CN1245404C - 巯基乙酰胺衍生物、其制备方法及其用途 - Google Patents
巯基乙酰胺衍生物、其制备方法及其用途 Download PDFInfo
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- CN1245404C CN1245404C CNB028081005A CN02808100A CN1245404C CN 1245404 C CN1245404 C CN 1245404C CN B028081005 A CNB028081005 A CN B028081005A CN 02808100 A CN02808100 A CN 02808100A CN 1245404 C CN1245404 C CN 1245404C
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Abstract
本发明公开和要求了一系列式(I)的巯基乙酰胺衍生物。还公开和要求了包含这些化合物的药物组合物和制备所述化合物的方法。同样也公开和要求了所述化合物用于抑制血管紧张素转化酶和中性内肽酶的用途和用于治疗高血压和充血性心衰的用途。
Description
本申请要求2001年4月12日提交的美国临时申请号60/283,305的权益。
发明背景
1.发明领域:
本发明涉及同时具有血管紧张素转化酶抑制活性和中性内肽酶抑制活性的新化合物及制备这种化合物的方法。本发明还涉及含有这种具有双重抑制活性的化合物或其可药用盐的药物组合物以及它们在制备药物中的用途。
2.现有技术概述
血管紧张素转化酶(ACE)是可催化血管紧张素I转化为血管紧张素II的肽基二肽酶。血管紧张素II是一种血管收缩剂,其也可刺激肾上腺皮质分泌醛固酮。抑制ACE可同时防止血管紧张素I向血管紧张素11的转化和缓激肽的代谢,从而使循环血管紧张素II和醛固酮减少并使循环缓激肽的浓度增加。除了这些神经激素的变化外,还可以观察到外周阻力和血压的降低,特别是在循环肾素较高的个体中。其它与抑制ACE有关的药理学效应包括左心室肥大消退、心衰临床症状改善以及充血性心衰(CHF)患者或心肌梗塞后左心室机能障碍患者的死亡率降低。
中性内肽酶(NEP)是对心钠素(ANP)代谢起作用的酶。抑制NEP可引起ANP浓度增加,而ANP浓度的增加可导致尿钠排泄、多尿以及血管内容积、静脉回流和血压的降低。ANP是由心房肌细胞对心房扩张或血管内体积增加产生响应而释放的。已证实:ANP的血浆浓度升高是多种疾病状态包括充血性心衰、肾衰、原发性高血压和肝硬化中的可能的代偿机制。
心房肌细胞分泌ANP可引起血管舒张、多尿、尿钠排泄以及对肾素释放和醛固酮分泌的抑制。相比之下,血管紧张素II可引起血管收缩、钠和水的重吸收以及醛固酮的生成。这两种激素系统以相应或相抗衡的方式相互作用,以使血管和血液动力学应答维持正常的生理状态。
美国专利5,430,145公开了可用作ACE和NEP抑制剂的三环巯基乙酰胺衍生物。本发明涉及美国专利US 5,430,145的一般公开所包括的具体化合物,这些化合物与所述专利中例证的化合物相比具有令人惊异的改善的ADME(吸收、分布、代谢、排泄)性质。
发明概述
因此,本发明提供了式I化合物:
其中,
R1是氢、-CH2OC(O)C(CH3)3或酰基;
R2是氢;-CH2O-C(O)C(CH3)3;C1-C4-烷基;芳基、芳基-(C1-C4-烷基);或二苯甲基;
X是-(CH2)n,其中n是整数0或1;-S-;-O-;
其中R3是氢、C1-C4-烷基、芳基或芳基-(C1-C4-烷基)并且R4是-CF3、C1-C10烷基、芳基或芳基-(C1-C4-烷基);
B1和B2各自独立地是氢;羟基;或-OR5,其中R5是C1-C4-烷基、芳基或芳基-(C1-C4-烷基);或当B1和B2与相邻的碳原子相连时,B1和B2可与所述相邻碳原子一起形成苯环或亚甲二氧基。
