CN1264512C - 含有氨基噻唑衍生物、用于治疗结肠运动功能障碍的药用组合物 - Google Patents
含有氨基噻唑衍生物、用于治疗结肠运动功能障碍的药用组合物 Download PDFInfo
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- CN1264512C CN1264512C CNB018153046A CN01815304A CN1264512C CN 1264512 C CN1264512 C CN 1264512C CN B018153046 A CNB018153046 A CN B018153046A CN 01815304 A CN01815304 A CN 01815304A CN 1264512 C CN1264512 C CN 1264512C
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
本发明提供了可以有效改善结肠运动功能障碍比如肠易激惹综合症、便秘或肠无力的药物而不会对中枢神经系统产生副作用。这些结肠运动功能障碍药物包含下述通式(I)所示的氨基噻唑衍生物或者它的盐或水合物作为活性成分:其中R1、R2和R3可能相同或不同,各自独立地代表氢原子或羟基、低级烷基、低级烷氧基、氨基、硝基或氰基;R4和R5可能相同或不同,各自独立地代表氢原子或低级烷基;n是2到4的整数。
Description
技术领域
本发明涉及用于结肠运动功能障碍的药物,更确切的是指含有氨基噻唑衍生物作为活性成分的结肠运动功能障碍药物。本发明也涉及结肠运动功能障碍的一种治疗方法。
技术背景
从解剖学角度来看,消化道可以大概分为上消化道和下消化道。上消化道包括食道、胃和十二指肠,而下消化道则包括小肠、大肠和直肠。对于各个部位的疾病和症状,采用相应的治疗。
例证性上消化道疾病是食道部位疾病,比如食管癌、食管狭窄和反流性食管炎;胃部疾病,比如胃溃疡、胃炎和胃癌;十二指肠部位疾病,比如十二指肠溃疡和十二指肠癌;和常常发生在胃部和十二指肠部位的疾病,比如非溃疡性消化不良(NUD,Non-Ulcer Dyspepsia)和胃十二指肠的运动障碍。这些与胃十二指肠运动障碍有关的上消化道疾病的症状包括心下悸、恶心、呕吐、胃灼热、食欲缺乏、腹痛和胃胀。
例证性下消化道疾病是结肠癌、colonpolyp、溃疡性结肠炎、克罗恩氏病、肠易激惹综合症、便秘、肠无力,和药物导致的运动障碍。其中的肠易激惹综合症、便秘、肠无力,和药物导致的运动障碍可归因于大肠运动障碍,已知会导致排泄紊乱,比如便秘或腹泻,和/或腹痛。药物导致的运动障碍,在另一方面,被认为是使用钙拮抗剂、精神调节药物或抗抑郁药的结果。(心脏病学(Cardiology),89(suppl.1),10-15,1998;临床精神药理学杂志(J.Clin.Psychopharmacol.),19,401-406,1999;药物疗法(Pharmacotherapy),11,179-195,1991)
用于改善肠易激惹综合症的药物,人们知道的有马来酸曲美布汀(trimebutine maleate)、盐酸阿洛司琼(allosetron hydrochloride)和马来酸替加色罗(tegaseroid maleate)。这些药物中,已经发现马来酸曲美布汀会通过阿片类受体对中枢神经系统产生副作用(瞌睡,头晕之类)。对于分别对腹泻性肠易激惹综合症和便秘性肠易激惹综合症有效的盐酸阿洛司琼和tegaseroid maleate,人们尤其关注药物过量时便秘的副作用,因为药效与血清素受体作用相关。
作为上消化道药物的胃动力药,人们知道的有西沙必利、胃复安、盐酸依托必利、柠檬酸莫沙必利等。(胃肠病学(gastroenterology),118,S32-S47,2000)然而,已经报道了这些药物对于伴随有结肠运动功能障碍引发的肠易激惹综合症的便秘无效。(临床药理学杂志(J.Clin.Pharmacol.),19,617-625,1979;.斯堪的纳维亚胃肠病学杂志(Scand.J.Gastroenterol.),33,128-131,1998;食物药理学和治疗学(Aliment.Pharmacol.Ther.),11,387-394,1997)
在PCT国际公开WO96/36619和WO98/17654中提及,氨基噻唑衍生物可增强胃动力,改善心下悸、恶心、呕吐、胃灼热、食欲缺乏、腹痛和胃胀。然而这些出版物没有提到对结肠运动功能障碍引发的下消化道疾病有改善效果。
因而,急切需要发展改善结肠运动功能障碍疾病的药物,而且它没有对常规肠易激惹综合症药物观察到的、通过阿片类受体或血清素受体产生的那些副作用。
发明内容
本发明提供了一种结肠运动功能障碍药物,其包含作为活性成分的由通式(I)所示的氨基噻唑衍生物或它的盐或者水合物:
其中R1、R2和R3可能相同或不同,各自独立地代表氢原子或羟基、低级烷基、低级烷氧基、氨基、硝基或氰基;R4和R5可能相同或不同,并且彼此独立地代表氢原子或低级烷基基团;n是2到4的整数。
本发明也提供了通式(I)所示的氨基噻唑衍生物或者它的盐或水合物用于生产结肠运动功能障碍药物的用途。
本发明也提供了一种结肠运动功能障碍的治疗方法,它包括给予有效量的如通式(I)所示的氨基噻唑衍生物或者它的盐或水合物。
实施发明的最好方式
在可用于本发明的氨基噻唑衍生物(I)中,名词“低级烷基”是指直链、支链或环状的饱和烃基团,其中优选含有1到6个碳原子。另一方面,名词“低级烷氧基”是指由直链、支链或环状饱和烃组成的基团,其中优选含有1到6个碳原子和与烃相键合的氧原子。
因此,R1、R2、R3、R4和R5说明中的“低级烷基”是指含有1到6个碳原子的直链、支链或环状烷基,比如甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、仲丁基、叔丁基、环丁基、戊基、1-甲丁基、2-甲丁基、异戊基、叔戊基、1,2-二甲基丙基、新戊基、1-乙基丙基、环戊基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、异己基、1-乙基丁基、2-乙基丁基、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-甲基-1-乙基丙基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,2,2-三甲基丙基和环己基。在它们之中,优选含有1到4个碳原子的直链或支链低级烷基。尤其R4和R5优选异丙基。尤其R1、R2和R3优选是氢、羟基、甲氧基、氨基、硝基和氰基。
R1、R2和R3说明中的“低级烷氧基”是指含有1到6个碳原子的直链、支链或环状烷氧基团,比如甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、环丁氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、异戊氧基、叔戊氧基、1,2-二甲基丙氧基、新戊氧基、1-乙基丙氧基、环戊氧基、己氧基、1-甲基戊氧基、2-甲基戊氧基、3-甲基戊氧基、异己氧基、1-乙基丁氧基、2-乙基丁氧基、1,1-二甲基丁氧基、1,2-二甲基丁氧基、1,3-二甲基丁氧基、2,2-二甲基丁氧基、2,3-二甲基丁氧基、3,3-二甲基丁氧基、1-甲基-1-乙基丙氧基、1-乙基-2-甲基丙氧基、1,1,2-三甲基丙氧基、1,2,2-三甲基丙氧基和环己氧基。在它们之中,优选含有1到4个碳原子的直链或支链烷氧基。尤其优选甲氧基。
对于n,尤其优选2。
可用于实施本发明的氨基噻唑衍生物(I)优选实施例包括这样的化合物,其中R1、R2和R3相同或不同,各自独立地代表羟基或含有1到6个碳原子的直链或支链或环状烷氧基,尤其是甲氧基,或者R1、R2和R3中的一个是氨基、硝基或氰基,剩余两个取代基是氢原子;R4和R5是相同的,而且各代表含有1到6个碳原子的烷基,特别是异丙基;n是2。尤其优选的化合物例如是N-(N’,N’-二异丙基氨基乙基)-[2-(2-羟基-4,5-二甲氧基苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺、N-(N’,N’-二异丙基氨基乙基)-[2-(3-氰基-苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺和N-(N’,N’-二异丙基氨基乙基)-[2-(3-氨基苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺。
本发明中也很有用的氨基噻唑衍生物(I)盐的例子包括无机酸盐,比如盐酸化物、硫酸盐、硝酸盐、磷酸盐、氢溴酸盐、氢碘酸盐;有机酸盐,比如醋酸盐、草酸盐、丙二酸盐、丁二酸盐、马来酸盐、延胡索酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐和乙磺酸盐。优选盐是盐酸化物。
可用于本发明的氨基噻唑衍生物(I)包括多种溶剂化物比如水合物。
可用于本发明的氨基噻唑衍生物(I)可以用PCT国际公开WO96/36619或WO98/17654所公布的方法制备。
在本发明中,氨基噻唑衍生物(I)可以和药学可接受载体配制成适于口服或非肠道给药的组合物。作为口服用组合物,可用于本发明的氨基噻唑衍生物(I)可以通过使用适当添加剂配制成片剂、粉剂、颗粒剂或胶囊剂。添加剂包括例如赋形剂,比如乳糖、甘露醇、玉米淀粉或结晶纤维素;粘合剂,比如纤维素衍生物、阿拉伯树胶或明胶;崩解剂,比如羧甲基纤维素钙;润滑剂,比如滑石粉或硬脂酸镁;等等。进-步的,可以使用包衣基质比如羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素醋酸琥珀酸酯、纤维素醋酸邻苯二甲酸酯或者异丁烯酸酯共聚物,将这些固体制剂配制成经肠制剂。作为非肠道给药的组合物,可用于本发明的氨基噻唑衍生物(I)可以配制成注射用液体制剂,例如通过用水、乙醇、甘油、普通用表面活性剂等等配制,或者用栓剂基质配制成栓剂。
