CN1054534A - 抗菌素与二价和/或三价金属分别形成的复合物和螯合物在制备抗溃疡药中的用途，抗菌素与二价和/或三价金属分别形成的新复合物和螯合物及制备它们的方法 - Google Patents
抗菌素与二价和/或三价金属分别形成的复合物和螯合物在制备抗溃疡药中的用途，抗菌素与二价和/或三价金属分别形成的新复合物和螯合物及制备它们的方法 Download PDFInfo
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- CN1054534A CN1054534A CN91101355A CN91101355A CN1054534A CN 1054534 A CN1054534 A CN 1054534A CN 91101355 A CN91101355 A CN 91101355A CN 91101355 A CN91101355 A CN 91101355A CN 1054534 A CN1054534 A CN 1054534A
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- azithromycin
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- 239000013522 chelant Substances 0.000 title claims abstract description 30
- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 24
- 229940088710 antibiotic agent Drugs 0.000 title claims abstract description 24
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 23
- 239000002184 metal Substances 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 230000000767 anti-ulcer Effects 0.000 title claims abstract description 6
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims abstract description 29
- 229960004099 azithromycin Drugs 0.000 claims abstract description 28
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 239000011777 magnesium Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- FIUBOPPLFYFRMW-UHFFFAOYSA-E aluminum;trimagnesium;carbonate;heptahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Al+3].[O-]C([O-])=O FIUBOPPLFYFRMW-UHFFFAOYSA-E 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- 159000000013 aluminium salts Chemical class 0.000 claims description 4
- 229910000329 aluminium sulfate Inorganic materials 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 3
- 229960004889 salicylic acid Drugs 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 229910052797 bismuth Inorganic materials 0.000 claims 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 claims 1
- ZREIPSZUJIFJNP-UHFFFAOYSA-K bismuth subsalicylate Chemical compound C1=CC=C2O[Bi](O)OC(=O)C2=C1 ZREIPSZUJIFJNP-UHFFFAOYSA-K 0.000 claims 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims 1
- 239000001095 magnesium carbonate Substances 0.000 claims 1
- 241000192023 Sarcina Species 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000590002 Helicobacter pylori Species 0.000 description 4
- 229940037467 helicobacter pylori Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- 241000589875 Campylobacter jejuni Species 0.000 description 3
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229940069428 antacid Drugs 0.000 description 3
- 239000003159 antacid agent Substances 0.000 description 3
- 230000001458 anti-acid effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 238000009834 vaporization Methods 0.000 description 2
- 230000008016 vaporization Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229910018134 Al-Mg Inorganic materials 0.000 description 1
- 229910018467 Al—Mg Inorganic materials 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229930006677 Erythromycin A Natural products 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- REKWPXFKNZERAA-UHFFFAOYSA-K bismuth;2-carboxyphenolate Chemical compound [Bi+3].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O REKWPXFKNZERAA-UHFFFAOYSA-K 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical class Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 239000002905 metal composite material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical group 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- MNQYNQBOVCBZIQ-JQOFMKNESA-A sucralfate Chemical compound O[Al](O)OS(=O)(=O)O[C@@H]1[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](COS(=O)(=O)O[Al](O)O)O[C@H]1O[C@@]1(COS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)O1 MNQYNQBOVCBZIQ-JQOFMKNESA-A 0.000 description 1
- 229960004291 sucralfate Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明涉及抗菌素，尤其是azithromycin与二
