CN1165298C - 化合物作为抗菌剂的新用途 - Google Patents

化合物作为抗菌剂的新用途 Download PDF

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CN1165298C
CN1165298C CNB008082162A CN00808216A CN1165298C CN 1165298 C CN1165298 C CN 1165298C CN B008082162 A CNB008082162 A CN B008082162A CN 00808216 A CN00808216 A CN 00808216A CN 1165298 C CN1165298 C CN 1165298C
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A·埃克
J·劳德
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract

本发明涉及公开了释放NO的NSAID，特别是式(I)的释放NO的NSAID、或其可药用盐或其对映体，用于生产治疗细菌感染，特别是因幽门螺杆菌引起或介导的细菌感染的药物的新用途。本发明还公开了释放NO的NSAID与酸敏感的质子泵抑制剂联合用于治疗细菌感染的新用途。

Description

化合物作为抗菌剂的新用途
发明领域
本发明涉及释放一氧化氮的非甾族抗炎药(释放NO的NSAID)的新用途。更具体地说，本发明涉及释放NO的NSAID用于生产治疗细菌感染的，特别是因幽门螺杆菌引起或介导的感染的，药物的用途以及与酸敏感的质子泵抑制剂联合用于治疗细菌感染的用途。
发明背景和现有技术
NSAID，是世界范围内最常开处方和使用的药物之一。尽管NSAID具有治疗效果，但是它们的用途受到限制。使用NSAID由于抑制了前列腺素的产生，这增加了胃肠副作用的危险，因此可能导致胃粘膜损坏。
最近对降低与NSAID治疗有关的副作用的提议是使用释放一氧化氮的NSAID衍生物(释放NO的NSAID)(del Soldato P等人，释放NO的NSAID：一类新型，安全有效的抗炎剂(NO-releasing NSAID：s，A novel class of safer and effective antiinflammatory agents)；Inflammopharmacology，1996；4，181-188)。尽管释放NO的NSAID降低了胃肠副作用，但是仍然具有常用的NSAID的药理活性特征。
释放NO的NSAID及其可药用盐例如描述在WO94/04484、WO94/12463、WO95/09831和WO95/30641中。
幽门螺杆菌为定居于肠粘膜的革兰氏阴性螺菌形细菌。如今很好地确定了1983年由Warren提出的胃肠紊乱与幽门螺杆菌感染之间的关系(Rarren JR Lancet 1983；1.1273)。
为了治疗幽门螺杆菌感染，已提出了许多不同治疗方法。常用的是联合治疗。最常用的包括将质子泵抑制剂与一种或多种抗菌化合物如克拉霉素和阿莫西林联合。例如WO93/00327公开了将对胃酸分泌具有抑制效果从而增加胃内pH的一种物质与可酸降解的抗菌化合物联合。这些治疗方法中一些还包括例如WO98/03219和WO98/22117中列出的铋化合物，后一申请公开了一种含铋、抗菌剂和非甾族抗炎剂的组合物，用于治疗因幽门螺杆菌引起或介导的胃肠紊乱。
鉴于许多人患因例如幽门螺杆菌感染的细菌感染引起或介导的胃肠紊乱，并且还由于许多菌株呈现出对常用的抗生素的抗药性的事实，因此一直需要一种具有抗菌效果的安全、有效的药物，特别是用于治疗幽门螺杆菌感染的。
发明概述
现已出人意料地发现，释放NO的NSAID具有抗菌效果，这使它们可以用于治疗细菌感染。
本发明涉及释放NO的NSAID及其可药用盐或其对映体用于生产治疗细菌感染用的药物的用途。
优选该释放NO的NSAID是由式I所定义的。
其中M选自以下任意一种：
Figure C0080821600082
并且X为一间隔区，即在一氧化氮供给基团和NSAID部分之间形成一桥的化合物，或其可药用盐或对映体；
X优选选自直链、支链或环状-(CH2)-n，其中n为2-10的整数；-(CH2)m-O-(CH2)p-，其中m和p为2-10的整数；和-CH2-pC6H4-CH2-。
