CN1262620A - 抗疟疾的β-烷氧基丙烯酸酯 - Google Patents
抗疟疾的β-烷氧基丙烯酸酯 Download PDFInfo
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- CN1262620A CN1262620A CN98807016A CN98807016A CN1262620A CN 1262620 A CN1262620 A CN 1262620A CN 98807016 A CN98807016 A CN 98807016A CN 98807016 A CN98807016 A CN 98807016A CN 1262620 A CN1262620 A CN 1262620A
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Abstract
本发明涉及式(ⅠA)或(ⅠB)的β-烷氧基丙烯酸酯(其中R、R1、R6、R7、R8、X和Z如本文所定义)作为治疗活性物质的用途,尤其是在治疗或预防疟疾中的用途以及涉及含有这些物质的药物。
Description
本发明涉及通式IA或IB的化合物,其中R1是低级烷基,X是N或CH,IA中的R是
其中
Y是S或O;并且
A1是苯基,其可以被一个或多个取代基取代,所述取代基选自卤素、低级烷氧基、低级烷基、CF3、NO2、NH2、苯氧基或CF3-苯氧基;萘基;异噻唑-3-基;噻唑-2-基,其可任意地被低级烷氧基烷氧基烷基、低级烷基、低级烷氧羰基或低级乙酰氧烷基取代;噻二唑-2-基,其可任意地被低级烷硫基、低级炔硫基、环烷基-烷硫基、CF3或-NHC6H4CF3取代;喹喔啉-2-基,其可任意地被卤素或低级烷基取代;苯并噁唑-2-基;苯并三嗪,其可任意地被一个氧代基团取代;和喹啉-2-基;或
其中
R2是氢、低级烷氧羰基、CF3、低级烷基、环烷基、低级烷氧基烷基、低级烷硫基烷基或低级烷氧基;并且A2是苯基,其可被一个或多个取代基取代,所述取代基选自低级烷基、CF3、卤素、低级烷硫基、低级烷氧基或NO2;-C(O)C6H5;-C(CH3)=CH-C6H4-低级烷基;-CH=CH-C6H5;吡啶-2-基;吡啶-3-基;吡啶-4-基;噻唑-5-基,其可任意地被低级烷基取代;噻吩-3-基,其可任意地被低级烷基取代;噻吩-2-基,其可任意地被卤素取代;喹啉-2-基;萘基,苯并[b]噻吩-2-基,其可任意地被低级烷基或卤素取代;或苯并[b]呋喃-2-基;或
其中
W是S、O、NH或CH2;
R3是氢或低级烷基;并且
其中
A4是苯基,其可被一个或多个取代基取代,所述取代基选自NO2、低级烷氧基、卤素、CF3、苯氧基、苯乙烯基-苯基或(2-CF3-或Cl-苯基)-呋喃-2-基;苯并[1,3]间二氧杂环戊烯-5-基,其可任意地被卤素取代;异噁唑-4-基,其可任意地被苯基或低级烷氧基烷氧基取代;喹啉-3-基;吡啶-2-基;吡啶-3-基;吡啶-4-基;呋喃基;噻吩-2-基;噻吩-3-基;-C≡C-C(CH3)3;-C≡C-C6H5;中氮茚-2-基,其可任意地被低级烷基取代;苯并呋喃-2-基;苯并吡喃-3-基或二氢苯并[b]噻吩-5-基;或
其中
R4是氢或低级烷基;并且
A5是苯基,其可被一个或多个取代基取代,所述取代基选自低级烷基、低级烷氧基、NO2、卤素、氰基或CF3;吡啶-2-基;吡啶-4-基;喹啉-2-基;喹啉-3-基;萘基;吡咯-2-基,其可任意地被低级烷基取代;呋喃-2-基;呋喃-3-基;噻吩-2-基;噻吩-3-基,其可任意地被卤素或低级烷基取代;噻唑-2-基,其可任意地被C6H4Cl取代;噻唑-4-基,其可任意地被苯基取代;苯并[b]噻吩-2-基,其可任意地被卤素取代;或苯并[b]噻吩-3-基;或
其中
其中
A7是苯基,其可任意地被CF3取代;或 -(CH2)n-A8 Ia8
其中
n是4;并且
A8是苯基,其可被一个或多个取代基取代,所述取代基选自CF3、
卤素或-CH=N-OCH2-CO-OCH3;萘基或吡啶-4-基;或
其中
其中
V是O、-N(CH3)-、-S-;并且
B1是苯基,其可任意地被卤素或烷基取代;喹啉-8-基;嘧啶-2-基;-CH(CH3)-C6H5;或-CH2-C6H5;或
其中
m是0或1;并且
B2是苯基,其可任意地被卤素、低级烷基或CF3取代;或苯并[b]噻吩-5-基;或
其中
其中
R5是氢、低级烷基或低级烷氧基烷基;并且
其中
B5是苯基;-C≡C-C(CH3)3;或噻吩-3-基;以及式IA和IB化合物的可药用盐。式IA和IB化合物还包括所有可能的立体异构体和它们的外消旋体。
现已出人意料地发现本发明的化合物可用于抗疟疾。每年,有3~5亿人患疟疾。其中有近3百万人死于该病,他们大多是儿童且几乎所有都生活在热带非洲。五十年前,许多人认为疟疾可被完全根除。但在过去的二十年中,疟疾又再度复发。多年来,氯喹一直是标准疗法,但在某些地区疟原虫对氯喹和几乎所有的老抗疟药的联合应用产生耐药性。约40%全球人口生活在发现有疟疾的地区。
本发明的化合物不仅对氯喹敏感性疟原虫具有活性,还对耐氯喹的疟原虫具有活性。因此,它们非常适用于预防和治疗疟疾,尤其是在疟原虫对氯喹具有耐药性的情况下。
大多数上述的β-烷氧基丙烯酸酯和它们的盐是已知化合物。它们记述于下列文献中:EP 379098、EP 299694、WO 9007493、EP 278595、EP 463488、EP 370629、EP 475158、EP 474042、EP 178826、DE3519280、EP 433233、EP 460575和EP 254426,其中它们作为杀真菌活性的化合物用于农业。
式IA5的下列化合物及其可药用盐是新颖的:其中R1是低级烷基,X是N或CH,R4是氢或低级烷基,并且A5是苯基,其可以是未取代的或被一个或多个取代基取代,所述取代基选自低级烷基、低级烷氧基、NO2、卤素、氰基或CF3;吡啶-2-基;吡啶-4-基;喹啉-2-基;喹啉-3-基;萘基;吡咯-2-基,其可任意地被低级烷基取代;呋喃-2-基,呋喃-3-基;噻吩-2-基;噻吩-3-基,其可任意地被卤素和低级烷基取代;噻唑-2-基,其可任意地被C6H4Cl取代;噻唑-4-基,其可任意地被苯基取代;苯并[b]噻吩-2-基,其可任意地被卤素取代;或苯并[b]噻吩-3-基。
本发明的目的是所述式IA和IB化合物及其可药用盐抗氯喹敏感性疟原虫和耐氯喹的疟原虫的用途,这些化合物用于制备相应药物的用途,含有这些化合物及其盐的药物以及式IA5的新化合物本身。
本说明书中采用的通用术语的下列定义适用于它们单独出现或联合应用的情况。
本文中采用的术语“低级烷基”是指含1~4个碳原子的直链或支链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。
术语“卤素”是指氯、碘、氟或溴。
