CN1278805A - 新的杂环取代的α-羟基羧酸衍生物、其制备及其作为内皮素受体拮抗剂的用途 - Google Patents
新的杂环取代的α-羟基羧酸衍生物、其制备及其作为内皮素受体拮抗剂的用途 Download PDFInfo
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- CN1278805A CN1278805A CN98811085A CN98811085A CN1278805A CN 1278805 A CN1278805 A CN 1278805A CN 98811085 A CN98811085 A CN 98811085A CN 98811085 A CN98811085 A CN 98811085A CN 1278805 A CN1278805 A CN 1278805A
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- phenyl
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- alkyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及式(Ⅰ)的羧酸衍生物,其中A表示NR8R9、叠氮基、OR10、SR10或C1-C4烷基,R1表示四唑或基团(1),其中R定义如下:a)基团OR5;b)通过氮原子键接的5元芳杂环;c)基团(2);d)基团(3)。而其它取代基定义如说明书。本发明还涉及本发明衍生物的制备及其作为内皮素受体拮抗剂的用途。
Description
本发明涉及新的羧酸衍生物、其制备和用途。
内皮素是由21个氨基酸构建的肽,其由血管内皮合成并释放。内皮素存在三种异构形式:ET-1、ET-2和ET-3。在下文中,“内皮素”或“ET”指内皮素的一种或所有异构形式。内皮素是强的血管收缩剂并对血管紧张具有很强的作用。已知这种血管收缩是由内皮素与其受体的结合引起的(Nature,332(1988),411-415;FEBS Letters,231(1988),440-444及Biochem.Biophys.Res.Commun.,154(1988),868-875)。
内皮素释放的增加或异常引起外周、肾和脑血管的持续血管收缩,这样可导致疾病的发生。如文献中所报道,内皮素参与了一些疾病的发病过程。这些疾病包括:高血压、急性心肌梗塞、肺动脉高血压、雷诺氏综合征、脑血管痉挛、中风、良性前列腺肥大、动脉硬化、哮喘和前列腺癌(J.Vascular Med.Biology 2(1990),207;J.Am.Med.Association 264(1990),2868;Nature 344(1990),114;N.Engl.J.Med.322(1989),205;N.Engl.J.Med.328(1993),1732;Nephron 66(1994),373;Stroke 25(1994),904;Nature365(1993),759;J.Mol.Cell.Cardiol.27(1995),A234;CancerResearch 56(1996),633;Nature Medicine 1(1995),944)。
在文献中现已描述了至少两种内皮素受体亚型,ETA和ETB受体(Nature,348,(1990),730;Nature 348(1990),732)。因此,抑制内皮素与这两种受体中的一个或两个结合的物质,应拮抗内皮素的生理作用,并于是可用于药物。
本发明的一个目的是提供内皮素受体拮抗剂,它们结合ETA和/或ETB受体。
其中R定义如下:
a)基团OR5,其中R5是:
氢原子、碱金属阳离子、碱土金属阳离子、生理可耐受的有机铵离子如叔C1-C4-烷基铵离子或铵离子;
C3-C8-环烷基、C1-C8-烷基、CH2-苯基,其可以被一个或多个下列基团取代:卤素、硝基、氰基、C1-C4-烷基、C1-C4-卤代烷基、羟基、C1-C4-烷氧基、巯基、C1-C4-烷硫基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2;
C3-C8-链烯基或C3-C8-炔基,这些基团又可带有1至5个卤原子;
R5还可以是苯基,该苯基可以带有1至5个卤原子和/或1至3个下列基团:硝基、氰基、C1-C4-烷基、C1-C4-卤代烷基、羟基、C1-C4-烷氧基、巯基、C1-C4-烷硫基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2;
b)通过氮原子连接的5元芳杂环,如吡咯基、吡唑基、咪唑基或三唑基,其可带有1或2个卤原子,或者1或2个C1-C4-烷基或者1或2个C1-C4-烷氧基。
c)基团
其中k可以是0、1或2,p是1、2、3或4,而R6是
C1-C4-烷基、C3-C8-环烷基、C3-C8-链烯基、C3-C8-炔基或苯基,其可以被下列基团单至三取代:卤素、硝基、氰基、C1-C4-烷基、羟基、C1-C4-烷氧基、C1-C4-烷硫基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、巯基。
d)基团
其中R7是:
C1-C4-烷基、C3-C8-链烯基、C3-C8-炔基、C3-C8-环烷基,这些基团可以带有C1-C4-烷氧基、C1-C4-烷硫基和/或如c)所述的苯基;
C1-C4-卤代烷基或苯基,其可以如c)所述取代。
其它取代基的含义如下:
A是NR8R9、叠氮基、OR10、SR10或C1-C4-烷基。
X是氧原子、硫原子、CR11或NR12;其条件是如果X=CR11,则Y=氧原子或硫原子或NR14。
Y是氧原子、硫原子、CR13或NR14;其条件是如果Y=氧原子或硫原子或NR14,则X=CR11。
R2和R3(可相同或不同)为:
苯基或萘基,其可以被一个或多个如下基团取代:卤素、硝基、氰基、羟基、巯基、C1-C4-烷基、C2-C4-链烯基、C2-C4-炔基、C1-C4-卤代烷基、C1-C4-烷氧基、苯氧基、C1-C4-卤代烷氧基、C1-C4-烷硫基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2或苯基,该苯基可以被如下基团单或多取代,例如,单至三取代:卤素、硝基、氰基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基或C1-C4-烷硫基;或
苯基或萘基,其通过一个直接键、亚甲基、亚乙基或亚乙烯基、氧原子或硫原子或SO2、NH或N(C1-C4-烷基)基团,在邻位与另一个基团连接;
C5-C6-环烷基,在每种情况下这些基团可以被如下基团单或多取代:卤素、羟基、巯基、羧基、硝基、氰基、C1-C4-烷基、C2-C4-链烯基、、C2-C4-炔基、C1-C4-烷氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基。
R4和R11(可相同或不同)为:
氢原子、卤素、C1-C4-烷氧基、C1-C4-卤代烷氧基、C3-C6-链烯基氧基、C3-C6-炔基氧基、C1-C4-烷硫基、C1-C4-烷基羰基、C1-C4-烷氧羰基、羟基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2;
C1-C4-烷基、C2-C4-链烯基、C2-C4-炔基,这些基团可以被卤素、羟基、巯基、羧基、氰基取代;
或者CR4与CR11一起形成5或6元亚烷基或亚烯基环,其可以无取代或被取代,且在每种情况下一个或多个亚甲基可以被氧原子、硫原子、-NH或-N(C1-C4-烷基)代替。
R8是氢原子、C1-C8-烷基、C3-C8-链烯基或C3-C8-炔基、C1-C5-烷基羰基,这些基团在每种情况下都可以被以下基团单或多取代:卤素、羟基、巯基、羧基、硝基、氨基、氰基、C1-C4-烷氧基、C3-C6-链烯基氧基、C3-C6-炔基氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基、C1-C4-烷氧羰基、C3-C8-烷基羰基烷基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、C3-C8-环烷基、苯氧基或苯基,上述芳基部分又可以被单或多取代,例如,单至三取代,取代基为卤素、羟基、巯基、羧基、硝基、氰基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、苯基或C1-C4-烷硫基;
苯基或萘基,其在每种情况下可以被一个或多个下列基团取代:卤素、硝基、氰基、羟基、氨基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、苯氧基、C1-C4-烷硫基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、二氧代亚甲基或二氧代亚乙基;
C3-C8-环烷基,在每种情况下这些基团可被如下基团单或多取代;卤素、羟基、巯基、羧基、硝基、氰基、C1-C4-烷基、C2-C4-链烯基、C2-C4-炔基、C1-C4-烷氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基;
或者R8和R9一起形成C3-C7亚烷基链闭合成环,该环可以被如下基团单或多取代:C1-C4-烷基、C1-C4-烷硫基、C1-C4-烷氧基、C1-C4-卤代烷基、C1-C4-卤代烷氧基,且其中亚烷基可以被氧原子或硫原子代替,如-(CH2)4-、-(CH2)5-、-(CH2)6-、-(CH2)7-、-(CH2)2-O-(CH2)2-、-(CH2)2-S-(CH2)2-。
R9是氢原子、C1-C4-烷基;
或者如R8中所述R9与R8连接成环。
R10是氢原子、C1-C8-烷基、C3-C8-链烯基或C3-C8-炔基,每种情况下这些基团可被如下基团单或多取代:卤素、羟基、巯基、羧基、硝基、氨基、氰基、C1-C4-烷氧基、C3-C6-链烯基氧基、C3-C6-炔基氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基、C1-C4-烷氧羰基、C3-C8-烷基羰基烷基、甲酰胺(carboxamide)、CONH(C1-C4-烷基)、CON(C1-C4-烷基)2、CONR15R16、NH(C1-C4-烷基)、N(C1-C4-烷基)2、C3-C8-环烷基、杂芳氧基或杂芳基,其中杂环是5或6元环,含有1至3个氮原子和/或硫原子或氧原子,苯氧基或苯基,上述所有芳基部分又可被如下基团单或多取代,例如,单至三取代:卤素、羟基、巯基、羧基、硝基、氰基、C1-C4-烷基、C1-C4-烷基羧基、R19、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、苯基或C1-C4-烷硫基;
苯基或萘基,其在每种情况下可以被一个或多个下列基团取代:卤素、硝基、氰基、羟基、氨基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、苯氧基、C1-C4-烷硫基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、二氧代亚甲基或二氧代亚乙基;
C3-C8-环烷基,在每种情况下这些基团可被如下基团单至三取代;卤素、羟基、巯基、羧基、硝基、氰基、C1-C4-烷基、C2-C4-链烯基、C2-C4-炔基、C1-C4-烷氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基。
R12是氢原子、C1-C4-烷基;或者NR12与CR4一起形成5或6元亚烷基或亚烯基环,该环可以被C1-C4-烷基单至三取代,并且在每种情况下,一个或多个亚甲基可以被氧原子或硫原子代替。
R13是氢原子、卤素、C1-C4-烷基、C2-C4-链烯基,这些基团可以被卤素取代。
R14是氢原子、C1-C4-烷基。
R15和R16:
R15和R16一起形成C3-C7-亚烷基或C4-C7-亚烯基链,闭合成环,在其上稠合有苯环,其可以被以下基团单至三取代:卤素、C1-C4-烷基、C1-C4-烷硫基、C1-C4-烷氧基、C1-C4-卤代烷基、C1-C4-卤代烷氧基、羟基、羧基、氨基。
R19是C1-C4-烷基、C1-C4-烷硫基、C1-C4-烷氧基,其可以带有下列基团之一:羟基、羧基、C1-C4-烷氧羰基、氨基、NH(C1-C4烷基)、N(C1-C4-烷基)2、甲酰胺或CON(C-C4-烷基)2。
下列定义在此及下文中使用:
碱金属是,例如,锂、钠、钾;
碱土金属是,例如,钙、镁、钡;
C3-C8-环烷基是,例如,环丙基、环丁基、环戊基、环己基、环庚基或环辛基;
C1-C4-卤代烷基可以是直链或支链,例如,氟甲基、二氟甲基、三氟甲基、一氯二氟甲基、二氯一氟甲基、三氯甲基、1-氟乙基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、2-氯-2,2-二氟乙基、2,2-二氯-2-氟乙基、2,2,2-三氯乙基或五氟乙基;
C1-C4-卤代烷氧基可以是直链或支链,例如,二氟甲氧基、三氟甲氧基、一氯二氟甲氧基、1-氟乙氧基、2,2-二氟乙氧基、1,1,2,2-四氟乙氧基、2,2,2-三氟乙氧基、2-氯-1,1,2-三氟乙氧基、2-氟乙氧基或五氟乙氧基;
C1-C4-烷基可以是直链或支链,例如,甲基、乙基、1-丙基、2-丙基、2-甲基-2-丙基、2-甲基-1-丙基、1-丁基或2-丁基;
C2-C4-链烯基可以是直链或支链,例如,乙烯基、1-丙-烯-3-基、2-丙烯-3-基、1-丙烯-1-基、2-甲基-1-丙烯基、1-丁烯基或2-丁烯基;
C2-C4-炔基可以是直链或支链,例如,乙炔基、1-丙炔-1-基、1-丙炔-3-基、1-丁炔-4-基或2-丁炔-4-基;
C1-C4-烷氧基可以是直链或支链,例如,甲氧基、乙氧基、丙氧基、1-甲基乙氧基、丁氧基、1-甲基丙氧基、2-甲基丙氧基或1,1-二甲基乙氧基;
C3-C6-链烯基氧基可以是直链或支链,例如,烯丙基氧基、2-丁烯-1-基氧基或3-丁烯-2-基氧基;
C3-C6-炔基氧基可以是直链或支链,例如,2-丙炔-1-基氧基、2-丁炔-1-基氧基或3-丁炔-2-基氧基;
C1-C4-烷硫基可以是直链或支链,例如,甲硫基、乙硫基、丙硫基、1-甲基乙硫基、丁硫基、1-甲基丙硫基、2-甲基丙硫基或1,1-二甲基乙硫基;
C1-C4-烷基羰基可以是直链或支链,例如,乙酰基、乙基羰基或2-丙基羰基;
C1-C4-烷氧羰基可以是直链或支链,例如,甲氧羰基、乙氧羰基、正丙氧羰基、异丙氧羰基或正丁氧羰基;
C3-C8-烷基羰基烷基可以是直链或支链,例如,2-氧代丙-1-基、3-氧代丁-1-基或3-氧代丁-2-基;
C1-C8-烷基可以直链或支链,例如,C1-C4-烷基、戊基、己基、庚基或辛基;
卤素是,例如,氟、氯、溴、碘。
本发明还涉及可以从其中释放式Ⅰ化合物的那些化合物(前药)。
优选的前药如主要在身体某些部位如胃、肠、血循环、肝中的条件下释放。
本发明还涉及上述羧酸衍生物在制备药物,特别是制备ETA和ETB受体的抑制剂中的用途。
化合物Ⅰ及其制备过程中的中间体,例如,式Ⅱ,可以具有一个或多个不对称取代的碳原子。这些化合物可以以纯对映体或纯非对映异构体或其混合物的形式存在。优选使用对映体纯的化合物作为活性化合物。
式Ⅱb的化合物,其中A是SR10或OR10,可以通过酸催化的醚交换反应,例如,描述于DE 19636046.3的方法,得到对映体纯的形式。
可以用适宜的对映体纯的碱将式Ⅱ的外消旋或非对映异构化合物进行经典拆分,进一步得到式Ⅱ的对映体纯的化合物。此类适宜的碱为,例如,4-氯苯基乙胺以及WO 96/11914中提及的碱。
本发明的化合物Ⅰa,其中A是C1-C4-烷基、叠氮基、SR10或OR10而其它取代基定义如式Ⅰ下,例如,可以通过将式Ⅱa的羧酸衍生物(其中取代基的定义如上)与式Ⅲ的化合物反应制备。
在式Ⅲ中,R17是卤素或R18-SO2,R18可以是C1-C4-烷基、C1-C4-卤代烷基或苯基。此反应优选在惰性溶剂或稀释剂中,加入适当的碱,即将中间体Ⅱa去质子化的碱,在室温至溶剂沸点的温度下进行。
