CN1049665A - 羧基酰胺衍生物 - Google Patents
羧基酰胺衍生物 Download PDFInfo
- Publication number
- CN1049665A CN1049665A CN90103962A CN90103962A CN1049665A CN 1049665 A CN1049665 A CN 1049665A CN 90103962 A CN90103962 A CN 90103962A CN 90103962 A CN90103962 A CN 90103962A CN 1049665 A CN1049665 A CN 1049665A
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- Prior art keywords
- carboxylamide
- preparation
- formula
- carboxylamide derivatives
- derivatives
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
式(1)所示的羧基酰胺衍生物具有降低血脂的活
性,且副作用低,如低毒性,消除了常规已知的治疗高
脂血症药物的所有弱点。
Description
本发明涉及羧基酰胺衍生物。具体讲,本发明涉及该羧基酰胺衍生物,其制备方法,以及以该羧基酰胺衍生物为活性成分的,用于治疗高脂血症的药物组合物。
由于近来生活条件的改善,饮食习惯的西方化,以及老年人口的增加,据报道,由此而引起的高脂血症和动脉硬化患者人数迅速增加。
通常,高脂血症被定义为由血清中脂类的异常增高而导致的病理状况,即由血液中所含的胆固醇、磷脂或游离脂肪酸的三甘油脂中任何一种的异常增加所引起的。此外,高脂血症是动脉硬化的一个很重要且危险的因素,尤其是冠状动脉硬化,因此,改善治疗和预防这些疾病的方法即成为一个社会问题,以防止这类疾病患者人数增加。
已经使用的治疗高脂血症的方法有几种,如饮食疗法,运动疗法,及药物疗法等。一些药物已经被研究和加以改善以用于上述药物疗法,其中一些已经市售。在市售的药物中,如:祛脂乙酯类药物已经过改进,用于降低血脂浓度,如胆固醇,三甘油脂等。这些已知的药物根据药理作用机制进行下列分类。
(1)脂吸收抑制剂
(2)脂生物合成抑制剂
(3)脂异化一排泄促进剂
(4)脂蛋白代谢改进剂;及
(5)过氧化脂减少剂。
对于该治疗高脂血症的药物特别重要的是,要求其安全性尽可能高,因为鉴于该病的性质,要长期服用这些药物。
然而,目前广泛应用于该领域的治疗高脂血症的药物,如祛脂乙酯具有某些弱点及副作用。例如,他们引起皮疹、肌肉疼痛、触痛,肝功能障碍、等等。因此,在使用这类药物时,应引起人们的对这些药物的关注和观察。根据国外所做的动物实验结果,当长时间内给予大量祛脂乙酯时,观察到肝肿瘤形成。(参考“YAKK YOKU”(Pharmacy),Vol.31,No.11,page 31,(1980))。
除上述的祛脂乙酯类药物外,其它治疗高脂血症的药物,安全性均不够好,其中一些引起肝病变,该副作用在长期给药时,将造成严重问题。
进一步讲,市售的用于治疗高脂血症的任何一种药物均不能表明降脂活性,因此多年来用于该目的的任何药物,都期待着得到更优的药理活性。
以前的文献涉及到与本发明的羧基酰胺衍生物类似的羧基酰胺化合物,已在Japanese Patent Application Kokai(Laidopen)No.61-151199(1986)和EP-A-273444申请中披露。然而,这些以前的技术文献亦未包括涉及本发明的羧基酰胺衍生物的具体内容。以前的这些技术文献指明,羧基酰胺化合物仅适用于抗炎制剂及钙拮抗剂,但文献中未述及任何有关羧基酰胺化合物在治疗和预防高脂血症的应用。
