HRP940256A2 - New complexes or antibiotic helates with two- and/or three- valent metals and processes for the preparation thereof - Google Patents
New complexes or antibiotic helates with two- and/or three- valent metals and processes for the preparation thereof Download PDFInfo
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- HRP940256A2 HRP940256A2 HRP-455/90A HRP940256A HRP940256A2 HR P940256 A2 HRP940256 A2 HR P940256A2 HR P940256 A HRP940256 A HR P940256A HR P940256 A2 HRP940256 A2 HR P940256A2
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- Prior art keywords
- azithromycin
- meaning
- indicated
- metal
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Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 24
- 239000002184 metal Substances 0.000 title claims abstract description 24
- 150000002739 metals Chemical class 0.000 title claims abstract description 17
- 230000003115 biocidal effect Effects 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- 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 37
- 229960004099 azithromycin Drugs 0.000 claims abstract description 35
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 11
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 10
- 239000000499 gel Substances 0.000 claims description 18
- 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 11
- 150000003839 salts Chemical class 0.000 claims description 9
- LHPJBAIYHPWIOT-UHFFFAOYSA-K aluminum;magnesium;carbonate;hydroxide Chemical compound [OH-].[Mg+2].[Al+3].[O-]C([O-])=O LHPJBAIYHPWIOT-UHFFFAOYSA-K 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052782 aluminium Inorganic materials 0.000 claims description 6
- 239000013522 chelant Substances 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 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 claims description 4
- 229960004291 sucralfate Drugs 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- ZREIPSZUJIFJNP-UHFFFAOYSA-K bismuth subsalicylate Chemical compound C1=CC=C2O[Bi](O)OC(=O)C2=C1 ZREIPSZUJIFJNP-UHFFFAOYSA-K 0.000 claims description 3
- 229960000782 bismuth subsalicylate Drugs 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 150000001805 chlorine compounds Chemical class 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229910052797 bismuth Inorganic materials 0.000 claims 2
- 150000002500 ions Chemical class 0.000 claims 2
- 229910018626 Al(OH) Inorganic materials 0.000 claims 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims 1
- 239000001095 magnesium carbonate Substances 0.000 claims 1
- 229910000000 metal hydroxide Inorganic materials 0.000 claims 1
- 150000004692 metal hydroxides Chemical class 0.000 claims 1
- 239000003699 antiulcer agent Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 18
- 241000191938 Micrococcus luteus Species 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 7
- 241000700159 Rattus Species 0.000 description 5
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910018134 Al-Mg Inorganic materials 0.000 description 3
- 229910018467 Al—Mg Inorganic materials 0.000 description 3
- 241000590002 Helicobacter pylori Species 0.000 description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- 229940069428 antacid Drugs 0.000 description 3
- 239000003159 antacid agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940037467 helicobacter pylori Drugs 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000126 substance Substances 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 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 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
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 241000589875 Campylobacter jejuni Species 0.000 description 1
- 229910002249 LaCl3 Inorganic materials 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910021604 Rhodium(III) chloride Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 238000001704 evaporation Methods 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
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- ICAKDTKJOYSXGC-UHFFFAOYSA-K lanthanum(iii) chloride Chemical compound Cl[La](Cl)Cl ICAKDTKJOYSXGC-UHFFFAOYSA-K 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Oblast tehnike u koju spada izum
Int. Cl. C07H 17/08 A61K 31/70
Tehnički problem
Izum se odnosi na nove komplekse odnosno helate antibiotika s dvovalentnim i/ili trovalentnim metalima i na postupke za njihovo dobivanje
Stanje tehnike
Poznato je, da neki organski spojevi s metalima stvaraju komplekse i helate kojom im prilikom mogu promijeniti fizikalno-kemijska svojstva (topivost, stabilnost, talište i dr.), a biološki aktivnim spojevima farmakokinetiku pa i farmakodinamiku. Kod makrolidnih antibiotika posebno eritromicina, izvorne supstance za dobivanje N-metil-11-aza-10-deokso-10-dihidroeritromicina A, sa generičnim nazivom azitromicin (SumamedR) (BE pat.892.357), opisano je nastajanje kompleksa sa Co+2, dok se u J. Pharm. Pharmac. 18, (1966) 727, tvrdi, da s drugim dvovalentnim metalnim (Cu+2, Ca+2, Mg+2, Ni+2 i Zn+2) ionima kompleksi ne nastaju. Naprotiv mi smo ustanovili, da azitromicin kompleksira s bivalentnim metalima, stvarajući produkte s visokom antibiotskom aktivnošću (HU pat 198.507). Poznato je, da se između ostalih, Al-Mg gel upotrebljava kao antacid u liječenju čira na dvanaestercu odnosno želucu oblažući stijenku želuca i podržavajući pH želučanog soka između 4.5-5.5.
Za istu svrhu upotrebljavaju se i neki antibiotici, koji bi trebali eradicirati mikroorganizme Helicobacter pylori i Campylobacter jejuni za koje se smatra da su jedan od uzročnika nastajanja ili recidiva čira na želucu odnosno dvanaestercu. Kako se pretpostavlja, da se Helicobacter pylori nalazi u mukoznom dijelu želučane stijenke, čime se i tumači često neuspjela eradikacija a time i recidivi, to su za liječenje korištene sve veće koncentracije kroz sve duže vrijeme raznih antibiotika. Ni azitromicin nije izuzetak. Ustanovili smo, što predstavlja predmet ovog izuma, da se kompleksi odnosno helati antibiotika s dvovalentnim i/ili trovalentnim metalima u obliku gela mogu upotrijebiti za dobivanje antiulkusnih lijekova, što prema prijavitelju poznatom i utvrđenom stanju tehnike do sada nije opisano. Kompleksi odnosno helati antibiotika s dvovalentnim i/ili trovalentnim metalima su novi i oni predstavljaju slijedeći predmet izuma. Predmet izuma su postupci za dobivanje kompleksa odnosno helata antibiotika s dvovalentnim i/ili trovalentnim metalima u visokom iskorištenju, kao i farmaceutskih pripravaka pogodnih za liječenje ulkusnih bolesti.
Specifično navodimo azitromicin.
Kao metali za formiranje kompleksa odnosno helata upotrebljavaju se metali iz II i III grupe, koji tvore fiziološki podnošljive spojeve.
Specifično navodimo Mg+2, Al+3, Fe+3, Rh+3, La+3 i Bi+3.
Postupak za dobivanje komleksa odnosno helata azitromicina izvodi se reakcijom antibiotika kao slobodne baze ili u obliku soli, poželjno hidroklorida, sa solima dvovalentnih i/ili trovalentnih metala kao što su Mg+2, Al+3, Fe+3, Rh+3, La+3 i Bi+3, poželjno kloridima, u omjeru 2:1, kod sobne temperature, u vodenoj otopini ili smjesi alkohol-voda, kod pH 8.0 do 11.0, odnosno sa hidroksidima i/ili karbonatima, subsalicilatima metala odnosno njihovim gelovima, koji se koriste kao antacidi, kao što su aluminijev hidroksid-magnezijev karbonat, sukralfat i bizmut subsalicilat, u omjeru 1:1 do 1:4, pri čemu se proces najprikladnije provodi s bazom antibiotika u alkoholu kao što je metanol ili etanol. Produkt se izolira na uobičajen način, npr. uparavanjem otapala (alkohola) iz reakcione smjese pod sniženim pritiskom i izolacijom produkta filtracijom. Produkt se poznatim metodama prevodi u za liječenje pogodne farmaceutske oblike kao što su granule ili tablete za žvakanje ili suspenzije u vodi.
Kako je nađeno, da se helati azitromicina s aluminijem i magnezijem u obliku gela kao i sa drugim gelovima koji se upotrebljavaju kao antacidi, u odnosu 1:1 do 1:4, zadržavaju u 1.5-60 puta većoj koncentraciji (tabela 1 i 2) koje prelaze minimalne inhibitorne i baktericidne koncentracije za Helicobacter pylori i Campilobacter jejuni u mukoznom dijelu želuca štakora kroz 24 sata, to se ovakvi pripravci mogu uspješnije primijeniti u liječenju bolesti želuca kao što su čir na želucu i dvanaestercu, nego matični azitromicin. Ovo tim prije, što su toksikološka ispitivanja pokazala, da farmaceutski pripravci ne mijenjaju toksičnost matične supstancije.
