CN86104968A - 强心的杂环羰基及乙酰基噻唑酮类化合物 - Google Patents
强心的杂环羰基及乙酰基噻唑酮类化合物 Download PDFInfo
- Publication number
- CN86104968A CN86104968A CN86104968.3A CN86104968A CN86104968A CN 86104968 A CN86104968 A CN 86104968A CN 86104968 A CN86104968 A CN 86104968A CN 86104968 A CN86104968 A CN 86104968A
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- CN
- China
- Prior art keywords
- pyridyl
- formula
- compound
- alkyl
- thiazolone
- 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
- LEEUKHWEVYTBMO-UHFFFAOYSA-N 1-(1-oxo-1,3-thiazol-2-yl)ethanone Chemical class CC(=O)C1=NC=CS1=O LEEUKHWEVYTBMO-UHFFFAOYSA-N 0.000 title abstract 2
- 230000003177 cardiotonic effect Effects 0.000 title description 7
- -1 Heterocyclic carbonylthiazolones Chemical class 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- IHDKBHLTKNUCCW-UHFFFAOYSA-N 1,3-thiazole 1-oxide Chemical compound O=S1C=CN=C1 IHDKBHLTKNUCCW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 229910052801 chlorine Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
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- MOMFXATYAINJML-UHFFFAOYSA-N acetylthiazole Natural products CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
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- 238000002360 preparation method Methods 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
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- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- ZMEVDFFLOPFGCR-UHFFFAOYSA-N 4-methyl-3h-1,3-thiazol-2-one Chemical compound CC1=CSC(O)=N1 ZMEVDFFLOPFGCR-UHFFFAOYSA-N 0.000 description 2
- ZCILURHURNEWKZ-UHFFFAOYSA-N 4-methyl-5-(pyridine-4-carbonyl)-3h-1,3-thiazol-2-one Chemical compound N1C(=O)SC(C(=O)C=2C=CN=CC=2)=C1C ZCILURHURNEWKZ-UHFFFAOYSA-N 0.000 description 2
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- 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- LWBPNIJBHRISSS-UHFFFAOYSA-L beryllium dichloride Chemical compound Cl[Be]Cl LWBPNIJBHRISSS-UHFFFAOYSA-L 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