本发明的一个目的是,提供一种治疗高脂血症新药,该新药具有优良的药理活性,要求是具有降低血脂的活性,而且安全性高,即副作用小,如低毒性,它可消除了用于该目的的已知常规药物的所有弱点。本发明的羧基酰胺衍生物的上述特点在以前的技术文献中,既未被预料也没被先有技术中已知的羧基酰胺化合物包括。
本发明的另一个目的,是提供羧基酰胺衍生物的制备方法。
本发明进一步的目的是,提供治疗高脂血症的,以羧基酰胺衍生物为活性成分的药物组合物。
另外,本发明的目的还在于提供:通过服用一种具体的羧基酰胺衍生物,治疗高脂血症的方法。
考虑到已知的治疗高脂血症药物的上述情况,本发明者进行了深入研究以改进药物,并发现下列式(1)代表的具体的羧基酰胺衍生物具有治疗高脂血症适宜的药理活性,尤其是其具有降低血脂的优良活性,同时具有低毒性和高安全性。因此本发明完成得很成功。
根据本发明,提供了式(1)的羧基酰胺衍生物。
(其中R为低级烷基;X为卤原子)。
在通式(1)中,符号R所表示的低级烷基可以是例如:甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基等。
此外,X所指的卤原子可以是例如:氟原子,氯原子,溴原子和碘原子。
式(1)所表示的羧基酰胺衍生物具有降低血脂的优良活性,可用于治疗高脂血症,如高胆固醇血症,高三甘油血症,高磷脂血症,高游离脂肪酸血症等。
式(1)所表示的、具有优良降血脂活性的,用于预防和治疗高脂血症的羧基酰胺衍生物,在苯环上氨基的邻位或对位上有CN-取代基。X所表示的卤原子接于苯环的对位或邻位,如:下列的式(1a)和(1b):
式(1a):
(其中R和X如上述定义)。
式(1b):
(其中R和X同上述定义)。
式(1)所表示的羧基酰胺衍生物,尤其是式(1a)和(1b)所代表的羧基酰胺衍生物具有优良的降低血脂浓度的活性,除其活性以外,还具有良好的安全性,无副作用(如溶血)。因此式(1)所表示的羧基酰胺衍生物是治疗和预防上述疾病的非常适用的药物。
本发明的式(1)所表示的羧基酰胺衍生物,可通过各种方法制备,典型的方法可由下列的反应路线1来描述:
反应路线1
(其中,R和X同上述定义)。
根据反应路线1,本发明的羧基酰胺衍生物(1)可以通过胺(2)与酰氯衍生物(3)的反应进行制备。
反应通常在适宜的溶剂中,在脱酸剂的存在下进行。至于用于该反应中的脱酸剂,可选用不引起副反应的、任何类型用于该目的脱酸剂。例如,叔胺如三乙基胺,N,N-二乙基苯胺、N-甲基吗啉,吡啶,4-二甲基氨基吡啶等可以是优选使用的。至于本反应中所用的溶剂,例如:可以使用的有:芳香及脂肪烃类如:苯、甲苯、二甲苯、石油醚等;链及环醚类如乙醚,二甲氧基乙烷,四氢呋喃(THF),1,4-二恶烷等;酮类如:丙酮、甲基乙基酮、乙酰苯,以及卤化烃如:二氯甲烷、氯仿、四氯化碳,1,2-二氯乙烷等。
在上述反应中酰氯(3)的用量与胺(2)的用量的比是明确限制的,通常相对于后者,等摩尔至过量的前者可以使用。上述脱酸剂通常使用的量为:与酰氯(3)等摩尔或稍过量。反应可以在任何条件下进行,如在冷却、室温或是加热条件下,通常反应在室温到所用溶剂的回流温度范围内进行,通常反应在0.5到10小时内完成。
通过上述反应路线1得到的本发明的产物羧基酰胺衍生物(1)可以用常规分离方法从反应体系中分离出,随后进行纯化,至于上述的分离方法,可以应用的有:常规溶剂提取,蒸馏,重结晶,柱层析,制备薄层层析等。
