de) | 2003-05-27 | 2006-07-15 | Binder Eva Dkfm | Verwendung von oxicam-verbindungen |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU518216B2 (en) * | 1977-09-06 | 1981-09-17 | Hafslund Nycomed Pharma Aktiengesellschaft | Thienothiazine derivatives |
EP0103142B1 (de) * | 1982-09-09 | 1987-04-22 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Thieno(2,3-e)-1,2-thiazin-Derivate |
US4551452A (en) * | 1983-12-21 | 1985-11-05 | Pfizer Inc. | Anti-inflammatory 2-methyl-2H-1,2-benzo-(or -thieno-)thiazine-3-carboxamide 1,1-dioxide derivatives, compositions, and method of use therefor |
-
1988
- 1988-10-06 NZ NZ226477A patent/NZ226477A/xx unknown
- 1988-10-06 IL IL87951A patent/IL87951A/xx not_active IP Right Cessation
- 1988-10-12 MY MYPI88001131A patent/MY103782A/en unknown
- 1988-10-12 NO NO884543A patent/NO174928C/no unknown
- 1988-10-13 CA CA000580051A patent/CA1314883C/en not_active Expired - Fee Related
- 1988-10-14 AT AT88117090T patent/ATE109152T1/de not_active IP Right Cessation
- 1988-10-14 DE DE3850845T patent/DE3850845D1/de not_active Expired - Fee Related
- 1988-10-14 EP EP88117090A patent/EP0313935B1/de not_active Expired - Lifetime
- 1988-10-14 ES ES88117090T patent/ES2056868T3/es not_active Expired - Lifetime
- 1988-10-17 ZA ZA887731A patent/ZA887731B/xx unknown
- 1988-10-18 US US07/262,499 patent/US4927821A/en not_active Expired - Fee Related
- 1988-10-20 SK SK6951-88A patent/SK695188A3/sk unknown
- 1988-10-20 CZ CS886951A patent/CZ278281B6/cs unknown
- 1988-10-25 YU YU199288A patent/YU48037B/sh unknown
- 1988-10-27 PL PL1988275523A patent/PL150950B1/pl unknown
- 1988-10-27 AU AU24403/88A patent/AU613416B2/en not_active Ceased
- 1988-10-27 KR KR1019880014013A patent/KR970011395B1/ko active IP Right Grant
- 1988-10-27 CN CN88107381A patent/CN1019577B/zh not_active Expired
- 1988-10-27 DD DD88321145A patent/DD275689A5/de not_active IP Right Cessation
- 1988-10-28 SU SU884356752A patent/SU1591813A3/ru active
- 1988-10-28 FI FI884976A patent/FI86855C/fi not_active IP Right Cessation
- 1988-10-28 JP JP63271064A patent/JP2588598B2/ja not_active Expired - Lifetime
- 1988-10-28 DK DK600188A patent/DK168384B1/da not_active Application Discontinuation
- 1988-10-28 HU HU885638A patent/HU201082B/hu not_active IP Right Cessation
- 1988-10-28 UA UA4356752A patent/UA5916A1/uk unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH054983A (ja) | イソキノリノン誘導体、その製造方法およびその誘導体を有効成分として含有する5−ht3 レセプター拮抗剤 | |
JPH06135963A (ja) | 置換ベンジルアミノキヌクリジン | |
CN1007352B (zh) | 新的4h-1-苯并吡喃-4-酮的生产方法 | |
CA1053672A (en) | 1,1-diaryl-1-oxadiazol-alkylamines | |
GB2101589A (en) | Crystalline benzothiazine dioxide salts. | |
GB2243832A (en) | 2-substituted 4-acetamido-5-chloro-n-[2-(diethylamino)ethyl]-benzamide derivative | |
IE44639B1 (en) | Oxadiazoloyl-substituted compounds having pharmacological activity | |
CH649995A5 (de) | Piperazinderivate, verfahren zu ihrer herstellung und arzneimittel, die diese verbindungen enthalten. | |
CN1019577B (zh) | 6-氯-4-羟基-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1,1-二氧化物烯醇醚类化合物制备方法 | |
WO1988007858A1 (en) | Sulfinyl and sulfonyl substituted 3-benzazepines | |
JPS6126996B2 (zh) | ||
US5049637A (en) | 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino-[1,2-a]azepino derivatives and 10-aza, 10-oxa and 10-thia analogues | |
JP2610718B2 (ja) | N−置換トリフルオロメチルフェニルテトラヒドロピリジンおよびこれを含む薬剤組成物 | |
CN1024798C (zh) | 制备新的碱性基取代的5-卤代-噻吩并异噻唑-3(2h)-酮1,1-二氧化物的方法 | |
CN1034122C (zh) | 新的抗病毒四氢咪唑并苯并二氮杂䓬(硫)酮的制备方法 | |
CS228930B2 (cs) | Způsob výroby krystalických, nehygroskopických, ve vodě rozpustných solí N- (2-pyridyl) -2-methyl-4-hydroxy-2H-l,2-benzothiazin-3- -karboxamid-l,l-dioxidu | |
JPH0344051B2 (zh) | ||
DE2239311A1 (de) | 2-amino-(4,5 b)-oxazolpyridin und derivate | |
US3243443A (en) | m-sulfamidobenzylidene-3, 3-bis-4-hydroxycoumarions | |
US3503957A (en) | 6-aminoalkyl morphanthridine derivatives | |
US4355041A (en) | 4,5-Bis-(4-fluorophenyl)-1-(4-nitrobenzyl)-2-[((1,1,2,2-tetrafluoroethyl)sulfonyl]-1H-imidazole, composition and use | |
HU214591B (hu) | Eljárás egy naftoxazinszármazék malonátsójának és az ilyen hatóanyagot tartalmazó gyógyszerkészítmények előállítására | |
EP0172526A1 (de) | Neue Benzodiazepine, Verfahren zu ihrer Herstellung sowie ihre Verwendung | |
JPH01272575A (ja) | ナフトチアゼピノン類 | |
CN1035765C (zh) | 六氢化-8-羟基-2,6-亚甲基-2h-喹嗪-3(4h)-酯的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C53 | Correction of patent of invention or patent application | ||
CB02 | Change of applicant information |
Applicant after: Chemisch Pharmazeutische Forschungsgesellschaft m.b.H Applicant before: Farmar CL company |
|
COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: CL WEIGHTS CO., LTD. TO: CHEMICAL PHARMACY RESEARCH INC. |
|
C13 | Decision | ||
GR02 | Examined patent application | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |