公开(公告)号：US4060682A

公开(公告)日：1977-11-29

申请号：US598379

申请日：1975-07-23

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Osamu Tsuchiya ,  Eiichi Akita ,  Takeo Miyazawa ,  Yukio Horiuchi ,  Shunzo Fukatsu

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Osamu Tsuchiya ,  Eiichi Akita ,  Takeo Miyazawa ,  Yukio Horiuchi ,  Shunzo Fukatsu

IPC分类号： C07H15/224 ,  B01J25/00 ,  C07B61/00 ,  C07H15/222 ,  C07H15/23 ,  C07H15/234 ,  C07H15/244 ,  A61K31/71 ,  C07H15/22

CPC分类号： C07H15/222 ,  Y02P20/55

摘要： 3'-Deoxy derivatives of neamine, 6'-N-alkylneamine, kanamycin B, 6'-N-alkylkanamycin B, ribostamycin, 6'-N-alkylribostamycin and paromamine may be produced by a new process comprising reducing the 3',4'-.alpha.-anhydro derivative (namely, the 3',4'-epoxide derivative) of the aminoglycosidic antibiotics with hydrogen in an alkaline lower alkanol medium containing an alkali metal hydroxide or alkoxide dissolved therein and in the presence of a reducing catalyst such as Raney nickel. The 3',4'-.alpha.-anhydro derivative may be prepared by treating the 3'-sulfonylated derivative of the amino-protected and hydroxyl-protected neamine, 6'-N-alkylneamine, kanamycin B, 6'-N-alkylkanamycin B, ribostamycin, 6'-N-alkylribostamycin or paromamine with an alkali metal hydroxide or alkoxide in a lower alkanol to effect epoxidation between the 4'-hydroxyl group and the carbon atom substituted by the 3'-sulfonic ester group.

摘要翻译： 神经胺，6'-N-烷基胺，卡那霉素B，6'-N-烷基卡那霉素B，核糖霉素，6'-N-烷基三苯甲酰霉素和帕罗明胺的3'-脱氧衍生物可以通过新的方法制备，包括将3'，4'- 在含有碱金属氢氧化物或醇盐的碱性低级烷醇介质中，在氨基糖苷类抗生素的α-脱氢衍生物（即3'，4'-环氧化物衍生物） 阮内镍 3'，4'-α-脱水衍生物可以通过处理氨基保护的和羟基保护的神经胺，6'-N-烷基胺，卡那霉素B，6'-N-烷基卡那霉素B的3'-磺酰化衍生物 ，核糖霉素，6'-N-烷基三苯甲酰霉素或碱性金属氢氧化物或醇盐在低级链烷醇中进行环氧化，以实现4'-羟基和被3'-磺酸酯基取代的碳原子之间的环氧化。

公开(公告)号：US4170641A

公开(公告)日：1979-10-09

申请号：US911522

申请日：1978-06-01

申请人： Eiichi Akita ,  Yukio Horiuchi ,  Takeo Miyazawa ,  Hamao Umezawa

发明人： Eiichi Akita ,  Yukio Horiuchi ,  Takeo Miyazawa ,  Hamao Umezawa

IPC分类号： C07H15/23 ,  A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/7036 ,  A61P31/04 ,  C07H15/232 ,  C07H15/234 ,  C07H15/236 ,  A61K31/71 ,  C07H15/22

CPC分类号： C07H15/234 ,  Y02P20/55

摘要： A new 1-N-(.omega.-aminoalkanesulfonyl) derivative of an aminoglycosidic antibiotic such as ribostamycin, 3'-deoxy- or 3',4'-dideoxy-ribostamycin, kanamycin A or B, and 3'-deoxy- or 3',4'-dideoxy-kanamycin B exhibits a broader, antibacterial spectrum than the parent aminoglycosidic antibiotic and is useful in the therapeutic treatment of infections caused by gram-positive and gram-negative bacteria including drug-resistant strains thereof. The aforesaid derivative may be made by reaction between the parent antibiotic and an amino-protected .omega.-aminoalkanesulfonic acid halide and removal of the amino-protecting group from the condensation product.