Tabela 1.
KONCENTRACIJA AZITROMICINA U STIJENCI ŽELUCA NAKON JEDNOKRATNOG DAVANJA AZITROMICIN Al-Mg GELA 1:1, AZITROMICIN SUKRALFAT GELA 1:1 I AZITROMICIN Bi-SUBSALICILAT GELA 1:1 (60 mg/štakoru p.o.) U USPOREDBI S AZITROMICINOM (30 mg/štakoru p.o.)
[image]
Tabela 2.
KONCENTRACIJA AZITROMICINA U STIJENCI DUODENUMA NAKON JEDNOKRATNOG DAVANJA AZITROMICIN Al-Mg GELA 1:1, AZITROMICIN SUKRALFAT GELA 1:1 I AZITROMICIN Bi-SUBSALICILAT GELA 1:1 (60 mg/štakoru p.o.) U USPOREDBI S AZITROMICINOM (30 mg/štakoru p.o.)
[image]
Postupak priprave kompleksa odnosno helata ilustriran je slijedećim primjerima, koji ga ni u čemu ne ograničuju.
Primjer 1
U 50 ml 0.02 M otopine azitromicina u 95%-tnom etanolu otopi se 0.067 g AlCl3 (0.01 M otopina obzirom na Al+3) te nakon podešavanja pH s 0.1 N NaOH do pH 8.6 miješa 1 sat na sobnoj temperaturi u struji dušika. Reakciona smjesa se nakon dodatka 30 ml vode upari pod sniženim pritiskom na oko pola volumena a zatim slijedi dalje miješanje 2 sata uz konstantno održavanje pH (ph stat) s 0.1 N NaOH na pH 8.9. Bijeli talog se odsiše, ispere s 3x10 ml vode te suši, dajući 0.68 g produkta (89.0%), T.t. 125-128oC.
Analiza Al (metoda atomske apsorpcione spektrometrije):
Izrač. 1.77 % Nadj. 1.73 %
Aktivitet: 852 j/mg Sarcina lutea ATCC 9341
Primjer 2
Prema postupku opisanom u primjeru 1, s jedinom razlikom da se umjesto AlCl3 doda 0,136 g FeCl3 x 6H2O i održava pH vrijednost 9.0. Dobiveno je 0,72 g svijetlo smeđeg produkta (92.5 %), T.t. 130-133oC.
Analiza Fe (metoda atomske apsorpcione spektrometrije):
Izrač. 3.59 % Nadj. 3.71 %
Aktivitet: 840 j/mg Sarcina lutea ATCC 9341
Primjer 3
Odvagne se 0.750 g azitromicina u tikvicu od 100 ml te se otopi uz dodatak 1 N HCl (pH oko 6.0) u 50 ml vode. Nakon toga doda se 0.136 g FeCl3 x 6H20 i nastavi miješanjem uz postepeni dodatak 0.1 N NaOH do pH 8.9. Reakciona smjesa miješa se 2 sata uz konstantno održavanje pH, svijetlo smeđi produkt se odsiše, ispere s 3 x 10 ml vode, te suši. Dobiveno je 0.70 g ( 89.9 % ) produkta. Analiza produkta identična je primjeru 2.
Primjer 4
Prema postupku opisanom u primjeru 1, s jedinom razlikom da se umjesto AlCl3 doda 0.132 g RhCl3 x 3H2O dobiveno je 0.67 g svijetlo smeđeg produkta (83.6 %), T.t. 120-123oC.
Analiza Rh (polarografska metoda, 1 M piridin-1 M KCl,
E1/2= -0.40 V prema ZKE):
Izrač. 6.42 % Nadj. 6.15 %
Aktivitet: 834 j/mg Sarcina lutea ATCC 9341
Primjer 5
Prema postupku opisanom u primjeru 1, s jedinom razlikom da se umjesto AlCl3 doda 0.186 g LaCl3 x 7H2O i održava pH vrijednost 9.2, dobiveno je 0.66 g bijelog produkta (80.5 %), T.t. 118-122oC.
