CN1051560C - 抗菌素与络合金属盐的螯合物的制备方法 - Google Patents

抗菌素与络合金属盐的螯合物的制备方法 Download PDF

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CN1051560C
CN1051560C CN97109555A CN97109555A CN1051560C CN 1051560 C CN1051560 C CN 1051560C CN 97109555 A CN97109555 A CN 97109555A CN 97109555 A CN97109555 A CN 97109555A CN 1051560 C CN1051560 C CN 1051560C
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斯罗泊丹·德约基克
斯拉克·瓦特尼尔
沃吉·克吉威斯
尼维卡·罗泊塔
利笛嘉·克拉尼-巴比克
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    • A61K33/00—Medicinal preparations containing inorganic active ingredients
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Abstract

本发明涉及抗菌素与络合金属盐的螯合物的制备方法。

Description

抗菌素与络合金属盐的螯合物的制备方法
本发明涉及抗菌素与络合金属盐的螯合物的制备方法。
已知一些有机化合物形成金属复合物螯合物可改变它们的理化性质(溶解度，稳定性，熔点等)和生物活性化合物的药动学和药效学性质。
BE专利892,357记载了大环内脂抗菌素的Co+2复合物，尤其是由红霉素起始制备的N-甲基-11-氮杂-10-脱氧-10-二氢红霉素A(非专利名称为阿齐红霉素；专利名称为Sumamed(PLIVA，Zagreb，Yugoslavia)，但J.Pharm Pharmac.18，(1966)727表明没有和其它金属离子(Cu+2，Ca+2，Mg+2，Ni+2和Zn+2)形成复合物。相反的是，我们已发现阿齐红霉素可和二价金属形成复合物从而生成具有高抗菌活性的产物(Hcl专利198,507)。
已知Al-Mg凝胶可在治疗十二指肠或胃溃疡中作为抗酸药并可使胃粘膜得到缓解及保持胃液的PH于4.5-5.5。为此目的，还已用一些抗菌素以便杀灭微生物幽门螺旋菌(Helicobacter pylori)和空肠弯曲杆菌(Campylobacterjejuni)，这些菌是造成十二指肠或胃溃疡发展和复发的因素之一。既然已认为幽门螺旋菌抑制了胃膜的粘膜区，因此即使用增加剂量的各种抗菌素及延长治疗时间，也常常不能成功地杀灭该菌及抑制复发。即使阿齐红霉素也不例外。
本发明的主题之一是抗菌素与二价和/或三价金属分别形成的复合物和螯合物以凝胶形式用于制备抗溃疡药。该主题未被先有技术记载过。
具体的抗菌素是阿齐红霉素。
形成复合物和螯合物的金属是可形成生理耐受化合物的II族和III族金属。
具体的金属是Mg+2，Al+3，Fe+3，Rh+3，La+3和Bi+3。
制备阿齐红霉素的复合物和螯合物的方法是通过将游离碱或盐(尤指盐酸盐形式)的抗菌素与二价和/或三价金属(如Mg+2，Al+3，Fe+3，Rh+3，La+3和Bi+3)的盐(尤指氯化物)，按2∶1比例，于室温，在水溶液或水/醇混合物中及PH8.0-11.0下反应。或与金属的氢氧化物和/或碳酸盐，碱式水杨酸盐或其凝胶(该凝胶用作抗酸药，如氢氧化铝-碳酸镁，蔗糖硫酸酯碱式铝盐(Sucralfate)和水杨酸铋)，按1∶1至1∶4的比例进行反应。该方法最适宜将抗菌素碱于醇(如甲醇或乙醇)中进行。产物以常规方法分离，如减压蒸除反应混合物中溶剂(醇)和过滤分离。
该产物可通过已知方法配成药剂如粒剂或咀嚼片剂或水悬浮液。
已发现阿齐红霉素与凝胶及其它凝胶形式的铝和镁，按1∶1至1∶4比例形成的螯合物可用做抗酸药，其可以1.5-60倍(表1和2)于对幽门螺旋菌和空肠弯曲杆菌的最小抑制细菌浓度的浓度在大鼠的胃粘膜区中停留24小时；因此，该制剂比母阿齐红霉素具有更强的治疗溃疡疾病(如胃和十二指肠溃疡)作用。毒性研究表明，该药物组合物未改变活性成份的毒性。
                            表I与阿齐红霉素(30mg/大鼠，口服)比较，口服(60mg/大鼠)-阿齐红霉素Al-mg凝胶1∶1
-阿齐红霉素蔗糖硫酸酯碱式铝盐凝胶1∶1
-阿齐红霉素双碱式水杨酸盐凝胶：1∶1
后在大鼠胃粘膜中阿齐红霉素浓度
    时间     阿齐红霉素Al-Mg凝胶ug/组织(g)        阿齐红霉素蔗糖硫酸酯碱式铝盐ug/组织(g)      阿齐红霉素双碱式水杨酸盐ug/组织(g)      阿齐红霉素ug/组织(g)
