CN1040324C - 新的噻唑烷二酮及含有这些化合物的药剂 - Google Patents
新的噻唑烷二酮及含有这些化合物的药剂 Download PDFInfo
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- CN1040324C CN1040324C CN94192240A CN94192240A CN1040324C CN 1040324 C CN1040324 C CN 1040324C CN 94192240 A CN94192240 A CN 94192240A CN 94192240 A CN94192240 A CN 94192240A CN 1040324 C CN1040324 C CN 1040324C
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- Prior art keywords
- compound
- formula
- phenyl
- methyl
- thiazolidinedione
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- 239000003814 drug Substances 0.000 title claims abstract description 7
- 150000001467 thiazolidinediones Chemical class 0.000 title claims 2
- 229940079593 drug Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 6
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 6
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 17
- 229910052721 tungsten Inorganic materials 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
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- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 claims 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 8
- 125000005842 heteroatom Chemical group 0.000 abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 5
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Abstract
式Ⅰ化合物及其互变异构体、对映体和非对映体，生理上可接受的盐：
式中：
A表示含有5个或6个碳原子的碳环，或者杂原子数最多为4的杂环，这些杂原子可以相同或者不同，代表氧、氮或硫，如果需要，杂环的一个或几个氮原子上可带有氧原子，
B表示-CH＝CH-、-N＝CH-、-CH＝N-，O或S，
W表示CH2、O、(CH(OH)、CO或-CH＝CH-，
X表示S、O或NR2，其中的R2基团是氢或C1～C6烷基，
Y是CH或N，
R表示萘基、吡啶基、呋喃基、噻吩基或苯基，如果需要R基团可被C1～C3烷基、CF3、C1～C3烷氧基、F、Cl或Br一取代或二取代，
R1表示氢或C1～C6烷基，和
n等于1～3。
及它们的制备方法，还有含有这些化合物用以治疗糖尿病的药剂。
Description
本发明涉及噻唑烷二酮，它们的制备方法及含有这些化合物的药剂。
本发明涉及通式I的噻唑烷二酮，以及它们的互变异构体、对映体、非对映体和生理上可接受的盐。
式中：A表示含有5个或6个碳原子的碳环，或者杂原子数最多为4的杂环，这些杂原子可以相同或者不同，代表氧、氮或硫，如果需要，杂环的一个或几个氮原子上可带有氧原子，B表示-CH＝CH-、-N＝CH-、-CH＝N-、O或S，W表示CH2、O、CH(OH)、CO或-CH＝CH-，X表示S、O或NR2，其中的R2基团是氢或C1～C6烷基，Y是CH或N，R表示萘基、吡啶基、呋喃基、噻吩基或苯基，如果需要R基团可被C1～C3烷基、CF3、C1～C3烷氧基、F、Cl或Br-取代或二取代，R1表示氢或C1～C6烷基，和n等于1～3。