如果R1是COOH的中间体Ⅱa用两个当量的适宜的碱去质子化并与化合物Ⅲ反应,则可以直接以此方式得到R1是COOH的式Ⅰa化合物。此反应也在惰性溶剂中并在室温至溶剂沸点的温度下进行。
这些溶剂或稀释剂的实例为脂族、脂环族和芳香族的烃,其中每种情况下,其可以或可以不被氯代,例如,己烷,环己烷,石油醚,石脑油,苯,甲苯,二甲苯,二氯甲烷,氯仿,四氯化碳,氯乙烷和三氯乙烯,醚如异丙醚、乙醚、丁醚、甲基叔丁基醚、1,2-环氧丙烷、二噁烷和四氢呋喃,腈如乙腈和丙腈,酰胺如二甲基甲酰胺、二甲基乙酰胺和N-甲基吡咯烷酮,亚砜和砜如二甲基亚砜和四氢噻吩砜。
式Ⅲ的化合物是已知的并可以按照一般的已知方式制备,例如:
H.Erlenmeyer,G.Bischoff,Helv.Chim.Acta,29(1946),280-283,
G.kjellin,J.Sandstr_m,Acta Chim.Scand.,23(1969),2879,
E.R.Buchmann,A.O.Reims,H.Sargent,J.Org.Chem.,6(1941),764-766,
F.C.James,H.D.Krebs,Aust.J.Chem.,35(1982),385-391,
G.R.Humphrey,S.H.B.Wright,J.heterocyclic Chem.,26(1989),23。
所用碱可以是碱金属或碱土金属氢化物如氢化钠、氢化钾或氢化钙,碳酸盐如碱金属碳酸盐,例如,碳酸钠或碳酸钾,碱金属或碱土金属氢氧化物如氢氧化钠或氢氧化钾,有机金属化合物如丁基锂或碱金属氨化物如二异丙基氨化锂或氨化锂。
式Ⅱb的化合物可以按照类似于DE 19726146.9描述的方法反应得到化合物Ⅰb。
也可以由相应的羧酸,即其中R1是COOH的式Ⅰ化合物开始,并将其先按照常规方法转变为活化形式如酰卤、酸酐或酰咪唑,然后再将其与适当的羟基化合物HOR5反应,来制备式Ⅰ的化合物。此反应可以在常规溶剂中进行,并常需要加入碱,上述碱是适宜的。这两步也可以简化,例如,通过让羧酸与此羟基化合物在脱水试剂如碳二亚胺的存在下反应。
此外,也可以由相应羧酸的盐开始制备式Ⅰ的化合物,即由R1是COOM的式Ⅰ化合物开始,M可以是碱金属阳离子或碱土金属阳离子等价物。这些盐可以与式R-W的很多化合物反应,W是常规离核离去基团,例如,卤素如氯、溴、碘或芳基或烷基磺酰基,其无取代或被卤素、烷基或卤代烷基取代,例如,甲苯磺酰基和甲磺酰基或其它等价的离去基团。具有反应性取代基W的式R-W化合物是已知的,并且按照普通技术人员的知识可容易地得到。此反应可以在常规溶剂中进行,而加入碱是有利的,上述碱是适宜的。
在一些情况下,为了制备本发明式Ⅰ的化合物,需要使用普遍已知的保护基技术。例如,如果R10=4-羟基苯基,则此羟基可以先被保护为苄基醚,其在随后反应的适当步骤中再裂解掉。
可以按照WO 96/11914所述制备R1是四唑的式Ⅰ化合物。
考虑到生物作用,对于式Ⅰ的羧酸衍生物,不论是纯对映体还是非对映异构体或其混合物,优选取代基含义如下:
A是NR8R9、叠氮基、OR10、SR10或C1-C4-烷基。
X是氧原子、硫原子、CR11或NR12;其条件是如果X=CR11,则Y=氧原子或硫原子或NR14。
Y是氧原子、硫原子、CR13或NR14;其条件是如果Y=氧原子或硫原子或NR14,则X=CR11。
R2和R3(可相同或不同)为:
苯基或萘基,其可以被一个或多个如下基团取代:卤素、氰基、羟基、巯基、氨基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、苯氧基、C1-C4-烷硫基、NH(C1-C4-烷基)、N(C1-C4-烷基)2或苯基,该苯基可以被如下基团单至三取代:卤素、氰基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基或C1-C4-烷硫基;或
苯基或萘基,其通过一个直接键、亚甲基、亚乙基或亚乙烯基、氧原子或硫原子或SO2、NH或N(C1-C4-烷基)基团,在邻位与另一个基团连接;
C5-C6-环烷基,在每种情况下这些基团可能被如下基团单至三取代:卤素、C1-C4-烷基、C1-C4-烷氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基。
R4和R11(可相同或不同)为:
C1-C4-烷基,这些基团可以被卤素、羟基取代;
氢原子、卤素、C1-C4-烷氧基、C1-C4-卤代烷氧基、C1-C4-烷硫基、羟基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2;
或者CR4与CR11一起形成5或6元亚烷基或亚烯基环,其可以被C1-C4-烷基单至三取代,且在每种情况下一个至三个亚甲基可以被氧原子或硫原子代替。
R8氢原子、C1-C8-烷基、C1-C5-烷基羰基,这些基团在每种情况下都可以被以下基团单至三取代:卤素、羟基、羧基、氨基、C1-C4-烷氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基、C1-C4-烷氧羰基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、C5-C6-环烷基、苯氧基或苯基,上述芳基部分可以被单至三取代,取代基为卤素、羟基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、苯基或C1-C4-烷硫基;
苯基或萘基,其在每种情况下可以被一个至三个下列基团取代:卤素、羟基、氨基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、苯氧基、C1-C4-烷硫基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、二氧代亚甲基或二氧代亚乙基;
C3-C8-环烷基,在每种情况下这些基团可被如下基团单至三取代:卤素、C1-C4-烷基、C1-C4-烷氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基;
或者R8和R9一起形成C4-C6亚烷基链闭合成环,该环可以被如下基团单至三取代:C1-C4-烷基、C1-C4-卤代烷基,且其中亚烷基可以被氧原子或硫原子代替,如-(CH2)4-、-(CH2)5-、-(CH2)6-、-(CH2)2-O-(CH2)2-、-(CH2)2-S-(CH2)2-。
R9是氢原子、C1-C4-烷基;
或者如R8中所述R9与R8连接成环。
R10是氢原子、C1-C8-烷基、C3-C8-链烯基或C3-C8-炔基,每种情况下这些基团可被如下基团单至三取代:卤素、羟基、巯基、羧基、氨基、C1-C4-烷氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基、C1-C4-烷氧羰基、甲酰胺、CONH(C1-C4-烷基)、CON(C1-C4-烷基)2、CONR15R16、NH(C1-C4-烷基)、N(C1-C4-烷基)2、C5-C6-环烷基、苯氧基或苯基,其中上述芳基部分又可被如下基团单至三取代:卤素、羟基、C1-C4-烷基、C1-C4-烷基羧基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、苯基、C1-C4-烷硫基或R19;
苯基或萘基,其在每种情况下可以被一个至三个下列基团取代:卤素、羟基、氨基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、C1-C4-烷硫基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、二氧代亚甲基或二氧代亚乙基;
C3-C8-环烷基,在每种情况下这些基团可被如下基团单至三取代:卤素、C1-C4-烷基、C1-C4-烷氧基、C1-C4-卤代烷基。
R12是氢原子、甲基;或者
NR12与CR4一起形成5或6元亚烷基环,该环可以被甲基单至三取代。
R13是氢原子、卤素、C1-C4-烷基,这些基团可以被卤素一至三取代。
R14是氢原子、甲基。
R15和R16:
R15和R16一起形成C3-C7-亚烷基或C4-C7-亚烯基链,闭合成环,在其上稠合有苯环,如7-氮杂-双环[4.2.0]-辛-1,3,5-三烯、2,3-二氢吲哚、吲哚、1,3-二氢异吲哚、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉,其中苯环可以被以下基团单至三取代:卤素、C1-C4-烷基、C1-C4-烷氧基、C1-C4-卤代烷基、C1-C4-卤代烷氧基。
R19是甲基、乙基、甲氧基或乙氧基,其带有下列基团之一:羟基、羧基、C1-C4-烷氧羰基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、甲酰胺或CON(C-C4-烷基)2。
特别优选的式Ⅰ化合物(纯对映体或非对映异构体或其混合物)为取代基含义如下的化合物:
A是NR8R9、叠氮基、OR10、SR10或C1-C4-烷基。
X是氧原子、硫原子或CR11;其条件是如果X=CR11,则Y=氧原子或硫原子。
Y是氧原子、硫原子或CR13;其条件是如果Y=氧原子或硫原子,则X=CR11。
R2和R3(可相同或不同)为:
苯基或萘基,其可以被一个至三个如下基团取代:卤素、羟基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、苯氧基或苯基,其又可以被如下基团单至三取代:卤素、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基或C1-C4-卤代烷氧基;或
苯基或萘基,其通过一个直接键、亚甲基、亚乙基或亚乙烯基、氧原子或硫原子或SO2、NH或N(C1-C4-烷基)基团,在邻位与另一个基团连接;
环己基。
R4和R11(可相同或不同)为:
氢原子、卤素、C1-C4-烷基、三氟甲基、羟基亚甲基、C1-C4-烷氧基、C1-C4-烷硫基、N(C1-C4-烷基)2;
或者CR4与CR11一起形成5或6元亚烷基或亚烯基环,其可以被甲基单或二取代,且在每种情况下一个亚甲基可以被氧原子代替。
R8是氢原子、C1-C4-烷基、C1-C4-烷基羰基,这些基团在每种情况下都可以被以下基团单至三取代:卤素、羟基、羧基、氨基、C1-C4-烷氧基、C1-C4-烷硫基、C1-C4-卤代烷氧基、C1-C4-烷氧羰基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、C5-C6-环烷基、或苯基,其又可以被单至三取代,取代基为卤素、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、C1-C4-烷硫基;
苯基,其在每种情况下可以被一个至三个下列基团取代:卤素、羟基、C1-C4-烷基、三氟甲基、C1-C4-烷氧基、C1-C4-烷硫基、二氧代亚甲基或二氧代亚乙基;
C5-C6-环烷基,在每种情况下这些基团可被如下基团单至三取代:卤素、C1-C4-烷基、C1-C4-烷氧基;
或者R8和R9一起形成C4-C6亚烷基链闭合成环,该环可以被如下基团单至三取代:C1-C4-烷基、C1-C4-卤代烷基,且其中亚烷基可以被氧原子代替,如-(CH2)4-、-(CH2)5-、-(CH2)6-、-(CH2)2-O-(CH2)2-。
R9是氢原子、C1-C4-烷基;
或者如R8中所述R9与R8连接成环。
R10是氢原子、C1-C4-烷基,每种情况下这些基团可被如下基团单至三取代:卤素、羟基、羧基、C1-C4-烷氧基、C1-C4-烷氧羰基、甲酰胺、CONH(C1-C4-烷基)、CON(C1-C4-烷基)2、CONR15R16、NH(C1-C4-烷基)、N(C1-C4-烷基)2、C5-C6-环烷基、苯基,其又可被如下基团单至三取代:卤素、羟基、C1-C4-烷基、C1-C4-烷基羧基、三氟甲基、C1-C4-烷氧基、NH(C1-C4-烷基)、R19、N(C1-C4-烷基)2、苯基或C1-C4-烷硫基;
苯基,其在每种情况下可以被一个至三个下列基团取代:卤素、羟基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-烷硫基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、二氧代亚甲基或二氧代亚乙基;
C3-C8-环烷基,在每种情况下这些基团可被如下基团单至或多取代:卤素、C1-C4-烷基、C1-C4-烷氧基。
R13是氢原子、卤素、C1-C4-烷基、三氟甲基。
R15和R16:
R15和R16一起形成C3-C7-亚烷基,闭合成环,在其上稠合有苯环,如2,3-二氢吲哚、吲哚、1,3-二氢异吲哚、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉,其中苯环可以被以下基团单至三取代:卤素、C1-C4-烷基、C1-C4-烷氧基、羟基;
R19是甲氧基或乙氧基,其带有下列基团之一:羟基、羧基、C1-C4-烷氧羰基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2、甲酰胺或CON(C-C4-烷基)2。
本发明化合物给治疗高血压、肺动脉高血压、心肌梗塞、心绞痛、心律失常、急性/慢性肾衰、慢性心脏功能不全、肾功能不全、脑血管痉挛、脑局部缺血、蛛网膜下出血、片头痛、哮喘、动脉硬化、中毒性休克、内毒素引起的器官衰竭、血管内凝血、血管成形术及搭桥术后再狭窄、良性前列腺增生、肾衰竭或局部缺血及中毒引起的高血压、间质肿瘤的转移和生长如前列腺瘤、造影剂引起的肾衰竭、胰腺炎、胃肠道溃疡提供了新的治疗潜力。
本发明还涉及式Ⅰ的内皮素受体拮抗剂和肾素-血管紧张素系统抑制剂的联合形式。肾素-血管紧张素系统的抑制剂是肾素抑制剂、血管紧张素Ⅱ拮抗剂和血管紧张素转化酶(ACE)抑制剂。优选式Ⅰ的内皮素受体拮抗剂和ACE抑制剂的联合形式。
本发明还涉及式Ⅰ的内皮素受体拮抗剂与钙离子拮抗剂如维拉帕米的联合形式。
本发明还涉及式Ⅰ的内皮素受体拮抗剂与β-阻断剂的联合形式。
本发明还涉及式Ⅰ的内皮素受体拮抗剂与利尿剂的联合形式。
本发明还涉及式Ⅰ的内皮素受体拮抗剂与阻断VEGF(血管内皮生长因子)作用的物质的联合形式。这些物质为,例如,直接抗VEGF的抗体或特异性结合蛋白或另类低分子量物质,它们可以特异性地抑制VEGF释放或受体结合。
上述联合形式可以同时或连续给药。它们可以以单一药物制剂的形式使用,或以分离的直接的形式使用。此给药形式也可以不同,例如,内皮素受体拮抗剂可以口服,而VEGF抑制剂可以非肠道给药。
这些联合制剂特别适于治疗和预防高血压及其后遗症,并也适于治疗心功能不全。
这些化合物的良好作用可以从下列的实验中看出:
受体结合研究
对于结合研究,使用克隆的表达人ETA或ETB受体的CHO细胞。
膜制备
将表达了ETA或ETB受体的CHO细胞在DMEM NUT MIX F12培养基(Gibco,No.21331-020)中,其中含有10%胎牛血清(PAALaboratories GmbH,Linz,No.A15-022)、1mM谷酰胺(Gibco,No.25030-024)、100U/ml的青霉素和100μg/ml的链霉素(Gibco,SimgaNo P-0781)。48小时后,用PBS洗涤这些细胞并用含0.05%胰蛋白酶的PBS在37℃孵育5分钟。用培养基中和,并通过以300×g离心收集细胞。
为了制备膜,将细胞的浓度调节为108细胞/ml缓冲液(50mMTris-HCl缓冲液,pH 7.4),并随后通过超声Branson Sonifier 250分裂,仪器参数以40-70秒/常数/输出20)。
结合实验
