CN1334806A - 新型β-酰氨基-和β-氨磺酰羧酸衍生物,它们的制备和作为内皮缩血管肽受体拮抗物的应用 - Google Patents
新型β-酰氨基-和β-氨磺酰羧酸衍生物,它们的制备和作为内皮缩血管肽受体拮抗物的应用 Download PDFInfo
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- CN1334806A CN1334806A CN99814580A CN99814580A CN1334806A CN 1334806 A CN1334806 A CN 1334806A CN 99814580 A CN99814580 A CN 99814580A CN 99814580 A CN99814580 A CN 99814580A CN 1334806 A CN1334806 A CN 1334806A
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- 239000002287 radioligand Substances 0.000 description 1
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- 238000001525 receptor binding assay Methods 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 238000010129 solution processing Methods 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
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- 239000003053 toxin Substances 0.000 description 1
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- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
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Abstract
本发明涉及式(Ⅰ)的羧酸衍生物,其中,取代基具有下列含义:R1是四唑基或基(a);W和Z可以相同或不同,是氮或次甲基,但须,如果W和Z是次甲基,那么Q是氮;X是氮或CR9;Y是氮或CR10;Q是氮或CR11但须,如果Q是氮,那么X是CR5和Y是CR10;R2和R3相同或不同,是可能被取代的苯基或萘基,或者在邻位通过直接的键,亚甲基,1,2-亚乙基或亚乙烯基,氧或硫原子或SO2-,NH-或N-烷基被连接在一起的苯基或萘基,或者可能被取代的C5~C6环烷基;R4是基(b)或(c);R5是氢,C1~C4烷基。本发明进一步涉及它们的制备和作为内皮缩血管肽受体拮抗物的应用。本发明还涉及式(Ⅱ)的化合物和式(d)的结构片段,其中,基R1,R2,R3,R4和R5具有权利要求1中的含义;以及它们作为内皮缩血管肽受体拮抗物中的结构单元的应用。
Description
本发明涉及新型羧酸衍生物,它们的制备和应用。
内皮缩血管肽是一种肽,它由21个氨基酸构成,是通过血管内皮合成和释放的。内皮缩血管肽以三种异构形式存在,即,ET-1、ET-2和ET-3。下文的“内皮缩血管肽”或“ET”表示内皮缩血管肽的一种或全部异构形式。内皮缩血管肽是一种有效的血管收缩剂,对血管健康状况具有强烈作用。已知这种血管收缩作用是由内皮缩血管肽与它的受体结合而引起的[自然(Nature),332,411~415,1988;欧洲生物化学学会联合会快报(FEBS Letters),231,440~444,1988;以及生物化学与生物物理学研究通讯(Biochem.Biophys.Res.Commun.),154,868~875,1988]。
内皮缩血管肽的释放增多或异常引起外周血管、肾血管和脑血管的持久血管收缩,这样可导致疾病。如文献中报导的那样,内皮缩血管肽涉及一些疾病。这些疾病包括:高血压、急性心肌梗死、肺动脉高压、雷诺综合征、脑血管痉挛、中风、良性前列腺肥大、动脉粥样硬化、哮喘和前列腺癌[血管医学和血管生物学杂志(J.VascularMed.Biology),2,207,(1990);美国医学学会杂志(J.Am.Med.Association),264,2868,(1990);自然,344,114,(1990);英格兰医学杂志(N.Engl.J.Med.),322,205,(1989);英格兰医学杂志,328,1732,(1993);肾单位(Nephron),66,373,(1994);中风(Stroke),25,904,(1994);自然,365,759,(1993);分子心脏病学与细胞心脏病学杂志(J.Mol.Cell.Cardiol.),27,A234(1995);癌症研究(Cancer Research),56,663,(1996);自然医学(Nature Medicine),1,944,(1995)]。
目前文献中描述了至少两种内皮缩血管肽受体亚型:ETA受体和ETB受体[自然,348,730,(1990);自然,348,732,(1990)]。因此,抑制内皮缩血管肽与一种或两种受体结合的物质应该拮抗内皮缩血管肽的生理效果,所以代表有价值的药物。
DE 19726146.9描述了β-氨基羧酸衍生物和β-叠氮基羧酸衍生物和它们作为内皮缩血管肽受体拮抗物的应用。进一步的研究表明,相关的芳族甲酰胺和氨磺酰衍生物相对于受体亲和性和受体结合模式来说具有有益的特性。本专利涉及它们的制备和应用。
本发明涉及式I的β-酰氨基羧酸衍生物和β-氨磺酰羧酸衍生物其中,R1是四唑基或基其中,R具有如下含义:a) 基OR6,其中,R6是:氢,碱金属的阳离子,碱土金属的阳离子或生理上耐受的有机铵离子(例如叔C1~C4烷基铵离子)或铵离子;C3~C8环烷基,C1~C8烷基,CH2-苯基,它可被一个或多个下列基取代:卤素,硝基,氰基,C1~C4烷基,C1~C4卤烷基,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烯基或C3~C8炔基,这些基可能又携带1~5个卤原子;R6还可以是苯基,它可能携带1~5个卤原子和/或1~3个如下 基:硝基,氰基,C1~C4烷基,C1~C4卤烷基,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) 一个通过氮原子连接的5元杂芳族体系,例如吡咯基,吡唑基,咪唑基和三唑基,它可能携带一个或两个卤原子或者一个或两个C1~C4烷基或者一个或两个C1~C4烷氧基;c) 基其中,k可以是0,1和2的值,p可以是1,2,3和4的值,而且R7是:C1~C4烷基,C3~C8环烷基,C3~C8烯基,C3~C8炔基或苯基,它可被一个或多个(例如1~3个)下列基取代: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) 基其中,R8是:C1~C4烷基,C3~C8烯基,C3~C8炔基,C3~C8环烷基,这些基可能携带一个C1~C4烷氧基,C1~C4烷硫基和/或如c)提及的苯基;C1~C4卤烷基或苯基,它未被取代或尤其如c)提及的那样被取代
了。其它取代基具有下列含义:W 和Z(它们可以相同或不同)是:
氮或次甲基;但须,如果W和Z=次甲基,那么Q=氮;X 是氮或CR9;Y 是氮或CR10;Q 是氮或CR11;但须,如果Q=氮,那么X=CR9和Y=CR10;R2 和R3(它们可以相同或不同)是:
苯基或萘基,它们各自可被一个或多个下列基取代:卤素,硝基,
氰基,羟基,巯基,C1~C4烷基,C2~C4烯基,C2~C4炔基,C1
~C4卤烷基,C1~C4烷氧基,苯氧基,C1~C4卤烷氧基,C1~C4
烷硫基,氨基,NH(C1~C4烷基),N(C1~C4烷基)2或苯基,它可
被下列基取代一次或多次(例如1~3次):卤素,硝基,氰基,
C1~C4烷基,C1~C4卤烷基,C1~C4烷氧基,C1~C4卤烷氧基
或C1~C4烷硫基;或者
苯基或萘基,它们在邻位通过直接的键,亚甲基,1,2-亚乙基或
亚乙烯基,氧或硫原子或SO2,NH或N-烷基被连接在一起;
C5~C6环烷基,这些基有可能在各情况下被下列基取代一次或多
次:卤素,羟基,巯基,羧基,硝基,氰基,C1~C4烷基,C2~C4
烯基,C2~C4炔基,C1~C4烷氧基,C1~C4烷硫基,C1~C4卤
1~3个氮原子和/或一个硫或氧原子,所述基可能被下列基
取代一次或多次:卤素,硝基,氰基,羟基,巯基,C1~C4
烷基,C1~C4羟烷基,C1~C4卤烷基,C1~C4烷氧基,C1~
C4烷基羰基,羧基,C1~C4卤烷氧基,C1~C4烷硫基,氨基,
NH(C1~C4烷基),N(C1~C4烷基)2,H2NSO2,(C1~C4烷基)NHSO2,
(C1~C4烷基)2NSO2,或者苯氧基或苯基,它们各自可能被下
列基取代一次或多次(例如1~3次):卤素,硝基,氰基,
C1~C4烷基,C1~C4卤烷基,C1~C4烷氧基,C1~C4卤烷
氧基和/或C1~C4烷硫基b) 基
其中,R13是:C1~C4烷基,C1~C4卤烷基或苯基,所述苯基又可
能携带1~5个卤原子和/或1~3个下列基:C1~C4烷
基,C1~C4卤烷基,C1~C4烷氧基,C1~C4卤烷氧基和/
或C1~C4烷硫基;R5 是氢,C1~C4烷基;R9 和R10(它们可以相同或不同)是:
氢,卤素,C1~C4烷氧基,C1~C4卤烷氧基,C3~C6烯氧基,C3
~C6炔氧基,C1~C4烷硫基,C1~C4烷基羰基,C1~C4烷氧羰基,
羟基,NH2,NH(C1~C4烷基),N(C1~C4烷基)2;
C1~C4烷基,C2~C4烯基,C2~C4炔基,这些基可能被卤素,羟
基,巯基,羧基,氰基取代;
或者CR9或CR10被连接到CR11(如关于R11指出的那样)而给出一个5
元或6元环;R11是氢,卤素,C1~C4烷氧基,C1~C4卤烷氧基,C3~C6烯氧基,
C3~C6炔氧基,C1~C4烷硫基,C1~C4烷基羰基,C1~C4烷氧
羰基,NH(C1~C4烷基),N(C1~C4烷基)2,羟基,羧基,氰基,
氨基,巯基;
C1~C4烷基,C2~C4烯基,C2~C4炔基,这些基可能被卤素,羟