在一个实施方案中,本发明提供了其中R1为乙酰基的式I化合物。在另一个实施方案中,本发明提供了其中R1为氢的式I化合物。在其它实施方案中,本发明提供了其中R2为氢的式I化合物。在其它实施方案中,本发明提供了其中B1和/或B2为氢的式I化合物。而且在其它实施方案中,本发明还提供了其中X为-CH2的式I化合物。
在一个实施方案中,本发明提供了式IA化合物:
其中R1是乙酰基或氢。
本发明的优选实施方案的结构为以下式IB和IC的化合物:
式I化合物,包括式IA、IB和IC化合物,特别地可用作ACE和NEP的双重抑制剂。
因此,本发明提供了包含抑制ACE和/或NEP有效量的式I化合物与一种或多种可药用的载体或赋形剂混合或以其它方式联合的药物组合物。
发明详述
这里使用的术语“C1-C4-烷基”指的是具有一、二、三或四个碳原子的饱和直链或支链单价烃链,其包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等基团。术语“C1-C10-烷基”指的是具有1至10个碳原子的饱和直链或支链单价烃链,其包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基、异戊基、己基、2,3-二甲基-2-丁基、庚基、2,2-二甲基-3-戊基、2-甲基-2-己基、辛基、4-甲基-3-庚基等基团。
这里使用的“芳基”指的是未取代或被1至3个取代基取代的苯基或萘基,所述取代基选自亚甲二氧基、羟基、C1-C4-烷氧基、氟和氯。包括在术语“芳基-(C1-C4-烷基)”范围内的基团有苯甲基(苄基)、苯乙基、对甲氧基苄基、对氟苄基和对氯苄基。
这里使用的“C1-C4-烷氧基”指的是一个单价取代基,其由与醚氧原子相连的具有1至4个碳原子的直链或支链烃链组成,并且其游离价键在醚氧原子端,其包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁氧基、叔丁氧基等基团。
这里使用的“杂环”指的是任何其中一个或多个环原子是除碳以外的元素的闭合环部分,其包括但不限于以下杂环:哌啶基、吡啶基、异噁唑基、四氢呋喃基、吡咯烷基、吗啉基、哌嗪基、苯并咪唑基、噻唑基、噻吩基、呋喃基、吲哚基、1,3-苯并间二氧杂环戊烯基、四氢吡喃基、咪唑基、四氢噻吩基、吡喃基、二噁烷基、吡咯基、嘧啶基、吡嗪基、噻嗪基、噁唑基、嘌呤基、喹啉基和异喹啉基。
这里使用的“卤素”或“Hal”指的是氟、氯、溴或碘之一。
这里使用的“酰基”指的是脂肪族和芳香族酰基和那些源自杂环化合物的酰基。例如,酰基可以是低级的或是C1-C4烷酰基如甲酰基或乙酰基;芳香烃酰基如苯甲酰基;或者是含有一种或多种杂原子O、N和S的杂环酰基,例如基团
这里使用的“立体异构体”是仅仅是其原子空间取向不同的单独分子的所有异构体的统称术语。术语“立体异构体”包括镜像异构体(旋光异构体)、几何(顺/反或E/Z)异构体和含有不止一个手性中心、相互不是镜像的化合物的异构体(非对映异构体)。
这里使用的“R”和“S”在有机化学中经常用来表示手性中心的具体构型。术语“R”(右)是指当沿着指向最低次序基团的键观察时,基团次序(从最高到次低)为顺时针的手性中心的构型。术语“S”(左)是指当沿着指向最低次序基团的键观察时,基团次序(从最高到次低)为逆时针的手性中心的构型。基团优先次序取决于定序规则,其中优先次序首先取决于原子序数(按原子序数降序)。在“有机化合物的立体化学”(Stereochemistry of Organic Compounds),Ernest L.Eliel,Samuel H.Wilen和Lewis N.Mander,编者Wiley-Interscience,John Wiley & Sons,Inc.,New York,1994)中包括优先次序的列表和讨论。