Analiza La (metoda atomske apsorpcione spektrometrije):
Izrač. 8.47 % Nadj. 8.10 %
Aktivitet: 830 j/mg Sarcina lutea ATCC 9341
Primjer 6
Prema postupku opisanom u primjeru 1, s jedinom razlikom da se umjesto AlCl3 doda 0.158 g BiCl3. Dobiveno je 0.70 produkta (82.0 %) T.t. 128-133oC.
Analiza Bi (metoda atomske apsorpcione spektrometrije):
Izrač. 12.25 % Nadj. 12.00 %
Aktivitet: 812 j/mg Sarcina lutea ATCC 9341
Primjer 7
Prema postupku opisanom u primjeru 3, s jedinom razlikom da se umjesto FeCl3 doda 0.102 g MgCl2 x 6H2O i održava pH vrijednost 8.6. Dobiveno je 0.55 g (75.0 %) bijelog produkta, T.t. 121-124oC.
Analiza Mg (metoda atomske apsorpcione spektrometrije):
Izrač. 1.22 % Nadj. 1.54 %
Aktivitet: 850 j/mg Sarcina lutea ATCC 9341
Primjer 8
Odvagne se 5.0 g azitromicina u tikvicu od 100 ml, te otopi u 50 ml metanola. Nakon dodatka 5.0 g aluminij hidroksid-magnezij karbonat gela nastavi se miješanjem 2 sata. Postupak se provodi na sobnoj temperaturi u struji dušika. Suspenzija se zatim upari do suha uz sniženi pritisak, a dobiveni produkt (9.5 g) suši na zraku.
Aktivitet: 430 j/mg Sarcina lutea ATCC 9341
Primjer 9
Prema postupku opisanom u primjeru 8, s jedinom razlikom da se umjesto 5.0 g doda 10.0 g aluminij hidroksid-magnezij karbonat gela i da se kao otapalo umjesto metanola koristi 100 ml 95%-tnog etanola. Dobiveno je 14.3 g produkta.
Aktivitet: 295 j/mg Sarcina lutea ATCC 9341
Primjer 10
Prema postupku opisanom u primjeru 8, s jedinom razlikom da se umjesto 5.0 g doda 20.0 g aluminij hidroksid-magnezij karbonat gela. Dobiveno je 23.5 g produkta.
Aktivitet: 160 j/mg Sarcina lutea ATCC 9341
Primjer 11
Prema postupku opisanom u primjeru 8, s jedinom razlikom da se umjesto aluminij hidroksid-magnezij karbonat gela doda 5.0 g sukralfata. Dobiveno je 9.5 g produkta.
Aktivitet: 435 j/mg Sarcina lutea ATCC 9341
Primjer 12
Prema postupku opisanom u primjeru 8, s jedinom razlikom da se umjesto aluminij hidroksid-magnezij karbonat gela doda 5.0 g bizmut subsalicilata. Dobiveno je 9.3 g
produkta.
Aktivitet: 420 j/mg Sarcina lutea ATCC 9341
Claims (12)
1. Kompleksi odnosno helati antibiotika s dvovalentnim i/ili trovalentnim metalima, naznačeni time, gdje antibiotik ima značenje azitromicina, a metali imaju značenje Mg+2,Al+3, Fe+3, Rh+3, La+3 ili Bi+3 iona odnosno soli Mg i Al, Al ili Bi u obliku gela.
2. Kompleksi odnosno helati azitromicina prema zahtjevu 1, naznačeni time, da je omjer azitromicina i metalnih iona 2:1 odnosno azitromicina i metalnih soli 1:1 do 1:4.