基,巯基,羧基,氰基,氨基,C1~C4烷氧基取代一次或多次;
或者CR11与CR9或CR10一起形成一个5元或6元亚烷基或亚烯基环,
它可被一个或两个C1~C4烷基取代,其中,在每种情况下,一个
或多个亚甲基可被氧,硫,-NH或-N(C1~C4烷基)替代。
上下文应用的定义是:
碱金属例如是锂,钠,钾;
碱土金属例如是钙,镁,钡;
有机铵离子是质子化的胺,例如乙醇胺,二乙醇胺,乙二胺,二乙胺或哌嗪;
C3~C8环烷基例如是环丙基,环丁基,环戊基,环己基,环庚基或环辛基;
C1~C4卤烷基可以是线型或支化的基,例如氟甲基,二氟甲基,三氟甲基,氯二氟甲基,二氯氟甲基,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卤烷氧基可以是线型或支化的基,例如二氟甲氧基,三氟甲氧基,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烷基可以是线型或支化的基,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烯基可以是线型或支化的基,例如乙烯基,1-丙烯-3-基,1-丙烯-2-基,1-丙烯-1-基,2-甲基-1-丙稀基,1-丁烯基或2-丁烯基;
C2~C4炔基可以是线型或支化的基,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烷氧基可以是线型或支化的基,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烯氧基可以是线型或支化的基,例如烯丙氧基,2-丁烯-1-基氧基或3-丁烯-2-基氧基;
C3~C6炔氧基可以是线型或支化的基,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烷硫基可以是线型或支化的基,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~C5烷基羰基可以是线型或支化的基,例如乙酰基,乙基羰基或2-丙基羰基;
C1~C8烷基可以是线型或支化的基,例如C1~C4烷基,戊基,己基,庚基或辛基;
C3~C8烯基可以是线型或支化的基,例如1-丙烯-3-基,1-丙烯-2-基,1-丙烯-1-基,2-甲基-1-丙烯基,1-丁烯-4-基,2-丁烯-3-基,1-戊烯-5-基,1-己烯-6-基,3-己烯-6-基,2-庚烯-7-基或1-辛烯-8-基;
C3~C8炔基可以是线型或支化的基,例如1-丙炔-1-基,1-丙炔-3-基,1-丁炔-4-基,2-丁炔-4-基,2-戊炔-5-基,3-己炔-6-基,3-庚炔-7-基,2-辛炔-8-基;
卤素例如是氟,氯,溴,碘。
本发明还涉及可释出式I化合物的那些化合物(称为前体药物)。
优选的前体药物是在身体的某些隔室中(例如胃中,肠中,血液循环中,肝中)普通的条件下进行释放的那些。
化合物I和制备它们的中间体(例如II和III)可具有一个或多个不对称取代的碳原子。这类化合物可作为纯的对映体或纯的非对映体或者作为其混合物存在。优选应用对映纯的化合物作为活性组分。
本发明进一步涉及上述羧酸衍生物在生产药物、尤其生产ETA和/或ETB受体的抑制剂中的应用。所述新型化合物适用作开头定义的拮抗物。
本发明的式I化合物可通过DE 19726146.9中描述的途径制备。
该途径的一个可能的备选方法是通过通式III的中间体制备;这些衍生物或者可通过由通常已知的方法还原式II的叠氮化物(参见DE19726146.9)合成,或者通过打开通式IV的噁唑啉衍生物(描述于WO95/07266中)合成。
式IV的噁唑啉衍生物可通过在合适的加溶剂存在下用强酸(例如盐酸、氢溴酸、硫酸、高氯酸、三氟乙酸、甲苯磺酸、甲磺酸或三氟甲磺酸)的水溶液处理而打开。所有水混溶性溶剂,只要它们对应用的试剂呈惰性,都可用于该目的。
这样的加溶剂实例有:醇,例如甲醇,乙醇,正丙醇,异丙醇;醚,例如四氢呋喃或二噁烷;腈,例如乙腈或丙腈;酰胺,例如二甲基甲酰胺或二甲基乙酰胺;亚砜和砜,例如二甲亚砜;羧酸,例如乙酸或丙酸。
该情况下的反应优选在0℃和溶剂或溶剂混合物的沸点之间范围内的温度下进行。
本发明的化合物(其中R4R5N是芳族或杂芳族羧酰胺)可这样制备,例如,通过酰化式III的氮,或者酰化式III的氨基和羟基,然后应用通常已知的方法消去酯酰基。为此,在合适的稀释剂存在下将通式III的化合物与酰化剂以1∶1~1∶6的摩尔比反应。对应用的试剂呈惰性的所有溶剂都可用于该目的。这样的溶剂或稀释剂实例有:脂肪烃、脂环烃和芳烃,它们在各情况下可任选被氯化,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,乙基氯和三氯乙烯;醚,例如二异丙醚,二丁醚,甲基叔丁基醚,二噁烷和四氢呋喃;腈,例如乙腈和丙腈;酰胺,例如二甲基甲酰胺、二甲基乙酰胺和N-甲基吡咯烷酮;亚砜和砜,例如二甲亚砜和环丁砜。
该情况下的反应优选在0℃和溶剂或溶剂混合物的沸点之间范围内的温度下进行。
反应催化剂的存在可能是有利的。该情况下合适的催化剂例如是二甲氨基吡啶。
式VI中的R14是卤素或R15-SO2-,其中,R15可以是C1~C4烷基,C1~C4卤烷基或苯基,而且,W,X,Y,Z和Q的定义是前文给出的那些。该反应优选在如下条件下进行,即,在从室温到溶剂的沸点范围内的温度下,在惰性溶剂或稀释剂中,添加了合适的碱(即,使中间体V脱质子化的碱)。
式VI的化合物都是已知的,它们中的某些可以购买,或者可按通常已知的方法制备它们。
如果通式Ia的化合物中的R1是酯,可用酸或碱或者通过氢解分解酯基而给出R1=COOH的游离羧酸。不过,R1=COOH的Ia型化合物也可通过用三当量适当的碱对中间体V(其中,R1=COOH)的脱质子化并与通式VI的化合物反应而直接获得。又一次地,该反应在从室温到溶剂的沸点范围内的温度下在惰性溶剂中进行。
可应用的碱是碱金属氢化物或碱土金属氢化物,例如氢化钠、氢化钾或氢化钙;碳酸盐,例如碱金属碳酸盐(例如碳酸钠或碳酸钾);碱金属氢氧化物或碱土金属氢氧化物,例如氢氧化钠或氢氧化钾;有机金属化合物,例如丁基锂;或者氨基碱金属,例如二异丙基氨基锂或氨基锂。
通式I的本发明化合物(其中,R4R5N是氨磺酰)可从通式VII的胺获得和按DE 19726146.9中描述的那样制备。为此,通过通常已知的方法将VII与磺酰卤反应,而且如果R1是酯,用酸或碱或者通过氢解分解该酯基。
式I的化合物还可从合适的羧酸开始制备,即,首先按常规方式将式I的化合物(其中,R1是COOH)转化为活性形式(例如酰基卤、酸酐或咪唑化物),然后将后者与合适的羟基化合物(HOR6)或磺酰胺(H2NSO2R8)反应。该反应可在常规溶剂中进行,通常需要添加碱,此时,上文提及的那些碱是合适的。还可简化这两步,例如,通过在脱水剂(例如碳二亚胺)存在下使羧酸作用于羟基化合物或磺酰胺。
另外还可能从合适的羧酸盐开始制备式I的化合物,即,从式I的化合物(其中,R1是基COOM)开始,此时,M可以是碱金属阳离子或碱土金属阳离子的等效物。可将这些盐与式R-D的很多化合物反应,其中,D是常规离核的离去基,例如:卤素(例如氯、溴、碘),或者是任选被卤素、烷基或卤烷基取代的芳磺酰或烷基磺酰(例如甲苯磺酰和甲磺酰),或者是其它等效的离去基。具有活性取代基D的式R-D的化合物是已知的或者可容易用一般专业知识获得。该反应可在常规溶剂中进行,而且有利地在碱的存在下进行,此时,上文提及的那些碱是合适的。
式I的化合物(其中,R1是四唑基)可按WO 96/11914中描述的方法从相应的羧酸(R1=COOH的式I)制备。
在某些情况下,有必要应用通常已知的保护基技术来制备本发明的化合物I。如果,例如,R4R5N=4-HO-苯基-CONH-,开始可以作为苄基醚保护羟基,然后在反应程序中的适当阶段将它分解。
式I和V的化合物可呈对映纯的形式获得,即,用合适的对映纯的碱(例如WO 96/11914中描述的那些)通过对式I和V的外消旋或非对映化合物进行经典的外消旋物拆分。
为了生理效果,优选的通式I的羧酸衍生物-既作为纯的对映体或纯的非对映体又作为它们的混合物-是那些,即,其中,取代基具有下列含义:R1是四唑基或基其中,R具有如下含义:a) 基OR6,其中,R6是:氢,碱金属的阳离子,碱土金属的阳离子或生理上耐受的有机铵 离子(例如叔C1~C4烷基铵离子)或铵离子;C3~C8环烷基,C1~C8烷基,CH2-苯基,它可被一个或多个下列基取代:卤素,C1~C4烷基,C1~C4卤烷基,羟基,C1~C4烷氧基,巯基,C1~C4烷硫基,NH(C1~C4烷基),N(C1~C4烷基)2;C3~C8烯基或C3~C8炔基,这些基可能又携带1~5个卤原子;R6还可以是苯基,它可能携带1~5个卤原子和/或1~3个如下基:C1~C4烷基,C1~C4卤烷基,羟基,C1~C4烷氧基,巯基,C1~C4烷硫基,NH(C1~C4烷基),N(C1~C4烷基)2;b) 一个通过氮原子连接的5元杂芳族体系,例如吡唑基,咪唑基和三唑基,它可能携带一个或两个卤原子或者一个或两个C1~C4烷基或者一个或两个C1~C4烷氧基;c) 基其中,k可以是0,1和2的值,p可以是1,2,3和4的值,而且R7是:C1~C4烷基,C3~C8环烷基,C3~C8烯基,C3~C8炔基或苯基,它可被一个或多个(例如1~3个)下列基取代:卤素,C1~C4烷基,羟基,C1~C4烷氧基,C1~C4烷硫基,NH(C1~C4烷基),N(C1~C4烷基)2,巯基;d) 基 其中,R8是:C1~C4烷基,C3~C8烯基,C3~C8炔基,C3~C8环烷基,这些基可能携带一个C1~C4烷氧基,C1~C4烷硫基和/或如c)提及的苯基;C1~C4卤烷基或苯基,任选尤其如c)提及的那样被取代了。W 和Z(它们可以相同或不同)是:
氮或次甲基;但须,如果W和Z=次甲基,那么Q=氮;X 是氮或CR9;Y 是氮或CR10;Q 是氮或CR11;但须,如果Q=氮,那么X=CR9和Y=CR10;R2 和R3(它们可以相同或不同)是:
苯基或萘基,它们各自可被一个或多个下列基取代:卤素,氰基,
羟基,巯基,C1~C4烷基,C1~C4卤烷基,C1~C4烷氧基,苯氧
基,C1~C4卤烷氧基,C1~C4烷硫基,氨基,NH(C1~C4烷基),
N(C1~C4烷基)2或苯基,它可被下列基取代一次或多次(例如1~
3次):卤原子,氰基,C1~C4烷基,C1~C4卤烷基,C1~C4烷
氧基,C1~C4卤烷氧基或C1~C4烷硫基;或者