除了(R)-(S)体系,较老的D-L体系也可在此用于表示绝对构型,特别是涉及氨基酸时。在这个体系中,确定Fischer投影式以使主链1号碳处于顶端。前缀“D”用于表示其官能团(决定基团)在手性碳右边的异构体的绝对构型,“L”表示官能团在手性碳左边的异构体的绝对构型。
这里使用的“治疗”是指任何治疗,包括但不限于缓和症状、暂时或永久消除症状起因,或者是预防或延缓指定疾病、紊乱或病情的症状出现和进展。
在此所述的术语“患者”是指温血动物如患有特定疾病、紊乱或病情的哺乳动物。可清楚知道的是豚鼠、狗、猫、大鼠、小鼠、马、牛、羊和人均是术语含义范围内的动物实例。
这里使用的术语“可药用盐”指的是无论是已知的还是尚未公开的、本领域普通技术人员使用的、适于作为药物使用的无毒有机或无机加成盐的任何盐。可形成适宜的盐的碱的例子包括碱金属或碱土金属的氢氧化物如钠、钾、钙或镁的氢氧化物;氨和脂肪族、环状或芳香族胺如甲胺、二甲胺、三乙胺、二乙胺、异丙基二乙胺、吡啶和甲基吡啶。可形成适宜的盐的酸的例子包括无机酸如,例如盐酸、氢溴酸、硫酸、磷酸等;有机羧酸如乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、丙二酸、丁二酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸和二羟基马来酸、苯甲酸、苯乙酸、4-氨基苯甲酸、4-羟基苯甲酸、邻氨基苯甲酸、肉桂酸、水杨酸、4-氨基水杨酸、2-苯氧基苯甲酸、2-乙酰氧基苯甲酸、杏仁酸等;以及有机磺酸如甲磺酸和对甲苯磺酸。
这里使用的“药用载体”指的是已知可用于制备用于施用的药学活性化合物、并且在使用条件下基本是无毒和无致敏性的药物赋形剂。这些赋形剂的确切比例取决于活性化合物的溶解度和化学性质、所选择的给药途径以及标准药学习惯。
化学合成
本发明的化合物可按如下方法制备。
式I化合物的三环部分可利用本领域普通技术人员熟知并常用的方法和技术制备。美国专利5,430,145描述了适当的方法的实施例,因此该文献的内容在此引入作为参考。以下描述了一个如方案A中阐明的这种方法:
方案A
R1=COCH3、COPh
R2=CHPh2
在步骤a中,通过在适宜的非质子溶剂如二甲基甲酰胺中使具有结构1的适当的(S)-苯丙氨酸衍生物与邻苯二甲酸酐反应,可制得具有结构2的、被邻苯二甲酰亚胺保护的适当的(S)-苯丙氨酸衍生物。
在步骤b中,具有结构2的、被邻苯二甲酰亚胺保护的适当的(S)-苯丙氨酸衍生物可被转化为相应的酰氯,接着与具有结构3的适当的氨基酸甲酯发生偶联反应。例如在适宜的非质子溶剂如二氯甲烷中,具有结构2的、被邻苯二甲酰亚胺保护的适当的(S)-苯丙氨酸衍生物可与乙二酰氯反应。然后,在适宜的非质子溶剂如二甲基甲酰胺中,使用适当的碱如N-甲基吗啉可将生成的酰氯与具有结构3的适当的氨基酸甲酯偶联,得到具有结构4的适当的1-氧代-3-苯丙基-氨基酸甲酯衍生物。
在步骤c中,具有结构4的适当的1-氧代-3-苯丙基-氨基酸甲酯衍生物的羟基亚甲基官能团可通过本领域已知和常用的氧化技术被氧化为具有结构5的适当的醛。例如,在适宜的非质子溶剂如二氯甲烷中,以Swern氧化方式、用乙二酰氯和二甲基亚砜可将具有结构4的适当的1-氧代-3-苯丙基-氨基酸甲酯衍生物的羟基亚甲基官能团氧化为具有结构5的适当的醛。
在步骤d中,通过酸催化可将具有结构5的适当的醛环化为具有结构6的适当的烯胺。例如,在适宜的非质子溶剂如二氯甲烷中,具有结构5的适当的醛经三氟醋酸处理可被环化为具有结构6的适当的烯胺。
在步骤e中,通过酸催化的Friedel-Crafts反应可将具有结构6的适当的烯胺转化为相应的具有结构7的三环化合物。例如,在适宜的非质子溶剂如二氯甲烷中,用三氟甲磺酸和三氟醋酸酐的混合物处理具有结构6的适当的烯胺,可将其转化为具有结构7的三环化合物。
