CN87104167A - 抗高血压新药 - Google Patents

抗高血压新药 Download PDF

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CN87104167A
CN87104167A CN198787104167A CN87104167A CN87104167A CN 87104167 A CN87104167 A CN 87104167A CN 198787104167 A CN198787104167 A CN 198787104167A CN 87104167 A CN87104167 A CN 87104167A CN 87104167 A CN87104167 A CN 87104167A
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加里·A·弗莱恩
贝特·道格拉斯·W
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Sanofi Aventis UK Holdings Ltd
Aventis Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives

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Abstract

本发明是关于稠环吖庚因-2-酮类的衍生物，其中间体及其制备方法，以及关于它们作为血管紧张素转换酶抑制剂和最终作为抗高血压药的应用。

Description

抗高血压新药
本发明是关于稠环吖庚因-2-酮之衍生物、其中间体及其制备过程，以及其作为血管紧张素转换酶抑制剂及最终作为降压药的用途。
更具体地说本发明是关于下式稠环吖庚因-2-酮的衍生物及其可供药用的盐类，其中R为C1-6的低级烷基，最好为乙基。
式I化合物可用图A所述的反应过程制备，所用的是肽化学中熟知的技术。主要的非对映异构体如图所示。无疑地它含有这些非对映异构体的混合物以及对映体及其混合物，
反应图式A——————————
Figure A8710416700041
其中R为C1-6低级烷基，最好为乙基。Ph+h与N(氮)原子一起表示酞酰亚胺保护基(如式4中所示)，LDA为二异丙酰氨锂，HMPA为六甲基磷酰胺，EEDQ为N-乙氧甲酰基-2-乙氧基-1，2-二氢喹啉，Tf为三氟甲磺酰基(CFSO-)。
通常，上述反应过程是从适当的甘氨酸甲酯席夫氏碱开始，经强碱去质子化(如用LDA在四氢呋喃(THF)中进行)后。在HMPA存在下以4-溴-1-丁烯烷基化，所得中间体以稀无机酸水解成游离胺。所需的不饱和α-氨基酯借标准偶合试剂EEDQ的作用，与N-酞酰基-L-苯丙氨酸偶合。所得非对映异构酰胺在含有甲醇的惰性溶剂中，于-70℃下以臭氧处理。饱和后以臭氧化物以二甲硫还原并以吡啶稳化。将此粗产品分离出并在惰性溶剂中以强酸脱水，便得可用色谱法分离的酰基烯胺。然后将其用三氟甲磺酸处理便得三环丙酰胺异构体的混合物。异构化的部位是在带终端甲氧甲酰基的碳原子附近。各个异构化合物序贯用肼和氢氧化锂处理脱去保护基。所需的两性离子与R-三氟甲磺酸酯(9)偶合便得需要的前药单酯。
例1
2-氨基-5-己烯酸，甲酯
于15.4毫升(110毫克分子)二异丙胺和250毫升四氢呋喃组成的溶液中，于-78℃下加入39毫升2.7克分子浓度的正丁基锂(105毫克分子)己烷溶液，搅拌30分钟后，在30分钟内加入苯甲醛-甘氨酸甲酯席夫氏碱(2)17.7克(100毫克分子)的25毫升四氢呋喃溶液。在加入六甲基磷酰胺20毫升后，随后加入13.5克(100毫克分子)4-溴-1-丁烯的20毫升四氢呋喃溶液。该溶液温热至25℃并搅拌3小时。反应混合物倒入盐水中以停止反应并以醚提取。有机层反复以盐水洗，以硫酸镁干燥并浓缩。残留物(25克)溶入400毫升醚中并混以150毫升1N盐酸，搅拌2小时，分出水层并调至PH＝9。以氯仿取得8.5克(60％收率)轻油；核磁(CDCl3重氢氯仿)；5.7(多峰，1H)；5.0(多峰，2H)；3.7(单峰，3H)；3.42(二双峰，1H，Ja＝7Hz，Jb＝6Hz)；1.6-2.3(单峰，4H)。
例2
2-〔〔2-(1，3-二氢-1，3-二氧-2H-异吲哚-2-基)-1-氧-3-苯基丙基〕氨基〕-5-己烯酸，甲酯
于6.0克(20毫克分子)N-酞酰基-L-苯基丙氨酸和6.0克(24毫克分子)EEDQ的30毫升干燥二氯甲烷溶液中，在搅拌和充氮下于25℃加入3.0克(21毫克分子)2-氨基-5-己烯酸甲酯的5毫升二氯甲烷溶液。搅拌18小时后，将该溶液倾入100毫升二氯甲烷中，以2×100毫升10％HCl洗，再以饱和NaHCO溶液洗，以MgSO干燥，浓缩，便得8.3克黄色油状物。核磁(CDCl)；7.70(多峰，4H)；7.10(多峰，5H)；6.65(双峰，1H，J＝7Hz)；4.95(多峰，3H)；5.41(多峰，1H)；3.60(单峰，3H)；3.45(双峰，2H，J＝7Hz)；1.7-2.3(多峰，4H)；与非对映异构的酰胺相符合。
例3
