CN1072663C - 新颖苄酰基胍衍生物,其制法及其在药物组合物制备中的用途 - Google Patents

新颖苄酰基胍衍生物,其制法及其在药物组合物制备中的用途 Download PDF

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CN1072663C
CN1072663C CN97191727A CN97191727A CN1072663C CN 1072663 C CN1072663 C CN 1072663C CN 97191727 A CN97191727 A CN 97191727A CN 97191727 A CN97191727 A CN 97191727A CN 1072663 C CN1072663 C CN 1072663C
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埃里克·伯格
克里斯琴·艾克迈耶
奥托·鲁斯
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Abstract

本发明是关于新颖苄酰基胍衍生物，其制备方法及其在药物组合物制备中的用途。该新颖苄酰基胍衍生物相当于通式(Ⅰ)是：

Description

新颖苄酰基胍衍生物，其制法 及其在药物组合物 制备中的用途
本发明是关于新颖苄酰基胍衍生物，其制造方法及其在药物组合物制备中的用途。
该新颖苄酰基胍衍生物相当于通式(Ⅰ)
Figure C9719172700061
其中R1是R3-SO2-或R3-NH-SO2,F,Cl或CF3；A是通过氮原子键合到苄酰基胍系统上的二价基团之一：
-CmH2m-NR4-    -CmH2m-NR4-CpH2p-NR4′-    -NR4-CmH2m-NR4′
Figure C9719172700062
Figure C9719172700071
m是0,1,2,3,4,5或6的整数n是0或1的整数p是0,1,2,3或4的整数B是以任何次序的下列基团中之一个或多个：(CH2)a,(-CHOH-)b,(-CO-)c,(-CS-)d和/或(-NR11-)，且a是0至8，优选是1,2,3或4,b是0,1或2，优选是1，c是0,1或2，优选是1，d是0,1或2，优选是1；R2是未取代的或取代的C1-8-烷基，未取代的或取代的芳基，-NR5R6或优选是5-或6-员的杂环基团
Figure C9719172700072
该基团可按需要与一或二个苯基系统进行稠合，且其中U,V,W,X,Y及必要时的Z是：CH2,CH,CO,NR7,N,O或S，其中带有氢的基团或R7必要时可被B取代；R3指C1-8-烷基，卤素-或苯基取代的C1-8-烷基，其中苯基可含至多三个选自包括卤素，C1-4-烷基或C1-4-烷氧基的取代基，R4及R4′，可相同或不同，是氢，C1-4-烷基，R4及R4′也可以是苯基，苄基及C3-7-环烷基；R5是氢或C1-8-烷基，芳基，芳烷基；R6是氢或C1-8-烷基，芳基，芳烷基；R7是氢或C1-4-烷基，芳基，芳烷基；
优选的通式Ⅰ化合物是这样的化合物其中R1是R3-SO2-或R3-NH-SO2-；A是通过氮原子键合到苄酰基胍系统上的二价基团中之一