在步骤e中,由于后处理条件的限制,有必要再次将羧基官能团酯化。例如,在适宜的非质子溶剂如二甲基甲酰胺中,用溴二苯甲烷和非亲核性的碱如碳酸铯处理粗产品,可得到相应的二苯甲基酯。
在步骤f中,通过本领域熟知的技术和方法可将具有结构7的适当的三环化合物的邻苯二甲酰亚胺保护基团脱去。例如,在适宜的质子溶剂如甲醇中,用肼一水合物可将具有结构7的适当的三环化合物的邻苯二甲酰亚胺保护基团脱去,得到相应的具有结构8的氨基化合物。
在步骤g中,使具有结构8的适当的氨基化合物与具有结构9的适当的(S)-醋酸酯反应,可制得具有结构10的适当的(S)-醋酸酯化合物。例如,在适宜的非质子溶剂如二氯甲烷中,在偶联试剂如EEDQ(1-乙氧羰基-2-乙氧基-1,2-二氢喹啉)、DCC(1,3-二环己基碳二亚胺)或二乙基氰基膦酸酯存在下,具有结构8的适当的氨基化合物可与具有结构9的适当的(S)-醋酸酯化合物反应,得到具有结构10的适当的(S)-乙酰氧基化合物。
在步骤h中,在适宜的溶剂混合物如四氢呋喃与乙醇的混合物中,用碱如氢氧化锂可将具有结构10的适当的酰胺化合物的(S)-醋酸酯官能团水解为相应的具有结构11a的(S)-醇。
在步骤i中,具有结构11a的适当的酰胺化合物的(S)-醇官能团可被转化为相应的具有结构12a的(R)-硫羟乙酸酯或(R)-硫羟苯甲酸酯。例如,在适宜的非质子溶剂如四氢呋喃中,通过使用三苯基膦和DIAD(偶氮二甲酸二异丙酯)的Mitsunobu反应,用硫羟乙酸处理具有结构11a的适当的(S)-醇。
在步骤j中,具有结构11a的适当的酰胺化合物的(S)-醇官能团可被转化为相应的具有结构11b的(R)-醇。例如,在适宜的非质子溶剂如四氢呋喃中,通过使用三苯基膦和DIAD的Mitsunobu反应,用乙酸处理具有结构11a的适当的(S)-醇。然后,所得到的(R)-醋酸酯可用适当的碱如氢氧化锂进行水解。
在步骤k中,具有结构11b的适当的酰胺化合物的(R)-醇官能团可被转化为相应的具有结构12b的(S)-硫羟乙酸酯或(S)-硫羟苯甲酸酯。例如,在适宜的非质子溶剂如四氢呋喃中,通过使用三苯基膦和DIAD的Mitsunobu反应,用硫羟乙酸处理具有结构11b的适当的(R)-醇。
如表1中所总结的:具有结构12a和12b的化合物的R1和R2基团可用本领域普通技术人员熟知和常用的技术和方法处理,得到相应的具有结构13a-14a和13b-14b的化合物。
例如,用三氟乙酸可脱去具有结构12a的适当的化合物的二苯基甲酯官能团,得到具有结构13a的适当的羧酸化合物。同样,用三氟乙酸可脱去具有结构12b的适当的化合物的二苯基甲酯官能团,得到具有结构13b的羧酸化合物。
在适宜的溶剂混合物如四氢呋喃与乙醇的混合物中,用氢氧化锂可将具有结构13a的适当的化合物的(R)-硫羟乙酸酯或(R)-硫羟苯甲酸酯官能团脱去,得到具有结构14a的适当的(R)-硫代化合物。同样,在适宜的溶剂混合物如四氢呋喃与乙醇的混合物中,用氢氧化锂可将具有结构13b的适当的化合物的(S)-硫羟乙酸酯或(S)-硫羟苯甲酸酯脱去,得到具有结构14b的适当的(S)-硫代化合物。
表1
R1和R2的处理 | ||
化合物 | R1 | R2 |
13a和13b | COCH3或COPh | H |
14a和14b | H | H |
虽然方案A概述的一般方法表示了其中-COOR2基团为(S)-构型的式I化合物的制备方法,但是其中-COOR2基团为(R)-构型的式I化合物也可通过类似的方法、通过在步骤b中用具有结构3的适当的(R)-氨基酸甲酯替换(S)-氨基酸甲酯而制备。
方案A概述的一般合成方法所使用的原料是本领域普通技术人员易于得到的。例如,具有结构9的种(R)-和(S)-羧基乙酸酯或苯甲酸酯原料可如下制备:(如J.Org.Chem.
47,1606(1982)、J.Org.Chem.
49,1316(1984)和J.Am.Chem.Soc.