2，3-二氢-1-〔2-(1，3-二氢-1，3-二氧-2H-异吲哚-2-基)-1-氧-3-苯丙基〕-1H-吡咯-2-羧酸，甲酯
将不饱和酰胺(4)和100毫升二氯甲烷及10毫升无水甲醇组成之溶液于搅拌下冷至-70℃，通入臭氧直至兰色持续不退。过量的臭氧以氮气除去，冰冷的反应物以5毫升二甲硫和0.5毫升吡啶处理。将该溶液缓慢升温至25℃并搅拌18小时，以10％HCl，水和盐水洗。有机以层以MgSO4干燥并浓缩。残留物(4.5克)溶于150毫升三氯乙烷(CH3CCl3)中加入0.5毫升三氟乙酸回流18小时。溶液冷却，浓缩并以35～50％酯酸乙酯/己烷闪式快速色谱分离。得700毫克极性较小之酰基烯胺(Rf＝0.70；1∶1酯酸乙酯/己烷)；核磁(CDCl3)；7.70(多峰，4H)；7.20(多峰，5H)；6.50(多峰，1H)；6.2-6.4(多峰，2H)；4.8(二双峰，1H，Ja＝11Hz，Jb＝6Hz)；3.76(单峰，3H)；3.68(二双峰，1H，Ja＝17Hz、Jb＝11Hz)；3.50(二双峰，1H，Ja＝17Hz，Jb＝6Hz)；2.4-3.2(多峰，2H)。和600毫克极性较大之酰基烯胺(Rf＝0.62，1∶1醋酸乙酯/己烷)：核磁(CDCl3)；7.70(多峰，4H)；7.20(多峰，5H)；6.55(多峰，1H)；6.2-6.4(多峰，2H)；4.9(二双峰，1H，Ja＝11Hz，Jb＝6Hz)；3.66(单峰，3H)；3.64(二双峰，1H，Ja＝17Hz，Jb＝11Hz)；3.45(二双峰，1H，Ja＝17Hz，Jb＝6Hz)；2.3-3.3(多峰，2H)。
例4
7-(1，3-二氢-1，3-二氧-2H-异吲哚-2-基)-1，2，3，4，6，7，8，12b-八氢-6-氧基-吡啶并〔2，1-a〕〔2〕苯并吖庚因-4-羧酸，甲酯(异构体的混合物)
酰基烯胺(5)和(6)分别环合。极性较小之酰基烯胺(5)(700毫克)溶于5毫升干燥CH2Cl2中，加入毫升CF3SO3H(三氟甲磺酸)，于25℃在通氮下搅拌18小时。反应混合物倾入水中以停止反应并用醋酸乙酯提取有机提取物以水充份洗涤，用MgSO4干燥，并以过量重氮甲烷(CH2N2)处理。闪式色谱分离得305毫克极性较大之产物(Rf＝0.30，1∶1醋酸乙酯/己烷)。此物带以高压液体色谱分析，表明为1∶3之异构环状产物。极性较大之酰基烯胺(6)(600毫克)用上述方法环合，得300毫克混合产物，这与从酰基烯胺(5)所得产物的组成是一致的。此混合产品以高压液体色谱分离(35％醋酸乙酯/己烷)。极性较小的部份(125毫克)，其核磁(CDCl3)为；7.60(多峰，4H)；7.0-7.3(多峰，4H)；5.34(多峰，2H)；4.86(二双峰，1H，Ja＝5Hz，Jb＝6Hz)；3.60(单峰，3H)；3.37(多峰，2H)，2.0-2.7(多峰，4H)。较大极性之部份(400毫克)，核磁(CDCl3)；7.60(多峰，4H)；7.0-7.3(多峰，4H)；5.34(多峰，2H)；4.60(二双峰，1H，Ja＝6Hz，Jb＝5Hz)；3.70(单峰，3H)；3.40(多峰，2H)；2.0-2.7(多峰，4H)。
可以推断，这些异构环合产物是在带终端甲氧甲酰基之碳原子附近异构的。
例5
6-氨基-2，3，5，6，7，11b-六氢-5-氧-1H-吡咯并〔2，1-a〕〔2〕苯并吖庚因-3-羧酸(异构体之混合物)
在搅拌下于101毫克(0.25毫克分子)酞酰亚胺(7a)的1毫升甲醇溶液中，加入0.5毫升1N浓度的水合肼(H2N NH2 H2O的甲醇溶液)于25℃和充氮下反应三日。该溶液以氯仿稀释并过滤浓缩滤液，重新溶入2毫升甲醇中，并以0.5毫升1N的氢氧化锂处理。搅拌10小时后，浓缩此溶液，残留物溶于2毫升水中并以0.5毫升1N盐酸酸化。过滤得55毫克(0.21毫克分子)两性离子(8a)：核磁(CD3CN，TFA即重氢乙腈和三氟乙酸)；7.0-7.3(多峰，4H)；4.80(二双峰，1H，Ja＝6Hz，Jb＝3Hz)；4.50(二双峰，1H，Ja＝8Hz，Jb＝4Hz)；4.05(二双峰，1H，Ja＝9Hz，Jb＝6Hz)；3.43(二双峰，1H，Ja＝17Hz，Jb＝6Hz)；2.85(二双峰，1H，Ja＝17Hz，Jb＝9Hz)；

Claims (2)

1.制备下式化合物
Figure A8710416700021
或其可供药用的盐的方法，其中R为C1-6烷基，Ph为苯基，该方法包括将下式的稠环内酰胺
Figure A8710416700022
与通式为
Figure A8710416700023
(其中R为三氟甲磺酸酯，Tf为三氟甲磺酰基)的化合物相偶合。上述的偶合反应是在碱存在下经提及的反应物相接触来完成。
2.根据权利要求1中的方法，其中R为乙基。
CN198787104167A 1986-06-13 1987-06-12 抗高血压新药 Pending CN87104167A (zh)

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PT85071A (en) 1987-07-01
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