术语“低级烷氧基”是指通过氧原子连接的前述定义的烷基。术语“环烷基”是指含3~6个碳原子的饱和环状烃残基。
本发明包括所有可能的外消旋体和它们的光学对映体。
还优选式IA2的化合物其中R1是甲基,X是CH,R2是氢或低级烷基并且A2是被CF3、氯、氟、甲基、叔丁基或SCH3取代的苯基。
另一组优选化合物是式IA1的化合物:其中R1是甲基,X是CH,Y是O或S并且A1是苯基,其可任意地被甲基、异丙基、叔丁基、溴、氯、CF3或甲氧基取代;萘基;或噻二唑基,其可任意地被硫甲基或丙炔硫基环丙基取代。
式IA和IB化合物可按照上述引用文献中描述的方法制备。
此外,式IA1~IA9和IB1~IB5的化合物可按照反应方案1~14制备。
反应方案2
反应方案3其中取代基具有上述含义。
反应方案4其中取代基具有上述含义。
反应方案10其中取代基具有上述含义。
式IA5的新化合物可按照反应方案5并通过实施例164~206制备。
如前所述,本发明的通式IA和IB的β-烷氧基丙烯酸酯和它们的可药用盐具有有价值的药物性质。
具体地说,它们具有非常良好的抗疟原虫活性。对耐氯喹的疟原虫与对氯喹敏感性疟原虫,它们具有同样良好的活性。因此,本发明的化合物也可用于预防和治疗疟疾,即使是在疟原虫对氯喹没有反应的情况下。
优选的化合物还有式IA1化合物,其中R1是甲基,X是CH,Y是S或O,A1是苯基,其可被一个或多个取代基取代,所述取代基选自卤素、低级烷氧基、低级烷基、CF3、NO2、NH2、苯氧基或CF3-苯氧基。这类化合物,例如下列具体化合物可按照EP 278595的实施例1的方法制备:
(E)-2-[2-(2-溴-苯氧基甲基)-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-3-甲氧基-2-[2-(4-苯氧基-苯氧基甲基)-苯基]-丙烯酸甲酯;
(E)-3-甲氧基-2-[2-(4-(4-三氟甲基-苯氧基)-苯氧基甲基)-苯基]-丙烯酸甲酯;
(E)-3-甲氧基-2-[2-(4-甲氧基-2-硝基-苯氧基甲基)-苯基]-丙烯酸甲酯;
(E)-2-[2-(2,4-二溴-苯氧基甲基)-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-(2-氯-4-甲基-苯氧基甲基)-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-(2-氯-4-三氟甲基-苯氧基甲基)-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-3-甲氧基-2-(2-五氟苯氧基甲基-苯基)-丙烯酸甲酯;
(E)-2-[2-(2,4-二氯-苯硫基甲基)-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-(2-氨基-4-三氟甲基-苯硫基甲基)-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-(2-氨基-4-甲氧基-苯氧基甲基)-苯基]-3-甲氧基-丙烯酸甲酯;
优选的化合物还有式IA3的化合物,其中R1是甲基,X是CH-,R3是H2,W是S、O,A3是苯基,其可被一个或多个取代基取代,所述取代基选自卤素、CF3、低级烷基或为5-乙酰氧基-6-乙酰氧基甲基-5,6-二氢-2H-吡喃。这类化合物,如下列额外化合物可按照实施例118中描述的方法制备:
(E)-2-[2-[(E)-3-(5-乙酰氧基-6-乙酰氧基甲基-5,6-二氢-2H-吡喃-2-基氧)-丙烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(E)-3-(2-氯-苯硫基)-丙烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(E)-3-(2-氯-4-甲基-苯氧基)-丙烯基]-苯基]-3-甲氧基-丙烯酸甲酯;和
优选的化合物还有式IA4化合物,其中R1是甲基,X是CH,并且A4是苯基,其可被一个或多个取代基取代,所述取代基选自卤素、低级烷氧基、NO2、苯乙烯基-苯基或(2-CF3-或Cl-苯基)-呋喃-2-基。这类化合物,例如下列的化合物可按照实施例126(EP 475158 A2 920318)的方法制备:
(E)-3-甲氧基-2-[2-[(E)-2-[5-(2-三氟甲基-苯基)-呋喃-2-基]-乙烯基]-苯基]-丙烯酸甲酯;
(E)-2-[2-[(E)-2-(2-氯-3,4-二甲氧基-6-硝基-苯基)-乙烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(E)-2-[5-(2-氯-苯基)-呋喃-2-基]-乙烯基]-苯基]-3-甲氧基-丙烯酸甲酯;和
优选的化合物还有式IA5化合物,其中R1是甲基,X是CH,R4是H并且A5是苯基,其可被一个或多个取代基取代,所述取代基选自低级烷基、低级烷氧基、NO2、卤素、氰基或CF3。这类化合物如下列化合物可按照实施例164的方法制备:
(E)-2-[2-[(1E,3E)-4-(2-氯-3,4-二甲氧基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(1E,3E)-4-(2-溴-4,5-二甲氧基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(1E,3E)-4-(2-氰基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-3-甲氧基-2-[2-[(1E,3E)-4-(3-甲氧基-2-硝基-苯基)-丁-1,3-二烯基]-苯基]-丙烯酸甲酯;
(E)-2-[2-[(1E,3E)-4-(4-氟-2-三氟甲基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(1E,3E)-4-(4-叔丁基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(1E,3E)-4-(2-氯-4-氟-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(1E,3E)-4-(2,4-二氟-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(1E,3E)-4-(2-氯-4-甲基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;
(E)-2-[2-[(1E,3E)-4-(2,4-二甲基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯;和
(E)-2-[2-[(1E,3E)-4-(2-氟-4-三氟甲基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯。
