CN1249053C - 抗溃疡药物硝酸盐 - Google Patents

抗溃疡药物硝酸盐 Download PDF

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CN1249053C
CN1249053C CNB998035343A CN99803534A CN1249053C CN 1249053 C CN1249053 C CN 1249053C CN B998035343 A CNB998035343 A CN B998035343A CN 99803534 A CN99803534 A CN 99803534A CN 1249053 C CN1249053 C CN 1249053C
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P·德尔索达托
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Abstract

具有式(A)和(B)的抗溃疡药物硝酸盐,其中在(A)类化合物中:R=H,OCH3,OCHF2;R1=CH3,OCH3;R2=H,CH3;R3=CH3,CH2-CF3,(CH2)3-OCH3;在(B)类化合物中:R3 I和R4 I彼此相同或不同,它们分别表示自由价、氢、-N=C(NH2)2、-CH2-N(CH3)2;Y=S,N-R6 I,CR7 IR8 I;X=O,S,N-R1 1;R2 I=H,CH3;n=0,1;Z=N-CN,N-SO2NH2,CH-NO2或式(VIIA),R5 I=H,-NH-CH3,NH2;R6 I、R7 I、R8 I、R1 I彼此相同或不同,它们是氢、自由价。本发明还包括上述盐的制备方法。

