CN1039419A - 呋喃衍生物制备方法 - Google Patents
呋喃衍生物制备方法 Download PDFInfo
- Publication number
- CN1039419A CN1039419A CN89104959A CN89104959A CN1039419A CN 1039419 A CN1039419 A CN 1039419A CN 89104959 A CN89104959 A CN 89104959A CN 89104959 A CN89104959 A CN 89104959A CN 1039419 A CN1039419 A CN 1039419A
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- Prior art keywords
- bismuth
- methyl
- acid
- title complex
- salt
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
本发明涉及由雷尼替丁(ranitidine)与铋同一种羧酸的配合物所成的盐以及这些盐的溶剂化物。适用的羧酸为柠檬酸、酒石酸及松蕈三酸。
这些盐适用于医治胃肠机能紊乱,特别是胃十二指肠症状。该等盐显示与雷尼替丁有关的抑分泌活性,还有抗Campylobacter pylori的抗菌活性,也具有细胞保护性能。
Description
本发明涉及对组胺受体有作用的呋喃衍生物盐类,其制备方法,含有这些盐的药物组合物以及在治疗中的用途。更具体讲是涉及与羧酸的铋配合物形成的ranitidine(雷尼替丁)盐。
雷尼替丁是下列化合物的批准用名:N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺,它及它的生理合格盐在英国专利1565966中有所描述,在该专利中还提到与无机和有机酸形成的生理合格盐,这些盐包括盐酸盐、氢溴酸盐、硫酸盐以及与脂族单羧酸及二羧酸所成的盐,如乙酸盐,马来酸盐和富马酸盐。
雷尼替丁是强效的组胺H2拮抗剂,其盐酸盐形式广泛应用于治疗降低胃酸后有利的那些症状。这类症状包括十二指肠及胃溃疡,反流食管炎,Zollinger-Ellison症状。雷尼替丁还可在外科手术中起预防作用,以及用于治疗已知组胺是介体的变应及发炎症状。
一些铋盐和制剂,如柠檬酸铋、柠檬酸铋和柠檬酸铵,酒石酸铋钠,酸式酒石酸铋钠,铋的酸式溶液,铋的浓溶液以及柠檬酸铋和铵的溶液,例如在英国药典(1949)中所述,久已用作抗酸剂,用于治疗胃酸过多及消化不良。此外,在发明组胺H2-拮抗剂之前,这些铋制剂也用于治疗胃肠道溃疡,现在它们已基本上为前者所取代。
近年来已得到证据,Campylobacter pylori是与组织性胃炎、非溃疡性消化不良及胃酸过少症有关系的,并可能涉及到胃及十二指肠溃疡疾病的发病机制。
Campylobacter pylori对于铋化合物有易感性,例如次柠檬酸铋(例如是二柠檬酸根合铋酸三钾的形式)和次水杨酸铋。
上面提出的铋化合物中有许多是酸式配合物,是由铋与一种羧酸如柠檬酸或酒石酸或其盐与氨或一种碱金属所形成。现已发现,碱性的H2-受体拮抗剂雷尼替丁将与这些配合物形成盐,并且所形成的产物具有有用和有益的活性。
本发明是提供由雷尼替丁和铋与一种羧酸的配合物所成的新型盐,以及这些盐的溶剂化物。适用的羧酸是与铋形成配合物,并且这些配合物又能与雷尼替丁形成盐的那些羧酸。
用于本发明能与铋形成铋-羧酸配合物的羧酸例如可以是除含有用于与雷尼替丁形成盐的羧基之外,至少还含三个官能团的羧酸。关于所述另外至少三个官能团,例如可以是羧基和/或羟基,它们应能与三价铋配合而形成三价铋配合物。
对于羧酸能形成旋光和或几何异构体的场合,本发明是意指包括外消旋物在内的所有旋光异构体和/或几何异构体。溶剂化物,包括水合物也包括在本发明范围内。
适用于按本发明与铋形成配合物的羧酸有柠檬酸、酒石酸和乙二胺四乙酸,其它适用的羧酸有丙基柠檬酸和松蕈三酸,以酒石酸,特别是柠檬酸为优选。松蕈三酸是本发明的另一种优选原料。