对于ETA或ETB受体结合实验,将膜悬浮于孵育缓冲液(50mMTris-HCl,pH 7.4和5mM MnCl2,40mg/ml杆菌肽和0.2%BSA)中,其中每个实验批号中浓度为50μg蛋白质,并在25℃与25 pM[125I]-ET1(ETA受体实验)或25 pM[125I]-ET3(ETB受体实验)一起,在被测物质存在或不存在下孵育。用10-7M ET1测定非特应性结合。30分钟后,通过GF/B玻璃纤维过滤器(Whatman,英国)在Skatron细胞收集器(Skatron,Lier,Norway)上过滤分裂游离和结合的放射配体,并用冰冷的含0.2% BSA的Tris-HCl缓冲液(pH 7.4)洗涤过滤器。用Packard 2200 CA液体闪烁计数器对过滤器中收集的放射活性进行定量检测。
体内实验ET拮抗剂:
用异戊巴比妥麻醉重250-300g的雄性SD大鼠,进行气管插管、切断迷走神经并刺毁脑脊髓。将颈动脉和颈静脉进行插管。
在对照的动物中,静脉注射1mg/kg的ET1,产生明显的血压升高,其持续较长的时间。
在ET1使用前30分钟,给实验动物静脉注射(1ml/kg)被测化合物。为了测定ET-拮抗性,将实验动物的血压变化与对照动物的进行比较。
p.o.实验混合的ETA或ETB拮抗作用:
口服被测物质以预处理重250-350g的雄性张力正常的大鼠。80分钟后,用尿烷麻醉动物,并进行颈动脉插管(检测血压)和颈静脉插管(以进行大量内皮素/内皮素1给药)。
稳定阶段后,静脉内使用大的内皮素(20μg/kg,给药量0.5ml/kg)或ET1(0.3μg/kg,给药量0.5ml/kg)。30分钟内,连续记录血压和心率。以曲线下面积(AUC)计算明显和持续时间长的血压变化。为了确定被测物质的拮抗作用,比较该物质处理动物和对照动物的AUC。
本发明的化合物可以口服或非肠道(皮下、静脉、肌内、腹膜内)以常规的方式给药。给药也可通过鼻咽途径用气雾剂或喷雾剂进行。
剂量依赖于患者的年龄、状况和体重,并也依赖于给药方式。一般来说,每天活性化合物剂量,对于口服为约0.5至100mg/kg体重,而对于非肠道给药为0.1至10mg/kg体重。
这些新化合物可以以固体或液体形式给药,给药剂型为常规药物剂型,例如,片剂、膜包衣片剂、胶囊、散剂、颗粒剂、糖锭剂、栓剂、溶液剂、软膏、霜剂或喷雾剂。它们是以常规方式制备的。此情况下,这些活性化合物可以与常规药物辅剂一起加工,如片剂粘合剂、填充剂、防腐剂、片剂崩解剂、流动调节剂、增塑剂、湿润剂、分散剂、乳化剂、溶剂、释放延迟剂、抗氧剂和/或抛射剂(参见H.Sucker等:Pharmazeutische Technologie[药物学技术],Thieme-Verlag,Stuttgart,1991)。所得施用剂型一般含约0.1至90%(重量)的活性化合物。
合成实施例
实施例1:
2-甲基磺酰基-4,5-二甲基噻唑
在冰浴下,先将2.7g 2-甲硫基-4,5-二甲基噻唑加入二氯甲烷中,并加入5.9g mCPBA。将此反应在室温下搅拌16小时,然后用碳酸氢钠溶液和硫代硫酸钠溶液各萃取一次。用硫酸镁干燥有机相,将溶剂蒸馏掉,分离出2.88g油状物,将其直接用于下步反应。1H-NMR(200 MHz):3.25 ppm(3 H,s),2.50(3 H,s),2.40(3 H,s)。ESI-MS:M+=191
实施例2:
2-甲硫基-4,5-环戊烯并噻唑
先将10.4g二硫代氨基甲酸铵加入到乙醇中,并加入7.5g 2-氯环戊酮。30分钟后,反应完毕并将此反应混合物加入到水中。用氢氧化钠溶液将水相调节为强碱性,用二氯甲烷萃取,然后用浓盐酸调节pH至2。用乙酸乙酯萃取水相,用硫酸镁干燥此有机相,并蒸馏掉溶剂。将此残余物在甲苯中回收,加入一药刀尖量的对甲苯磺酸,并在60℃下蒸馏掉溶剂。将7.9g油状物溶解于75ml水和2.4g氢氧化钠中,并快速滴加5.7ml硫酸二甲酯。1小时后,反应完毕,并将此混合物加入到水中。用乙醚萃取水相,用硫酸镁干燥此有机相,并蒸馏掉溶剂。不经纯化将此残余物直接用于下步反应。
实施例3:
2-甲基磺酰基-4,5-环戊烯并噻唑
冰浴下,先将1.9g 2-甲硫基-4,5-环戊烯并噻唑加入到二氯甲烷中,并加入7.3g mCPBA。将此反应在室温下搅拌16小时,然后用1N氢氧化钠溶液和硫代硫酸钠溶液各萃取一次。用硫酸镁干燥有机相,将溶剂蒸馏掉,分离出2.25g油状物,将其直接用于下步反应。1H-NMR (200 MHz): 3.26 ppm (3H,s), 3.05 (2H,dd), 2.95(2H,dd), 2.55 (2H,dddd).ESI-MS:M+=203
实施例4:
2-甲基磺酰基-4,5-二甲基噁唑
在冰浴温度下,将3g 2-甲硫基-4,5-二甲基噁唑溶解于100ml二氯甲烷中,并加入13g mCPBA。将此反应搅拌3小时,然后加入硫代硫酸钠溶液。用碳酸氢钠中和,并用二氯甲烷萃取产物。用硫酸镁干燥后,蒸馏掉溶剂,分离出2g粗品,可将其直接用于下步反应。1H-NMR (200 MHz): 3.30 ppm (3H,s), 2.35(3H,s), 2.15(3H,s)。ESI-MS:M+=175
实施例5:
(S)-2-(4,5-二甲基噻唑-2-基氧基)-3-甲氧基-3,3-二苯基-丙酸(Ⅰ-1)
将320mg的55%氢化钠加入到1g S-2-羟基-3-甲氧基-3,3-二苯基丙酸在20ml THF/20ml DMF的混合物中,并将此混合物搅拌15分钟。向此混合物中加入700mg 2-甲基磺酰基-4,5-二甲基噻唑,并在室温下搅拌16小时。用水处理此反应,并用枸橼酸将此混合物酸化,并用乙醚萃取产物。用硫酸镁干燥并蒸馏掉溶剂后,将其进行色谱纯化,并用乙醚/正己烷将此产物结晶。分离出522mg结晶。1H-NMR (200 MHz): 7.35-7.20 ppm (10H,m), 6.25 (1H,s), 3.30(3H,s), 2.25(3H,s), 2.20 (3H,s)。ESI-MS:M+=383
实施例6:
2-(4,5-环戊烯并噻唑-2-基氧基)-3-(2-(3,4-二甲氧基苯基)-乙氧基)-3,3-二苯基丙酸(Ⅰ-17)1H-NMR (200 MHz):7.30-7.20 ppm(10H,m),6.80-6.60(3H,m),6.25(1H,s),3.85(3H,s),3.80(3H,s),3.70-3.40(2H,m),2.9-2.6(4H,m),2.30-2.25(2H,m)。ESI-MS:M+=545
2-(4,5-二甲基噁唑-2-基氧基)-3-(2-(3,4-二甲氧基苯基)-乙氧基)-3,3-二苯基丙酸(Ⅰ-15)1H-NMR (200 MHz):7.30-7.20 ppm(10H,m),6.80-6.60(3H,m),6.00(1H,s),3.85(3H,s),3.80(3H,s),3.70-3,40(2H,m),2.80(2H,tr),2.10(3H,s),1.90(3H,s)。ESI-MS:M+=517
(S)-2-(苯并噻唑-2-基氧基)-3-甲氧基-3,3-二苯基丙酸(Ⅰ-6)1H-NMR (200 MHz):7.70-7.50(2H,m),7.35-7.20(12H,m),6.50(1H,s),3.30(3H,s)。ESI-MS:M+=405
(S)-2-(4,5-环戊烯并噻唑-2-基氧基)-3-甲氧基-3,3-二苯基丙酸(Ⅰ-5)1H-NMR (200 MHz):7.50-7.20 ppm(10H,m),6.40(1H,s),3.30(3H,s),2.80-2.60(4H,m),2.30(2H,m)。ESI-MS:M+=395
(S)-2-(4,5-二甲基噁唑-2-基氧基)-3-甲氧基-3,3-二苯基丙酸(Ⅰ-5)1H-NMR(200 MHz):7.50-7.20ppm(10H,m),6.10(1H,s),3.25(3H,s),2.1(3H,s),1.90(3H,s)。ESI-MS:M+=367
(S)-2-(4,5-二甲基噻唑-2-基氧基)-3-(2-(3,4-二甲氧基苯基)-乙氧基)-3,3-二苯基丙酸(Ⅰ-13)1H-NMR (200 MHz):7.30-7.20ppm(10H,m),6.70-6.50(3H,m),6.20(1H,s),3.90(3H,s),3.85(3H,s),3.70-3.40(2H,m),2.80(2H,tr),2.20(3H,s),1.15(3H,s)。ESI-MS:M+=533。
表Ⅰ中的化合物可以类似地制备或如一般方法所述制备。
表Ⅰ
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-1 | COOH | 苯基 | MeO | CMe | Me | S |
Ⅰ-2 | COOH | 4-Cl-苯基 | MeO | CMe | Me | S |
Ⅰ-3 | COOH | 4-F-苯基 | MeO | CMe | Me | S |
Ⅰ-4 | COOH | 苯基 | MeO | CMe | Me | O |
Ⅰ-5 | COOH | 苯基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-6 | COOH | 苯基 | MeO | C-CH=CH-CH=CH | S | |
Ⅰ-7 | COOH | 苯基 | (4-MeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-8 | COOH | 苯基 | (4-MeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-9 | COOH | 4-F-苯基 | (4-MeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-10 | COOH | 4-Cl-苯基 | (4-MeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-11 | COOH | 苯基 | (4-MeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-12 | COOH | 苯基 | (4-MeO-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-13 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-14 | COOH | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-15 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-16 | COOH | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-17 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-18 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-19 | COOH | 苯基 | (4-MeO-苯基)CH2O | CMe | Me | S |
Ⅰ-20 | COOH | 4-F-苯基 | (4-MeO-苯基)CH2O | CMe | Me | S |
Ⅰ-21 | COOH | 4-Cl-苯基 | (4-MeO-苯基)CH2O | CMe | Me | S |
Ⅰ-22 | COOH | 苯基 | (4-MeO-苯基)CH2O | CMe | Me | O |
Ⅰ-23 | COOH | 苯基 | (4-MeO-苯基)CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-24 | COOH | 苯基 | (4-MeO-苯基)CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-25 | COOH | 苯基 | (4-MeO-苯基)O | CMe | Me | S |
Ⅰ-26 | COOH | 苯基 | (4-MeO-苯基)O | CMe | Me | O |
Ⅰ-27 | COOH | 苯基 | (4-MeO-苯基)O | C-CH2-CH2-CH2 | S | |
Ⅰ-28 | COOH | 苯基 | (4-MeO-苯基)O | C-CH=CH-CH=CH | S | |
Ⅰ-29 | COOH | 苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-30 | COOH | 4-Cl-苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-31 | COOH | 苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-32 | COOH | 4-F-苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-33 | COOH | 苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-34 | COOH | 苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-35 | COOH | 4-F-苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-36 | COOH | 苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-37 | COOH | 苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-38 | COOH | 4-Cl-苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-39 | COOH | 苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-40 | COOH | 苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | C-CH=CH | -CH=CH | S |
Ⅰ-41 | COOH | 苯基 | (3-MeO-4-Me2NCH2CH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-42 | COOH | 4-F-苯基 | (3-MeO-4-Me2NCH2CH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-43 | COOH | 4-Cl-苯基 | (3-MeO-4-Me2NCH2CH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-44 | COOH | 苯基 | (3-MeO-4-Me2NCH2CH2O-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-45 | COOH | 苯基 | (3-MeO-4-Me2NCH2CH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-46 | COOH | 苯基 | (3-MeO-4-Me2NCH2CH2O-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-47 | COOH | 苯基 | (4-HO2C-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-48 | COOH | 苯基 | (4-HO2C-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-49 | COOH | 苯基 | (4-HO2C-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-50 | COOH | 苯基 | (4-HO2C-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-51 | COOH | 苯基 | (4-HO2C-苯基)CH2O | CMe | Me | S |