106,1531(1984)中所述的)通过用高山硼烷(alpineboranes)立体选择性地还原相应的丙酮酸酯化合物、随后用乙酸酐或苯甲酸酐处理生成的醇,得到相应的具有结构9的(R)-或(S)-羧基乙酸酯或苯甲酸酯化合物。
或者,一些具有结构7的三环化合物可按照欧洲专利申请EP 249223A中所述的方法制备。
本发明提供了一种用于制备上述式I化合物的方法,其包括在碱如碱金属碳酸盐存在下使式II化合物
其中R2、X、B1和B2如前所定义,Hal是卤素,
与式R1SH的化合物反应,其中R1如前所定义。
本发明还提供了制备式II化合物的方法,其包括将式III化合物
其中R2、X、B1和B2如前所定义,与式IV化合物反应,
其中Hal是卤素。
根据本发明,用于制备式I化合物的备选方法包括使式III化合物
其中R2、X、B1和B2如前所定义,与式V化合物反应
其中R1如前所定义。
在后一种方法中,适当的式III氨基化合物可与适当的式V(S)-或(R)-硫羟乙酸酯反应,分别得到以上方案A步骤g中所述的相应的式I(S)-或(R)-硫羟乙酸酯。
方案B提供了另一种用于制备式I化合物的一般合成方法。
方案B
R1=COCH3、COPh
X=O、S、NH或(CH2)n
n=0或1。
在步骤a中,在与以上方案A步骤g中所述的相似条件下,使具有结构28的适当的氨基化合物(其中X为O、S、NH或(CH2)n,其中n为0或1)与具有结构33的适当的(R)-溴代酸反应,可得到相应的具有结构34的(R)-溴酰胺化合物(其中X为O、S、NH或(CH2)n,其中n为0或1)。
或者,如以上方案A步骤g中所述:使具有结构28的适当的氨基化合物(其中X为O、S、NH或(CH2)n,其中n为0或1)与适当的(S)-溴代酸反应可得到相应的(S)-溴酰胺(其中X为O、S、NH或(CH2)n,其中n为0或1),或者使具有结构28的适当的氨基化合物(其中X为O、S、NH或(CH2)n,其中n为0或1)与适当的溴代酸的对映体混合物反应,可得到相应的溴酰胺(其中X为O、S、NH或(CH2)n,其中n为0或1)的非对映异构混合物。
在步骤b中,具有结构34的适当的(R)-溴酰胺化合物(其中X为O、S、NH或(CH2)n,其中n为0或1)的(R)-溴官能团可被转化为相应的具有结构36的(S)-硫羟乙酸酯或(S)-硫羟苯甲酸酯(其中X为O、S、NH或(CH2)n,其中n为0或1)。
或者,适当的(S)-溴酰胺(其中X为O、S、NH或(CH2)n,其中n为0或1)的(S)-溴官能团可被转化为相应的(R)-硫羟乙酸酯或(R)-硫羟苯甲酸酯(其中X为O、S、NH或(CH2)n,其中n为0或1)。
例如,在碱如碳酸锂或碳酸钠存在下,使具有结构34的适当的(R)-溴酰胺化合物(其中X为O、S、NH或(CH2)n,其中n为0或1)与具有结构35的硫羟乙酸或硫羟苯甲酸反应。通常,使反应物在适宜的有机溶剂如二甲基甲酰胺与四氢呋喃的混合物中接触,将反应物在室温一起搅动1至8小时。生成的具有结构36的(S)-硫羟乙酸酯或(S)-硫羟苯甲酸酯(其中X为O、S、NH或(CH2)n,其中n为0或1)通过本领域已知的萃取法从反应区域回收而得。可通过色谱法对其进行纯化。
或者,将以上所述的溴酰胺化合物(其中X为O、S、NH或(CH2)n,其中n为0或1)的适当的非对映异构体混合物的溴官能团转化为相应的硫羟乙酸酯或硫羟苯甲酸酯(其中X为O、S、NH或(CH2)n,其中n为0或1)的非对映异构体混合物。
虽然方案B提供了用于制备其中当例如X为-CH2时,其三环部分具有(S)-构型的4-羧基官能团的式I化合物的方法,但是,通过以适当的(4R)-羧基氨基化合物代替具有结构28的氨基化合物(其制备如方案A中所述),也可以制备其中羧基官能团为(R)-构型的式I化合物。
实施例
下述实施例给出了如方案B中所述的一般合成方法。这些实施例应被理解为仅仅是说明性的而不是以任何方式限制本发明的范围。这里使用的以下术语有指定的含义:“g”表示克;“mmol”表示毫摩尔;“ml”表示毫升;“℃”表示摄氏度。
实施例1
(R)-2-溴-3-甲基丁酸(结构33)的制备
30分钟内将亚硝酸钠(6.90g,100mmol)的50ml水溶液加入到-10℃下的、D-缬氨酸(12.7g,100mmol)在100ml 2.5N硫酸和49%HBr(33g,200mmol)中的冷却溶液中。在-5℃至-10℃下继续保持搅拌3小时。用2×150ml二氯甲烷萃取反应混合物,用MgSO4干燥并浓缩,得到浅琥珀色的油状物(9.7g,50%,53.6mmol)。
实施例2
