公开(公告)号：US4008362A

公开(公告)日：1977-02-15

申请号：US390217

申请日：1973-08-21

申请人： Eiichi Akita ,  Tsutomu Tsuchiya ,  Shinichi Kondo ,  Shuntaro Yasuda ,  Sumio Umezawa ,  Hamao Umezawa

发明人： Eiichi Akita ,  Tsutomu Tsuchiya ,  Shinichi Kondo ,  Shuntaro Yasuda ,  Sumio Umezawa ,  Hamao Umezawa

IPC分类号： A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/7036 ,  A61K31/704 ,  A61P31/04 ,  C07H15/224 ,  C07H15/23 ,  C07H15/244

CPC分类号： C07H15/224 ,  C07H15/23

摘要： An 1-N-((S)-.alpha.-substituted-.omega.-aminoacyl)-neamine or -ribostamycin of the formula ##STR1## wherein R is a hydrogen atom or .beta.-D-ribofuranosyl group of the formula ##STR2## and R.sub.3 is hydroxyl, amino-NH.sub.2 or acylamino group --NHR.sub.4 in which R.sub.4 is an acyl group, and n is a whole number of 1 to 4, may be produced by subjecting the corresponding O-((S)-.alpha.-substituted-.omega.-aminoacyl)-neamine or -ribostamycin of the formula ##STR3## or its hydroxyl-masked and maino-masked form, to the action of a basic medium to produce an acyl-migration product of the formula: ##STR4## and, optionally converting the amino-masking groups into hydrogen atoms and also the hydroxyl-masking group into hydroge atom in a known manner if said amino-masking groups and said hydroxyl-masking groups are present in the acyl-migration product. The 1-N-((S)-.alpha.-substituted-.omega.-aminoacyl)-neamine or -ribostamycin produced is characterized by its useful activity inhibitory to the growth of bacteria resistant to the parent substance neamine or ribostamycin.

摘要翻译： 式（1）的1-N - （（S）-α-取代的ω-氨基酰基） - 单胺或-ribostamycin，其中R为氢原子或式为“IMAGE”的β-D-呋喃核糖基，R3为 是其中R 4为酰基，n为整数1至4的羟基，氨基-NH 2或酰基氨基-NHR 4，其可以通过使相应的O - （（S）-α-取代的ω- 氨基酰基） - 奈米霉素或结晶霉素或其羟基掩蔽和主掩蔽形式，与碱性介质的作用产生下式的酰基迁移产物：和/或将 如果所述氨基掩蔽基团和所述羟基掩蔽基团存在于酰基迁移产物中，则以已知方式将氨基掩蔽基团转化成氢原子，并将羟基掩蔽基团转变成水解原子。 产生的1-N - （（S）-α-取代的ω-氨基酰基） - 单胺或 - 生物素 - 特异霉素的特征在于其对母体neamine或核糖霉素具有抗性的细菌的生长有抑制作用。

公开(公告)号：US4008218A

公开(公告)日：1977-02-15

申请号：US559771

申请日：1975-03-19

申请人： Eiichi Akita ,  Tsutomu Tsuchiya ,  Shinichi Kondo ,  Shuntaro Yasuda ,  Sumio Umezawa ,  Hamao Umezawa

发明人： Eiichi Akita ,  Tsutomu Tsuchiya ,  Shinichi Kondo ,  Shuntaro Yasuda ,  Sumio Umezawa ,  Hamao Umezawa

IPC分类号： C07H15/224 ,  C07H15/23 ,  C07G11/00

CPC分类号： C07H15/224 ,  C07H15/23

摘要： An 1-N-((S)-.alpha.-substituted-.omega.-aminoacyl)-neamine or -ribostamycin of the formula: ##STR1## wherein R is a hydrogen atom or .beta.-D-ribofuranosyl group of the formula ##STR2## and R.sub.3 is hydroxyl, amino-NH.sub.2 or acylamino group --NHR.sub.4 in which R.sub.4 is an acyl group, and n is a whole number of 1 to 4, may be produced by subjecting the corresponding O-((S)-.alpha.-substituted-.omega.-aminoacyl)-neamine or -ribostamycin of the formula ##STR3## or its hydroxyl-masked and amino-masked form, to the action of a basic medium to produce an acyl-migration product of the formula: ##STR4## and, optionally converting the amino-masking groups into hydrogen atoms and also the hydroxyl-masking group into hydrogen atom in a known manner if said amino-masking groups and said hydroxyl-masking groups are present in the acyl-migration product. The 1-N-((S)-.alpha.-substituted-.omega.-aminoacyl)-neamine or -ribostamycin produced is characterized by its useful activity inhibitory to the growth of bacteria resistant to the parent substance neamine or ribostamycin.

摘要翻译： 具有下式的1-N - （（S）-α-取代的ω-氨基酰基） - 微量胺或 - 瑞波霉素：其中R是式“IMAGE”的氢原子或β-D-呋喃核糖基， R 3是羟基，氨基-NH 2或酰基氨基-NHR 4，其中R 4是酰基，n是整数1至4，可以通过使相应的O - （（S）-α-取代的-ω- - 氨基酰基） - 或者其羟基掩蔽和氨基掩蔽形式的微生物胺或β-内啡霉素或碱性培养基，以产生下式的酰基迁移产物： 如果所述氨基掩蔽基团和所述羟基掩蔽基团存在于酰基迁移产物中，则以已知的方式将氨基掩蔽基团转化成氢原子，并将羟基掩蔽基团转变为氢原子。 产生的1-N - （（S）-α-取代的ω-氨基酰基） - 单胺或 - 生物霉素的特征在于其对母体neamine或核糖霉素具有抗性的细菌的生长有抑制作用。

公开(公告)号：US4914192A

公开(公告)日：1990-04-03

申请号：US244500

申请日：1988-09-14

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Tomio Takeuchi ,  Akihiro Tanaka ,  Shuichi Sakamoto

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Tomio Takeuchi ,  Akihiro Tanaka ,  Shuichi Sakamoto

IPC分类号： A61K31/70 ,  A61K31/7042 ,  A61K31/7048 ,  A61P31/04 ,  C07H17/08

CPC分类号： C07H17/08 ,  Y02P20/55

摘要： Mycaminosyl tylonolide derivatives represented by the following general formula ##STR1## (wherein R.sup.1 denoted hydroxyl group, a lower alkanoyloxy group, benzyloxy group, azido group, or amino group which may optionally be substituted with a lower alkyl or a lower alkanoyl radical; R.sup.2 stands for hydrogen atom or hydroxyl group; R.sup.3 expresses hydrogen atom or formyl group; and means a double bond or a radical represented by ##STR2## and salts thereof.