-CmH2m-NR4-    -CmH2m-NR4-CpH2p-NR4′-    -NR4-CmH2m-NR4′
Figure C9719172700081
Figure C9719172700082
Figure C9719172700084
m是0,1,2,3,4,5或6的整数，n是0或1的整数，p是0,1,2,3或4的整数；B是以任何次序的下列基团中之一个或多个：(-CH2-)a,(-CHOH-)b,(-CO-)c,(-CS-)d和/或(-NR11-)，且
a是0至4的整数，
b是0或整数1，
c是0或整数1，
d是0或整数1，R2是未取代的或取代的C1-4-烷基，未取代的或取代的芳基，-NR5R6或是5-或6-员的杂环基团
Figure C9719172700085
该基团必要时可与一个或二个苯基系统进行稠合，其中U,V,W,X,Y及必要时的Z可以是：CH2,CH,CO,NR7,N,O或S，其中，带有氢的基团或R7必要时可被B取代；R3是C1-4-烷基；R4及R4′，可相同或不同，是氢，C1-4-烷基，R4及R4′也可以是苯基，苄基及C3-7-环烷基；R5是氢或C1-4-烷基，芳基，芳烷基；R6是氢或C1-4-烷基，芳基，芳烷基；R7是C1-4-烷基，芳基，或芳烷基。
特别优选的式Ⅰ化合物是这样的化合物，其中R1是CH3-SO2-；A是B是以任何次序的下列基团之一个或多个：(-CH2-)a,(-CHOH-)b,(-CO-)c,(-CS-)d和/或(-NR11-)，且a是0至4的整数，b是0或整数1，c是0或整数1，d是0或整数1，R2是5-员的杂环基团
该基团必要时可与一个或二个苯基系统进行稠合，且其中U,V,W,X,Y及必要时的Z是：CH2,CH,NR7,N,O或S，其中，带有氢的基团或R7必要时可被B取代；且环系统中只有一个杂原子；R3指C1-4-烷基；R4及R4′，可相同或不同，是氢，C1-4-烷基；R5是氢或C1-4-烷基，芳基，芳烷基；R6是氢或C1-4-烷基，芳基，芳烷基；R7是氢，C1-4-烷基，芳基，或芳烷基。
除非另有说明，一般定义是如下使用：C1-4-烷基及C1-8-烷基一般代表1至4或8个碳原子的支链或直链的烃属基团，该基团必要时可被一个或多个卤素原子，优选是氟取代，且该取代基可相同或不同。作为实例可列举下面的烃基团：
甲基，乙基，丙基，1-甲乙基(异丙基)，正丁基，1-甲基丙基，2-甲基丙基，1,1-二甲基乙基，戊基，1-甲基丁基，2-甲基丁基，3-甲基丁基，1,1-二甲基丙基，1,2-二甲基丙基，2,2-二甲基丙基，1-乙基丙基，己基，1-甲基戊基，2-甲基戊基，3-甲基戊基，4-甲基戊基，1,1-二甲基丁基，1,2-二甲基丁基，1,3-二甲基丁基，2,2-二甲基丁基，2,3-二甲基丁基，3,3-二甲基丁基，1-乙基丁基，2-乙基丁基，1,1,2-三甲基丙基，1,2,2-三甲基丙基，1-乙基-1-甲基丙基和1-乙基-2-甲基丙基。除非另有说明，优选的是有1至4个碳原子的低级烷基，如甲基，乙基，丙基，异丙基，正丁基，1-甲基丙基，2-甲基丙基或1,1-二甲基乙基。