    5182432      X＝159.4±28.66X＝107.4±32.04X＝71.8±20.41X＝7.9±2.88      X＝100.2±32.94X＝75.1±21.54X＝74.5±33.45X＝36.6±7.53      X＝32.5±8.60X＝31.3±10.02X＝26.1±5.26X＝21.1±3.90      X＝99.4±16.61X＝98.3±30.71X＝1.3±0.08X＝0
                             表2与阿齐红霉素(30mg/大鼠，口服)比较，口服(60mg/大鼠)-阿齐红霉素Al-mg凝胶1∶1
-阿齐红霉素蔗糖硫酸酯碱式铝盐凝胶1∶1
-阿齐红霉素双碱式水杨酸盐凝胶：1∶1
后在大鼠十二指肠粘膜中阿齐红霉素浓度
时间 阿齐红霉素Al-Mg凝胶ug/组织(g) 阿齐红霉素蔗糖硫酸酯碱式铝盐ug/组织(g) 阿齐红霉素双碱式水杨酸盐ug/组织(g) 阿齐红霉素ug/组织(g)
    5182432      X＝90.0±14.78X＝91.3±13.46X＝74.3±29.00X＝7.6±1.07      X＝98.1±14.17X＝82.8±27.11X＝55.8±17.04X＝35.6±18.87      X＝73.8±20.77X＝62.2±20.55X＝40.5±13.33X＝42.4±11.25    X＝103.5±7.35X＝86.1±33.45X＝0X＝0
本发明通过下面实施例描述：
实施例1
将0.067gAlCl3(0.01M Al+3溶液)溶于50ml(0.02摩尔)阿齐红霉素的95％乙醇溶液中，用0.1N NaOH调节pH至8.6，并于氮气中室温下保持搅拌1小时。往反应混合物加30ml水后，减压蒸发到其一半体积，然后保持搅拌2小时，用0.1N NaOH将pH保持在8.9。吸出沉淀，用3×10ml水洗涤，然后干燥，生成0.68g产物(89.0％)，m.p 125-128℃，
分析：Al(原子吸收谱法)
      理论：1.77％。
      实际：1.73％
活性：852E/mg虅黄八叠球菌ATCC9341
实施例2
按实施例1所述方法，用0.136gFeCl3·6H2O代替AlCl3，pH保持在9.0，得到0.72g浅灰色产物(92.5％)； m.p.130-133℃。
分析：Fe(原子吸收谱法)：
理论：3.59％
实际：3.71％
活性：840E/mg虅黄八叠球菌ATCC9341
实施例3
将0.750g阿齐红霉素置于100ml烧瓶中，然后在加1N HCl(pH大约6.0)下溶于50ml水。随后加入0.136gFeCl3·6H2O，保持搅拌，用0.1 NaOH调节pH至8.9。反应混合物在pH恒定下保持搅拌2小时，吸出浅灰色产物，用3×10ml水洗涤，干燥。得0.72g产物(89.9％)。产品分析同实施例2中一样。
实施例4
按实施例1所述方法，用0.132gRhCl3·3H2O代替AlCl3，得0.67g浅灰色产物(83.6％)；m.p.120-123℃。
分析：Rh(极谱分析法；1M吡啶-1MKCl，
E1/2＝-0.40V；SCE(饱和甘汞电极)
理论：6.42％
实际：6.15％
活性：834E/mg虅
Figure C9710955500091
黄八叠球菌ATCC9341
实施例5
按实施例1所述方法，用0.186gLaCl3·7H2O代替AlCl3，pH保持在9.2，得0.66g白色产物(80.5％)；m.p.118-122℃。
分析：La(原子吸收谱法)
理论：8.47％
实测：8.10％
活性：830E/mg虅
Figure C9710955500092
黄八叠球菌ATCC9341
实施例6
按实施例1所述方法，用0.158gBiCl3代替AlCl3，得0.70g产物(82.0％)。
分析：Bi(原子吸收谱法)：
理论：12.25％
实测：12.00
活性：812E/mg虅
Figure C9710955500101
黄八叠球菌ATCC9341
实施例7
按实施例3所述方法，用0.102gMgCl2·6H2O代替FeCl3，保持pH于8.6，得0.55g(75.0％)白色产物。
分析；Mg(原子吸收谱法)：
理论：1.22％
实测：1.54％
活性：850 E/mg虅黄八叠球菌ATCC9341
实施例8
将5.0g阿齐红霉素置于100ml烧瓶中并溶于50ml甲醇。加入5.0g氢氧化铝-碳酸镁凝胶后，在氮气流中保持搅拌2小时。然后减压蒸发该悬浮液至干，所得产物(9.5g)空气干燥。
活性：430E/mg虅黄八叠球菌ATCC9341
实施例9
按实施例8所述方法，用10.0g氢氧化铝-碳酸镁凝胶代替实施例8中的5.0g，用100ml95％乙醇代替甲醇，得14.3g产物。
活性：295E/mg虅黄八叠球菌ATCC9341
实施例10
按实施例8所述方法，用20.0g氢氧化铝-碳酸镁代替实施例8中的5.0g，得23.5g产物。
活性：160E/mg虅黄八叠球菌ATCC9341
实施例11
按实施例8所述方法，用5.0g蔗糖硫酸酯碱式铝盐代替氢氧化铝-碳酸镁凝胶，得9.5g产物。
活性：435E/mg虅黄八叠球菌。
实施例12
按实施例8所述方法，用5.0g碱式水杨酸二铋代替氢氧化铝-碳酸镁，得9.3g产物。
活性：420E/mg虅黄八叠球菌ATCC9341

