公开(公告)号：US4169939A

公开(公告)日：1979-10-02

申请号：US851019

申请日：1977-11-14

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

IPC分类号： C07H15/234 ,  C07H15/236 ,  C07H15/22

CPC分类号： C07H15/234 ,  Y02P20/55

摘要： A clinically valuable antibiotic, 3',4'-dideoxykanamycin B is now produced by a reduced number of consecutive steps in an improved overall yield by new processes starting from kanamycin B via intermediate derivatives of kanamycin B in which all the five amino groups are protected with an unsubstituted or substituted benzyloxycarbonyl group and possibly the 2"-hydroxyl group may be protected with a lower alkylsufonyl, arylsulfonyl or aralkylsulfonyl group.

公开(公告)号：US4156078A

公开(公告)日：1979-05-22

申请号：US745015

申请日：1976-11-26

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

IPC分类号： C07H15/234 ,  B01J23/00 ,  B01J25/00 ,  C07B61/00 ,  C07H15/236 ,  C07H15/22

CPC分类号： C07H15/234 ,  Y02P20/55

摘要： A useful antibiotic, 3',4'-dideoxykanamycin B can be prepared in shortened steps and in an improved overall yield by a new process starting from kanamycin B via new intermediate derivatives of kanamycin B in which all the amino groups and possibly the 2"-hydroxyl group are protected with sulfonyl-type protecting groups selected from lower alkyl-, aryl- and aralkyl-sulfonyl groups.

摘要翻译： 一种有用的抗生素，3'，4'-双脱氧卡那霉素B可以通过新的卡那霉素B通过卡那霉素B的新中间体衍生物从卡那霉素B开始的新方法以缩短的步骤和总产率提高，其中所有氨基和可能的2' ' - 羟基被选自低级烷基 - ，芳基 - 和芳烷基 - 磺酰基的磺酰基型保护基保护。

公开(公告)号：US4845082A

公开(公告)日：1989-07-04

申请号：US899100

申请日：1986-08-22

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Yoshihiko Kobayashi

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Yoshihiko Kobayashi

IPC分类号： C07H15/234 ,  A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/7036 ,  A61P31/04 ,  C07H15/236

CPC分类号： C07H15/234 ,  Y02P20/55

摘要： New compound, 3',4'-dideoxy-3'-fluorokanamycin B is now provided, which is useful as antibacterial agent.3',4'-Dideoxy-3'-fluorokanamycin B is prepared by a process comprising halogenating an N,O-protected derivative of 3'-deoxy-3'-fluoro-4'-O-sulfonylkanamycin B with a metal halide, reducing the resulting 4'- halogenated 3'-deoxy-3'-fluorokanamycin B derivative to convert its 4'-halo group into a hydrogen atom, and thereby to produce an N,O-protected derivative of 3',4'-dideoxy-3'-fluorokanamycin B, and removing the remaining amino-protecting groups and the remaining hydroxyl-protecting groups from the reduction product by conventional deprotecting methods.

摘要翻译： 现在提供新的化合物3'，4'-二脱氧-3'-氟卡那霉素B，其可用作抗菌剂。 3'，4'-二脱氧-3'-氟卡那霉素B通过包括用金属卤化物卤化3'-脱氧-3'-氟-4'-O-磺酰基卡那霉素B的N，O-保护的衍生物的方法制备， 减少所得的4'-卤代3'-脱氧-3'-氟卡那霉素B衍生物以将其4'-卤基转化成氢原子，从而产生3'，4'-二脱氧的N，O-保护的衍生物 -3'-氟卡那霉素B，并通过常规去保护方法从还原产物中除去剩余的氨基保护基团和剩余的羟基保护基团。