烷氧基一般代表有1至8个碳原子的经氧原子键合的直链或支链的烃属基团。优选的是有1至4个碳原子的低级烷氧基。尤以甲氧基为特佳。
芳基一般是有6至10个碳原子的芳香基团，包括由一或多个低级烷基，三氟甲基，氰基，烷氧基，硝基，氨基和/或一个或多个相同或不同的卤素原子取代的芳香族基团；优选的芳基是必要时被取代的苯基，其中优选的取代基是卤素(如氟，氯或溴)，氰基及羟基。
芳烷基一般指有7至14个碳原子的通过亚烷基键合的芳基，其中芳香基团可被一个或多个低级烷基，烷氧基，硝基，氨基和/或一个或多个相同或不相同的卤素原子取代。优选的芳烷基是其脂肪基部分有1至6个碳原子而其芳香基部分有6个碳原子。
除非另有说明，优选的芳烷基是苄基，苯乙基和苯丙基。
卤素是氟，氯，溴及碘。优选是氯及溴。
除非另有说明，氨基是NH2基团，该基团必要时可被一个或二个相同或不同的C1-8-烷基、芳基或芳烷基所取代。
烷氨基指，例如，甲氨基，乙氨基，丙氨基，1-亚甲基乙氨基，丁氨基，1-甲基丙氨基，2-甲基丙氨基或1,1-二甲基乙氨基。
二烷基氨基指，例如，二甲基氨基，二乙基氨基，二丙基氨基，二丁基氨基，二-(1-甲基乙基)氨基，二-(1-甲基丙基)氨基，二-2-甲基丙基氨基，乙基甲基氯基，甲基丙基氨基。
环烷基一般是指有5至9个碳原子的饱和的或不饱和的环形烃基，该基团必要时被一个或多个相同或不同的卤素原子，优选是氟，所取代。优选的是有3至6个碳原子的环状烃基。作为实例包括环丙基，环丁基，环戊基，环戊烯基，环己基，环己烯基，环庚基，环庚烯基，环庚二烯基，环辛基，环辛烯基，环辛二烯基及环壬炔基。
杂芳基，在上述范围内，一般是指含有氧、硫和/或氮的杂原子的5-或6-员的环，该环上还可稠合有其他芳香环。优选的是含一个氧、一个硫和/或至多二个氮的5-或6-员的环，且必要时是苯并稠合的。
作为特定的杂环系统例如：吖啶基，吖啶酮基，烷基吡啶基，蒽醌基，抗坏血酰基，氮杂薁基(azaazulenyl)，氮苯并蒽基，氮苯并蒽烯基，氮杂基，氮杂环吖嗪基，氮杂吲哚基，氮杂并四苯基，氮杂萘基，氮杂异戊二烯基，氮杂苯并菲基，氮杂基，吖嗪吲哚基，丫嗪吡咯基，苯并吖啶基，苯并氮杂基，苯并呋喃基，苯并二氮杂萘基，苯并吡喃酮基(Benzopyranonyl)，苯并吡喃基，苯并吡喃酮基(Benzopyronyl)，苯并喹啉基，苯并喹啉嗪基，苯并噻基，苯并苯硫基，苄基异喹啉基，双吡啶基，丁内酯基，己内酰胺基，咔唑基，咔啉基，儿茶素基，色烯吡喃酮基，色烯吡喃基，α-苯并吡喃酮基，苯并呋喃基(Cumaronyl)，十氢喹啉基，十氢喹啉酮基，二氮杂蒽基，二氮杂菲基，二苯并氮杂基，二苯并呋喃基，二苯并苯硫基，二亚铬酰基(Dichromylenyl)，二氢呋喃基，二氢异苯并吡喃酮基，二氢异喹啉基，二氢吡喃基，二氢吡啶基，二氢吡啶酮基，二氢吡喃酮基，二氢硫吡喃基，diprylenyl，二噁蒽烯基(Dioxanthylenyl)，庚内酰胺基，黄烷基，黄酮基，荧烷基，荧光素基，呋喃二酮基，呋喃并苯并二氢吡喃基，呋喃酮基，呋喃并喹啉基，呋喃基，呋喃吡喃基，呋喃吡喃酮基，杂薁基，六氢吡嗪并异喹啉基，氢呋喃基，氢呋喃酮基，氢吲哚基，氢吡喃基，氢吡啶基，氢吡咯基，氢喹啉基，氢硫色烯基，氢苯硫基，中氮茚啶基(Indolizidinyl)，中氮茚基，吲哚酮基，靛