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：US4469683A

公开(公告)日：1984-09-04

申请号：US473921

申请日：1983-03-10

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Tetsuo Shitara ,  Shuichi Sakamoto

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Tetsuo Shitara ,  Shuichi Sakamoto

IPC分类号： A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/7036 ,  A61P31/04 ,  C07H15/238 ,  A61K31/71 ,  C07H15/22

CPC分类号： C07H15/238 ,  Y02P20/55

摘要： New semi-synthetic antibiotics, 3"-epistreptomycin and 3"-epidihydrostreptomycin are now provided, which are useful as antibacterial agents. 3"-Epidihydrostreptomycin is produced by a process comprising hydrolyzing an appropriately N,O-protected 2",3"-N,O-carbonyl-3"-epidihydrostreptomycin which is prepared by skilled introduction of amino-protecting groups and hydroxyl-protecting groups of appropriately selected natures into dihydrostreptomycin and intermolecular condensation of a particular pair of amino-protecting and hydroxyl-protecting groups so introduced. 3"-Epistreptomycin is produced by a process comprising oxidizing the 3'-hydroxymethyl group of an appropriately N,O-protected 3"-epidihydrostreptomycin as prepared by skilled introduction of amino-protecting groups and hydroxyl-protecting groups of appropriately selected natures, and then removing the remaining protective groups from the resultant N,O-protected 3"-epistreptomycin obtained as the oxidation product.SUMMARY OF THE INVENTIONThis invention relates to new streptomycin derivatives which are new substances and useful as antibacterial agents. More particularly, this invention relates to 3"-epistreptomycin and 3"-epidihydrostreptomycin and also to processes for the production of these new streptomycin derivatives.BACKGROUND OF THE INVENTIONStreptomycin is a well known antibiotic which was discovered by Wasksman. Streptomycin, and dihydrostreptomycin which is obtained by reduction of the aldehyde group of streptomycin are widely used as medicine in therapeutic treatment of bacterial infections. However, as streptomycin and dihydrostreptomycin become widely used, such strains of bacteria resistant to these antibiotics have occurred, and owing to this the therapeutic effects of streptomycin and dihydrostreptomycin have considerably been reduced. The occurrence of such resistant bacteria is generally observed not only with the antibiotics of streptomycin type but also with other antibiotics such as kanamycins, lividomycins and the like. These historical facts are detailed in the general remarks as reported by Hamao Umezawa who is one of the present inventors and is a first discoverer of the mechanism of resistance of bacteria against aminoglycosidic antibiotics (H. Umezawa; "Advances in Carbohydrate Chemistry and Biochemistry" Vol. 30, page 183, Academic Press 1974). With the streptomycins, it has been found that the hydroxyl group at 3"-position of the molecule of streptomycins can be adenylated by such resistant bacteria capable of producing streptomycin adenyl-transferase and thereby 3"-O-adenylstreptomycins are formed, with a consequence that streptomycins can be inactivated in respect of their antibacterial effects (Umezawa et al.; "Journal of Antibiotics" Vol. 21, page 81 (1968)). In these circumstances, we, the present inventors, have conducted studies in an attempt to remove the 3"-hydroxyl group from the streptomycin molecule and thereby to eliminate the possibility of inactivation of streptomycin which would occur due to the adenylation of the 3"-hydroxyl group of streptomycin, so that there was provided a new derivative of streptomycin which would be active also against the bacteria resistant to streptomycin. As a result of our study, we succeeded in synthesizing 3"-deoxydihydrostreptomycin from streptomycin, and we found that this 3"-deoxydihydrostreptomycin is active against the resistant bacteria (see Japanese patent application prepublication "Kokai" No. 105154/77; and "Journal of Antibiotics" Vol. 29, page 978 (1976)).We have made our further study and have now succeeded in effecting the epimerization of the 3"-hydroxyl group of streptomycin and dihydrostreptomycin, and we have now found that the 3"-epistreptomycin and 3"-epidihydrostreptomycin now newly synthetized are active against a variety of streptomycin-resistant bacteria. Thus, we have accomplished this invention.DETAILED DESCRIPTION OF THE INVENTIONAccording to a first embodiment of this invention, therefore, there are provided as new compounds a 3"-epistreptomycin compound represented by the general formula ##STR1## wherein R denotes a hydroxymethyl group--CH.sub.2 OH for 3"-epidihydrostreptomycin and R denotes an aldehyde group --CHO for 3"-epistreptomycin, and a pharmaceutically acceptable acid-addition salt thereof.The pharmaceutically acceptable acid-addition salt of the new compound of the above general formula (I) includes a salt of 3"-epistreptomycin or 3"-epidihydrostreptomycin with an ordinary, non-toxic acid such as an inorganic acid, for example, hydrochloric acid, sulfuric acid, phosphoric acid and the like, as well as an organic acid, for example, acetic acid, malonic acid, citric acid and the like.3"-Epistreptomycin tri-hydrochloride mono-hydrate according to this invention is in the form of a colorless, solid substrance which shows a specific optical rotation [.alpha.].sub.D.sup.23 -80.degree. (c 1, water) but shows no definite melting point. Its elemental analysis (Found: C 35.22, H 6.51, N 13.58%) was coincident with the theoretical value of the empirical formula C.sub.21 H.sub.39 N.sub.7 O.sub.12. 3HCl.H.sub.2 O (Calculated: C 35.58, H 6.26, N 13.83%).3"-Epidihydrostreptomycin 3/2 carbonate according to this invention is in the form of a colorless, solid substance which shows a specific optical rotation [.alpha.].sub.D.sup.23 -79.degree. (c 0.9, water) but shows no definite melting point. Its elemental analysis (Found: C 39.63, H 6.47, N 14.33%) was coincident with the theoretical value of the empirical formula (C.sub.21 H.sub.41 N.sub.7 O.sub.12.3/2H.sub.2 CO.sub.3) (Calculated: C 39.94, H 6.55, N 14.49%).The antibacterial activities of 3"-epistreptomycin and 3"-epidihydrostreptomycin are demonstrated in Table 1 below, which exhibits the minimum inhibitory concentrations (mcg/ml) of the new compounds of this invention as estimated according to a standard serial dilution method using a nutrient agar medium as the incubation medium, the incubation being made at 37.degree. C. for 17 hours. Minimum inhibitory concentrations (mcg/ml) of streptomycin and dihydrostreptomycin were also estimated in the same manner as above for the comparison purpose and are shown in Table 1 below. As shown in Table 1, the new compounds of the formula (I) according to this invention exhibit antibacterial spectra similar to those of the comparative dihydrostreptomycin and show remarkably improved antibacterial activities against gram-negative bacteria, especially against various resistant strains of Escherichia coli. TABLE 1 __________________________________________________________________________ MIC (mcg/ml) Dihydro- 3"-Epidihydro- 3"-Epi- streptomycin Streptomycin Test organism streptomycin streptomycin (comparative) (comparative) __________________________________________________________________________Staphylococcus aureus 209P 3.12 3.12 3.12 3.12 Staphylococcus aureus AP01 