CH3 | H | H | -OCH3 | H | 248 |
CH3 | Cl | H | H | H | 249 |
CH3 | H | H | H | CH3 | 250 |
在体外各种人病原性恶性疟原虫(Plasmodium falciparum)的生长抑制测定中,显示了这些化合物对抗耐氯喹的疟原虫和对抗氯喹过敏性疟原虫的高效活性,如下表1所示。由对尤其是耐氯喹的病原虫的生长抑制与对氯喹敏感的病原虫的生长抑制之间的比率可得到衡量是否存在与氯喹交叉耐药的“耐药指数”。由于所有新化合物的耐药指数在0.7~2.5之间,它们对敏感型以及耐药型病原虫的生长抑制同等有效。因此,它们也适于预防疟疾,还适于治疗甚至氯喹无效的疟疾。动物实验也显示了对抗疟原虫的良好活性。口服和皮下给药于被疟原虫感染的小鼠后测得的有效剂量显示于下表2。
体外测定对抗恶性疟原虫活性的试验方法
按照Desjardin等的方法(Desjardins,R.E.等:采用半自动微量稀释技术定量评价体外抗疟活性,Antimicrob.Agents Chemother.16,710-718,(1979))在恶性疟原虫的红细胞内阶段用不同时期的培养物试验制剂。
培养介质包括加有25mM HEPES、25mM NaHCO3、100μg/ml新霉素和10%人血清(A+)的RPMI 1640。人-A+红细胞被用作恶性疟原虫的宿主细胞。使疟原虫保持在37℃下和3%氧气、4%二氧化碳、93%氮气和95%相对湿度的环境中。
为测定活性,将制剂溶于DMSO,在培养介质中预先稀释至适宜的起始浓度,随后在第2阶段经过6-7步在微滴板上滴定。加入疟原虫培养物(2.5%的红细胞悬浮体中含0.7%血内疟原虫)后,将试验平板在上述条件下温育72小时。与同一试验平板中的未处理对照培养物相比,用[G-3H]-次黄嘌呤掺入测定不同制剂浓度中的疟原虫生长。按照对元回归分析由剂量-活性曲线计算50%生长抑制(IC50)。
测试制剂对抗至少一种耐氯喹的和一种氯喹敏感性恶性疟原虫的活性。其它表征包括另外的敏感性和耐药性疟原虫。
体内测定对抗Plasmodium berghei活性的试验方法
用感染了疟原虫(Plasmodium berghei)的小鼠对制剂进行试验。将重约25g的雄性白化病小鼠(IBM:MORO(SPF),FUELLINSDORF)作为试验动物。将它们保持在21-22℃的驯化室中,每笼一组5只动物。它们可随意进食低PABA含量(NAFAG FUTTER“No.9009 PAB-45,PABA含量45mg/kg)的食物和饮用水。试验第一天(DO)使试验动物感染Plasmodium berghei(ANKA株)。为此,使用含约30%血内疟原虫的供体小鼠的肝素化血液,将其用生理盐水稀释以使其每毫升含108疟原虫寄生的红细胞。将0.2ml的该悬浮体静脉内(i.v.)注入待处理的小鼠和对照小鼠。在未处理的对照动物中,在感染后第3天(D+3)血内疟原虫通常达到30-40%,在+5和+7天,试验动物死亡。
将待试验的物质在蒸馏水中或在7%Tween 80、3%乙醇(96%)和水的混合液中溶解或悬浮。通常,将0.25ml该溶液或悬浮体一次性地皮下或经口给药于每组5只的试验动物。治疗在感染后24小时进行。10只对照动物以相同方式,每次试验用溶剂或悬浮体介质进行处理。
在第一次试验中,将所有的试验物质以100或10mg/kg的单次剂量进行试验。仅有在该试验(10mg/kg)中显示了血内疟原虫减少超过90%的那些物质用于滴定。为获得精确的活性滴定,采用适宜稀释度的试验物质。
处理后48小时(D+3)用所有动物的尾动脉血制备血涂片并用吉姆萨染色剂染色。通过在显微镜下计数测定对照组以及试验化合物处理组的平均红细胞感染率(血内疟原虫,%)。计算对照组(100%)和处理组的感染率平均值的差异并以百分减少(GI%)表示。通过JMP程序(非线性拟合)精确计算ED50或ED90。ED50(ED90)(mg/kg)是与对照组相比单次给药后使平均红细胞感染率减少50%(90%)的剂量。表1
对人病原性恶性疟原虫NF54株(作为氯喹敏感性株实例)和人病原性恶性疟原虫K1(作为耐氯喹株实例)生长抑制的体外测量值(IC50值,以μg/ml为单位)。
表2
通式 | 实施例号 | 体外 | |
NF 54株 IC50 72小时 | K1株IC50 72小时 | ||
IA1 | 11 | 1.17 | 4.9 |
IA1 | 28 | 17.7 | 19.1 |
IA2 | 105 | 0.21 | 1.01 |
IA2 | 110 | 20 | 65.8 |
IA2 | 111 | 1.6 | 4.3 |
IA3 | 120 | 1.75 | 2.51 |
IA4 | 126 | 1.2 | 3.3 |
IA4 | 136 | 1.04 | 2.9 |
IA5 | 185 | 0.06 | 0.15 |
IA5 | 199 | 0.06 | 0.13 |
IA5 | 203 | 0.07 | 0.28 |
IA5 | 206 | 0.4 | 1.4 |
IA6 | 207 | 10.8 | 25.8 |
IA7 | 209 | 3.21 | 5.7 |
IA8 | 210 | 0.85 | 1.35 |
IA8 | 211 | 0.33 | 1.34 |
IA9 | 217 | 23.7 | 60.8 |
IB1 | 222 | 22.6 | 64.3 |
IB4 | 238 | 17.5 | 40.9 |
IB5 | 241 | 1.4 | 7.4 |
IB5 | 243 | 6.7 | 22.6 |
IB | 244 | 147.3 | 419.2 |
IB | 250 | 184.4 | 550.3 |
IB2 | 233 | 29.5 | 67.3 |
IB3 | 236 | 44.2 | 174.7 |
III | 251 | 64.9 | 111 |
经口(po)或皮下(sc)给药100(10)mg/kg剂量的试验物质后对小鼠中Plasmodium berghei以血内疟原虫的百分减少体内测定的活性,ED50是试验物质的有效给药剂量。
通式 | 实施例号 | 体内 | |
po活性% | sc活性% | ||
IA1 | 11 | 80 | tox |
IA3 | 120 | 46 | 91 |
IA4 | 126 | 79 | 76 |
IA4 | 136 | 40 | tox |
IA5 | 185 | 99.0(10mg/kg) | 99.95 |
IA5 | 199 | 100(10mg/kg) | 99.97 |
IA5 | 203 | 76(10mg/kg) | 90 |
IA5 | 206 | 46 | 44 |
IA8 | 210 | 82 | 99 |