Ⅰ-52 | COOH | 苯基 | (4-HO2C-苯基)CH2O | CMe | Me | O |
Ⅰ-53 | COOH | 4-F-苯基 | (4-HO2C-苯基)CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-54 | COOH | 苯基 | (4-HO2C-苯基)CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-55 | COOH | 苯基 | (4-HO2C-苯基)CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-56 | COOH | 苯基 | (4-Me-苯基)O | CMe | Me | S |
Ⅰ-57 | COOH | 4-F-苯基 | (4-Me-苯基)O | CMe | Me | S |
Ⅰ-58 | COOH | 4-Cl-苯基 | (4-Me-苯基)O | CMe | Me | S |
Ⅰ-59 | COOH | 苯基 | (4-Me-苯基)O | CMe | Me | O |
Ⅰ-60 | COOH | 苯基 | (4-Me-苯基)O | C-CH2-CH2-CH2 | S | |
Ⅰ-61 | COOH | 苯基 | (4-Me-苯基)O | C-CH=CH-CH=CH | S | |
Ⅰ-62 | COOH | 苯基 | (4-Me-苯基)CH2O | CMe | Me | S |
Ⅰ-63 | COOH | 苯基 | (4-Me-苯基)CH2O | CMe | Me | O |
Ⅰ-64 | COOH | 苯基 | (4-Me-苯基)CH2O | C-CH2-CH2-CH2 | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-65 | COOH | 4-F-苯基 | (4-Me-苯基)CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-66 | COOH | 苯基 | (4-Me-苯基)CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-67 | COOH | 苯基 | (4-Cl-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-68 | COOH | 苯基 | (4-Cl-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-69 | COOH | 苯基 | (4-Cl-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-70 | COOH | 苯基 | (4-Cl-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-71 | COOH | 苯基 | (4-Me-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-72 | COOH | 苯基 | (4-Me-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-73 | COOH | 苯基 | (4-Me-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-74 | COOH | 苯基 | (4-Me-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-75 | COOH | 苯基 | (3-HO2CCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-76 | COOH | 4-Cl-苯基 | (3-HO2CCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-77 | COOH | 4-l)-苯基 | (3-HO2CCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-78 | COOH | 苯基 | (3-HO2CCH2O-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-79 | COOH | 苯基 | (3-HO2CCH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-80 | COOH | 苯基 | (3-HO2CCH2O-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-81 | COOH | 苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-82 | COOH | 4-F-苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-83 | COOH | 4-Cl-苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-84 | COOH | 苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-85 | COOH | 苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-86 | COOH | 苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-87 | COOH | 苯基 | (3-Me2NCH2CH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-88 | COOH | 苯基 | (3-Me2NCH2CH2O-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-89 | COOH | 苯基 | (3-Me2NCH2CH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-90 | COOH | 苯基 | (3-Me2NCH2CH2O-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-91 | COOH | 苯基 | N-Me-N-苯基-NOCCH2O | CMe | Me | S |
Ⅰ-92 | COOH | 4-F-苯基 | N-Me-N-苯基-NOCCH2O | CMe | Me | S |
Ⅰ-93 | COOH | 4-Cl-苯基 | N-Me-N-苯基-N0CCH2O | CMe | Me | S |
Ⅰ-94 | COOH | 苯基 | N-Me-N-苯基-NOCCH2O | CMe | Me | O |
Ⅰ-95 | COOH | 苯基 | N-Me-N-苯基-NOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-96 | COOH | 苯基 | N-Me-N-苯基-NOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-97 | COOH | 苯基 | N-Bu-N-苯基-NOCCH2O | CMe | Me | S |
Ⅰ-98 | COOH | 4-F-苯基 | N-Bu-N-苯基-NOCCH2O | CMe | Me | S |
Ⅰ-99 | COOH | 4-Cl-苯基 | N-Bu-N-苯基-NOCCH2O | CMe | Me | S |
Ⅰ-100 | COOH | 苯基 | N-Bu-N-苯基-NOCCH2O | CMe | Me | O |
Ⅰ-10l | COOH | 苯基 | N-Bu-N-苯基-NOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-102 | COOH | 苯基 | N-Bu-N-苯基-NOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-103 | COOH | 苯基 | Bu2NOCCH2O | CMe | Me | S |
Ⅰ-104 | COOH | 苯基 | Bu2NOCCH2O | CMe | Me | S |
Ⅰ-105 | COOH | 4-F-苯基 | Bu2NOCCH2O | CMe | Me | S |
Ⅰ-106 | COOH | 4-Cl-苯基 | Bu2NOCCH2O | CMe | Me | O |
Ⅰ-107 | COOH | 苯基 | Bu2NOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-108 | COOH | 苯基 | Bu2NOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-109 | COOH | 苯基 | 苯基-HNOCCH2O | CMe | Me | S |
Ⅰ-110 | COOH | 4-Cl-苯基 | 苯基-HNOCCH2O | CMe | Me | S |
Ⅰ-111 | COOH | 4-F-苯基 | 苯基-HNOCCH2O | CMe | Me | S |
Ⅰ-112 | COOH | 苯基 | 苯基-HNOCCH2O | CMe | Me | O |
Ⅰ-113 | COOH | 苯基 | 苯基-HNOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-114 | COOH | 苯基 | 苯基-HNOCCH2O | C-CH=CH-CH=CH | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-115 | COOH | 苯基 | (2,6-二乙基-苯基)-HNOCCH2O | CMe | Me | S |
Ⅰ-116 | COOH | 4-Cl-苯基 | (2,6-二乙基-苯基)-HNOCCH2O | CMe | Me | S |
Ⅰ-117 | COOH | 4-F-苯基 | (2,6-二乙基-苯基)-HNOCCH2O | CMe | Me | S |
Ⅰ-118 | COOH | 苯基 | (2,6-二乙基-苯基)-HNOCCH2O | CMe | Me | O |
Ⅰ-119 | COOH | 苯基 | (2,6-二乙基-苯基)-HNOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-120 | COOH | 苯基 | (2,6-二乙基-苯基)-HNOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-121 | COOH | 苯基 | (-CH2CH2CH2CH2CH2CH2-)NOCCH2O | CMe | Me | S |
Ⅰ-122 | COOH | 苯基 | (-CH2CH2CH2CH2CH2CH2-)NOCCH2O | CMe | Me | O |
Ⅰ-123 | COOH | 苯基 | (-CH2CH2CH2CH2CH2CH2-)NOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-124 | COOH | 苯基 | (-CH2CH2CH2CH2CH2CH2-)NOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-125 | COOH | 苯基 | (-CH2CH2CH2CH2-)NOCCH2O | CMe Me | S | |
Ⅰ-126 | COOH | 苯基 | (-CH2CH2CH2CH2-)NOCCH2O | CMe | Me | O |
Ⅰ-127 | COOH | 苯基 | (-CH2CH2CH2CH2-)NOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-128 | COOH | 苯基 | (-CH2CH2CH2CH2-)NOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-129 | COOH | 苯基 | Me | CMe | Me | S |
Ⅰ-130 | COOH | 4-F苯基 | Me | CMe | Me | S |
Ⅰ-131 | COOH | 4-Cl-苯基 | Me | CMe | Me | S |
Ⅰ-132 | COOH | 苯基 | Me | CMe | Me | O |
Ⅰ-133 | COOH | 苯基 | Me | C-CH2-CH2-CH2 | S | |
Ⅰ-134 | COOH | 苯基 | Me | C-CH=CH-CH=CH | S | |
Ⅰ-135 | COOH | 苯基 | MeS | CMe | Me | S |
Ⅰ-136 | COOH | 4-F-苯基 | MeS | CMe | Me | S |
Ⅰ-137 | COOH | 4-Cl-苯基 | MeS | CMe | Me | S |
Ⅰ-138 | COOH | 苯基 | MeS | CMe | Me | O |
Ⅰ-139 | COOH | 4-F-苯基 | MeS | C-CH2-CH2-CH2 | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-140 | COOH | 苯基 | MeS | C-CH2-CH2-CH2 | S | |
Ⅰ-141 | COOH | 苯基 | MeS | C-CH=CH-CH=CH | S | |
Ⅰ-142 | COOH | 苯基 | CH3CONH | CMe | Me | S |
Ⅰ-143 | COOH | 4-F-苯基 | CH3CONH | CMe | Me | S |
Ⅰ-144 | COOH | 4-Cl-苯基 | CH3CONH | CMe | Me | S |
Ⅰ-145 | COOH | 苯基 | CH3CONH | CMe | Me | O |
Ⅰ-146 | COOH | 苯基 | CH3CONH | C-CH2-CH2-CH2 | S | |
Ⅰ-147 | COOH | 苯基 | CH3CONH | C-CH=CH-CH=CH | S | |
Ⅰ-148 | COOH | 苯基 | (CH3)3CCONH | CMe | Me | S |
Ⅰ-149 | COOH | 4-F-苯基 | (CH3)3CCONH | CMe | Me | S |
Ⅰ-150 | COOH | 4-Cl-苯基 | (CH3)3CCONH | CMe | Me | S |
Ⅰ-15l | COOH | 苯基 | (CH3)3CCONH | CMe | Me | O |
Ⅰ-152 | COOH | 苯基 | (CH3)3CCONH | C-CH2-CH2-CH2 | S | |
Ⅰ-153 | COOH | 苯基 | (CH3)3CCONH | C-CH=CH-CH=CH | S | |
Ⅰ-154 | COOH | 苯基 | (-CH2CH2-)CHCONH | CMe | Me | S |
Ⅰ-155 | COOH | 苯基 | (-CH2CH2-)CHCONH | CMe | Me | |
Ⅰ-156 | COOH | 苯基 | (-CH2CH2-)CHCONH | C-CH2-CH2-CH2 | S | |
Ⅰ-157 | COOH | 苯基 | (-CH2CH2-)CHCONH | C-CH=CH-CH=CH | S | |
Ⅰ-158 | COOH | 苯基 | Et | CMe | Me | S |
