CN1359386A - 新的6-脱氧红霉素衍生物、其制备方法以及作为药物的应用 - Google Patents
新的6-脱氧红霉素衍生物、其制备方法以及作为药物的应用 Download PDFInfo
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- CN1359386A CN1359386A CN99808934A CN99808934A CN1359386A CN 1359386 A CN1359386 A CN 1359386A CN 99808934 A CN99808934 A CN 99808934A CN 99808934 A CN99808934 A CN 99808934A CN 1359386 A CN1359386 A CN 1359386A
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- 238000000034 method Methods 0.000 title description 5
- 229940079593 drug Drugs 0.000 title description 4
- ZUGIGWIPEYNYJV-FZWPAWTOSA-N (3r,4s,5r,6s,7s,9r,11r,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-12,13-dihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione Chemical class 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@H](C)[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 ZUGIGWIPEYNYJV-FZWPAWTOSA-N 0.000 title description 3
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
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- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 description 1
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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
-
- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
-
- 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
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明涉及式(I)化合物及其可药用酸加成盐,其中:X表示(NH)a、CH2或SO2或氧原子;a表示0或1;Y表示(CH2)m-(CH=CH)n-(CH)o,其中m+n+o≤8,n=0或1;Ar表示任选被取代的芳基或杂芳基;W表示氢原子或卤原子;Z表示氢原子或酸的剩余基团。式(I)化合物具有抗生性质。
Description
本发明涉及新的6-脱氧红霉素衍生物、其制备方法以及作为药物的应用。
本发明的目的是式(I)化合物及其可药用酸加成盐:其中-X表示(NH)a、CH2或SO2或氧原子,a表示0或1,-Y表示(CH2)m-(CH=CH)n-(CH)o,其中m+n+o≤8,n=0或1,-Ar表示任选被取代的芳基或杂芳基,-W表示氢原子或卤原子,-Z表示氢原子或酸的残基。
可以提及的酸加成盐是与下列酸形成的盐:乙酸、丙酸、三氟乙酸、马来酸、酒石酸、甲磺酸、苯磺酸、对甲苯磺酸以及特别是硬脂酸、乙基琥珀酸或月桂基磺酸。
芳基优选苯基或萘基。
取代的或非杂环基可以是噻吩基、呋喃基、吡咯基、噻唑基、噁唑基、咪唑基,例如4-(3-吡啶基)、1H-咪唑基、噻二唑基、吡唑基或异吡唑基、吡啶基、嘧啶基、哒嗪基或吡嗪基,还有吲哚基、苯并呋喃基、苯并噻唑基或喹啉基。
这些芳基可以含有一个或多个选自下列一组的基团:羟基、卤原子、NO2、C≡N、烷基、链烯基或炔基、O-烷基、O-链烯基或O-链炔基、S-烷基、S-链烯基或S-炔基和N-烷基、N-链烯基或N-炔基,这些烷基、链烯基或炔基含有多达12个碳原子并且任选地被一个或多个卤原子取代,下式基团其中Ra和Rb相同或不同,它们表示氢原子或含有多达12个碳原子的烷基,下式基团其中R3表示含有多达12个碳原子的烷基、或者任选取代的芳基或杂芳基、芳基、O-羧基芳基或S-羧基芳基或芳基、含有一个或多个杂原子、任选被一个或多个下述取代基取代的5或6元O-杂环芳基或S-杂环芳基。
Hal优选表示氟、氯或溴原子。
本发明一个非常具体的目的是实施例2的产物。
通式(I)的产物对格兰氏阳性菌例如葡萄球菌、链球菌、肺炎双球菌具有非常好的抗生活性。
因此,本发明化合物可用作治疗细菌敏感性感染的药物,特别是葡萄球菌感染例如葡萄球菌败血病、面部或皮肤噁性葡萄球菌感染、脓性皮炎、脓毒性或化脓性创伤、疖、炭疽、蜂窝织炎、丹毒和痤疮,葡萄球菌感染例如原发性或流感后急性咽峡炎、支气管肺炎、肺化脓,链球菌感染例如急性咽峡炎、耳炎、窦炎、猩红热,肺炎双球菌例如肺炎、支气管炎、波状热、白喉、淋病双球菌感染。