摘要翻译： 一种氨基糖苷类抗生素的新的1-N-（ω-氨基烷基磺酰基）衍生物，如核糖霉素，3'-脱氧-3或4'二脱氧核糖霉素，卡那霉素A或B，3'-脱氧-3或3' ，4'-双脱氧卡那霉素B比母体氨基糖苷类抗生素显示更广泛的抗菌谱，并且可用于治疗由革兰氏阳性和革兰氏阴性菌引起的感染的治疗性治疗，包括其耐药菌株。 上述衍生物可以通过亲本抗生素与氨基保护的ω-氨基链烷磺酸卤化物之间的反应和从缩合产物中除去氨基保护基团而进行。

公开(公告)号：US4169890A

公开(公告)日：1979-10-02

申请号：US800857

申请日：1977-05-26

申请人： Takeo Miyazawa ,  Yukio Horiuchi ,  Eiichi Akita ,  Hamao Umezawa ,  Sumio Umezawa

发明人： Takeo Miyazawa ,  Yukio Horiuchi ,  Eiichi Akita ,  Hamao Umezawa ,  Sumio Umezawa

IPC分类号： C07H15/23 ,  A61K31/71 ,  C07H15/22

CPC分类号： C07H15/23

摘要： A process for preparing a novel antibiotic, 5"-amino-3',5"-dideoxy-ribostamycin, which comprises subjecting a ribostamycin derivative represented by the formula: ##STR1## to selective sulfonylation to form a 3',5"-O-disulfonyl derivative, SUBJECTING THE THUS PRODUCED DERIVATIVE TO AZIDE-FORMING REACTION WITH SODIUM AZIDE,Subjecting the thus produced ribostamycin 3'-O-sulfonyl-5"-azido derivative to deoxylation by treating it with sodium borohydride in an aprotic and polar solvent,Subjecting the thus obtained 3' deoxy derivative to catalytic hydrogenation in the presence of a catalyst to form a 5"-amino derivativeAnd then, removing the remaining protective groups of the last-mentioned derivative.

公开(公告)号：US4078138A

公开(公告)日：1978-03-07

申请号：US638045

申请日：1975-12-05

申请人： Eiichi Akita ,  Yukio Horiuchi ,  Takeo Miyazawa ,  Toshio Yoneta ,  Sumio Umezawa ,  Hamao Umezawa

发明人： Eiichi Akita ,  Yukio Horiuchi ,  Takeo Miyazawa ,  Toshio Yoneta ,  Sumio Umezawa ,  Hamao Umezawa

IPC分类号： A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/7036 ,  A61K31/704 ,  A61P31/04 ,  C07H15/224 ,  C07H15/23 ,  C07H15/234 ,  C07H15/236 ,  C07H15/244 ,  C07H15/22

CPC分类号： C07H15/224 ,  C07H15/23 ,  C07H15/234

摘要： 3',4'-.alpha.-Epoxyneamine and its related aminoglycosidic antibiotic derivatives containing 3',4'-.alpha.-epoxyneamine moiety in the molecule thereof are now provided, which may be in the form of their amino-protected and partially hydroxyl-protected product and which are useful as intermediates for use in the synthetic production of therapeutically valuable 3'-deoxy derivatives of aminoglycosidic antibiotics.

摘要翻译： 现在提供了分子中含有3'，4'-α-环氧基胺部分的3'，4'-α-氧苯胺及其相关的氨基糖苷类抗生素衍生物，其可以是其氨基保护和部分羟基保护的形式 并且其可用作用于合成生产氨基糖苷类抗生素治疗有价值的3'-脱氧衍生物的中间体。

公开(公告)号：US3948882A

公开(公告)日：1976-04-06

申请号：US489243

申请日：1974-07-17

申请人： Hamao Umezawa ,  Sumio Umezawa ,  Eiichi Akita ,  Yukio Horiuchi ,  Shuntaro Yasuda ,  Osamu Tsuchiya

发明人： Hamao Umezawa ,  Sumio Umezawa ,  Eiichi Akita ,  Yukio Horiuchi ,  Shuntaro Yasuda ,  Osamu Tsuchiya