Ⅰ-159 | COOH | 苯基 | Et | CMe | Me | O |
Ⅰ-160 | COOH | 苯基 | Et | C-CH2-CH2-CH2 | S | |
Ⅰ-16l | COOH | 苯基 | Et | C-CH=CH-CH=CH | S | |
Ⅰ-162 | COOH | 苯基 | 苯基-CH2CH2S | CMe | Me | S |
Ⅰ-163 | COOH | 苯基 | 苯基-CH2CH2S | CMe | Me | O |
Ⅰ-164 | COOH | 苯基 | 苯基-CH2CH2S | C-CH2-CH2-CH2 | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-165 | COOH | 苯基 | 苯基-CH2CH2S | C-CH=CH-CH=-H | S | |
Ⅰ-166 | COOH | 苯基 | (4-MeS-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-167 | COOH | 4-Cl-苯基 | (4-MeS-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-168 | COOH | 4-F-苯基 | (4-MeS-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-169 | COOH | 苯基 | (4-MeS-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-170 | COOH | 苯基 | (4-MeS-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-17l | COOH | 苯基 | (4-MeS-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-172 | CONHSO2Me | 苯基 | Me | CMe | Me | S |
Ⅰ-173 | CONHSO2Me | 4-F-苯基 | Me | CMe | Me | S |
Ⅰ-174 | CONHSO2Me | 4-Cl-苯基 | Me | CMe | Me | S |
Ⅰ-175 | CONHSO2Me | 苯基 | Me | CMe | Me | O |
Ⅰ-176 | CONHSO2Me | 苯基 | Me | C-CH2-CH2-CH2 | S | |
Ⅰ-177 | CONHSO2Me | 苯基 | Me | C-CH=CH-CH=CH | S | |
Ⅰ-178 | CONHSO2Me | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-179 | CONHSO2Me | 4-Cl-苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Mc | S |
Ⅰ-180 | CONHSO2Me | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-181 | CONHSO2Me | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-182 | CONHSO2Me | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-183 | CONHSO2Me | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-184 | CONHSO2Me | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-185 | COOH | 苯基 | (4-HO-3-MeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-186 | COOH | 苯基 | (4-HO-3-MeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-187 | COOH | 苯基 | (4-HO-3-MeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-188 | COOH | 苯基 | (4-HO-3-MeO-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-189 | COOH | 苯基 | HOCH2(HOCH)CH2O | CMe | Me | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-190 | COOH | 4-F-苯基 | HOCH2(HOCH)CH2O | CMe | Me | S |
Ⅰ-191 | COOH | 4-Cl-苯基 | HOCH2(HOCH)CH2O | CMe | Me | S |
Ⅰ-192 | COOH | 苯基 | HOCH2(HOCH)CH2O | CMe | Me | O |
Ⅰ-193 | COOH | 苯基 | HOCH2(HOCH)CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-194 | COOH | 苯基 | HOCH2(HOCH)CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-195 | COOH | 苯基 | HOOCCH2O | CMe | Me | S |
Ⅰ-196 | COOH | 苯基 | HOOCCH2O | CMe | Me | O |
Ⅰ-197 | COOH | 苯基 | HOOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-198 | COOH | 苯基 | HOOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-199 | CONHSO2Me | 苯基 | MeO | CMe | Me | S |
Ⅰ-200 | CONHSO2Me | 4-F-苯基 | MeO | CMe | Me | S |
Ⅰ-201 | CONHSO2Me | 4-Cl-苯基 | MeO | CMe | Me | S |
Ⅰ-202 | CONHSO2Me | 苯基 | MeO | CMe | Me | O |
Ⅰ-203 | CONHSO2Me | 苯基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-204 | CONHSO2Me | 苯基 | MeO | C-CH=CH-CH=CH | S | |
Ⅰ-205 | COOH | 苯基 | (4-EtO-3-MeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-206 | COOH | 苯基 | (4-EtO-3-MeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-207 | COOH | 苯基 | (4-EtO-3-MeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-208 | COOH | 苯基 | (4-EtO-3-MeO-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-209 | COOH | 苯基 | EtOOCCH2O | CMe | Me | S |
Ⅰ-210 | COOH | 苯基 | EtOOCCH2O | CMe | Me | O |
Ⅰ-211 | COOH | 苯基 | EtOOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-212 | COOH | 苯基 | EtOOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-213 | COOH | 苯基 | (3-MeO-4-EtO2CCH2O-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-214 | COOH | 苯基 | (3-MeO-4-EtO2CCH2O-苯基)CH2CH2O | CMe | Me | O |
序号 | R1 | A | X | R4 | Y | |
Ⅰ-215 | COOH | 苯基 | (3-MeO-4-EtO2CCH2O-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-216 | COOH | 苯基 | (3-MeO-4-Et2CCH2O-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-217 | COOMe | 苯基 | MeO | CMe | Me | S |
Ⅰ-218 | COOMe | 苯基 | MeO | CMe | Me | O |
Ⅰ-219 | COOMe | 苯基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-220 | COOMe | 苯基 | MeO | C-CH=CH-CH=CH | S | |
Ⅰ-221 | COOH | 苯基 | (4-Me-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-222 | COOH | 苯基 | (4-Me-苯基)CH2CH2CH2O | CMe | Me | O |
Ⅰ-223 | COOH | 苯基 | (4-Me-苯基)CH2CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-224 | COOH | 苯基 | (4-Me-苯基)CH2CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-225 | COOH | 苯基 | (4-MeO-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-226 | COOH | 4-Cl-苯基 | (4-McO-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-227 | COOH | 4-F-苯基 | (4-MeO-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-228 | COOH | 苯基 | (4-MeO-苯基)CH2CH2CH2O | CMe | Me | O |
Ⅰ-229 | COOH | 苯基 | (4-MeO-苯基)CH2CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-230 | COOH | 苯基 | (4-MeO-苯基)CH2CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-23l | COOH | 苯基 | (4-HOOC-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-232 | COOH | 4-F-苯基 | (4-HOOC-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-233 | COOH | 4-Cl-苯基 | (4-HOOC-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-234 | COOH | 苯基 | (4-HOOC-苯基)CH2CH2CH2O | CMe | Me | O |
Ⅰ-235 | COOH | 苯基 | (4-HOOC-苯基)CH2CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-236 | COOH | 苯基 | (4-HOOC-苯基)CH2CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-237 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-238 | COOH | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-239 | COOH | 4-Cl-苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | CMe | Me | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-240 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | CMe | Me | O |
Ⅰ-241 | COOH | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-242 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-243 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-244 | COOH | 苯基 | (4-Cl-苯基)CH2CH2CH2O | CMe | Me | S |
Ⅰ-245 | COOH | 苯基 | (4-Cl-苯基)CH2CH2CH2O | CMe | Me | O |
Ⅰ-246 | COOH | 苯基 | (4-Cl-苯基)CH2CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-247 | COOH | 苯基 | (4-Cl-苯基)CH2CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-248 | CONHSO2苯基 | 苯基 | MeO | CMe | Me | S |
Ⅰ-249 | CONHSO2苯基 | 4-F-苯基 | MeO | CMe | Me | S |
Ⅰ-250 | CONHSO2苯基 | 4-a-苯基 | MeO | CMe | Me | S |
Ⅰ-251 | CONHSO2苯基 | 苯基 | MeO | CMe | Me | O |
Ⅰ-252 | CONHSO2苯基 | 4-F-苯基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-253 | CONHSO2苯基 | 4-C1-苯基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-254 | CONHSO2苯基 | 苯基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-255 | CONHSO2苯基 | 苯基 | MeO | C-CH=CH-CH=CH | S | |
Ⅰ-256 | CONHSO2苯基 | 苯基 | Me | CMe | Me | S |
Ⅰ-257 | CONHSO2苯基 | 4-F-苯基 | Me | CMe | Me | S |
Ⅰ-258 | CONHSO2苯基 | 4-Cl-苯基 | Me | CMe | Me | S |
Ⅰ-259 | CONHSO2苯基 | 苯基 | Me | CMe | Me | O |
Ⅰ-260 | CONHSO2苯基 | 苯基 | Me | C-CH2-CH2-CH2 | S | |