公开(公告)号：US4357466A

公开(公告)日：1982-11-02

申请号：US198612

申请日：1980-10-20

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Tomo Jikihara

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Tomo Jikihara

IPC分类号： C07H15/234 ,  C07H15/236 ,  A61K31/71 ,  C07H15/22

CPC分类号： C07H15/234

摘要： 3'-Deoxykanamycin A useful as antibacterial agent is produced from a protected kanamycin A derivative either by a process comprising imidazolylthiocarbonylation of the 3'- and 2"-hydroxyl groups of 4",6"-O-cyclohexylidene-4'-0:6'-N-carbonyl-5,2'-O-isopropylidene-1,3,3"-tri-N-tosylkanamycin A, preferential removal of the 3'-imidazolylthiocarbonyloxy group with tributyltin hydride for the 3'-deoxygenation, followed by removal of the 2"-O-imidazolylthiocarbonyl group with aqueous ammonia, removal of the N-tosyl groups with alkali or alkaline earth metal in liquid ammonia, hydrolytic fission of the 4',6'-cyclic carbamate ring and concurrent removal of the 5,2'-O-isopropylidene group and 4",6"-O-cyclohexylidene group, or by a process comprising selective acetylation of the 2"-hydroxyl group of said protected kanamycin A derivative with acetyl chloride in pyridine, trifluoromethanesulfonylation of the 3'-hydroxyl group, followed by concurrent removal of the 3'-trifluoromethanesulfonyloxy group and N-tosyl groups with alkali metal in liquid ammonia, removal of the 2"-O-acetyl group concurrently with hydrolytic fission of 4',6'-cyclic carbamate, and hydrolytic removal of the 5,2'-O-isopropylidene and 4",6"-O-cyclohexylidene groups.

摘要翻译： 可用作抗菌剂的3'-脱氧卡那霉素A由受保护的卡那霉素A衍生物制备，其通过包含4'，6“-O-亚环己基-4'的3'和2” - 羟基的咪唑基硫代羰基化的方法制备， -0：6'-N-羰基-5,2'-O-异亚丙基-1,3,3“ - 三-N-甲苯磺酰基卡那霉素A，优选用三丁基氢化锡将3'-咪唑硫基羰基氧基除去3' 脱氧，然后用氨水除去2“-O-咪唑基硫代羰基，在液氨中用碱金属或碱土金属除去N-甲苯磺酰基，4'，6'-环状氨基甲酸酯环的水解裂变 并且同时去除5,2'-O-异亚丙基和4“，6”-O-亚环己基，或通过包括将所述受保护的卡那霉素A衍生物的2'-羟基选择性乙酰化的方法与 吡啶中的乙酰氯，3'-羟基的三氟甲磺酰化，然后同时除去3'-三氟甲磺酸 氧基和N-甲苯磺酰基与液氨中的碱金属反应，与4'，6'-环状氨基甲酸酯的水解裂解同时除去2'-乙酰基，并除去5,2'-O 异亚丙基和4“，6”-O-亚环己基。

公开(公告)号：US4297485A

公开(公告)日：1981-10-27

申请号：US90591

申请日：1979-11-02

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Yasushi Takagi ,  Tomo Jikihara

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Yasushi Takagi ,  Tomo Jikihara

IPC分类号： C07H15/234 ,  C07H23/00 ,  C07H15/22

CPC分类号： C07H23/00 ,  C07H15/234

摘要： Aminoglycosidic antibiotic comprising a 6-0-(3"-aminoglycosyl)-2-deoxystreptamine optionally having a 4-0-(aminogycosyl) group, such as kanamycins, gentamicins, sisomicin, forms reversible complex with zinc cations by association of the zinc cations with some pairs of aminohydroxyl groups in the aminoglycoside, and the zinc-complexed amino groups are blocked from acylation. Reaction of this zinc complex with an acylation reagent having an amino-blocking acyl group brings about acylation of the non-complexed amino groups to give an N-acylated zinc complex, namely a complex of zinc cation with an N-acylated aminoglycosidic antibiotic derivative. Removal of zinc cations from N-acylated zinc complex yields a partially N-acylated aminoglycosidic antibiotic where 1- and 3"-amino groups are unprotected but all other amino groups protected with acyl group. Further reaction of this partially N-acylated product with a certain alkanoic acid or N-formyl-imidazole results in preferential acylation of 3"-amino group without 1-amino group being acylated, affording a 1-N-unprotected and other N-fully-protected derivative of the aminoglycosidic antibiotic which is valuable to be 1-N-acylated with .alpha.-hydroxy-.omega.-aminoalkanoic acid for high-yield production of known semi-synthetic 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl)-aminoglycosidic antibiotic.

摘要翻译： 包含任选具有4-0-（氨基糖基）基团的6-0-（3“ - 氨基糖基）-2-脱氧神经胺的氨基糖苷类抗生素，如卡那霉素，庆大霉素，西索米星，与锌阳离子形成与锌阳离子的可逆复合物， 在氨基糖苷中具有一对氨基羟基的阳离子和锌络合的氨基被封闭以进行酰化。 该锌络合物与具有氨基封闭酰基的酰化试剂的反应导致非络合氨基的酰化，得到N-酰化锌络合物，即锌阳离子与N-酰化氨基糖苷类抗生素衍生物的络合物。 从N-酰化锌络合物中除去锌阳离子产生部分N-酰化的氨基糖苷类抗生素，其中1-和3“ - 氨基未被保护，但是用酰基保护的所有其它氨基。 该部分N-酰化产物与某种链烷酸或N-甲酰基 - 咪唑的进一步反应导致3'-氨基的优先酰化而没有1-氨基被酰化，得到1-N-未保护的和其它N- 氨基糖苷类抗生素的完全保护的衍生物，其有价值的是用α-羟基-ω-氨基链烷酸1-N-酰化，用于高产量生产已知的半合成的1-N-（α-羟基 - ω-氨基烷酰基） 氨基糖苷类抗生素。