Description

抗溃疡药物硝酸盐
技术领域
本发明涉及用于治疗和预防溃疡复发以及大多数消化不良的组合物。特别是,本发明涉及具有改善的胃保护活性以及抑制高胃酸分泌活性的组合物。
背景技术
本领域已知的和市售的用于治疗溃疡的产物是具有抗酸分泌的化合物(酸分泌抑制剂)。参见例如“New Guide to Medicine&Drugs”Brit.Medical Assoc.Editor,1997,第108-109页。具有较高治疗作用的已知产物显示高抗酸活性,并且用于急性和长期(6个月或更久)治疗。这些产物的缺陷在于它们的胃保护活性(如果有的话)差。从实践的角度来看,这就意味着胃保护作用不是最佳的,并且尤其会对长期治疗造成不便。在这种情况下,由于胃粘膜衰弱导致的经常出现的消化不良是值得注意的。
为了克服这些困难,本领域已知的是在所述药物中加入其它具有胃保护活性的抗溃疡药物:前列腺素、铋盐(例如柠檬酸铋)和抗菌素。通过这种方式可以除去致溃疡的病因。然而,这些组合在其耐受性方面通常是不能令人满意的。例如,众所周知,前列腺素在肠道引起副作用(腹泻);铋盐经常会引起恶心和胃灼热。抗菌素则引起不希望的胃肠道反应。
因此,需要提供在溃疡和胃消化不良治疗中具有改善的治疗特性和耐受性的组合物,这些组合物总体和局部地、特别是具有改善的胃保护活性同时具有抗酸分泌活性。
本申请人出人意料地和意外地发现了具有上述所需性质的抗溃疡药物组合物。
发明内容
本发明的一个目的是药物组合物,该组合物主要含有选自下列一组化合物的一种或多种成分的硝酸盐:
Figure C9980353400051
在(A)类化合物中,
R=H,OCH3,OCHF2
R1=CH3,OCH3
R2=H,CH3
R3=CH3,CH2-CF3,(CH2)3-OCH3
在(B)类化合物中,
RI 3和RI 4彼此相同或不同,它们分别表示自由价、氢、-N=C(NH2)2、-CH2-N(CH3)2
Y=S,N-RI 6,C RI 7 RI 8
X=O,S,N-RI 1
RI 2=H,CH3
n=0,1;
Z=N-CN,N-SO2NH2,CH-NO2
Figure C9980353400052
RI 5=H,-NH-CH3,NH2
RI 6、RI 7、RI 8、RI 1彼此相同或不同,它们是氢、自由价。
优选的具有式(A)前体的硝酸盐是下列:
当R=OCH3,R1=CH3,R2=CH3,R3=CH3时,奥美拉唑残基;与奥美拉唑类似,不同的是R=OCHF2,R1=OCH3,R2=H,泮托拉唑残基;
与奥美拉唑类似,不同的是R=H,R2=H,R3=(CH2)3-OCH3,雷贝拉唑残基;
与雷贝拉唑类似,不同的是R3=CH2-CF3,兰索拉唑残基。
在(A)类化合物中还包括具有下列分子内环的化合物,它们可以通过在酸的含水介质中处理其前体而获得(参见“A Textbook of DrugDesign and Development”,哈佛大学出版社(Harwood academicpublisher),1991,第140页):
其中NAI和CAII分别是在式(A)的吡啶环1和2位的氮原子和碳原子,CB2和NB3分别是在咪唑环2和3位的碳原子和氮原子(咪唑环的1位是质子氮)。
优选的具有式(B)前体的硝酸盐是下列:
当式(B)中X=N-RI 1(其中RI 1是自由价),Y=N-RI 6(其中RI 6=H),RI 3=H,RI 4是自由价并与RI 1形成双键,RI 2=CH3,n=1,RI 5=-NH-CH3,Z=N-CN时,西咪替丁残基;
当X=N-RI 1(其中RI 1是自由价),Y=S,RI 3=-N=C(NH2)2,RI 4是自由价并与RI 1形成双键,RI 2=H,n=1,RI 5=H,Z=(VIIA)时,乙溴替丁残基;
与乙溴替丁类似,不同的是n=0,RI 5=NH2并且Z=N-SO2NH2,法莫替丁残基;
与乙溴替丁类似,不同的是RI 3=-CH2-N(CH3)2,RI 5=-NH-CH3并且Z=CH-NO2,尼唑替丁残基;
与尼唑替丁残基类似,不同的是X=氧,Y=C RI 7RI 8(其中RI 7是氢,RI 8是自由价),RI 4是自由价并与RI 8形成双键,雷尼替丁残基。
在本发明组合物中还可以使用属于(A)和(B)类的化合物的异构体。
在本发明组合物中,上式化合物的盐在每摩尔化合物中含有至少1摩尔硝酸根离子。硝酸根离子与前体的摩尔比优选等于1。当分子中存在其它足以成盐的碱性氨基基团时,可以得到具有较高摩尔比的盐。
属于上述各类的盐的前体是按照“The Merck Index,第12版”(1996)所述方法制备的,在此,将其引入本文作为参考。
本发明的盐可以按照下述方法之一制备。
当成盐物质是可溶于有机溶剂、优选不含羟基的有机溶剂(例如乙腈、乙酸乙酯、四氢呋喃等)中的游离碱或者其相应盐时,则通过将该物质以优选等于或大于10%w/v的浓度溶解在上述溶剂中,加入与化合物中存在的可成盐氨基基团相应摩尔数的浓硝酸。硝酸优选以同样的溶剂稀释。优选在加入硝酸的过程中或者之后,将该混合物冷却到20-0℃的温度范围。通常经过滤回收产物并用溶剂洗涤。