本发明的羧基酰胺衍生物(1)可以各种类型的药物组合物的常规制剂使用。上述药物制剂可以使用常规稀释剂进行制备,如:填充剂、粒状剂、粘合剂、润湿剂、崩解剂、表面活性剂、润滑剂等或赋形剂。至于药物制剂的类型,可以根据不同的治疗目的选择,例如:片剂、丸剂,粉剂,液体剂,混悬剂,乳剂,颗粒,胶囊,栓剂,注射剂(液体剂、混悬剂等)等等。在制备片剂时,可以使用赋形剂,如:乳糖,白糖、氯化钠,葡萄糖,尿素,淀粉,碳酸钙,高岭土,结晶纤维素,硅酸等,粘合剂如水、乙醇、丙醇、单糖浆、葡萄糖溶液。淀粉溶液、明胶溶液,羧甲基纤维素,紫胶,甲基纤维素,碳酸钾、聚乙烯吡咯烷酮等;崩解剂如:羧甲基纤维素或其钙盐,微晶纤维素,藻酸钠,琼脂粉,昆布多糖粉,碳酸氢钠,碳酸钙,聚氧乙烯山梨醇的脂肪酸酯,十二烷基硫酸钠,硬脂酸单甘油酯,淀粉,乳糖等;崩解抑制剂如:白糖、硬脂精,椰子脂,氢化植物油等;促吸收剂,如:季铵碱、十二烷基硫酸钠等;润湿剂如甘油、淀粉等;吸收剂,如:淀粉、乳糖、高岭土、皂土、胶体硅酸等;润滑剂如精制滑石,硬脂酸盐、硼酸粉、聚乙二醇等。如需要,片剂可进一步用包衣材料进行包衣,使其成包衣片,如:糖衣片,明胶膜包衣片,肠衣片,膜色衣片或双层片,以及复合层片剂等。
在制备丸剂时,可以使用任何广泛应用于该领域的载体,例如:赋形剂如葡萄糖、乳糖、淀粉、椰子脂、氢化植物油,高岭土,滑石等;粘合剂如阿拉伯胶粉,黄蓍胶粉,明胶,乙醇,等;崩解剂如:昆布,琼脂等。
在制备栓剂时,可使用在该领域中广泛应用的任何载体,如聚乙二醇、椰子脂、高级醇、高级醇脂,明胶,半合成甘油酯等。
在制备胶囊时,本发明的羧基酰胺衍生物(1)与上述的载体混合,将所得到的混合物填充到硬明胶胶囊或软胶囊。
在制备注射剂时,溶液剂、乳剂或混悬剂进一步灭菌,且最好与血液等渗,在注射剂的制备中,可以使用该领域中广泛应用的任何载体,例如:水、乙醇、聚乙二醇、丙二醇、乙氧化异硬脂醇、聚氧化异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。在这些情况下,可以往所制的注射剂中加入适量的氯化钠,葡萄糖或甘油使其与血液等渗。而且,还可以加入通常所用的助溶剂、缓冲液,止痛剂等。如需要,还可向注射剂中加入着色剂、防腐剂、芳香剂、矫味剂、甜味剂及其它药物。
本发明的药物制剂中所含的本发明的羧基酰胺衍生物(1)的量没有明确的限制,可以在很宽的范围内选择适宜的量。通常药物组合物中可含有1-70%重量的羧基酰胺衍生物(1)。
上述的药物组合物的给药方法并无明确的限制,可根据各种药剂类型、年龄、性别、症状的程度及患者的其它条件加以确定。例如:片剂、丸剂、液体剂、混悬剂、乳剂,颗粒剂及胶囊剂可以口服给药。注射剂可单独静注给药,也可随输液给药,如葡萄糖溶液、氨基酸溶液等,如需要,注射剂还可通过单独肌注、皮内注射、皮下注射、或腹腔内注射。栓剂通过直肠给药。
上述药物制剂的给药剂量可根据给药方法、患者的年龄、性别,及其它情况,以及症状的程度进行适宜的选择,通常每公斤体重每天所用的药剂中约含有0.05-80mg羧基酰胺衍生物(1),且每天给药次数可分为1-4次。
实例
为了更详细地解释本发明,将羧基酰胺衍生物(1)的制备,药理试验以及药剂的制备等项实例描述如下。
实施例1
4-二乙氧基膦酰基甲基-N-(4-溴-2-氰基苯基)苯甲酰胺
将3.94g(20mM)2-氨基-5-溴苄腈,2.22g(22mM)三乙基胺和0.49g(4mM)4-二甲基氨基吡啶溶于40ml干燥二氯甲烷,在冰浴条件下往该溶液中缓缓滴加40ml含有5.81g(20mM)4-二乙氧基膦酰基甲基苯甲酰氯的干燥二氯甲烷溶液,并不断搅拌,在室温下连续搅拌10小时后,往反应混合物中加50ml水,将整个混合物用氯仿提取,氯仿提取液用无水硫酸钠干燥,减压蒸除溶剂,所得残留物用硅胶柱层析进行纯化(用氯仿∶乙酸乙酯=1∶2的混合物洗脱)。随后用苯-正己烷重结晶,得到2.94g的4-二乙氧基膦酰基甲基-N-(4-溴-2-氰苯基)苯甲酰胺,为无色结晶,熔点:165-166℃(苯-正己烷重结晶)。