苯基或萘基,它们在邻位通过直接的键,亚甲基,1,2-亚乙基或
其中,R12是:苯基,萘基或一个五元或六元杂芳族体系,它包含
1~3个氮原子和/或一个硫或氧原子,所述基可能被下列基
取代一次或多次:卤素,氰基,羟基,巯基,C1~C4烷基,
C1~C4羟烷基,C1~C4卤烷基,C1~C4烷氧基,C1~C4卤
烷氧基,C1~C4烷硫基,氨基,NH(C1~C4烷基),N(C1~C4
烷基)2,H2NSO2,(C1~C4烷基)NHSO2,(C1~C4烷基)2NSO2,
或者苯氧基或苯基,它们各自可能被下列基取代一次或多次
(例如1~3次):卤素,氰基,C1~C4烷基,C1~C4卤烷基,
其中,R13是:C1~C4烷基,C1~C4卤烷基或苯基,所述苯基又可
能携带1~5个卤原子和/或1~3个下列基:C1~C4烷
基,C1~C4卤烷基,C1~C4烷氧基;R5 是氢,甲基;R9 和R10(它们可以相同或不同)是:
氢,卤素,C1~C4烷氧基,C1~C4卤烷氧基,C1~C4烷硫基,NH(C1
~C4烷基),N(C1~C4烷基)2;
C1~C4烷基,C2~C4烯基,这些基可能被卤素,羟基,巯基,氰
基取代;
或者CR9或CR10被连接到CR11(如关于R11指出的那样)而给出一个5
元或6元环;R11是氢,卤素,C1~C4烷氧基,C1~C4卤烷氧基,C1~C4烷硫基,
NH(C1~C4烷基),N(C1~C4烷基)2,氰基;
C1~C4烷基,C2~C4烯基,这些基可能被卤素,氰基,C1~C4
烷氧基取代一次或多次;
或者CR11与CR9或CR10一起形成一个5元或6元亚烷基或亚烯基环,
它可被一个或两个C1~C4烷基取代,其中,在每种情况下,一个
或多个亚甲基可被氧,硫,-NH或-N(C1~C4烷基)替代。
特别优选的式I的化合物-既作为纯的对映体或纯的非对映体又作为它们的混合物-是那些,即,其中,取代基具有下列含义:R1是四唑基或基其中,R具有如下含义:a) 基OR6,其中,R6是:氢,碱金属的阳离子,碱土金属的阳离子或铵离子;C1~C8烷基,CH2-苯基,它可被一个或多个下列基取代:卤素,C1~C4烷基,C1~C4卤烷基,C1~C4烷氧基;R6还可以是苯基,它可能携带1~5个卤原子和/或1~3个如下基:C1~C4烷基,C1~C4卤烷基,C1~C4烷氧基;b) 一个通过氮原子连接的5元杂芳族体系,例如咪唑基和三唑基,它可能携带一个或两个卤原子或者一个或两个C1~C4烷基或者一个或两个C1~C4烷氧基;c) 基
其中,k可以是0,1和2的值,p可以是1,2,3和4的值,而且R7是:
C1~C4烷基,C3~C8环烷基或苯基,它可被一个或多个(例如1~
其中,R8是:
C1~C4烷基,C3~C8环烷基,这些基可能携带一个C1~C4烷氧
基和/或如c)提及的苯基;
C1~C4卤烷基或苯基,它任选尤其如c)提及的那样被取代了。W 和Z(它们可以相同或不同)是:
氮或次甲基;但须,如果W和Z=次甲基,那么Q=氮;X 是氮或CR9;Y 是氮或CR10;Q 是氮或CR11;但须,如果Q=氮,那么X=CR9和Y=CR10;R2 和R3(它们可以相同或不同)是:
苯基,它可被一个或多个下列基取代:卤素,C1~C4烷基,C1~C4
卤烷基,C1~C4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,它可被下列基取代一次或多次(例
如1~3次):卤素,C1~C4烷基,C1~C4卤烷基,C1~C4烷氧
基或C1~C4烷硫基;或者
苯基,它们在邻位通过直接的键,亚甲基,1,2-亚乙基或亚乙烯基,
个氮原子和/或一个硫或氧原子,所述基可能被下列基取代一
次或多次:卤素,羟基,C1~C4烷基,C1~C4卤烷基,C1~
C4烷氧基,C1~C4卤烷氧基,苯氧基,C1~C4烷硫基,NH(C1
~C4烷基),N(C1~C4烷基)2,(C1~C4烷基)NHSO2,(C1~C4
烷基)2NSO2或苯基,它可能被下列基取代一次或多次(例如1~
3次):卤素,C1~C4烷基,C1~C4卤烷基,C1~C4烷氧基
和/或C1~C4卤烷氧基;b) 基
其中,R13是:C1~C4烷基,C1~C4卤烷基或苯基,苯基又可能携
带1~5个卤原子和/或1~3个下列基:C1~C4烷基,
C1~C4卤烷基,C1~C4烷氧基;R5 是氢,甲基;R9 和R10(它们可以相同或不同)是:
氢,C1~C4烷氧基,C1~C4烷硫基,N(C1~C4烷基)2;
C1~C4烷基,这些基可能被卤素取代;
或者CR9或CR10与CR11(如关于R11指出的那样)连接而给出一个5
元或6元环;R11是氢,C1~C4烷氧基,C1~C4烷硫基,氰基;
C1~C4烷基,这些基在各情况下可能被卤素取代一次或多次;
或者CR11与CR9或CR10一起形成一个5元或6元亚烷基或亚烯基环,
它可被一个或两个C1~C4烷基取代,其中,在每种情况下,一个
或多个亚甲基可被氧,硫,-NH或-N(C1~C4烷基)替代。
本发明的化合物提供对下列疾病的新型有效的治疗:高血压、肺动脉高压、心肌梗死、慢性心力衰竭、心绞痛、急性/慢性肾衰竭、肾功能不全、脑血管痉挛、脑缺血、蛛网膜下出血、偏头痛、哮喘、动脉粥样硬化、内毒素性休克、内毒素引起的器官衰竭、血管内凝血、血管成形术后的再狭窄、良性前列腺肥大、局部缺血引起的和中毒引起的肾衰竭或高血压、环孢菌素引起的肾衰竭、勃起功能障碍、转移瘤和间充质瘤的生长、癌、前列腺癌、造影剂引起的肾衰竭、胰腺炎、胃肠溃疡。
本发明还涉及组合产品,它包含式I的内皮缩血管肽受体拮抗物和肾素-血管紧张肽系统的抑制剂。肾素-血管紧张肽系统的抑制剂有:肾素抑制剂、血管紧张肽II拮抗物和尤其血管紧张肽转化酶(ACE)抑制剂。
这些组合产品特别适合治疗和预防高血压和它的后遗症,以及治疗心力衰竭。
所述化合物的良好效果可在下列试验中得到证实:
受体结合研究
将克隆的人ETA或ETB受体表达CHO细胞用于结合研究。
膜制剂
将ETA或ETB受体表达CHO细胞在DMEM NUT MIX F12培养基(Gibco,No.21331-020)中生长,所述培养基含10%胎牛血清(PAALaboratories GmbH,Linz,No.A15-022)、1mM谷氨酰胺(Gibco,No.25030-024)、100U/ml青霉素和100μg/ml链霉素(SigmaNo.P-0781)。48小时后,用PBS洗涤细胞,与含0.05%胰蛋白酶的PBS在37℃下保温5分钟。接着,用培养基中和,通过在300xg下离心收集细胞。
至于膜制剂,将细胞调节到浓度为108个细胞/ml缓冲剂(50mMTris-HCl缓冲剂,pH 7.4)。然后用超声波(Branson超声波仪250,40~70秒/恒定的输出功率20)崩解。
结合分析
至于ETA或ETB受体结合分析,将所述膜以每分析混合物50μg蛋白质的浓度悬浮于保温缓冲液(50mM Tris-HCl,pH 7.4,含5mM MnCl2、40μg/ml杆菌肽和0.2%BSA)中,在25℃下当存在和不存在试验物质时与25pM[125I]-ET1(ETA受体分析)或25pM[125I]-ET3(ETB受体分析)保温。应用10-7M ET1测定非特异性结合。30min后,通过GF/B玻璃纤维过滤器(Whatman,England)过滤,收集在Skatron细胞收集器(Skatron,Lier,Norway)中,分离游离的和结合的放射性配体,用冰冷的Tris-HCl缓冲液(pH 7.4,含0.2%BSA)洗涤过滤器。应用Packard 2200 CA液体闪烁计数器定量分析在过滤器上收集的放射性活度。
体内ET拮抗物的测试:
用异戊巴比妥麻醉重量为250~300g的雄性SD大鼠,人工通气,切断迷走神经和刺毁脑脊髓。对颈动脉和颈静脉插管。
在对比动物中,静脉内施用1mg/kg ET1导致血压的显著升高,它持续了很长一段时间。
在施给ET1之前30min对实验动物静脉内注射(1mg/kg)试验化合物。为了测定ET-拮抗特性,将实验动物中的血压变化和对比动物中的比较。
经口测试ET受体拮抗物:
用试验物质经口预处理重量为250~350g的雄性血压正常的大鼠(Sprague Dawley,Janvier)。80分钟后,用尿烷麻醉动物,对颈动脉(为了测定血压)和颈静脉(施用大内皮缩血管肽/内皮缩血管肽1)插管。
稳定期后,经静脉内施给大内皮缩血管肽(20μg/kg,施用体积为0.5ml/kg)或ET1(0.3μg/kg,施用体积为0.5ml/kg)。连续记录血压和心率达30分钟。以曲线下的面积(AUC)计算血压显著的和持久的变化。为了测定试验物质的拮抗效果,比较用试验物质处理的动物的AUC与对比动物的AUC。
所述新型化合物可按常规方法经口施用或肠胃外(皮下,静脉内,肌内,腹膜内)施用。还可通过鼻咽空间用蒸汽或喷雾剂进行施药。
剂量取决于患者的年龄、健康状况和体重以及施药方式。总体来说,活性组分的日剂量为约0.5~50mg/kg体重(经口施药)和约0.1~10mg/kg体重(肠胃外施药)。
所述新型化合物可呈常规固体或液体药物形式,例如,作为未包衣的或(薄膜)包衣的片剂,胶囊,粉末,颗粒,栓剂,溶液,软膏,乳膏或喷雾剂。这些药剂是按常规方法生产的。可用下列常规药物助剂加工用于该目的的活性组分:例如,片剂粘合剂、增量剂、防腐剂、片剂崩解剂、流动调节剂、增塑剂、润湿剂、分散剂、乳化剂、溶剂、缓释剂、抗氧化剂和/或喷射气体[参见H.Sucker等:PharmazeutischeTechnologie,Thieme-Verlag,Stuttgart,1991]。这样获得的施药形式通常包含0.1~90wt%活性组分。
合成实施例
实施例1:
3-氨基-2-羟基-3,3-二苯基丙酸甲酯
将0.2g 10%的钯/碳氢化催化剂加到3-叠氮基-2-羟基-3,3-二苯基丙酸甲酯(5.71g;19.2mmol)的甲醇(100ml)溶液中。在室温下的氢气氛中将混合物搅拌48小时;然后滤出催化剂,蒸出溶剂。将残余物溶于5%浓度的柠檬酸水溶液中,用乙醚萃取形成的溶液。用稀氢氧化钠溶液使水相呈碱性,再用乙醚萃取。在硫酸镁上干燥从碱相获得的萃取液,真空除去溶剂。获得4.03g(14.9mmol,77%产率)纯胺。1H-NMR(200MHz):7,5(m,2H);7,2-7,4(m,8H),5,0(s,1H);4,2(s br,1H),3,4(s,3H);2,0-2,4(s br,2H)-
实施例2:
2-(4-甲氧基苯甲酰氨基)-1-甲氧羰基-2,2-二苯基乙基-4-甲氧基苯甲酸酯
