CN1031827C - 取代的苯并咪唑的制备方法 - Google Patents
取代的苯并咪唑的制备方法 Download PDFInfo
- Publication number
- CN1031827C CN1031827C CN92114364A CN92114364A CN1031827C CN 1031827 C CN1031827 C CN 1031827C CN 92114364 A CN92114364 A CN 92114364A CN 92114364 A CN92114364 A CN 92114364A CN 1031827 C CN1031827 C CN 1031827C
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- Prior art keywords
- methyl
- compound
- formula
- benzoglyoxaline
- pyridyl
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- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
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- 229960002317 succinimide Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 150000003682 vanadium compounds Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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Abstract
式I的新型化合物,
式中R1和R2不同,各是甲基、-C(O)CH3或-C(O)OCH3,因而R1或R2中有一个总是甲基;M是生理上可接受的阳抗衡离子;以及所述化合物的制备方法,含有所述化合物作为活性组分的药物组合物,和这些化合物在医学上的使用。
Description
本发明的目的是提供能抑制外原或内源刺激的胃酸分泌从而用于预防和治疗消化系统溃疡的新型化合物。
本发明也涉及本发明的化合物对抑制哺乳动物包括人体的胃酸分泌的用途。在更普遍的意义上,本发明的化合物可用于预防和治疗胃肠炎性疾病,以及哺乳动物包括人体内与胃酸有关的疾病,例如胃炎、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。此外,这些化合物还可用于治疗其它需要胃抗分泌效应的胃肠失调,如用于胃泌素瘤(gastrinomas)患者和急性上胃肠出血患者。它们也可用于处在强化护理情况下的患者,并在手术前后用以防止酸吸入和紧张性溃疡作用。本发明的化合物也可用于治疗和预防哺乳动物包括人体的炎症,尤其涉及溶菌酶的炎症。可以具体提到的炎症是类风湿性关节炎和痛风。本发明也涉及含有本发明的化合物作为活性成分的药物组合物。另一方面,本发明涉及这一类新化合物的制备工艺,并涉及使用这些活性化合物制备上述医学用途的药物组合物。
本发明的化合物不会阻碍甲状腺对碘的摄取。早些时候已在本公司的若干文书中披露本发明者正在研究甲状腺毒性取决于这些化合物是否亲脂。本发明者现已意外地发现,亲脂性并不是决定性参数。这些请求获得专利权的化合物,包括稍微亲水的化合物,不产生任何甲状腺毒性效应,同时具有高的酸分泌抑制效应。
本发明的化合物在水中也将显示高溶解度和高化学稳定性。
类似的二取代2-〔〔3,4-二烷氧基-2-吡啶基)甲基〕亚磺酰)-1H-苯并咪唑-1-基化合物详见PCT/SE91/00415,该文献在本专利办理瑞典基本申请时尚不能公开得到,但在此后不久就发表了。
在许多专利文书中公开了旨在抑制胃酸分泌的苯并咪唑衍生物。其中可以提到GB1,500,043;GB1,525,958;US4,182,766;US4,255,431;US4,599,347;BE898,880;EP124,495;EP208,452;EP221,041;EP279,149;EP176,308和Derwent文摘87-294449/42。US4,359,465中公开了建议用于治疗或预防特殊胃肠炎性疾病的苯并咪唑衍生物。
本发明的化合物能有效地用作哺乳动物包括人的胃酸分泌抑制剂,同时不阻碍甲状腺对碘的摄取。
此外,本发明的化合物在水中显示高溶解度和高化学稳定性。
因此,本发明的化合物尤其适用于不经肠的,特别是经静脉的和经肌肉的给药。高溶解度和化学稳定性也使得本发明的化合物适合于其它给药途径,例如经口和经直肠给药。
化学式I的化合物的结构异构体可以单独使用,或者以相等或不相等混合物使用。
化学式I的本发明化合物在硫原子上有一个不对称中心,即以两种光学异构体(对映体)形式存在。两者的纯对映体外消旋混合物(每种对映体各50%)和不相等混合物都属于本发明的范围。
可以认为化学式I的化合物在发挥其作用之前就被代谢。这样的代谢发生于苯并咪唑核1位上的N取代基,即含磷基团。
制备
本发明的化合物可按照如下方法制备:
所得到的盐可转变成一种医疗上适用的盐,例如分别通过添加NaOH和KOH或通过离子交换,转变成钠盐和钾盐。
这个氧化可以用一种氧化剂进行,例如用硝酸,过氧化氢、(任选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、硝酸铵高铈、溴、氯、和硫酰氯。氧化通常在一种溶剂如卤代烃、醇、醚、酮中进行。
也可以利用氧化酶进行酶法氧化,或利用适当的微生物进行微生物法氧化。
所得到的结构异构体可以用结晶法或色谱法分离。
所得到的外消旋物可以按照已知的方法,如用光学活性溶剂重结晶,进行分离。
为了临床应用,将本发明的化合物配制成可供经口、经直肠、非经肠或其它方式给药的药物配方。尤其好的是,将本发明的化合物配制成可供非经肠给药的药物配方。这种药物配方含有一种与医药上可接受的载体组合的本发明化合物。载体形式可以是固体、半固体或液体稀释剂,或一种胶囊。这些药物制剂是本发明的进一步目的。活性化合物的含量通常为制剂的0.1~95%(重量),在非经肠用途的制剂中为0.2~20%(重量),而在经口给药的制剂中为1~50%(重量)。
在以经口给药剂量单元形式含有本发明化合物的药物配方的制备中,所选择的化合物可以混合一种固体粉末载体,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,或另一种适用载体,并可混合润滑剂如硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠和聚乙二醇蜡。然后将混合物加工成颗粒或压成片剂。含有亚砜的颗粒或片剂可以包覆一种肠溶衣涂料,只要该剂量形式保留在胃中,这种涂料就能保护活性化合物免于酸催化降解。肠溶衣涂料选自医药上可接受肠溶衣涂层材料,如蜂蜡、虫胶,或阴离子型成膜聚合物,如乙酸邻苯二甲酸纤维素、邻苯二甲酸羟丙基甲基纤维素,部分甲酯化的甲基丙烯酸聚合物等,如果愿意,还可并用一种适当增塑剂。为了区别有不同活性化合物或者不同存在量的活性化合物的片剂或颗粒,可以在这种涂料中加入各种染料。
软胶囊可以用含有本发明的一种或多种活性化合物,植物油、脂肪或其它适用软胶囊赋形剂的混合物的胶囊制备。软胶囊也可以按如上所述包覆肠溶衣。硬胶囊可以含有活性化合物的颗粒或包覆了肠溶衣的颗粒。硬胶囊也可以含有与固体粉末载体如乳糖、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组合的活性化合物。硬胶囊可以按如上所述包覆肠溶衣。
经直肠给药的剂量单元可以制备成含有与中性脂肪基混合的活性物质的栓剂形式,或可将其制备成含有与植物油、石蜡油或其它适用直肠胶囊赋形剂混合的活性物质的直肠胶囊剂形式,或可将其制备成成品微灌肠剂形式,或可将其制备成只需在给药前用适当溶剂重新调制的干微灌肠剂配方形式。
经口给药的液体制剂可制备成糖浆或悬浮液形式,例如含有0.2%至2%(重量)活性组分的溶液或悬浮液,其余部分为糖或糖醇及乙醇、水、甘油、丙二醇和聚乙二醇的混合物。如果希望,这样的液体制剂还可以含有着色剂、香味剂、糖精和羧甲基纤维素或其它增稠剂。经口给药的液体制剂也可以制备成能在使用前用适当溶剂重新调制的干粉剂形式。
非经肠给药的溶液可以制备成本发明的一种化合物在医药上可接受的溶剂中的溶液,其浓度较好为0.1%至10%(重量)。这些溶液也可含有稳定剂和/或缓冲剂,并可制造成不同的单元剂量安瓿剂或管形瓶剂。非经肠给药的溶液也可以制备成能在使用前临时用适当溶剂重新调制的干制剂。
这种活性物质的典型日剂量差异很大,并将取决于各种因素,例如每位患者的个人需要,给药途径和疾病。一般来说,经口和非经肠剂量范围将是5~500毫克活性物质/天。
以下实例说明本发明。
实例1磷酸〔5-乙酰基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐,或磷酸〔6-乙酰基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐的制备。
在搅拌下将三丁胺(1.7毫升,7.0毫摩尔)加入到85%磷酸(0.24毫升,3.6毫摩尔)的乙醇(2毫升)溶液中。蒸发溶剂,残留物用二氯甲烷(2.5毫升)收取。有机相用硫酸钠干燥、过滤和蒸发。把5-乙酰基-1-氯甲基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑或者6-乙酰基-1-氯甲基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑(0.12克,0.28毫摩尔)和以上制备的磷酸三丁铵盐溶于二氯甲烷(6毫升)中。把二氯甲烷蒸出,残留物在60℃的水浴上加热5分钟。把残留物溶于二氯甲烷(6毫升)中,再次将二氯甲烷蒸出,油状产品混合物在。0℃水浴上加热5分钟。这个步骤重复4次,直至反应完成。残留物溶于二氯甲烷(4毫升)中,用3份(4毫升)水洗涤。在搅拌下将氢氧化钠溶液(0.2M)添加到有机相中,同时仔细控制水相的PH。当水相的PH达到9~9.5时,将混合物离心分离。水相用3份(4毫升)二氯甲烷洗涤,然后冻干,给出40毫克27%标题化合物。