公开(公告)号：US4438107A

公开(公告)日：1984-03-20

申请号：US402812

申请日：1982-07-28

申请人： Isamu Watanabe ,  Takashi Yamaguchi ,  Kazuhiro Kamiya ,  Toshihito Mori ,  Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

发明人： Isamu Watanabe ,  Takashi Yamaguchi ,  Kazuhiro Kamiya ,  Toshihito Mori ,  Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

IPC分类号： A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/7036 ,  A61P31/04 ,  C07D303/16 ,  C07H15/224 ,  C07H15/226 ,  C08B37/00

CPC分类号： C07H15/224 ,  C07D303/16 ,  C07H15/226

摘要： An aminoglycoside compound of the following formula ##STR1## wherein one of R.sub.1 and R.sub.2 represents a hydrogen atom and the other, a methyl group, R.sub.3 represents a hydrogen atom or an amino acyl group having 2 to 5 carbon atoms, R.sub.4 represents a lower alkyl group substituted by one or two substituents selected from the class consisting of hydroxy and amino groups, or a hexopyranosyl group whose hydroxy groups may be substituted by amino groups,and a pharmaceutically acceptable acid addition salt thereof; and an antibiotic composition comprising said compound and its pharmaceutically acceptable acid addition salt.

摘要翻译： 下式的氨基糖苷类化合物其中R 1和R 2中的一个表示氢原子，另一个是甲基，R 3表示氢原子或具有2至5个碳原子的氨基酰基，R 4表示 被一个或两个选自羟基和氨基的取代基取代的低级烷基或其羟基可被氨基取代的六吡喃糖基及其药学上可接受的酸加成盐; 以及包含所述化合物及其药学上可接受的酸加成盐的抗生素组合物。

公开(公告)号：US4349666A

公开(公告)日：1982-09-14

申请号：US196586

申请日：1980-10-14

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Toshiaki Miyake

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Toshiaki Miyake

IPC分类号： C07H15/234 ,  C07H15/236 ,  C07H15/22

CPC分类号： C07H15/234 ,  Y02P20/55

摘要： 3'-Deoxykanamycin B, namely tobramycin is produced in an improved yield with a reduced reaction time under moderate reaction conditions, starting from a penta-N-protected 3'-mono-O-alkyl-, aralkyl- or arylsulfonylated derivative of kanamycin B in which all the 1, 3, 2' and 3"-amino groups and possibly the 6'-amino group have been protected by an arylsulfonyl group, especially tosyl group; the 3'-hydroxyl group of kanamycin B has been alkyl-, aralkyl- or arylsulfonylated; the 4"- and 6"-hydroxyl groups have been blocked with a di-valent hydroxyl-protecting group; and possibly the 4'-hydroxyl group and 6'-amino group have been blocked by being converted into the form of a 4', 6'-cyclic carbamate formed between the 4'-hydroxyl group and the 6'-amino group, by subjecting to a process essentially comprising reaction of said protected kanamycin B derivative with a metal halide for a reaction time of 30 min. to 2 hours at a reaction temperature of 0.degree. C..about.150.degree. C. to produce the corresponding 3'-halo compound, reductive replacement of the 3'-halo group by hydrogen and deprotection.

摘要翻译： 3-脱氧卡那霉素B，即在中等反应条件下，以5-N保护的3'-单-O-烷基 - 芳烷基 - 或芳基磺酰化衍生物开始，在中等反应条件下，产率提高，产量提高，反应时间缩短。 其中所有1,3,2'和3“ - 氨基和可能的6'-氨基都被芳基磺酰基，尤其是甲苯磺酰基保护; 卡那霉素B的3'-羟基已经是烷基 - ，芳烷基 - 或芳基磺酰化; 4“和6” - 羟基已被二价羟基保护基封闭; 并且可能的4'-羟基和6'-氨基已经通过在4'-羟基和6'-氨基之间形成的4'，6'-环状氨基甲酸酯的形式被阻断，通过 进行基本上包含所述受保护的卡那霉素B衍生物与金属卤化物的反应的方法，反应时间为30分钟。 在0℃的反应温度下反应2小时。在150℃降解产生相应的3'-卤代化合物，通过氢还原取代3'-卤代基团并脱保护。