价和/或三价金属形成的复合物和螯合物在制备抗
溃疡药中的用途，抗菌素与二价和/或三价金属形成
的新的复合物和螯合物及制备它们的方法。
Description
本发明涉及抗菌素与二价和/或三价金属分别形成的复合物和螯合物在制备抗溃疡药中的用途，抗菌素与二价和/或三价金属分别形成的新复合物和螯合物及制备它们的方法。
已知一些有机化合物形成金属复合物和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azithromycin;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azithromycin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（Campylobacter jejuni），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azitromycin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。
抗菌素与二价和/或三价金属分别形成的复合物和螯合物是新的并代表了本发明另一主题。
本发明再一主题是以高产率制备抗菌素与二价和/或三价金属分别形成的复合物和螯合物及用于治疗溃疡疾病的药物制剂的方法。
具体的抗菌素是azithromycin。
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azithromycin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azithromyecir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azithromycin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。
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）azithromycin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.p125-128℃，
分析：Al（原子吸收谱法）
理论：1.77%。
实际：1.73%
活性：852E/mg 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 黄八叠球菌ATCC9341
实施例3
将0.750g 
azithromycin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0.1NaOH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 黄八叠球菌ATCC9341
实施例5
按实施例1所述的方法，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 
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 
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：850E/mg 黄八叠球菌ATCC9341
实施例8
将5.0g azithromycin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 
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 黄八叠球菌ATCC9341
实施例10
按实施例8所述的方法，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 
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 
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 
黄八叠球菌ATCC9341
Claims (24)
1、抗菌素与二价或三价金属分别形成的复合物和螯合物在制备抗溃疡药中用途。
2、按权利要求1中要求的用途，其中抗菌素是azithromycin。
3、按权利要求1要求的用途，其中金属选自Mg+2，Al+3，Fe+3，Rh+3，La+3和Bi+3。
4、按权利要求1要求的用途，其指azithromycin与选自以凝胶形式的Al，Mg和Bi盐形成的螯合物的用途。
5、按权利要求3要求的用途，其指azithromycin与凝胶形式的氢氧化铝-碳酸镁形成螯合物的用途。
6、按权利要求3要求的用途，其指azithromycin与凝胶形式的蔗糖硫酸酯碱式铝盐形成的螯合物的用途。
7、按权利要求3要求的用途，其指azithromycin与凝胶形式的碱式水杨酸二铋形成的螯合物的用途。
8、抗菌素与二价和/或三价金属分别形成的复合物和螯合物。
9、按权利要求8要求的复合物和螯合物，其中抗菌素是azithromycin。
10、按权利要求8要求的复合物和螯合物，其中金属选自Mg+2，Al+3，Fe+3，Rh+3，La+3和Bi+3。
11、azithromycin与选自凝胶形式的Al，Mg和Bi盐形成的复合物和螯合物。
12、azithromycin与凝胶形式的氢氧化铝-碳酸镁形成的螯合物。
13、azithromycin与凝胶形式的蔗糖硫酸酯碱式铝盐形成的螯合物。
14、azithromycin与凝胶形式的碱式水杨酸二铋形成的螯合物。
15、azithromycin与Mg+2的复合物。
16、azithromycin与Al+3的复合物。
17、azithromycin与Fe+3的复合物。
18、azithromycin与Rh+3的复合物。
19、azithromycin与La+3的复合物。
20、azithromycin与Bi+3的复合物。
21、azithromycin与Mg+2，Al+3，Fe+3，Rh+3，La+3和Bi+3按1∶1-1∶4比例形成的复合物和螯合物。
22、azithromycin与Mg+2，Al+3，Fe+3，Rh+3，La+3和Bi+3按2∶1比例形成的复合物和螯合物。
23、制备抗菌素的复合物和螯合物的方法，其包括：将游离碱或盐（尤指盐酸盐）形式的抗菌素与二价或三价金属（如Mg+2，Al+3，Fe+3，Rh+3，La+3和Bi+3）的盐按2∶1的比例，于室温，在水溶液或水醇混合物中，于PH8.0-11.0进行反应，或与金属的氢氧化物和/或碳酸盐，碱式水杨酸盐或它们的凝胶，如氢氧化铝-碳酸镁，蔗糖硫酸酯碱或铝盐和碱式水杨酸铋，在1∶1-1∶4比例，于醇如甲醇或乙醇中进行反应。
24、如权利要求23要求的方法，其中抗菌素azithromycin。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU45590A YU45590A (sh) | 1990-03-07 | 1990-03-07 | Novi kompleksi odnosno helati antibiotika s dvovalentnim i/ili trovalentnim metalima i postupci za njihovo dobijanje |
| YUP-455/90 | 1990-03-07 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97109555A Division CN1051560C (zh) | 1990-03-07 | 1997-04-18 | 抗菌素与络合金属盐的螯合物的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1054534A true CN1054534A (zh) | 1991-09-18 |
| CN1041166C CN1041166C (zh) | 1998-12-16 |
Family
ID=25550003
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91101355A Expired - Fee Related CN1041166C (zh) | 1990-03-07 | 1991-03-06 | 抗菌素与二价和/或三价金属形成的螯合物在制备抗溃疡药中的用途 |
