DK2578595T3 - Krystallinsk levoisovalerylspiramycin i - Google Patents
Krystallinsk levoisovalerylspiramycin i Download PDFInfo
- Publication number
- DK2578595T3 DK2578595T3 DK11786085.8T DK11786085T DK2578595T3 DK 2578595 T3 DK2578595 T3 DK 2578595T3 DK 11786085 T DK11786085 T DK 11786085T DK 2578595 T3 DK2578595 T3 DK 2578595T3
- Authority
- DK
- Denmark
- Prior art keywords
- levoisovalerylspiramycin
- spiramycin
- levoisovaleryl
- composition
- legionella
- Prior art date
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Classifications
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- 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
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- A—HUMAN NECESSITIES
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- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1025—Acyltransferases (2.3)
- C12N9/1029—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
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- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
- C12P19/62—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin the hetero ring having eight or more ring members and only oxygen as ring hetero atoms, e.g. erythromycin, spiramycin, nystatin
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Claims (15)
1. Levoisovalerylspiramycin I forbindelse, hvor, den kemiske strukturformel af levoisovalerylspiramycin I forbindelse er vist som formel (I), på betingelse af at chloroform er opløsningsmiddel, temperatur 25°C, og koncentration 0,02g/ml, den målte specifikke optiske rotation [o]d er -49° til -62°, og smeltepunktet er 116 til 122°C;
hvor levoisovalerylspiramycin I er en krystallinsk forbindelse, røntgenpulverdiffraktion målt ved Cu-K-alfa stråling har karakteristiske toppe ved 2Θ = 7,6°, 8,0°, 10,0°, 11,4°, 16,4°, 17,0°, 17,5°, 17,9°, 19,5°, 22,7°, 23,7° og 24,4°.
2. Levoisovalerylspiramycin I forbindelse ifølge krav 1, hvor, på betingelse af at chloroform er opløsningsmiddel, temperatur 25°C, og koncentration 0,02g/ml, den målte specifikke optiske rotation [o]d er -51° til -58°.
3. Præparat indeholdende det krystallinske levoisovalerylspiramycin I ifølge krav 1, hvor, præparatet indeholder levoisovalerylspiramycin I, et farmaceutisk salt af levoisovalerylspiramycin I, levoisovalerylspiramycin I og en farmaceutisk acceptabel adjuvans, eller et farmaceutisk salt of levoisovalerylspiramycin I og en farmaceutisk acceptabel adjuvans, renheden af levoisovalerylspiramycin I er over 90 vægtprocent.
4. Præparatet ifølge krav 3, hvor: præparatet omfatter følgende enhedsdosis: indholdet af levoisovalerylspiramycin I er 10 til 1500 mg.
5. Præparatet ifølge krav 3, hvor: vægtprocentandelen af levoisovalerylspiramycin I er 10 til 95%.
6. Præparatet ifølge krav 3, hvor: præparatet omfatter opløsning til injektion, pulver til injektion eller lyofiliseret pulver fremstillet af levoisovalerylspiramycin I og mindst en af citronsyre, adipinsyre, maleinsyre.