3.12 3.12 1.56 3.12 Sarcia lutea PCI 1001 1.56 3.12 1.56 1.56 Bacillus subtilis NRRL B558 3.12 1.56 3.12 0.78 Salmonella typhi T-63 0.78 1.56 25 25 Escherichia coli K-12 1.56 1.56 1.56 1.56 Escherichia coli K-12 R5 6.25 6.25 >100 >100 Escherichia coli K-12 ML1629 1.56 3.12 100 >100 Escherichia coli K-12 ML1630 3.12 3.12 >100 >100 Escherichia coli K-12 ML1630 25 25 >100 >100 R8125 Escherichia coli W677 1.56 1.56 0.78 1.56 Escherichia coli JR66/W677 12.5 12.5 >100 >100 Escherichia coli C600 R135 3.12 3.12 50 50 Providencia sp. pv16 6.25 3.12 25 25 Pseudomonas aeruginosa 33 3.12 6.25 1.56 3.12 Pseudomonas aeruginosa No. 12 25 25 25 25 Pseudomonas aeruginosa 13--13 50 50 >100 >100 Mycobacterium smegmatis 607 0.78 1.56 0.78 0.78 __________________________________________________________________________The new compounds of this invention, namely 3"-epistreptomycin and 3"-epidihydrostreptomycin can be administered to living animals, including men, safely as much as the known streptomycin and dihydrostreptomycin for therapeutical treatment of bacterial infections, because they are of low toxicity as will be shown by the fact that when acute toxicity of 3"-epistreptomycin or 3"-epidihydrostreptomycin was estimated by intravenous injection of these compounds in groups of mice (ICR mice, adult, female, body weight 20 g..+-.0.5 g. six in each group), all the treated mice survived for more than 14 days after the new compound of this invention was administered intravenously into each mouse at a dosage of 4 mg/kg (LD.sub.50 more than 200 mg/kg).Processes for the production of the new compounds of the formula (I) according to this invention are described in the following.Briefly, 3"-epidihydrostreptomycin of this invention is produced starting from the known dihydrostreptomycin, and 3"-epistreptomycin of this invention is produced form the 3"-epidihydrostreptomycin now newly synthetized.Firstly, a summary of a process for the production of 3"-epidihydrostreptomycin is illustrated by the following first flow diagram which shows the production of 3"-epidihydrostreptomycin from dihydrostreptomycin via about eight stages. In the first flow diagram and also in the another flow diagrams shown later, such intermolecular sites of the compound which just have undergone chemical change or modification through the chemical reaction at a particular stage of the concerned process are preferentially represented in the respective flow diagrams, so that such substituent or substituents which is or are existing in the compound in one particular stage but is or are remaining unchanged in the compound in the next stage (that is, the stage just following said particular stage) are sometimes omitted from being shown in the next stage of the flow diagram, for sake of simplicity. In the following flow diagrams, Ac denotes an acetyl group. ##STR2##Now, a process of producing 3"-epidihydrostreptomycin is described with reference to the respective stages of the process shown in the first flow diagram as above and is fully illustrated by Example 1 given later.Dihydrostreptomycin which is used as the starting substance in this process is the compound represented by the formula (1) in the first flow diagram. To synthetize 3"-epidihydrostreptomycin of this invention with starting from dihydrostreptomycin, at first, the 2"-methylamino group of the compound of the formula (1) is selectively protected in Stage A of the process by a known aminoprotecting group such as an aralkyloxycarbonyl group, preferably benzyloxycarbonyl group. To this end, the starting compound of the formula (1) may preferably be reacted with a 1 molar or substantially 1 molar proportion of benzyloxycarbonyl chloride in a mixture of water and acetone at a temperature of -20.degree. C. to 50.degree. C., preferably at 0.degree. C. under ice-cooling in the presence of a base, preferably an alkali metal carbonate such as sodium carbonate, whereby the preferential benzyloxycarbonylation of the 2"-methylamino group takes place to produce 2"-N-benzyloxycarbonyldihydrostreptomycin briefly represented by the formula (2) in the first flow diagram.Then, in Stage B of this process, a pair of two 3'- and 3'a-hydroxyl groups as well as a pair of two 4"- and 6"-hydroxyl groups of the compound of the formula (2) are protected by a known di-valent hydroxyl-protecting group such as an alkylidene group, preferably isopropylidene group. For this purpose, the compound of the formula (2) may preferably be reacted with 2,2-dimethoxypropane in anhydrous dimethylformamide (DMF) in the presence of a reaction catalyst such as p-toluenesulfonic acid, whereby the pair of the two 3'- and 3'a-hydroxyl groups as well as the pair of the two 4"- and 6"-hydroxyl groups of the compound of the formula (2) are each protected simultaneously by a single isopropylidene group, to afford 2"-N-benzyloxycarbonyl-3',3'a; 4", 6"-di-O-isopropylidene-dihydrostreptomycin briefly represented by the formula (3) in the first flow diagram.Thereafter, in Stage C of this process, all the remaining free (four) hydroxyl groups and all the two guanidyl groups of the compound of the formula (3) are protected, respectively. To this end, all these functional hydroxyl and guanidyl groups may preferably be blocked by acetyl groups. The acetylation reagent available for this purpose may be acetic anhydride as used in the presence of sodium acetate. Thus, the compound of the formula (3) is reacted with acetic anhydride in the presence of sodium acetate using an excess of acetic anhydride as the reaction medium, when there is produced tetra-N-.sup.G -acetyl-2,5,6,3"-tetra-O-acetyl-2"-N-benzyloxycarbonyl-3',3'a; 4", 6"-di-O-isopropylidene-dihydrostreptomycin represented by the formula (4) in the first flow diagram.Further, in Stage D of this process, the compound of the formula (4) is treated so as to remove preferentially the 2"-N-benzyloxycarbonyl group therefrom and thereby liberate the free 2"-methylamino group. For this purpose, the compound of the formula (4) may preferably be subjected to catalytic hydrogenolysis with hydrogen in the presence of a known hydrogenolysis catalyst such as palladium black as be conducted conventionally in the deprotection technique for removal of the amino-protecting benzyloxycarbonyl group. There is thus formed tetra-N.sup.G -acetyl-2,5,6,3"-tetra-O-acetyl-3',3'a; 4",6"-di-O-isopropylidene-dihydrostreptomycin briefly represented by the formula (5) in the first flow diagram.Moreover, in Stage E of the present process, the compound of the formula (5) is treated so as to remove preferentially the blocking acetyl group from the 3"-hydroxyl group of the compound (5). For this purpose, the compound (5) is dissolved in a volume of ethanol, and the resulting ethanolic solution is allowed to stand at a temperature of 20.degree.