CN1058212A - 取代的莱并咪唑、其制备方法和其在药物上的用途 - Google Patents
取代的莱并咪唑、其制备方法和其在药物上的用途 Download PDFInfo
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- CN1058212A CN1058212A CN91105024A CN91105024A CN1058212A CN 1058212 A CN1058212 A CN 1058212A CN 91105024 A CN91105024 A CN 91105024A CN 91105024 A CN91105024 A CN 91105024A CN 1058212 A CN1058212 A CN 1058212A
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- Prior art keywords
- compound
- methyl
- dimethoxy
- benzoglyoxaline
- pyridyl
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Abstract
通式I的新化合物
Description
本发明的目的是提供新的化合物,这些化合物抑制外原或内原刺激的胃酸分泌,因此这些化合物可用于消化道溃疡的预防和治疗。
本发明还涉及到,用本发明的化合物抑制哺乳动物(包括人)的胃酸分泌。从更一般的意义上说,本发明的化合物可用于预防和治疗哺乳动物(包括人)的胃肠炎性疾病和与胃酸有关的疾病,如胃炎、胃溃疡、十二指肠溃疡、消化性食管炎和佐林格-埃利森综合症。而且,这些化合物可用于治疗需要抗胃分泌作用的其他胃肠疾病,如用于胃瘤病人及急性上部胃肠出血病人。这些化合物还可用于集中护理中的病人,以及用于手术前和手术后防止酸吸入和应激反应溃疡的形成。本发明的化合物还可用于治疗或预防哺乳动物、包括人的炎性疾病,尤其是那些与溶菌酶有关的疾病。特别需要指出的疾病是风湿性关节炎和痛风。这些化合物还可用于治疗与身体新陈代谢紊乱有关的疾病以及用于治疗青光眼。本发明还涉及到含有本发明的化合物作为活性组分的药物组合物。另一方面,本发明涉及到制备这些新化合物的方法以及用这些活性化合物制备用于上述医疗用途的药物组合物。
本发明具体的主要目的是提供具有高水平的生物药效率的化合物。本发明的化合物还显示出在中性和酸性PH下的优良的稳定性质以及对抑制胃酸分泌的高效能力。本发明的化合物不会阻滞碘摄入甲状腺。在本发明人所从事工作的公司的几次讲座中早己揭示出,甲状腺毒性取决于化合物是否亲脂。发明人现在意外地发现亲脂性并非关键参数。本发明要求保护的化合物,包括颇为亲水的化合物,不产生任何甲状腺毒性作用,并且与此同时具有高的抑制胃酸分泌效力、好的生物药效率和稳定性。
许多专利文献公开了用来抑制胃酸分泌的苯并咪唑衍生物。这些文献中可以指出的有GB1500043、GB1525958、US4182766、US4255431、US4599347、BE898880、EP124495、EP208452、EP221041、EP279149、EP176308和德温特文摘87-284449/42。US4359465公开了提出用作治疗或预防特殊胃肠炎性疾病的苯并咪唑衍生物。
式Ⅰ化合物能有效地用作哺乳动物(包括人)的胃酸分泌抑制剂,而且不会阻滞碘摄入甲状腺。还发现下列式Ⅰ化合物表现出高的生物药效率。而且,本发明的化合物在中性和酸性PH下的溶液中表现出高的化学稳定性。酸性PH下的高的化学稳定性还使这些化合物用于非肠衣包覆的口服制剂。
本发明的化合物具有下列通式Ⅰ:
其中
R1和R2,它们不相同,各自是H、含1-4个碳原子的烷基或-C(O)-R6,R1或R2中的一个总是选自-C(O)-R6基团;其中
R6是含1-4个碳原子的烷基或含1-4个碳原子的烷氧基;
R3是-CH2OCOOR7基团,其中R7是含1-6个碳原子的烷基或苄基;
R4和R5可以相同或不同,它们选自-CH3、-C2H5、 、 和-CH2CH2OCH3,或者R4和R5与连在吡啶环上的相邻氧原子和吡啶环上的碳原子一起成环,其中由R4和R5构成的部分是-CH2CH2CH2-、-CH2CH2-或-CH2-。
短语“烷基”或“烷氧基”应当理解为包括直链和支链结构。
实施例1-6描述的本发明的结构异构体可以单独使用或以等量或不等量的混合物使用。
通式Ⅰ的本发明化合物在硫原子上有一个不对称中心,也就是说以两种光学异构体(对映体)形式存在;或者如果这些化合物还含有一个或多个不对称碳原子,它们就具有两个或多个非对映体形式,每个非对映体还存在两种对映体形式。纯的对映体、外消旋混合物(每个对映体各占50%)以及此二者的不等量混合物都包括在本发明的范围之内。还应当理解为所有可能的非对映体形式(纯的对映体或外消旋混合物)也在本发明的范围之内。
优选的几组通式Ⅰ的化合物是:
1、其中R3是-CH2OCOOCH2CH3的化合物。
2、化合物,其中R1和R2选自H、甲基或-C(O)-R6,其中R6是含1-4个碳原子的烷基或含1-4个碳原子的烷氧基。