IA8 | 211 | 59(10mg/kg) | 92 |
III | 251 | 40 | 74 |
式IA或IB化合物和式IA或IB化合物的可药用酸加成盐可用作药物,例如呈药物制剂形式。药物制剂可口服,例如以片剂、包衣片剂、糖衣丸、硬和软明胶胶囊、溶液、乳液或悬浮剂形式给药。但也可通过直肠给药,例如以栓剂形式;或胃肠外给药,例如以注射液形式;或经鼻给药。
式IA或IB化合物和式I化合物的可药用酸加成盐可与药物惰性的无机或有机载体一起加工生产药物制剂。乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等可用作例如片剂、包衣片剂、糖衣丸和硬明胶胶囊的载体。软明胶胶囊的适宜载体是,例如植物油、蜡、脂肪类、半固体和液体多元醇等。但取决于活性成分的性质,在软明胶胶囊的情况下通常不需要载体。用于生产溶液和糖浆的适宜载体是,例如水、多元醇、甘油、植物油等。栓剂的适宜载体是,例如天然的或硬化的油、蜡、脂肪类、半固体或液体多元醇等。
药物制剂还可含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲剂、包衣剂或抗氧剂。它们还可含有其它治疗上有价值的物质。
本发明的目的还有含式IA或IB化合物或者其可药用酸加成盐和治疗学上惰性的载体的药物,以及它们的制备方法,该方法包括将一种或多种式IA或IB化合物或其可药用酸加成盐与一种或多种治疗学上惰性的载体一起制成盖仑制剂形式。
依据本发明,通式IA或IB的化合物及其可药用酸加成盐可用于治疗或预防疟疾,因此可生产相应的药物。剂量可在较宽的限制范围内变化,当然个体需要将视具体情况而定。在口服给药的情况下,剂量范围为每日约10mg至约2.5g通式IA或IB化合物或相应量的其可药用酸加成盐,但需要时也可超过该上限。
下列实施例旨在说明本发明,而非以任何方式对其范围构成限制,其中所有的温度均以摄氏度给出。250 MHz-1H-NMR光谱在室温测得;化学位移值δ(ppm)是相对于δ(TMS)=0.0ppm的。
式IA5的新化合物可按照下述制备。所有温度均以℃给出。实施例164(E)-2-[2-[(1E,3E)-4-(4,5-二甲氧基-2-硝基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯
a)在室温下,将甲醇钠(335mg,6.19mmol)加到1,3-二噁烷-2-基甲基三丁基溴化鏻(C.Spangler;R.McCoy,Synthetic communications,18,51,(1988))(5.17ml,1M DMF溶液,5.71mmol)和4,5-二甲氧基-2-硝基苯甲醛(1.25g,4.76mmol)在DMF(20ml)中的溶液中。将该混合物在50℃加热过夜后,倾入水中,用乙醚萃取,用盐水洗涤并经硫酸镁干燥。蒸发溶剂,将残余物溶于THF(100ml)中并用2N盐酸(50ml)处理。将该混合物在室温搅拌2小时后,蒸发THF,将黄色固体过滤,悬浮在乙醚/乙酸乙酯4∶1中。将该悬浮液在室温搅拌1小时,过滤并用乙醚洗涤,得到黄色固体(E)-3-(4,5-二甲氧基-2-硝基-苯基)-丙烯醛(624mg,55%),熔点:103-105℃。IR(KBr):1689,1605cm-1。MS(EI):237(M)。b)在0℃下,将氢化钠(40mg,0.954mmol)加到(E)-2-[2-(二甲氧基膦酰甲基)-苯基]-3-甲氧基-丙烯酸甲酯(EP 203606)(250mg,0.79mmol)的THF(5ml)溶液中。将该混合物在室温搅拌30分钟,用(E)-3-(4,5-二甲氧基-2-硝基-苯基)-丙烯醛(189mg,0.79mmol)的二氯甲烷(2ml)溶液处理。该混合物在室温搅拌3小时后,回流1.5小时,之后将反应混合物冷却到室温,用乙酸(1ml)处理。在室温搅拌10分钟后,反应混合物用乙酸乙酯萃取,用碳酸氢钠溶液、盐水、水洗涤并经硫酸镁干燥。蒸发溶剂,并经色谱(己烷/乙酸乙酯1∶1)得到白色固体(E)-2-[2-[(1E,3E)-4-(4,5-二甲氧基-2-硝基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯(116mg,34%),熔点:198-200℃。IR(KBr):1710,1630cm-1。MS(EI):425(M)。
按照上面实施例描述的方法,制备下列化合物:实施例165(E)-2-[2-[(1E,3E)-4-(2,4-二氯-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基-丙烯酸甲酯熔点:143-145℃。IR(KBr):1707,1629 cm-1。MS(EI):388(M)。实施例166(E和/或Z)-3-甲氧基-2-[邻-[(全-E)-4-(2-吡啶基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:106-108℃实施例167(E和/或Z)-2-[邻-[(全-E)-4-(2,3-二氯苯基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:141-145℃实施例168(E和/或Z)-2-[邻-[(全-E)-4-(2,3-二氟苯基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:142-144℃实施例169(E和/或Z)-3-甲氧基-2-[邻-[(全-E)-4-(2-喹啉基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:137-138℃实施例170(E和/或Z)-3-甲氧基-2-[邻-[(全-E)-4-(1-萘基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:138-140℃实施例171(E和/或Z)-3-甲氧基-2-[邻-[(全-E)-4-(1-甲基吡咯-2-基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:139-142℃实施例172(E和/或Z)-3-甲氧基-2-[邻-[(全-E)-4-(4-吡啶基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:175-177℃实施例173(E和/或Z)-2-[邻-[(全-E)-4-(2-呋喃基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:136-137℃实施例174(E和/或Z)-3-甲氧基-2-[邻-[(全-E)-4-(2-噻吩基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:142-145℃实施例175(E和/或Z)-