-30.degree. C. for 1 day or usually for a period of about 3 days, whereby the selective removal of the 3"-O-acetyl group takes place through the ethanolysis. This unique fact that the blocking acetyl group can be removed only from the 3"-hydroxyl group of the compound (5) while the other blocking O-acetyl groups are not cleaved out of the 2-, 5- and 6-hydroxyl groups of said compound is unexpected and surprising. Through this Stage E, there is formed tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-3',3'a; 4",6"-di-O-isopropylidenedihydrostreptomycin briefly represented by the formula (6) in the first flow diagram.Then, in Stage F of the present process, the 2"-methylamino group of the compound of the formula (6) is again protected by a benzyloxycarbonyl group. To this end, the compound of the formula (6) may either be reacted with benzyloxycarbonyl chloride in the same manner as in the aforesaid Stage A, or may be reacted with benzyloxycarbonyl chloride in chloroform in the presence of sodium hydrogen carbonate. In this way, there is produced tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-2"-N-benzyloxycarbonyl-3',3'a; 4",6"-di-O-isopropylidenedihydrostreptomycin birefly represented by the formula (7) in the first flow diagram.Thereafter, in Stage G of the present process, the compound of the formula (7) is dissolved into a volume of a suitable organic solvent such as dichloromethane and the resultant solution of the compound (7) is reacted with a 1-10 molar proportion of trifluoromethanesulfonic acid anhydride in the presence of pyridine under cooling (preferably at a temperature of approximately -50.degree. C..about.+50.degree. C.), so that there is once formed an unstable 3"-O-trifluoromethylsulfonyl derivative of the compound (7) as a glassy material. This glassy material is then dissolved into a volume of pyridine and allowed to stand at a temperature of 10.degree. C..about.100.degree. C., preferably at ambient temperature, when the 3"-trifluoromethylsulfonyl group is interacted and condensed with the 2"-benzyloxycarbonylmethylamino group, so that the cyclisation reaction takes place to form a cyclic carbamate group, giving the compound of the formula (8) briefly shown in the first flow diagram, namely tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-2",3"-N,O-carbonyl-3"-epi-3',3'a; 4",6"-di-O-isopropylidenedihydrostreptomycin.Finally, in Stage H of the present process, the compound of the formula (8) is subjected to an N,O-deprotecting treatments as well as removal of the 2",3"-N,O-carbonyl group by a hydrolytic ring-fission thereof. That is, the removal of the N,O-protecting acetyl groups and the removal of the cyclic carbamate group (the 2",3"-N,O-carbonyl group) from the compound of the formula (8) are effected in this Stage H. For this purpose, the compound of the formula (8) may conveniently by hydrolyzed in aqueous tetrahydrofuran in the presence of barium hydroxide, so that both of the acetyl groups and the cyclic carbamate group can be removed at once. The liberated 3"-hydroxyl group which has undergone the decarbonylation just at this stage of removal of the 2",3"-N,O-carbonyl group is remaining inversed in the epi-position, so that there is formed 3"-epi-3',3'a; 4",6'-di-O-isopropylidenedihydrostreptomycin. The latter compound is further necessary in this Stage H to be subjected to removal of the 3',3'a; 4",6"-di-O-isopropylidene groups therefrom, and this can be achieved according to a conventional method for removing the isopropylidene group known in the usual deprotection technique. For instance, the removal of the 3',3'a; 4",6"-di-O-isopropylidene groups may be accomplished by hydrolyzing the intermediate 3"-epi-3',3'a; 4",6"-di-O-isopropylidenedihydrostreptomycin in aqueous acetic acid. In this way, there is produced the aimed 3"-epidihydrostreptomycin, represented by the formula (I') in the first flow diagram.In the foregoing descriptions, the process of producing the compound of the formula (I') of this invention is described with reference to such a case where the benzyloxycarbonyl group, isopropylidene group and acetyl group are particularly selected as the protective groups. It will be self-evident, however, that the required, N,O-protection of the concerned compounds can be achieved using such a known amino-protecting group which serves equivalently to the benzyloxycarbonyl group; and such a known guanidyl-amino (or imino) protecting group which serves equivalently to the acetyl group, as well as such known hydroxyl-protecting groups which serve equivalently to the isopropylidene group and acetyl group, respectively.According to a second embodiment of this invention, therefore, there is provided a process for the production of 3"-epidihydrostreptomycin, which comprises the consecutive steps of:(a) Reacting tetra-N.sup.G -acetyl-2,5,6,3"-tetra-O-acetyl-3',3'a; 4", 6"-di-O-isopropylidene-dihydrostreptomycin of the formula ##STR3## wherein Ac denotes an acetyl group, with ethanol at a temperature of 20.degree.-30.degree. C. to effect preferential removal of the 3"-O-acetyl group from the above N,O-protected dihydrostreptomycin compound and thereby to produce tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-3',3'a; 4", 6"-O-isopropylidenedihydrostreptomycin,(b) Reacting the product of the step (a) just above with benzyloxycarbonyl chloride to produce tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-2"-N-benzyloxycarbonyl-3',3'a; 4",6"-di-O-isopropylidene-dihydrostreptomycin,(c) Reacting the product of the step (b) just above with trifluoromethanesulfonic acid anhydride in pyridine at a temperature of -50.degree. C. to 50.degree. C. to form the 30"-O-trifluoromethylsulfonyl derivative thereof, followed by allowing the latter derivative to stand in solution in pyridine at a temperature of 10.degree. C. to 100.degree. C. to produce tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-2",3"-N,O-carbonyl-3"-epi-3',3'a; 4",6"-di-O-isopropylidene-dihydrostreptomycin of the formula ##STR4## wherein Ac is as defined as above.(d) Hydrolyzing the product of the step (c) just above with water in the presence of barium hydroxide to remove all the acetyl groups and the 2",3"-N,O-carbonyl group therefrom and thus to produce 3"-epi-3',3'a; 4",6"-di-O-isopropylidene-dihydrostreptomycin, and(e) Hydrolyzing the product of the step (d) just above to remove the 3',3'a; 4",6"-di-O-isopropylidene groups therefrom and thus to produce the desired 3"-epidihydrostreptomycin.Besides, the second new compound of this invention, namely 3"-epistreptomycin can be produced with starting from the 3"-epidihydrostreptomycin now newly synthetized as above. A summary of such a process of producing 3"-epistreptomycin is illustrated by the following second flow diagram, where such intermolecular sites of the compound which just have undergone chemical change or modification through the chemical reaction at one particular stage of the process concerned are preferentially represented, so that such substituent or substituents which is or are existing in the concerned compound in one particular stage but is or are remaining unchanged in the next stage following said particular stage are sometimes omitted from being shown in the next stage of the second flow diagram, for sake of simplicity. ##STR5##In the following, a process of producing 3"-epistreptomycin from 3"-epidihydrostreptomycin is described with reference to the respective stages of the process shown in the second flow diagram as above and is fully illustrated by Example 2 given later.3"-Epidihydrostreptomycin which is employed as the starting substance in this process is the compound of the formula (I') shown in the first flow diagram given hereinbefore. In Stage I of this process, the 2"-methylamino group of the starting compound of the formula (I') is at first protected preferentially with benzyloxycarbonyl group