将吡啶(1.17g;14.7mmol)、一刮勺端二甲氨基吡啶和对-甲氧基苯甲酰氯(2.52g;14.7mmol)依次加入3-氨基-2-羟基-3,3-二苯基丙酸甲酯(2.00g;7.37mmol)的二氯甲烷(10ml)溶液中。在室温下将混合物搅拌4小时,然后进行后处理:与水混合,用乙醚萃取。用柠檬酸水溶液和饱和盐水洗涤合并的有机相,接着在硫酸镁上干燥。真空蒸出溶剂而给出粗的双酰化产品,未进一步纯化而将它直接应用(1.37g;28%产率,根据HPLC分析的纯度为82%)。
实施例3:
2-羟基-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸甲酯
将2-(4-甲氧基苯甲酰氨基)-1-甲氧羰基-2,2-二苯基乙基-4-甲氧基苯甲酸酯(1.37g;2.08mmol,纯度为82%)溶于甲醇(20ml),添加碳酸钾(863mg,6.25mmol)。在室温下搅拌形成的混合物达16小时,真空除去溶剂。将残余物溶于水,用乙醚萃取;在此过程中形成无色固体沉淀,通过过滤分离,与标题化合物完全相同。然后又用乙酸乙酯萃取水相。合并有机相,在硫酸镁上干燥,真空除去溶剂。通过从二氯甲烷/乙醚/正己烷中结晶而纯化粗产品,生成无色固体(503mg;60%产率)。
实施例4:
2-羟基-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸苄酯
将2.11ml的1摩尔氢氧化钠溶液加到2-羟基-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸甲酯(503mg;1.24mmol)于1∶2水/四氢呋喃(50ml)的溶液中,在室温下搅拌60小时。原料经过这样处理后基本上被转化了;为了使反应完全,再次添加1摩尔氢氧化钠溶液(2.11ml),继续搅拌1小时。用水稀释混合物,用乙醚萃取,用柠檬酸酸化,再次用乙醚萃取。在硫酸镁上干燥从酸相获得的萃取液,真空除去溶剂。将残余物(406mg)溶于二甲基甲酰胺(20ml),依次添加碳酸钾(179mg;1.30mmol)和苄基溴(195mg;1.14mmol)。在室温下搅拌形成的混合物达20小时,然后添加5%浓度的柠檬酸水溶液。用水稀释后,先后用二氯甲烷和乙醚进行萃取(产品只适度地溶于乙醚)。先后用水和饱和盐水充分洗涤合并的有机萃取液,在硫酸镁上干燥,真空除去溶剂。通过用少量1∶1乙醚/正己烷洗涤残余物而除去痕量的苄基溴和二甲基甲酰胺。获得487mg(79%)纯的苄基酯。
实施例5:
2-(4,6-二乙基[1,3,5]三嗪-2-基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸苄酯
将碳酸钾(80mg;0.58mmol)和2-氯-4,6-二乙基-[1,3,5]三嗪(74mg;0.43mmol)依次加到2-羟基-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸苄酯(139mg;0.29mmol)于二甲基甲酰胺(15ml)的溶液中。将混合物加热到60℃,在此温度下搅拌4小时。添加5%浓度的柠檬酸(10ml)终止反应。用水稀释,接着用乙醚萃取,用饱和盐水洗涤合并的有机相,在硫酸镁上干燥。蒸去溶剂;通过急骤层析法(洗脱剂:乙酸乙酯在环己烷中30~50%)纯化残余物。获得124mg纯度为90%(根据HPLC)的靶化合物(63%产率)。
实施例6:
2-(4,6-二乙基[1,3,5]三嗪-2-基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸(I-4)
将10%钯/碳氢化催化剂(一刮勺端)加到2-(4,6-二乙基[1,3,5]三嗪-2-基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸苄酯(124mg;0.18mmol,纯度为90%)的乙酸乙酯(15ml)溶液中,在室温下的氢气氛中搅拌3小时。滤出催化剂,真空蒸出溶剂。将残余物从二氯甲烷/乙醚/正己烷中结晶,生成99mg(73%产率)纯羧酸。1H-NMR(200MHz):7,8(m,3H);7,6(dd,2H);7,1-7,4(m,8H);6,9(d,2H);6,6(s,1H);3,8(s,3H); 2,7(q,4H);1,2(t,6H).ESI-MS:M+=526.
类似地合成了下列化合物:
2-(4,6-二乙基[1,3,5]三嗪-2-基氧基)-3-(3,5-二甲氧基苯甲酰氨基)-3,3-二苯基丙酸(I-327)1H-NMR(200 MHz):7,9(s,1H);7,6(m,2H),7,2-7,5(m,8H);6,9(d,2H);6,7(s,1H),6,6(t,1H);3,8(s,6H);2,7(q,4H);1,2(t,6H).ESI-MS:M+=556.
3-(3,5-二甲氧基苯甲酰氨基)-2-(4,6-二甲基-2-嘧啶基氧基)-3,3-二苯基丙酸(I-248)1H-NMR(200MHz):8,1(s br,1H);7,7(m,2H);7,2-7,5(m,8H);7,0(d,2H);6,70(s,1H);6,65(s,1H);6,60(t,1H);3,8(s,6H); 2,3(s,6H).ESI-MS:M+=527.
3-苯甲酰氨基-2-(4,6-二甲基-2-嘧啶基氧基)-3,3-二苯基丙酸(I-66)1H-NMR(200MHz):8,2(s br,1H);7,8(m,2H);7,6(m,2H);7,1-7,5(m,11H);6,70(s,1H);6,65(s,1H);2,3(s,6H).ESI-MS:M+=467.
2-(4,6-二甲基-2-嘧啶基氧基)-3-(4-甲基苯甲酰氨基)-3,3-二苯基丙酸(I-199)1H-NMR(200MHz):8,0(s br,1H);7,7(d,2H);7,6(m,2H);7,1-7,5(m,10H);6,7(s,2H);2,4(s,3H);2,3(s,6H).EST—MS:M+=481。
实施例7:
2-甲基-4,4-二苯基-4,5-二氢噁唑-5-羧酸苄酯
将醚合三氟化硼(8.04g;56.7mmol)小心地加到3,3-二苯基环氧乙烷-2-羧酸苄酯(10.0g;28.3mmol)的乙腈(100ml)溶液中。在室温下将混合物搅拌1小时,然后在旋转式蒸发器中浓缩。将残余物溶于水,用氯化钠饱和,用乙酸乙酯萃取。在硫酸镁上干燥有机相,真空除去溶剂;未进一步纯化而应用残余物(13.5g)。
实施例8:
3-氨基-2-羟基-3,3-二苯基丙酸苄酯
在室温下将2-甲基-4,4-二苯基-4,5-二氢噁唑-5-羧酸苄酯(13.5g;粗的)在甲醇(25ml)、水(50ml)和浓盐酸(50ml)的混合物中搅拌60小时。然后滗析溶液中的不溶性物质;将残余物在上述混合物中再次搅拌3小时。重复滗析操作;弃去残余物。合并两份液相,用氢氧化钠溶液调节到pH 8~9,于是开始结晶。用乙醚洗涤晶体,进行抽吸过滤;获得4.65g纯度为97%的氨基醇。1H-NMR(200MHz):7,4(m,2H);7,1-7,3(m,11H);,7,0(m,2H);5,0(s,1H);4,9(d,1H);4,7(d,1H);1,9-2,5(s br,2H).
实施例9:
2-羟基-3,3-二苯基-3-(4-三氟甲基苯甲酰氨基)丙酸苄酯
将吡啶(94mg;1.00mmol)、一刮勺端二甲氨基吡啶和对-三氟甲基苯甲酰氯(215mg;1.00mmol)依次加入3-氨基-2-羟基-3,3-二苯基丙酸苄酯(365mg;1.00mmol)的二氯甲烷(50ml)溶液中。在室温下将混合物搅拌60小时,然后通过用稀的柠檬酸萃取进行后处理。在硫酸镁上干燥有机相,真空除去溶剂。将残余物(540mg)溶于氯仿(50ml),在添加了吡啶(36mg;0.45mmol)和少量二甲氨基吡啶晶体之后,回流4小时。冷却后,通过用稀的柠檬酸萃取进行后处理。在硫酸镁上干燥有机相,真空除去溶剂。将残余物从乙醚/正己烷中结晶;获得235mg纯产品(45%产率)。1H-NMR(200MHz):7,7(d,2H);7,5(d,2H); 7,2-7,4(m,13H);7,1(d,2H);5,5(d br,1H);5,0(m,2H);4,6-4,8(s br,1H).
实施例10:
2-(4,6-二甲基-2-嘧啶基氧基)-3,3-二苯基-3-(4-三氟甲基苯甲酰氨基)丙酸苄酯
将碳酸钾(100mg;0.72mmol)和2-甲磺酰-4,6-二甲基嘧啶(96mg;0.51mmol)依次加到2-羟基-3,3-二苯基-3-(4-三氟甲基苯甲酰氨基)丙酸苄酯(220mg;0.42mmol)于二甲基甲酰胺(15ml)的溶液中。将混合物加热到80℃,在此温度下搅拌1小时。通过添加稀的柠檬酸和水(200ml)终止反应。用乙醚萃取后,在硫酸镁上干燥有机相,真空浓缩。将残余物从乙醚/正己烷中结晶;获得158mg(60%)的纯标题化合物。
实施例11:
2-(4,6-二甲基-2-嘧啶基氧基)-3,3-二苯基-3-(4-三氟甲基苯甲酰氨基)丙酸(I-201)
将10%钯/碳氢化催化剂(一刮勺端)加到2-(4,6-二甲基-2-嘧啶基氧基)-3,3-二苯基-3-(4-三氟甲基苯甲酰氨基)丙酸苄酯(150mg;0.24mmol)的乙酸乙酯(50ml)溶液中,在室温下的氢气氛中将混合物搅拌2小时。然后滤出催化剂,真空蒸出溶剂。将残余物从乙醚/正己烷中结晶,生成100mg(78%)纯羧酸。1H-NMR(200MHz):8,3(s br,1H);7,9(d,2H);7,7(m,4H);7,1-7,4(m,8H);6,7(s,1H);6,6(s,1H);2,3(s,6H).ESI-MS:M+=535.
类似地制备了下列化合物:
3-(3,4-二甲氧基苯甲酰氨基)-2-(4,6-二甲基-2-嘧啶基氧基)-3,3-二苯基丙酸(I-48)1H-NMR(200MHz):8,2(s br,1H);7,7(m,2H);7,1-7,5(m,10H);6,8(d,1H);6,7(s,1H);6,6(s,1H);3,9(s,3H);3,8(s,3H);2,3(s,6H).ESI-MS:M+=527.
3-(3,4-二氟苯甲酰氨基)-2-(4,6-二甲基-2-嘧啶基氧基)-3,3-二苯基丙酸(I-340)1H-NMR(200MHz):8,2(s br,1H);7,5-7,8(m,5H);7,1-7,4(m,8H);6,7(s,1H);6,6(s,1H);2,3(s,6H).ESI-MS:M+=503.