具备抗糖尿病作用的类似化合物已在现有文献中提及。专利申请US 4,617,312中描述了具有降血糖作用的噻唑烷二酮，其中在噻唑烷二酮的邻位必须有烷氧基。在Chem.Pharm.Bull.，30，3563，1982中记载了5-[4-(2-甲基-2-苯基丙氧基)苄基]噻唑烷-2，4-二酮的合成和它们的抗糖尿病作用。美国专利4,340,605，4,725,610和EP-A-389,699中包括了烷基部分为杂环取代的具有降低血糖作用的4-烷氧基苄基噻唑烷二酮。欧洲专利申请EP-A-332,332也提到了有抗糖尿病作用的苄基噻唑烷二酮，该类化合物可在邻位被各种基团取代。美国专利4,703,052描述了连有二环的抗糖尿病衍生物，但是带有噻唑烷基团的该二环的芳环不带有任何其它的取代基。欧洲专利申请EP-A-283,035和EP-A-299,620中包括了具有抗糖尿病作用的连有苯并噁唑和连有苯并呋喃的噻唑烷二酮。
已经令人惊奇地发现，在同一个环体系内被一个噻唑烷二酮基团和被另一个取代基取代，且另有一个五元或六元芳族环与其稠合的芳环具有有价值的药理学性能。
本发明的化合物特别适用于生产口服治疗糖尿病，尤其是治疗II型或IIb型糖尿病的抗糖尿病药。根据现有知识，做为老年性糖尿病主要原因之一，胰岛素和葡萄糖的使用过程中的损伤在其中起了重要的作用。这种使用过程中的损伤造成了血胰岛素过多，后者被视作大血管病变综合症形成的危险因素。对于肥胖II型糖尿病的调查表明，本发明的物质可用来降低葡萄糖及胰岛素水平。由于其特殊的作用机制，这类物质还具有下述优点：它们不造成低血糖，而且可以降低II型糖尿病患者动脉硬化的危险性，因为这些物质还能降低胰岛素水平。故而它们还适合用于动脉硬化疾病的预防。此外它们还有提高血压和降低甘油三酯和胆固醇水平的积极作用。
环体系A的优选基团是带有5个或6个碳原子的碳环，或者是带有1个或2个杂原子的五元或六元杂环，其中的杂原子是氧、氮或硫，它们可以相同，也可以不同。
优选的B基团是-CH＝CH-、-N＝CH-或-CH＝N-。
优选的W是CH2、O、CH(OH)或CO。
优选的X是S、O或NH。
优选的Y是N。
优选的R基团是萘基、吡啶基、呋喃基、噻吩基或苯基，如果需要，R基团也可以用甲基、CF3、甲氧基、氟、氯或溴一取代或二取代。
特别优选的A基团是带有6个碳原子的芳族碳环，或者是带有一个杂原子的五元或六元芳族杂环，其中的杂原子可以是氧、氮或硫。特别优选的A是苯环或吡啶环。
特别优选的B基团是-CH＝CH-、-N＝CH-和-CH＝N-。
O、CH(OH)和CO被认为是特别优选的W。
特别优选的X是S或O。
特别优选的R基团是吡啶基、呋喃基、噻吩基或苯基，如果需要R基团可被甲基、甲氧基、氟或氯一取代或二取代。此时苯基、甲苯基、甲氧基苯基、氟苯基或氯苯基是特别优选的。
特别优选的R1是氢、甲基或乙基。
n特别优选为2。
为了制成药剂，可将通式I化合物按已知方法与合适的制药载体物质、芳香剂、调味剂和颜料用已知方法混合，并被制成片剂或包衣的片剂，或者将其与其它的附加物质悬浮或溶解在水或如橄榄油的油中。
通式I的物质可以以液体或固体形式口服给药或非肠道给药。优选用水作为注射介质，该介质中含有通常用于注射液中的稳定剂、增溶剂和/或缓冲剂，这些添加剂的例子有：酒石酸盐或硼酸盐缓冲液、乙醇、二甲亚砜、配位剂(如乙二胺四乙酸)、用以调节粘度的分子聚合物(例如液体聚环氧乙烷)或山梨醇酐的聚乙烯衍生物。
固体载体的例子有淀粉、乳糖、甘露糖醇、甲基纤维素、滑石、高分散硅酸、大分子脂肪酸(如硬脂酸)、明胶、琼脂、磷酸钙、硬脂酸镁、动植物脂肪或固体高分子聚合物(如聚乙二醇)。如果需要，合适的口服配方可含有调味剂和甜味剂。
给药剂量依受体的年龄、健康状况和体重、疾病的程度、治疗的类型(这些治疗可能同时进行)、治疗的频率和所需作用的类型而定。活性化合物的日剂量通常为0.1～50mg/kg体重。为了取得所需的效果，以每天一次或几次的形式按0.5～40mg/kg/天，优选1.0-20mg/kg/天的剂量使用是有效的。
本发明的通式I化合物按照文献中已知的方法制备(J.Med.Chem.35，1835，1992 J.Med.Chem.35，2617，1992，Chem.Pharm.Bull.30，3580，1982，Chem.Pharm.Bull 30，3563，1982)，其中a)使通式II化合物与噻唑烷二酮反应
(式中A、B、W、X、Y、R、R1和n的含义同上)生成通式III化合物：(式中A、B、W、X、Y、R、R1和n的含义与上相同)，随后通过还原双键制得通式I的化合物，或b)使通式IV化合物与NaNO2在丙烯酸酯和HCl或HBr存在下反应(式中A、B、W、X、Y、R、R1和n的含义与上相同)生成通式V化合物(式中A、B、W、X、Y、R、R1和n的含义与上相同)，Hal代表氯或溴，R3表示C1～C6烷基；随后使通式V化合物与硫脲成环制得通式VI化合物
(式中A、B、W、X、Y、R、R1和n的含义与上相同)，通过用酸处理将其转化为通式I化合物。
通式II化合物与噻唑烷二酮的反应可在极性和非极性溶剂中进行。如果需要，可在-40℃至所选溶剂的沸点之间的温度下向溶剂中加入如乙酸钠或三乙胺的辅助碱。随后的通式III化合物的还原优选与氢在金属催化剂如Pt或Pd存在下进行，或于-20℃至溶剂沸点之间的温度下在惰性溶剂中通过均相催化进行。如果需要，也可以通过增加压力来促进催化加氢。
通式IV化合物向通式V化合物的转换优选在如盐酸和氢溴酸的酸的存在下，于含有NaNO2的含水溶剂中进行，其中做为中间体形成的重氮盐与丙烯酸酯衍生物反应，如果需要，可再加入Cu(I)盐。