Ⅰ-261 | CONHSO2苯基 | 苯基 | Me | C-CH=CH-CH=CH | S | |
Ⅰ-262 | CONHSO2苯基 | 苯基 | (3,4-DjMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-263 | CONHSO2苯基 | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-264 | CONHSO2苯基 | 4-Cl-苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-265 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-266 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-267 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-268 | CONHSO2苯基 | 苯基 | N-Me-N-苯基-NOCCH2O | CMe | Me | S |
Ⅰ-269 | CONHSO2苯基 | 苯基 | N-Me-N-苯基-NOCCH2O | CMe | Me | O |
Ⅰ-270 | CONHSO2苯基 | 苯基 | N-Me-N-苯基-NOCCH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-271 | CONHSO2苯基 | 苯基 | N-Me-N-苯基-NOCCH2O | C-CH=CH-CH=CH | S | |
Ⅰ-272 | COOH | 苯基 | (4-Me-苯基)O | CMe | Me | S |
Ⅰ-273 | COOH | 苯基 | (4-Me-苯基)O | CMe | Me | O |
Ⅰ-274 | COOH | 苯基 | (4-Me-苯基)O | C-CH2-CH2-CH2 | S | |
Ⅰ-275 | COOH | 苯基 | (4-Me-苯基)O | C-CH=CH-CH=CH | S | |
Ⅰ-276 | COOH | 4-F-苯基 | MeO | S | Me | CH |
Ⅰ-277 | COOH | 4-Cl-苯基 | MeO | S | Me | CH |
Ⅰ-278 | COOH | 苯基 | MeO | O | Me | CMe |
Ⅰ-279 | COOH | 苯基 | MeO | S | Me | CH |
Ⅰ-280 | COOH | 苯基 | MeO | O | Me | CH |
Ⅰ-281 | COOH | 4-F-苯基 | (4-MeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-282 | COOH | 4-Cl-苯基 | (4-MeO-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-283 | COOH | 4-Cl-苯基 | (4-MeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-284 | COOH | 苯基 | (4-MeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-285 | COOH | 苯基 | (4-MeO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-286 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-287 | COOH | 4-Cl-苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-288 | COOH | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-289 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | O | Me | CMe |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-290 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | Me | CH | |
Ⅰ-291 | COOH | 苯基 | (4-MeO-苯基)CH2O | S | Me | CH |
Ⅰ-292 | COOH | 苯基 | (4-MeO-苯基)CH2O | O | Me | CH |
Ⅰ-293 | COOH | 苯基 | (4-MeO-苯基)O | Me | CH | |
Ⅰ-294 | COOH | 苯基 | (4-MeO-苯基)O | O | Me | CH |
Ⅰ-295 | COOH | 苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-296 | COOH | 苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-297 | COOH | 4-F-苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-298 | COOH | 4-Cl-苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-299 | COOH | 苯基 | (3-MeO-4-HO2CCH2O-苯基)CH2CH2O | O | Me | CH |
Ⅰ-300 | COOH | 苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-301 | COOH | 苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | S | Me | CMe |
Ⅰ-302 | COOH | 4-F-苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-303 | COOH | 4-Cl-苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-304 | COOH | 苯基 | (3-MeO-4-Me2NOCCH2O-苯基)CH2CH2O | O | Me | CH |
Ⅰ-305 | COOH | 苯基 | (3-MeO-4-Me2NCH2CH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-306 | COOH | 苯基 | (4-HO2C-苯基)CH2CH2O | S | Me | CH |
Ⅰ-307 | COOH | 苯基 | (4-HO2C-苯基)CH2CH2O | O | Me | CH |
Ⅰ-308 | COOH | 苯基 | (4-HO2C-苯基)CH2O | S | Me | CH |
Ⅰ-309 | COOH | 苯基 | (4-HO2C-苯基)CH2O | O | Me | CH |
Ⅰ-310 | COOH | 苯基 | (4-Me-苯基)O | S | Me | CH |
Ⅰ-311 | COOH | 苯基 | (4-Me-苯基)O | O | Me | CH |
Ⅰ-312 | COOH | 苯基 | (4-Me-苯基)CH2O | S | Me | CH |
Ⅰ-313 | COOH | 苯基 | (4-Me-苯基)CH2O | O | Me | CH |
Ⅰ-314 | COOH | 苯基 | (4-Cl-苯基)CH2CH2O | S | Me | CH |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-315 | COOH | 苯基 | (4-Cl-苯基)CH2CH2O | O | Me | CH |
Ⅰ-316 | COOH | 苯基 | (4-Me-苯基)CH2CH2O | S | Me | CH |
Ⅰ-317 | COOH | 苯基 | (4-Me-苯基)CH2CH2O | Me | CH | |
Ⅰ-318 | COOH | 4-F-苯基 | (3-HO2CCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-319 | COOH | 4-Cl-苯基 | (3-HO2CCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-320 | COOH | 苯基 | (3-HO2CCH2O-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-321 | COOH | 苯基 | (3-HO2CCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-322 | COOH | 苯基 | (3-HO2CCH2O-苯基)CH2CH2O | O | Me | CH |
Ⅰ-323 | COOH | 苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-324 | COOH | 4-F-苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-325 | COOH | 4-Cl-苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-326 | COOH | 苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-327 | COOH | 苯基 | (3-Me2NOCCH2O-苯基)CH2CH2O | O | Me | CH |
Ⅰ-328 | COOH | 苯基 | (3-Me2NCH2CH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-329 | COOH | 苯基 | (3-Me2NCH2CH2O-苯基)CH2CH2O | O | Me | CH |
Ⅰ-330 | COOH | 苯基 | N-Me-N-苯基-NOCCH2O | S | Me | CH |
Ⅰ-331 | COOH | 4-F-苯基 | N-Me-N-苯基-NOCCH2O | S | Me | CH |
Ⅰ-332 | COOH | 4-Cl-苯基 | N-Me-N-苯基-NOCCH2O | S | Me | CH |
Ⅰ-333 | COOH | 苯基 | N-Me-N-苯基-NOCCH2O | O | Me | CMe |
Ⅰ-334 | COOH | 苯基 | N-Me-N-苯基-NOCCH2O | O | Me | CH |
Ⅰ-335 | COOH | 苯基 | N-Bu-N-苯基-NOCCH2O | S | Me | CH |
Ⅰ-336 | COOH | 苯基 | N-Bu-N-苯基-NOCCH2O | O | Me | CH |
Ⅰ-337 | COOH | 苯基 | Bu2NOCCH2O | S | Me | CH |
Ⅰ-338 | COOH | 4-F-苯基 | Bu2NOCCH2O | S | Me | CH |
Ⅰ-339 | COOH | 4-Cl-苯基 | Bu2NOCCH2O | S | Me | CH |
序号 | R1 | R2,R3 | A | X | Y | |
Ⅰ-340 | COOH | 苯基 | Bu2NOCCH2O | O | Me | CMe |
Ⅰ-341 | COOH | 苯基 | Bu2NOCCH2O | O | Me | CH |
Ⅰ-342 | COOH | 苯基 | 苯基-HNOCCH2O | S | Me | CH |
Ⅰ-343 | COOH | 苯基 | 苯基-HNOCCH2O | O | Me | CH |
Ⅰ-344 | COOH | 苯基 | (2,6-二乙基-苯基)-HNOCCH2O | S | Me | CH |
Ⅰ-345 | COOH | 4-F-苯基 | (2,6-二乙基-苯基)-HNOCCH2O | S | Me | CH |
Ⅰ-346 | COOH | 4-Cl-苯基 | (2,6-二乙基-苯基)-HNOCCH2O | S | Me | CH |
Ⅰ-347 | COOH | 苯基 | (2,6-二乙基-苯基)-HNOCCH2O | O | Me | CMe |
Ⅰ-348 | COOH | 苯基 | (2,6-二乙基-苯基)-HNOCCH2O | O | Me | CH |
Ⅰ-349 | COOH | 苯基 | (-CH2CH2CH2CH2CH2CH2-)NOCCH2O | S | Me | CH |
Ⅰ-350 | COOH | 苯基 | (-CH2CH2CH2CH2CH2CH2-)NOCCH2O | O | Me | CH |
Ⅰ-351 | COOH | 苯基 | (-CH2CH2CH2CH2-)NOCCH2O | S | Me | CH |
Ⅰ-352 | COOH | 苯基 | (-CH2CH2CH2CH2-)NOCCH2O | O | Me | CH |
Ⅰ-353 | COOH | 苯基 | Me | S | Me | CH |
Ⅰ-354 | COOH | 4-F-苯基 | Me | S | Me | CH |
Ⅰ-355 | COOH | 4-Cl-苯基 | Me | S | Me | CH |
Ⅰ-356 | COOH | 苯基 | Me | O | Me | CMe |
Ⅰ-357 | COOH | 苯基 | Me | O | Me | CH |
Ⅰ-358 | COOH | 苯基 | MeS | S | Me | CH |
Ⅰ-359 | COOH | 苯基 | MeS | O | Me | CH |
Ⅰ-360 | COOH | 苯基 | CH3CONH | S | Me | CH |
Ⅰ-361 | COOH | 4-F-苯基 | CH3CONH | S | Me | CH |
Ⅰ-362 | COOH | 4-Cl-苯基 | CH3CONH | S | Me | CH |
Ⅰ-363 | COOH | 苯基 | CH3CONH | O | Me | CMe |
Ⅰ-364 | COOH | 苯基 | CH3CONH | O | Me | CH |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-365 | COOH | 苯基 | (CH3)3CCONH | S | Me | CH |
Ⅰ-366 | COOH | 苯基 | (CH3)3CCONH | O | Me | CH |
Ⅰ-367 | COOH | 苯基 | (-CH2CH2-)CHCONH | S | Me | CH |
Ⅰ-368 | COOH | 苯基 | (-CH2CH2-)CHCONH | O | Me | CH |
Ⅰ-369 | COOH | 苯基 | Et | S | Me | CH |
Ⅰ-370 | COOH | 苯基 | Et | O | Me | CH |
Ⅰ-371 | COOH | 苯基 | 苯基-CH2CH2S | S | Me | CH |
Ⅰ-372 | COOH | 苯基 | 苯基-CH2CH2S | O | Me | CH |
Ⅰ-373 | COOH | 苯基 | (4-MeS-苯基)CH2CH2O | S | Me | CH |
Ⅰ-374 | COOH | 4-F-苯基 | (4-MeS-苯基)CH2CH2O | S | Me | CH |
Ⅰ-375 | COOH | 苯基 | (4-MeS-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-376 | COOH | 苯基 | (4-MeS-苯基)CH2CH2O | O | Me | CH |