3、特别优选的苯并咪唑结构是:
4、特别优选的是其中R4和R5是甲基的化合物。
5、特别优选的本发明的具体化合物是列于下表的化合物。
R1R2R3R4R5
CH3C(O)OCH3CH2OCOOCH2CH3CH3CH3
C(O)OCH3CH3CH2OCOOCH2CH3CH3CH3
CH3C(O)CH3CH2OCOOCH2CH3CH3CH3
C(O)CH3CH3CH2OCOOCH2CH3CH3CH3
人们认为通式Ⅰ化合物在发挥其作用之前要代谢为其中R3是H的相应的化合物。
制备
本发明的化合物可按照下面的方法制备:
a)使式Ⅱ化合物
与烷基氯甲基碳酸酯或苄基氯甲基碳酸酯反应。在式Ⅱ中,R1、R2、R4和R5如通式Ⅰ所定义,以及Z或者是金属阳离子如Na+、K+、Li+或Ag+,或者是季铵盐离子如四丁基铵。
b)使式Ⅱ化合物,其中R1、R2、R4和R5如通式Ⅰ所定义以及Z是羟甲基,与式Ⅲ化合物反应,
其中R7如前述定义,并且X是Cl或咪唑或对硝基苯氧基或功能等价基团。该反应在合适的碱如三乙胺存在下进行。
根据a)和b)的反应应当在保护气体存在和无水情况下进行。合适的溶剂是烃如甲苯或苯、或卤代烃如二氯甲烷或氯仿、或丙酮、乙腈或二甲基甲酰胺。反应可在室温和反应混合物沸腾温度之间的温度下进行。
c)氧化式Ⅳ化合物
其中R1、R2、R3、R4和R5如通式Ⅰ所定义。
可使用氧化剂进行该氧化反应。这些氧化剂的例子有硝酸、过氧化氢、(可任意地在钒化合物存在下)、过酸、过酸酯、臭氧、四氧化二氮、亚碘酰苯、N-卤代琥珀酰亚胺、1-氯苯并三唑、次氯酸叔丁基酯、二氮杂双环-[2,2,2]-辛烷溴配合物、偏高碘酸钠、二氧化硒、二氧化锰、铬酸、硝酸高铈铵、溴、氯和磺酰氯。该氧化反应通常在溶剂如卤代烃、醇、醚和酮中进行。
该氧化反应也可使用氧化酶在酶催化下进行,或使用合适的微生物以微生物方法进行。得到的结构异构体可通过结晶或色谱法进行分离。
得到的外消旋物可根据已知的方法分离,如从旋光的溶剂中重结晶。在外消旋非对映的混合物情况下,这些混合物可通过色谱法或分级结晶分离成非对映的纯对映体。
方法a)-c)中使用的起始原料在一些情况下是未知的。这些未知的起始原料可根据本质上已知的方法而得到。
烷基氯甲基碳酸酯和苄基氯甲基碳酸酯可通过在吡啶存在下,用氯甲酸氯甲酯处理适当的醇而得到。
式Ⅱ的中间物,其中Z是羟甲基,可通过在N-1位置带H的相应苯并咪唑化合物与甲醛反应而得到。
式Ⅲ的起始原料可由已知的方法得到,例如通过用光气或1,1'-羰基二咪唑或氯甲酸对硝基苯酯处理醇HOR7得到。
为了临床应用,将本发明的化合物配成口服,直肠或其他给药方式的药物制剂。在药物制剂中,本发明的化合物通常与药学上可接受的载体结合在一起。载体的形态可以是固体、半固体或液体稀释剂、或胶囊。这些药物制剂是本发明的又一目的。通常,活性化合物的量占制剂的0.1-95%wt,对于口服给药活性化合物的量则占制剂的1-50%wt。
在制备含本发明化合物的药物制剂中,当其以口服剂量单位形式存在时,所选择的化合物可与固体、粉末状载体如乳糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、支链淀粉、纤维素衍生物、明胶或其他合适的载体,与稳定化物质如碱性化合物(例如钠、钾、钙、镁等的碳酸盐、氢氧化物和氧化物),以及与润滑剂如硬脂酸镁、硬脂酸钙、富马酸硬脂酰酯钠和聚乙二醇蜡相混合。接着将该混合物加工成粒剂或压成片剂。粒剂和片剂可用肠衣包覆;只要药剂形式存在于胃中,肠衣就保护活性化合物免受酸催化降解。肠衣可在药学上可接受的肠衣材料如蜂蜡、紫胶片或阴离子膜形成的聚合物(例如邻苯二甲酸乙酸纤维素、邻苯二甲酸羟基丙基-甲基纤维素、部分甲酯化的甲基丙烯酸聚合物等)中选择,若为优选还可与合适的成形剂结合使用。为了区分带有不同的活性化合物的或存在的活性化合物的不同含量的片剂或粒剂,在包衣中加入各种染料。
软明胶胶囊可用胶囊剂制备,该胶囊剂含有由本发明的活性化合物、植物油、油脂或其他合适的软明胶囊赋形剂组成的混合物。软明胶囊也可按上面描述的方法用肠衣包覆。硬明胶囊可包含活性化合物的粒剂或肠衣包覆的粒剂。硬明胶囊还可含有与固体粉末状载体如乳糖、蔗糖、山梨糖醇、甘露糖醇、马铃薯淀粉、支链淀粉、纤维素衍生物或明胶结合在一起的活性化合物。硬明胶囊可按上述的方法用肠衣包覆。
用于直肠给药的剂量单位可以制成栓剂的形式,该栓剂含有与中性脂肪碱相混合的活性物质;或者它们可以制成明胶直肠胶囊的形式,这些胶囊含有与植物油、石蜡油或其他合适的明胶直肠胶囊赋形剂相混合的活性物质;或者它们可以制成现成的微灌肠剂形式;或者将它们制成干燥微灌肠剂制剂的形式,该制剂在给药之前要在合适的溶剂中重新配制。
用于口服给药的液体制剂可以制成糖浆或悬浮液的形式,例如制成含0.2%-20%wt活性成份的溶液或悬浮液,其余部分由糖或糖醇以及乙醇、水、甘油、丙二醇和/或聚乙二醇的混合物构成。如果需要,该液体制剂可含有着色剂、香味剂、糖精和羧甲基纤维素或其他增稠剂。用于口服给药的液体制剂还可以制成干燥粉末的形式,该粉末在使用前用合适的溶剂重新配制。