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- QYIPLRSOBRETNC-UHFFFAOYSA-N 4-ethyl-5-(2-pyridin-2-ylacetyl)-3h-1,3-thiazol-2-one Chemical compound N1C(=O)SC(C(=O)CC=2N=CC=CC=2)=C1CC QYIPLRSOBRETNC-UHFFFAOYSA-N 0.000 description 1
- DUHNAPTUHOLVKQ-UHFFFAOYSA-N 4-ethyl-5-(pyridine-3-carbonyl)-3h-1,3-thiazol-2-one Chemical compound N1C(=O)SC(C(=O)C=2C=NC=CC=2)=C1CC DUHNAPTUHOLVKQ-UHFFFAOYSA-N 0.000 description 1
- KFZLJUUBLYEBNA-UHFFFAOYSA-N 4-methyl-5-(2-thiophen-2-ylacetyl)-3h-1,3-thiazol-2-one Chemical compound N1C(=O)SC(C(=O)CC=2SC=CC=2)=C1C KFZLJUUBLYEBNA-UHFFFAOYSA-N 0.000 description 1
- DSRFGNOSKLFSPF-UHFFFAOYSA-N 4-methyl-5-(pyridine-3-carbonyl)-3h-1,3-thiazol-2-one Chemical compound N1C(=O)SC(C(=O)C=2C=NC=CC=2)=C1C DSRFGNOSKLFSPF-UHFFFAOYSA-N 0.000 description 1
- MATDFQJFNOQQAT-UHFFFAOYSA-N 5-(furan-2-carbonyl)-4-methyl-3h-1,3-thiazol-2-one Chemical compound N1C(=O)SC(C(=O)C=2OC=CC=2)=C1C MATDFQJFNOQQAT-UHFFFAOYSA-N 0.000 description 1
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Abstract
杂环羰基噻唑酮和乙酰噻唑酮类化合物可增强心肌收缩力并在治疗心力衰竭中用作强心剂。
Description
本发明是关于某些杂环羰基和乙酰基噻唑酮类化合物、它们在治疗心力衰竭时用作强心剂的用途以及它们的增强心肌收缩力能力。
心力衰竭是由于心室心肌不能使周身组织保持足够的血流而产生的生理状态,包括充血性心力衰竭、后向性和前向性心力衰竭、右心室和左心室的心力衰竭以及高输出量和低输出量的心力衰竭。心力衰竭可由心肌缺血、心肌梗塞形成,过量服用酒精、肺栓塞、感染、贫血、心律失常及系统性高血压病引起。症状包括心动过速、疲倦、呼吸困难、端坐呼吸及肺水肿。
治疗方法包括去除和制止潜在的原因,或者是控制心力衰竭状态。可用增加心脏输出量或减轻心脏负担的办法处理或控制。传统上是在通过减少身体的活动以及使身体和精神得到休息减轻心脏负担的同时,用毛地黄药物治疗来增加心脏输出量。毛地黄促进心脏收缩力,后者使心脏的输出量增加并改善心室的排空。按这种方法,进行毛地黄治疗可使静脉血压正常,并减小周围血管收缩、循环性充血及器官环流的减慢。
不幸的是,毛地黄的最适宜剂量是随病人的年龄、身材及情况而变,治疗与中毒的比例十分狭窄。在大多数病人中致死剂量仅约为最小有效剂量的5至10倍,在仅为有效剂量的1.5-2.0倍时就有明显的毒性。由于这些原因,必须小心地确定适合于个人的剂量,还需经常作临床检查和心电图来监测毛地黄中毒的早期征兆。尽管这样小心,据报道仍有高达五分之一的住院治疗的病人有毛地黄中毒。
很明显需要有较小毒性的强心剂。申请人已发现某些噻唑酮类化合物具有很强的强心活性,与毛地黄相比毒性较小。
本发明的目的是获得药物活性的式Ⅰ杂环羰基及乙酰噻唑酮类化合物,
式中R1为一氢或(C1-C4)烷基,R2是被以下基团中的一个任意取代的吡啶基或吡啶甲基,这些基团有(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷硫基、(C1-C4)烷基亚磷酰基、(C1-C4)烷基磺酰基、羧基、(C1-C4)烷氧基羰基、卤素、三氟甲基及氰基,或R2为一呋喃基、呋喃甲基、噻吩基或噻吩甲基。
式Ⅰ化合物能增强心肌收缩力,在治疗心力衰竭时可用作强心剂。
式Ⅰ化合物在结构上象式2所示以两种互变异构形式存在,
式中R1和R2的含义如前所述。在本发明公开的全部内容中,式1的杂环羰基噻唑酮或乙酰噻唑酮包括式2的互变异构体。
式1化合物的环氮可被(C1-C4)烷基、诸如酰基的链烷酰基或苯甲酰基取代。这些氮取代了的化合物相当于原来未取代的化合物,这是因为取代基在病人用药后即断裂,但也因为许多氮取代的化合物独立地具有明显的增强心肌收缩力的能力并且是有用的强心剂。
本文中所用的术语(C1-C4)烷基以及烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基及烷氧羰基诸基团中的烷基部分是指含1-4个碳原子的直链或支链烷基。(C1-C4)烷基的说明实例有:甲基、乙基、异丙基、丁基及仲丁基。卤素一词指氟、氯、溴或碘。