by reacting the starting compound (I') with benzyloxycarbonyl chloride in the same manner as in Stage A of the process according to the first flow diagram. There is thus formed 2"-N-benzyloxycarbonyl-3"-epidihydrostreptomycin of the formula (9) shown in the second flow diagram, which is usually obtained in the form of its hydrochloride.In Stage J of this process, a pair of two 3'- and 3'a-hydroxyl groups of the compound of the formula (9) is protected with a known di-valent hydroxyl-protecting group such as an alkylidene group. To this end, the compound of the formula (9) may be reacted with an excess over the 1 molar proportion of 2,2-dimethoxypropane in anhydrous DMF in the presence of p-toluenesulfonic acid, so that the desired mono-O-isopropylidenated product is formed in mixture with some poly-O-isopropylidenated products. The poly-O-isopropylidenated products can be converted into the desired mono-O-isopropylidenated product by treatment with aqueous acetic acid. There is thus produced 2"-N-benzyloxycarbonyl-3"-epi-3',3'a-O-isopropylidenedihydrostreptomycin of the formula (10) briefly shown in the second flow diagram.In the next stage K of this process, all the remaining free hydroxyl groups and all the guanidyl groups of the compound of the formula (10) are protected with suitable protective groups. For this purpose, the compound of the formula (10) may preferably be acetylated in the same manner as in Stage C of the process according to the first flow diagram, that is, by reacting with a 10 molar proportion or more of acetic anhydride in the presence of sodium acetate. By this Stage K, there is produced tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epi-3',3'a-O-isopropylidenedihydrostreptomycin of the formula (11) briefly shown in the second flow diagram.In Stage L of this process, the compound of the formula (11) is then subjected to removal of the 3',3'a-O-isopropylidene group therefrom in the same manner as in Stage H of the process according to the first flow diagram, by hydrolyzing the compound (11) in aqueous acetic acid, so that there is produced the compound of the formula (12) briefly shown in the second flow diagram, namely tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epidihydrostreptomycin.Next, in Stage M of the present process, the 3'-hydroxymethyl group (the methylol group) of the compound of the formula (12) is oxidized into the aldehyde group --CHO. To this end, the compound of the formula (12) may preferably be reacted with dimethylsulfoxide as an oxidation reagent in the presence of pyridine, trifluoroacetic acid and dicyclohexylcarbodiimide. There is thus produced tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epistreptomycin (which is not shown in the second flow diagram). The latter aldehyde compound is then subjected to removal of the acetyl groups therefrom, and this deacetylation may conveniently be effected by hydrolysing said aldehyde compound with concentrated aqueous ammonia in methanol. In this way, there is produced 2"-N-benzyloxycarbonyl-3"-epistreptomycin of the formula (13) shown in the second diagram.After the above deacetylation step, in the final Stage N of the present process, the compound of the formula (13) is subjected to removal of the 2"-N-benzyloxycarbonyl group therefrom to give the desired 3"-epistreptomycin of the formula (I") shown in the second diagram. To remove the 2"-N-benzyloxycarbonyl group from the compound (13), the latter compound may conveniently be subjected to a conventional catalytic hydrogenolysis with hydrogen in the presence of a known hydrogenolysis catalyst such as palladium black according to the known deprotection technique.According to a third embodiment of this invention, therefore, there is provided a process for the production of 3"-epistreptomycin which comprises the consecutive steps of:(a) Reacting 3"-epidihydrostreptomycin with a 1 molar or substantially 1 molar proportion of benzyloxycarbonyl chloride in a mixture of water and acetone at a temperature of -20.degree. C. to 50.degree. C. in the presence of an alkali metal carbonate to selectively benzyloxycarbonylate the 2"-methylamino group of 3"-epidihydrostreptomycin and thereby to produce 2"-N-benzyloxycarbonyl-3"-epidihydrostreptomycin,(b) Reacting the product of the step (a) just above with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid to produce 2"-N-benzyloxycarbonyl-3"-epi-3',3'a-O-isopropylidene-dihydrostreptomycin,(c) Reacting the product of the step (b) just above with acetic anhydride in the presence of sodium acetate to produce tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epi-3,3'a-O-isopropylidene-dihydrostreptomycin,(d) Hydrolyzing the product of the step (c) just above with aqueous acetic acid to produce tetra-N.sup.G -acetyl-2,5,6,3",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epidihydrostreptomycin,(e) Oxidizing the 3'-hydroxymethyl group of the product of the step (d) just above by reacting the latter compound with dimethylsulfoxide in the presence of pyridine, trifluoroacetic acid and dicyclohexylcarbodiimide to produce tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epistreptomycin,(f) Removing all the acetyl groups from the product of the step (e) just above by hydrolysis to produce 2"-N-benzyloxycarbonyl-3"-epistreptomycin, and(g) Subjecting the 2"-N-benzyloxycarbonyl-3"-epistreptomycin to a catalytic hydrogenolysis to remove the 2"-N-benzyloxycarbonyl group therefrom and thus to produce the desired 3"-epistreptomycin.We have further found it also possible to produce 3"-epidihydrostreptomycin of the formula (I') through a route different from the route of the process according to the first flow diagram, via the 2"-N-benzyloxycarbonyl-dihydrostreptomycin of the formula (2) obtained as an intermediate product. Thus, a further process of producing 3"-epidihydrostreptomycin via the intermediate compound of the formula (2) is briefly shown in the following third flow diagram and is fully illustrated by Example 3 given later. The third flow diagram is shown in brief similarly to the first and second flow diagrams in such way that the intermolecular sites of the compound which just have undergone chemical change or modification at one particular reaction stage are preferentially shown while such sites of the compound which are remaining unchanged at that particular reaction stage are not shown in the third flow diagram. ##STR6##In the process according to the third flow diagram as above, Stage O of this process is to effect the protective N,O-acetylation of the 2"-N-benzyloxycarbonyl-dihydrostreptomycin, namely the compound of the formula (2) shown in the first flow diagram and may be conducted in a similar manner to Stage C of the process according to the first flow diagram or to Stage K of the process according to the second flow diagram. In Stage O of this process, therefore, the compound of the formula (2) may preferably be reacted with a 11 molar proportion or more of acetic anhydride in the presence of sodium acetate using an excess of the acetic anhydride as the reaction medium to acetylate all the remaining free hydroxyl groups (seven) (excepting the 3'-hydroxyl group) and all the two guanidyl groups of the compound of the formula (2) and thereby to produce tetra-N.sup.G -acetyl-2,5,6,3'a,3",4",6"-hepta-O-acetyl-2"-N-benzyloxycarbonyldihydrostreptomycin represented by the formula (14) in the third flow diagram.Step P of this process is to de-benzyloxycarbonylate the compound of the formula (14) and may be carried out in the same manner as in Stage D of the process according to the first flow diagram. Thus, the compound of the formula (14) may be subjected to a conventional catalytic hydrogenolysis with hydrogen in the presence of a known hydrogenolysis catalyst such as palladium black to remove the 2"-N-benzyloxycarbonyl group from said compound and thereby to produce tetra-N.sup.G -acetyl-2,5,6,3'a,3",4",6"-hepta-O-acetyl-dihydrostreptomycin briefly represented by the formula (15) in the third flow diagram.Stage Q of this process is to effect a preferential removal of the 3"-O-acetyl group from the compound of the formula (15) and may be carried out in the same manner as in Stage E of the process according to the first flow diagram. Thus, the compound of the formula (15) is dissolved in a volume of ethanol and the resultant ethanolic solution is allowed to stand at a temperature of 20.degree.