按本发明的具体盐有:N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-丙烷三羧酸铋(3+)配合物亦称为雷尼替丁柠檬酸铋;N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-硝基-1,1-乙二胺[(R-R*R*)]-2,3-二羟基丁二酸铋(3+)配合物,亦称为雷尼替丁酒石酸铋;N-[2[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-十九烷三羧酸铋(3+)配合物,亦称为雷尼替丁松蕈三酸铋;还有N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺N,N′-亚乙基双[N-(羧甲基)甘氨酸]铋(3+)配合物,亦称为雷尼替丁乙二胺四乙酸铋。
按本发明的优选盐为N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-丙烷三羧酸铋(3+)配合物,亦称为雷尼替丁柠檬酸铋;N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-硝基-1,1-乙二胺(R-R*R*)]-2,3-二羟基丁二酸铋(3+)配合物,亦称为雷尼替丁酒石酸铋。
按本发明另一优选盐为N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-十九烷三羧酸铋(3+)配合物,亦称为雷尼替丁松蕈三酸铋。
本发明特别优选的化合物是雷尼替丁柠檬酸铋。
本发明的这些盐具有治疗以下病症的有利综合效果:胃肠机能紊乱,特别是消化性溃疡症和其它胃十二指肠症状,例如胃炎及非溃疡性消化不良。
因此,本发明的盐具有与雷尼替丁有关的H2-拮抗剂抑制分泌性能,还具有抵御Campylobacter pylori的抗菌活性。此外,本发明的盐还具有细胞保护性能。它们也显示抑制人类胃蛋白酶的活性,特别是能抑制胃蛋白酶1,这是与消化性溃疡有关的胃蛋白酶同功酶。关于本发明化合物的抑制分泌活性已在Heidenhain pouch狗的活体内抗组胺诱致的胃酸分泌试验中显示有效。关于在活体外进行的此等盐对于Campylobacterpylori的抗菌活性试验以及抑人类胃蛋白酶试验亦显示有效。在大身活体内由此等盐抑制乙醇引致胃损伤试验也显示有效。
本发明的盐还有一项特征,就是具水溶性,并且水溶液稳定。在一般情况下,许多铋盐和铋配合物,包括与用于本发明形成盐的那些羧酸所成的配合物都是不溶性的。例如,柠檬酸铋的溶解度(中性水溶液中)仅为0.2%(w/v),而雷尼替丁柠檬酸铋在水中溶解度达到50%(w/v)以上。
因此,本发明盐的所述性质,例如雷尼替丁柠檬酸铋的性质就可以说明它们是特殊的化学实体物质,而与雷尼替丁同羧酸和铋所成配合物的简单混合物(例如等摩尔加混物)是迥然不同的。
本发明的盐与雷尼替丁同羧酸与铋所成配合物的简单混合物所得红外光谱也是不同的。所以,从雷尼替丁与羧酸-铋配合物的简单混合物到本发明的盐是发生了重大的光谱变化。例如雷尼替丁与柠檬酸铋简单混合物的红外光谱在νmax1131、988和603cm-1位置有大的峰,而在雷尼替丁柠檬酸铋就没有这些峰。关于本发明的盐的制备可以在适当溶剂例如水中,将雷尼替丁与适当的铋-羧酸配合物(例如柠檬酸铋或柠檬酸铋铵反应,然后从溶液中分离出所形成的盐。
按本发明由雷尼替丁与铋-羧酸配合物形成盐的另一方案,包括将由雷尼替丁与铋-羧酸配合物所得的盐溶剂化。
按本发明提供雷尼替丁柠檬酸铋的另一方案,包括将雷尼替丁与铋-柠檬酸配合物的反应产物进行溶剂化。
按本发明由雷尼替丁与适当铋-羧酸配合物反应而成盐的方法是优选在升温条件下,例如40-100℃范围进行。反应完毕后(例如由pH测定达到中性和/或产物能完全溶解),将该溶液或悬浮液冷却并过滤,蒸发滤液,剩余物用醇例如甲醇或乙醇或酮例如丙酮或醚例如乙醚进行萃取并进行研制。另外的方式是将反应混合物直接蒸发,然后萃取并研制所得剩余物。还有一种方式是将滤液喷雾干燥,或将滤液(任选在例如用水稀释后)加入到高温的适当反溶剂中(例如一种醇,例如乙醇,例如在回流温度),从而使所得产物沉淀。