本发明产物还具有抗细菌引起感染的活性,所述细菌是例如流感嗜血菌、立克次氏体属、肺炎枝原体、衣原体属、军团菌属、尿枝原体、弓形体属,或具抗分支杆菌属的细菌引起感染的活性。
因此,本发明的目的还包括如上定义的式(I)产物及其与可药用无机酸或有机酸的加成盐,作为药物,特别是抗生药物。
本发明更具体的目的是各实施例的产物及其可药用盐,作为药物,特别是抗生药物。
本发明的目的还包括药物组合物,其中含有至少一种如上定义的药物作为活性成分。
这些组合物可以经口腔、直肠、肠胃道外途径,或者经局部途径、局部施用到皮肤和粘膜上,但是优选的给药途径是口腔。
这些组合物可以是固态或液态的,并且可以以常用于人用药的药物形式存在,例如裸片或糖衣片、明胶胶囊、颗粒、栓剂、可注射制剂、油膏、软膏、凝胶;这些组合物可以按照常用的方法制备。可以将活性成分与常用于这些药物组合物的赋形剂混合在一起,所述赋形剂是例如滑石、阿拉伯胶、乳糖、淀粉、硬脂酸镁、可可脂、含水或非水赋形剂、动物或植物来源的脂肪物质、石蜡衍生物、二醇类、各种润湿剂、分散剂或乳化剂、防腐剂。
这些组合物还可以呈粉末形式,这些粉末用于即时溶解在合适的载体例如不致热的无菌水中。
给药剂量根据所治疗的疾患、接受治疗的患者、给药途径和所用的产物变化。对于实施例2的产品,成人可以例如每天口服50-300mg。
本发明的目的还包括制备方法,其特征在于在含水介质中使式(II)化合物与二脱氧甲基已糖水解剂作用,得到式(III)化合物,用阻断剂与式(III)化合物的2′位羟基官能团作用,得到式(IV)化合物:其中OM表示被保护的羟基,用氧化剂使式(IV)化合物的3位羟基作用,得到式(V)化合物:然后,根据需要,释放出2′位的羟基,得到式(VI)化合物:然后,根据需要,将式(V)或(VI)化合物中任何一个与能够在11、12位产生双键的试剂反应,得到式(VII)化合物:其中OM′表示游离的或被保护的羟基,将式(VII)化合物与羰基二咪唑作用,得到式(VIII)化合物:式(VIII)化合物与其中Y、X和Ar如上所定义的式ArYXNH2化合物作用,得到相应的式(IA)化合物其中W表示氢原子,根据需要,将式(IA)化合物与卤化试剂作用,得到其中W表示卤原子的式(IB)化合物,然后,根据需要释放出2′位的羟基和/或根据需要将该化合物与酸作用,形成盐。
用作本发明方法原料的式(II)化合物是已知产物,描述于EP0216169、EP 41355和EP 0180415的实施例中。-使用盐酸水溶液或者在甲醇中进行二脱氧甲基已糖水解。-用酸或酸的功能衍生物例如酸酐、酰卤或硅衍生物阻断2′位的水解。-在二甲基亚砜DMSO存在下、用二酰亚胺(diimide)使3位羟基氧化。-通过与CDI和DBU反应,首先将式(V)或(VI)产物的11、12位转化为碳酸盐,然后在30℃±5℃搅拌,转化为产物(VII)。-在溶剂例如乙腈、二甲基甲酰胺或者还有四氢呋喃、二甲氧基乙烷或二甲基亚砜中,将化合物(VIII)与ArYXNH2反应。-用甲醇或盐酸水溶液使2′位酯官能团水解。-采用标准方法,用酸成盐。-使用下式化合物,可以进行2位的卤化,例如氟化
在该方法中所用的式(III)、(IV)、(V)、(VI)、(VII)和(VIII)化合物是新的,并且其本身也是本发明的目的。
下列实施例用于说明、而非限制本发明。实施例1:3-脱-[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基(ribo-hexopyranosyl))-氧]-3-氧代-12,11-[氧羰基[[4-[4-(3-吡啶基)-1H-咪唑-1-基]丁基]亚氨基]]-6,11,12-三脱氧-红霉素和(10S)3-脱-[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)-氧]-3-氧代-12,11-[氧羰基[[4-[4-(3-吡啶基)-1H-咪唑-1-基]丁基]亚氨基]]-6,11,12-三脱氧-红霉素步骤A:6-脱氧-3-O-脱(2,6-二脱氧-3-C-甲基-α-L-吡喃己核糖基)-红霉素
将100ml去离子水、50ml盐酸标准溶液和9.58g的6,12-二脱氧-红霉素和3″-O-脱甲基-6,12-二脱氧-红霉素的混合物在室温搅拌3小时。
用乙酸乙酯萃取并用水洗涤后,收集水相,并在10℃将其倒入氢氧化铵溶液中,然后用乙酸乙酯萃取,用水洗涤,干燥,过滤并浓缩。所得产物经硅胶色谱纯化,用CH2Cl2/MeOH/NH4OH混合物(95-5-0.5)洗脱。回收Rf=0.4的馏分。由此得到0.246g所需产物。步骤B:6-脱氧-3-O-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)-红霉素的2′-乙酸盐
将18ml乙酸乙酯、0.42ml乙酸酐和1.755g步骤A产物的溶液在室温搅拌1小时45分钟。将反应物倒入水中,用饱和碳酸钠溶液调节pH至9/10,然后用乙酸乙酯萃取,用碳酸钠水溶液和水洗涤,干燥,过滤并浓缩。由此得到1.826g所需产物。步骤C:6-脱氧-3-O-脱[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)氧]-3-氧代-红霉素的2′-乙酸盐