活性物质的一般日剂量取决于各种因素,例如取决于每个病人的个体需要、给药途径和疾病。通常,每日的口服剂量在5-500mg活性物质范围内。
本发明通过下列实施例说明。
实施例1
制备作为异构体混合物的5-甲酯基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯和6-甲酯基-5-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
向0.45g(1.1mmol)5-甲酯基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑和0.25g(1.8mmol)无水碳酸钾在45ml无水乙腈的悬浮液中,加入溶于5ml乙腈中的0.21(1.5mmol)氯甲基乙基碳酸酯。反应混合物在室温下搅拌过夜。然后真空下除去溶剂,剩余物用二氯甲烷和水稀释。有机溶剂用无水硫酸钠干燥。真空下除去溶剂得到粗产物,将其用硅胶色谱分离,用乙酸乙酯洗脱得到0.94g黄色油状物,该黄色油状物慢慢结晶。用乙醇重结晶得到0.25g(44%)标题化合物,为异构体混合物。
产物的NMR数据在下面给出。
实施例2
制备6-甲酯基-5-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H苯异咪唑-1-基甲基乙基碳酸酯。
从乙醇中结晶实施例1所得到的异构体混合物便得到标题化合物。
NMR数据在下面给出。
实施例3
制备作为异构体混合物的5-乙酰基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯和6-乙酰基-5-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
向磁力搅拌的无水碳酸钾(0.48g,3.47mmol)在80ml无水乙腈中的悬浮液滴加溶在10ml乙腈中的0.80g(2.14mmol)5-乙酰基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑和0.39g(2.8mmol)氯甲基乙基碳酸酯。室温下持续搅拌20小时。真空下除去溶剂,剩余物用二氯甲烷稀释,以水洗涤二氯甲烷溶液,并用无水硫酸钠干燥。真空下除去溶剂得到粗产物,将其用硅胶色谱分离,以乙酸乙酯洗脱得到0.63g几乎是白色的晶状固体。产物用乙酸乙酯重结晶得到0.50g(49%)标题化合物,为异构体混合物。
产物的NMR数据在下面给出。
实施例4
制备5-乙酰基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
通过色谱法在硅胶柱上以二氯甲烷-乙腈(比例6∶4)作为洗脱液,将标题化合物从实施例3所得到的异构体混合物中分离出来。标题化合物用乙醇结晶。
NMR 数据在下面给出。
实施例5
制备6-乙酰基-5-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
通过色谱法在硅胶柱上以二氯甲烷-乙腈(比例6∶4)作为洗脱液,将标题化合物从实施例3所得到的异构体混合物中分离出来。标题化合物用乙醇结晶。
NMR数据在下面给出。
实施例6
制备作为异构体混合物的5-乙酯基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯和6-乙酯基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
向0.28g(0.72mmol)5-乙酯基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H苯并咪唑和0.16g(1.2mmol)无水碳酸钾在20ml无水乙腈的悬浮液中加入溶于2ml无水乙腈中的0.16g(1.2mmol)氯甲基乙基碳酸酯。混合物在室温下搅拌过夜。挥发掉溶剂,粗产物在硅胶柱上进行色谱分离,以乙酸乙酯作为洗脱液。在乙醇中结晶得到标题化合物(0.13g,37%),为异构体混合物。
产物NMR数据在下面给出。
表1
实施例 溶剂 NMR数据δppm
1 CDCl31.20-1.30(m,3H),2.70(s,1.8H),
(300MHz) 2.75(s,1.2H),3.85-3.95(m,9H),
4.15-4.25(m,2H),4.85-5.05(m,
2H),6.40-6.55(m,2H),6.75(d,1H),7.45(s,0.6H),7.65(s,0.4H),
8.10(d,1H),8.20(s,0.4H),8.40(s,
0.6H)。
2 CDCl31.30(t,3H),2.70(s,3H),3.90(s,3H)
(300MHz) 3.90(s,3H),3.95(s,3H),4.25(q,2H),4.95(d,1H),5.05(d,1H),6.50
(m,2H),6.75(d,1H),7.65(s,1H),
8.10(d,1H),8.20(s,1H)
3 CDCl31.30(t,3H),2.60-2.70(m,6H),
(300MHz) 3.85-3.90(m,6H),4.25(q,2H),4.