NMR(核磁共振)数据在以下给出。
实例2磷酸〔5-甲氧甲酰-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐,或磷酸(6-甲氧甲酰-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基〕甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐的制备。
在搅拌下将三丁胺(1.8毫升,7.8毫摩尔)加入到85%磷酸(0.26毫升,3.9毫摩尔)的乙醇(2.5毫升)溶液中。蒸发溶剂,残留物用二氯甲烷(3毫升)收取。有机相用硫酸钠干燥、过滤和蒸发。把5-甲氧甲酰-1-氯甲基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑或6-甲氧甲基-1-氯甲基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑(0.14克,0.32毫摩尔)和以上制备的磷酸三丁铵盐溶于二氯甲烷(6.5毫升)中。将二氯甲烷蒸出,残留物在60℃水浴上加热5分钟。把残留物溶于二氯甲烷(6.5毫升)中,再次蒸出二氯甲烷,油状产物混合物在60℃水浴上加热5分钟。这个步骤重复4次,直至反应完成。残留物溶于二氯甲烷(4毫升)中,用3份(4毫升)水洗涤。在搅拌下将氢氧化钠溶液(0.2M)添加到有机相中,同时仔细控制水层的pH。当水相的PH达到9~9.5时,将混合物离心分离。水层用3份(4毫升)二氯甲烷洗涤,然后冻干,给出11毫克6%标题化合物。
NMR数据在以下给出。
表1
水的质子定为4.80。
实例 溶剂 NMR数据δppm
1 D2O 2.67(s,3H),2.78(s,3H),3.85
(s,3H),
(300MHz) 3.98(s,3H),4.98(d,1H),5.08(d,
1H),5.98(m,2H),7.15(d,1H),7.78
(s,1H),8.12(d,1H),8.18(s,1H).
2 D2O 2.75(s,3H),3.83(s,3H),3.97(s,
3H),
(300MHz) 4.05(s,3H),4.98(d,1H),5.08(d,
1H),5,95(m,2H),7.15(d,1H),7.83
(s,1H),8.15(d,1H),8.28(s,1H).
中间体制备
实例I1
5-乙酰基-1-羟甲基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑或6-乙酰基-1-羟甲基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑的制备
向5-乙酰基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑(2.00克,5.4毫摩尔)和二氯甲烷(100毫升)的混合物中添加5M甲醛水溶液(5.0毫升,25毫摩尔)。混合物摇荡3分钟。分离后,有机溶液用Na2SO4干燥、减压蒸发,给出一种红色浆状物(1.7克,78%)。产品主要含标题化合物的结构异构体以及少量起始原料。
NMR数据在以下给出。
实例I2
5-乙酰基-1-氯甲基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑或6-乙酰基-1-氯甲基-5-甲基-2-〔〔(3,4二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑的制备
5-乙酰基-1-羟甲基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑和6-乙酰基-1-羟甲基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑(1.7克,4.2毫摩尔)在乙腈(40毫升)中的悬浮液冷却至-15℃。按给定的顺序滴加亚硫酰二氯(0.50克,4.2毫摩尔)和三乙胺(0.50克,4.2毫摩尔)。混合物在室温搅拌5分钟,然后减压蒸发。残留物用乙酸乙酯和二氯甲烷的混合物作为洗脱剂,在硅胶(70克)上进行色谱分离。乙酸乙酯的数量在色谱分离期间是增加的。产品0.14克(8%)主要由结构异构体之一组成。
NMR数据在以下给出。
实例I3
5-甲氧甲酰-1-羟甲基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑或6-甲氧甲酰-1-羟甲基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑的制备
向5-甲氧甲酰-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑(0.34克,0.87毫摩尔)的二氯甲烷(25毫升)溶液中,添加5M甲醛水溶液(1.7毫升,8.5毫摩尔)。混合物摇荡3分钟。分离后,有机溶液用Na2SO4干燥、减压蒸发,给出一种红色浆状物(0.36克,100%)。产品组成主要是标题化合物的结构异构体之一及少量起始材料。