3. Kompleks azitromicina, naznačen time, da metal ima značenje Mg+2.
4. Kompleks azitromicina, naznačen time, da metal ima značenje Al+3.
5. Kompleks azitromicina, naznačen time, da metal ima značenje Fe+3.
6. Kompleks azitromicina, naznačen time, da metal ima značenje Rh+3.
7. Kompleks azitromicina, naznačen time, da metal ima značenje La+3.
8. Kompleks azitromicina, naznačen time, da metal ima značenje Bi+3.
9. Helat azitromicina, naznačen time, da sol Mg i Al ima značenje Al(OH)3-MgCO3.
10. Helat azitromicina, naznačen time, da sol Al ima značenje sukralfata.
11. Helat azitromicina, naznačen time, da sol Bi ima značenje subsalicilata.
12. Postupak za pripravu kompleksa odnosno helata antibiotika s dvovalentnim i/ili trovalentnim metalima, gdje antibiotik ima značenje azitromicina, a metali imaju značenje Mg+2,Al+3, Fe+3, Rh+3, La+3 ili Bi+3 iona odnosno soli Mg i Al, Al ili Bi u obliku gela, naznačen time, da azitromicin kao slobodna baza ili u formi hidroklorida reagira sa solima metala iz grupe Mg+2,Al+3, Fe+3, Rh+3, La+3 i Bi+3 kao što su kloridi, u molarnom omjeru 2:1, u vodenoj otopini ili smjesi alkohol-voda, kod sobne temperature i održavanja konstantnog pH od 8.0 do 11.0 odnosno sa metal hidroksidima i/ili karbonatima, subsalicilatima ili njihovim gelovima, kao što su aluminij hidroksid-magnezij karbonat gel, sukralfat i bizmut subsalicilat, u omjeru 1:1 do 1:4, kod sobne temperature u alkoholu, kao što je metanol ili etanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HRP-455/90A HRP940256B1 (en) | 1990-03-07 | 1994-04-18 | New complexes or antibiotic helates with two- and/or three- valent metals and processes for the preparation thereof |
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 |
| HRP-455/90A HRP940256B1 (en) | 1990-03-07 | 1994-04-18 | New complexes or antibiotic helates with two- and/or three- valent metals and processes for the preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HRP940256A2 true HRP940256A2 (en) | 1997-06-30 |
| HRP940256B1 HRP940256B1 (en) | 1998-10-31 |
Family
ID=25550003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP-455/90A HRP940256B1 (en) | 1990-03-07 | 1994-04-18 | New complexes or antibiotic helates with two- and/or three- valent metals and processes for the preparation thereof |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5498699A (hr) |
| EP (1) | EP0445743B1 (hr) |
| JP (1) | JP2731636B2 (hr) |
| CN (2) | CN1041166C (hr) |
| AT (1) | ATE143266T1 (hr) |
| BG (1) | BG61230B1 (hr) |
| CA (1) | CA2037663C (hr) |
| CZ (1) | CZ280181B6 (hr) |
| DE (1) | DE69122282T2 (hr) |
| DK (1) | DK0445743T3 (hr) |
| ES (1) | ES2094763T3 (hr) |
| GR (1) | GR3021947T3 (hr) |
| HR (1) | HRP940256B1 (hr) |
| HU (2) | HU209455B (hr) |
| PL (1) | PL166279B1 (hr) |
| RO (1) | RO107660B1 (hr) |
| RU (2) | RU2039060C1 (hr) |
| SI (1) | SI9010455B (hr) |
| SK (1) | SK279278B6 (hr) |
| YU (1) | YU45590A (hr) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (hr) * | 1992-07-30 | 1996-03-01 | Pfizer | |
| US6117412A (en) * | 1995-01-26 | 2000-09-12 | Nycomed Imaging As | Non-cluster type bismuth compounds |
| 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 |
| EP1671979B1 (en) | 2001-05-22 | 2008-08-13 | Pfizer Products Inc. | New Cristal Form of Azithromycin |
| CZ2004232A3 (cs) * | 2001-08-21 | 2005-10-12 | Pfizer Products Inc. | Jednorázová dávka azithromycinu |
| 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 |
| US8440646B1 (en) | 2006-10-11 | 2013-05-14 | Paratek Pharmaceuticals, Inc. | Substituted tetracycline compounds for treatment of Bacillus anthracis infections |