中间体铋-羧酸配合物一般可按英国药典(1949)所述方法制备。例如,可将一种适当铋盐(例如氧硝酸铋)和适当的羧酸(例如柠檬酸或酒石酸)在溶剂(例如水)中的悬浮液加热至90-100℃,判断反应完成是将一滴反应混合物加入稀氨水中能得透明溶液。然后将悬浮液任选用水稀释,并过滤回收所要的铋-羧酸配合物。若需要可在就地制备柠檬酸铋铵,即将柠檬酸铋与适量氨水反应而得。
本发明的盐可以任何方便方式配成药物制剂,并且本发明范围包括了包含本发明的盐并用作人类或兽药的药物组合物。这些组合物主要供口服用药,可以用一种或多种适于药用的载体或赋形剂而配成。片剂是优选的组合物剂型。
对于口服,该药物组合物可以是片剂(包括可嚼碎或可吸服的片剂)或胶囊剂。这些组合物可与适于药用的赋形剂以常规方式制成,赋形剂如粘结剂(如预凝胶化玉米淀粉,聚乙烯基吡咯烷酮,羟丙基甲基纤维素);填充剂(如乳糖、微晶纤维素或磷酸氢钙);润滑剂(例如硬脂酸镁,滑石粉,二氧化硅);崩解剂(如马铃薯淀粉,乙醇酸淀粉钠);润滑剂(如月桂基硫酸钠)。片剂可以用本领域熟知方法加糖衣。口服用药的液体制剂可以是溶液、糖浆或悬浮液,或是供应干产品,临到用药时冲水或其他适宜载体。液体制剂可与适于药用的添加剂用常规方法配成,添加剂如悬浮剂(如山梨醇糖浆,纤维素衍生物或氢化食用油脂);乳化剂(如卵磷脂或阿拉伯树胶);非水质载体(如杏仁油,油类的酯,乙醇或分馏植物油);防腐剂(如对羟基苯甲酸甲酯或丙酯或山梨酸)。制剂中也可含有缓冲盐,香味剂,增甜剂。
本发明盐的建议剂量对于人类内服为每单位剂量含有活性物100毫克-1克,较好是100-800毫克,最好是150-600毫克。每天可用1-4次单位剂量,最好1或2次。准确剂量取决于所医病症的特点和严重程度,最好按患者年龄和体重来作例行剂量调整。
由以下实例阐明本发明,除另有指明者外,其中温度为℃,薄层色谱(t.l.c.)是用硅胶,洗脱剂体系A是二氯甲烷∶乙醇∶比重0.88氨水=70∶8∶1,体系B是乙酸乙酯∶异丙醇∶0.88比重氨水∶水=25∶15∶4∶2,使用紫外线(u.v.),碘铂酸盐和冲锰酸钾进行检测。
制备1
2-羟基-1,2,3-丙烷三羧酸铋(3+)配合物(1∶1)(“柠檬酸铋”)
将氧硝酸铋(22.96克)和柠檬酸(33.60克)在水(80毫升)中的混合物在水蒸汽浴上加热30分钟并不时搅拌,到该时,将一滴该悬浮液加入稀氨水中应成透明溶液。
用水稀释该混合物,过滤,剩余物用水充分洗涤,直至无硝酸根和过量柠檬酸为止。真空干燥剩余物,得到本标题化合物32.18克。
元素分析:C6H5BiO7.0.11H2O
实测值:C,18.08;H,1.34;O,28.80;Bi,52.
计算值:C,18.01;H,1.32;O,28.44;Bi,52.2%.
制备2
[R-(R*R*)]-2,3-二羟基丁二酸铋(3+)配合物(2∶1)(“酒石酸铋”)
将27克(+)-酒石酸及8.61克氧硝酸铋在50毫升水中的混合物加热至90-100°,经30分钟并不时搅拌,到该时,少量产物能完全溶于稀氨水。混合物冷却至室温,过滤,剩余物用水充分洗涤,直至无水溶性物质为止,真空中70-80°干燥,得本标题化合物14.7克。
元素分析:C8H9Bi.O12.0.43H2O
实测值:C,18.44;H,1.81;0,39.04;Bi,40.
计算值:C,18.70;H,1.93;O,38.70;Bi,40.7%.
水测定,得1.54%水,相当于0.43摩尔。
制备3
2-羟基-1,2,3-十九烷三羧酸铋(3+)配合物(1∶1)(“松蕈三酸铋”)
将9.15克(-)-2-羟基-1,2,3-十九烷三羧酸(松蕈三酸),5.74克氧硝酸铋在50毫升水中混合物加热至90-95°,历时4小时。过滤此酸性混合物,剩余物用水充分洗涤,直至滤液为中性。剩余物用甲醇(3×50毫升)洗涤,然后干燥,得本标题化合物12.286克。
元素分析:C22H37BiO7.0.1C22H40O7.0.11H2O
实测值:C,43.52;H,6.34;O,18.49;
Bi,31.
计算值:C,43.63;H,6.24;O,18.76%;Bi,31.4%.