NMR数据在以下给出。
实例I4
5-甲氧甲酰-1-氯甲基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑或6-甲氧甲酰-1-氯甲基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑的制备
将5-甲氧甲酰-1-羟甲基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑和6-甲氧甲酰-1-羟甲基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑(0.36克,0.87毫摩尔)的乙腈(20毫升)溶液冷却到-20℃。按给定的顺序滴加亚硫酰二氯(0.066毫升,0.9毫摩尔)和三乙胺(0.10克,1.0毫摩尔)。混合物在室温下搅拌5分钟,然后减压蒸发。残留物用乙酸乙酯和二氯甲烷的混合物作为洗脱剂在硅胶(20克)上进行色谱分离。乙酸乙酯的数量在色谱分离期间是增加的。产品0.16克(43%)的组成主要是结构异构体之一。
NMR数据在以下给出。
表2
实例 溶剂 NMR数据δppm
I1 CDCl3 2.60(s,3H),2.70(s,3H),3.90(s,3H),
3.95(s,3H),4.8-5.1(m,2H),5.70(d,
1H),6.10(d,1H)6.75(d,1H),7.40(s,
1H),
7.90(d,1H),8.10(s,1H).I2 CDCl3 2.66(s,3H),2.72(s,3H),3.90(s,3H),
3.91(s,3H),4.91(d,1H),5.02(d,1H),
6.23(d,1H),6.55(d,1H),6.80(d,1H),
7.39(s,1H),8.15(d,1H),8.20(s,1H).I3 CDCl3 2.75(s,3H),3.8-4.0(m,9H),4.7-5.1(m,
2H),5.75(d,1H),6.10(d,1H),
6.75(d,1H),7.40(s,1H),7.90(d,1H),
8.30(s,1H).I4 CDCl3 2.79(s,3H),3.89(s,3H),3.91(s,3H),
3.93(s,3H),4.90(d,1H),5.02(d,1H),
6.23(d,1H),6.57(d,1H),6.80(d,1H),
7.39(s,1H),8.15(d,1H),8.40(s,1H).
表3
化学式I中所包括的化合物的实例列于下表。
产率 鉴定
实例 R1 R2 M % 数据 备注1 CH3 C(O)CH3
或 Na+ 27 NMR 分离的
异构体
C(O)CH3 CH32 CH3 C(O)OCH3
或 Na+ 6 NMR 分离的
异构体
C(O)OCH3 CH33 C(O)CH3 CH3
或 Na+ - - 分离的
异构体
CH3 C(O)CH34 C(O)OCH3 CH3
或 Na+ - - 分离的
异构体
C(O)OCH3 CH35 CH3 C(O)CH3 Na+ - - 异构体
混合物
C(O)CH3 CH36 CH3 C(O)OCH3 Na+ - - 异构体
C(O)OCH3 CH3 混合物
目前已知的实施本发明的最佳方式是使用按照实例2的一种化合物。
含有本发明的化合物作为活性组分的医药制剂,用下列配方加以说明。
糖浆
从下列组分制备一种含1%(重量/体积)活性物质的糖浆:
按照实例1的化合物 1.0克糖、粉末 30.0克糖精 0.6克甘油 5.0克香味剂 0.05克乙醇,96% 5.0克蒸馏水,补足到最终体积为 100毫升
糖和糖精溶于60克温水中。冷却后,将活性化合物添加到糖溶液中,并添加溶于乙醇中的香味剂溶液。混合物用水稀释到最终体积为100毫升。
肠溶衣包覆的片剂
从下列组分制备一种含有20毫克活性化合物的,包覆了肠溶衣的片剂:I 按照实例2的化合物混合物 200克
乳糖 700克
甲基纤维素 6克
交联的聚乙烯基吡咯烷酮 50克
硬脂酸镁 15克
碳酸钠 6克
蒸馏水 适量II 乙酸邻苯二甲酸纤维素 200克
鲸蜡醇 15克
异丙醇 2000克
二氯甲烷 2000克I按照实例2的化合物粉末与乳糖混合,并用甲基纤维素和碳酸钠的水溶液造粒。湿物料被强制通过一个筛子,颗粒在炉中干燥。干燥后,颗粒与聚乙烯基吡咯烷酮和硬脂酸镁混合。在压片机上用6毫米直径冲压器,把干混合物压成每片含20毫克活性物质的片芯(10000片)。Ⅱ乙酸邻苯二甲酸纤维素和鲸蜡醇的异丙醇/二氯甲烷溶液用一台Accela CotaR,Manesty涂布设备喷洒到这些片上。得到最后片重为110毫克。
经静脉给药的溶液
从下列组分制备一种每毫升含4毫克活性化合物的,经静脉用的非经肠配方:按照实例2的化合物 4克无菌水,补足到最终体积为 1000毫升
活性化合物溶于水中,补足到最终体积为1000毫升。溶液通过一个0.22微米过滤器过滤,立即分配到10毫升无菌安瓿中。将安瓿密封。