2-(4,6-二甲基-2-嘧啶基氧基)-3-(4-氟苯甲酰氨基)-3,3-二苯基丙酸(I-170)1H-NMR(200MHz):8,2(s br,1H);7,8(dd,2H);7,6(m,2H);7,0-7,5(m,10H);6,7(s,1H);6,6(s,1H);2,3(s,6H).ESI-MS:M+=485.
实施例12:
2-(4,6-二甲氧基-2-嘧啶基氧基)-3-甲磺酰氨基-3,3-二苯基丙酸甲酯
将甲磺酰氯(83mg;0.73mmol)、吡啶(82mg;1.04mmol)和二甲氨基吡啶(一刮勺端)加入3-氨基-2-(4,6-二甲氧基-2-嘧啶基氧基)-3,3-二苯基丙酸甲酯(213mg;0.52mmol)的二氯甲烷(15ml)溶液中。在室温下将混合物搅拌一周。由于转化不完全,所以又添加0.2摩尔当量的甲磺酰氯,再在室温下将混合物搅拌三天。至于后处理,用乙醚稀释混合物,依次用稀的柠檬酸、碳酸氢钠溶液和饱和盐水洗涤。在硫酸镁上干燥有机相,真空除去溶剂。中和柠檬酸萃取液,用乙醚萃取;如上述那样干燥由此获得的有机相和蒸发。未进一步纯化而直接应用残余物(206mg)。
实施例13:
2-(4,6-二甲氧基-2-嘧啶基氧基)-3-甲磺酰氨基-3,3-二苯基丙酸(I-156)
将0.50ml的1摩尔氢氧化钠溶液加到2-(4,6-二甲氧基-2-嘧啶基氧基)-3-甲磺酰氨基-3,3-二苯基丙酸甲酯(181mg;粗的)于1∶2水/四氢呋喃(30ml)的溶液中,在室温下将混合物搅拌5天。为了使反应完全,又添加0.5摩尔当量的1摩尔氢氧化钠溶液,再次将混合物搅拌24小时。用水稀释和用乙醚萃取后,用柠檬酸酸化水相,再次用乙醚萃取。在硫酸镁上干燥从酸相获得的萃取液,真空除去溶剂。将残余物从二氯甲烷/正己烷结晶而给出纯的靶化合物(71mg;两步33%产率)。1H-NMR(200MHz):7,6-7,7(m,2H);7,3-7,5(m,8H),6,5(s,1H);6,3(s br,1H),5,8(s,1H);3,9(s,6H); 2,2(s,3H).ESI-MS:M+=473.
类似地或按概述部分中描述的那样可制备表1中列出的化合物。
表1
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-1 | COOH | 苯基 | 4-OMe-苯基 -CONH | CH | C-OMe | N | C-OMe | N |
I-2 | COOH | 苯基 | 5-F-3-吡啶基 -CONH | N | C-Me | CH | C-Me | N |
I-3 | COOH | 苯基 | 2-噻唑基 -CONH | N | C-Me | CH | C-OMe | N |
I-4 | COOH | 苯基 | 4-OMe-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-5 | COOH | 苯基 | 4-OMe-苯基 -CONH | N | C-OMe | N | C-OMe | N |
I-6 | COOH | 苯基 | 4-OMe-苯基 -CONH | N | C-乙基 | CH | C-乙基 | N |
I-7 | COOH | 苯基 | 3,4-Di-F-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-8 | COOH | 苯基 | 3,5-Di-F-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-9 | COOH | 4-F-苯基 | 4-OMe-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-10 | COOH | 苯基 | 2-噻唑基 -CONH | N | C-Me | CH | C-Me | N |
I-11 | COOH | 苯基 | 4-噻唑基 -CONH | N | C-Me | N | C-Me | N |
I-12 | COOH | 4-F-苯基 | 4-OMe-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-13 | COOH | 4-F-苯基 | 4-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-14 | COOH | 4-F-苯基 | 4-OMe-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-15 | COOH | 苯基 | 3,4-Di-F-苯基 -CONH | CH | C-OMe | N | C-Me | N |
I-16 | COOH | 苯基 | 3,5-Di-F-苯基 -CONH | CH | C-Me | N | C-Me | N |
I-17 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-OMe | CH | C-OMe | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-18 | COOH | 苯基 | 4-噻唑基 -CONH | CH | C-OMe | N | C-Me | N |
I-19 | COOH | 苯基 | 2-噻唑基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-20 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-Me | CH | C-Me | N |
I-21 | COONa | 苯基 | 4-OMe-苯基 -CONMe | N | C-OMe | CH | C-Me | N |
I-22 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-乙基 | N | C-乙基 | N |
I-23 | COOH | 苯基 | 3,5-Di-F-苯基 -CONH | CH | C-OMe | N | C-OMe | N |
I-24 | COOH | 苯基 | 3,4-Di-F-苯基 -CONH | N | N | C-Me | C-OMe | N |
I-25 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-Me | N | C-Me | N |
I-26 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-O-CH2-CH2-C | C-OMe | N | |
I-27 | COOH | 苯基 | 5-Me-2-噻唑基 -CONH | N | C-Me | CH | C-SEt | N |
I-28 | COOH | 苯基 | 4-Cl-2-噻唑基 -CONH | N | C-Me | CH | C-Me | N |
I-29 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-O-CH2-CH2-C | C-Me | N | |
I-30 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-OMe | C-Me | CH | N |
I-31 | COOH | 苯基 | 3,4-Di-F-苯基 -CONH | CH | C-OMe | CH | C-Me | N |
I-32 | COOH | 4-OMe-苯基 | 3,4-Di-F-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-33 | COOH | 苯基 | 4-OMe-苯基 -CONMe | CH | C-Me | N | C-OMe | N |
I-34 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-Me | CH | C-CF3 | N |
I-35 | COOH | 苯基 | 5-CN-2-噻唑基 -CONH | N | C-OMe | CH | C-OMe | N |
I-36 | COOH | 苯基 | 5-CN-2-吡咯基 -CONH | N | C-Me | CH | C-Me | N |
I-37 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | C-OMe | N | C-乙基 | N |
I-38 | COOH | 苯基 | 4-OMe-苯基 -CONMe | N | N | C-OMe | C-乙基 | N |
I-39 | COOH | 4-Me-苯基 | 3,4-Di-F-苯基 -CONH | N | C-OMe | CH | C-乙基 | N |
I-40 | COOH | 苯基 | 3,4-Di-F-苯基 -CONH | N | C-Me | C-CN | C-OEt | CH |
I-41 | COOH | 4-F-苯基 | 4-OMe-苯基 -CONMe | N | C-OMe | CH | C-OMe | N |
I-42 | COOH | 2-Cl-苯基 | 4-OMe-苯基 -CONMe | N | C-乙基 | CH | C-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-43 | COOH | 苯基 | 5-CN-2-吡咯基 -CONH | N | C-OMe | CH | C-Me | N |
I-44 | COOH | 苯基 | 2-吡咯基 -CONH | N | C-乙基 | CH | C-SMe | N |
I-45 | COOH | 苯基 | 4-SMe-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-46 | COOH | 苯基 | 4-SMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-47 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-48 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-49 | COOH | 苯基 | 4-SMe-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-50 | COONa | 苯基 | 4-SMe-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-51 | COOH | 苯基 | 2-吡咯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-52 | COOH | 苯基 | 5-Me-2-吡咯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-53 | COOH | 苯基 | 4-SMe-苯基 -CONH | CH | C-OMe | N | C-Me | N |
I-54 | COOH | 4-Cl-苯基 | 4-SMe-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-55 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-56 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-57 | COOH | 苯基 | 4-SMe-苯基 -CONMe | N | C-Me | CH | C-Me | N |
I-58 | COOH | 苯基 | 苯基 -CONH | CH | C-Me | N | C-Me | N |
I-59 | COOH | 苯基 | 2-萘基 -CONH | N | C-CH2-CH2-CH2-C | C-Me | N | |
I-60 | COOH | 苯基 | 2-萘基 -CONH | N | C-Me | CH | C-Me | N |
I-61 | COOH | 4-F-苯基 | 苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-62 | COOH | 4-F-苯基 | 苯基 -CONH | N | C-Me | CH | C-Me | N |
I-63 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-64 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-CH2-CH2-CH2-C | C-Me | N | |
I-65 | COOH | 苯基 | 苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-66 | COOH | 苯基 | 苯基 -CONH | N | C-Me | CH | C-Me | N |
I-67 | COOH | 苯基 | 2-萘基 -CONH | N | C-OMe | CH | C-Me | N |
I-68 | COOH | 苯基 | 2-萘基 -CONH | N | C-CH2-CH2-CH2-C | C-OMe | N | |
I-69 | COOH | 苯基 | 苯基 -CONH | N | C-OMe | CH | C-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-70 | COO-苄基 | 苯基 | 苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-71 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONMe | N | C-OMe | CH | C-OMe | N |
I-72 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONMe | N | C-Me | CH | C-Me | N |
I-73 | COOH | 苯基 | 苯基 -CONH | N | C-Me | N | C-Me | N |
I-74 | COOMe | 苯基 | 苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-75 | COOH | 苯基 | 2-萘基 -CONH | N | C-Me | CH | C-NHMe | N |
I-76 | COOH | 苯基 | 5-OMe-2-萘基 -CONH | N | C-OMe | CH | C-Me | N |
I-77 | COOH | 苯基 | 苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-78 | COOH | 苯基 | 苯基 -CONH | CH | C-OMe | N | C-Me | N |
I-79 | COOH | 4-F-苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-CH2-CH2-CH2-C | C-OMe | N | |
I-80 | COOH | 苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-81 | COOH | 苯基 | 苯基 -CONH | CH | C-OMe | N | C-OMe | N |
I-82 | COOH | 苯基 | 苯基 -CONH | N | N | C-OMe | C-Me | N |
I-83 | COOH | 苯基 | 5-Cl-萘基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-84 | COOH | 苯基 | 6-OMe-2-萘基 -CONH | N | C-Me | CH | C-Me | N |
I-85 | COOH | 苯基 | 4-OH-苯基 -CONH | N | C-Me | N | C-Me | N |
I-86 | COOH | 4-Me-苯基 | 4-OH-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-87 | COOH | 2-Cl-苯基 | 3,4-Di-OMe-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-88 | COOH | 苯基 | 3,4-Di-OCF3-苯基 -CONH | N | N | C-OMe | C-苯基 | N |
I-89 | COOH | 苯基 | 4-OH-苯基 -CONMe | N | C-OMe | CH | C-OMe | N |