[4S-[4α,7α(S),12bβ]]-7-[[2(S)-乙酰硫基-3-甲基-1-氧代丁基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸二苯甲基酯
方案B,步骤a:[4S-[4α,7α(S),12bβ]]-7-[[2(R)-溴-3-甲基-1-氧代丁基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸二苯甲基酯
将(R)-2-溴-3-甲基丁酸(900mg,5.0mmol)和[4S-[4α,7α(S),12bβ]]-7-(氨基)-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-羧酸二苯甲基酯(1.76g,4.0mmol)溶解于无水二氯甲烷(5ml)中,并用EDC(1.0g,5.0mmol)在25℃下处理2小时。18小时后仅残余痕量的[4S-[4α,7α(S),12bβ]]-7-(氨基)-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸二苯甲基酯。混合物用二氯甲烷(75ml)稀释、用10%盐酸洗涤并用碳酸氢钠饱和。然后将混合物干燥(MgSO4)、真空浓缩,并用快速色谱法纯化,得到标题化合物(C33H35N2O4Br)(2.4g,4.0mmol)。
方案B,步骤b:[4S-[4α,7α(S),12bβ]]-7-[[2(S)-乙酰硫基-3-甲基-1-氧代丁基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸二苯甲基酯
在氮气环境下将硫羟乙酸(456mg,6.0mmol)和碳酸铯(325.8mg,3.0mmol)溶解于甲醇(5ml)中并蒸发至干燥。将溶解于5ml无水二甲基甲酰胺中的从步骤a中得到浓缩产物(4.0mmol)加入混合物中,随后在氮气环境下搅拌2小时。使混合物在乙酸乙酯(100ml)和盐水中分配、用10%HCl和饱和碳酸氢钠溶液洗涤、干燥(MgSO4)、过滤并浓缩,得到浅黄泡沫状的粗产品(2.2g)。将此产品溶解于二氯甲烷中,并通过色谱法(25%乙酸乙酯/己烷)、使用20%乙酸乙酯在200ml硅胶上进行纯化。合并各部分并浓缩,得到标题酯化合物(2.15g)。
实施例3
[4S-[4α,7α(S),12bβ]]-7-[[2(S)-乙酰硫基-3-甲基-1-氧代丁基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸的制备。
将实施例2中生产的粗产品(3.5mmol)溶解于二氯甲烷(6.0ml)和苯甲醚(1.0ml)中,冷却至-50℃并用三氟乙酸(6.0ml)处理。将混合物加热至25℃、搅拌2小时、真空浓缩,并通过色谱法(1∶1乙酸乙酯/己烷加上1%乙酸)纯化,得到标题化合物。
分子量=432.54
分子式=C22H28N2O5S
MDL107688的1H-和13C-NMR数据(DMSO-d6,300K,编号与IUPAC规则不一致)
位置 | 13C(ppm) | 1H(ppm) |
1 | 171.79 | - |
1-COOH | - | 12.07 |
2 | 50.53 | 4.99m |
3 | 24.98 | 2.21m,1.69m |
4 | 16.93 | 1.67m,1.67m |
5 | 24.69 | 2.38m,1.92m |
6 | 49.78 | 5.60 |
7 | 171.37 | - |
8 | 48.10 | 5.60 |
9 | 35.60 | 3.22dd,2.97dd |
10 | 136.72 | - |
11 | 136.89 | - |
12 | 124.83 | 7.19d |
13 | 125.21 | 7.08t |
14 | 126.67 | 7.13t |
15 | 130.10 | 7.07d |
16 | - | 8.33d |
17 | 169.11 | - |
18 | 53.82 | 4.12d |
19 | 30.69 | 2.14m |
20* | 20.18 | 0.99d |
21* | 19.29 | 0.94d |
24 | 194.36 | - |
25 | 30.34 | 2.36s |
*20和21位没有明显差别 |
实施例4
[4S-[4α,7α(S),12bβ]]-7-[[3-甲基-1-氧代-2(S)-巯基丁基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸的制备