7. Præparatet ifølge krav 3, hvor: procentandelen af levoisovalerylspiramycin I er 75 til 95%.
8. Fremgangsmåden til fremstilling af levoisovalerylspiramycin I ifølge krav 1, hvor, fremgangsmåden omfatter: fremstille levocarrimycin, og oprense levoisovalerylspiramycin I, hvor fremgangsmåden til at fremstille levocarrimycin omfatter: dyrkning og biologisk fermentering af klonede svampestammer WSJ-195 fremstillet af spiramycin-indeholdende 4"- isovaleryltransferasegen, og ekstrahere en fermenteringsvæske; fermentering forløber på betingelserne af at pH er 6,0 til 9,0, pH-kurvevariationen med tid viser tre på hinanden følgende faser, hvor, den første fase opfylder formel yi = kixi + 6,0, hvor 0,0227 < ki < 0,1364, 0 < xi < 22; den anden fase opfylder formel yi = kixi + b2, hvor -0,0735 < k2 < 0, 6,5 < b2 < 10,62, 22 < X2 < 56; og den tredje fase opfylder formel y3 = k3X3 + b3, hvor 0 < k3 < 0,0078, 6,06 < b3 < 6,5, 56 < X3 < 120; trinnet til oprensning af levoisovalerylspiramycin I omfatter: oprensning af levocarrimycinprøven med kromatografifremgangsmåden, udføre gradienteluering og adskille komponentmåltoppen af levoisovalerylspiramycin I via ODS kromatografisk søjle i acetonitril og ammoniumacetat-bufferopløsning; i oprensningen af levoisovalerylspiramycin I, eliminere acetonitril i det opsamlede levoisovalerylspiramycin I med rotationsinddampningsfrem-gangsmåden, derefter anvende ethylacetat til ekstraktion, eliminere ethylacetat i ekstrakten ved inddampning for at opnå pastaprøver; re-opløse prøven med petroleumsether, eliminere petroleumsetheren ved inddampning for respektivt at opnå det hvide pulver af levoisovaleryl-spiramycin I; hvor, fremgangsmåden til fremstilling af krystallinsk forbindelse af levoisovalerylspiramycin I omfatter: opløse fast levoisovalerylspiramycin I forbindelse i et blandet opløsningsmiddel af ethylacetat, absolut ethylalkohol og vandfri acetone, tilsætte rent vand og omrøre blandingen samtidigt, afkøle til 5°C til 15°C efter tilsætning af rent vand, fortsætte omrøring når der afkøles, derefter opnå en krystallinsk forbindelse af levoisovalerylspiramycin I, hvor, volumenforholdet af ethylacetat, absolut ethylalkohol og vandfri acetone i den blandede opløsning er 1:0,1 til 10:0,5 til 1, fortrinsvis 1:2 til 8:0,8 til 1.
9. Fremgangsmåden ifølge krav 8, hvor: en dyrkningsfremgangsmåden af fremgangsmåden til at fremstille levocarrimycinet er: dyrke de klonede svampestammer WSP-195 fremstillet af spiramycin indeholdende 4"-isovaleryl transferasegen på et agar-skråstivnet dyrkningsmedium indeholdende 2% sojabønnekagemel, 1% glucose, 3% stivelse, 0,5% CaCC>3, 0,4% NaCI og 2% agar i 8 til 15 dage under pH 6,5 til 7,5 og temperatur 28 til 38°C, derefter inokulere til et podemedium indeholdende 1,5% sojabønnekagemel, 3,0% stivelse, 0,4% NaCI, 0,5% CaCC>3, 0,3% fiskepepton og 0,05% KH2PO4 og dyrke i 40 til 80 timer under pH 6,5 til 7,5 og temperatur 25 til 30°C, implantere til et fermenteringsmedium indeholdende 0,5% glucose, 6,0% stivelse, 0,5% gærpulver, 2,0% fiskemel, 0,6% NH4NO3, 1,0% NaCI, 0,5% CaCOs, 0,05% KH2PO4, 0,1% MgSC>4, 0,5% sojabønneolie og 0,02% antiskumningsmiddel og dyrke i 72 til 120 timer under 26 til 30°C, 0,1 til 20% inokuleringsmængde, for at opnå fermenteringsvæsken.
10. Fremgangsmåden ifølge krav 8, hvor: trinnet til at ekstrahere biologisk fermenteringsvæske omfatter: forarbejde fermenteringsvæsken med aluminumsulfat for at opnå filtrat, regulere filtratets pH til 8,5 til 9,0, under anvendelse af butylacetat til ekstraktion, rense butylacetatekstrakt med ikke-saltvand og 1% NaH2PC>4, derefter anvende pH 2,0 til 2,5 vand for ekstraktion for at opnå en vandig ekstrakt, regulere pH til 4,5 til 5,5, afdampe og eliminere rest-butylacetatet for at opnå vandekstrakt, filtrere og regulere pH til 8,5 til 9,0, udfælde filtratet og vaske med oprenset vand for at opnå det våde produkt, og tørre det for at opnå levocarrimycin.
11. Fremgangsmåden ifølge krav 8, hvor: i oprensningen af levoisovaleryl-spiramycin I, optage UV-spektrumdiagrammet af levoisovalerylspiramycin I gennem præparativ højtydende væskekromatografi og UV-beskyttelse, og opsamle levoisovalerylspiramycin I prøve baseret på retentionstid 44,759 min.
12. Fremgangsmåden ifølge krav 8, hvor: mobil fase er et blandet opløsningsmiddel af acetonitril A og 150mM ammoniumacetatopløsning med pH 8,5, de krævede betingelser til oprensning af levoisovalerylspiramycin I er: lineær gradient: 0 til 60 minutter, A er 25% til 65%; og 61 til 90 minutter, A er 65% til 90%; strømningshastighed: 260 mL/min; prøvestørrelse: lOmL; prøvekoncentration: 0,5g/mL; målebølgelængde: 231nm; måde for opsamling: opsamling via UV triggering.