在室温,向含有55ml二氯甲烷和3.5ml DMSO的溶液中加入3.45g 1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐。在室温搅拌反应物25分钟。然后加入1.82g前一步骤的产物,之后再搅拌15分钟。冷却至15℃后,加入在25ml二氯甲烷中的3.47g三氟乙酸吡啶。搅拌30分钟,然后经硅胶色谱纯化,用丙基醚/异丙醇/TEA混合物(8-1-1)洗脱。(Rf=0.38)。用在乙酸乙酯中的氢氧化铵洗涤并干燥后,得到156mg所需产物。步骤D:6-脱氧-3-O-脱-[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)-氧]-3-氧代-红霉素
将含有0.5ml甲醇和61mg步骤C产物的溶液在5℃搅拌40小时。使反应物恢复到室温,然后在室温搅拌8小时,并蒸发溶剂。所得产物经硅胶色谱纯化,用CH2Cl2/异丙醇/NH4OH(94-4-0.5)洗脱。得到14mg所需产物。步骤E:6-脱氧-3-脱[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)氧]-3-氧代-红霉素的环状2′-乙酸盐和11,12-碳酸盐以及10,11-二脱氢-6,11-二脱氧-3-脱[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)氧]-3-氧代-红霉素的2′-乙酸盐
将3.5ml乙酸乙酯、0.346g步骤C产物、9μl DBU、0.127g 1,1′-羰基二咪唑的溶液在室温搅拌5小时。在30℃搅拌15小时,然后倒入水中,用乙酸乙酯萃取,用水洗涤,干燥,过滤并浓缩,得到0.301g产物。该产物经硅胶色谱纯化,用二氯甲烷、异丙醇、氢氧化铵混合物(95-5-0.5)洗脱。CCM监测表明馏分是同质的。将该产物浓缩,溶于乙酸乙酯中,干燥,过滤并浓缩。得到0.162g所需产物。步骤F:10,11-二脱氢-6,11-二脱氧-3-脱[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)氧]-3-氧代-红霉素的2′-乙酸盐和12-[(1H-咪唑-1-基)甲酸盐]
将含有2ml THF、0.155g前一步骤的产物、6μl DBU和0.064g1,1′-羰基二咪唑的溶液在0℃搅拌3小时。然后在10℃搅拌15小时,之后将其倒入水中,用乙酸乙酯萃取,用水洗涤,干燥,过滤并浓缩。由此得到所需产物。步骤G:3-脱-[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)-氧]-3-氧代-12,11-[氧羰基[[4-[4-(3-吡啶基)-1H-咪唑-1-基]丁基]亚氨基]]-6,11,12-三脱氧-红霉素(产物A)和(10S)3-脱-[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)-氧]-3-氧代-12,11-[氧羰基[[4-[4-(3-吡啶基)-1H-咪唑-1-基]丁基]亚氨基]]-6,11,12-三脱氧-红霉素(产物B)
将含有1.5ml乙腈、0.15ml水、0.17g前一步骤的产物和0.199g 4-(3-吡啶基)-1H-咪唑-1-丁胺在60℃搅拌4小时。将反应物倒入水中,然后用乙酸乙酯萃取,用水洗涤,干燥,过滤并浓缩。得到0.184g产物,将该产物倒入2ml甲醇和25μl DBU溶液中。在室温搅拌16小时,然后蒸发甲醇,经硅胶色谱纯化,用二氯甲烷/甲醇/氢氧化铵混合物(93-7-0.5)洗脱。收集Rf=0.38的馏分,用在乙酸乙酯中的氢氧化铵洗涤,并用硫酸镁干燥,得到37mg产物A。还收集Rf=0.36的馏分,再经硅胶色谱纯化,用二氯甲烷/甲醇/氢氧化铵混合物(93-7-1)洗脱,然后用二氯甲烷、异丙醇、氢氧化铵混合物(9-1-0.5)洗脱,并浓缩。将残余物溶于二氯甲烷中,干燥,过滤并浓缩。得到13mg产物B。药物组合物的实施例
制备含有以下成分的片剂:实施例1的产物 150mg赋形剂 适量至 1g赋形剂具体的是:淀粉,滑石,硬脂酸镁。
也用成盐产物制备可感染溶液。
本发明产物的药学研究A-在液体基质中的稀释液方法
准备一系列其中含有同样量无菌营养培养基的试管。向每只试管中加入增加量的试验产物,然后向每只试管中接种细菌菌株。在加热室中、于37℃孵育24小时后,通过透照对生长抑制进行评价,测出最小抑制浓度(C.M.I.),以微克/厘米3表示。
用实施例的产物得到以下结果:(24小时后读数)
金色链球菌(S.aureus) | 011UC4 | 0.300 |
无乳链球菌(S.agalactiae) | 02B1HT1 | <+0.02 |
粪肠球菌(E.faecalis) | 02D2UC1 | 0.080 |
屎肠球菌(E.faecium) | 02D3HT1 | 0.040 |
链球菌属(S treptococcus gr;G) | 02GOGR5 | 0.040 |
缓症链球菌(S.mitis) | 02MitCB1 | 0.040 |
酿脓链球菌(S.pyogenes) | 02A1SJc | |
无乳链球菌(S.agalactiae) | 02B1SJ1c | 2.500 |
链球菌属(S treptococcus gr;G) | 02Gogr4c | |
缓症链球菌(S.mitis) | 02MitGR16i | 0.300 |
肺炎链球菌(S.pneumoniae) | 032UC1 | <=0.02 |
肺炎链球菌(S.pneumoniae) | 030GR20 | 0.600 |
肺炎链球菌(S.pneumoniae) | 030SJ5i | 0.600 |