| CN97109555A Expired - Fee Related CN1051560C (zh) | 1990-03-07 | 1997-04-18 | 抗菌素与络合金属盐的螯合物的制备方法 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97109555A Expired - Fee Related CN1051560C (zh) | 1990-03-07 | 1997-04-18 | 抗菌素与络合金属盐的螯合物的制备方法 |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5498699A (zh) |
| EP (1) | EP0445743B1 (zh) |
| JP (1) | JP2731636B2 (zh) |
| CN (2) | CN1041166C (zh) |
| AT (1) | ATE143266T1 (zh) |
| BG (1) | BG61230B1 (zh) |
| CA (1) | CA2037663C (zh) |
| CZ (1) | CZ280181B6 (zh) |
| DE (1) | DE69122282T2 (zh) |
| DK (1) | DK0445743T3 (zh) |
| ES (1) | ES2094763T3 (zh) |
| GR (1) | GR3021947T3 (zh) |
| HR (1) | HRP940256B1 (zh) |
| HU (2) | HU209455B (zh) |
| PL (1) | PL166279B1 (zh) |
| RO (1) | RO107660B1 (zh) |
| RU (2) | RU2039060C1 (zh) |
| SI (1) | SI9010455B (zh) |
| SK (1) | SK279278B6 (zh) |
| YU (1) | YU45590A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892694A (zh) * | 2015-05-24 | 2015-09-09 | 广西师范学院 | 蔗糖硫酸酯铜类化合物及其制作方法和用途 |
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|---|---|---|---|---|
| CA2064634C (en) * | 1991-04-04 | 1998-08-04 | James V. Heck | 9-deoxo-8a-aza-8a-homoerythromycin a derivatives modified at the 4"- and8a-positions |
| GB9120131D0 (en) * | 1991-09-20 | 1991-11-06 | Glaxo Group Ltd | Medicaments |
| TW271400B (zh) * | 1992-07-30 | 1996-03-01 | Pfizer | |
| 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 |
| US5900410A (en) * | 1996-08-27 | 1999-05-04 | Hartmann; John F. | Monotherapy of peptic ulcers and gastritis |
| US6861411B1 (en) * | 1997-12-02 | 2005-03-01 | Pfizer, Inc. | Method of treating eye infections with azithromycin |
| US6239113B1 (en) | 1999-03-31 | 2001-05-29 | Insite Vision, Incorporated | Topical treatment or prevention of ocular infections |
| US7056893B2 (en) | 1999-03-31 | 2006-06-06 | Insite Vision, Inc. | Topical treatment for prevention of ocular infections |
| HRP20010301A2 (en) * | 2001-04-27 | 2001-12-31 | Pliva D D | New therapeutic indication for azithromycin in the treatment of non-infective inflammatory diseases |
| SI1390377T1 (sl) | 2001-05-22 | 2006-06-30 | Pfizer Prod Inc | Nova kristalna oblika azitromicina |
| OA12845A (en) * | 2001-08-21 | 2006-09-15 | Pfizer Prod Inc | Single dose azithromycin for treating respiratory infections. |
| US20060046970A1 (en) * | 2004-08-31 | 2006-03-02 | Insite Vision Incorporated | Topical otic compositions and methods of topical treatment of prevention of otic infections |
| WO2006047671A2 (en) * | 2004-10-25 | 2006-05-04 | Paratek Pharmaceuticals, Inc. | 4-aminotetracyclines and methods of use thereof |
| WO2008045507A2 (en) | 2006-10-11 | 2008-04-17 | Paratek Pharmaceuticals, Inc. | Substituted tetracycline compounds for treatment of bacillus anthracis infections |
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| US3862225A (en) * | 1961-08-18 | 1975-01-21 | Pfizer | D-ring substituted tetracyclines |
| US3622627A (en) * | 1967-09-13 | 1971-11-23 | Pfizer | 4-dedimethylaminatetracycline and 5a, 6-anhydro derivatives thereof |
| HU167946B (zh) * | 1973-04-16 | 1976-01-28 | ||
| SI8110592A8 (en) * | 1981-03-06 | 1996-06-30 | Pliva Pharm & Chem Works | Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof |
| JPS62502967A (ja) * | 1985-04-18 | 1987-11-26 | ザ・プロクター・アンド・ギャンブル・カンパニー | 非潰瘍消化不良症の治療 |
| EP0462631B1 (en) * | 1985-06-13 | 1996-03-20 | Barry James Dr. Marshall | Methods and compositions for the treatment of gastrointestinal disorders |
| IT1200774B (it) * | 1985-10-10 | 1989-01-27 | Pierrel Spa | Procedimento di sentisi dell'amikacina |
| SI8611592A8 (en) * | 1986-09-12 | 1995-04-30 | Pliva Pharm & Chem Works | Process for preparing complexes of N-methyl-11-aza-10-deoxo-10-dihydroeritromicine A and 11-aza-10-deoxo-10-dihydroeritromicine A with metals |
| EP0283055B1 (en) * | 1987-09-03 | 1990-08-29 | SOUR PLIVA farmaceutska, Kemijska prehrambena i kozmeticka industrija, n.sol.o. | 10-dihydro-10-deoxo-11-azaerythronolide-a-compounds, methods and intermediates for the manufacture thereof and their use in pharmaceuticals and in the manufacture thereof |