公开(公告)号：US4125706A

公开(公告)日：1978-11-14

申请号：US676792

申请日：1976-04-14

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

IPC分类号： C07H15/23 ,  C07H15/20

CPC分类号： C07H15/23

摘要： A 1-N-(.alpha.-substituted-.omega.-aminoacyl)-3'-deoxyribostamycin, which is a useful antibiotic active against various drug-resistant bacteria, can be prepared advantageously by a process starting from a protected derivative of ribostamycin in the form of 1,6-carbamate and comprising the 3'-deoxygenation, the splitting of the carbamate linkage and the 1-acylation.

摘要翻译： 作为抗各种药物抗性细菌的有用的抗生素的1-N-（α-取代的ω-氨基酰基）-3'-脱氧肉豆蔻霉素可以有利地通过以下形式开始制备：以保护的核糖霉素衍生物形式 的1,6-氨基甲酸酯并且包含3'-脱氧，氨基甲酸酯键的分解和1-酰化。

公开(公告)号：US4104372A

公开(公告)日：1978-08-01

申请号：US678560

申请日：1976-04-20

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya

IPC分类号： C07H15/234 ,  A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/7036 ,  A61P31/04 ,  B01J23/00 ,  B01J25/00 ,  C07B61/00 ,  C07H15/236 ,  A61K31/71 ,  C07H15/22

CPC分类号： C07H15/234 ,  Y02P20/55

摘要： 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl)-derivatives of 3'-deoxykanamycin A or 6'-N-methyl-3'-deoxykanamycin A are provided as new and useful compounds which are active against gram-negative and gram-positive bacteria, including drug-resistant strains of these bacteria. Examples of these compounds include 1-N-((SR)-.beta.-amino-.alpha.-hydroxypropionyl)-3'-deoxykanamycin A, 1-N-((S)-.gamma.-amino-.alpha.-hydroxybutyryl)-3'-deoxykanamycin A, 1-N-((S)-.delta.-amino-.alpha.-hydroxyvaleryl)-3'-deoxykanamycin A and 1-N-((S)-.gamma.-amino-.alpha.-hydroxybutyryl)-6'-N-methyl-3'-deoxykanamycin A. The compounds may be prepared by selective acylation of the 1-amino group of 3'-deoxykanamycin A or 6'-N-methyl-3'-deoxykanamycin A with a corresponding .alpha.-hydroxy-.omega.-amino-alkanoic acid.

摘要翻译： 提供3'-脱氧卡那霉素A或6'-N-甲基-3'-脱氧卡那霉素A的1-N-（α-羟基 - ω-氨基烷酰基）衍生物作为对革兰氏阴性和革兰氏阴性菌具有活性的新的有用化合物 阳性细菌，包括这些细菌的耐药菌株。 这些化合物的实例包括1-N - （（SR）-β-氨基-α-羟基丙酰基）-3'-脱氧卡那霉素A，1-N - （（S）-γ-氨基-α-羟基丁酰基） 脱氧卡那霉素A，1-N - （（S）-δ-氨基-α-羟基戊酰基）-3'-脱氧卡那霉素A和1 -N（（S）-γ-氨基-α-羟基丁酰基）-6'-N- 甲基-3'-脱氧卡那霉素A.该化合物可以通过将3-脱氧卡那霉素A或6'- N-甲基-3'-脱氧卡那霉素A的1-氨基选择性酰化与相应的α-羟基 - 氨基 - 链烷酸。

公开(公告)号：US4065616A

公开(公告)日：1977-12-27

申请号：US710949

申请日：1976-08-02

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Isamu Watanabe

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Isamu Watanabe

IPC分类号： B01J23/00 ,  B01J25/00 ,  C07B61/00 ,  C07H15/224 ,  C07H15/23 ,  C07H15/22

CPC分类号： C07H15/224 ,  C07H15/23

摘要： This invention relates to new processes for the production of a 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl)-3'-deoxy-5-O-pentofuranosylneamine, including 3'-deoxybutirosins A and B, as a semi-synthetic antibiotic. This invention further relates to new and useful semi-synthetic antibiotics which are produced by the above new processes.

摘要翻译： 本发明涉及用于制备1-N-（α-羟基 - ω-氨基烷酰基）-3'-脱氧-5-O-呋喃鸟糖苷的新方法，包括3'-脱氧胆红素A和B作为半合成 抗生素。 本发明还涉及通过上述新方法生产的新的和有用的半合成抗生素。