3-甲氧基-2-[邻-[(全-E和/或Z)-4-(3-噻吩基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:194-195℃实施例176(E和/或Z)-3-甲氧基-2-[邻-[(全-E)-4-(3-喹啉基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:173-175℃实施例177(E)-3-甲氧基-2-[邻-[(全-E)-4-(α,α,α-三氟对甲苯基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:190-191℃实施例178(E)-2-[邻-[(全-E)-4-(对氟苯基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:156-157℃实施例179(E)-2-[邻-[(全-E)-4-(邻乙氧基苯基)-1,3-丁二烯基]-苯基]-3-苯氧基丙烯酸甲酯熔点:152-153℃实施例180(E)-2-[邻-[(全-E)-4-(2-氯-6-氟苯基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:165℃实施例181(E)-3-甲氧基-2-[邻-[(全-E)-4-(α,α,α-三氟-间-甲苯基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:152-153℃实施例182(E)-2-[邻-[(全-E)-4-(3-呋喃基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:174-175℃实施例183(E)-2-[邻-[(全-E)-4-(2-(对氯苯基)-4-噻唑基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:167-171℃实施例184(E)-2-[邻-[(全-E)-4-(邻氯苯基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:158-162℃实施例185(E)-3-甲氧基-2-[邻-[(全-E)-4-(α,α,α-三氟-甲苯基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:148-149℃实施例186(E)-2-[邻-[(全-E)-4-(间氟苯基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯IR(KBr):1705,1628cm-1,MS(EI):338(M)实施例187(E)-3-甲氧基-2-[邻-[(全-E)-4-(5-苯基-4-噻唑基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:167℃实施例188(E)-2-[邻-[(全-E)-4-(5-溴-2-噻吩基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:160-161℃实施例189(E)-3-甲氧基-2-[邻-[(全-E)-4-(对甲氧基苯基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:164-166℃实施例190(E)-3-甲氧基-2-[邻-[(全-E)-4-[3-甲氧基苯并[b]噻吩-2-基]-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:202-203℃实施例191(E)-3-甲氧基-2-[邻-[(全-E)-3-(2-噻唑基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:131-133℃实施例192(E)-3-甲氧基-2-[邻-[(全-E)-4-(5-甲基-2-噻吩基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:131-133℃实施例193(E)-3-甲氧基-2-[邻-[(全-E)-4-(3-甲基-2-噻吩基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:168℃实施例194(E)-3-甲氧基-2-[邻-[4-(2-萘基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:172℃实施例195(E)-2-[邻-[(全-E)-4-苯并[b]噻吩-2-基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:223-225℃实施例196(E)-2-[邻-[(全-E)-4-苯并[b]噻吩-3-基-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:157℃实施例197(E)-3-甲氧基-2-[邻-[(全-E)-4-苯基-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:165-167℃实施例198(E)或(Z)-2-[2-[4-(3,5-二-三氟甲基苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基丙烯酸甲酯IR(KBr):1703,1630 cm-1MS(EI):456(M)实施例199(E)或(Z)-2-[2-[4-(2,4-二-三氟甲基苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:176-177℃IR(KBr):1703,1630cm-1MS(EI):456(M)实施例2002-[邻-[(全-E)-4-(间溴苯基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯IR(KBr):1701,1626cm-1MS(EI):399(M)实施例201(E)-2-[邻-[(全-E)-4-(对氯苯基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:209℃实施例202(E)-2-[邻-[(全-E)-4-(间氯苯基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:121-122℃实施例203(E)-2-[邻-[(全-E)-4-(邻溴苯基)-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯熔点:150-151℃实施例204(E)-3-甲氧基-2-[邻-[(全-E)-4-(3,4,5-三甲氧基苯基)-1,3-丁二烯基]-苯基]丙烯酸甲酯熔点:98-102℃实施例205(E)-2-[邻-[(全-E)-4-(对叔丁基苯基)-3-甲基-1,3-丁二烯基]-苯基]-3-甲氧基丙烯酸甲酯IR(KBr):1709,1632cm-1MS(EI):390(M)实施例206(Z)-或(E)-甲氧基亚氨基-[2-[(1E,2E)-4-(2-三氟甲基苯基)-丁-1,3-二烯基]-苯基]-乙酸甲酯