可在质子溶剂中，于-20℃至该溶剂的沸点之间的温度下用脲便利地将这些卤代羧酸酯转化为通式VI的化合物，如果需要可再加入如乙酸钠或NEt3的辅助性碱。可使用如盐酸的酸或如氢氧化钠的碱将上述化合物水解制得通式I化合物，水解优选在需要时可加热的质子溶剂中进行。
可使用外消旋物拆分(与旋光活性的酸或碱形成的盐)或在合成中使用旋光活性的起始物料来制备式I化合物的纯的对映体。
除了实施例中提到的化合物和权利要求书中提到的所有取代基组合(所对应的)化合物之外，下述式I化合物也在本发明范围之内，这些化合物可以以外消旋混合物形式或者以如纯R和S对映体的旋光活性形式存在：1. 5-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-1-萘甲基]-2，4-噻唑烷二酮2. 5-[7-[2-(5-甲基-2-萘基-4-噁唑基)乙氧基]-4-吲哚基甲基]-2，4-噻唑烷二酮3. 5-[7-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-4-
苯并呋喃基甲基]-2，4-噻唑烷二酮4. 5-[7-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-4-苯并噻吩基甲基]-2，4-噻唑烷二酮5. 5-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-7-吲哚基甲基]-2，4-噻唑烷二酮6. 5-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-7-
苯并呋喃基甲基]-2，4-噻唑烷二酮7. 5-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-7-苯并噻吩基甲基]-2，4-噻唑烷二酮8. 5-[8-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-5-喹啉基甲基]-2，4-噻唑烷二酮9. 5-[8-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-5-异喹啉基甲基]-2，4-噻唑烷二酮10. 5-[5-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-8-
异喹啉基甲基]-2，4-噻唑烷二酮11. 5-[5-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-8-
喹啉基甲基]-2，4-噻唑烷二酮12. 5-[1-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-4-
异喹啉基甲基]-2，4-噻唑烷二酮13. 5-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-1-
异喹啉基甲基]-2，4-噻唑烷二酮14. 5-[4-[2-(5-甲基-2-(4-甲基苯基)-4-噁唑基)乙
氧基]-1-萘甲基]-2，4-噻唑烷二酮15. 5-[4-[2-(5-甲基-2-(2-噻吩基)-4-噁唑基)乙氧
基]-1-萘甲基]-2，4-噻唑烷二酮16. 5-[4-[2-[5-甲基-2-(4-吡啶基)-4-噁唑基)乙氧
基]-1-萘甲基]-2，4-噻唑烷二酮17. 5-[4-(5-甲基-2-苯基-4-噁唑基)甲氧基]-1-萘甲
基]-2，4-噻唑烷二酮18. 5-[4-[3-(5-甲基-2-苯基-4-噁唑基)丙酰基]-1-
萘甲基]-2，4-噻唑烷二酮19. 5-[4-[3-(5-甲基-2-苯基-4-噁唑基)-1-羟基丙
基]-1-萘甲基]-2，4-噻唑烷二酮20. 5-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙酰基]-1-
萘甲基]-2，4-噻唑烷二酮21. 5-[4-[2-(5-甲基-2-苯基-4-噻唑基)乙氧基]-1-
萘甲基]-2，4-噻唑烷二酮22. 5-[4-[2-(5-甲基-2-苯基-4-咪唑基)乙氧基]-1-
萘甲基]-2，4-噻唑烷二酮实施例15-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-1-萘甲基]-2，4-噻唑烷二酮a)将8.6g(0.05mol)4-羟基萘-1-醛，13.07g(0.05mol)5-甲基-2-苯基-4-(2-溴乙基)噁唑和3.4g(0.05mol)NaOEt在100ml乙醇中回流加热16小时。随后进行蒸发浓缩，残余物溶于CH2Cl2中，干燥并浓缩。用异丙醇结晶得到5.2g 4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]萘-1-醛，熔点：130～133℃。b)将5.07g(0.014mol)前述化合物，3.87g(0.042mol)噻唑烷二酮和0.28ml哌啶于150ml乙醇中回流8小时。