Claims (2)

1.制备阿齐红霉素与络合金属盐的螯合物的方法，其中所述盐选自氢氧化铝-碳酸镁或蔗糖硫酸酯碱式铝盐，该方法包括将阿齐红霉素与所述盐在醇中按1∶1-1∶4比例反应，然后蒸发所述醇得到干燥的残余物，所述螯合物从中分离出来。
2.权利要求1的方法，其中所述醇是甲醇或乙醇。
CN97109555A 1990-03-07 1997-04-18 抗菌素与络合金属盐的螯合物的制备方法 Expired - Fee Related CN1051560C (zh)

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CA2037663C (en) 1999-01-19
CN1054534A (zh) 1991-09-18
RU2039061C1 (ru) 1995-07-09
CN1041166C (zh) 1998-12-16
HU209455B (en) 1994-06-28
SK279278B6 (sk) 1998-09-09
JPH06184186A (ja) 1994-07-05
HU910740D0 (en) 1991-09-30
CA2037663A1 (en) 1991-09-08
DE69122282D1 (de) 1996-10-31
BG61230B1 (bg) 1997-03-31
EP0445743A2 (en) 1991-09-11
HUT56849A (en) 1991-10-28
DK0445743T3 (zh) 1997-02-17
CS9100587A2 (en) 1991-10-15
JP2731636B2 (ja) 1998-03-25
PL166279B1 (pl) 1995-04-28
RU2039060C1 (ru) 1995-07-09
SI9010455A (en) 1997-08-31
ATE143266T1 (de) 1996-10-15
GR3021947T3 (en) 1997-03-31
HU211475A9 (en) 1995-11-28
EP0445743B1 (en) 1996-09-25
HRP940256B1 (en) 1998-10-31
DE69122282T2 (de) 1997-04-24
EP0445743A3 (en) 1992-10-07
RO107660B1 (ro) 1993-12-30
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YU45590A (sh) 1992-07-20
US5498699A (en) 1996-03-12
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CZ280181B6 (cs) 1995-11-15
CN1168891A (zh) 1997-12-31

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