a)在24℃下,将Bu3SnH(0.56ml,2.1mmol)加到(2-乙炔基-苯基)-甲氧基亚氨基-乙酸甲酯(151mg,0.7mmol)和AIBN(cat.)的甲苯(0.5ml)溶液中。将该混合物在80℃搅拌3.5小时后,减压蒸发溶剂并进行色谱(己烷/乙酸乙酯9∶1),得到黄色液体状甲氧基亚氨基-[2-(E,Z)-(2-三丁基锡烷基(stannanyl)-乙烯基)-苯基]-乙酸甲酯(1∶1的混合物)(155mg,44%)。IR(KBr):1731,1600cm-1。MS(EI):508(M)。
b)将1-(2,2-二溴-乙烯基)-2-三氟甲基-苯(989mg,3mmol)和(Et)2POH(0.75ml,6mmol)在三乙胺(0.83ml,6mmol)中的溶液在5℃搅拌4小时。加入己烷,并再搅拌10分钟。混合物用己烷萃取,用盐水洗涤并经硫酸钠干燥。蒸发溶剂,进行色谱(己烷),得到无色液体状1-(2-溴-乙烯基)-2-三氟甲基-苯(674mg,90%)。IR(KBr):1600,940cm-1。MS(EI):251(M)。
c)在24℃下,将Pd[PPh3]4(21mg,0.02mmol)加到1-(1-溴-乙烯基)-2-三氟甲基-苯(151mg,0.6mmol)和甲氧基亚氨基-[2-(E,Z)-(2-三丁基锡烷基-乙烯基)-苯基]-乙酸甲酯(304mg,0.6mmol)在甲苯(5ml)中的溶液中。将该混合物在110℃搅拌5小时,冷却到室温,用甲苯萃取,盐水洗涤并经硫酸钠干燥。蒸发溶剂并进行色谱(己烷/乙酸乙酯3∶2)得到棕色油状的(Z)-或(E)-甲氧基亚氨基-[2-[(1E,2E)-4-(2-三氟甲基苯基)-丁-1,3-二烯基]-苯基]-乙酸甲酯(48 mg,21%)。IR(KBr):1734,1610cm-1。MS(EI):389(M)。实施例251(III)(E)-3-甲氧基-2-[(E)-2-[(R)-和(S)-3-(四氢-吡喃-2-基氧基)-丙烯基]-苯基]-丙烯酸甲酯(活性中间体)
在24℃下,将Pd[PPh3]4(58mg,0.05mmol)加到(E)-三丁基-[3-(R)-和(S)-(四氢-吡喃-2-基氧基)-丙烯基]-锡烷(2.2g,5.1mmol)(E.J.Corey;J.W.Suggs,《有机化学杂志》40,2554,(1975))和(E)-2-(2-溴-苯基)-3-甲氧基-丙烯酸甲酯(1.38mg,5.1mmol)(EP 0307101 A2 890315)在甲苯(20ml)中的溶液中。将该混合物在110℃搅拌2天,冷却到室温,用甲苯萃取,用盐水洗涤,并经硫酸钠干燥。蒸发溶剂并进行色谱(己烷/乙酸乙酯9∶1)得到白色固体(E)-3-甲氧基-2-[(E)-2-[(R)-和(S)-3-(四氢-吡喃-2-基氧基)-丙烯基]-苯基]-丙烯酸甲酯(884mg,52%),熔点:66-68℃。IR(KBr):1711,1633cm-1。MS(EI):216(M-MeOH-二氢吡喃)。实施例252(IV)(E)-2-[2-[3-羟基-丙烯基]-苯基]-3-甲氧基-丙烯酸甲酯(活性中间体)
在24℃下,将甲苯-4-磺酸一水合物(1.11g,0.4mmol)加到(E)-3-甲氧基-2-[(E)-2-[(R)-和(S)-3-(四氢-吡喃-2-基氧基)-丙烯基]-苯基]-丙烯酸甲酯(4.866g,14mmol)的乙醇(70ml)溶液中。该混合物搅拌6小时后,用碳酸钾溶液中和,蒸发溶剂并将粗品溶于乙酸乙酯中,用盐水和水洗涤,经硫酸钠干燥。蒸发溶剂,得到白色固体(E)-2-[2-[3-羟基-丙烯基]-苯基]-3-甲氧基-丙烯酸甲酯(3.4g,93%),熔点:78-80℃。IR(KBr):1683,1619cm-1。MS(EI):216(M-MeOH)。实施例A
按照本身已知的方法,可以(E)-2-[2-(1E,3E)-4-[4,5-二甲氧基-2-硝基-苯基)-丁-1,3-二烯基]-苯基]-3-甲氧基丙烯酸甲酯为活性成分配制下列组成的药物制剂:1、500mg片剂
活性成分 500mg
乳糖粉 149mg
聚乙烯吡咯烷酮 15mg
二辛基磺基琥珀酸酯钠 1mg
羧甲基淀粉钠 30mg
硬脂酸镁 5mg
700mg
2、50mg片剂
活性成分 50mg
乳糖粉 50mg
微晶纤维素 82mg
羧甲基淀粉钠 15mg
200mg
3、100mg胶囊
活性成分 100.0mg
乳糖粉 104.7mg
玉米淀粉 70.0mg
羟丙基甲基纤维素 10.0mg
二辛基磺基琥珀酸酯钠 0.3mg
滑石 12.0mg
硬脂酸镁 3.0mg
300mg
4、500mg栓剂
活性成分 500mg
栓剂基质 加至2000mg
5、100mg软明胶胶囊
活性成分 100mg
中链甘油三酯 300mg
400mg
Claims (20)
其中
Y是S或O;并且
A1是苯基,其可以被一个或多个取代基取代,所述取代基选自卤素、低级烷氧基、低级烷基、CF3、NO2、NH2、苯氧基或CF3-苯氧基;萘基;异噻唑-3-基;噻唑-2-基,其可任意地被低级烷氧基烷氧基烷基、低级烷基、低级烷氧羰基或低级乙酰氧烷基取代;噻二唑-2-基,其可任意地被低级烷硫基、低级炔硫基、环烷基-烷硫基、CF3或-NHC6H4CF3取代;喹喔啉-2-基,其可任意地被卤素或低级烷基取代;苯并噁唑-2-基;苯并三嗪,其可任意地被一个氧代基团取代;和喹啉-2-基;或
其中
R2是氢、低级烷氧羰基、CF3、低级烷基、环烷基、低级烷氧基烷基、低级烷硫基烷基或低级烷氧基;并且
A2是苯基,其可被一个或多个取代基取代,所述取代基选自低级烷基、CF3、卤素、低级烷硫基、低级烷氧基或NO2;-C(O)C6H5;-C(CH3)=CH-C6H4-低级烷基;-CH=CH-C6H5;吡啶-2-基;吡啶-3-基;吡啶-4-基;噻唑-5-基,其可任意地被低级烷基取代;噻吩-3-基,其可任意地被低级烷基取代;噻吩-2-基,其可任意地被卤素取代;喹啉-2-基;萘基,苯并[b]噻吩-2-基,其可任意地被低级烷基或卤素取代;或苯并[b]呋喃-2-基;或
其中
W是S、O、NH或CH2;
R3是氢或低级烷基;并且
其中
A4是苯基,其可被一个或多个取代基取代,所述取代基选自NO2、低级烷氧基、卤素、CF3、苯氧基、苯乙烯基-苯基或(2-CF3-或C1-苯基)-呋喃-2-基;苯并[1,3]间二氧杂环戊烯-5-基,其可任意地被卤素取代;异噁唑-4-基,其可任意地被苯基或低级烷氧基烷氧基取代;喹啉-3-基;吡啶-2-基;吡啶-3-基;吡啶-4-基;呋喃基;噻吩-2-基;噻吩-3-基;-C≡C-C(CH3)3;-C≡C-C6H5;中氮茚-2-基,其可任意地被低级烷基取代;苯并呋喃-2-基;苯并吡喃-3-基或二氢苯并[b]噻吩-5-基;或