IPC分类号： C07H15/224 ,  C07H15/23 ,  C07H15/244 ,  C07G3/00

CPC分类号： C07H15/224 ,  C07H15/23

摘要： Process of producing a 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3',4'-dideoxyneamine or -3',4'-dideoxyribostamycin, a useful semi-synthetic antibiotic in which the corresponding 6-O-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3',4'-dideoxyneamine or -3',4'-dideoxyribostamycine undergoes the acyl-migration reaction by treating with a basic medium.This invention relates to a process for the production of a 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3',4'-dideoxyribostamycin which is useful for the treatment of various bacterial infections. More particularly, this invention relates to a process for the production of 1-N-((S)-.alpha.-hydroxy-.gamma.-amino-n-butyryl)- 3',4'-dideoxyneamine or -3',4'-dideoxyribostamycin.Kanamycins and neamine (that is, neomycin A) are well known aminoglycosidic antibiotics, and riboostamycin is also a known aminoglycosidic antibiotic, originally designated vistamycin or Antibiotic SF-733 (see the "Journal of Antibiotics" Vol. 23, No. 3, pages 115-161 and No. 4, pages 173-183 (1970)). Ribostamycin has been identified as 5-0-.beta.-D-ribofuranosylneamine. These aminoglycosidic antibiotics have widely been used as valuable, chemotherapeutic agents, but many drug-resistant strains which are resistant to these known antibiotic have occurred in recent years. In these circumstances, the mechanism of resistance of the drug-resistant bacteria to the known aminoglycosidic antibiotics has been studied. For instance, one of the present inventors, H. Umezawa et al. have found that some R-factor carrying strains of gram-negative bacteria, Staphylococcus aureus and Pseudomonas aeruginosa isolated from patients are resistant to the action of kanamycins and that these kanamycin-resistant strains have the mechanism of resistance that they produce an enzyme capable of phosphorylating the 3'-hydroxyl group of kanamycins and inactivate the kanamucins with aid of this phosphorylating enzyme (see the "Science" Vol. 157, page 1559 (1967)).On the basis of this finding, H. Umezawa et al have prepared semi-synthetically 3'-deoxykanamycin and 3',4'-dideoxykanamycin B wherein the 3'-hydroxyl group of the kanamycin molecule has been removed therefrom, as well as 3',4'-dideoxyneamine and 3',4'-dideoxyribostamycin (namely, 3',4'-dideoxyvistamycin) as described in the "Journal of Antibiotics" Ser. A, Vol. 21, pages 274-275 (1971); Vol. 24, pages 485-487; Vol. 24, pages 711-712 (1971) and Vol. 25, pages 613-617 (1972). 3'-deoxykanamycin; 3',4'-dideoxykanamycin B; 3',4'-dideoxyneamine and 3',4'-dideoxyribostamycin are actually effective against the above-mentioned kanamycin-resistant strains, but these deoxy-derivatives have now been found to be practically inactive against another kind of kanamycin-resistant strains such as Escherichia coli JR66/W677 which has been isolated from another patients. H. Umezawa et al. have found that the latter kind of the kanamycin-resistant strains has the mechanism of resistance that they produce an enzyme capable of adenylylating the 2"-hydroxyl group of the kanamycin or 3',4'-dideoxykanamycin molecule with ATP (adenosine triphosphate) and inactivate kanamycin and 3',4'-dideoxykanamycin through the action of this adenylylating enzyme (see the "Journal of Antibiotics" Vol. 24, pages 911-913 (1971)). Furthermore, it has been found that a class of the drug-resistant gram-negative bacteria such as R-factor carrying strains of Escherichia coli for example, Escherichia coli JR66/W 677 and LA290R55 has the mechanism of resistance that it produces an enzyme capable of nucleotidylating the 2"-hydroxyl group of kanamycin A and 3',4'-dideoxykanamycin B molecule and inactivates the kanamycin and 3',4'-dideoxykanamycin B with aid of this enzyme (see the "Journal of Antibiotics" Vol. 25, page 492 (1972)).On the other hand, it is known that butirosin B which is an aminoglycosidic antibiotic produced by a microorganism Streptomyces species is active against some kanamycin-resistant bacteria as well as against some ribostamycin-resistant bacteria. Butirosin B has been identified as 1-N-((S)-.alpha.-hydroxy-.gamma.