冷却后吸滤分出沉淀，乙醚洗涤，再与50ml乙酸乙酯快速加热至50℃，加入100ml乙醚后再次吸滤，并用乙醚洗涤残余物，得到3.28g 5-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]萘基]亚甲基]-2，4-噻唑烷二酮，熔点：248-250℃。c)将456mg前述化合物于50℃，6bar及200mg Pd/C(10％)存在下在40ml THF中催化加氢36小时。分出催化剂并蒸去溶剂后用乙醇结晶，得到265mg标题化合物，熔点：188-191℃。实施例2a)用5-甲基-2-(4-吡啶基-4-(2-溴乙基))噁唑为起始物料，仿照实施例1制得标题化合物5-[4-[2-(5-甲基-2-(4-吡啶基)-4-噁唑基]乙氧基]-1-萘甲基]-2，4-噻唑烷二酮，熔点238℃(分解温度)。b)用5-甲基-2-(2-噻吩基)-4-(2-溴乙基))噁唑为起始物料，仿照实施例1制得标题化合物5-[4-[2-(5-甲基-2-(2-噻吩基)-4-噁唑基]乙氧基]-1-萘甲基]-2，4-噻唑烷二酮，熔点159～162℃。实施例35-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-7-苯并噻吩甲基]-2，4-噻唑烷二酮a)将5.15g(0.034mol)4-羟基苯并噻吩溶于130ml甲乙酮中，并与9.4g(0.068mol)K2CO3和20g(0.068mol)5-甲基-2-苯基-4-(2-溴乙基)噁唑混合。将反应物回流沸腾72小时，蒸发、溶于乙酸乙酯中并用2N NaOH振摇萃取三次。冷却和蒸去有机相之后用乙酸乙酯/异己烷结晶，得到8.8g 4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]苯并噻吩，熔点130-132℃。b)在冷却条件下，用1.3ml(3mmol)100％HNO3在30ml冰醋酸中硝化10g(30mmol)前述化合物。1小时后于25℃加入水、乙酸乙酯萃取、蒸发，残余物用硅胶色谱提纯(流动相：庚烷/甲乙酮4∶1)，得到4.1g 4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-7-硝基苯并噻吩，熔点148～149℃。c)用0.6g Pd/C(10％)在150ml THF中给3.1g(8.06mmol)前述化合物加氢。除去催化剂并蒸去溶剂后得到2.8g 4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-7-氨基苯并噻吩，该化合物不需进一步提纯即可用于下一步合成。d)将2.85g(8.2mmol)前述化合物悬浮于80ml丙酮和3ml 48％HBr中。在0℃，向该悬浮液中滴加4ml水中的0.55gNaNO2。15分钟后滴加10.3ml丙烯酸甲酯，然后再在10℃加入20mg CuBr。将反应物加热至30℃并于此温度下再保持1小时。随后进行蒸发，乙酸乙酯溶解，水洗涤，冷却并再次蒸发。残余物用硅胶色谱提纯(流动相：庚烷/甲乙酮4∶1)，得到1.2g 3-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]苯并噻吩-7-基]-2-溴丙酸甲酯，熔点99～100℃。e)将25ml乙醇中的1g(2mmol)前述化合物与0.23g硫脲和0.16g乙酸钠回流沸腾6小时。随后进行蒸发并向残余物中加入水/乙醚/异己烷，再进行吸滤。随后将固体残余物与20ml 2N HCl和30ml乙二醇单乙醚回流沸腾5小时。蒸发后加入碳酸氢盐溶液，吸滤出沉淀并用乙酸乙酯研制，得到0.6g标题化合物，熔点200-202℃。实施例4药理实验
下述研究是用ob/ob小鼠进行的。该ob/ob小鼠是具有如下特征的模型：饮食亢进、高血糖、血胰岛素过高和外周血胰岛素抗性。该模型因此特别适用于试验对外周血胰岛素抗性有效的物质。根据现代科学的观点，外周血胰岛素抗性涉及II型糖尿病的成因。
用上述模型试验实施例1、2a、2b和3的化合物。为此每天给ob/ob小鼠按100mg/kg口服相应的物质共5天，对照组只服用增溶剂甲基纤维素。在第5天杀死小鼠，测定收集的血液中的血糖浓度和胰岛素浓度。血糖浓度用动力学己糖基酶法(Schmidit，F.H.，Klin.Wschr.39，1244，1961)，使用EPOS-analyser5060＂Eppendorf Gerateban＂测定。胰岛素浓度用PharmaciaDiagnostics AB Uppsala，Sweden的放射性免疫测定法(Pharmacia InsulinRIA 100)测定。
结果列于所附表中。血糖EndK和胰岛素EndK代表5天后对照组的值，血糖和胰岛素栏代表服用所述物质后得到的值。由此可以清楚地看到实施例1、2a、2b和3的化合物降血糖和降胰岛素的效果。
**＝p＜0.01
| 化合物实施例序号 | 血糖EndK | 血糖 | 胰岛素EndK | 胰岛素 |
| 202±14 | 498±34 | |||