其中
R4是氢或低级烷基;并且
A5是苯基,其可被一个或多个取代基取代,所述取代基选自低级烷基、低级烷氧基、NO2、卤素、氰基或CF3;吡啶-2-基;吡啶-4-基;喹啉-2-基;喹啉-3-基;萘基;吡咯-2-基,其可任意地被低级烷基取代;呋喃-2-基;呋喃-3-基;噻吩-2-基;噻吩-3-基,其可任意地被卤素或低级烷基取代;噻唑-2-基,其可任意地被C6H4Cl取代;噻唑-4-基,其可任意地被苯基取代;苯并[b]噻吩-2-基,其可任意地被卤素取代;或苯并[b]噻吩-3-基;或
其中
A6是苯基,其可任意地被CF3取代;或
其中
A7是苯基,其可任意地被CF3取代;或 -(CH2)n-A8 Ia8
其中
n是4;并且
A8是苯基,其可被一个或多个取代基取代,所述取代基选自CF3、
卤素或-CH=N-OCH2-CO-OCH3;萘基或吡啶-4-基;或
其中
A9是苯基,其可任意地被CF3取代;并且其中在式IB中,R6~R8是氢、低级烷基或低级烷氧基,并且Z是氢;低级烷氧基;低级烷基;或卤素或
其中
V是O、-N(CH3)-、-S-;并且
其中
m是0或1;并且
B2是苯基,其可任意地被卤素、低级烷基或CF3取代;或苯并[b]噻吩-5-基;或
其中
B3是苯基,其可任意地被CF3取代;或
其中
R5是氢、低级烷基或低级烷氧基烷基;并且
其中
B5是苯基;-C≡C-C(CH3)3;或噻吩-3-基。
2、根据权利要求1的用途,分别用于对抗氯喹敏感性和耐氯喹的病原虫以及制备相应药物。
3、式IA化合物的根据权利要求1或2的用途,所述化合物选自式IA1化合物组:
其中R1、X、Y和A1具有权利要求1中给出的含义。
5、式IA化合物的根据权利要求1或2的用途,所述化合物选自式IA3化合物组:
其中R1、X、R3、W和A3具有权利要求1中给出的含义。
6、式IA化合物的根据权利要求1或2的用途,所述化合物选自式IA4化合物组:
其中R1、X和A4具有权利要求1中给出的含义。
8、式IA化合物的根据权利要求1或2的用途,所述化合物选自式IA6化合物组:
其中R1、X和A6具有权利要求1中给出的含义。
11、式IA化合物的根据权利要求1或2的用途,所述化合物选自式IA9化合物组:
其中R1、X和A9具有权利要求1中给出的含义。
12、式IB化合物的根据权利要求1或2的用途,所述化合物选自式IB1化合物组:
其中R1、X、V和B1具有权利要求1中给出的含义。
14、式IB化合物的根据权利要求1或2的用途,所述化合物选自式IB3化合物组:
其中R1、X和B3具有权利要求1中给出的含义。
17、式IB化合物的根据权利要求1或2的用途,其中R6、R7和R8具有权利要求1中给出的含义并且Z是低级烷氧基、低级烷基、卤素或氢。
19、一种特别是用于治疗和/预防疟疾的药物,其含有一种或多种根据权利要求1-16任一项的化合物和至少一种治疗学上惰性的赋形剂。
20、如上文描述的本发明。
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AU (1) | AU748990B2 (zh) |
BR (1) | BR9810556A (zh) |
CA (1) | CA2294931A1 (zh) |
DE (1) | DE69810629T2 (zh) |
DK (1) | DK0996439T3 (zh) |
ES (1) | ES2189206T3 (zh) |
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WO (1) | WO1999002150A1 (zh) |
Cited By (2)
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CN103601716A (zh) * | 2013-11-20 | 2014-02-26 | 厦门大学 | 一种苯并噻吩取代肟醚类化合物及其制备方法与应用 |
CN103980179A (zh) * | 2014-05-29 | 2014-08-13 | 厦门大学 | 一种吲哚取代肟醚类化合物及其制备方法与应用 |
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WO2002000641A2 (en) * | 2000-06-28 | 2002-01-03 | Eli Lilly And Company | Spla2 inhibitors |
CN100443463C (zh) * | 2005-06-28 | 2008-12-17 | 沈阳化工研究院 | 取代的对三氟甲基苯醚类化合物及其制备与应用 |
WO2007113170A1 (de) * | 2006-03-29 | 2007-10-11 | Basf Se | Verwendung von strobilurinen zur behandlung von störungen des eisen-stoffwechsels |
US8772290B2 (en) | 2010-04-21 | 2014-07-08 | Oscotech Inc. | Alpha-arylmethoxyacrylate derivative, preparation method thereof, and pharmaceutical composition containing same |
KR101885219B1 (ko) | 2013-08-27 | 2018-08-14 | 시노켐 코포레이션 | 치환체 벤질옥시 그룹 함유 에테르 화합물을 포함하는 항종양제. |
WO2016063301A2 (en) * | 2014-10-21 | 2016-04-28 | Council Of Scientific & Industrial Research | Anti-malarial compounds and process for preparation thereof |
MX2017015558A (es) | 2015-06-02 | 2018-02-23 | Syngenta Participations Ag | Composiciones para el control de vectores mosquitos, metodos y productos que utilizan las mismas. |
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NZ213630A (en) * | 1984-10-19 | 1990-02-26 | Ici Plc | Acrylic acid derivatives and fungicidal compositions |