本发明中较好的化合物是那些R1为氢、甲基或乙基的式1化合物。较好的化合物还有R2为任意取代的吡啶基的式1化合物。更好的是R2为一未取代的吡啶基的式1化合物。最好的是R1为一甲基、R2为4-吡啶基的式1化合物。
作为式1的化合物的例子可举出以下几种:
4-甲基-5-(4-吡啶基羰基)-2(3H)-噻唑酮、
4-乙基-5-(3-吡啶基羰基)-2(3H)噻唑酮、
5-〔4-(2-甲基吡啶基)羰基〕-2(3H)-噻唑酮、
4-异丙基-5-(2-呋喃基乙酰基)-2(3H)-噻唑酮、
4-乙基-5-(2-吡啶基乙酰基)-2(3H)-噻唑酮以及
4-丙基-(5-噻吩羰基)-2(3H)-噻唑酮。
式1化合物可按本技术领域技术人员所知道的任一种标准技术方法制备。例如式1化合物可由式3的噻唑酮的傅氏酰化法(Friedel-Crafts acylation)制得,
式中R1的含义如前所述。酰化试剂可以是式4的酰卤,
式中R2如前所述;X是溴或者更好是氯。此外,傅氏反应的酰化剂可以是相当于式4酰卤的游离酸或酸酐。也可以用混合酸酐。本技术领域的技术人员对傅氏反应是很熟悉的,并已由P.H Gore在“Friedel-Crafts and Related Reactions”一书的卷3第一部分中作了综述,该书由G.A.Glah编辑,Interscience Publications于1964年于纽约出版。
傅氏反应这样进行:先将约1摩尔当量适当的式3噻唑酮与约1摩尔当量到约10摩尔当量(最好是约2-3摩尔当量)的路易斯(Lewis)酸催化剂在适宜的溶剂中混合在一起,适宜溶剂例如有石油醚、象1,2,4-三氯苯或邻-二氯苯这样的氯代芳族化合物、二硫化碳、硝基苯或氯代烃(如四氯化碳、氯化乙烯、二氯甲烷、氯仿或更好的是四氯乙烷)。将约1摩尔当量至约10摩尔当量(最好是约1.1摩尔当量)的式4的适宜酰卤加至(最好是滴加)噻唑酮、路易斯酸和溶剂三者的混合物中,然后反应约半小时至约100小时,最好是约1至约10小时,这决定于反应物、溶剂及温度,温度可以是约-78°到约150℃,更好是约60℃到约150℃,最好是约100-120℃。最好蒸去溶剂。所得的杂环噻唑酮或乙酰基噻唑酮可用任何一种适宜的、本技术领域中已知的方法从反应混合物中分出,最好在反应混合物中加入冰水使反应终止,最后通过过滤或萃取并除去溶剂而得到产品,或者在冷的反应混合物中加入盐酸以终止反应,随后过滤收集固体产品。纯化例如可用重结晶法(最好用乙醇重结晶)来完成。
这里所述的傅氏反应中适用的路易斯酸催化剂例如有金属(如铝、铈、铜、铁、钼、钨或锌)、质子酸(Bronsted acid)〔如磷酸、硫酸、磺酸或氢卤酸(如盐酸或氢溴酸)〕、卤乙酸(如氯乙酸或三氟乙酸)或一种金属卤化物(如三卤化硼、二氯化锌、二溴化锌、氯化铍、氯化铜、三溴化铁、三氯化铁、二氯化汞、氯化亚汞、三溴化锑、三氯化锑、四溴化钛、四氯化钛、三氯化钛、三溴化铝或更好是三氯化铝)。
式3的噻唑酮类化合物通常是可以买到的,或按标准的实验室方法可以很容易地制得。例如4-甲基-2(3H)-噻唑酮可按Tcherniac的方法〔见J.Chem.Soc.115,1071(1919)〕,由氯化丙酮和硫氰化钾在有碳酸氢钠水溶液存在时反应制成。
式1化合物是治疗心力衰竭的强心剂。这些化合物也可用于治疗需要加强心肌收缩力的任何其他病症。
式1化合物作为强心剂的效用是通过将混在一种适宜的赋形剂中的试验化合物(0.1-100毫克/公斤)以静脉注射、腹膜内、十二指肠内或胃内的给药方式给予杂种狗(雌雄皆可)来测定的。先把试验狗麻醉并分离出合适的动脉〔例如股动脉(femoralcarotid)或普通颈动脉〕和静脉〔例如股静脉(femoral jugular)或外颈静脉〕,插入充有0.1%肝素钠的聚乙烯导管以分别记录动脉血压和药用的化合物。可用在中线上分开胸骨或在左边第五肋间窝处切开的办法打开胸腔。在心脏旁放一支架以支持心脏。在左心室或右心室缝合一Walton-Brodie应力表以监测心肌收缩力。可在升主动脉的根旁放一电磁流量探子以测量心脏输出的较小的冠状血流。心力衰竭是由服用戊巴比妥纳(20-40毫克/公斤)之后再向注入心脏的血中连续输注0.25-2毫克/公斤/分钟的药,或服用心得安盐酸盐(4毫克/公斤)之后再连续输注0.18毫克/公斤/分钟的药而引起的。在这两种心脏抑制剂中的任一种给药后,右心室压显著增加,而心输出量严重降低。由试验化合物引起这些结果的逆转表明了它的强心活性。
化合物可以各种方式给药以达到预期效果。对接受治疗的患者可以使用纯化合物或以其药物制剂形式给药。可局部用药、口服或非口服,亦即静脉给药或肌内给药。化合物的给药量将随病人心力衰竭的严重程度及用药方式不同而不同。
对于局部用药、口服或非口服用药,化合物的强心有效量和需要加强心肌收缩力的量为每日约0.1-约400毫克/公斤体重,最好是每日约0.3-约120毫克/公斤体重。