| 3 | 105±1** | 84±9** | ||
| 193±16 | 387±36 | |||
| 1 | 129±3** | 59±6** | ||
| 248±41 | 324±46 | |||
| 2a | 187±17 | 366±45 | 366±45 | |
| 2b | 135±13** | 95±13** | ||
Claims (5)
1.式I化合物或其互变异构体、对映体、非对映体或生理可接受的盐：
式中：A是苯环或噻吩环，B是-CH＝CH-，W是O，X是O，Y是N，R是苯基、吡啶基、噻吩基，R1表示氢或C1～C6烷基，和n等于2。
2.按照权利要求1的化合物，它是5-[4-[2-(5-甲基-2-苯基-4-噁唑基)乙氧基]-7-苯并噻吩甲基]-2，4-噻唑烷二酮。
3.式I化合物或其互变异构体、对映体、非对映体或生理可接受的盐的制备方法：
式中：A是苯环或噻吩环，B是-CH＝CH-，W是O，X是O，Y是N，R是苯基、吡啶基、噻吩基，R1表示氢或C1～C6烷基，和n等于2，其中，以已知的方法：a)使通式II化合物与噻唑烷二酮类反应
(式中A、B、W、X、Y、R、R1和n的含义同上)生成通式III化合物：(式中A、B、W、X、Y、R、R1和n的含义与上相同)，随后通过还原双键制得通式I的化合物，或b)使通式IV化合物与NaNO2在丙烯酸酯和HCl或HBr存在下反应
(式中A、B、W、X、Y、R、R1和n的含义与上相同)生成通式V化合物
(式中A、B、W、X、Y、R、R1和n的含义与上相同)，Hal代表氯或溴，R3表示C1～C6烷基；随后使通式V化合物与硫脲成环制得通式VI化合物(式中A、B、W、X、Y、R、R1和n的含义与上相同)，通过用酸处理将其转化为通式I化合物，
如果需要，随后将所得的化合物转化成它们的互变异构体，生理可接受的盐以及它们的旋光异构体。
4.含有至少一种通式I化合物及常规载体和辅助物质的药剂。
5.使用权利要求1的化合物生产治疗糖尿病的药剂的用途。
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| DEP4317320.9 | 1993-05-25 | ||
| DE4317320A DE4317320A1 (de) | 1993-05-25 | 1993-05-25 | Neue Thiazolidindione und diese enthaltende Arzneimittel |
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| EP (1) | EP0700397B1 (zh) |
| JP (1) | JP3162721B2 (zh) |
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| CN (1) | CN1040324C (zh) |
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| AU (1) | AU682699B2 (zh) |
| CA (1) | CA2163028C (zh) |
| CL (1) | CL2004001167A1 (zh) |
| CY (1) | CY2415B1 (zh) |
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| DE (2) | DE4317320A1 (zh) |
| DK (1) | DK0700397T3 (zh) |
| ES (1) | ES2180581T3 (zh) |
| FI (1) | FI955685L (zh) |
| HU (1) | HU217065B (zh) |
| NO (1) | NO307832B1 (zh) |
| NZ (1) | NZ267410A (zh) |
| PL (1) | PL180046B1 (zh) |
| PT (1) | PT700397E (zh) |
| RO (1) | RO114328B1 (zh) |
| RU (1) | RU2122002C1 (zh) |
| SK (1) | SK282618B6 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH07138258A (ja) * | 1993-11-16 | 1995-05-30 | Taiho Yakuhin Kogyo Kk | チアゾリジンジオン誘導体又はその塩 |
| JP3923079B2 (ja) * | 1995-07-31 | 2007-05-30 | 塩野義製薬株式会社 | ホスホリパーゼａ２阻害活性を有するピロリジン誘導体 |
| JPH09176162A (ja) * | 1995-12-22 | 1997-07-08 | Toubishi Yakuhin Kogyo Kk | チアゾリジンジオン誘導体及びその製造法並びにそれを含む医薬組成物 |