红基，靛红原酰基，异苯并呋喃二酮基，异苯并呋喃基，异苯并二氢吡喃，异黄酮基，异二氢吲哚基，异吲哚并苯并氮杂基，异吲哚基，异喹啉基，异喹宁环基(1sochinuclidinyl)，内酰胺基，内酯基，马来酰亚胺基，单氮杂苯并萘次甲基，萘基，萘咪唑并吡啶二酮基，萘中氮茚二酮基，萘并二氢吡喃基，萘并呋喃基，1,5-二氮杂萘基，氧杂基(Oxepinyl)，羟吲哚基，oxolenyl，过氢吡咯吡啶基，过氢吲哚基，菲并醌基，苯并呋喃酮异醌基，苯二甲酰亚氨基，邻羧基苯乙酮基，哌啶基，哌啶酮基，脯氨酰基，对羟基联苯基(Parazinyl)，吡喃吖嗪基，吡喃吡咯基(Pyrazolyl)，吡喃基吡喃二酮基，吡喃基吡啶基，吡喃基喹啉基，吡喃基吡嗪基，吡喃基，吡唑并吡啶基，吡啶亚硫酰基，吡啶并萘基，吡啶并吡啶基(Pyrdinopyridinyl)，吡啶基，吡啶可啉基，吡啶吲哚基，吡啶并吡啶基(Pyridopyridinyl)，吡啶嘧啶基，吡啶吡咯基，吡啶喹啉基，吡喃酮基，吡咯可啉基，吡咯啶基(pyrrolizidinyl)，吡咯嗪基(pyrrolizinyl)，吡咯并二嗪基(pyrrolodioazinyl)，吡咯酮基，吡各并嘧啶基，吡咯并喹诺酮基，吡咯基，喹吖啶酮基，喹啉基，喹嗪啶基(chinolizidinyl)，喹嗪基，喹诺酮基，喹宁环基(chinuclidinyl)，若丹明基，螺α-苯并吡喃酮基(spirocumaranyl)，丁二酰亚氨基，四氢噻吩砜基，亚四氢噻吩砜基，四氢呋喃基，四氢异喹啉基，四氢吡喃基，四氢吡啶基，四氢噻吡喃基，四氢笨硫基，四氢硫吡喃酮基，四氢硫吡喃基，季酮酰基，噻苯基，噻苯并二氢吡喃基，噻萘烷基，硫茚基，噻喃基，噻喃酮基，噻唑并吡啶基，噻吩并吡啶基，噻吩并吡咯基，噻吩并苯硫基，thiepinyl，硫代色烯基，硫代α-苯并吡喃酮基，硫代吡喃基，三氮杂蒽基，三嗪吲哚基，三吡咯并吡啶基，托烷基，呫吨基，黄原酰基，呫吨氢基，腺嘌呤基，阿脲酰基，咯嗪基，氨茴酰基，氮杂苯蒽基，氮杂苯并环烷基，氮杂并四苯基，氮杂苯噁嗪基，氮杂嘌呤基，吖嗪基，吡咯吖嗪基，吡咯基，巴比土酸，苯并吖嗪基，苯并咪唑亚硫酰基，苯并咪唑啉酮基，苯并异噻唑基，苯并异噁唑基，苯并噌啉基，苯并二氮肉桂酰基(Benzodiazocinnyl)，苯并二氧五环基(Benzodioxolanyl)，苯并间二氧杂环戊烯基(Benzodioxolyl)，苯并哒嗪基，苯并噻氮杂基，苯并噻嗪基，苯并噻唑基，苯并噁嗪基，苯并噁唑啉酮基，苯并噁唑基，噌啉基，缩酚啶基(Depsidinyl)，二氮杂菲基，二氮杂基，二嗪基，二苯并噁基，二氢苯并咪唑基，二氢苯并噻嗪基，二氢噁唑基，二氢哒嗪基，二氢嘧啶基，二氢噻嗪基，二噁烷基，二噁烯基，二氧戊烯基，二氧壬基，二氧五环基，二氧五环酮基，二氧哌嗪基，二嘧啶吡嗪基，二硫戊环基，二硫戊烯基，二硫杂环戊二烯基(Dithiolyl)，黄素基，呋喃并嘧啶基，胍基乙酸内酰胺基，鸟嘌呤基，六氢吡嗪异喹啉基，六氢哒嗪基，乙内酰脲基，氢咪唑基，hydroparazinyl，氢吡唑基，氢哒嗪基，氢嘧啶基，咪唑啉基，咪唑基，咪唑并喹唑啉基，咪唑并噻唑基，吲唑苯并吡唑基，吲哚噁嗪基(indoxazenyl)，肌苷基，异咯嗪基，异噻唑基，异噁唑烷基，异噁唑啉酮基，异噁唑啉基，异噁唑酮基、异噁唑基、二氧四氢蝶啶基，甲基胸腺嘧啶基，甲基尿嘧啶基、吗啉基，萘咪唑基，乳清酸基，氧硫杂环己烷基，氧硫戊环基，噁嗪酮基，噁唑啶酮基，噁唑烷基，噁唑烷酮基，噁唑啉酮基，噁噁啉基，噁唑酮基，噁唑嘧啶基，噁唑基，过氢噌啉基，过氢吡咯嗪基，过氢吡咯噻嗪基，过氢噻嗪酮基， 