M并不限于上面定义的，而是可以为通过水解式I的化合物提供相应NSAID的任意其它化合物。
在本发明的一个优选实施方案中，M选自
Figure C0080821600092
并且X选自直链-(CH2)n-、-(CH2)2-O-(CH2)2-和-CH2-pC6H4-CH2-，其中n为2-6的整数。
在本发明更优选的一个实施方案中，释放NO的NSAID为相应于下式任意一种的化合物：
Figure C0080821600121
和
在本发明的一个特别优选的实施方式中，释放NO的NSAID为式Ia的化合物。
本发明另一方面是释放NO的NSAID，优选上面式I的化合物在生产用于治疗幽门螺杆菌感染，特别是治疗因幽门螺杆菌引起或介导的胃肠紊乱，的药物的用途。
本发明又一方面是一种治疗细菌感染，特别是幽门螺杆菌感染，的方法，其中将有效量的含有释放NO的NSAID，优选式I的化合物作为活性剂的药物施用于患所述细菌感染的患者。
适用于治疗细菌感染的药物制剂也在本发明的范围内，该制剂含有释放NO的NSAID，优选式I的化合物。
而且，本发明涉及释放NO的NSAID，优选式I的化合物与酸敏感的质子泵抑制剂或其盐或对映体或者该对映体的盐组合在生产打算同时、单独或顺序地给药以治疗细菌感染，特别是幽门螺杆菌感染的药用制剂中的用途。
本发明可以和通常与治疗细菌感染有关的其它试剂，例如抗菌剂一起使用。
酸敏感的质子泵抑制剂例如为通式II的化合物
其中
Het1为
或
Figure C0080821600142
Het2为
或 或
或
其中
苯并咪唑部分中的N意思是被R6-R9取代的碳原子中一个可以任选地用没有任何取代基的氮原子所替换；
R1、R2和R3可以相同或不同，并选自氢、烷基、烷氧基，其任选被氟取代、烷硫基、烷氧基烷氧基、二烷基氨基、哌啶基、吗啉基、卤原子、苯基和苯基烷氧基；
R4和R5可以相同或不同，并选自氢、烷基和芳烷基；
R6’为H、卤素、三氟甲基、烷基和烷氧基；
R6-R9可以相同或不同，并选自氢、烷基、烷氧基、卤素、卤代烷氧基、烷基羰基、烷氧基羰基、噁唑基、三氟烷基，或者相邻基团R6-R9形成可以进一步被取代的环状结构；
R10为H或者与R3一起形成亚烷基链，并且
R11和R12可以相同或不同，并选自氢、卤素或烷基、烷基、烷氧基及其部分。这些取代基可以为支链或直链C1-C9-链或者包括环状烷基，例如环烷基-烷基。
根据式II的质子泵抑制剂的例子为
奥美拉唑
Figure C0080821600152
兰索拉唑
泮托帕唑
帕里拉唑
来明拉唑
Figure C0080821600162
在所要求的组合中，质子泵抑制剂也可以可药用盐或单一对映体的形式使用。
优选将质子泵抑制剂奥美拉唑、或奥美拉唑的碱性盐如镁盐、或(S)-奥美拉唑或(S)-奥美拉唑的碱性盐如镁盐用于所要求的组合中。
适宜的质子泵抑制剂例如公开在EP-A1-0005129、EP-A1-174726、EP-A1-166287、GB2163747和WO90/06925，并且进一步这些特别适宜的化合物描述在WO95/01977和WO94/27988中。
根据本发明，还提供了一种治疗细菌感染，特别是幽门螺杆菌感染的方法，该方法包括向患细菌感染的患者同时、单独或顺序地给药一种或多种含有释放NO的NSAID，优选式I的化合物，和酸敏感的质子泵抑制剂的药用制剂。同样，同时、单独或顺序地给药以用于治疗细菌感染的、含有释放NO的NSAID，优选式I的化合物，和酸敏感的质子泵抑制剂的药物制剂也在本发明的范围内。
释放NO的NSAID单独或与酸敏感的化合物组合，可以为经口服、直肠、硬膜外、静脉内、肌内、皮下、输注、鼻或者适宜给药的任意其它方式给药的剂量形式。优选将该活性化合物口服给药。
将该活性化合物每天给药1至几次，优选每天1次或2次。该活性化合物的典型日剂量进行改变并将取决于各种因素如患者的个体需要、给药方式和疾病类型。通常每一剂量形式将含0.5-5000mg，优选5-1000mg的释放NO的NSAID。如果与质子泵抑制剂联合使用，在每一剂量形式中或者在两个单独的剂量形式中将含有0.5-5000mg的释放NO的NSAID和0.1-200mg质子泵抑制剂。优选在每一剂量形式中的释放NO的NSAID的量为5-1000mg，并且质子泵抑制剂的量为10-80mg。
发明详述
下面通过非限制性实施例更详细地描述本发明。