肺炎链球菌(S.pneumoniae) | 030CR18c | |
肺炎链球菌(S.pneumoniae) | 030PW23c | 0.300 |
肺炎链球菌(S.pneumoniae) | 030RO1i | 0.600 |
Claims (12)
1.式(I)化合物及其可药用酸加成盐:其中-X表示(NH)a、CH2或SO2或氧原子,a表示0或1,-Y表示(CH2)m-(CH=CH)n-(CH)o,其中m+n+o≤8,n=0或1,-Ar表示任选被取代的芳基或杂芳基,-W表示氢原子或卤原子,-Z表示氢原子或酸的基团。
2.权利要求1的式(I)化合物,其中Z表示氢原子。
3.权利要求1和2中任何一项的式(I)化合物,其中W表示氢原子。
4.权利要求1、2和3中任何一项的式(I)化合物,其中X表示CH2。
5.权利要求1-4中任何一项的式(I)化合物,其中Y表示(CH2)3或(CH2)4。
7.作为权利要求1所定义的新化学产物的3-脱-[(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-吡喃己核糖基)氧]-3-氧代-12,11-[氧羰基[[4-[4-(3-吡啶基)-1H-咪唑-1-基]丁基]亚氨基]]-6,11,12-三脱氧-红霉素。
8.作为药物的权利要求1-6中任何一项的化合物及其可药用盐。
9.作为药物的权利要求7的化合物及其可药用盐。
10.药物组合物,含有至少一种权利要求8或9的药物作为药物。
11.权利要求1-7中任何一项定义的式(I)化合物的制备方法,其特征在于,在含水介质中使式(II)化合物与二脱氧甲基己糖水解剂作用,得到式(III)化合物,用阻断剂与式(III)化合物的2′位羟基官能团作用,得到式(IV)化合物:其中OM表示被保护的羟基,用氧化剂使式(IV)化合物的3位羟基作用,得到式(V)化合物:然后,根据需要,释放出2′位的羟基,得到式(VI)化合物:然后,根据需要,将式(V)或(VI)化合物中任何一个与能够在11、12位产生双键的试剂作用,得到式(VII)化合物:其中OM′表示游离的或被保护的羟基,将式(VII)化合物与羰基二咪唑作用,得到式(VIII)化合物:式(VIII)化合物与其中Y、X和Ar如权利要求1所定义的式ArYXNH2化合物作用,得到相应的式(IA)化合物:其中W表示氢原子,根据需要,将式(IA)化合物与卤化试剂作用,得到其中W表示卤原子的式(IB)化合物,然后,根据需要释放出2′位的羟基和/或根据需要将该化合物与酸作用,形成盐。
12.作为新化学产物的权利要求11中所定义的式(III)、(IV)、(V)、(VI)、(VII)和(VIII)的化合物。
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2003523938A (ja) * | 1999-04-16 | 2003-08-12 | コーサン バイオサイエンシーズ, インコーポレイテッド | マクロライド系抗感染剤 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5141926A (en) * | 1990-04-18 | 1992-08-25 | Abbott Laboratories | Erythromycin derivatives |
IL114589A (en) * | 1990-11-21 | 1999-12-22 | Roussel Uclaf | Intermediates for the preparation of the history of erythromycin |
FR2692579B1 (fr) * | 1992-06-19 | 1995-06-02 | Roussel Uclaf | Nouveaux dérivés de la picromycine, leur procédé de préparation et leur application comme médicaments. |
US5527780A (en) * | 1992-11-05 | 1996-06-18 | Roussel Uclaf | Erythromycin derivatives |
FR2697524B1 (fr) * | 1992-11-05 | 1994-12-23 | Roussel Uclaf | Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments. |
FR2719587B1 (fr) * | 1994-05-03 | 1996-07-12 | Roussel Uclaf | Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments. |
US5747466A (en) * | 1995-11-08 | 1998-05-05 | Abbott Laboratories | 3-deoxy-3-descladinose derivatives of erythromycins A and B |
US6274715B1 (en) * | 1995-11-08 | 2001-08-14 | Abbott Laboratories | Tricyclic erythromycin derivatives |
FR2742757B1 (fr) * | 1995-12-22 | 1998-01-30 | Roussel Uclaf | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