临使用前,把溶于10毫升无菌水中的活性化合物转移到100毫升标准输注盐水溶液中,使总体积为约110毫升。这种溶液用约30分钟的时间以经静脉输注形式给药。
片剂
从下列组分制备含有30毫克活性化合物的片剂:按照表3中实例3的化合物 300克乳糖 700克甲基纤维素 6克交联的聚乙烯基吡咯烷酮(PVP-XL) 62克磷酸氢二钠 2克硬脂酸镁 30克纯水 适量
活性化合物与乳糖和部分PVP-XL混合,用甲基纤维素和磷酸氢二钠的溶液造粒。湿物料被强制通过一个筛子,在流态床干燥器中干燥。在添加硬脂酸镁和其余PVP-XL并混合后,把药剂混合物压成平均重量为110毫克的片剂,每片含30毫克活性化合物。
肠溶衣包覆的片剂
对500克上述片剂进行肠溶衣包覆。下述组成的一种溶液,用Wurster涂布技术喷洒到流态床设备中的片剂上。
涂布溶液:乙酸邻苯二甲酸纤维素 40克鲸蜡醇 2克异丙醇 400克二氯甲烷 400克
最后的包覆片剂重117毫克。
栓剂
用熔接步骤从下列组分制备栓剂。每个栓剂含40毫克活性化合物。按照表3中实例4的化合物混合物 4克Witepsol H-15 180克
活性化合物混合物在41℃的温度与Witepsol H-15均匀混合。熔融物料整体灌装到预制的栓剂包中,达到净重为1.84克。冷却后,将这些包热封。每个栓剂含有40毫克活性化合物。
糖浆
从下列组分制备一种含有1%活性物质的糖浆:按照表3中实例3的化合物 1.0克糖,粉末 30.0克糖精 0.6克香味剂 0.05克乙醇,96% 5.0克纯化水,补足到 100毫升
糖和糖精溶于60克温水中。冷却后,将活性化合物添加到糖溶液中,并添加溶于乙醇中的香味剂溶液。混合物用水稀释到最终体积为100毫升。
经静脉或经肌肉注射的溶液按照实例1的化合物 60克注射用水,配成 1000毫升
把活性化合物溶于水中,达到最后体积为1000毫升。溶液通过一个无菌0.22微米过滤器过滤,用无菌法分配到1毫升无菌安瓿中。将安瓿密封。
经静脉输注的配方按照实例2的无菌化合物 60毫克无菌注射管形瓶和塞子
把无菌活性化合物60毫克放进10毫升无菌注射管形瓶中。管形瓶用无菌橡皮塞塞住。在无菌生产区的无菌条件下,以垂直层流方式进行vokale灌装操作。
生物效应
对甲状腺摄取碘的影响
在本发明范围内化学式I的化合物对甲状腺摄取碘的影响,是用本发明范围内的化合物代谢中所产生的活性化合物对125I在甲状腺中的积累的影响来衡量的。
对125I在甲状腺中的积累的影响
125I在甲状腺中的积累是用试验前禁食24小时的雄性Sprague-Dawley大鼠进行研究的。采用Searle,CE等人的实验方案(Biochem J,1950;47:77-81)。
悬浮于0.5%缓冲(pH9)甲基纤维素中的试验物质,用经口管饲法以5毫升/千克体重的体积给药。1小时后,125I(300千贝克勒尔/千克,3毫升/千克)经腹膜内注射给药。125I给药后4小时,用CO2室息法杀死这些动物,并放血。甲状腺连同一段气管一起切下来,放在一根小试管中用γ计数器(LKB-Wallacmodel 1282 Compugamma)测定放射活性。抑制百分率是按照公式100(1-T/P)计算的,式中T和P分别是用试验剂和无效对照剂(缓冲的甲基纤维素)处理的动物的甲状腺的平均放射活性。试验剂和无效对照剂处理的动物之间差别的统计意义是用Mann-Whitney U试验(双尾)评价的。P<0.05被认为有意义。
生物试验结果
表4列出本发明的化合物可得的试验数据。
表4生物试验数据
试验化合物 400微摩尔/千克对甲状腺摄取(n=动物数目) 125I的抑制百分率实例1、3和5的活性 -7代谢物(n=5)实例2、4和6的活性 0代谢物(n=5)
Claims (8)
2.按权利要求1的方法,其中制得的化合物中的M是Na、K、Ag或三烷基铵。
3.按照权利要求1的方法,其中生成的产物是磷酸〔5-乙酰基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐和磷酸〔6-乙酰基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐的混合物。
4.按照权利要求1的方法,其中生成的产物是磷酸〔5-甲氧甲酰-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐和磷酸〔6-甲氧甲酰-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐的混合物。
5.按照权利要求1的方法,其中制得的化合物是磷酸〔5-乙酰基-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐。
6.按照权利要求1的方法,其中制得的化合物是磷酸〔6-乙酰基-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐。
7.按照权利要求1的方法,其中制得的化合物是磷酸〔5-甲氧甲酰-6-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐。