在本发明中,氨基噻唑衍生物(I)的剂量可以在0.1到2000毫克/天的范围之内,优选1到300毫克/天,这依赖于年龄、体重、症状、治疗效果、给药方法和给药周期。在这个剂量优选每天用药1到3次。
由于可用于本发明的氨基噻唑衍生物(I)具有优异的增强结肠动力效果和此处后面将会提及的高安全性,它可以作为哺乳动物包括人的结肠运动功能障碍药物。结肠运动功能障碍的代表性例子包括肠易激惹综合症、便秘、肠无力和药物导致的运动障碍。它不作用于血清素受体或多巴胺受体(肠胃病学,116(4)part2,A1094,1999),与常规药物不同,不会有副作用比如中枢神经系统副作用,例如,锥体束外紊乱和头晕,以及过量时引起的便秘。
实施例
本发明随后会用实施例来详细描述。然而,应该注意本发明不仅仅局限于这些实施例。
【药理学试验】
下面描述本发明的特定氨基噻唑衍生物(I)的药理学试验。下面是试验所用药物(试验化合物)。
(化合物1)
N-(N’,N’-二异丙基氨基乙基)-[2-(2-羟基-4,5-二甲氧基苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺三水合物[根据WO96/36619的实施例38方法合成]
(化合物2)
N-(N’,N’-二异丙基氨基乙基)-[2-(3-氰基-苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺氢氯化物[根据WO98/17654的实施例1方法合成]
(化合物3)
N-(N’,N’-二异丙基氨基乙基)-[2-(3-氨基苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺[根据WO96/36619的实施例157方法合成]
试验1[对于胃部和结肠动力的效果]
把测力传感器(“F-12IS”,商品名;星光医疗技术公司(Starmedical Technologies,Inc.)制造)长期缝合在雄性狗(体重:9到11千克,每组5到6只狗)的胃窦和大肠(Itoh Z.等人,美国疾病症断杂志(Am.J.Dig.Dis.)22,117-124,1977)。放大和记录进食后相应区域的收缩信号(“RTA-1200”,商品名;Nihon Kohden公司制造)。对收集在电脑中的收缩信号用软件(“DSSDDWHD V.30”,商品名;Nihon Kohden公司提供)分析,计算出运动指数(motor index)。试验药物用预先长期植入十二指肠的导管分别给药。假设给药前30分钟的运动系数是100%,计算出给药1个小时后运动指数的百分数。结果如表1所示。
表1胃肠道动力效果
试验药物 | 剂量(毫克/千克体重) | 运动指数百分数 | |
胃窦 | 大肠 | ||
对照 | 91.8 | 98.1 | |
化合物1 | 10 | 163.7 | 136.1 |
化合物2 | 10 | 189.5 | 221.7 |
化合物3 | 10 | 244.6 | 249.9 |
西沙必利 | 1 | 158.7 | 114.5 |
盐酸依托必利 | 10 | 132.7 | 122.1 |
莫沙必利 | 3 | 146.2 | 119.2 |
从表1可以明显看出,所有试验药物都显示了胃动力活性,但是对于结肠动力,常规药物西沙必利、依托必利和莫沙必利没有显著效果,而本发明化合物1到3显示了显著增强结肠动力活性。
试验2[通便的效果]
通过腹腔给雄性SD大鼠(每组8只大鼠)用试验药物。给药60分钟后收集粪便,并称取干重。假设对照组粪便平均重量为100%,计算出每个给药组粪便重量百分数的平均值。结果如表2所示。
表2对大鼠的通便效果
试验药物 | 剂量(毫克/千克体重) | 粪便重量百分数(%) |
对照 | - | 105.6 |
化合物1 | 10 | 361.8 |
化合物2 | 10 | 766.7 |
化合物3 | 10 | 733.3 |
从表2可以明显看出,所有试验药物化合物1到3都确实显示了显著的粪便重量增加。顺便提及,这些粪便的状态都正常。
【急性毒性试验】
把4到5周龄ICR小鼠进行分组,每组3只小鼠。每个试验化合物单独用0.5%甲基纤维素溶液悬浮,口服1000毫克/千克体重,观察小鼠一周。给化合物1到3的任何一组都没有出现死亡。
制备实施例1
化合物1 20克
乳糖 315克
玉米淀粉 125克
结晶纤维素 25克
均匀混合上面描述的成分,再加入7.5%羟丙基纤维素水溶液(200毫升)。将得到的混合物通过直径0.5毫米的筛制成绿色颗粒。立即用制药丸机将绿色颗粒做成圆形,之后干燥成颗粒剂。