相反,当成盐物质溶解性不好,或者使用其难溶于上述溶剂的盐时,可以使用与羟基化溶剂的相应混合物。这些羟基化溶剂的实例是甲醇、乙醇和水。在加入硝酸后,通过用非极性溶剂稀释所得的混合物,可以迅速产生沉淀。
当原料与盐酸成盐时,可以向溶液中直接加入硝酸银制备硝酸盐。滤出氯化银之后,将溶液浓缩并按照上述方法进行处理,以回收硝酸盐。
当原料是盐时,还可以通过用碳酸氢钠或碳酸氢钾或者碳酸钠或碳酸钾饱和溶液处理、或者用氢氧化钠或氢氧化钾稀溶液处理,以释放出相应的碱。然后用合适的有机溶剂(例如卤代溶剂、酯、醚)萃取碱,之后将其干燥。将有机溶液蒸发,然后进行上述制备,将碱溶解在乙腈或上述其它溶剂中。
目前出人意料地发现,与上述提及的已知组合相比,本发明组合物可以全面改善前体化合物的药理-毒理学特性、在溃疡和胃消化不良治疗中提高治疗功效及其全身和局部耐受性,以及改善胃保护活性。
可以按照本领域已知的技术、用常规的赋形剂,将本发明组合物配制成相应的药物组合物;参见例如“Remington’s PharmaceuticalSciences 15a Ed.”。
本发明盐的剂量是其前体(A)和(B)的常规剂量。
通过将一种或多种(A)和(B)类化合物的硝酸盐或其药物组合物与常规的胃保护剂结合得到的本发明组合物是本发明的另一目的。例如可以提及的是前列腺素、铋盐、抗胃肠粘膜致病微生物的活性抗菌素。出人意料地发现,本发明组合物的胃保护活性非常高。这使得已知胃保护活性药物与本发明化合物或其制剂结合使用时,可以避免已知胃保护活性药物的不希望的作用。实际上,以本发明的联合用药形式使用的已知胃保护活性剂的用量低于已知的用量,并且不会引起不希望的副作用。本领域的专业人员可以容易地确定与本发明药物组合物结合的常规胃保护剂的最大用量,因为这是与已知胃保护剂通常的副作用不存在相应的。在任何情况下,用于本发明联合给药的常规胃保护剂的用量低于本领域所述联合给药中的用量。
具体实施方式
下面的实施例用于说明本发明,而不是对本发明的限制。
实施例1
制备西米替丁硝酸盐
将10克西米替丁溶解在于4℃冷却的100毫升乙腈/四氢呋喃/水1∶1∶2(体积比)混合物中。逐渐加入含有2.5毫升70%硝酸的10毫升乙腈溶液。该溶液用乙醚稀释,保持温度在4℃直至产物开始沉淀。几小时后滤出沉淀的固体,用乙醚洗涤并干燥。回收得到12.1克西米替丁一硝酸盐,熔点158-159℃(分解)。
1H-NMR(D2O):8,55(1H,s),3,83(2H,s),3,32(2H,s),2,77(3H,s),2,68(2H,t),2,32(3H,s).
元素分析:
计算值(%)    C 38.09      H 5.43      N 31.09     S 10.17
实测值(%)    C 37.99      H 5.41      N 31.16     S 10.25
实施例2
制备雷尼替丁硝酸盐
在20℃,将5克雷尼替丁盐酸盐溶解在140毫升乙腈/甲醇6∶1混合物中。加入4.2克硝酸银粉末。滤出氯化银沉淀,沉淀用乙腈/甲醇6∶1溶液洗涤,合并有机相、干燥并处理,得到干燥的残余物。由此得到相应于雷尼替丁一硝酸盐的非晶形固体。
1H-NMR(D2O):6,70(1H,d),6,40(1H,d),4,34(2H,s),3,83(2H,s),3,43(2H,t),2,93(2H,m),2,87(9H,s).
计算值(%)    C 41.37    H 6.14    N 18.56    S 8.50
实测值(%)    C 41.12    H 6.20    N 18.44    S 8.38
药理实验
实施例3
急性毒性
以2%w/v羧甲基纤维素水悬浮液的形式,经插管给10只各重20克的一组大鼠单次口服施用相当于100毫克/公斤剂量的前述实施例制备的西米替丁和雷尼替丁硝酸盐。
对这些实验动物监测14天。该组动物中没有一只观察到中毒症候。
实施例4
抗溃疡活性
根据A.Robert等所述试验模型对抗溃疡活性进行评价(“前列腺素对大鼠的细胞保护作用。预防由乙醇、HCl、NaOH、高渗NaCl和热损伤引起的胃坏死”,Gastroenterology 77,433-43 1979)。
使每组10只的5组大鼠从前一天晚上开始空腹,在喂入无水乙醇(1毫升)前15分钟,口服:
-5毫升/公斤2%的羧甲基纤维素水悬浮液。
-50毫克/公斤剂量的5毫升/公斤西咪替丁的2%的羧甲基纤维素水悬浮液。
-62.5毫克/公斤剂量的5毫升/公斤西咪替丁硝酸盐(相当于50毫克/公斤西咪替丁)的2%的羧甲基纤维素水悬浮液。
-50毫克/公斤剂量的5毫升/公斤雷尼替丁的2%的羧甲基纤维素水悬浮液。
-60毫克/公斤剂量的5毫升/公斤雷尼替丁硝酸盐(相当于60毫克/公斤雷尼替丁)的2%的羧甲基纤维素水悬浮液。
1小时后,将动物处死,并对胃损伤的发生率进行评价。所得结果记载于表1中,该结果表明与起始产物相比,西咪替丁和雷尼替丁的硝酸盐具有改善的胃保护活性。
             表1
  处理   胃损伤(%)
  赋形剂   100
  西咪替丁   100
  西咪替丁·HNO3   50
  雷尼替丁   80
  雷尼替丁·HNO3   40