对于口服用药,一单位剂量例如可含有活性成分5-700毫克,更好的是15-235毫克。对于非口服用药,一单位剂量可含有活性成分5-700毫克,更好的是15-210毫克。可以每日重复服用这些化合物,服量将随病人的情况和用药方式而改变。
本文所用“患者”一词是指热血动物,例如禽类象小鸡和火鸡,以及哺乳动物,诸如羊、马、母牛和公牛、猪、狗、猫、鼠及包括人在内的灵长类。
对于口服用药,可把化合物配制成固体或液体制剂,诸如胶囊、丸剂、片剂、锭剂、粉剂、溶液、混悬液或乳液。固体单位剂型可以是胶囊,这种胶囊可以是普通药用明胶型,其中含有例如润滑剂及象乳糖、蔗糖或玉米淀粉这样的惰性填料。在其他实施方案中,通式1的化合物可以同传统的片基与粘合剂、崩解剂以及润滑剂一起制成片剂,片基例如有乳糖、蔗糖或玉米淀粉,粘合剂如阿拉伯树胶、玉米淀粉或药用胶,崩解剂例如有马铃薯或藻朊酸,润滑剂例如有硬脂酸或硬脂酸镁。
对于非口服用药,可将化合物制成注射剂,即化合物在含有药物载体的生理上可接受的稀释剂中的溶液或混悬液进行给药,药物载体可以是消过毒的液体,象水、醇类、油类及其它可以接受的有机溶剂,其中可以加也可不加表面活性剂及其它药物学上可接受的辅药。这些制剂中可以使用的油类的例子有:石油、动物油、植物油或合成油,例如花生油、豆油及矿物油。通常,水、食盐水、葡萄糖水溶液及类似的糖溶液,乙醇及二醇类象丙二醇、聚乙二醇或2-吡咯烷酮是较好的液体载体,尤其是用于注射液。
以下的具体例子可进一步说明式1化合物的制备和使用,但并非有意限制本发明的范围。
实施例1
4-甲基-5-(4-吡啶基羰基)-2(3H)-噻唑酮
将二氯甲烷(100毫升)、4-甲基-2(3H)-噻唑酮(11.5克,0.1摩尔)及三氯化铝(39.9克,0.3摩尔)的混合物在室温下搅拌20分钟。将异菸酰氯(12.5克,0.1摩尔)溶于二氯甲烷(50毫升)并经10分钟逐滴加入,随后蒸去溶剂。反应混合物于115℃热3小时,然后放冷并加入水。加入碳酸氢钠水溶液将混合物酸度调至PH=6。滤去固体铝盐后蒸去溶剂。残余物在硅胶上进行层析,然后以甲醇重结晶,得到纯的标题化合物,熔点255-257℃。
以同样方法但以菸酰氯、呋喃甲酰氯或2-噻吩乙酰氯代替以上实施例中的异菸酰氯,可制得:
4-甲基-5-(3-吡啶基羰基)-2(3H)-噻唑酮、
4-甲基-5-(2-呋喃甲酰)-2(3H)-噻唑酮或
4-甲基-5-(2-噻吩乙酰基)-2(3H)-噻唑酮。
实施例2
一种片剂制自
4-甲基-5-(4-吡啶基羰基)-2(3H)-噻唑酮250毫克
淀粉 40毫克
滑石 10毫克
硬脂酸镁 10毫克
实施例3
一种胶囊制自
4-乙基-5-(3-呋喃乙酰基)-2(3H)-噻唑酮400毫克
滑石 40毫克
羧甲基纤维素钠 40毫克
淀粉 120毫克
Claims (7)
1、一种制备下式的噻唑酮的方法,
其中R1为氢或(C1-C4)烷基,R2为一被以下基团之一任意取代的吡啶基或吡啶甲基,这些基团有(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、羧基、(C1-C4)烷氧基羰基、卤素、三氟甲基以及氰基,或者R2为一呋喃基、呋喃甲基、噻吩基或噻吩甲基,该方法包括将1-10摩尔当量的下式的酰卤加至一混合物内,式中R2的含义如上所述,
式中X为溴或氯,所述混合物主要由1至10摩尔当量的路易斯(Lewis)酸催化剂,下式的化合物(式中R1的含义如上所述)和一
种合适的溶剂所构成,让反应在约60至150℃间进行1-10小时并分离出产品。
2、根据权利要求1的一种方法,其中R1为氢、甲基或乙基。
3、根据权利要求1的一种方法,其中R2为一吡啶基或取代的吡啶基。
4、根据权利要求2的一种方法,其中R2为一吡啶基或取代的吡啶基。
5、根据权利要求1的一种方法,其中R2为一4-吡啶基。
6、根据权利要求2的一种方法,其中R2为一4-吡啶基。
7、根据权利要求1的一种方法,其中R1为一甲基,R2为一4-吡啶基。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US787,225 | 1985-10-15 | ||
US06/787,225 US4623651A (en) | 1985-10-15 | 1985-10-15 | Cardiotonic heterocyclocarbonyl- and acetyl-thiazolones |
Publications (2)
Publication Number | Publication Date |
---|---|
CN86104968A true CN86104968A (zh) | 1987-04-22 |
CN1020730C CN1020730C (zh) | 1993-05-19 |
Family
ID=25140796
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86104968A Expired - Fee Related CN1020730C (zh) | 1985-10-15 | 1986-08-02 | 制备新的噻唑酮衍生物的方法 |