Ⅰ-377 | CONHSO2Me | 苯基 | Me | S | Me | CH |
Ⅰ-378 | CONHSO2Me | 4-F-苯基 | Me | S | Me | CH |
Ⅰ-379 | CONHSO2Me | 4-Cl-苯基 | Me | S | Me | CH |
Ⅰ-380 | CONHSO2Me | 苯基 | Me | O | Me | CMe |
Ⅰ-381 | CONHSO2Me | 苯基 | Me | O | Me | CH |
Ⅰ-382 | CONHSO2Me | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-383 | CONHSO2Me | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-384 | CONHSO2Me | 4-Cl-苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-385 | CONHSO2Me | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-386 | CONHSO2Me | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-387 | COOH | 苯基 | (4-HO-3-MeO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-388 | COOH | 4-F-苯基 | (4-HO-3-MeO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-389 | COOH | 4-Cl-苯基 | (4-HO-3-MeO-苯基)CH2CH2O | S | Me | CH |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-390 | COOH | 苯基 | (4-HO-3-MeO-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-391 | COOH | 苯基 | (4-HO-3-MeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-392 | COOH | 苯基 | HOCH2(HOCH)CH2O | O | Me | CH |
Ⅰ-393 | COOH | 苯基 | HOCH2(HOCH)CH2O | S | Me | CH |
Ⅰ-394 | COOH | 苯基 | HOOCCH2O | O | Me | CH |
Ⅰ-395 | COOH | 苯基 | HOOCCH2O | S | Me | CH |
Ⅰ-396 | CONHSO2Me | 苯基 | MeO | O | Me | CH |
Ⅰ-397 | CONHSO2Me | 4-F-苯基 | MeO | S | Me | CH |
Ⅰ-398 | CONHSO2Me | 4-Cl-苯基 | MeO | S | Me | CH |
Ⅰ-399 | CONHSO2Me | 苯基 | MeO | O | Me | CMe |
Ⅰ-400 | CONHSO2Me | 苯基 | MeO | S | Me | CH |
Ⅰ-401 | COOH | 苯基 | (4-EtO-3-MeO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-402 | COOH | 苯基 | (4-EtO-3-MeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-403 | COOH | 苯基 | EtOOCCH2O | O | Me | CH |
Ⅰ-404 | COOH | 苯基 | EtOOCCH2O | S | Me | CH |
Ⅰ-405 | COOH | 苯基 | (3-MeO-4-EtO2CCH2O-苯基)CH2CH2O | O | Me | CH |
Ⅰ-406 | COOH | 苯基 | (3-MeO-4-EtO2CCH2O-苯基)CH2CH2O | S | Me | CH |
Ⅰ-407 | COOMe | 苯基 | MeO | O | Me | CH |
Ⅰ-408 | COOMe | 4-Cl-苯基 | MeO | S | Me | CH |
Ⅰ-409 | COOMe | 4-F-苯基 | MeO | S | Me | CH |
Ⅰ-410 | COOMe | 苯基 | MeO | O | Me | CMe |
Ⅰ-411 | COOMe | 苯基 | MeO | S | Me | CH |
Ⅰ-412 | COOH | 苯基 | (4-Me-苯基)CH2CH2CH2O | O | Me | CH |
Ⅰ-413 | COOH | 苯基 | (4-Me-苯基)CH2CH2CH2O | S | Me | CH |
Ⅰ-414 | COOH | 苯基 | (4-MeO-苯基)CH2CH2CH2O | O | Me | CH |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-415 | COOH | 苯基 | (4-MeO-苯基)CH2CH2CH2O | S | Me | CH |
Ⅰ-416 | COOH | 苯基 | (4-HOOC-苯基)CH2CH2CH2O | O | Me | CH |
Ⅰ-417 | COOH | 苯基 | (4-HOOC-苯基)CH2CH2CH2O | S | Me | CH |
Ⅰ-418 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | O | Me | CH |
Ⅰ-419 | COOH | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | S | Me | CH |
Ⅰ-420 | COOH | 4-Cl-苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | S | Me | CH |
Ⅰ-421 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | O | Me | CMe |
Ⅰ-422 | COOH | 苯基 | (3,4-DiMeO-苯基)CH2CH2CH2O | O | Me | CH |
Ⅰ-423 | COOH | 苯基 | (4-Cl-苯基)CH2CH2CH2O | S | Me | CH |
Ⅰ-424 | COOH | 苯基 | (4-Cl-苯基)CH2CH2CH2O | O | Me | CH |
Ⅰ-425 | COOH | 苯基 | (4-Me-苯基)O | S | Me | CH |
Ⅰ-426 | COOH | 苯基 | (4-Me-苯基)O | O | Me | CH |
Ⅰ-427 | CONHSO2苯基 | 苯基 | MeO | O | Me | CH |
Ⅰ-428 | CONHSO2苯基 | 4-F-苯基 | MeO | S | Me | CH |
Ⅰ-429 | CONHSO2苯基 | 4-Cl-苯基 | MeO | S | Me | CH |
Ⅰ-430 | CONHSO2苯基 | 苯基 | MeO | O | Me | CMe |
Ⅰ-431 | CONHSO2苯基 | 苯基 | MeO | S | Me | CH |
Ⅰ-432 | CONHSO2苯基 | 苯基 | Me | S | Me | CH |
Ⅰ-433 | CONHSO2苯基 | 4-F-苯基 | Me | S | Me | CH |
Ⅰ-434 | CONHSO2苯基 | 4-Cl-苯基 | Me | S | Me | CH |
Ⅰ-435 | CONHSO2苯基 | 苯基 | Me | O | Me | CMe |
Ⅰ-436 | CONHSO2苯基 | 苯基 | Me | O | Me | CH |
Ⅰ-437 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-438 | CONHSO2苯基 | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-439 | CONHSO2苯基 | 4-Cl-苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-440 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-441 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-442 | COOH | 苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-443 | COOH | 4-F-苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-444 | COOH | 4-Cl-苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-445 | COOH | 苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-446 | COOH | 苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-447 | COOH | 苯基 | (iprO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-448 | COOH | 4-F-苯基 | (iPrO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-449 | COOH | 4-Cl-苯基 | (iPrO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-450 | COOH | 苯基 | (iPrO-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-451 | COOH | 苯基 | (iPrO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-452 | COOH | 苯基 | 正丁基 | S | Me | CH |
Ⅰ-453 | COOH | 4-F-苯基 | 正丁基 | S | Me | CH |
Ⅰ-454 | COOH | 4-Cl-苯基 | 正丁基 | S | Me | CH |
Ⅰ-455 | COOH | 苯基 | 正丁基 | O | Me | CMe |
Ⅰ-456 | COOH | 苯基 | 正丁基 | O | Me | CH |
Ⅰ-457 | COOH | 苯基 | (环己基)CH2CH2O | S | Me | CH |
Ⅰ-458 | COOH | 4-F-苯基 | (环己基)CH2CH2O | S | Me | CH |
Ⅰ-459 | COOH | 4-Cl-苯基 | (环己基)CH2CH2O | S | Me | CH |
Ⅰ-460 | COOH | 苯基 | (环己基)CH2CH2O | O | Me | CMe |
Ⅰ-461 | COOH | 苯基 | (环己基)CH2CH2O | O | Me | CH |
Ⅰ-462 | COOH | 苯基 | (环戊基)CH2CH2O | S | Me | CH |
Ⅰ-463 | COOH | 4-F-苯基 | (环戊基)CH2CH2O | S | Me | CH |
Ⅰ-464 | COOH | 4-Cl-苯基 | (环戊基)CH2CH2O | S | Me | CH |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-465 | COOH | 苯基 | (环戊基)CH2CH2O | O | Me | CMe |
Ⅰ-466 | COOH | 苯基 | (环戊基)CH2CH2O | O | Me | CH |
Ⅰ-467 | COOH | 苯基 |
|
S | Me | CH |
Ⅰ-468 | COOH | 4-F-苯基 |
|
S | Me | CH |
Ⅰ-469 | COOH | 4-Cl-苯基 |
|
S | Me | CH |
Ⅰ-470 | COOH | 苯基 |
|
O | Me | CMe |
Ⅰ-471 | COOH | 苯基 |
|
O | Me | CH |
Ⅰ-472 | COOH | 苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | S | Me | CH |
Ⅰ-473 | COOH | 4-F-苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | S | Me | CH |
Ⅰ-474 | COOH | 4-Cl-苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | S | Me | CH |
Ⅰ-475 | COOH | 苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | O | Me | CMe |
Ⅰ-476 | COOH | 苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | O | Me | CH |
Ⅰ-477 | COOH | 苯基 | HOCH2CH2 | S | Me | CH |
Ⅰ-478 | COOH | 4-F-苯基 | HOCH2CH2 | S | Me | CH |
Ⅰ-479 | COOH | 4-Cl-苯基 | HOCH2CH2 | S | Me | CH |
Ⅰ-480 | COOH | 苯基 | HOCH2CH2 | O | Me | CMe |
Ⅰ-481 | COOH | 苯基 | HOCH2CH2 | O | Me | CH |
Ⅰ-482 | COOH | 苯基 | (3,5-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-483 | COOH | 4-F-苯基 | (3,5-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-484 | COOH | 4-Cl-苯基 | (3,5-DiMeO-苯基)CH2CH2O | S | Me | CH |
Ⅰ-485 | COOH | 苯基 | (3,5-DiMeO-苯基)CH2CH2O | O | Me | CMe |
Ⅰ-486 | COOH | 苯基 | (3,5-DiMeO-苯基)CH2CH2O | O | Me | CH |
Ⅰ-487 | COOH | 苯基 | (3,5-DiMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-488 | COOH | 4-Cl-苯基 | (3,5-DiMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-489 | COOH | 4-F-苯基 | (3,5-DiMeO-苯基)CH2CH2O | CMe | Me | S |
序号 | R1 | R2,R3 | A | X | Y | |