FR2745290B1 (fr) * | 1996-02-28 | 1998-04-03 | Roussel Uclaf | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
ES2203800T3 (es) * | 1996-05-07 | 2004-04-16 | Abbott Laboratories | Derivados de 3-descladinosa-2, 3-anhidroeritromicina. |
FR2751656B1 (fr) * | 1996-07-24 | 1998-10-16 | Hoechst Marion Roussel Inc | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
CA2370743A1 (en) * | 1999-04-16 | 2000-10-26 | Dennis Hlasta | Ketolide antibacterials |
-
1998
- 1998-07-21 FR FR9809259A patent/FR2781484B1/fr not_active Expired - Fee Related
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1999
- 1999-07-20 EA EA200100163A patent/EA003776B1/ru not_active IP Right Cessation
- 1999-07-20 ES ES99932916T patent/ES2188193T3/es not_active Expired - Lifetime
- 1999-07-20 TR TR2001/00178T patent/TR200100178T2/xx unknown
- 1999-07-20 PT PT99932916T patent/PT1098901E/pt unknown
- 1999-07-20 DE DE69904940T patent/DE69904940T2/de not_active Expired - Lifetime
- 1999-07-20 IL IL14097699A patent/IL140976A0/xx unknown
- 1999-07-20 CZ CZ2001237A patent/CZ2001237A3/cs unknown
- 1999-07-20 AU AU49132/99A patent/AU761551B2/en not_active Ceased
- 1999-07-20 DK DK99932916T patent/DK1098901T3/da active
- 1999-07-20 MX MXPA01000559A patent/MXPA01000559A/es unknown
- 1999-07-20 CA CA2338172A patent/CA2338172C/fr not_active Expired - Lifetime
- 1999-07-20 BR BRPI9912266A patent/BRPI9912266B8/pt not_active IP Right Cessation
- 1999-07-20 EP EP99932916A patent/EP1098901B1/fr not_active Expired - Lifetime
- 1999-07-20 US US09/744,320 patent/US6706692B1/en not_active Expired - Lifetime
- 1999-07-20 HU HU0103997A patent/HUP0103997A3/hu unknown
- 1999-07-20 KR KR1020017000839A patent/KR20010071993A/ko not_active Application Discontinuation
- 1999-07-20 AT AT99932916T patent/ATE231161T1/de not_active IP Right Cessation
- 1999-07-20 JP JP2000561195A patent/JP4583601B2/ja not_active Expired - Lifetime
- 1999-07-20 WO PCT/FR1999/001769 patent/WO2000005239A1/fr not_active Application Discontinuation
- 1999-07-20 CN CN99808934A patent/CN1359386A/zh active Pending
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2001
- 2001-01-19 ZA ZA200100566A patent/ZA200100566B/xx unknown
- 2001-01-19 NO NO20010332A patent/NO20010332L/no not_active Application Discontinuation
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