| DE3887353T2 (de) * | 1987-10-12 | 1994-05-05 | Exomed Australia Pty Ltd | Behandlungsverfahren für magen-darm-krankheiten. |
| US5246708A (en) * | 1987-10-28 | 1993-09-21 | Pro-Neuron, Inc. | Methods for promoting wound healing with deoxyribonucleosides |
| DE68900339D1 (de) * | 1989-04-03 | 1991-11-21 | Ranbaxy Lab Ltd | Verfahren zur herstellung von alpha-6-deoxytetracyclinen. |
| US5348946A (en) * | 1991-02-28 | 1994-09-20 | Biochem Immunosystems, Inc. | Heteroanthracycline antitumor analogs |
| MA28714B1 (fr) * | 2005-12-15 | 2007-07-02 | Green Technlology Sarl | Une arabinogalactane proteine ayant la propriete d'absorber les graisses et le procede d'obtention de cette arabinogalactane proteine |
-
1990
- 1990-03-07 YU YU45590A patent/YU45590A/sh unknown
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- 1991-03-05 DE DE69122282T patent/DE69122282T2/de not_active Expired - Fee Related
- 1991-03-05 AT AT91103336T patent/ATE143266T1/de not_active IP Right Cessation
- 1991-03-05 DK DK91103336.3T patent/DK0445743T3/da active
- 1991-03-05 ES ES91103336T patent/ES2094763T3/es not_active Expired - Lifetime
- 1991-03-05 EP EP91103336A patent/EP0445743B1/en not_active Expired - Lifetime
- 1991-03-06 US US08/022,398 patent/US5498699A/en not_active Expired - Fee Related
- 1991-03-06 RO RO147062A patent/RO107660B1/ro unknown
- 1991-03-06 CA CA002037663A patent/CA2037663C/en not_active Expired - Fee Related
- 1991-03-06 RU SU914894967A patent/RU2039060C1/ru active
- 1991-03-06 CN CN91101355A patent/CN1041166C/zh not_active Expired - Fee Related
- 1991-03-06 SK SK587-91A patent/SK279278B6/sk unknown
- 1991-03-06 BG BG93995A patent/BG61230B1/bg unknown
- 1991-03-06 CZ CS91587A patent/CZ280181B6/cs not_active IP Right Cessation
- 1991-03-07 PL PL91289333A patent/PL166279B1/pl unknown
- 1991-03-07 JP JP3041832A patent/JP2731636B2/ja not_active Expired - Lifetime
- 1991-03-07 HU HU91740A patent/HU209455B/hu not_active IP Right Cessation
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- 1992-04-23 RU SU925011653A patent/RU2039061C1/ru active
-
1994
- 1994-04-18 HR HRP-455/90A patent/HRP940256B1/xx not_active IP Right Cessation
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1995
- 1995-06-30 HU HU95P/P00704P patent/HU211475A9/hu unknown
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- 1996-12-10 GR GR960403364T patent/GR3021947T3/el unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892694A (zh) * | 2015-05-24 | 2015-09-09 | 广西师范学院 | 蔗糖硫酸酯铜类化合物及其制作方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| HRP940256B1 (en) | 1998-10-31 |
| CA2037663A1 (en) | 1991-09-08 |
| DK0445743T3 (zh) | 1997-02-17 |
| DE69122282D1 (de) | 1996-10-31 |
| SI9010455A (en) | 1997-08-31 |
| ES2094763T3 (es) | 1997-02-01 |
| CS9100587A2 (en) | 1991-10-15 |
| RU2039060C1 (ru) | 1995-07-09 |
| CN1041166C (zh) | 1998-12-16 |
| SK279278B6 (sk) | 1998-09-09 |
| HU910740D0 (en) | 1991-09-30 |
| ATE143266T1 (de) | 1996-10-15 |
| RO107660B1 (ro) | 1993-12-30 |
| HRP940256A2 (en) | 1997-06-30 |
| BG61230B1 (bg) | 1997-03-31 |
| CN1051560C (zh) | 2000-04-19 |
| HUT56849A (en) | 1991-10-28 |
| US5498699A (en) | 1996-03-12 |
| EP0445743B1 (en) | 1996-09-25 |
| SI9010455B (sl) | 2000-04-30 |
| EP0445743A2 (en) | 1991-09-11 |
| CZ280181B6 (cs) | 1995-11-15 |
| CA2037663C (en) | 1999-01-19 |
| PL166279B1 (pl) | 1995-04-28 |
| HU211475A9 (en) | 1995-11-28 |
| DE69122282T2 (de) | 1997-04-24 |
| EP0445743A3 (en) | 1992-10-07 |
| YU45590A (sh) | 1992-07-20 |
| GR3021947T3 (en) | 1997-03-31 |
| JPH06184186A (ja) | 1994-07-05 |
| HU209455B (en) | 1994-06-28 |
| RU2039061C1 (ru) | 1995-07-09 |
| CN1168891A (zh) | 1997-12-31 |
| JP2731636B2 (ja) | 1998-03-25 |
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