I-90 | COOH | 苯基 | 4-OH-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-91 | COOH | 苯基 | 1-萘基 -CONH | N | C-Me | CH | C-Me | N |
I-92 | COOH | 苯基 | 1-萘基 -CONH | N | C-OMe | CH | C-Me | N |
I-93 | COOH | 苯基 | 3-OH-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-94 | COOH | 苯基 | 4-OH-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | O | Y | Z |
I-95 | COOH | 苯基 | 3,4-Di-OCF3-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-96 | COOH | 苯基 | 3,4-Di-OCF3-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-97 | COOH | 苯基 | 4-OH-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-98 | COOH | 苯基 | 4-OH-苯基 -CONH | CH | C-OMe | N | C-Me | N |
I-99 | COOH | 苯基 | 1-萘基 -CONH | N | C-Me | N | C-Me | N |
I-100 | COOH | 苯基 | 1-萘基 -CONH | N | C-OMe | CH | C-OMe | N |
I-101 | COOH | 4-F-苯基 | 4-OH-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-102 | COOH | 苯基 | 4-OH-苯基 -CONMe | N | C-Me | CH | C-Me | N |
I-103 | COOH | 苯基 | 3,4-Di-OCF3-苯基 -CONH | CH | C-OMe | N | C-Me | N |
I-104 | COOH | 苯基 | 3,4-Di-OCF3-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-105 | COOEt | 苯基 | 4-Br-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-106 | COOH | 苯基 | 4-Br-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-107 | COOH | 苯基 | 1- 萘基 -CONH | CH | C-OMe | N | C-OMe | N |
I-108 | COOH | 苯基 | 4-Br-2-萘基 -CONH | N | C-Me | CH | C-Me | N |
I-109 | COOH | 苯基 | 4-Br-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-110 | COOH | 苯基 | 4-Br-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-111 | COOH | 苯基 | 3,4-Di-OCF3-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-112 | COOH | 苯基 | 3,4-Di-OH-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-113 | COOH | 4-Me-苯基 | 4-Br-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-114 | COOH | 苯基 | 4-Br-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-115 | COOH | 苯基 | 5-CN-2-萘基 -CONH | N | C-OMe | CH | C-Me | N |
I-116 | COOH | 苯基 | 5-OH-2-萘基 -CONH | N | C-乙基 | CH | C-OMe | N |
I-117 | COOH | 苯基 | 3-Br-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-118 | COOH | 苯基 | 3-Br-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-119 | COOH | 苯基 | 3,4-Di-OH-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-120 | COOH | 3-F-苯基 | 3,4-Di-OH-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-121 | COOH | 苯基 | 3-Br-苯基 -CONH | N | C-Me | CH | C-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-122 | COOH | 苯基 | 3-Br-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-123 | COOH | 苯基 | 3-CN-1-萘基 -CONH | N | C-OMe | CH | C-OMe | N |
I-124 | COOH | 苯基 | 3-Cl-1-萘基 -CONH | N | C-Me | N | C-Me | N |
I-125 | COOH | 苯基 | 3-Br-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-126 | COOH | 4-Me-苯基 | 3-Br-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-127 | COOH | 苯基 | 3-OH-4-OMe-苯基 -CONH | CH | C-乙基 | N | C-OMe | N |
I-128 | COOH | 苯基 | 3-OH-4-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-129 | COOH | 苯基 | 3-OMe-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-130 | COOH | 苯基 | 3-OMe-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-131 | COOH | 苯基 | 3-OMe-1-萘基 -CONH | N | C-OMe | CH | C-Me | N |
I-132 | COOH | 苯基 | 2- 咪唑基 -CONH | N | C-Me | CH | C-Me | N |
I-133 | COOH | 苯基 | 3-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-134 | COOH | 苯基 | 3-OMe-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-135 | COOH | 苯基 | 3-OH-4-OMe-苯基 -CONH | N | C-乙基 | N | C-NHMe | N |
I-136 | COOH | 苯基 | 3-OMe-4-OH-苯基 -CONH | N | N | C-乙基 | C-OMe | CH |
I-137 | COOH | 苯基 | 3-OMe-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-138 | COOH | 4-F-苯基 | 3-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-139 | COOH | 苯基 | 2- 咪唑基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-140 | COOH | 苯基 | 2- 咪唑基 -CONH | N | C-乙基 | CH | C-OMe | N |
I-141 | COOH | 苯基 | 3-OMe-苯基 -CONMe | N | C-OMe | CH | C-OMe | N |
I-142 | COOH | 苯基 | 3-OMe-苯基 -CONMe | N | C-Me | CH | C-Me | N |
I-143 | COOH | 苯基 | 3-OMe-4-OH-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-144 | COOH | 苯基 | 3-F-4-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-145 | COOH | 苯基 | 4-Cl-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-146 | COOH | 苯基 | 4-Cl-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-147 | COOH | 苯基 | MeSO2NH | N | N | CH | C-Me | N |
I-148 | COOH | 苯基 | MeSO2NH | N | C-OMe | CH | C-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-149 | COOH | 苯基 | 4-Cl-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-150 | COOH | 苯基 | 4-Cl-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-151 | COOH | 苯基 | 3-F-4-OMe-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-152 | COOH | 苯基 | 3-Cl-4-OMe-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-153 | COOH | 4-Me-苯基 | 4-Cl-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-154 | COOH | 苯基 | 4-Cl-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-155 | COOH | 苯基 | MeSO2NH | CH | C-Me | N | C-OMe | CH |
I-156 | COOH | 苯基 | MeSO2NH | N | C-OMe | CH | C-OMe | N |
I-157 | COOH | 苯基 | 3-Cl-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-158 | COOK | 苯基 | 3-Cl-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-159 | COOH | 苯基 | 3-OMe-4-F-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-160 | COOH | 苯基 | 3-OMe-4-F-苯基 -CONH | N | C-Me | CH | C-NMe2 | N |
I-161 | COOH | 苯基 | 3-Cl-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-162 | COOH | 苯基 | 3-Cl-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-163 | COOH | 苯基 | MeSO2NH | CH | C-OMe | N | C-OMe | N |
I-164 | COOH | 苯基 | MeSO2NH | N | C-CH2-CH2-CH2-C | C-Me | N | |
I-165 | COOH | 苯基 | 3-Cl-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-166 | COOH | 4-Me-苯基 | 3-Cl-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-167 | COOH | 3-Me-苯基 | 3-OMe-4-F-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-168 | COOH | 苯基 | 3-CN-4-OMe-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-169 | COOH | 苯基 | 4-F-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-170 | COOH | 苯基 | 4-F-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-171 | COOH | 4-F-苯基 | MeSO2NH | N | C-OMe | CH | C-OMe | N |
I-172 | COOH | 苯基 | MeSO2NH | N | C-O-CH2-CH2-C | C-Me | N | |
I-173 | COOH | 苯基 | 4-F-苯基 -CONH | N | C-OMe | CH | C-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-174 | COOH | 苯基 | 4-F-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-175 | COOH | 苯基 | 3-CN-4-OMe-苯基 -CONH | N | C-Me | N | C-OMe | N |
I-176 | COOH | 苯基 | 3-OMe-4-CN-苯基 -CONH | CH | C-OMe | N | C-Me | N |
I-177 | COOH | 4-Me-苯基 | 4-F-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-178 | COOH | 苯基 | 4-F-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-179 | COOH | 苯基 | MeSO2NH | N | C-乙基 | N | C-乙基 | N |
I-180 | COOH | 4-乙基-苯基 | MeSO2NH | N | C-乙基 | CH | C-OMe | N |
I-181 | COOH | 苯基 | 3-F-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-182 | COOH | 苯基 | 3-F-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-183 | COOH | 苯基 | 3-Me-4-OMe-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-184 | COOH | 苯基 | 3-Me-4-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-185 | COOH | 苯基 | 3-F-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-186 | COOH | 苯基 | 3-F-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-187 | COOH | 苯基 | 苯基 -SO2NH | N | C-OMe | CH | C-OMe | N |
I-188 | COOH | 4-F-苯基 | 苯基 -SO2NH | N | C-OMe | CH | C-OMe | N |