Country Status (21)
Country | Link |
---|---|
US (1) | US4623651A (zh) |
EP (1) | EP0219625B1 (zh) |
JP (1) | JPS6287586A (zh) |
KR (1) | KR890005203B1 (zh) |
CN (1) | CN1020730C (zh) |
AR (1) | AR243887A1 (zh) |
AT (1) | ATE48275T1 (zh) |
AU (1) | AU588900B2 (zh) |
CA (1) | CA1287833C (zh) |
DE (1) | DE3667175D1 (zh) |
DK (1) | DK368986A (zh) |
ES (1) | ES2000594A6 (zh) |
FI (1) | FI863159A (zh) |
GR (1) | GR862045B (zh) |
HU (1) | HU197004B (zh) |
IL (1) | IL79343A0 (zh) |
NO (1) | NO863113L (zh) |
NZ (1) | NZ217068A (zh) |
PH (1) | PH22193A (zh) |
PT (1) | PT83137B (zh) |
ZA (1) | ZA865839B (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4927939A (en) * | 1985-10-15 | 1990-05-22 | Merrell Dow Pharmaceuticals | Cardiotonic aroylthiazolones |
US4734422A (en) * | 1985-10-15 | 1988-03-29 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic aroylthiazolones and the use thereof |
US4762849A (en) * | 1985-10-15 | 1988-08-09 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic alkanoylthiazolones |
US4670450A (en) * | 1985-11-13 | 1987-06-02 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic thiazolones |
US4868182A (en) * | 1986-11-05 | 1989-09-19 | Merrell Dow Pharmaceuticals Inc. | Enhancement of prazosin |
US4866182A (en) * | 1988-02-18 | 1989-09-12 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic alkanoyl and aroyl oxazolones |
US5095028A (en) * | 1988-01-14 | 1992-03-10 | Kureha Kagaku Kogyo Kabushiki Kaisha | 2-(4-chlorobenzyl)-1-(1H-imidazole-1-ylmethyl)-1-cyclohexanol and cycloheptanol |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3514465A (en) * | 1966-12-30 | 1970-05-26 | Degussa | Certain thiazolyl- and pyridinylaminoketones |
FR2209560A1 (en) * | 1972-12-07 | 1974-07-05 | Degussa | N-(Trialkoxyaroyl)-ethylenediamine derivs - useful as cardioactive medicaments, exhibit anti-ischaemic activity comparable to nitroglycerin |
-
1985
- 1985-10-15 US US06/787,225 patent/US4623651A/en not_active Expired - Lifetime
-
1986
- 1986-07-04 IL IL79343A patent/IL79343A0/xx not_active IP Right Cessation
- 1986-07-28 JP JP61175848A patent/JPS6287586A/ja active Pending
- 1986-07-28 CA CA000514804A patent/CA1287833C/en not_active Expired - Lifetime