Ⅰ-490 | COOH | 苯基 | (3,5-DiMeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-491 | COOH | 苯基 | (3,5-DiMeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-492 | COOH | 苯基 | HOCH2CH2 | CMe | Me | S |
Ⅰ-493 | COOH | 苯基 | HOCH2CH2 | CMe | Me | O |
Ⅰ-494 | COOH | 4-F-苯基 | HOCH2CH2 | CMe | Me | S |
Ⅰ-495 | COOH | 4-Cl-苯基 | HOCH2CH2 | CMe | Me | O |
Ⅰ-496 | COOH | 苯基 | HOCH2CH2 | C-CH2-CH2-CH2 | S | |
Ⅰ-497 | COOH | 苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | CMe | Me | S |
Ⅰ-498 | COOH | 4-F-苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | CMe | Me | S |
Ⅰ-499 | COOH | 苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | CMe | Me | O |
Ⅰ-500 | COOH | 4-F-苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-501 | COOH | 苯基 | (3,4-二氧亚甲基苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-502 | COOH | 苯基 |
|
CMe | Me | S |
Ⅰ-503 | COOH | 4-F-苯基 |
|
CMe | Me | S |
Ⅰ-504 | COOH | 4-Cl-苯基 |
|
CMe | Me | S |
Ⅰ-505 | COOH | 苯基 |
|
CMe | Me | O |
Ⅰ-506 | COOH | 苯基 |
|
C-CH2-CH2-CH2 | S | |
Ⅰ-507 | COOH | 苯基 | (环戊基)CH2CH2O | CMe | Me | S |
Ⅰ-508 | COOH | 苯基 | (环戊基)CH2CH2O | CMe | Me | O |
Ⅰ-509 | COOH | 苯基 | (环戊基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-510 | COOH | 苯基 | (环戊基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-511 | COOH | 苯基 | (环己基)CH2CH2O | CMe | Me | S |
Ⅰ-512 | COOH | 4-Cl-苯基 | (环己基)CH2CH2O | CMe | Me | S |
Ⅰ-513 | COOH | 苯基 | (环己基)CH2CH2O | CMe | Me | O |
Ⅰ-514 | COOH | 4-F-苯基 | (环己基)CH2CH2O | C-CH2-CH2-CH2 | S |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-515 | COOH | 苯基 | (环己基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-516 | COOH | 4-F-苯基 | 正丁基 | CMe | Me | S |
Ⅰ-517 | COOH | 苯基 | 正丁基 | CMc | Me | S |
Ⅰ-518 | COOH | 苯基 | 正丁基 | CMe | Me | O |
Ⅰ-519 | COOH | 4-Cl-苯基 | 正丁基 | C-CH2-CH2-CH2 | S | |
Ⅰ-520 | COOH | 苯基 | 正丁基 | C-CH2-CH2-CH2 | S | |
Ⅰ-52l | COOH | 苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-522 | COOH | 苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-523 | COOH | 4-F-苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-524 | COOH | 4-Cl-苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-525 | COOH | 苯基 | (2,3,4-TriMeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-526 | COOH | 苯基 | (iPrO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-527 | COOH | 苯基 | (iPrO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-528 | COOH | 苯基 | (iPrO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-529 | COOH | 苯基 | (iPrO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-530 | COOH | 苯基 | (iPrO-苯基)CH2CH2O | C-CH=CH-CH=CH | S | |
Ⅰ-53l | CONHSO2苯基 | 苯基 | MeO | CMe | Me | S |
Ⅰ-532 | CONHSO2苯基 | 4-Cl-苯基 | MeO | CMe | Me | S |
Ⅰ-533 | CONHSO2苯基 | 4-F-苯基 | MeO | CMe | Me | S |
Ⅰ-534 | CONHSO2苯基 | 苯基 | MeO | CMe | Me | O |
Ⅰ-535 | CONHSO2苯基 | 苯基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-536 | CONHSO2苯基 | 苯基 | Me | CMe | Me | S |
Ⅰ-537 | CONHSO2苯基 | 苯基 | Me | CMe | Me | O |
Ⅰ-538 | CONHSO2苯基 | 4-F-苯基 | Me | CMe | Me | S |
Ⅰ-539 | CONHSO2苯基 | 4-Cl-苯基 | Me | CMe | Me | O |
序号 | R1 | R2,R3 | A | X | R4 | Y |
Ⅰ-540 | CONHSO2苯基 | 苯基 | Me | C-CH2-CH2-CH2 | S | |
Ⅰ-541 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-542 | CONHSO2苯基 | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-543 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | CMe | Me | O |
Ⅰ-544 | CONHSO2苯基 | 4-F-苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-545 | CONHSO2苯基 | 苯基 | (3,4-DiMeO-苯基)CH2CH2O | C-CH2-CH2-CH2 | S | |
Ⅰ-546 | COOH | 苯基,4-Cl-苯基 | MeO | CMe | Me | S |
Ⅰ-547 | COOH | 4-Cl-苯基,4-F-苯基 | MeO | CMe | Me | S |
Ⅰ-548 | COOH | 4-F-苯基,苯基 | MeO | CMe | Me | S |
Ⅰ-549 | COOH | 4-Me-苯基,萘基 | MeO | CMe | Me | O |
Ⅰ-550 | COOH | 2-F-苯基,苯基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-55l | COOH | 2-F-苯基,4-Me-苯基 | MeO | C-CH=CH-CH=CH | S | |
Ⅰ-552 | COOH | 萘基,苯基 | (4-MeO-苯基)CH2CH2O | CMe | Me | S |
Ⅰ-553 | COOH | 苯基,4-Cl-苯基 | CH3CH2O | CMe | Me | S |
Ⅰ-554 | COOH | 4-Cl-苯基,-4-F-苯基 | CH3CH2O | CMe | Me | S |
Ⅰ-555 | COOH | 4-F-苯基,苯基 | 异丙氧基 | CMe | Me | S |
Ⅰ-556 | COOH | 萘基,萘基 | MeO | CMe | Me | S |
Ⅰ-557 | COOH | 萘基,萘基 | MeO | C-CH2-CH2-CH2 | S | |
Ⅰ-558 | COOH | 4-F-苯基,4-Cl-苯基 | (4-MeO-苯基)CH2CH2O | CMe | Me | O |
实施例7:
按照如上所述的结合实验,检测如下化合物的受体结合数据。
结果见表2。
表2
受体结合数据(Ki值)
化合物 | ETA[nM/l] | ETB[nM/l] |
Ⅰ-1 | 13 | 650 |
Ⅰ-15 | 215 | 485 |
Ⅰ-6 | 900 | >7100 |
Ⅰ-5 | 50 | >700 |
Ⅰ-4 | 29 | 3100 |
Ⅰ-13 | 145 | 210 |
Claims (9)
1.下式杂环取代的α-羟基羧酸衍生物,及其生理可耐受盐,以及可能的对映体纯及非对映异构体纯的形式:
R1是四唑或基团
其中R定义如下:
a)基团OR5,其中R5是:
氢原子、碱金属阳离子、碱土金属阳离子、生理可耐受的有机铵离子;
C3-C8-环烷基、C1-C8-烷基、CH2-苯基、C3-C8-链烯基、C3-C8-炔基或苯基,在每种情况下其无取代或被取代;
b)通过氮原子连接的5元芳杂环;
c)基团
其中k可以是0、1或2,p是1、2、3或4,而R6是
C1-C4-烷基、C3-C8-环烷基、C3-C8-链烯基、C3-C8-炔基或者未被取代或被取代的苯基;
其中R7是:
C1-C4-烷基、C3-C8-链烯基、C3-C8-炔基、C3-C8-环烷基,这些基团可以带有C1-C4-烷氧基、C1-C4-烷硫基和/或苯基;
C1-C4-卤代烷基或苯基,其未被取代或被取代;
A是NR8R9、叠氮基、OR10、SR10或C1-C4-烷基;
X是氧原子、硫原子、CR11或NR12;其条件是如果X=CR11,则Y=氧原子或硫原子或NR14;
Y是氧原子、硫原子、CR13或NR14;其条件是如果Y=氧原子或硫原子或NR14,则X=CR11;
R2和R3(可相同或不同)为:
苯基或萘基,其未被取代或被取代,或
苯基或萘基,其通过一个直接键、亚甲基、亚乙基或亚乙烯基、氧原子或硫原子或SO2、NH或N(C1-C4-烷基)基团,在邻位与另一个基团连接;
C5-C6-环烷基,其未被取代或被取代;
R4和R11(可相同或不同)为:
氢原子、卤素、C1-C7-烷氧基、C1-C4-卤代烷氧基、C3-C6-链烯基氧基、C3-C6-炔基氧基、C1-C4-烷硫基、C1-C4-烷基羰基、C1-C4-烷氧羰基、羟基、氨基、NH(C1-C4-烷基)、N(C1-C4-烷基)2;
C1-C4-烷基、C2-C4-链烯基、C2-C4-炔基,这些基团可未被取代或被取代;
或者CR4与CR11一起形成5或6元亚烷基或亚烯基环,其可以无取代或被取代,且在每种情况下一个或多个亚甲基可以被氧原子、硫原子、-NH或-N(C1-C4-烷基)代替;
R8是氢原子、C1-C8-烷基、C3-C8-链烯基或C3-C8-炔基、C1-C5-烷基羰基,这些基团可未被取代或被取代;
苯基或萘基,其未被取代或被取代;
未被取代或被取代的C3-C8-环烷基;
或者R8和R9一起形成C3-C7-亚烷基链,其可未被取代或被取代,并闭合成环,且其中亚烷基可以被氧原子或硫原子代替;
R9是氢原子、C1-C4-烷基;
或者如R8中所述R9与R8连接成环;
R10是氢原子、C1-C8-烷基、C3-C8-链烯基、C3-C8-炔基,这些基团可未被取代或被取代;
未被取代或被取代的苯基或萘基;
未被取代或被取代的C3-C8-环烷基;
R12是氢原子、C1-C4-烷基;
或者NR12与CR4一起形成5或6元亚烷基或亚烯基环,其未被取代或被取代,并且在每种情况下,一个或多个亚甲基可以被氧原子或硫原子代替。
R13是氢原子、卤素、C1-C4-烷基、C2-C4-链烯基,这些基团可以未被取代或被取代;
R14是氢原子、C1-C4-烷基。
2.权利要求1所述的杂环取代的α-羟基羧酸衍生物Ⅰ治疗疾病的用途。
3.权利要求2所述的化合物Ⅰ作为内皮素受体拮抗剂的用途。
4.权利要求1所述的杂环取代的α-羟基羧酸衍生物Ⅰ在制备治疗发生内皮素水平升高的疾病的药物中的用途。
5.权利要求1所述的杂环取代的α-羟基羧酸衍生物Ⅰ在制备治疗内皮素促使其形成和/或恶化的疾病的药物中的用途。
6.权利要求1所述的杂环取代的α-羟基羧酸衍生物Ⅰ治疗慢性心功能不全、再狭窄、高血压、肺动脉高血压、急性/慢性肾衰竭、脑局部缺血、哮喘、良性前列腺增生和前列腺癌的用途。
7.权利要求1所述的杂环取代的α-羟基羧酸衍生物Ⅰ与一种或多种活性化合物的联合形式,该活性化合物选自肾素-血管紧张素系统的抑制剂如肾素抑制剂、血管紧张素Ⅱ拮抗剂、血管紧张素转化酶(ACE)抑制剂、混合的ACE/中性内肽酶(NEP)抑制剂、β-阻断剂、利尿剂、钙离子拮抗剂和VEGF-阻断物质的活性化合物。
8.口服及非经胃肠道使用的药物制剂,其中除常规药物辅剂外每单位剂型中含有至少一种权利要求1所述的羧酸衍生物Ⅰ。
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WO1999025701A1 (de) | 1999-05-27 |
ZA9810425B (en) | 2000-05-15 |
DE19750529A1 (de) | 1999-05-20 |
BR9814157A (pt) | 2000-10-03 |
NO20002154L (no) | 2000-05-12 |
ID24819A (id) | 2000-08-24 |
EP1037883A1 (de) | 2000-09-27 |
HUP0004341A3 (en) | 2001-12-28 |
IL135461A0 (en) | 2001-05-20 |
KR20010032083A (ko) | 2001-04-16 |
NO20002154D0 (no) | 2000-04-27 |
JP2001523671A (ja) | 2001-11-27 |
CO4990973A1 (es) | 2000-12-26 |
AU1487899A (en) | 1999-06-07 |
US6358983B1 (en) | 2002-03-19 |
TR200001365T2 (tr) | 2000-09-21 |
NZ504289A (en) | 2002-03-01 |
HRP980591A2 (en) | 1999-08-31 |
SK4932000A3 (en) | 2001-02-12 |
AR017581A1 (es) | 2001-09-12 |
CA2308746A1 (en) | 1999-05-27 |
BG104400A (en) | 2001-01-31 |
HUP0004341A1 (hu) | 2001-10-28 |
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