13. Fremgangsmåden ifølge krav 8, hvor det hvide pulver af levoisovalerylspira-mycin I er fremstillet i krystaller, hvor, volumenforholdet af ethylacetat, absolut ethylalkohol og vandfri acetone i den blandede opløsning er 1:2 til 8:0,8 til 1.
14. Anvendelse af levoisovalerylspiramycin I ifølge krav 1 eller krav 2, eller præparatet ifølge et hvilket som helst af kravene 3 til 7, i fremstillingen af lægemidler til behandling og/eller forebyggelse af infektionssygdomme.
15. Anvendelse af levoisovalerylspiramycin I ifølge krav 14, eller præparatet ifølge et hvilket som helst af kravene 3 til 7, i fremstillingen af antibiotika der er aktive mod bakterier omfattende streptococcus pneumoniae, Gruppe A streptococcus, pyogene streptococcus, enterococcus, staphylococcus aureus, S. epidermids, Catarrhal coccus, gonococcus, bacillus influenzae, escherichia coli, enterotoxigene escherichia coli, enteropatogene escherichia coli, enteroinvasive Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, bacillus proteus vulgaris, typhoid bacillus, acinetobacter, citrobacter, Serratia marcescens, S.Sonnei, Sh.flexneri, Tritirachium album; legionella-lignende legionella pneumophila, legionella gormanii, legionella bozemanii, legionella dumoffii, legionella jordanis, og legionella micdadei; anaerob-lignende bacteroides fragilis, B.thetaiotaomicron, B.vulgatus, B.distasonis, B. prevotella, Prevotella asaccharolyticus, Prevotella oralis, Fusobacteriumnu cleatum, Fusobacterium russell, bifidobacteria, lactobacillus, peptostreptococcus, propionibacterium acnes, Clostridium perfringens, og gær-lignende svampe.
Applications Claiming Priority (4)
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| CN201010182108 | 2010-05-25 | ||
| CN201010182111 | 2010-05-25 | ||
| CN201010182109 | 2010-05-25 | ||
| PCT/CN2011/074644 WO2011147313A1 (zh) | 2010-05-25 | 2011-05-25 | 左旋异戊酰螺旋霉素i、ii或iii，及其制剂、制备方法及应用 |
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| DK2578595T3 true DK2578595T3 (da) | 2017-07-10 |
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| DK11786085.8T DK2578595T3 (da) | 2010-05-25 | 2011-05-25 | Krystallinsk levoisovalerylspiramycin i |
| DK17166117.6T DK3210990T3 (da) | 2010-05-25 | 2011-05-25 | Levoisovalerylspiramycin iii og præparater, fremstillingsfremgangsmåder og anvendelser deraf |
| DK17166118T DK3210991T3 (da) | 2010-05-25 | 2011-05-25 | Krystallinsk form af levoisovalerylspiramycin ii og præparater, fremstillingsfremgangsmåder og anvendelser deraf |
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| Application Number | Title | Priority Date | Filing Date |
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| DK17166117.6T DK3210990T3 (da) | 2010-05-25 | 2011-05-25 | Levoisovalerylspiramycin iii og præparater, fremstillingsfremgangsmåder og anvendelser deraf |
| DK17166118T DK3210991T3 (da) | 2010-05-25 | 2011-05-25 | Krystallinsk form af levoisovalerylspiramycin ii og præparater, fremstillingsfremgangsmåder og anvendelser deraf |
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| US (1) | US8778896B2 (da) |