- 1986-07-29 EP EP86110452A patent/EP0219625B1/en not_active Expired
- 1986-07-29 AT AT86110452T patent/ATE48275T1/de active
- 1986-07-29 DE DE8686110452T patent/DE3667175D1/de not_active Expired - Fee Related
- 1986-08-01 GR GR862045A patent/GR862045B/el unknown
- 1986-08-01 DK DK368986A patent/DK368986A/da not_active Application Discontinuation
- 1986-08-01 AR AR86304762A patent/AR243887A1/es active
- 1986-08-01 KR KR1019860006365A patent/KR890005203B1/ko not_active IP Right Cessation
- 1986-08-01 NO NO863113A patent/NO863113L/no unknown
- 1986-08-01 FI FI863159A patent/FI863159A/fi not_active Application Discontinuation
- 1986-08-01 HU HU863356A patent/HU197004B/hu not_active IP Right Cessation
- 1986-08-01 NZ NZ217068A patent/NZ217068A/xx unknown
- 1986-08-02 CN CN86104968A patent/CN1020730C/zh not_active Expired - Fee Related
- 1986-08-04 ES ES8600851A patent/ES2000594A6/es not_active Expired
- 1986-08-04 PH PH34106A patent/PH22193A/en unknown
- 1986-08-04 ZA ZA865839A patent/ZA865839B/xx unknown
- 1986-08-04 AU AU60842/86A patent/AU588900B2/en not_active Ceased
- 1986-08-04 PT PT83137A patent/PT83137B/pt not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
PH22193A (en) | 1988-06-28 |
DE3667175D1 (de) | 1990-01-04 |
GR862045B (en) | 1986-12-24 |
JPS6287586A (ja) | 1987-04-22 |
DK368986A (da) | 1987-04-16 |
ATE48275T1 (de) | 1989-12-15 |
NO863113D0 (no) | 1986-08-01 |
CN1020730C (zh) | 1993-05-19 |
DK368986D0 (da) | 1986-08-01 |
NZ217068A (en) | 1989-01-27 |
AR243887A1 (es) | 1993-09-30 |
NO863113L (no) | 1987-04-21 |
ES2000594A6 (es) | 1988-03-01 |
PT83137B (pt) | 1988-07-29 |
ZA865839B (en) | 1987-03-25 |
AU6084286A (en) | 1987-04-16 |
KR870004025A (ko) | 1987-05-07 |
KR890005203B1 (ko) | 1989-12-18 |
EP0219625A1 (en) | 1987-04-29 |
PT83137A (en) | 1986-09-01 |
IL79343A0 (en) | 1986-10-31 |
EP0219625B1 (en) | 1989-11-29 |
CA1287833C (en) | 1991-08-20 |
AU588900B2 (en) | 1989-09-28 |
HUT44785A (en) | 1988-04-28 |
HU197004B (en) | 1989-02-28 |
FI863159A (fi) | 1987-04-16 |
US4623651A (en) | 1986-11-18 |
FI863159A0 (fi) | 1986-08-01 |
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