水测定,得0.31%水,相当期0.11摩尔。
制备4
N,N′-1,2-亚乙基双[N-(羧甲基)甘氨酸]铋(3+)配合物(1∶1)(“乙二胺四乙酸铋”)
将20.09克氧硝酸铋和17.57克N,N′-1,2-亚乙基双[N-(羧甲基)甘氨基](乙二胺四乙酸)在100毫升水中的混合物加热至90-95°,历时2小时。过滤热的悬浮液,剩余物加水(4×70毫升)再热至90-95°,直至几乎全部固体物溶解。在每次萃取时,过滤悬浮液并将强酸性滤液真空蒸发至约70毫升。各次萃取所得混合物冷却至18°,过滤沉淀之固体物,用冷水洗涤至无游离硝酸,然后用乙醇及乙醚洗涤,干燥得18.52克本标题化合物。
元素分析:C19H13BiN2O8,0.5H2O
实测值:C,23.27;H,2.49;N,5.41;O,26.43;Bi,41.
计算值:C,23.68;H,2.78;N,5.52;O,26.81;Bi,41.2%
水测定,得1.819%水,相当于0.5摩尔。
实例1
N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′,-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-丙烷三羧酸铋(3+)配合物(1∶1∶1)(“雷尼替丁柠檬酸铋”)
将2.08克柠檬酸铋,1.57克N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺(雷尼替丁)在15毫升水中混合物加热至90-95°,直至pH试纸试得中性为止(约15分钟)。混合物冷却至室温,过滤除去未反应的柠檬酸铋(0.657克)。真空蒸发滤液至干,得硬胶状物。向其中加入50毫升甲醇,混合物蒸发得剩余物,与70毫升甲醇一起加热并冷却。将浑浊的上层液体析,用50毫升甲醇研制剩余物得粉末物,将悬浮液过滤。用甲醇洗涤剩余物,干燥得本标题化合物(1.98克)。t.l.c.(体系A),Rf=0.35(雷尼替丁),Rf=0(柠檬酸铋)。
元素分析:C19H27BiN4O10S,0.1C6H5BiO7,0.16C2H5OH,0.48H2O
测定值:C,30.67;H,3.97;N,7.10;0,23.60;S,3.97;Bi,29.
计算值:C,31.14;H,3.86;N,7.29;0.23.65;S,4.17;Bi,29.9%.
水测定,得1.06%水,相当于0.48摩尔;
n.m.r.测定,有0.16摩尔乙醇。
实例2
N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-丙烷三羧酸铋(3+)配合物(1∶1∶1)(“雷尼替丁柠檬酸铋”)
向柠檬酸铋(3.98克)和水(15毫升)的混合物中,加入足量比重0.88氨水,使固体物溶解。溶液通过Hyflo过滤,合并滤液及洗涤液,真空蒸发。溶液加水再蒸发,直至剩余物上方的蒸汽对于pH1-14试纸不再呈碱性为止(用水4×70毫升)。向该剩余物于水(15毫升)中溶液加入3.14克雷尼替丁,真空蒸发所成溶液至干。加水至可溶性剩余物,再蒸发,至检测不到碱性蒸汽为止(用16×80毫升)。真空旋转蒸发剩余物(80-90°),用乙醚除掉粉末状剩余物。将剩余物研磨成细粉末,混悬于乙醚中,过滤,干燥,得本标题化合物(6.814克)。
t.l.c.(体系A),Rf=0.3(雷尼替丁),Rf=0(柠檬酸铋)。
N.m.r.δ(DMSO-d6)2.57(2H,d, 2AB of CH2CO),2.8-2.9(m,CH3NH,CH2CH2S和 2AB of CH2CO),2.87(s,(CH3)2N+),3.47(2H,t,CH2CH2NH),3.86(2H,s,CH2S),4.35(2H,s,CH2N+),6.10和6.67(2H,d+d,呋喃=CH′s).
I.r.νmax(石蜡糊)3454(-OH),3267和3200(-NH-),和1620,1570和1260(-NHC(=CHNO2)NH-+-CO2 -)cm-1.
元素分析:C13H22N4O3S.C6H5BiO7.0.34H2O
实测值:C,31.54;H,4.04;N,8.02;O,23.31;S,4.32;Bi,28.
计算值:C,31.75;H,3.88:N,7.80:O,23.02;S,4.46%;Bi,29.1%.