下面这些实施例支持释放NO的NSAID具有抗幽门螺杆菌活性，并且其抗菌活性为浓度依赖型。
实施例1
菌株：幽门螺杆菌参照菌株NCTC 11 637(National Type CultureCollection，from Smittskyddsinstitutet in Solna，Sweden)，一种抗菌敏感型参照菌株
物质：
Figure C0080821600181
将幽门螺杆菌在直径为90mm的血液琼脂平皿上在微需氧条件和37℃下生长3天。将该细菌悬浮于PBS(磷酸缓冲剂盐水)中至约108cfu/ml。将约2ml的该悬浮液加入一琼脂平皿中并均匀平铺于该琼脂的表面上。用一注射器去除溢出物。在该琼脂平皿上通过去除琼脂制备直径为3mm的类似小洞的孔。使每个平皿中有3个孔。
制备式1a化合物的浓度为100000μg/ml的原液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：每个孔周围的抑制区大，即不能测定该区域的直径。
实施例2
菌株：幽门螺杆菌参照菌株NCTC 11 637(参见实施例1)，一种抗菌敏感型参照菌株
物质：
按照实施例1制备带有孔的平皿。
制备式1a化合物的浓度为10000μg/ml的原液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：每个孔周围的抑制区大，即不能测定该区域的直径。
实施例3
菌株：幽门螺杆菌参照菌株NCTC 11 637，一种抗菌敏感型参照菌株(参见实施例1)
物质：
Figure C0080821600192
按照实施例1制备带有孔的平皿。
制备式1a化合物的浓度为1000μg/ml的原液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：每个孔周围的抑制区为13mm。
实施例4
菌株：幽门螺杆菌参照菌株NCTC 11 637，一种抗菌敏感型参照菌株(参见实施例1)
物质：
Figure C0080821600193
按照实施例1制备带有孔的平皿。
制备式1a化合物的浓度为100μg/ml的原液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：每个孔周围的抑制区为10.4mm。
对比试验
实施例A
菌株：幽门螺杆菌参照菌株NCTC 11 637，一种抗菌敏感型参照菌株(参见实施例1)
物质：奈普生
按照实施例1制备带有孔的平皿。
制备奈普生的浓度为10000μg/ml的原液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：每个孔周围的抑制区为16.6mm。
实施例B
菌株：幽门螺杆菌参照菌株NCTC 11 637，一种抗菌敏感型参照菌株(参见实施例1)
物质：萘普生
按照实施例1制备带有孔的平皿。
制备奈普生的浓度为1000μg/ml的原液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：在这些孔周围没有形成抑制区。
实施例C
菌株：幽门螺杆菌参照菌株NCTC 11 637，一种抗菌敏感型参照菌株(参见实施例1)
物质：萘普生
按照实施例1制备带有孔的平皿。
制备奈普生的浓度为100μg/ml的原液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：在这些孔周围没有形成抑制区。
实施例D
菌株：幽门螺杆菌参照菌株NCTC 11 637，一种抗菌敏感型参照菌株(参见实施例1)
物质：S-亚硝基-N-乙酰基-青霉胺(SNAP)
按照实施例1制备带有孔的平皿。
制备SNAP的浓度为10000μg/ml的原液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：在这些孔周围没有形成抑制区。
实施例E
菌株：幽门螺杆菌参照菌株NCTC 11 637，一种抗菌敏感型参照菌株(参见实施例1)
物质：硫酸二甲酯氧化物(Di-methyl-sulphate-oxide)(DMSO)
按照实施例1制备带有孔的平皿。
制备DMSO的浓度为20μg/ml的溶液。将30μl该溶液加入到这些孔中。将这些平皿培养4天，之后检查这些孔周围的抑制区。
结果：在这些孔周围没有形成抑制区。