85-5.05(m,2H),6.75(d,1H),7.45
(s,0.7H),7.60(s,0.3H),8.05(s,0.3H),8.10(d,1H),8.20(s,0.7H)
4 CDCl31.30(t,3H),2.60(s,3H),2.70(s,
(300MHz) 3H),3.90(s,3H),3.90(s,3H),4.20
(q,2H),4.90(d,1H),5.05(d,1H),6.
50(m,2H),6.80(d,1H),7.50(s,
1H),8.15(d,1H),8.20(s,1H)
5 CDCl31.30(t,3H),2.60(s,3H),2.70(s,
(300MHz) 3H),3.90(s,3H),3.90(s,3H),4.25(q,2H),4.90(d,1H),5.05(d,1H)6.
55(m,2H),6.80(d,1H),7.60(s,
1H),8.05(s,1H),8.15(d,1H)
6 CDCl31.30(m,3H),1.45(m,3H),3.90(s,
(300MHz) 3H),3.90(s,3H),4.25(m,2H),4.45
(m,2H),5.00(m,2H),6.55(m,2H),
6.80(d,1H),7.70(d,0.55H),7.80
(D,0.45H),8.10(m,2H),8.35(s,0.
45H),8.50(d,0.55H)
中间体的制备
实施例Ⅰ1
制备5-甲酯基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]硫代]-1H-苯并咪唑
将在H2O(0.6ml)中的5-甲酯基-6-甲基-2-巯基-1H-苯并咪唑(0.67g,0.003mol)和NaOH(0.12g,0.003mol)溶于CH3OH(15ml)中,加入在CH3OH(10ml)中的粗原料3,4-二甲氧基-2-氯甲基吡啶盐酸化物(≈0.0036mol)和在水(0.72ml)中的NaOH(0.144g,0.0036mol)。将该混合物加热至回流,并使回流持续1小时。蒸发掉CH3OH,粗料在硅胶柱上以色谱法纯化,用CH2Cl2-CH3OH(98-2)作为洗脱液,得到纯的标题化合物(1.03g,92%)。
NMR数据在下面给出。
实施例Ⅰ2
制备5-甲酯基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑
将5-甲酯基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]硫代]-1H-苯并咪唑(1.03g,0.00276mol)溶于CH2Cl2(30ml)中,加入在H2O(10ml)中的NaHCO3(0.46g,0.0055mol),将该混合物冷却至+2℃。搅拌下滴加溶于CH2Cl2(5ml)中的间氯过苯甲酸69.5%(0.62g,0.0025mol)。在2℃继续搅拌15分钟。分层后,用0.2MNaOH水溶液(3×15ml,0.009mol)萃取有机层。分离后,将水溶液合并,并在CH2Cl2(25ml)存在下用甲酸甲酯(0.56ml,0.009mol)中和。分离后的有机层用Na2SO4干燥,并在减压下蒸发。剩余物用CH3CN(10ml)结晶便得到标题化合物(0.68g,70%)。
NMR数据在下面给出。
实施例Ⅰ3
制备5-乙酰基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]硫代]-1H-苯并咪唑
将5-乙酰基-6-甲基-2-巯基-1H-苯并咪唑(4.2g,20mmol)和在H2O(1ml)中的NaOH(0.8g,20mmol)溶于60ml乙醇,加入作为粗原料的3,4-二甲氧基-2-氯甲基吡啶盐酸化物(≈17mmol),将该混合物加热至沸腾。加入在H2O(1ml)中的NaOH(0.7g,17mmol),将回流继续6小时。蒸发掉溶剂,剩余物用二氯甲烷和水稀释。有机相用Na2SO4干燥,减压下除去溶剂,用乙腈结晶得到标题化合物(3.75g,62%)。
NMR数据在下面给出。
实施例Ⅰ4
制备5-乙酰基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑
将5-乙酰基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]硫代]-1H-苯并咪唑(3.75g,10mmol)溶于CH2Cl2(70ml),加入在H2O(25ml)中的NaHCO3(1.76g,21mmol),将该混合物冷却至≈+3℃。搅拌下滴加溶于CH2Cl2(20ml)中的间氯过苯甲酸69.5%(2.43g,9.8mmol)。继续搅拌10分钟。分相,有机相用Na2SO4干燥,并在减压下蒸发。剩余物用CH3CN结晶便得到标题化合物(2.25g,60%)。
NMR数据在下面给出。
实施例Ⅰ5
制备5-乙酰基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]硫代]-1H-苯并咪唑
将5-乙酯基-2-巯基-1H-苯并咪唑(2.0g,9mmol)和在H2O(1ml)中的NaOH(0.36g,9mmol)溶于乙醇(30ml),加入作为粗原料的3,4-二甲氧基-2-氯甲基吡啶盐酸化物(≈6.6mmol),将该混合物加热至沸腾,加入在H2O(1ml)中的NaOH(0.26g,6.6mmol),并继续回流6小时。蒸发掉溶剂,剩余物用二氯甲烷和水稀释。有机相用Na2SO4干燥,减压下除去溶剂。用CH3CN结晶得到所需要的产物(1.75g,71%)。
NMR数据在下面给出。
实施例Ⅰ6
制备5-乙酯基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑
将5-乙酯基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]硫代]-1H-苯并咪唑(纯度95.2%)(1.4g,0.0036mol)溶于CH2Cl2(30ml),加入在水(10ml)中的NaHCO3(0.6g,0.0072mol),将该混合物冷却至+2℃。搅拌下滴加溶于CH2Cl2(5ml)中的间氯过苯甲酸69.5%(0.87g,0.0035mol)。在2℃继续搅拌10分钟。分相,有机相用Na2SO4干燥,并在减压下蒸发。剩余物用CH3CN(15ml)结晶便得到标题化合物(0.76g,54%)。
NMR数据在下面给出。
表2
实施例 溶剂 NMR数据δppm
11 CDCl32.70(s,3H),3.90(s,3H),3.95(s,
(300MHz) 3H,),4.00(s,3H),4.40(s,2H),6.90
(d,1H),7.35(s,1H),8.20(s,1H),8.
25(d,1H).
12 CDCl32.70(s,3H),3.85(s,3H),3.90(s,
(300MHz) 3H),3.95(s,3H),4.70(d,1H),4.90
(d,1H),6.8(d,1H),7.30(b,1H),8.
20(d,1H),8.35(b,1H).
13 CDCl32.60(s,3H),2.65(s,3H),3.90
(300MHz) (s,3H),3.90(s,3H),4.35(s,2H),6.
85(d,1H),7.25(s,0.6H),7.40(s,0.
4H),7.85(s,0.4H),8.05(s,0.6H),
8.30(m,1H)
14 CDCl32.60(s,6H),3.85(s,3H),3.85
(300MHz) (s,3H),4.70(d,1H),4.90(d,1H),6.
80(d,1H),7.30(b,1H),8.15(d,1H),
8.20(b,1H)
15 CDCl31.40(m,3H),3.90(s,3H),3.90
(300MHz) (s,3H)4.40(m,4H),6.90(dd,1H),
7.45(d,0.4H),7.60(d,0.6H)7.90
(m,1H),8.20(s,0.6H),8.25(m,
1H),8.25(s,0.4H)
16 CDCl31.45(t,3H),3.85(s,3H),3.90
(300MHz) (s,3H),4.40(q,2H),4.65(d,1H),4.
40(d,1H),6.80(d,1H),7.50,7.80
(b,1H),8.05(d,1H),8.20(d,1H)8.