啶基，菲嗪基，菲噻嗪基，菲氧硫杂环己二烯基，菲噁嗪基，菲噁嗪酮基，2,3-二氮杂萘基，哌嗪二酮基，哌嗪并二酮基，聚喹喔啉基，蝶啶基，蝶呤基，嘌呤基，吡嗪基，吡唑烷基，吡唑烷酮基，吡唑啉酮基，parazolinyl，吡唑并苯并二氮杂基，吡唑酮基，吡唑并嘧啶基，吡唑并三嗪基，吡唑基，哒嗪基，哒嗪酮基，吡唑并吡嗪基，吡啶并嘧啶基，嘧啶亚硫酰基，嘧啶基，嘧啶酮基，嘧啶并氮杂基，嘧啶并蝶啶基，吡咯并苯并二氮杂基，吡咯并二嗪基，吡咯并嘧啶基，喹唑烷基，喹唑啉酮基，喹唑啉基，喹喔啉基(chinoxalinyl)，磺内酰氨基，sultinyl，磺内酯基，四氢噁唑基，四氢吡嗪基，四氢哒嗪基，四氢喹喔啉基，四氢噻唑基，噻氮杂基，噻嗪基，噻唑烷酮基，噻唑烷基，噻唑啉酮基，噻唑啉基，噻唑并苯并咪唑基，噻唑基，噻吩并嘧啶基，噻唑烷基、胸腺嘧啶基、三唑并嘧啶基、尿嘧啶基，黄嘌呤基，木糖醇基，氮杂苯并萘次甲基，benzofuroxanyl，苯并噻二嗪基，苯并三氮杂酮基，苯并三唑基，苯并噁二嗪基，二噁二嗪基，二噻哒唑基(Dithiadazolyl)，二噻唑基，呋咱基，furoxanyl，氢三唑基，羟基三嗪基，噁二嗪基，噁二唑基，噁噻嗪酮基，噁三唑基，五嗪基，五唑基，petrazinyl，聚噁二唑基，斯德酮基，四噁烷基，四氮杂基，四嗪基，四唑基，噻二嗪基，噻二唑啉基，噻二唑基，噻二噁嗪基，噻三嗪基，噻三唑基，三氮杂基，三嗪吲哚基，三嗪基，三唑啉二酮基，三唑啉基，三唑基，三噁烷基，三菲二噁嗪基，三菲二噻嗪基，三噻二氮杂基，trithianyl，或三氧戊烷(Trioxolanyl)基。
通式Ⅰ的化合物由于具有细胞Na+/H+交换的抑制剂作用，可作为药物组合物活性物质使用，或作为制造这种活性物质的中间体使用。根据本发明的化合物具有抗心律不齐，如发生于缺氧的心律不齐的效果。也可用于与局部缺血(如心、脑、胃肠道、肺及肾的缺血，以及肝缺血和骨骼肌缺血)有关的疾病。这类疾病包括，例如，冠心病，心绞痛，肺血栓，急性或慢性肾衰竭，慢性肾机能不全，脑血栓，血管阻塞溶解后脑部分血液供应回流时引起的再灌注伤害及脑的急性与慢性循环障碍。这里所述的化合物也可与血栓溶剂如t-PA，链激酶及尿激酶合用。
在缺血心脏再灌注期间(例如心绞痛或心脏梗塞发作后)，受影响的区域内的心肌细胞可能会有不能恢复的损伤。此外，根据本发明的化合物在这种情形下有心脏保护作用。
局部缺血的治疗也包括对移植损害的预防(例如在器官移值前、移植中或移植后以及移植器官的储存时间内对移植器官的保护)，这类损害可能发生在器官移植。这类化合物在心脏及周边血管作血管成形术时也是有保护作用的药物。
在原发性压力过高及糖尿病性肾病时，细胞的钠质子的交换增加。所以上述化合物适于作为这种交换的抑制剂，而对这类疾病可作预防性治疗。