| EP (3) | EP3210991B1 (da) |
| JP (1) | JP5945868B2 (da) |
| KR (2) | KR101706518B1 (da) |
| BR (1) | BR112012029913B1 (da) |
| CA (3) | CA2915236C (da) |
| DK (3) | DK2578595T3 (da) |
| ES (3) | ES2781425T3 (da) |
| MX (1) | MX340626B (da) |
| MY (1) | MY164231A (da) |
| PH (1) | PH12012502323A1 (da) |
| PL (3) | PL2578595T3 (da) |
| PT (1) | PT3210990T (da) |
| RU (3) | RU2647236C1 (da) |
| WO (1) | WO2011147313A1 (da) |
| ZA (3) | ZA201209738B (da) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101706519B1 (ko) * | 2010-05-25 | 2017-02-14 | 쉔양 통리엔 그룹 컴패니, 리미티드 | 레보캐리마이신, 약학 조성물, 제조방법 및 응용 |
| CN105497053B (zh) * | 2015-12-31 | 2018-02-13 | 沈阳福洋医药科技有限公司 | 可利霉素在抗结核分枝杆菌感染中的应用 |
| AU2018298187A1 (en) * | 2017-07-04 | 2020-02-06 | Shenyang Fuyang Pharmaceutical Technology Co., Ltd. | Use of isovalerylspiramycin I, II and/or III in preparation of drug for treating and/or preventing tumour, and drug |
| JP7152052B2 (ja) * | 2018-01-19 | 2022-10-12 | 沈陽福洋医薬科技有限公司 | カリマイシン又はその活性成分の用途 |
| US20200405739A1 (en) * | 2018-01-19 | 2020-12-31 | Shenyang Fuyang Pharmaceutical Technology Co., Ltd. | Mtor inhibitor, pharmaceutical composition and use thereof |
| CN110384710B (zh) * | 2018-04-17 | 2023-01-10 | 沈阳福洋医药科技有限公司 | 一种用于预防和/或治疗疼痛的药物、组合产品及其应用 |
| MX2020010938A (es) * | 2018-04-17 | 2021-01-29 | Shanghai Tonglian Pharmaceutical Co Ltd | Medicamento para prevenir y/o tratar el dolor y/o la fiebre, producto compuesto y uso del mismo. |
| KR20220008895A (ko) * | 2019-05-16 | 2022-01-21 | 쉔양 푸양 파마슈티컬 테크놀로지 컴퍼니 리미티드 | 섬유증을 예방, 완화 및/또는 치료하는 약물, 복합 제품 및 이의 응용 |
| CN112239483B (zh) * | 2019-07-18 | 2023-10-27 | 沈阳福洋医药科技有限公司 | 一种化合物及药物组合物 |
| US11351185B2 (en) | 2020-03-11 | 2022-06-07 | Asclea Corporation | Use of isovalerylspiramycins as anti-cancer agents to inhibit metastasis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5334788A (en) * | 1976-09-11 | 1978-03-31 | Sanraku Inc | Antibiotics spiramycin derivatives |
| CN1058295C (zh) | 1997-06-03 | 2000-11-08 | 中国医学科学院医药生物技术研究所 | 一种利用基因工程技术制造生技霉素的方法 |
| CN1169947C (zh) | 2002-11-19 | 2004-10-06 | 中国医学科学院医药生物技术研究所 | 必特螺旋霉素的基因工程菌株螺旋霉素链霉菌wsj-195 |
| CN1237976C (zh) * | 2003-12-23 | 2006-01-25 | 沈阳同联集团有限公司 | 必特螺旋霉素及其在抗感染性疾病中的应用 |
| RU2007108544A (ru) * | 2004-08-12 | 2008-09-20 | Глаксосмитклайн Истраживацки Центар Загреб Д.О.О.(Hr) | Применение клеточно-специфических конъюгатов для лечения воспалительных заболеваний желудочно-кишечного тракта |
| CN101054553A (zh) * | 2007-04-09 | 2007-10-17 | 中国医学科学院医药生物技术研究所 | 异戊酰螺旋霉素i基因工程菌株的构建 |
| CN101649325B (zh) * | 2009-07-03 | 2011-09-07 | 中国医学科学院医药生物技术研究所 | 一种提高基因工程异戊酰螺旋霉素主组分含量的基因串连技术 |
| CN101785779B (zh) | 2010-03-09 | 2014-03-05 | 沈阳同联集团有限公司 | 异戊酰螺旋霉素ii的分离制备 |
| CN101785778A (zh) * | 2010-03-09 | 2010-07-28 | 沈阳同联集团有限公司 | 异戊酰螺旋霉素i的分离制备及其应用 |
| CN101773510B (zh) * | 2010-03-09 | 2013-06-05 | 沈阳同联集团有限公司 | 异戊酰螺旋霉素iii的分离制备 |
| KR101706519B1 (ko) * | 2010-05-25 | 2017-02-14 | 쉔양 통리엔 그룹 컴패니, 리미티드 | 레보캐리마이신, 약학 조성물, 제조방법 및 응용 |
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