实例2-7
以类似于实例1中所用的方法,制备得到下列表1中所示的羧基酰胺化合物。在表1中,实例1中制备的羧基酰胺化合物的结构式亦予列出。
药理试验-1
用七周的Wistar种系雄性大鼠做为实验动物,各试验组有六只大鼠。将试验化合物分散于0.5%的羧甲纤维素(CMC)水溶液中,将所制备的含有试验化合物的混悬液,用探针强迫给大鼠口服给药两天,剂量为300毫克/5毫升/公斤/天。与试验组类似,给对照组的六只大鼠的每一只口服不含试验化合物的0.5%-CMC水溶液。
当最后一次给药后,受试大鼠被禁食20小时,取大鼠血样,血浆高密度脂蛋白胆固醇(HDLC)的浓度可用HDL-C Kit-N测量器(Nihon Shoji Kabushiki Kaisha制造)进行测量。
试验化合物所致的血浆HDLC浓度的增长率(%)由下式计算:
增长率(%)= ((试验组的血浆HDLC浓度))/((对照组的血浆HDLC浓度)) ×100%
所得结果见下列表2
药理试验-2(溶血试验)
七周龄的ddy种系雄性小鼠用做实验动物,实验组含六只小鼠,将试验化合物分散于0.5%的羧甲基纤维素(CMC)水溶液中,将如此制备的混悬液用探针给小鼠强迫口服给药10天,剂量为每天每公斤体重5ml混悬液(含试验化合物600mg)。与上述类似的方法,给对照组(6只)每只小鼠口服给不含试验化合物的0.5%-CMC水溶液。
最后一次给药后,小鼠被禁食20小时,随后将小鼠解剖,取血样并通过剜出术取脾样本,测定红细胞数及脾的重量。
红细胞数比值的计算,是将试验组的红细胞数的平均值除以对照组红细胞数的平均值,同样,脾重量的比值计算,是将试验组的脾重量的平均值除以对照组脾重量的平均值。所得结果见下列表3。
如表3中所示的数据可见,本发明的羧基酰胺衍生物无溶血副作用,因为试验组与对照组所得的数据未见任何显著性差异。
药剂制备实例-1
片剂制备
1,000片每片含有250mg的4-二乙氧基膦酰基甲基-N-(4-溴-2-氰基苯基)苯甲酰胺(以后称为“化合物A”)为活性成分的片剂按下列处方制备:
成分 重量(g)
化合物A 250
乳糖(日本药典级) 33.3
玉米淀粉(日本药典级) 16.4
羧甲基纤维素钙(日本药典级) 12.8
甲基纤维素(日本药典级) 6.0
硬脂酸镁(日本药典级) 1.5
总量320.0
按上述配方,将化合物A、乳糖、玉米淀粉、和羧甲基纤维素钙完全混合,随后用甲基纤维素水溶液将混合物制粒,所制得的颗粒过筛(#24),过筛后颗粒与硬脂酸镁混合、压片。
药剂制备实例-2
胶囊的制备
1,000粒每粒含4-二乙氧基膦酰基甲基-N-(2-氯-4-氰基苯基)苯甲酰胺(氧化称为“化合物B”)为活性成分的硬明胶胶囊按下列处方配制。
成分 重量(g)
化合物B 250
结晶纤维素(日本药典级) 30
玉米淀粉(日本药典级) 17
滑石(日本药典级) 2
硬脂酸镁(日本药典级) 1
总量 300g
按上述配方,将各成分研磨成细粉,随后充分混合使成均一混合物,将混合物填充入所需大小的口服明胶胶囊中,得到所需的胶囊剂。
药剂制备实例-3
颗粒剂的制备
1,000g颗粒剂,每克颗粒含有500mg的4-二乙氧基膦酰基甲基-N-(2-溴-4-氰基苯基)苯甲酰胺(以后称为“化合物C”)为活性成分,制备如下列处方。
成分 重量(g)
化合物C 500
玉米淀粉(日本药典级 250
乳糖(日本药典级) 100
结晶纤维素(日本药典级) 100
羧甲基纤维素钙(日本药典级) 40
羟丙基纤维素(日本药典级) 10
总量 1,000g