根据本发明的化合物的另一特点是对细胞的增生具有强力抑制作用。因此，该化合物对以细胞增生为主要或次要原因的疾病是有价值的药物，并可用作抗癌制剂，抗动脉粥样硬化剂，抗器官生活力不足制剂及抗增生剂，抗纤维性病变剂及抗糖尿病晚期并发症剂。药理学数据
对人肠癌细胞(HT-29)中Na+/H+交换的抑制：
将HT-29细胞于37℃的生长培养基，5％CO2下培养。经3-5天后取出生长培养基，洗涤细胞，装入7.5μM的BCECF-AM(pH敏感性荧光剂)，在37℃，无任何CO2。经30分钟后，洗涤细胞，用下面的介质酸化：70mM胆碱盐酸盐，20mM NH4Cl,1mM MgCl2,1.8mMClCl2,5mM葡萄糖和15mMHEPES,pH7.5。
在无CO2下37℃培养6分钟后，洗涤细胞，用洗涤介质培养5分钟：120mM胆碱盐酸盐，5mMKCl,1mMMgCl2,1.8mMCaCl,5mM葡萄糖和15mM MOPS,pH7.0。除去洗涤介质，加有或没有化合物的对照介质：120mMNaCl,5mM KCl,1mM MgCl2,1.8mM CaCl2,5mM葡萄糖，15mMMOPS,pH7.0。
将细胞在无CO2下于36 C培养4分钟，用荧光测定法(CytoFluor 2350)测定。于激发波长485毫微米(pH敏感性)及440毫微米(非pH敏感性)并于发射波长530毫微米测定染料BCECF的荧光。由485及440毫微米的荧光比计算胞质pH。用尼日利亚菌素(nigericin)测定外及内pH平衡后的荧光信号以校正荧光比。
实例 IC50/10-6mol/l
1 0.500
3 0.029
4 0.031
根据通式Ⅰ的活性物质可以水性可注射的溶液使用(例如供静脉内，肌肉内，或皮下给药)，以片剂、栓剂、膏剂(供皮肤给药的硬膏剂)给药，以供吸入肺内的喷雾剂或喷鼻剂给药。
片剂或栓剂内的活性物质的含量为5至200毫克，优选是10至50毫克。对吸入给药时，单剂量为0.05至20毫克，优选是0.2至5毫克。供非经肠注射给药时，单一剂量为0.1至50毫克，优选是0.5至20毫克。如有必要，这些剂量可一日数次给药。
下面为含该活性物质的药物制剂的实例：片剂通式Ⅰ的活性物质          20.0毫克硬脂酸镁                   1.0毫克玉米淀粉                  62.0毫克乳糖                      83.0毫克聚乙烯吡咯烷酮             1.6毫克供注射的溶液通过式Ⅰ的活性物质           0.3克氯化钠                       0.9克注射用水               加至100毫升
该溶液可用标准方法灭菌。供经鼻或吸入的水溶液通过式Ⅰ的活性物质           0.3克氯化钠          0.9克氯苄烷铵     0.01毫克纯化水    加至100毫升
上述溶液适于以喷雾形式供经鼻给药，或用产生颗粒大小优选为2至6微米的气雾剂的装置而给药入肺内。供吸入的胶囊
将通式Ⅰ化合物制成的微粒化形式(颗粒大小平均为2至6微米)，有必要则加入微粒化的载剂，如乳糖，并装入硬明胶胶囊内。这种胶囊可用习用的粉末吸入装置吸入。每一胶囊含有，例如，0.2至20毫克通式Ⅰ的活性物质及0至40毫克乳糖。供吸入的气雾剂通过式Ⅰ的活性物质    1份大豆卵磷脂          0.2份推进气混合物    加至100份