水测定,得0.85%水,相当于0.34摩尔
实例3
N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-丙烷三羧酸铋(3+)配合物(1∶1∶1),(“雷尼替丁柠檬酸铋”)
将44.0克雷尼替丁及40.0克柠檬酸铋在70毫升水中混合物加热至90-95°历时30分钟。过滤浑浊液,用20毫升水稀释,搅拌下用23分钟加入工业甲基化变性酒精(IMS,2,4升),加热回流。将所得混悬浮液加热15分钟,冷却至室温。过滤收集本标题化合物(63.0克),用IMS洗涤(2×200毫升),40℃真空干燥。
t.l.c.(体系B),Rf=0.49(雷尼替丁),Rf=0(柠檬酸铋),用紫外线,碘检测。
实例4
N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-丙烷三羧酸铋(3+)配合物(1∶1∶1)(“雷尼替丁柠檬酸铋”)
将44.0克雷尼替丁加入到55.7克柠檬酸铋在56毫升1.0M氨水及92毫升水的混悬液中。混合物加热至90°,经5分钟,过滤浑浊液,用10毫升水稀释。将所得溶液喷雾干燥(总体积195毫升的40毫升),得10.3克本标题化合物。
t.l.c.(体系B),Rf=0.49(雷尼替丁),Rf=0(柠檬酸铋),用紫外线,碘检测。
实例5
N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺[(R-(R*R*)]-2,3-二羟基丁二酸铋(3+)配合物(1∶1∶1)(“雷尼替丁酒石酸铋”)
将5.02克雷尼替丁加入到2.02克酒石酸铋在10毫升水的混悬液中,混合物微加热并搅拌,直至溶解为止。液体通过Hyflo过滤,合并滤液及洗涤液,真空蒸发得稠胶状物,进一步蒸发成泡沫状固体物。加入甲醇(3×50毫升)再蒸发,用热甲醇(3×50毫升)萃取胶状剩余物,直至形成奶油色细粒混悬液,然后过滤。用甲醇(20毫升)研制该剩余物,使剩余物成为细粒混悬液,过滤,用甲醇及乙醚洗涤剩余物,得1.853克本标题化合物。
t.l.c.(体系A),Rf=0.35(雷尼替丁),Rf=0(酒石酸铋)。
i.r.νmax(BKr)3600-2000(复杂系列谱带,-NH-+-OH),
1750-1500(系列谱带,-NHC(=CHNO2)NH-+-CO- 2+-CO2H),
1233(-NHC(=CHNO2)NH-)cm-1。
元素分析:C13H22N4O3S.C4H3O6Bi.0.33C8H9BiO12.0.15CH3OH
测定值:C,28.03;H,3.59;N,6.84;O,24.85;S,3.87.
计算值:C,28.22;H,3.42;N,6.65;O,24.90;S,3.81%.
n.m.r.测定表明,0.15摩尔甲醇。
实例6
N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-十九烷三羧酸铋(3+)配合物(1∶1∶1)(“雷尼替丁松蕈三酸铋”)
将松蕈三酸铋(4.26克,含松蕈三酸0.1摩尔,水0.11摩尔)和雷尼替丁(3.77克)在10毫升水中的混合物加热至90-95°并历时4小时。用水(15毫升)稀释,再加热1小时。趁热通过Hyflo过滤此带乳光液体,借助于乙醇将滤液蒸发至干。用乙醇(3×30毫升)将胶状剩余物再蒸发,得胶状物。将之溶于乙醇(50毫升),通过Hyflo过滤。合并滤液及洗涤液,真空蒸发得胶状物。将之与70毫升热丙酮混合。加热10分钟,析出上部液体。重复上步骤,用50毫升丙酮研制该半固体状剩余物,得细粒悬浮液,过滤,用丙酮充分洗涤剩余物。干燥,得浅黄色固体本标题化合物(4.69克)。
元素分析:C35H59N4O10SBi.0.05C22H40O7.0.5H2O
实测值:C,45.37;H,6.50;N,5.36;O,17.43;S,3.01
计算值:C,44.85;H,6.46;N,5.80;O,17.96;S,3.32%
水测定,得1.04%水,相当于0.5摩尔。
t.l.c.(体系A),Rf=0.35(雷尼替丁),Rf=0(松蕈三酸铋/松蕈三酸);
t.l.c.(氯仿∶甲醇∶乙醇∶水,15∶5∶1∶1),Rf=0.3(雷尼替丁),检测:紫外线,碘铂酸盐,高锰酸钾,溴甲酚绿染色;Rf=0.6(松蕈三酸),检测:溴甲酚绿染色。
实例7
N-[2-[[[5-[(二甲基氨基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺-N,N′-亚乙基双[N-(羧甲基]甘氨酸]铋(3+)配合物(1∶1∶1)(“雷尼替丁乙二胺四乙酸铋”)
向乙二胺四乙酸铋(2.99克)和雷尼替丁(2.2克)的混合物加入15毫升水,将之微热使溶解完全。通过Hyflo过滤所生成之少量沉淀物。真空蒸发溶液至干,用甲醇(2×15毫升)将剩余物再蒸发。剩余物溶于温热甲醇(20毫升)并通过Hyflo过滤。滤液蒸发至干,得半固体状物,将之溶解于10毫升甲醇。冷却,有油状物沉淀,静置60小时后,形成白色固体物。过滤,用甲醇洗涤剩余物。该固体物再悬浮于乙醇中,过滤,用甲醇洗涤剩余物,再用乙醚洗涤,干燥,得本标题化合物(3.786克)。
t.l.c.(体系A),Rf=0.35(雷尼替丁);Rf=0(乙二酸四乙酸铋)。
元素分析:C13H22N4O3S.C10H13BiN2O8.H2O
测定值:C,33.57;H,4.45;N,10.09;S,3.70;Bi,24.