25,8.55(b,1H)
迄今已知的实施本发明的最好方法是使用实施例3的化合物之混合物和实施例4的化合物。
表3
下表给出通式Ⅰ所包括的实施例化合物
实 R1R2R3R4R5产率 鉴定 备注
施 % 数据
例
1 C(O)OCH3CH3CH2OCOOC2H5CH3CH344 NMR 异构体
CH3C(O)OCH3混合物
2 CH3C(O)OCH3CH2OCOOC2H5CH3CH3NMR 分离的
异构体
3 C(O)CH3CH3CH2OCOOC2H5CH3CH349 NMR 异构体
CH2C(O)CH3混合物
4 C(O)CH3CH3CH2OCOOC2H5CH3CH3NMR 分离的
异构体
5 CH3C(O)CH3CH2OCOOC2H5CH3CH3NMR 分离的
异构体
6 C(O)OCH2CH3H CH2OCOOC2H5CH3CH337 NMR 异构体
H C(O)OCH2CH3混合物
糖浆
含1%(每体积重量)活性物质的糖浆由下列成份制备:
实施例4的化合物 1.0g
糖,粉末状 30.0g
糖精 0.6g
甘油 5.0g
吐温(聚氧乙烯山梨醇的脂肪酸酯) 1.0g
香味剂 0.05g
乙醇96% 5.0g
蒸馏水适量,至最终体积为 100ml
根据实施例,制备了在乙醇和吐温中的化合物之混合物溶液。将糖和糖精溶于60ml温水中,冷却后,向糖溶液中加入活性化合物溶液,再加入甘油和溶于乙醇中的香味剂溶液。混合物用水稀释,至最终体积为100ml。
片剂
含50mg活性化合物的片剂由下列成份制备:
Ⅰ 实施例3的化合物之混合物 500g
乳糖 700g
甲基纤维素 6g
交联的聚乙烯吡咯烷酮 50g
硬脂酸镁 15g
碳酸钠 6g
蒸馏水 适量
Ⅱ 羟基丙基甲基纤维素 36g
聚乙二醇 19g
着色二氧化钛 4g
纯化水 313g
Ⅰ 实施例3的化合物之混合物粉末与乳糖混合,并用甲基纤维素和碳酸钠的水溶液成粒。挤压湿润物质,使其通过筛子,得到的颗粒在烘箱中干燥。干燥后,使颗粒与聚乙烯吡咯烷酮和硬脂酸镁相混合。在造片机中,使用7mm直径的切口,将干燥混合物挤压成片剂核(10000片),每片含50mg活性物质。
Ⅱ 制备在纯化水中的羟基丙基甲基纤维素和聚乙二醇的溶液。二氧化钛分散在溶液中后,在Accela CotaR,Manesty涂层机中,将该溶液喷涂在Ⅰ的片核上。最后得到重量为125mg的片剂。
胶囊
含30mg活性化合物的胶囊可由下列成份制备:
实施例4的化合物 300g
乳糖 700g
微晶纤维素 40g
低取代的羟丙基纤维素 62g
纯化水 适量
活性化合物之混合物与干燥的成份混合,并用磷酸氢二钠溶液成粒。挤压湿润物质,使其通过挤出机,并在流化床干燥机上进行球化处理和干燥。
使用流化床涂层机,先以30g羟丙基甲基纤维素在600g水中的溶液对上面的500g药丸进行涂层。干燥后,药丸用下面给出的二次涂层溶液涂层。
涂层溶液:
邻苯二甲酸羟丙基甲基纤维素酯 70g
鲸蜡醇 4g
丙酮 600g
乙醇 200g
将最后的涂层药丸装入胶囊。
栓剂
应用熔接方法由下列成份制备栓剂。每支栓剂含有40mg活性化合物。
实施例4的化合物之混合物 4g
Witepsol H-15 180g
在41℃温度下,将活性化合物之混合物均匀地与Witepsol H-15相混合。该熔融物按体积注入预制好的栓剂管内,至净重达1.84g。冷却后加热密封栓管。每支栓剂含40mg活性化合物。
生物效果
生物药效率
评价生物药效率是通过计算其中R3是氢的通式Ⅰ化合物(这里定义为化合物A)的血浆浓度曲线下的面积(AUC)之间的商数,血浆来自1)将本发明的相应化合物经十二指肠(id)或口(po)给药的鼠和狗和2)将化合物A通过静脉内(iv)给药的鼠和狗。要使用低的治疗学上相应的剂量。数据在表4中给出。
胃酸分泌的抑制效力
在口服给药的雌鼠以及十二指肠和口服给药的狗中测定抑制胃酸分泌的效力。
效力数据在表4中给出。
对碘摄入甲状腺中的作用
本发明的通式Ⅰ化合物对碘摄入甲状腺中的作用是以通式Ⅰ的相应化合物(其中R3是氢,即通式Ⅰ的代谢化合物)对125I在甲状腺中的累积作用来测定的。
生物试验
对神志清醒雌鼠胃酸分泌的抑制作用。
使用Sprague-Dawley种的雌鼠,雌鼠的胃(腔)内装有插套瘘管,用来收集胃分泌物。试验开始前,外科手术后允许有十四天的恢复期。
分泌实验前20小时内,禁止试验动物吃食,但可以饮水。通过胃插管反复洗胃,皮下注射6ml林格(Ringer)葡萄糖。在2.5小时(1.2ml/h,皮下)内注入五肽促胃酸激素和卡巴可(分别为20和110umol/kgh),以此刺激胃酸分泌;在此时间内,每30分钟收集的胃分泌物算作一份。刺激开始前120分钟,将试验物质或赋形剂以5ml/kg的体积口服给药。胃液试样用0.1mol/l的NaOH滴定至PH7.0,胃酸量以滴定剂体积和浓度的数值计算。根据每组4-7只鼠的平均反应做进一步的计算。从鼠的胃酸产量绝对速率计算出抑制百分率。ED50-数值可从对数剂量-反应曲线上的图解内推得到,或假定所有的剂量-反应曲线具有类似的倾斜率,而从单个剂量实验估计。所得结果是基于药剂/赋形剂给药后第三个小时内的胃酸分泌量。
在雄鼠体内的生物药效率。
使用Sprague-Dawley种的成年雄鼠。在实验前的某一天,麻醉下将所有的鼠装上左颈动脉插管。用于静脉内实验的鼠也在颈静脉中装上插管。(参考V Popovic和P Popovic,J Applphysiol 1960;15,727-728)。用于十二指肠内实验的鼠,也要在其十二指肠的上部装上插管,插管被外置在颈背上。手术后的鼠要单独饲养,在服用试验物质之前,禁止其吃食,但不禁水。在约一分钟内将同样的剂量(4umol/kg)以块状经静脉内和十二指肠给药(2ml/kg)。