该制剂优选是装入配有计量阀的喷雾容器内，将每单次释出的剂量设定于0.5毫克。如使用指定的其他剂量时，制剂内可含更高或更低量的活性物质。膏剂(成分以克/100克膏剂表示)通式Ⅰ的活性物质               2克发烟盐酸                   0.011克焦亚硫酸钠                  0.05克等份的鲸蜡醇及硬脂醇混合物    20克白凡士林                       5克人造佛手油                 0.075克蒸馏水                     加至100
将各成分以常用方法混合成膏剂。
由相应的苯甲酸衍生物制备通式Ⅰ的苄酰基胍衍生物
Figure C9719172700171
的一般方法包括使通式Ⅱ的苯甲酸衍生物，
Figure C9719172700172
和由通式Ⅲ的化合物所要求的取代剂，进行亲核性取代，
式Ⅱ中P是离核的离去基团
R2BAQ    (Ⅲ)式Ⅲ中Q是可用亲电子试剂取代的离去基，将得到的通式Ⅳ的苯甲酸衍生物
Figure C9719172700173
悬浮于合适的，优选是无水的溶剂(优选为二甲基甲酰胺)内，与N-甲基吗啉及羰基二咪唑(CDI)混合，并再与碱，优选是氢化钠，于合适的无水溶剂，优选是二甲基甲酰胺内的溶液或悬浮液的混合物及胍盐，优选是胍盐酸盐，进行合并。
该活化的酸衍生物可以按已知的方式由通式Ⅳ的基本苯甲酸衍生物直接制备
Figure C9719172700181
基于通式Ⅳ的苯甲酸衍生物的制备活化的羧酸衍生物的适宜方法有多种，参阅文献J.March著Advanced Organic Chemistry，第三版(John Wiley &Sons,1985)350页。
活化的羧酸衍生物与胍盐的反应是，以已知方式在质子或非质子的极性但是惰性的有机溶剂内进行。
有些基本的式Ⅳ苯甲酸衍生物是已知的，并描述于文献中。迄今未知的Ⅳ化合物可用文献中已知方法制备。
相应的苯甲酸可用，例如，可将对应取代的哌嗪与4-氯-3-甲基磺酰基苯甲酸进行反应，其中亲核取代发生在4-位而制备。为此，将10mM 4-氯-3-甲基磺酰基苯甲酸和50mM哌嗪在惰性气体下在120℃加热4小时。用甲醇结晶，即制得对应取代的苯甲酸。
将10mM对应的苯甲酸衍生物悬浮在40毫升无水DMF中，并加入10mM N-甲基吗啉。在所得溶液内加入13mM羰基二咪唑(CDI)，在室温下搅拌2小时。在第二混合物中，将14mM NaH悬浮在30毫升无水DMF内，并与14mM胍盐酸盐在惰性气体下混合。将所得混合物于80℃搅拌1小时，待冷却后过滤除去不溶物质。将清澈的胍溶液加入上述溶液内，并在环境温度下搅拌12小时。减压蒸馏掉DMF后，残留物在硅胶上以适宜的溶剂对体系进行色谱分纯化。用乙醚化的的盐酸或其他药物上可用的酸处理，将苄酰基胍转化成对应的盐。
以此标准方法可制得下述化合物：实施1：熔点：＞250℃实例2：熔点220-222℃(分解)
Figure C9719172700192
实例3：熔点：175-177℃(分解)实例4：熔点：＞250℃实例5：熔点207-210℃(分解)
