CN1053611A - 新的β-内酰胺抗菌素的结晶盐酸盐及其制备方法 - Google Patents
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Abstract
本文介绍抗菌素7β-[2′-(R)-2′-苯基-2′
-氨基乙酰氨基]-3-氯-3-(1-carbadethiacephem)
-4-羧酸(“LY163892”)的结晶盐酸盐。该结晶盐酸
盐本身就是一种真正的抗菌素;也是相应的
LY163892一水合物型的有价值中间体。本文还介
绍制备LY163892结晶盐酸盐的方法。
Description
下式β-内酰胺抗菌素是一种新的有效口服活性抗菌素:
这种抗菌素可参见J.Hashiomto等的美国专利第4,335,211号,1982年6月15日公告(本文引为参考文献)。上述化合物本文命名为LY163892。
本发明涉及LY163892的结晶盐酸盐,这种化合物是母体化合物的精致的药物型。另外,LY163892结晶盐酸盐是一种纯化LY163892结晶-水合物的适宜中间体。LY163892结晶-水合物是一种母体化合物的精致的药物型,该母体化合物在很宽的湿度范围内和其它制造条件下均具有极好的稳定性和大量操作性能。LY163892结晶-水合物还可参见C.Pasini的欧洲专利申请第311,366号,1989年4月12日公开,题目为“新的β-内酰胺抗菌素的一水合物”。
本发明的一个方面是提供LY163892的结晶盐酸盐,更具体地说,本发明提供具有下面表1所列X射线粉末衍射图的LY163892结晶盐酸盐。本发明的其它方面是提供LY163892结晶盐酸盐的药物制剂。本发明的另一方面是提供制备LY163892结晶盐酸盐的方法,该方法包括在氯离子源存在下,于乙腈中酸化LY163892。
本发明涉及式Ⅰ抗菌素化合物LY163892的结晶盐酸盐:
式Ⅰ抗菌素的2′位碳原子存在“R”的绝对构型。此外,式Ⅰ化合物还可以以两性离子形式、也包括本发明各个方面的形式存在。本文将本发明化合物称作“LY163892结晶盐酸盐”或更简单地称作“结晶盐酸盐”。
结晶盐酸盐是一种白色结晶固体。本发明的最佳实施例是特征为表Ⅰ中X射线粉末衍射图的晶体盐酸盐。表Ⅰ如下:
表Ⅰ
结晶盐酸盐衍射图
d I/I1
13.57 0.56
9.30 .07
8.99 .10
7.37 .18
6.89 .37
5.86 .12
5.56 .53
5.26 .10
4.83 .07
4.32 .12
4.00 .10
3.77 .64
3.68 1.00
3.60 .58
3.47 .92
3.13 .25
用波长λ1.5405 的镍过滤的铜辐射获得表Ⅰ所列衍射图。采用扫描范围为4.0°至35.0°的两个θ角,晶面间隔在“d”栏内,相对强度在“Ⅰ/Ⅰ1栏内”。
本发明的另一方面是提供LY163892结晶盐酸盐的药物制剂。本发明的最佳实施例包括含特征为表Ⅰ衍射图的LY163892结晶盐酸盐的药物制剂。
本发明的另一实施例是提供制备LY163892结晶盐酸盐的方法。取各种形式母体化合物的任一种置于乙腈中可制得晶体盐酸盐,所述母体化合物包括脱水合物、水合物、乙醇溶剂化物、各种二甲基甲酰胺(DMF)溶剂化物或各种DMF溶剂化物-水合物的混合物。结晶盐酸盐的最佳起始原料是脱水合物。
按照本发明方法,在氯离子源存在下,于乙腈中形成LY163892的酸加成盐。从该混合物沉淀出LY163892结晶盐酸盐。
在稀悬浮液中,结晶盐酸盐开始沉淀之前,起始原料可完全溶解形成澄清溶液。在浓悬浮液中,虽然明显地有大量起始原料没有完全溶解,但局部产生同样现象。
最好将浓盐酸加到LY163892的乙腈溶液/悬浮液中,形成结晶盐酸盐。另外将另一种酸(例如硝酸、硫酸或磷酸)加到LY163892乙腈溶液/悬浮液或其溶剂化物中,也可形成LY163892的酸加成盐,此后加入氯离子源可从酸化混合物形成和沉淀出结晶盐酸盐。该氯离子源,最好是碱金属氯化物或其它水溶性氯化物或盐酸盐,可方便地引入酸化乙腈溶液中,例如水溶液。此外,氯离子源可在加酸之前或与酸同时加到该混合物中。业已发现仅仅溶剂乙腈,更确切地说是含约1至5%水(来自添加的酸)就可产生和沉淀出本发明的结晶盐酸盐。采用其它水混溶溶剂则不能得到LY163892结晶盐酸盐沉淀。
本发明的结晶盐酸盐本身,在干燥除去残留溶剂后也可用于药物制剂,或可以容易地转化为LY163892的精致的药用一水合物型。加入碱,使本发明结晶盐酸盐水溶液的pH缓慢调至约2至6,最好约为4.8,就可导致所需LY163892一水合物结晶。可以使用任一种碱,例如碱金属氢氧化物(如氢氧化钠和氢氧化钾)、有机碱(如三乙胺和二异丙胺)或相关的碱(如氢氧化铵)。采用常规过滤技术,例如Büchner漏斗真空过滤,使所得悬浮液过滤分离出产物一水合物,洗涤所收集的晶体,置于常温空气中干燥。另外,将温热的pH调整过的悬浮液(50℃)冷却至约20℃,搅拌,过滤,将收集的一水合物于30℃干燥24至48小时。