Claims (12)

1、释放NO的NSAID及其可药用盐或其对映体用于生产治疗因幽门螺杆菌引起或介导的胃肠道紊乱的药物的用途，其中释放NO的NSAID选自式Ia-Iq的化合物：
Figure C008082160002C1
Figure C008082160003C1
Figure C008082160004C1
和
2、释放NO的NSAID和酸敏感的质子泵抑制剂在制备治疗因幽门螺杆菌引起或介导的胃肠道紊乱的药物的用途，它们中任一种为盐或对映体或该对映体的盐的形式，该药物制剂打算同时、单独或顺序地给药，其中释放NO的NSAID如权利要求1所定义。
3、如权利要求1或2的用途，其中释放NO的NSAID为式Ia的化合物
Figure C008082160004C3
4、如权利要求2的用途，其中酸敏感的质子泵抑制剂为式II的化合物
Figure C008082160004C4
其中
Het1为
Figure C008082160005C1
或
Figure C008082160005C2
Het2为
Figure C008082160005C3
或
Figure C008082160005C4
或
或
其中
苯并咪唑部分中的N意思是被R6-R9取代的碳原子中的一个可以任选地用没有任何取代基的氮原子所替换；
R1、R2和R3可以相同或不同，并选自氢、烷基、烷氧基，其任选被氟取代、烷硫基、烷氧基烷氧基、二烷基氨基、哌啶基、吗啉基、卤素、苯基和苯基烷氧基；
R4和R5可以相同或不同，并选自氢、烷基和芳烷基；
R6′为氢、卤素、三氟甲基、烷基和烷氧基；
R6-R9可以相同或不同，并选自氢、烷基、烷氧基、卤素、卤代烷氧基、烷基羰基、烷氧基羰基、噁唑基、三氟烷基，或者相邻基团R6-R9形成可以进一步被取代的环状结构；
R10为氢或者与R3一起形成亚烷基链，并且
R11和R12可以相同或不同，并选自氢、卤素或烷基、烷基、烷氧基及其部分，它们可以为支链或直链C1-C9-链或者包括环烷基，例如环烷基-烷基。
5、如权利要求4的用途，其中酸敏感的质子泵抑制剂选自奥美拉唑、其碱性盐、(S)-奥美拉唑及其碱性盐。
6、如权利要求4的用途，其中酸敏感的质子泵抑制剂为兰索拉唑或其可药用盐或对映体或该对映体的盐。
7、如权利要求4的用途，其中酸敏感的质子泵抑制剂为泮托帕唑或其可药用盐或对映体或该对映体的盐。
8、如权利要求2的用途，其中释放NO的NSAID为式Ia的化合物并且酸敏感的质子泵抑制剂为奥美拉唑、其碱性盐、(S)-奥美拉唑或其碱性盐。
9、如权利要求1的用途，其中释放NO的NSAID在每一剂量形式中的量为0.5-5000mg。
10、如权利要求9的用途，其中释放NO的NSAID的量为5-1000mg。
11、如权利要求2或8的用途，其中共同在一个剂量形式中或者在两个单独剂量形式中释放NO的NSAID的量为0.5-5000mg，并且质子泵抑制剂的量为0.1-200mg。
12、如权利要求2或8的用途，其中释放NO的NSAID的量为5-1000mg，并且质子泵抑制剂的量为10-80mg。
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