Figure C9719172700201
实例6：熔点：170-173℃
Figure C9719172700202
实例7：熔点：170℃(分解)实例8：熔点：243℃(分解)

Claims (10)

1．通式(Ⅰ)的苄酰基胍衍生物
Figure C9719172700021
其中
R1是R3-SO2-
A是
Figure C9719172700022
B是选自(CH2)a和-CO-的基团，其中a是1至4的整数，
R2选自C1-C6-烷基，
以选自下列的基团任意取代的苯基：C1-C4-烷氧基，羟基，卤素，卤素-C1-C4-烷基，二-C1-C4-烷基胺，二-C1-C4-烷基胺-C1-C4-烷基和C1-C4-烷基，
以一个C1-C4-烷基任意取代的呋喃基，
苯硫基，吡啶基，吡咯基，
以一个卤素任意取代的萘基
和-NR5R6；
R3是C1-C4-烷基；
R5是C1-C4-烷基；
R6是C1-C4-烷基或其药学可接受的酸加成盐。
2．根据权利要求1的通式(Ⅰ)化合物，其中
R1是Me-SO2-；其中Me是甲基，
A是
B是选自(-CH2-)a和-CO-的基团，
R2表示选自下列的基团：
C1-C4-烷基，
以选自下列的基团任意取代的苯基：甲氧基，羟基，F,CF3，二甲基氨基，二甲基氨基甲基和甲基，
以一个甲基任意取代的呋喃基，
苯硫基，吡啶基，吡咯基，
以一个F任意取代的萘基，
和二甲基氨基，或其药学可接受的酸加成盐。
3．根据权利要求1或2的通式(Ⅰ)的化合物，其中
R1是Me-SO2-；其中Me是甲基，
A是
B是选自-CH2-,-CH2-CH2-和-CO-的基团
R2是选自下列的基团：
C1-C4烷基，
以一个甲基任意取代的呋喃基，
苯硫基，吡啶基，吡咯基和二甲基氨基，或其药学可接受的酸加成盐。
4．根据权利要求3的通式(Ⅰ)的化合物，其中
R1是Me-SO2-；其中Me是甲基，
A是
Figure C9719172700041
B是-CO-，和
R2选自呋喃基、苯硫基和吡咯基或其药学可接受的酸加成盐。
5．一种制备通式Ⅰ化合物的方法其特征在于，由通式Ⅱ的苯甲酸衍生物
Figure C9719172700043
与通式Ⅲ化合物的一取代基进行亲核取代反应，R2BAQ    (Ⅲ)通式Ⅱ中，P是离核离去基团通式Ⅲ中Q是可以亲电子试剂取代的离去基，再由所得通式Ⅳ的苯甲酸衍生物
Figure C9719172700051
悬浮在无水的溶剂内，并与N-甲基吗啉及羰基二咪唑反应，与碱溶解于或悬浮于合适的无水溶剂内的混合物以及胍盐相结合。
6．权利要求5的方法，其中所述无水溶剂是二甲基甲酰胺，所述碱是氢化钠，所述胍盐是胍盐酸盐。
7．一种药物组合物，它含有权利要求1至4中的任一化合物或其酸加成盐，以及药物上可用的赋形剂，稀释剂或载剂。
8．根据权利要求1至4中之任一化合物在药物组合物中的用途。
9．根据权利要求8的用途，其中所述药物组合物具有Na+/H+交换抑制作用。
10．根据权利要求1-4所定义的通式Ⅰ化合物，其立体异构物及其酸加成盐，在制备用于治疗缺血的药物组合物中的用途。
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