如上所述,本发明的另一方面提供了LY163892结晶盐酸盐的药用组合物。这类药用组合物可用于控制温血动物的革兰氏阳性和革兰氏阴性细菌感染,这类组合物包括适宜的赋形剂和治疗有效量的本发明结晶盐酸盐。
就口服组合物如片剂和胶囊而言,术语“适宜的赋形剂”意指普通的赋形剂,例如粘合剂(如糖浆、金合欢胶、明胶、山利醇、黄蓍胶、聚乙烯吡咯烷酮、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、蔗糖和淀粉);充填剂和载体,例如玉米淀粉、明胶、乳糖、蔗糖、微晶纤维素、高岭土、甘露糖醇、磷酸二钙、氯化钠和藻酸;崩解剂,例如Croscarmellose sodium、微晶纤维素、玉米淀粉、羟基乙酸淀粉钠,藻酸;适宜的润湿剂,例如十二烷基硫酸钠;润滑剂,例如硬脂酸镁和其它金属硬脂酸盐、硬脂酸、硅氧烷流体、滑石粉、蜡、油和胶态二氧化硅。还可采用调味剂,例如薄荷、冬青油、樱桃味等。理想的是加入着色剂造成更具美观效果或用在辨别药品的剂型。片剂还可通过公知方法包复。
本发明的药用组合物还可呈口服液体制剂形式,它们可以是a)悬浮液、溶液、乳状液或糖浆,或b)干粉剂,于使用前再与水或其它适宜赋形剂混合。当与这种口服液体制剂一起应用时,术语“适宜的赋形剂”意指常规添加剂,例如混悬剂如金合欢胶、甲基纤维素、羟乙基纤维素、羧甲基纤维素、带有羧甲基纤维素钠的纤维素(微晶纤维素 )、Xantham胶或淀粉,增甜剂,例如蔗糖、糖浆、葡萄糖、邻磺酰苯甲酰亚胺、山利醇或糖精;湿润剂,例如十二烷基硫酸钠、硅氧烷油、各种普卢兰尼 表面活性剂或甘油;防腐剂,例如甲基、丙基或对羟基苯甲酸丁酯或山梨酸;染剂、调味剂和盐类,例如氯化钠、柠檬酸、冬青油或柠檬酸钠;油和酯类,例如杏仁油、分馏椰子油、氢化蓖麻油、卵磷脂、硬脂酸铵等。
局部组合物可用“适宜的赋形剂”配制,例如疏水或亲水基质。这类基质包括软膏、乳油或洗剂。
含本发明抗菌素化合物的兽用药物组合物可以给饲养动物进食或饮水给药。另外,该化合物可与“适宜的赋形剂”(例如长效或速释基质配制成乳房内用的制剂。
本结晶盐酸盐的“治疗有效量”为每剂每公斤体重约为2.5mg至70mg化合物。这有效量对成人来说每天总量为200mg至7g左右。
用本结晶盐酸酸治疗期间,该结晶盐酸盐可以每天按单次剂量或多次剂量给药。治疗制度可能要求延长时间周期给药,例如几天或2至3周。每剂给药量或给药总量根据下述因素:感染的性质和严重程度、患者年令和全身健康状况、患者和微生物或包括在感染中的微生物对结晶盐酸盐的耐药力。
下述实施例进一步说明本发明,但并不构成对本发明任何方面的限制。
实施例1:LY163892结晶盐酸盐
将400mg LY163892脱水合物悬浮于10ml乙腈中,加入足够浓的盐酸,使悬浮的脱水合物转化为盐酸盐,通过真空过滤收集沉淀的LY163892结晶盐酸盐。该化合物的X射线粉末衍射参数和图形列于上述表1。
实施例2:LY163892结晶盐酸盐
将浓盐酸(1.5ml)加到5.0gLY163892脱水合物的50ml乙腈悬浮液中,真空过滤收集沉淀的晶体,用10ml乙腈洗涤,得到4.7gLY163892结晶盐酸盐,接着空气干燥过夜。
该结晶盐酸盐转化成LY163892-水合物如下所述。LY163892结晶盐酸盐(4.7g)与35ml水合并,得到pH1.6的溶液,加入氢氧化铵使该溶液pH升至约4,在该溶液中形成LY163892-水合物基片,通过真空过滤分离,产物经空气干燥,产生的X射线衍射图与LY163892-水合物的真实试样相比,确认一水合物的同一性。
实施例3:LY163892结晶盐酸盐
将0.25ml浓硝酸加到400mg LY163892DMF溶剂的10ml乙腈混悬浮液,当加入0.2ml饱和氯化钠溶液时,形成并沉淀出结晶盐酸盐,并通过真空过滤收集。
实施例4:用下述成分制备硬明胶胶囊剂型:
重量(mg/胶囊)
LY163892结晶盐酸盐 200
可流动淀粉粉末 186
含5%硅氧烷的可流动淀粉粉末 50
硬脂酸镁 2.5
将上述诸成分混合并充填成重438.5mg的硬明胶胶囊。
实施例5:用下述诸成分制备片剂型:
重量(mg/片剂)
LY163892结晶盐酸盐 200
微晶纤维素 200
二氧化硅(煅制的) 10
硬脂酸 5
将上述诸成分混合压制成每片重415mg的片剂。
实施例6:栓剂(每一栓剂含200mg活性成分)的制备方法如下所述:
LY163892结晶盐酸盐 200mg
饱和脂肪酸甘油脂 加至 2000mg
活性成分通过美国60目筛,悬浮于用最少热需量熔化的前述饱和脂肪酸甘油脂中,然后将该混合物倒进标称2g容量的栓剂模中进行冷却。
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US47048690A | 1990-01-26 | 1990-01-26 | |
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JP (1) | JPH04234880A (zh) |