Claims (12)

1.选自下列一组化合物的一种或多种成分的硝酸盐:
在(B)类化合物中:
X=N-RI 1,其中RI 1是自由价,Y=N-RI 6、其中RI 6=H,RI 3=H,RI 4是自由价并且与RI 1一起形成双键,RI 2=CH3,n=1,RI 5=-NH-CH3,Z=N-CN;
X=N-RI 1,其中RI 1是自由价,Y=S,RI 3=-N=C(NH2)2,RI 4是自由价并且与RI 1一起形成双键,RI 2=H,n=1,RI 5=H,Z=(VIIA):
Figure C998035340002C2
X=N-RI 1,其中RI 1是自由价,Y=S,RI 3=-N=C(NH2)2,RI 4是自由价并且与RI 1一起形成双键,RI 2=H,n=0,RI 5=NH2,Z=N-SO2NH2
X=N-RI 1,其中RI 1是自由价,Y=S,RI 3=-CH2-N(CH3)2,RI 4是自由价并且与RI 1一起形成双键,RI 2=H,n=1,RI 5=-NH-CH3,Z=CH-NO2
X=氧,Y=CRI 7RI 8、其中RI 7是氢并且RI 8是自由价,RI 3=-CH2-N(CH3)2,RI 4是自由价并且与RI 8一起形成双键,RI 2=H,n =1,RI 5=-NH-CH3,Z=CH-NO2
2.权利要求1的硝酸盐,其包括一种或多种(B)化合物的立体异构体。
3.含有权利要求1或2的硝酸盐的药物组合物,其中该药物组合物用于治疗溃疡和胃消化不良。
4.权利要求3的药物组合物在制备治疗溃疡和胃消化不良的药物中的应用。
5.权利要求2的硝酸盐在制备治疗溃疡和胃消化不良的药物中的应用。
6.治疗和预防溃疡和消化不良复发的组合物,其通过将一种或多种权利要求1或2所定义的硝酸盐与常规的胃保护剂结合制得,其中常规的胃保护剂选自前列腺素、铋盐和抗菌素。
7.治疗和预防溃疡和消化不良复发的组合物,其通过将权利要求3的药物组合物与常规的胃保护剂结合制得,其中常规的胃保护剂选自前列腺素、铋盐和抗菌素。
8.权利要求6或7的组合物在制备治疗和预防溃疡和消化不良复发的药物中的应用。
9.权利要求1或2的硝酸盐的制备方法,当成盐物质是可溶于有机溶剂中的游离碱或者其相应盐时,则通过将该物质以等于或大于10%w/v的浓度溶解在上述溶剂中,加入与化合物中存在的可成盐氨基基团相应摩尔数的浓硝酸,在加入硝酸的过程中或者之后,将该混合物冷却到20-0℃的温度范围,并经过滤回收产物。
10.权利要求1或2的硝酸盐的制备方法,其中当成盐物质溶解性不好,或者使用其难溶于上述溶剂的盐时,则使用与羟基化溶剂的相应混合物,在加入硝酸后,通过用非极性溶剂稀释所得的混合物,迅速产生沉淀。
11.权利要求1或2的硝酸盐的制备方法,其中当原料与盐酸成盐时,向该化合物溶液中直接加入硝酸银制备硝酸盐,滤出氯化银;将溶液浓缩并冷却以回收硝酸盐。
12.权利要求1或2的硝酸盐的制备方法,其中当原料是盐时,通过以下步骤的方法制备硝酸盐:
将所述盐用碳酸钠或碳酸钾或者碳酸氢钠或碳酸氢钾饱和溶液处理,或者用氢氧化钠或氢氧化钾稀溶液处理;
用有机溶剂从水相中萃取碱,将该有机溶液干燥并蒸发;
将该碱以等于或大于10%w/v的浓度溶解在有机溶剂中,加入与化合物中存在的可成盐氨基基团相应摩尔数的浓硝酸,在加入硝酸的过程中或者之后,将该混合物冷却到20-0℃的温度范围,并经过滤回收产物。
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