在氮气环境下,将实施例3中得到的产品(75mg,0.17mmol)溶解于1.0ml脱气甲醇中并用氢氧化锂(0.4ml 1N溶液)进行处理。在25℃下搅拌1.5小时后,使溶液在真空中浓缩,用水(2ml)稀释并用盐酸(0.5ml,1N溶液)酸化。将生成的产品过滤并真空干燥,得到白色固体状的标题化合物(55mg,0.14mmol,83%)。
分子量=390.50
分子式=C20H26N2O4S
MDL108048的1H-和13C-NMR数据(DMSO-d6,300K,编号与IUPAC规则不一致)
位置 | δ(13C) | m(13C) | δ(1H) | nJCH |
1 | 171.86 | s | - | 1.68 |
2 | 50.63 | d | 4.98 | 5.60,1.68 |
3 | 25.04 | t | 2.23,1.68 | 4.98,1.65 |
4 | 17.00 | t | 1.65 | 4.98,1.91,1.68(5.60) |
5 | 24.77 | t | 2.38,1.91 | 5.60,1.65 |
6 | 49.95 | d | 5.60 | 7.19,4.98,1.91 |
7 | 171.55 | s | - | 5.63,3.25,2.97 |
8 | 47.89 | d | 5.632 | 3.25,2.97 |
9 | 36.05 | t | 3.25,2.97 | 7.07,5.63 |
10 | 136.86* | s | - | 3.25,2.97,5.63,7.19 |
11 | 138.82* | s | - | 5.63,7.08,3.25,2.97 |
12 | 124.87 | d | 7.185 | 7.13,5.60,(3.25),(2.97) |
13 | 125.31 | d | 7.084 | 7.07,(3.25),(2.97) |
14 | 126.70 | d | 7.127 | 7.19 |
15 | 130.11 | d | 7.073 | 7.08,3.25,2.97 |
16 | NH | - | 8.30 | 5.63 |
17 | 171.29 | s | - | 8.30,3.33,1.94 |
18 | 48.85 | d | 3.326 | 1.94,0.98,0.94 |
19 | 32.46 | d | 1.936 | 3.33,0.99,0.94 |
20 | 19.32 | q | 0.987 | 0.94,1.94,3.33 |
21 | 20.58 | q | 0.944 | 0.99,1.94,3.33 |
*位置20和21没有明显差别 |
本发明的化合物可用于治疗患有疾病例如但不限于高血压、充血性心衰、心室肥大、肾衰和/或肝硬化的温血动物或哺乳动物,包括小鼠、大鼠和人。
式I化合物的抑制ACE和NEP的有效量是可有效抑制ACE和NEP、可引起例如低血压效应的量。
式I化合物抑制ACE和NEP的有效量可通过使用常规技术和在观察相似环境中得到的结果来确定。在确定有效量时,考虑了大量因素,包括但不限于动物种类;动物大小、年龄和综合健康状态;所涉及的具体疾病;疾病的程度或患病范围或严重程度;个体患者的响应;所施用的具体化合物;所选择的剂量方案以及辅药的使用。
式I化合物的双重抑制ACE和NEP的有效量一般在约0.01毫克每千克体重每天(mg/kg/天)至约20mg/kg/天之间变化。优选日剂量为约0.1mg/kg至约10mg/kg。
在对患者进行治疗的过程中,式I化合物可以以使所述化合物以有效量被生物利用的任何剂型或方式施用,包括口服和胃肠外途径。例如,所述化合物可经口服、皮下、肌内、静脉内、经皮、鼻内、经直肠等方式施用。通常优选口服施用。适当的剂型和给药模式可由药剂制备领域内的技术人员根据待治疗的疾病状态、疾病阶段和其它相关情况容易地选择。
制剂
式I化合物可以以药物组合物或药物的形式施用,所述药物组合物或药物是通过将式I化合物与可药用载体或赋形剂结合而制得,载体或赋形剂的比例和性质取决于选定的给药途径和标准药学习惯。
本发明提供了包含有效量的式I化合物与一种或多种可药用载体或赋形剂混合或者以其它方式结合的药物组合物。
药物组合物或药剂可以按照药学领域已知的方法制备。载体可以是可作为活性成分的载体或介质的固体、半固体或液体物质。适宜的载体或赋形剂是本领域已知的。药物组合物可用于口服或胃肠外给药,并且可以以片剂、胶囊、栓剂、溶液剂、混悬剂等形式向患者施用。适宜的药用载体和制剂技术可在教科书中找到,例如Remington:The Science and Practiceof Pharmacy(药学科学与实践),第19版,第1和2卷,1995,MackPublishing Co.,Easton,Pennsylvania,美国,其在此引入作为参考。