I-189 | COOH | 苯基 | 3-F-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-190 | COOH | 4-Me-苯基 | 3-F-苯基 -CONH | N | C-Me | N | C-Me | N |
I-191 | COOH | 苯基 | 苯基-SO2NH | N | C-S-CH2-CH2-C | C-OMe | N | |
I-192 | COOH | 苯基 | 4-CF3O-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-193 | COOH | 苯基 | 3-Me-4-OMe-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-194 | COOH | 苯基 | 3-OMe-4-Me-苯基 -CONH | N | C-Me | CH | C-CF3 | N |
I-195 | COOH | 苯基 | 4-CF3O-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-196 | COOH | 苯基 | 4-CF3O-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-197 | COOH | 苯基 | 苯基-SO2NH | N | N | C-Me | C-Me | CH |
I-198 | COOH | 苯基 | 4-CF3O-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-199 | COOH | 苯基 | 4-Me-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-200 | COOH | 4-Me-苯基 | 4-Me-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-201 | COOH | 苯基 | 4-CF3-苯基 -CONH | N | C-Me | N | C-Me | N |
I-202 | COOH | 苯基 | 4-CF3O-苯基 -CONH | CH | C-OMe | N | C-Me | N |
I-203 | COOH | 苯基 | 苯基 -SO2NH | CH | C-Me | N | C-NMe2 | N |
I-204 | COOH | 苯基 | 苯基 -SO2NH | N | C-OMe | N | C-OMe | N |
I-205 | COOH | 苯基 | 4-CF3O-苯基 -CONH | CH | C-Me | N | C-Me | N |
I-206 | COOH | 苯基 | 4-CF3-苯基 -CONH | CH | C-OMe | N | C-OMe | N |
I-207 | COOH | 苯基 | 4-Me-苯基 -CONMe | N | C-Me | CH | C-Me | N |
I-208 | COOH | 苯基 | 4-Me-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-209 | COOH | 苯基 | 4-CF3O-苯基 -CONH | N | N | C-Me | C-OMe | N |
I-210 | COOH | 苯基 | 4-CF3O-苯基 -CONH | CH | C-OMe | CH | C-Me | N |
I-211 | COOH | 苯基 | 苯基 -SO2NH | N | C-CH2-CH2-CH2-C | C-Me | N | |
I-212 | COOH | 苯基 | 苯基 -SO2NH | CH | C-Me | N | C-SMe | N |
I-213 | COOH | 苯基 | 4-CF3O-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-214 | COOH | 4-Me-苯基 | 4-CF3O-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-215 | COOH | 苯基 | 3-Me-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-216 | COOH | 苯基 | 4-Me-苯基 -CONH | N | C-乙基 | CH | C-乙基 | N |
I-217 | COOH | 苯基 | 4-CF3O-苯基 -CONMe | N | C-OMe | C-CN | C-OEt | CH |
I-218 | COOH | 苯基 | 4-CF3O-苯基 -CONMe | N | C-OMe | CH | C-OMe | N |
I-219 | COOH | 苯基 | 苯基 -SO2NH | N | C-OMe | CH | C-Me | N |
I-220 | COOH | 苯基 | 4-Me-苯基 -SO2NH | N | C-乙基 | CH | C-Me | N |
I-221 | COOH | 苯基 | 4-CF3O-苯基 -CONMe | N | C-Me | CH | C-Me | N |
I-222 | COOH | 苯基 | 4-CF3O-苯基 -CONMe | N | C-O-CH2-CH2-C | C-OMe | N | |
I-223 | COOH | 苯基 | 4-Me-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-224 | COOH | 苯基 | 4-Me-苯基 -CONH | CH | C-OMe | N | C-O-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-225 | COOH | 苯基 | 3-CF3O-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-226 | COOH | 苯基 | 3-CF3O-苯基 -CONH | CH | C-Me | N | C-Me | N |
I-227 | COOH | 苯基 | 4-Me-苯基 -SO2NH | N | C-OMe | CH | C-OMe | N |
I-228 | COOH | 苯基 | 4-Me-苯基 -SO2NH | CH | C-Me | N | C-Cl | CH |
I-229 | COOH | 苯基 | 3-CF3O-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-230 | COOH | 苯基 | 3-CF3O-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-231 | COOH | 4-F-苯基 | 4-Me-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-232 | COOH | 苯基 | 4-Me-苯基 -CONMe | N | C-Me | CH | C-Me | N |
I-233 | COOH | 苯基 | 4-CN-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-234 | COOH | 苯基 | 4-CN-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-235 | COOH | 苯基 | 4-Me-苯基 -SO2NH | N | C-OMe | C-F | C-OMe | N |
I-236 | COOH | 苯基 | 4-Me-苯基 -SO2NH | N | C-乙基 | N | C-乙基 | N |
I-237 | COOH | 苯基 | 4-CN-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-238 | COOH | 苯基 | 4-CN-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-239 | COOH | 苯基 | 3-Cl-4-Me2N-苯基 -CONH | C | C-OMe | CH | C-OMe | N |
I-240 | COOH | 苯基 | 3-Cl-4-Me2N-苯基 -CONH | N | N | CH | C-Me | N |
I-241 | COOH | 苯基 | 4-CN-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-242 | COOH | 苯基 | 4-CF3O-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-243 | COOH | 苯基 | 4-Me-苯基 -SO2NH | CH | C-SMe | N | C-Me | N |
I-244 | COOH | 苯基 | 3-Cl-苯基 -SO2NH | N | C-OMe | CH | C-OMe | N |
I-245 | COOH | 苯基 | 3-CN-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-246 | COOH | 苯基 | 4-CH3CO-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-247 | COOH | 苯基 | 3,5-Di-OMe-苯基 -CONMe | N | C-OMe | CH | C-OMe | N |
I-248 | COOH | 苯基 | 3,5-Di-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-249 | COOMe | 苯基 | 4-CF3O-苯基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-250 | COOH | 苯基 | 4-CH3CO-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-251 | COOH | 苯基 | 3-Cl-苯基 -SO2NH | N | C-Me | C-CF3 | N | CH |
I-252 | COOH | 苯基 | 3-Cl-苯基 -SO2NH | N | C-O-CH2-CH2-C | C-OMe | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-253 | COOH | 苯基 | 4-CH3CO-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-254 | COOH | 苯基 | 4-CH3CO-苯基 -CONH | N | N | C-乙基 | C-OMe | N |
I-255 | COOH | 苯基 | 3,5-Di-OMe-苯基 -CONH | N | C-CH2-CH2-CH2-C | C-OMe | N | |
I-256 | COOH | 3-Me-苯基 | 3,5-Di-OMe-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-257 | COOH | 苯基 | 4-EtO-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-258 | COOH | 苯基 | 4-EtO-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-259 | COOH | 苯基 | 4-Cl-苯基 -SO2NH | N | C-OMe | CH | C-SMe | N |
I-260 | COOH | 苯基 | 4-Cl-苯基 -SO2NH | N | C-乙基 | CH | C-乙基 | N |
I-261 | COOH | 苯基 | 3-EtO-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-262 | COOH | 苯基 | 4-EtO-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-263 | COOH | 苯基 | 4-吡啶基 -CONH | CH | C-Me | N | C-SMe | N |
I-264 | COOH | 苯基 | 4-吡啶基 -CONH | N | N | C-OEt | C-Me | N |
I-265 | COOH | 4-F-苯基 | 2-EtO-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-266 | COOH | 苯基 | 4-Me2NSO2-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-267 | COOH | 苯基 | 2-Cl-苯基 -SO2NH | N | C-OMe | CH | C-OMe | N |
I-268 | COOH | 苯基 | 4-NO2-苯基 -SO2NH | N | C-Me | CH | C-OMe | N |
I-269 | COOH | 苯基 | 4-Me2NSO2-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-270 | COOH | 苯基 | 4-Me2NSO2-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-271 | COOH | 苯基 | 4-吡啶基 -CONH | N | C-Me | CH | C-Me | N |
I-272 | COOH | 苯基 | 4-吡啶基 -CONH | N | C-OMe | CH | C-OMe | N |
I-273 | COOH | 苯基 | 4-Me2NSO2-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-274 | COOH | 苯基 | 4-Me2NSO2-苯基 -CONH | N | C-乙基 | N | C-Me | N |
I-275 | COOH | 苯基 | 4-NO2-苯基 -SO2NH | N | C-Me | CH | C-Me | N |
I-276 | COOH | 苯基 | 3-NO2-苯基 -SO2NH | N | C-Me | N | C-Me | N |
I-277 | COOH | 苯基 | 4-Me2NSO2-苯基 -CONH | N | C-CH2-CH2-CH2-C | C-Me | N | |
I-278 | COOH | 苯基 | 4-Me2NSO2-苯基 -CONH | CH | C-CF3 | N | C-Me | N |
I-279 | COOH | 苯基 | 4-吡啶基 -CONH | N | C-O-CH2-CH2-C | C-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-280 | COOH | 苯基 | 4-吡啶基 -CONH | N | C-Me | CH | C-SMe | N |
I-281 | COOH | 苯基 | 4-Me2NSO2-苯基 -CONH | CH | C-OMe | N | C-F | CH |
I-282 | COOH | 苯基 | 4-Me2N-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-283 | COOH | 苯基 | 4-NO2-苯基 -SO2NH | N | C-OMe | C-乙基 | N | CH |
I-284 | COOH | 苯基 | 4-NO2-苯基 -SO2NH | CH | C-乙基 | N | C-乙基 | N |
I-285 | COOH | 苯基 | 4-Me2N-苯基 -CONH | N | N | CH | C-Me | N |
I-286 | COOH | 苯基 | 4-Me2N-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-287 | COOH | 4-OMe-苯基 | 3-吡啶基 -CONH | N | C-OMe | CH | C-OMe | N |
I-288 | COOH | 苯基 | 3-吡啶基 -CONH | N | C-O-CH2-CH2-C | C-Me | N | |
I-289 | COOH | 苯基 | 4-Me2N-苯基 -CONH | CH | C-乙基 | N | C-乙基 | N |