| 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 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (hr) * | 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 |
| SG72632A1 (en) * | 1985-04-18 | 2000-05-23 | Procter & Gamble | Treatment of non-ulcer dyspepsia with bismuth salts |
| EP0707854B1 (en) * | 1985-06-13 | 2006-02-22 | Barry James Dr. Marshall | Compositions for the treatment of gastronitestinal disorders containing bismuth and an antimicrobial |
| IT1200774B (it) * | 1985-10-10 | 1989-01-27 | Pierrel Spa | Procedimento di sentisi dell'amikacina |
| YU44599B (en) * | 1986-09-12 | 1990-10-31 | Pliva Pharm & Chem Works | Process for preparing complex of n-methyl-11-aza-10-deoxo-10-dihydroeritromicine a and 11-aza-10-deoxo-10-dihydroeritromicine a with metals |
| HU198913B (en) * | 1987-09-03 | 1989-12-28 | Pliva Pharm & Chem Works | Process for producing 10-dihydro-10-deoxo-11-aza-erythronolide a-derivatives and pharmaceutical compositions containing them as active components |
| 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
- 1990-03-28 SI SI9010455A patent/SI9010455B/sl unknown
-
1991
- 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 ES ES91103336T patent/ES2094763T3/es not_active Expired - Lifetime
- 1991-03-05 EP EP91103336A patent/EP0445743B1/en not_active Expired - Lifetime
- 1991-03-05 DK DK91103336.3T patent/DK0445743T3/da active
- 1991-03-06 SK SK587-91A patent/SK279278B6/sk unknown
- 1991-03-06 CA CA002037663A patent/CA2037663C/en not_active Expired - Fee Related
- 1991-03-06 CN CN91101355A patent/CN1041166C/zh not_active Expired - Fee Related
- 1991-03-06 RO RO147062A patent/RO107660B1/ro unknown
- 1991-03-06 US US08/022,398 patent/US5498699A/en not_active Expired - Fee Related
- 1991-03-06 BG BG93995A patent/BG61230B1/bg unknown
- 1991-03-06 RU SU914894967A patent/RU2039060C1/ru active
- 1991-03-06 CZ CS91587A patent/CZ280181B6/cs not_active IP Right Cessation
- 1991-03-07 HU HU91740A patent/HU209455B/hu not_active IP Right Cessation
- 1991-03-07 JP JP3041832A patent/JP2731636B2/ja not_active Expired - Lifetime
- 1991-03-07 PL PL91289333A patent/PL166279B1/pl unknown
-
1992
- 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
-
1995
- 1995-06-30 HU HU95P/P00704P patent/HU211475A9/hu unknown
-
1996
- 1996-12-10 GR GR960403364T patent/GR3021947T3/el unknown
-
1997
- 1997-04-18 CN CN97109555A patent/CN1051560C/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| ES2094763T3 (es) | 1997-02-01 |
| HU209455B (en) | 1994-06-28 |
| HUT56849A (en) | 1991-10-28 |
| DE69122282T2 (de) | 1997-04-24 |
| DK0445743T3 (hr) | 1997-02-17 |
| CN1054534A (zh) | 1991-09-18 |
| EP0445743A3 (en) | 1992-10-07 |
| JPH06184186A (ja) | 1994-07-05 |
| RU2039061C1 (ru) | 1995-07-09 |
| CA2037663A1 (en) | 1991-09-08 |
| JP2731636B2 (ja) | 1998-03-25 |
| SK279278B6 (sk) | 1998-09-09 |
| SI9010455A (en) | 1997-08-31 |
| US5498699A (en) | 1996-03-12 |
| HU211475A9 (en) | 1995-11-28 |
| YU45590A (sh) | 1992-07-20 |
| BG93995A (bg) | 1993-12-24 |
| HU910740D0 (en) | 1991-09-30 |
| DE69122282D1 (de) | 1996-10-31 |
| CN1051560C (zh) | 2000-04-19 |
| CZ280181B6 (cs) | 1995-11-15 |
| RU2039060C1 (ru) | 1995-07-09 |
| CS9100587A2 (en) | 1991-10-15 |
| CA2037663C (en) | 1999-01-19 |
| EP0445743B1 (en) | 1996-09-25 |
| GR3021947T3 (en) | 1997-03-31 |
| PL166279B1 (pl) | 1995-04-28 |
| EP0445743A2 (en) | 1991-09-11 |
| BG61230B1 (bg) | 1997-03-31 |
| SI9010455B (sl) | 2000-04-30 |
| RO107660B1 (ro) | 1993-12-30 |
| CN1168891A (zh) | 1997-12-31 |
| HRP940256B1 (en) | 1998-10-31 |
| CN1041166C (zh) | 1998-12-16 |
| ATE143266T1 (de) | 1996-10-15 |
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