DE3519280A1 (de) * | 1985-05-30 | 1986-12-04 | Basf Ag, 6700 Ludwigshafen | Stilbenderivate und fungizide, die diese verbindungen enthalten |
GB8617648D0 (en) * | 1986-07-18 | 1986-08-28 | Ici Plc | Fungicides |
ES2052696T5 (es) * | 1987-02-09 | 2000-03-01 | Zeneca Ltd | Fungicidas. |
IL87020A (en) * | 1987-07-11 | 1996-09-12 | Schering Agrochemicals Ltd | History of acrylic acid and their use as pesticides |
ES2054025T5 (es) * | 1988-11-21 | 1998-02-16 | Zeneca Ltd | Fungicidas. |
AU4639089A (en) * | 1988-12-29 | 1990-08-01 | Ciba-Geigy Ag | Methyl esters of aldimino- or ketimino-oxy-ortho-tolylacrylic acid, manufacturing process and fungicides containing them |
DE3901607A1 (de) * | 1989-01-20 | 1990-08-16 | Basf Ag | Schwefelhaltige acrylsaeureester und diese enthaltende fungizide |
DE59008356D1 (de) * | 1989-12-14 | 1995-03-09 | Ciba Geigy Ag | Heterocyclische Verbindungen. |
PH11991042549B1 (zh) * | 1990-06-05 | 2000-12-04 | ||
DK0463488T4 (da) * | 1990-06-27 | 2004-05-10 | Basf Ag | 0-benzyloximethere og plantebeskyttelsesmidler indeholdende disse forbindelser |
DE4028391A1 (de) * | 1990-09-07 | 1992-03-12 | Basf Ag | (alpha)-arylacrylsaeurederivate, ihre herstellung und verwendung zur bekaempfung von schaedlingen und pilzen |
DE4029192A1 (de) * | 1990-09-14 | 1992-03-19 | Basf Ag | Verwendung von (alpha)-arylacrylsaeurederivaten zur bekaempfung von schaedlingen |
FR2670781B1 (fr) * | 1990-12-21 | 1994-09-16 | Roussel Uclaf | Nouveaux derives de l'acide alpha-methylene 6-styryl phenyl acrylique, leur procede de preparation et leur application comme pesticides. |
FR2670782A1 (fr) * | 1990-12-24 | 1992-06-26 | Valoris Chimie Fine Lab | Ethers couronnes acridiniques et ethers couronnes acridinoniques. |
DE4117371A1 (de) * | 1991-05-28 | 1992-12-03 | Basf Ag | Antimykotische mittel, die phenylessigsaeurederivate enthalten |
TW224042B (zh) * | 1992-04-04 | 1994-05-21 | Basf Ag |
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- 1998-07-06 TR TR2000/00005T patent/TR200000005T2/xx unknown
- 1998-07-06 DK DK98935020T patent/DK0996439T3/da active
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CN103601716A (zh) * | 2013-11-20 | 2014-02-26 | 厦门大学 | 一种苯并噻吩取代肟醚类化合物及其制备方法与应用 |
CN103980179A (zh) * | 2014-05-29 | 2014-08-13 | 厦门大学 | 一种吲哚取代肟醚类化合物及其制备方法与应用 |
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WO1999002150A1 (en) | 1999-01-21 |
BR9810556A (pt) | 2000-08-15 |
DE69810629T2 (de) | 2003-10-16 |
TR200000005T2 (tr) | 2000-09-21 |
PT996439E (pt) | 2003-04-30 |
KR20010014339A (ko) | 2001-02-26 |
US6084120A (en) | 2000-07-04 |
CN1109544C (zh) | 2003-05-28 |
AU8441198A (en) | 1999-02-08 |
ATE230718T1 (de) | 2003-01-15 |
EP0996439B1 (en) | 2003-01-08 |
CA2294931A1 (en) | 1999-01-21 |
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DE69810629D1 (de) | 2003-02-13 |
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