制备实施例2
化合物2 20克
乳糖 100克
玉米淀粉 36克
结晶纤维素 30克
羧甲基纤维素钙 10克
硬脂酸镁 4克
均匀混合上面描述的成分。用单打孔制片机经直径7.5毫米的孔将混合物制成200毫克/片的药片。
制备实施例3
化合物1 100毫克
醋酸钠 2毫克
醋酸 调pH到5.8
蒸馏水 补充体积到10毫升
总量:10ml/管
根据上面的配方,以本领域所知的方式制备注射用液。
工业适用性
可用于本发明实施的氨基噻唑衍生物(I)对于改善结肠运动功能障碍有优异的效果,而且不会通过血清素受体或多巴胺受体对中枢神经系统产生副作用。因此,它是肠易激惹综合症、便秘、肠无力、药物导致的结肠运动障碍等的有用药物。
Claims (7)
1.下述通式(I)所示的氨基噻唑衍生物或者它的盐或水合物在制备用于治疗结肠运动功能障碍的药物中的用途:
其中R1、R2和R3可能相同或不同,并且各自独立地代表氢原子或羟基、直链或支链或环状的含有1到6个碳原子的烷基、含有1到6个碳原子的直链或支链或环状烷氧基、氨基、硝基或氰基;R4和R5可能相同或不同,并且各自独立地代表氢原子或含有1-6个碳原子的直链或支链或环状烷基基团;n是2到4的整数。
2.权利要求1的用途,其中通式(I)中,R1、R2和R3可能相同或不同,并且各自独立地代表羟基或含有1到6个碳原子的直链或支链或环状烷氧基,R4和R5相同,各代表含有1到6个碳原子的直链或支链或环状烷基,n是2。
3.权利要求1的用途,其中通式(I)中,R1、R2和R3之一是氨基、硝基或氰基,而剩余两个取代基均是氢原子,R4和R5相同,各代表含有1到6个碳原子的烷基,n是2。
4.N-(N’,N’-二异丙基氨基乙基)-[2-(2-羟基-4,5-二甲氧基苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺或者它的盐或水合物在制备用于治疗结肠运动功能障碍的药物中的用途。
5.N-(N’,N’-二异丙基氨基乙基)-[2-(3-氰基-苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺或者它的盐或水合物在制备用于治疗结肠运动功能障碍的药物中的用途。
6.N-(N’,N’-二异丙基氨基乙基)-[2-(3-氨基苯甲酰基氨基)-1,3-噻唑-4-基]甲酰胺或者它的盐或水合物在制备用于治疗结肠运动功能障碍的药物中的用途。
7.权利要求1-6中任何一项的用途,其中所述结肠运动功能障碍是肠易激惹综合症、便秘、肠无力或药物导致的结肠运动障碍。
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JP2000273025 | 2000-09-08 | ||
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US (1) | US6673368B2 (zh) |
EP (1) | EP1315488B1 (zh) |
JP (1) | JP4876367B2 (zh) |
KR (1) | KR100776298B1 (zh) |
CN (1) | CN1264512C (zh) |
AT (1) | ATE343384T1 (zh) |
AU (2) | AU2001256685B2 (zh) |
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DK (1) | DK1315488T3 (zh) |
ES (1) | ES2273838T3 (zh) |
PT (1) | PT1315488E (zh) |
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EP1493441B1 (en) * | 2002-04-08 | 2011-08-31 | Zeria Pharmaceutical Co., Ltd. | Therapeutic agent for food competence disorder in stomach |
SG182849A1 (en) | 2003-04-25 | 2012-08-30 | Gilead Sciences Inc | Antiviral phosphonate analogs |
PT2258376T (pt) | 2004-07-27 | 2019-05-31 | Gilead Sciences Inc | Análogos fosfonatados de compostos inibidores do vih |
AU2005287692B2 (en) * | 2004-09-20 | 2012-07-12 | 4Sc Ag | Novel heterocyclic NF-kappaB inhibitors |