-30.degree. C. for 1 day or more, whereby the preferential removal of the 3"-O-acetyl gropu from the 3"-hydroxyl group of the compound (15) takes place through ethanolysis. This fact that the blocking acetyl group can be removed only from the 3"-hydroxyl group of the compound (15) while all the other blocking O-acetyl groups are not cleaved out of the compound (15) is unexpectable and surprising. Through this Stage Q, there is produced tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyl-dihydrostreptomycin briefly represented by the formula (16) in the third flow diagram.Stage R of this process is to effect re-introduction of benzyloxycarbonyl group into the 2"-methylamino group of the compound of the formula (16) and may be conducted in the same manner as in Stage F of the process according to the first flow diagram. Thus, the compound of the formula (16) may either be reacted with benzyloxycarbonyl chloride in a mixture of water and acetone under icecooling in the presence of an alkali metal carbonate or may be reacted with benzyloxycarbonyl chloride in chloroform in the presence of sodium hydrogen carbonate. By this Stage R, there is produced tetra-N.sup.G -acetyl-2,5,6,3'a,4"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-dihydrostreptomycin briefly represented by the formula (17) in the third flow diagram.Stage S of this process is to methanesulfonylate the 3"-hydroxyl group of the compound of the formula (17) and may be conducted by reacting the compound (17) with a 1 molar or substantially 1 molar proportion of methanesulfonyl chloride in pyridine at a temperature of -50.degree. C. to +50.degree. C. By this Stage S, there is produced tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-O-methylsulfonyl-dihydrostreptomycin briefly represented by the formula (18) in the third flow diagram.Stage T of the present process is to convert the compound of the formula (18) into a 2",3"-N,O-carbonylated derivative thereof. For this purpose, the compound of the formula (18) may be dissolved in a volume of 2-methoxy-ethanol and the resultant solution is heated to an elevated temperature of 50.degree. C. to 100.degree. C. in the presence of sodium acetate, or alternatively the compound of the formula (18) may be reacted with sodium methylate in methanol at a temperature of -20.degree. C..about.+50.degree. C., preferably at ambient temperature, whereby the 3"-methylsulfonyloxy group is interacted and condensed with the 2"-benzyloxycarbonyl-(methyl)amino group, so that the cyclisation reaction occurs to form the 2",3"-N,O-carbonyl group (the cyclic 2",3"-N,O-carbamate group), with concomitantly involving the reaction for removal of all the acetyl groups. In this way, there is produced 2",3"-N,O-carbonyl-3"-epidihydrostreptomycin of the formula (19) shown in the third flow diagram (see Example 3(f), (g) given later).Stage U of the present process is to effect the hydrolytic ring-fission of the cyclic cis-2",3"-N,O-carbamate group of the compound of the formula (19). Thus, this Stage U may be accomplished by hydrolyzing the compound of the formula (19) with water in the presence of barium hydroxide in tetrahydrofuran, whereby the 2",3"-N,O-carbonyl group (the cyclic 2",3"-N,O-carbamate group) can be removed by the ring-fission thereof from the compound of the formula (19) and the 3"-hydroxyl group so liberated is remaining inversed in the epi-position, to afford the desired 3"-epidihydrostreptomycin, namely the compound of the formula (I') in the third flow diagram.According to a fourth embodiment of this invention, therefore, there is provided a process for the production of 3"-epidihydrostreptomycin, which comprises the consecutive steps of:(a) Reacting tetra-N.sup.G -acetyl-2,5,6,3'a, 3",4",6"-hepta-O-acetyl-dihydrostreptomycin of the formula ##STR7## wherein Ac denotes an acetyl group, with ethanol at a temperature of 20.degree.-30.degree. C. to effect preferential removal of the 3"-O-acetyl group from the above-mentioned N,O-acetylated dihydrostreptomycin compound and thereby to produce tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyldihydrostreptomycin,(b) Reacting the product of the step (a) just above with benzyloxycarbonyl chloride to produce tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyldihydrostreptomycin,(c) Reacting the product of the step (b) just above with methanesulfonyl chloride in pyridine to produce tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-O-methylsulfonyl-dihydrostreptomycin,(d) Reacting the product of the step (c) just above either with 2-methoxyethanol at a temperature of 50.degree. C. to 100.degree. C. or with sodium methylate in methanol at a temperature of -20.degree. C..about.50.degree. C., to produce 2",3"-N,O-carbonyl-3"-epi-dihydrostreptomycin, and(e) Hydrolyzing the product of the step (d) just above with water in the presence of barium hydroxide to remove the 2",3"-N,O-carbonyl group therefrom and thus to produce the desired 3"-epidihydrostreptomycin.As stated hereinbefore, the new compounds of this invention, namely 3"-epistreptomycin and 3"-epidihydrostreptomycin are of a low toxicity. The new compounds of this invention are each effective in therapeutic treatment of bacterial infections when administered intramuscularly in a dosage of from about 100 mg to about 1000 mg per day in divided dosages three or four times a day. Generally, the new compounds of this invention may be administered orally, intraperitoneally, intravenously or intramuscularly using any pharmaceutical form known in the art for such administration and in a similar manner to streptomycin and dihydrostreptomycin. Examples of pharmaceutical forms for oral administration are powders, capsules, tablets, syrup and the like. The new compounds of this invention may also be formulated into an aqueous injectable solution.According to a fifth embodiment of this invention, therefore, there is provided an antibacterial composition comprising an antibacterially effective amount of 3"-epistreptomycin or 3"-epidihydrostreptomycin as the active ingredient, in combination with a pharmaceutically acceptable carrier for the active ingredient.This invention is now illustrated with reference to the following Examples which show the production of the new compounds of this invention.