| DE19619819A1 (de) * | 1996-05-16 | 1997-11-20 | Boehringer Mannheim Gmbh | Neue Thiazolidindione, Verfahren zu ihrer Herstellung und diese enthaltenden Arzneimittel |
| DE19711616A1 (de) * | 1997-03-20 | 1998-09-24 | Boehringer Mannheim Gmbh | Verbessertes Verfahren zur Herstellung von Thiazolidindionen |
| DE19711617A1 (de) * | 1997-03-20 | 1998-09-24 | Boehringer Mannheim Gmbh | Neue Thiazolidindione, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel |
| US6028088A (en) * | 1998-10-30 | 2000-02-22 | The University Of Mississippi | Flavonoid derivatives |
| GB9824893D0 (en) * | 1998-11-12 | 1999-01-06 | Smithkline Beckman Corp | Novel method of treatment |
| AU1740900A (en) * | 1998-11-20 | 2000-06-13 | Genentech Inc. | Method of inhibiting angiogenesis |
| ES2258431T3 (es) | 1999-08-02 | 2006-09-01 | F. Hoffmann-La Roche Ag | Proceso para la preparacion de derivados de benzotiofeno. |
| US6531609B2 (en) | 2000-04-14 | 2003-03-11 | Hoffmann-La Roche Inc. | Process for the preparation of thiazolidinedione derivatives |
| AU2001265914B2 (en) * | 2000-05-08 | 2005-11-03 | F. Hoffmann-La Roche Ag | Para-amine substituted phenylamide glucokinase activators |
| JP4149803B2 (ja) | 2000-06-27 | 2008-09-17 | エフ．ホフマン−ラ ロシュ アーゲー | 組成物の調製方法 |
| MXPA03005763A (es) * | 2000-12-25 | 2004-05-03 | Ono Pharmaceutical Co | Compuestos derivados de dihidronaftaleno y agente que comprende el derivado como ingrediente activo. |
| EP1392296A1 (en) * | 2001-04-06 | 2004-03-03 | F. Hoffmann-La Roche Ag | Thiazolidinediones alone or in conbination with other therapeutic agents for inhibiting or reducing tumour growth |
| SK287842B6 (sk) * | 2001-05-15 | 2011-12-05 | F. Hoffmann-La Roche Ag | Oxazole derivative, method for the preparation thereof and use, pharmaceutical compositions containing thereof |
| JP2003040877A (ja) * | 2001-07-24 | 2003-02-13 | Sumika Fine Chemicals Co Ltd | ５−［６−（２−フルオロベンジルオキシ）−２−ナフチル］メチル−２，４−チアゾリジンジオンの製造方法及びその精製方法 |
| US7102000B2 (en) * | 2002-03-08 | 2006-09-05 | Incyte San Diego Inc. | Heterocyclic amide derivatives for the treatment of diabetes and other diseases |
| CN100402510C (zh) * | 2002-07-03 | 2008-07-16 | 霍夫曼-拉罗奇有限公司 | 噁唑衍生物及其作为胰岛素敏化剂的应用 |