在给药后多至4小时的时间里,从颈动脉每隔一段时间重复取出血样(0.1-0.4g)。血样要尽可能快地冷冻,一直冷冻到对试验化合物进行分析。
对化合物A来说,其血液浓度对时间曲线下的面积,AUC,可通过线性梯形法则和无限外推来确定;所谓无限外推就是用后期的消除速率常数去除最后测定的血液浓度。本发明的通式Ⅰ化合物经十二指肠给药后,化合物A的系统生物药效率(F%)可按下式计算:
在神志清醒的狗中的胃酸分泌抑制和生物药效率。
使用任意性别的Harrier狗。在狗身上安装十二指肠瘘管用来将试验化合物或赋形剂引入体内,再装上胃插管或海登海因(Heidenhain)囊用来收集胃分泌物。分泌实验前,这些狗要禁食18小时,但可以自由地饮水。通过4小时二盐酸组胺的注入(12ml/h)刺激胃酸分泌,每次剂量产生个体最大分泌反应量的约80%;每连续30分钟收集的胃液算作一份。开始注入组胺1小时后,将试验物质或赋形剂经口、十二指肠或静脉内以0.5ml/(kg体重)的体积给药。应该指出,在经口给药的情况下,将试验化合物给药于带有海登海因囊的狗的分泌胃酸的主胃上。
通过滴定至PH7.0测定胃液试样的酸度,并计算出胃酸产量。在收集胃液期间,将服用试验物质或赋形剂后的胃酸产量用分数响应表示,而将用药前部分的胃酸产量指定为1.0。由试验化合物和赋形剂引起的分数响应计算抑制百分率。ED50数值可通过对数剂量-响应曲线上的图解内推得到,或在假定所有试验化合物的剂量-响应曲线具有相同倾斜率的情况下从单个剂量试验估计得到。报道的所有结果都基于用药后2小时的胃酸产量。
用药后多至3小时内每隔一段时间取出血样,这些血样用于分析试验化合物在血浆中的浓度。收集后30分钟内,将血浆分开并冷冻,然后进行分析。对化合物A来说,用药后时间从零至3小时的AUC(在血浆浓度-时间曲线下的面积)通过线性梯形法则计算。在将本发明的化合物经口或十二指肠给药后,化合物A的系统生物药效率(F%)按上面鼠的例子中描述的方法计算。
对125I在甲状腺中积累的作用
在雄性Sprague-Dawley鼠中研究125I在甲状腺中的积累作用,实验前这些鼠要禁食24小时。按照Searle,CE等人的实验方案(Biochem J 1950;47:77-81)。
悬浮于0.5%甲基纤维素缓冲液(PH9)中的试验物质,以5ml/(kg体重)的体积通过口服管饲法给药。1小时后,125I(300KBq/kg,3ml/kg)通过腹膜内注射给药。125I给药4小时后,用CO2室息法将动物杀死并放血。将甲状腺连同一段气管解剖出来,放在一支小试管里,在γ射线计数器(LKB-Wallacmodel 1282 Compugamma)中进行放射性分析。抑制百分率根据公式100(1-T/P)计算,其中T和P分别是用试验试剂或对照剂(甲基纤维素缓冲液)处理的动物甲状腺的平均放射强度。用Mann-Whitney U-试验(两尾法)测定出在用试验试剂和对照剂处理的动物之间的统计学意义之差。P<0.05就认为是有意义的。
化学稳定性
在37℃的不同PH值的缓冲水溶液中,本发明化合物的化学稳定性在低浓度下遵守动力学规律。表5中的结果示出在PH7下的半寿期(t1/2),也就是在这段时间后初始化合物的一半量保持不变;以及PH2下的t10%,也就是在这段时间后初始化合物的10%已经降解。
生物实验和稳定性试验结果
表4和表5总结了本发明化合物所得到的试验数据。
表5
稳定性数据
试验化合物的 化学稳定性
实施例编号 在PH7 在PH2
t1/2(h) t10%(h)
1 87 9.5
2 50 6.5
3 51 7.5
4 82 13
5 60 7
6 63 13
Claims (18)
2、根据权利要求1的通式Ⅰ化合物,即5-甲酯基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯和6-甲酯基-5-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯的混合物。
3、根据权利要求1的通式Ⅰ化合物,即5-乙酰基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯和6-乙酰基-5-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯的混合物。
4、根据权利要求1的化合物,即5-甲酯基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
5、根据权利要求1的化合物,即6-甲酯基-5-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
6、根据权利要求1的化合物,即5-乙酰基-6-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
7、根据权利要求1的化合物,即6-乙酰基-5-甲基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑-1-基甲基乙基碳酸酯。
8、根据权利要求1的化合物,其中R3是基团CH2OCOOCH2CH3。