I-290 | COOH | 苯基 | 4-Me2N-苯基 -CONH | N | C-Me | N | C-Me | N |
I-291 | COOH | 苯基 | 4-OMe-苯基 -SO2NH | N | C-乙基 | CH | C-OMe | N |
I-292 | COOH | 3-Cl-苯基 | 4-Me2N-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-293 | COOH | 苯基 | 4-SH-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-294 | COOH | 苯基 | 3-吡啶基 -CONH | N | C-Me | CH | C-Me | N |
I-295 | COOH | 4-F-苯基 | 3-吡啶基 -CONH | CH | C-Me | N | C-OMe | N |
I-296 | COOH | 苯基 | 4-SH-苯基 -CONH | N | C-乙基 | CH | C-乙基 | N |
I-297 | COOH | 苯基 | 3-SH-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-298 | COOH | 苯基 | 4-OMe-苯基 -SO2NH | N | C-OMe | CH | C-OMe | N |
I-299 | COOH | 苯基 | 4-SH-苯基 -CONH | CH | C-乙基 | N | C-乙基 | N |
I-300 | COOH | 苯基 | 3,5-Di-OCF3-苯基 -CONH | N | C-Me | CH | C-OMe | N |
I-301 | COOH | 苯基 | 3,5-Di-OCF3-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-302 | COOH | 苯基 | 3-SH-苯基 -CONH | N | C-Me | N | C-Me | N |
I-303 | COOH | 苯基 | 5-OMe-3-吡啶基 -CONH | N | C-Me | CH | C-Me | N |
I-304 | COOH | 苯基 | 5-OMe-3-吡啶基 -CONH | N | C-Me | CH | C-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-305 | COOH | 3-Cl-苯基 | 4-SH-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-306 | COOH | 苯基 | 3-Me2N-苯基 -CONH | N | C-O-CH2-CH2-C | C-OMe | N | |
I-307 | COOH | 苯基 | 4-OMe-苯基 -SO2NH | CH | C-Me | N | C-OEt | CH |
I-308 | COOH | 苯基 | 2-Cl-苯基 -CONH | N | C-CH2-CH2-CH2-C | C-Me | N | |
I-309 | COOH | 苯基 | 2-Cl-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-310 | COOH | 苯基 | 4-Cl-3-吡啶基 -CONH | N | C-Me | CH | C-Me | N |
I-311 | COOH | 苯基 | 5-F-3-吡啶基 -CONH | N | C-OMe | CH | C-OMe | N |
I-312 | COOH | 苯基 | 2-Cl-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-313 | COOMe | 苯基 | 3,5-Di-OCF3-苯基 -CONH | CH | C-OMe | N | C-Me | N |
I-314 | COOH | 苯基 | 3,5-Di-OCF3-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-315 | COOH | 苯基 | 2-Cl-苯基 -CONH | N | C-乙基 | N | C-Me | N |
I-316 | COOH | 苯基 | 4-OMe-苯基 -SO2NH | N | C-OMe | CH | C-OMe | N |
I-317 | COOH | 苯基 | 2-F-苯基 -CONH | CH | C-OMe | N | C-乙基 | N |
I-318 | COOH | 苯基 | 2-F-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-319 | COOH | 苯基 | 4-CN-3-吡啶基 -CONH | N | N | CH | C-Me | N |
I-120 | COOH | 苯基 | 4-F-3-吡啶基 -CONH | N | C-Me | CH | C-OMe | N |
I-321 | COOH | 4-OMe-苯基 | 2-F-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-322 | COOH | 苯基 | 3-OMe-5-OCF3-苯基-CONH | N | C-OMe | CH | C-OMe | N |
I-323 | COOH | 苯基 | 3,5-Di-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-324 | COOH | 苯基 | 2-F-苯基 -CONH | N | C-OMe | N | C-乙基 | N |
I-325 | COOH | 苯基 | 2-OMe-苯基 -CONH | N | C-乙基 | CH | C-Me | N |
I-326 | COOH | 4-F-苯基 | 3,5-Di-OMe-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-327 | COOH | 苯基 | 3,5-Di-OMe-苯基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-328 | COOH | 苯基 | 2-OMe-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-329 | COOH | 苯基 | 3-OMe-4-吡啶基 -CONH | N | C-Me | CH | C-Me | N |
Nr. | R1 | R2,R3 | R4R5N | W | X | Q | Y | Z |
I-330 | COOH | 苯基 | 3-OMe-4-吡啶基 -CONH | CH | C-OMe | N | C-Me | N |
I-331 | COOH | 苯基 | 2-OMe-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-332 | COOH | 4-OMe-苯基 | 2-OMe-苯基 -CONH | N | C-OMe | CH | C-Me | N |
I-333 | COOH | 苯基 | 4-OMe-苯基 -SO2NH | CH | C-乙基 | N | C-乙基 | N |
I-334 | COOH | 苯基 | 2-OMe-苯基 -CONH | CH | C-OMe | N | C-乙基 | CH |
I-335 | COOH | 4-F-苯基 | 3,5-Di-OMe-苯基 -CONH | N | C-乙基 | CH | C-NHMe | N |
I-336 | COOH | 苯基 | 3,5-Di-OH-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-337 | COOH | 苯基 | 3,4-Di-F-苯基 -CONH | N | C-OMe | CH | C-OMe | N |
I-338 | COOH | 苯基 | 4-OMe-3-吡啶基 -CONH | N | C-乙基 | N | C-乙基 | N |
I-339 | COOH | 苯基 | 5-Cl-3-吡啶基 -CONH | N | C-OMe | CH | C-OMe | N |
I-340 | COOH | 苯基 | 3,4-Di-F-苯基 -CONH | N | C-Me | CH | C-Me | N |
I-341 | COOH | 苯基 | 3,4-Di-F-苯基 -CONH | N | C-OMe | CH | C-Me | N |
实施例14:
应用上述结合测定法测定了下面列出的化合物的受体结合数据。
结果如表2中所示。
表2
受体结合数据(Ki值)
表2
化合物 | ETA[nM/l] | ETB[nM/l] |
I-4 | 74 | 2100 |
I-48 | 67 | 1400 |
I-66 | 63 | >3000 |
I-156 | 337 | >10000 |
I-170 | 140 | 4600 |
I-199 | 99 | 3400 |
I-201 | 84 | 5500 |
I-248 | 18 | 930 |
I-294 | 52 | 6700 |
I-340 | 225 | 5400 |
Claims (10)
1.式I的β-酰氨基-和β-氨磺酰羧酸衍生物其中,各取代基具有下列含义:R1是四唑基或基其中,R具有如下含义:a) 基OR6,其中,R6是:氢,C3~C8环烷基,C1~C8烷基,CH2-苯基,所述基可能任选被取代,任选被取代的C3~C8烯基或C3~C8炔基,或者任选被取代的苯基,b) 一个通过氮原子连接的5元杂芳族体系,c)基
其中,k可以是0,1和2的值,p可以是1,2,3和4的值,而且R7是:C1~C4烷基,C3~C8环烷基,C3~C8烯基,C3~C8炔基或任选取代的苯基,d) 基其中,R8是:C1~C4烷基,C3~C8烯基,C3~C8炔基,C3~C8环烷基,这些基可能携带一个C1~C4烷氧基,C1~C4烷硫基和/或苯基,C1~C4卤烷基或苯基,任选被取代了,W 和Z,它们可以相同或不同:氮或次甲基;但须,如果W和Z=次甲基,那么Q=氮;X 氮或CR9;Y 氮或CR10;Q 氮或CR11;但须,如果Q=氮,那么X=CR9和Y=CR10;R2和R3,它们可以相同或不同:苯基或萘基,任选被取代了,或者苯基或萘基,它们在邻位通过直接的键,亚甲基,1,2-亚乙基或亚乙烯基,氧或硫原子或SO2,NH或N-烷基被连接在一起,C5~C6环烷基,任选被取代了;R4a)基 其中,R12是:苯基,萘基或一个五元或六元杂芳族体系,它包含
1~3个氮原子和/或一个硫或氧原子,所述基可能任选被取
代了;b) 基其中,R13是:C1~C4烷基,C1~C4卤烷基,C1~C4烷氧基,C1~
C4卤烷氧基,C1~C4烷硫基,苯基或苯氧基,所述苯基可
能任选被取代了;R5氢,C1~C4烷基;R9和R10(它们可以相同或不同):氢,卤素,C1~C4烷氧基,C1~C4卤烷氧基,C3~C6烯氧基,C3~C6炔氧基,C1~C4烷硫基,C1~C4烷基羰基,C1~C4烷氧羰基,羟基,NH2,NH(C1~C4烷基),N(C1~C4烷基)2;C1~C4烷基,C2~C4烯基,C2~C4炔基,这些基可能任选被取代了;或者CR9或CR10如下述那样被连接到CR11给出一个5元或6元环;R11氢,卤素,C1~C4烷氧基,C1~C4卤烷氧基,C3~C6烯氧基,C3~C6炔氧基,C1~C4烷硫基,C1~C4烷基羰基,C1~C4烷氧羰基,NH(C1~C4烷基),N(C1~C4烷基)2,羟基,羧基,氰基,氨基,巯基;C1~C4烷基,C2~C4烯基,C2~C4炔基,这些基可能任选被取代了;或者CR11与CR9或CR10一起形成一个5元或6元亚烷基或亚烯基环,它可能任选被取代了,其中,在每种情况下,一个或多个亚甲基可被氧,硫,-NH或-N(C1~C4烷基)替代,以及生理上耐受的盐,以及可能的对映纯的和非对映纯的形式,下列化合物除外:2-(6-乙基-2-甲基-4-嘧啶基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸2-(2,6-二甲基-4-嘧啶基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸3-(4-甲氧基苯甲酰氨基)-2-(6-甲氧基-2-甲基-4-嘧啶基氧基)-3,3-二苯基丙酸3-(4-甲氧基苯甲酰氨基)-2-(6-甲氧基-5-甲基-2-吡嗪基氧基)-3,3-二苯基丙酸3-(4-甲氧基苯甲酰氨基)-2-(5-甲氧基-6-甲基[1,2,4]三嗪-3-基氧基)-3,3-二苯基丙酸2-(4-乙基-6-甲基[1,3,5]三嗪-2-基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸3-(4-甲氧基苯甲酰氨基)-2-(5-甲氧基-6-甲基-3-哒嗪基氧基)-3,3-二苯基丙酸2-(4,6-二甲基[1,3,5]三嗪-2-基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸3-(4-甲氧基苯甲酰氨基)-2-(4-甲氧基-6-甲基[1,3,5]三嗪-2-基氧基)-3,3-二苯基丙酸3-(4-甲氧基苯甲酰氨基)-2-(4-甲氧基-6,7-二氢-5H-环戊二烯并嘧啶-2-基氧基)-3,3-二苯基丙酸3-(4-甲氧基苯甲酰氨基)-2-(4-甲氧基-5,6-二氢呋喃并[2,3-d]嘧啶-2-基氧基)-3,3-二苯基丙酸2-(4,6-二甲氧基-2-嘧啶基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸2-(4-乙基-6-甲基-2-嘧啶基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸2-(4,6-二甲基-2-嘧啶基氧基)-3-(4-甲氧基苯甲酰氨基)-3,3-二苯基丙酸3-(4-甲氧基苯甲酰氨基)-2-(4-甲氧基-6-甲基-2-嘧啶基氧基)-3,3-二苯基丙酸2-(4,6-二甲基-2-嘧啶基氧基)-3-(4-羟基苯甲酰氨基)-3,3-二苯基丙酸2-(4-甲氧基-6-甲基-2-嘧啶基氧基)-3-(4-甲硫基苯甲酰氨基)-3,3-二苯基丙酸2-(4,6-二甲氧基-2-嘧啶基氧基)-3-(4-硝基苯甲酰氨基)-3,3-二苯基丙酸3-(4-氯苯甲酰氨基)-2-(4-乙基-6-甲基-2-嘧啶基氧基)-3,3-二苯基丙酸3-(4-乙基苯甲酰氨基)-2-(4-甲氧基-6,7-二氢-5H-环戊二烯并嘧啶-2-基氧基)-3,3-二苯基丙酸3,3-双-(4-氟苯基)-3-(4-甲氧基-苯甲酰氨基)-2-(4-甲氧基-5,6-二氢呋喃并[2,3-d]嘧啶-2-基氧基)丙酸3-(4-氯苯甲酰氨基)-2-(4,6-二甲基[1,3,5]三嗪-2-基氧基)-3,3-二苯基丙酸3-(3,4-二甲氧基苯甲酰氨基)-2-(4-甲氧基-6-甲基[1,3,5]三嗪-2-基氧基)-3,3-二苯基丙酸3-(3,4-二甲氧基苯甲酰氨基)-2-(4-乙基-6-甲基[1,3,5]三嗪-2-基氧基)-3,3-二苯基丙酸3-(4-氯苯甲酰氨基)-2-(5-甲氧基-6-甲基-3-哒嗪基氧基)-3,3-二苯基丙酸3-(3,4-二氯苯甲酰氨基)-2-(6-甲氧基-5-甲基-2-吡嗪基氧基)-3,3-二苯基丙酸3-(4-羟基-3-甲氧基苯甲酰氨基)-2-(5-甲氧基-6-甲基[1,2,4]三嗪-3-基氧基)-3,3-二苯基丙酸3-(3-氯苯甲酰氨基)-2-(2,6-二甲基-4-嘧啶基氧基)-3,3-二苯基丙酸3-(2-氯苯甲酰氨基)-2-(6-甲氧基-2-甲基-4-嘧啶基氧基)-3,3-二苯基丙酸2-(6-乙基-2-甲基-4-嘧啶基氧基)-3-(4-硝基苯甲酰氨基)-3,3-二苯基丙酸。
2.权利要求1的β-酰氨基-和β-氨磺酰羧酸衍生物在治疗疾病中的应用。
3.权利要求2的化合物I作为内皮缩血管肽受体拮抗物的应用。
4.权利要求1的β-酰氨基-和β-氨磺酰羧酸衍生物I在生产用于治疗出现内皮缩血管肽水平升高的疾病的药物中的应用。
5.权利要求1的β-酰氨基-和β-氨磺酰羧酸衍生物I在治疗下列疾病中的应用:慢性心力衰竭、再狭窄、高血压、肺动脉高压、急性/慢性肾衰竭、勃起功能障碍、脑缺血、良性前列腺增生和前列腺癌。
6.权利要求1的β-酰氨基-和β-氨磺酰羧酸衍生物I与下列物质组合的应用:肾素-血管紧张肽系统的抑制剂,例如肾素抑制剂、血管紧张肽II拮抗物和特别是血管紧张肽转化酶(ACE)抑制剂;混合的ACE/中性内肽酶(NEP)抑制剂;β封阻剂。
7.一种经口、肠胃外和腹膜内施药的药物制剂,除了常规药物辅助物质之外,它的单剂量还包含至少一种权利要求1的羧酸衍生物I。
10.作为内皮缩血管肽受体拮抗物的结构单元的下式结构片断其中,基R1、R2、R3、R4和R5具有权利要求1中规定的含义。
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