KR (1) | KR910014378A (zh) |
CN (1) | CN1053611A (zh) |
AU (1) | AU631960B2 (zh) |
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DE (1) | DE69118933T2 (zh) |
ES (1) | ES2087240T3 (zh) |
FI (1) | FI910365A (zh) |
HU (1) | HU208972B (zh) |
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IL (1) | IL96979A0 (zh) |
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NO (1) | NO910267L (zh) |
NZ (1) | NZ236868A (zh) |
PT (1) | PT96531A (zh) |
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US5352782A (en) * | 1993-06-04 | 1994-10-04 | Eli Lilly And Company | Process for preparing crystalline β-lactam monohydrate |
US5550231A (en) * | 1993-06-15 | 1996-08-27 | Eli Lilly And Company | Loracarbef hydrochloride C1-C3 alcohol solvates and uses thereof |
AU1234999A (en) * | 1997-11-10 | 1999-05-31 | Gist-Brocades B.V. | Crystallization of beta-lactam compounds |
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EG18529A (en) * | 1987-10-06 | 1993-04-30 | Lilly Co Eli | Process for preparing b-lactam hydrate |
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CA2002596A1 (en) * | 1988-11-14 | 1990-05-14 | Thomas M. Eckrich | Hydrates of b-lactam antibiotic |
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AU6992391A (en) | 1991-08-01 |
DE69118933T2 (de) | 1996-10-02 |
AU631960B2 (en) | 1992-12-10 |
ES2087240T3 (es) | 1996-07-16 |
FI910365A (fi) | 1991-07-27 |
KR910014378A (ko) | 1991-08-31 |
EP0439353A1 (en) | 1991-07-31 |
NO910267D0 (no) | 1991-01-23 |
ZA91428B (en) | 1992-09-30 |
CA2034592C (en) | 2001-06-05 |
HU910263D0 (en) | 1991-08-28 |
RU1825365C (ru) | 1993-06-30 |
NO910267L (no) | 1991-07-29 |
PT96531A (pt) | 1991-10-15 |
MX24247A (es) | 1993-11-01 |
YU12191A (sh) | 1994-01-20 |
DE69118933D1 (de) | 1996-05-30 |
HUT57207A (en) | 1991-11-28 |
FI910365A0 (fi) | 1991-01-24 |
IL96979A0 (en) | 1992-03-29 |
IE910251A1 (en) | 1991-07-31 |
CA2034592A1 (en) | 1991-07-27 |
JPH04234880A (ja) | 1992-08-24 |
HU208972B (en) | 1994-02-28 |
EP0439353B1 (en) | 1996-04-24 |
NZ236868A (en) | 1992-04-28 |
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