计算值:C,33.26;H,4.49;N,10.12;S,3.86;Bi,25.2%。
水测定,得2.24%水,相当于1.0摩尔。
以下实例A-D是按本发明的药物组合物,活性物为雷尼替丁柠檬酸铋。本发明的其他化合物也可照此配制。
实例A片剂
可用一般方法制备片剂,如直接压片或湿法造粒。
片剂可用适当成膜材料以常用方法加糖衣,例如用羟丙基甲基纤维素。
ⅰ)直接压片 毫克/片
活性成分 380
乳糖 145
微晶纤维素 140
交联聚乙烯基吡咯烷酮 28
硬脂酸镁 7
压成片重量 700毫克
活性成分、微晶纤维素、乳糖、交联聚乙烯基吡咯烷酮经过500微米筛过筛并用适当混合器混合。硬脂酸镁用250微米筛过筛,然后与活性混合物混合。用适当压机将混合物压成片剂。
ⅱ)湿法造粒 毫克/片
活性成分 380
乳糖 215
预凝胶淀粉 70
交联聚乙烯基吡咯烷酮 28
硬脂酸镁 7
压成重量 700毫克
将前三种料混合,并用水造成粒,将此湿粒干燥并磨碎,后二种料经250微米筛过筛并与这些粒混合,再将混合物压成片剂。
实例B可吸服/可嚼碎片剂
ⅰ) 毫克/片
活性成分 380
聚乙烯基吡咯烷酮 28
增甜剂/香味剂 适量
硬脂酸镁 7
甘露糖醇 加至 700
压成重量 700毫克
将前三种料混合并用聚乙烯基吡咯烷酮溶液造粒。将湿粒干燥,磨碎,加入硬脂酸镁润滑剂(事先用250微米筛过筛),将所得粒压制成片剂。
ⅱ) 毫克/片
活性成分 380
羟丙基甲基纤维素 20
硬脂酸镁 7
香味剂 适量
木糖醇 加至 700
压成重量 700毫克
将活性成分、木糖醇和香味剂混合,用羟丙基甲基纤维素的含水乙醇溶液造成粒,干燥。将粒磨碎,加入硬脂酸镁润滑剂(事先用250微米筛过筛),压制成片剂。
实例C胶囊剂
ⅰ) 毫克/丸
活性成分 380
预凝胶淀粉 65
硬脂酸镁 5
填充重量 450毫克
将前二种料经500微米筛过筛,混合,加入硬脂酸镁润滑剂(事先经250微米筛过筛),将混合料填入适当大小的硬明胶胶囊。
(ⅱ) 毫克/丸
活性成分 380
乳糖 75
聚乙烯基吡咯烷酮 20
交联聚乙烯基吡咯烷酮 20
硬脂酸镁 5
填充重量 500毫克
将前二种料混合并用第三种料的溶液制成团,干燥,磨碎并与第四种料及硬脂酸镁(事先经250微米筛过筛)混合,然后填入适宜大小的硬明胶胶囊。
实例D 口服糖浆剂
活性成分 380毫克
羟丙基甲基维纤素 45毫克
羟基苯甲酸丙酯 1.5毫克
羟基苯甲酸丁酯 0.75毫克
糖精钠 5毫克
山梨醇溶液 1.0毫克
适宜缓冲剂 适量
适宜香味剂 适量
净化水 加至 10毫升
将羟丙基甲基纤维素与两种羟基苯甲酸酯分散于一部分热的净化水中,使溶液冷至室温。将糖精钠、香味剂及山梨醇溶液加入到主溶液中。将活性成分溶解于另一部分水中并加入到主溶液中。可加入适当缓冲剂将pH值控制在最高稳定性范围。将溶液加至应有体积,过滤,灌入适当容器。
Claims (12)
1、一种由雷尼替丁(ranitidine)与铋同一种羧酸的配合物所成盐或该盐的溶剂化物的制备方法,包括在一种适当溶剂中使雷尼替丁与一种羧酸铋配合物反应,然后从溶液中分离所生成的盐。
2、权利要求1的方法,其中所述溶剂是水。
3、权利要求1或2的方法,其中所述反应是在高温进行。
4、权利要求1或2的方法,其中所述反应是在40-100℃进行。
5、权利要求1-4中任一项的方法,其中所述羧酸分子中除用于与雷尼替丁形成盐的羧基之外,还含有至少三个官能团。
6、权利要求1-4中任一项的方法,其中所述羧酸是柠檬酸、洒石酸、乙二胺四乙酸、丙基柠檬酸、松蕈三酸。
7、权利要求1-4中任一项的方法,其中该羧酸是柠檬酸或洒石酸。
8、权利要求1-4中任一项的方法,其中该羧酸是柠檬酸。
9、权利要求1-4中任一项的方法,由该方法制备N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-丙烷三羧酸铋(3+)配合物及其溶剂化物。
10、权利要求1-4中任一项的方法,由该方法制备N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺[(R-R*R*)]-2,3-二羟基丁二酸铋(3+)配合物及其溶剂化物。
11、权利要求1-4中任一项的方法,由该方法制备N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺2-羟基-1,2,3-十九烷三羧酸铋(3+)配合物及其溶剂化物。
12、权利要求1-4中任一项的方法,由该方法制备N-[2-[[[5-[(二甲基氨基)甲基]-2-呋喃基]甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙二胺N,N′-亚乙基双[N-(羧甲基)甘氨酸]铋(3+)配合物及其溶剂化物。
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Cited By (4)
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CN1102585C (zh) * | 1999-04-28 | 2003-03-05 | 常州兰陵制药有限公司 | 雷尼替丁枸橼酸铋盐的制备方法 |
CN102408398A (zh) * | 2011-09-20 | 2012-04-11 | 江苏汉斯通药业有限公司 | 枸橼酸铋雷尼替丁的制备方法 |
CN103896888A (zh) * | 2014-03-28 | 2014-07-02 | 常州兰陵制药有限公司 | 枸橼酸铋雷尼替丁的制备方法 |
CN104284672A (zh) * | 2012-04-18 | 2015-01-14 | 医疗保健博士西班牙运营有限公司 | 用于治疗或预防注意力缺陷多动障碍(adhd)的二胺氧化酶 |
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DE3874917T2 (de) * | 1987-03-09 | 1993-03-04 | Procter & Gamble | Zusammensetzungen und ihre verwendung zur behandlung von magen-darmstoerungen. |