摘要翻译： 现在提供新的半合成抗生素，3“ - 上链霉素和3” - 表型氢化链霉素，它们可用作抗菌剂。 3“ - 表型二氢链霉素通过包括水解适当的N，O-保护的2'，3” - N，O-羰基-3“ - 表达氢链霉素的方法产生，其通过熟练地引入氨基保护基团而制备， 适当选择性质的羟基保护基团转化为二氢链霉素，并引入特定的一对氨基保护基和羟基保护基团的分子间缩合。 3“ - 异链霉素通过包括氧化适当的N，O-保护的3” - 表型氢化链霉素的3'-羟甲基的方法产生，其通过熟练地引入氨基保护基团和适当选择的性质的羟基保护基团 ，然后从作为氧化产物获得的所得N，O-保护的3“ - 表链霉素中除去剩余的保护基团。

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：US4547492A

公开(公告)日：1985-10-15

申请号：US639392

申请日：1984-08-10

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Toshio Yoneta ,  Shunzo Fukatsu

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Toshio Yoneta ,  Shunzo Fukatsu

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

CPC分类号： C07H15/234 ,  Y02P20/55

摘要： 1-N-(L-3-amino-2-hydroxypropionyl)-2',-3'-dideoxykanamycin A and 1-N-(L-4-amino-2-hydroxybutyryl)-2',3'-dideoxykanamycin A are now provided which each is a new compound useful as antibacterial agent. The new compounds each is produced by acylating the 1-amino group of 2',3'-dideoxykanamycin A with L-3-amino-2-hydroxypropionic or L-4-amino-2-hydroxybutyric acid.