KR100670974B1 (ko) * | 2006-09-18 | 2007-02-28 | (주) 리드제넥스 | 티아졸 유도체의 조합화학적 방법에 의한 분자다양성구축기술 |
CN102089318B (zh) * | 2008-07-08 | 2014-05-21 | 吉里德科学公司 | Hiv抑制剂化合物的盐 |
WO2012141019A1 (ja) * | 2011-04-13 | 2012-10-18 | オリンパス株式会社 | 単一発光粒子検出を用いた光分析装置、光分析方法及び光分析用コンピュータプログラム |
CN104130207B (zh) * | 2014-07-07 | 2016-08-24 | 湖北华世通生物医药科技有限公司 | 阿考替胺氢溴酸盐水合物及其晶型的制备方法 |
ES2969496T3 (es) | 2017-08-01 | 2024-05-20 | Gilead Sciences Inc | Formas cristalinas de ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-il)-4-fluoro-2,5-dihidrofuran-2- il)oxi)metil)(fenoxi)fosforil)-L-alaninato de etilo para tratar infecciones virales |
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DE69307310D1 (de) | 1992-05-12 | 1997-02-20 | Zeria Pharm Co Ltd | Neue quaternäre ammoniumsalze und deren medizinische verwendung |
KR100424933B1 (ko) * | 1995-05-18 | 2004-07-27 | 제리아 신야쿠 고교 가부시키 가이샤 | 아미노티아졸유도체,이를함유하는의약및이화합물의중간체 |
US6121301A (en) | 1996-10-24 | 2000-09-19 | Zeria Pharmaceutical Co., Ltd. | Substituted benzoylaminothiazole derivatives and drugs containing the same |
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DK0994108T3 (da) | 1997-06-24 | 2003-08-18 | Zeria Pharm Co Ltd | Fremgangsmåde til fremstilling af 2-hydroxybenzamidderivater |
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US20020051805A1 (en) | 2002-05-02 |
TWI296522B (en) | 2008-05-11 |
US6673368B2 (en) | 2004-01-06 |
DE60124117T2 (de) | 2007-02-15 |
ATE343384T1 (de) | 2006-11-15 |
EP1315488B1 (en) | 2006-10-25 |
WO2002020010A1 (en) | 2002-03-14 |
AU5668501A (en) | 2002-03-22 |
JP4876367B2 (ja) | 2012-02-15 |
AU2001256685B2 (en) | 2005-12-22 |
DE60124117T8 (de) | 2007-05-31 |
CN1460020A (zh) | 2003-12-03 |
DK1315488T3 (da) | 2007-02-12 |
ES2273838T3 (es) | 2007-05-16 |
JP2004508328A (ja) | 2004-03-18 |
EP1315488A2 (en) | 2003-06-04 |
PT1315488E (pt) | 2007-01-31 |
KR100776298B1 (ko) | 2007-11-13 |
DE60124117D1 (de) | 2006-12-07 |
KR20030029881A (ko) | 2003-04-16 |
CA2419666C (en) | 2009-10-27 |
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