IL85472A (en) * | 1987-03-09 | 1991-06-30 | Procter & Gamble | Pharmaceutical compositions for treating gastrointestinal disorders |
AU641903B2 (en) * | 1988-10-26 | 1993-10-07 | Glaxo Group Limited | Carboxylic acid derivatives |
GB9004328D0 (en) * | 1990-02-27 | 1990-04-25 | Glaxo Group Ltd | Chemical compounds |
GB9009240D0 (en) * | 1990-04-25 | 1990-06-20 | Glaxo Group Ltd | Chemical compounds |
GB9009437D0 (en) * | 1990-04-26 | 1990-06-20 | Glaxo Group Ltd | Chemical compounds |
DK0540613T3 (da) * | 1990-07-20 | 1996-04-01 | Tillotts Pharma Ag | Produkter og fremgangsmåder til behandling af fordøjelseskanalen |
GB9019875D0 (en) * | 1990-09-11 | 1990-10-24 | Glaxo Group Ltd | Pharmaceutical compositions |
US5192752A (en) * | 1991-01-14 | 1993-03-09 | The Procter & Gamble Company | Swallowable pharmaceutical compositions containing colloidal bismuth subcitrate |
US5128140A (en) * | 1991-01-14 | 1992-07-07 | The Procter & Gamble Company | Swallowable pharmaceutical compositions |
GB9120131D0 (en) * | 1991-09-20 | 1991-11-06 | Glaxo Group Ltd | Medicaments |
DE69228738D1 (de) * | 1991-12-06 | 1999-04-29 | Glaxo Group Ltd | Zusammensetzungen zur Behandlung von entzündlichen Zuständen oder Analgesie, die Ranitidin Wismuth Citrat und einen NSAID enthalten |
AU1671295A (en) * | 1994-12-19 | 1996-07-10 | Lauteral Limited | Combinations of ranitidine hydrochloride-form 1 and bismuth compounds |
CN1177357A (zh) * | 1995-01-26 | 1998-03-25 | 耐克麦德英梅金公司 | 铋化合物 |
GB9501560D0 (en) * | 1995-01-26 | 1995-03-15 | Nycomed Imaging As | Contrast agents |
EP1035192A1 (de) * | 1999-01-26 | 2000-09-13 | Stefan Graichen | Additiv für einen Kühlschmierstoff |
US20060100271A1 (en) * | 2004-11-08 | 2006-05-11 | Keith Whitehead | Stabilized aqueous ranitidine compositions |
CN100402514C (zh) * | 2006-08-01 | 2008-07-16 | 丽珠医药集团股份有限公司 | 一种制备枸橼酸铋雷尼替丁的方法 |
CN101484132A (zh) * | 2007-07-09 | 2009-07-15 | 柏树制药公司 | 具有合意口味的雷尼替丁制剂 |
US9731999B2 (en) | 2011-09-23 | 2017-08-15 | Iqbal Gill | Chemical admixtures for hydraulic cements |
EP2929884A1 (en) | 2014-04-11 | 2015-10-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical combinations of dabigatran and h2-receptor antagonists |
EP2942058A1 (en) | 2014-05-09 | 2015-11-11 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical combinations of rivaroxaban and H2-receptor antagonists |
CN107382921A (zh) * | 2017-07-28 | 2017-11-24 | 常州兰陵制药有限公司 | 制备枸橼酸铋雷尼替丁的方法 |
WO2022034121A1 (en) | 2020-08-11 | 2022-02-17 | Université De Strasbourg | H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer |
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GB1565966A (en) * | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
FR2531706A1 (fr) * | 1982-08-13 | 1984-02-17 | Sanofi Sa | Benzamides, leurs sels, procede pour leur preparation et compositions pharmaceutiques les renfermant |
BE905235A (fr) * | 1986-08-05 | 1986-12-01 | Hasunor Ag | Ascorbates antagonistes des recepteurs h2 et leur procede de preparation. |
IT1215325B (it) * | 1987-01-07 | 1990-02-08 | Barisintex Sa | Composti antagonisti di recettori -h2 e procedimento per la loro preparazione. |
IL85472A (en) * | 1987-03-09 | 1991-06-30 | Procter & Gamble | Pharmaceutical compositions for treating gastrointestinal disorders |
DE3874917T2 (de) * | 1987-03-09 | 1993-03-04 | Procter & Gamble | Zusammensetzungen und ihre verwendung zur behandlung von magen-darmstoerungen. |
DE3710462A1 (de) * | 1987-03-30 | 1988-10-13 | Heumann Pharma Gmbh & Co | Pharmazeutische zubereitung zur behandlung von erkrankungen des magen-darm-traktes |
GB9004328D0 (en) * | 1990-02-27 | 1990-04-25 | Glaxo Group Ltd | Chemical compounds |
GB9009437D0 (en) * | 1990-04-26 | 1990-06-20 | Glaxo Group Ltd | Chemical compounds |
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1989
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- 1989-07-17 NL NL8901840A patent/NL192604C/nl not_active IP Right Cessation
- 1989-07-17 EG EG34289A patent/EG19368A/xx active
- 1989-07-17 DK DK351789A patent/DK168381B1/da not_active IP Right Cessation
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- 1989-07-17 CN CN89104959A patent/CN1022626C/zh not_active Expired - Fee Related
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- 1989-07-17 IL IL9100589A patent/IL91005A/en not_active IP Right Cessation
- 1989-07-17 JP JP1184402A patent/JP2523185B2/ja not_active Expired - Lifetime
- 1989-07-17 NO NO892936A patent/NO176319C/no not_active IP Right Cessation
- 1989-07-17 BE BE8900773A patent/BE1003254A5/fr not_active IP Right Cessation
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- 1989-07-18 KR KR1019890010213A patent/KR0122598B1/ko not_active IP Right Cessation
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1992
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1102585C (zh) * | 1999-04-28 | 2003-03-05 | 常州兰陵制药有限公司 | 雷尼替丁枸橼酸铋盐的制备方法 |
CN102408398A (zh) * | 2011-09-20 | 2012-04-11 | 江苏汉斯通药业有限公司 | 枸橼酸铋雷尼替丁的制备方法 |
CN104284672A (zh) * | 2012-04-18 | 2015-01-14 | 医疗保健博士西班牙运营有限公司 | 用于治疗或预防注意力缺陷多动障碍(adhd)的二胺氧化酶 |
CN103896888A (zh) * | 2014-03-28 | 2014-07-02 | 常州兰陵制药有限公司 | 枸橼酸铋雷尼替丁的制备方法 |
CN103896888B (zh) * | 2014-03-28 | 2015-11-18 | 常州兰陵制药有限公司 | 枸橼酸铋雷尼替丁的制备方法 |
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