药物组合物可例如与惰性稀释剂或可食用载体一起经口服施用。可将它们装入明胶胶囊中或压制成片。为便于口服治疗施用,可将式I化合物与赋形剂混合,以片剂、锭剂、胶囊、酏剂、混悬剂、糖浆剂、糯米纸囊剂、咀嚼胶等形式使用。这些制剂应当包含至少4%的活性成分式I化合物,但是也可根据特定剂型而变化,通常可为单位重量的4%至约70%。存在于组合物中的活性成分的量是可得到适于施用的单位剂量形式的量。
片剂、丸剂、胶囊、锭剂等也可包含一种或多种以下辅料:粘合剂如微晶纤维素、西黄耆胶或明胶;赋形剂如淀粉或乳糖,崩解剂如海藻酸、Primojel、玉米淀粉等;润滑剂如硬脂酸镁或Sterotex;助流剂如胶态二氧化硅;并可加入甜味剂如蔗糖或糖精,或矫味剂如薄荷油、水杨酸甲酯或桔味矫味剂。当单位剂量形式是胶囊时,除上述类型物质以外还可含有液态载体如聚乙二醇或脂油。其它单位剂量形式可含有其它多种可改进剂量单位物理形态的物质,例如包衣。因此,片剂或丸剂可用糖、虫胶或其它肠包衣剂包衣。糖浆剂除活性成分外可含有作为甜味剂的蔗糖和某种防腐剂、染料、着色剂和矫味剂。制备这些不同组合物中所使用的物质在使用量时应该是药学纯和无毒的。
为进行胃肠外施用,可将式I化合物加入溶液或混悬液中。这些制剂应含有至少0.1%的本发明的化合物,但其可在以重量计0.1%至约50%的范围内变化。在这种组合物中存在的活性成分的量是可获得适当剂量的量。
溶液或混悬液也可以包括一种或多种以下辅料:无菌稀释剂如注射用水、盐溶液、不挥发油、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗菌剂如苄醇或尼泊金甲酯;抗氧剂如抗坏血酸或亚硫酸氢钠;螯合剂如乙二胺四乙酸二钠;缓冲剂如乙酸盐、柠檬酸盐或磷酸盐以及张力调节剂如氯化钠或葡萄糖。胃肠外制剂可装入安瓿、一次性注射器或者由玻璃或塑料制成的多剂量小瓶中。
当然,应该理解的是:式I化合物可以多种同分异构体包括结构和立体异构体的形式存在。还应该理解的是:本发明包括作为单独的异构体或作为异构体混合物的式I化合物的每种结构和立体异构体。
生物学方法和结果
新的式I化合物有长效、增强的降压作用。此外,式I化合物可增加心衰患者的心输出量、减小左心室末期舒张压(LVEDP)并可增加冠状动脉血流量。通过图1总结的药理学数据可证明式I化合物的特别强的活性。
图1中的结果显示:与相同口服剂量的MDL 100 240相比,每个给药剂量的本发明的化合物均显著地增强了平均动脉压(MAP)的降低。
从大鼠充血性心衰模型得到的数据也显示:与已知化合物相比,式I化合物对心脏功能具有显著有利的效果。例如,在用MDL 100 240和MDL107 688对心衰大鼠进行测试的研究中发现:当MDL 107 688的使用剂量为MDL 100 240的一半时可得到相似的效果。
Claims (13)
2.权利要求1的化合物,其中R1为乙酰基或氢。
3.权利要求2的化合物,其中所述化合物为[4S-[4α,7α(S),12bβ]]-7-[[2(S)-乙酰硫基-3-甲基-1-氧代丁基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸二苯甲基酯。
4.权利要求2的化合物,其中R2为氢。
5.权利要求4的化合物,其中所述化合物为[4S-[4α,7α(S),12bβ]]-7-[[2(S)-乙酰硫基-3-甲基-1-氧代丁基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸。
6.权利要求4的化合物,其中所述化合物为[4S-[4α,7α(S),12bβ]]-7-[[3-甲基-1-氧代-2(S)-巯基丁基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1a][2]苯并氮杂-4-甲酸。
9.权利要求1的化合物在制备治疗心血管疾病的药物中的用途。
10.权利要求9的用途,其中所述的疾病为高血压。
11.权利要求9的用途,其中所述的疾病为充血性心衰。
12.药物组合物,其包含一种或多种权利要求1所述的化合物和可药用的载体。
13.制备药物组合物的方法,其包括将一种或多种权利要求1所述的化合物与可药用的载体混合的步骤。
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