按上述配方,将化合物C,玉米淀粉,乳糖,结晶纤维素和羧甲基纤维素钙充分混合,随后往混合物中加入羟丙基纤维素水溶液,随后揉制成团,并用挤压制粒机制粒,将颗粒于50℃干燥成所需的颗粒剂。
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JP (1) | JP2584336B2 (zh) |
KR (1) | KR950013577B1 (zh) |
CN (1) | CN1023896C (zh) |
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AU (1) | AU631209B2 (zh) |
CA (1) | CA2017692C (zh) |
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DE69422793T2 (de) * | 1993-08-20 | 2000-06-21 | Otsuka Pharma Co Ltd | Phosphonsäurediester-derivat |
TW570799B (en) | 1998-02-17 | 2004-01-11 | Otsuka Pharma Co Ltd | The agent for preventing and curing fatty liver |
JP2001226358A (ja) * | 1999-10-12 | 2001-08-21 | Japan Tobacco Inc | Lpl活性増強剤 |
WO2002028397A1 (fr) * | 2000-09-29 | 2002-04-11 | Otsuka Pharmaceutical Factory, Inc. | Medicaments anti-diabete |
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US4822780A (en) * | 1987-07-08 | 1989-04-18 | Otsuka Pharmaceutical Factory, Inc. | Carboxamide compounds |
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ES2080798T3 (es) | 1996-02-16 |
DK0402033T3 (da) | 1996-02-05 |
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CA2017692C (en) | 1998-12-29 |
KR900018128A (ko) | 1990-12-20 |
JPH0368592A (ja) | 1991-03-25 |
JP2584336B2 (ja) | 1997-02-26 |
CN1023896C (zh) | 1994-03-02 |
AU5601190A (en) | 1990-12-06 |
CA2017692A1 (en) | 1990-11-30 |
EP0402033A1 (en) | 1990-12-12 |
KR950013577B1 (ko) | 1995-11-09 |
DE69023045T2 (de) | 1996-04-11 |
ATE129250T1 (de) | 1995-11-15 |
EP0402033B1 (en) | 1995-10-18 |
AU631209B2 (en) | 1992-11-19 |
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