摘要翻译： 1-N-（L-3-氨基-2-羟基丙酰基）-2'，-3'-二脱氧卡那霉素A和1-N-（L-4-氨基-2-羟基丁酰基）-2'，3'-二脱氧卡那霉素A 现在提供它们各自是可用作抗菌剂的新化合物。 新化合物各自通过用L-3-氨基-2-羟基丙酸或L-4-氨基-2-羟基丁酸酰化2'，3'-二脱氧卡那霉素A的1-氨基而产生。

公开(公告)号：US4438109A

公开(公告)日：1984-03-20

申请号：US285747

申请日：1981-07-22

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Akihiro Tanaka

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Tsutomu Tsuchiya ,  Akihiro Tanaka

IPC分类号： C07H17/08 ,  A61K31/70

CPC分类号： C07H17/08

摘要： Tylosin derivatives shown by the general formula ##STR1## wherein R represents a hydrogen atom or a hydroxyl group; R.sub.1 represents a halogen atom, a hydroxyl group, a tetrahydrofuranyloxy group, a tetrahydropyranyloxy group, a tetrahydrothiofuranyloxy group, a tetrahydrothiopyranyloxy group, an alkanoyloxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, a lower alkylthiomethyloxy group, a heterocyclic thio group which may have a substituent, a mono- or di- lower alkylamino lower alkylthio group or a group of ##STR2## (wherein R.sub.4 represents a hydroxyl group or an alkanoyloxy group); R.sub.2 represents a hydrogen atom, a hydroxyl group, or an alkanoyloxy group; R.sub.3 represents a hydroxyl group or an alkanoyloxy group; and represents a single bond or a double bond, but represents a double bond when R.sub.2 is a hydrogen atom.These compounds are useful as antibiotics.

摘要翻译： 由通式表示的泰乐菌素衍生物，其中R表示氢原子或羟基; R 1表示卤素原子，羟基，四氢呋喃氧基，四氢吡喃氧基，四氢噻喃氧基，四氢噻喃氧基，烷酰氧基，芳基羰基氧基，芳烷基羰基氧基，低级烷基硫代甲氧基，可具有的杂环硫基 取代基，单 - 或二 - 低级烷基氨基低级烷硫基或一组（其中R 4表示羟基或烷酰氧基）。 R2表示氢原子，羟基或烷酰氧基; R3表示羟基或烷酰氧基; 并且表示单键或双键，但当R 2为氢原子时，表示双键。 这些化合物可用作抗生素。

公开(公告)号：US4298727A

公开(公告)日：1981-11-03

申请号：US114779

申请日：1980-01-23

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

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

IPC分类号： C07H15/234 ,  A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/7036 ,  A61P31/04 ,  C07H15/236 ,  C07H15/22

CPC分类号： C07H15/234 ,  Y02P20/55

摘要： 3',4'-Dideoxy derivative and 1-N-((S)-.alpha.-hydroxy-.omega.-aminoalkanoyl)-3',4'-dideoxy derivative of kanamycin A are now synthetized from kanamycin A and show a wider and/or higher antibacterial activity than the parent kanamycin A so that they are useful in therapeutic treatment of infections by gram-negative and gram-positive bacteria, including drug-resistant strains thereof. The production of these new derivatives may be made by preparing a protected kanamycin A derivative having its 3'- and 4'-hydroxyl groups unprotected and having its all or substantially all other functional groups protected from the initial material, kanamycin A, sulfonylating the 3'- and 4'-hydroxyl groups, removing the 3'- and 4'-sulfonyloxy groups from the resulting 3',4'-di-sulfonic acid ester product to give a 3'-eno-kanamycin A derivative, hydrogenating the 3'-eno-kanamycin A derivative to saturate the 3',4'-unsaturated bond and to yield a protected 3',4'-dideoxykanamycin A product, followed by removal of the remainiing protective groups, and optionally further followed by 1-N-acylation of the 1-amino group of the resulting 3',4'-dideoxykanamycin A with an (S)-.alpha.-hydroxy-.omega.-aminoalkanoic acid or its reactive equivalent.

摘要翻译： 卡那霉素A的3'，4'-二脱氧衍生物和1-N - （（S）-α-羟基-ω-氨基烷酰基）-3'，4'-二脱氧衍生物现在从卡那霉素A合成并显示出更宽和/ 或更高的抗菌活性，使得它们可用于革兰氏阴性和革兰氏阳性细菌（包括其耐药菌株）的感染的治疗性治疗。 这些新衍生物的生产可以通过制备其未被保护的3'和4'-羟基的保护的卡那霉素A衍生物和其全部或基本上所有其它保护起始材料的卡那霉素A的其他官能团来制备，磺酰化3 '和4'-羟基，从所得的3'，4'-二磺酸酯产物中除去3'-和4'-磺酰氧基，得到3'-烯 - 卡那霉素A衍生物，将3 ' - 卡那霉素A衍生物使3'，4'-不饱和键饱和并产生受保护的3'，4'-二脱氧卡那霉素A产物，然后除去剩余的保护基，并且任选地进一步加入1-N 所得的3'，4'-二脱氧卡那霉素A的1-氨基酸与（S）-α-羟基-ω-氨基链烷酸或其反应性等同物的酰基化。