| ATE483699T1 (de) * | 2002-08-30 | 2010-10-15 | Hoffmann La Roche | Neue 2-arylthiazolverbindungen als ppar-alpha und gamma agonisten |
| BR0314261A (pt) * | 2002-09-12 | 2005-07-26 | Hoffmann La Roche | Compostos, processo de preparação de um composto, composição farmacêutica que compreende o mesmo, utilização de um composto, método para tratamento e/ou profilaxia de enfermidades e utilização e/ou método de tratamento |
| PL377320A1 (pl) * | 2002-11-25 | 2006-01-23 | F. Hoffmann-La Roche Ag | Pochodne indolilowe |
| EP1641790A1 (en) * | 2003-06-26 | 2006-04-05 | F. Hoffmann-La Roche Ag | Process for the preparation of insulin sensitizer and intermediate compound thereof |
| CN101693202B (zh) * | 2009-10-21 | 2011-04-20 | 沧州那瑞化学科技有限公司 | 盐酸吡咯列酮关键中间体加氢反应催化剂及加氢反应方法 |
| WO2013082106A1 (en) | 2011-12-02 | 2013-06-06 | The General Hospital Corporation | Differentiation into brown adipocytes |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0207605A1 (en) * | 1985-05-21 | 1987-01-07 | Pfizer Inc. | Hypoglycemic thiazolidinediones |
| WO1989008652A1 (en) * | 1988-03-08 | 1989-09-21 | Pfizer Inc. | Thiazolidinedione derivatives as hypoglycemic agents |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1003445B (zh) * | 1984-10-03 | 1989-03-01 | 武田药品工业株式会社 | 噻唑烷二酮衍生物，其制备方法和用途 |
| GB8713861D0 (en) * | 1987-06-13 | 1987-07-15 | Beecham Group Plc | Compounds |
| DE3889222D1 (de) * | 1988-03-04 | 1994-05-26 | Volk Inc Kurt H | Gegenstand für den unmittelbaren versand per post mit einer postversandfähigen antwortkarte. |
| CA2086606A1 (en) * | 1990-07-03 | 1992-01-04 | Kunihiro Niigata | Bisheterocyclic compound |
| FR2688220A1 (fr) * | 1992-03-06 | 1993-09-10 | Adir | Nouveaux derives de thiazolidine-2,4-dione, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
-
1993
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0207605A1 (en) * | 1985-05-21 | 1987-01-07 | Pfizer Inc. | Hypoglycemic thiazolidinediones |
| WO1989008652A1 (en) * | 1988-03-08 | 1989-09-21 | Pfizer Inc. | Thiazolidinedione derivatives as hypoglycemic agents |
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Granted publication date: 19981021 |