9、根据权利要求1的化合物,其中R1和R2各自是H、甲基或-C(O)R6,其中R6是含1-4个碳原子的烷基或含1-4个碳原子的烷氧基。
10、含有权利要求1的化合物作为活性成份的药物组合物。
11、权利要求1所定义的化合物用于治疗。
12、权利要求1所定义的化合物用于抑制哺乳动物(包括人)的胃酸分泌。
13、权利要求1所定义的化合物用于治疗哺乳动物(包括人)的胃肠炎性疾病。
14、一种抑制胃酸分泌的方法,该方法通过给哺乳动物(包括人)服用权利要求1定义的化合物。
15、一种通过服用权利要求1定义的化合物治疗哺乳动物(包括人)的胃肠炎性疾病的方法。
16、权利要求1的化合物在生产抑制哺乳动物(包括人)胃酸分泌药物中的用途。
17、权利要求1的化合物在生产治疗哺乳动物(包括人)的胃肠炎性疾病药物中的用途。
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- 1991-06-20 CN CN91105024A patent/CN1058212A/zh active Pending
- 1991-06-20 CZ CS911894A patent/CZ279772B6/cs unknown
- 1991-06-20 IS IS3721A patent/IS3721A7/is unknown
-
1992
- 1992-11-27 OA OA60306A patent/OA09682A/en unknown
- 1992-12-10 NO NO924775A patent/NO924775D0/no unknown
- 1992-12-18 BG BG097200A patent/BG97200A/bg unknown
- 1992-12-18 FI FI925766A patent/FI925766A/fi not_active Application Discontinuation
-
1993
- 1993-08-27 LV LV931045A patent/LV10953A/xx unknown
- 1993-12-30 LT LTIP1712A patent/LT3952B/lt not_active IP Right Cessation
- 1993-12-30 LT LTIP1713A patent/LT3977B/lt not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101336240B (zh) * | 2006-04-14 | 2011-06-29 | 卫材R&D管理有限公司 | 亚磺酰基苯并咪唑化合物的盐、其结晶及无定形物 |
Also Published As
Publication number | Publication date |
---|---|
OA09682A (en) | 1993-05-15 |
CZ279772B6 (cs) | 1995-06-14 |
LV10953A (lv) | 1995-12-20 |
AP215A (en) | 1992-09-02 |
AP9100285A0 (en) | 1991-07-31 |
LT3977B (en) | 1996-06-25 |
ZA914296B (en) | 1992-03-25 |
ZA914297B (en) | 1992-03-25 |
YU104191A (sh) | 1994-01-20 |
IS3721A7 (is) | 1991-12-21 |
NO924775L (no) | 1992-12-10 |
WO1991019711A1 (en) | 1991-12-26 |
NO924775D0 (no) | 1992-12-10 |
HUT62881A (en) | 1993-06-28 |
FI925766A0 (fi) | 1992-12-18 |
IE912025A1 (en) | 1992-01-01 |
CS189491A3 (en) | 1992-04-15 |
AU649453B2 (en) | 1994-05-26 |
EP0535081A1 (en) | 1993-04-07 |
IL98470A0 (en) | 1992-07-15 |
LT3952B (en) | 1996-05-27 |
JPH05507713A (ja) | 1993-11-04 |
HU9204033D0 (en) | 1993-03-29 |
CA2083714A1 (en) | 1991-12-21 |
RO110493B1 (ro) | 1996-01-30 |
PT98035A (pt) | 1992-03-31 |
LTIP1713A (en) | 1995-08-25 |
AU8009791A (en) | 1992-01-07 |
FI925766A (fi) | 1992-12-18 |
TW216418B (zh) | 1993-11-21 |
SE9002206D0 (sv) | 1990-06-20 |
BG97200A (bg) | 1993-12-24 |
TNSN91049A1 (fr) | 1992-10-25 |
NZ238546A (en) | 1994-03-25 |
LTIP1712A (en) | 1995-08-25 |
MA22199A1 (fr) | 1992-04-01 |
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