8.按照权利要求1的方法,其中制得的化合物是磷酸〔6-甲氧甲酰-5-甲基-2-〔〔(3,4-二甲氧基-2-吡啶基)甲基〕亚磺酰〕-1H-苯并咪唑-1-基〕甲酯二钠盐。
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- 1992-12-08 AU AU31752/93A patent/AU665043B2/en not_active Ceased
- 1992-12-08 IL IL104025A patent/IL104025A0/xx unknown
- 1992-12-08 WO PCT/SE1992/000844 patent/WO1993012124A1/en not_active Application Discontinuation
- 1992-12-08 HU HU9401840A patent/HUT68270A/hu unknown
- 1992-12-08 JP JP5510832A patent/JPH07502503A/ja active Pending
- 1992-12-08 CA CA002124689A patent/CA2124689A1/en not_active Abandoned
- 1992-12-08 NZ NZ246220A patent/NZ246220A/en unknown
- 1992-12-14 AP APAP/P/1992/000463A patent/AP397A/en active
- 1992-12-15 MX MX9207269A patent/MX9207269A/es unknown
- 1992-12-16 MA MA23036A patent/MA22746A1/fr unknown
- 1992-12-18 SI SI19929200402A patent/SI9200402A/sl unknown
- 1992-12-18 TN TNTNSN92115A patent/TNSN92115A1/fr unknown
- 1992-12-18 IS IS3960A patent/IS3960A/is unknown
- 1992-12-18 CN CN92114364A patent/CN1031827C/zh not_active Expired - Fee Related
-
1994
- 1994-06-14 NO NO942230A patent/NO942230D0/no unknown
- 1994-06-17 FI FI942912A patent/FI942912A/fi not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
IS3960A (is) | 1993-06-20 |
NO942230L (no) | 1994-06-14 |
AU3175293A (en) | 1993-07-19 |
IL104025A0 (en) | 1993-05-13 |
SK73594A3 (en) | 1995-02-08 |
AU665043B2 (en) | 1995-12-14 |
ZA928836B (en) | 1993-07-05 |
HRP921400A2 (en) | 1994-08-31 |
MA22746A1 (fr) | 1993-07-01 |
MX9207269A (es) | 1993-06-01 |
CA2124689A1 (en) | 1993-06-24 |
FI942912A0 (fi) | 1994-06-17 |
AP397A (en) | 1995-08-14 |
KR940703840A (ko) | 1994-12-12 |
NZ246220A (en) | 1996-02-27 |
SI9200402A (en) | 1993-06-30 |
CZ146794A3 (en) | 1996-02-14 |
YU101692A (sh) | 1995-10-03 |
WO1993012124A1 (en) | 1993-06-24 |
SE9103776D0 (sv) | 1991-12-19 |
IS4079A (is) | 1993-06-20 |
TW224100B (zh) | 1994-05-21 |
HU9401840D0 (en) | 1994-09-28 |
FI942912A (fi) | 1994-06-17 |
CN1073446A (zh) | 1993-06-23 |
NO942230D0 (no) | 1994-06-14 |
TNSN92115A1 (fr) | 1993-06-08 |
EP0628049A1 (en) | 1994-12-14 |
JPH07502503A (ja) | 1995-03-16 |
AP9200463A0 (en) | 1993-01-31 |
HUT68270A (en) | 1995-06-28 |
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