-amino-n-butyryl)-ribostamycin (see the "Tetrahedron Letters" Vol. 28, page 2125 and pages 2617-2630 (1971) and German "Offenlegungsschrift" No. 1914527). From comparison of the antibacterial activity of ribostamycin with that of butirosin B, it has been appreciated that the (S)-.alpha.-hydroxy-.gamma.-amino-butyryl substituent at the 1-amino group of the butirosin b molecule has an important role in enabling the ribostamycin to be active even against the ribostamycin-resistant and -sensitive strains and that the presence of the (S)-.alpha.-hydroxy-.gamma.-amino-butyryl substituent at the 1-amino group of the butirosin B molecule results in such a steric hindrance of the butirosin B molecule owing to which the butirosin B can be prevented from being inactivated by the attack of the various inactivating enzymes which are produced by the kanamycin-resistant strains of ribostamycin-resistant strains.On the basis of these findings, H. Umezawa et al. have synthetized 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl) derivatives of neamine, 3',4'-dideoxyneamine, ribostamycin or 3',4'-dideoxyribostamycin and have found that these compounds exhibit usefully high antibacterial activity against the drug-resistant bacteria (see co-pending U.S. patent application Ser. No. 402,085; British patent application No. 46,397/73; German patent application No. P 23 50169.1 and French patent application No. 73 36291, as well as the "Journal of Antibiotics" Vol. 26, pages 304-309 (May 1973)). Accordingly, we have made our further research in an attempt to exploit a new efficient process according to which a 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3',4'-dideoxyneamine or -3',4'-dideoxyribostamycin can be synthetized in a facile way and in a favorable yield.3',4'-dideoxyneamine and 3',4'-dideoxyribostamycin may be represented by a general formula (I): ##SPC1##wherein R is a hydrogen atom or .beta.-D-ribofuranosyl group of the formula ##SPC2##3',4'-dideoxyneamine is shown by the above general formula (I) when R is a hydrogen atom, and 3',4'-dideoxyribostamycin is shown by the above general formula (I) when R is a .beta.-D-ribofuranosyl group (see the "Journal of Antibiotics" Vol. 24, pages 711-712 (1971) and Vol. 25, pages 613-616 (1972)).An object of this invention is to provide a new route according to which a 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3',4'-dideoxyneamine or -3',4'-dideoxyribostamycin of a general formula (II): ##SPC3##wherein R is a hydrogen atom or .beta.-D-ribofuranosyl group and n is a whole number of 1 to 4 inclusive, in a relatively facile way and in an improved yield, and in which the corresponding 6-0-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3',4'-dideoxyneamine or -3',4'-dideoxyribostamycin is at first prepared by esterifying the 6-OH group of the 3',4'-dideoxyneamine or 3', 4'-dideoxyribostamycin with the (S)-hydroxy-.omega.-aminoalkanoic acid or a reactive derivative thereof and is then subjected to the action of an alkaline medium so as to cause the (S)-.alpha.-hydroxy-.omega.-aminoacyl substituent ##EQU1## to migrate from the 6-OH group to the 1-NH.sub.2 group of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin. The symbol (S) shown in the formula (II) is an expression of the steric configuration of organic compounds (see R. S. Cahn, C. K. Ingold & V. Prelog; "Experitia" Vol. 12 pages 81-94 (1956). A further object of this invention is to provide a new process for the production of 1-N-((S)-.alpha.-hydroxy-.gamma.-amino-n-butyryl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin which may be carried out in a relatively facile way and gives the desired product in an improved yield. Another objects of this invention will be clear from the following descriptions.According to this invention, there is provided a process for the production of a 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (II): ##SPC4##wherein R is a hydrogen atom or .beta.-D-ribofuranosyl group of the formula ##SPC5##and n is a whole number of 1 to 4, which comprises subjecting a 6-0-(((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (III): ##SPC6##wherein R' is a hydrogen atom, a known hydroxyl-protecting group such as an acyl group or a .beta.-D-ribofuranosyl group of the formula ##SPC7##where each Y is independently a hydrogen atom or a known hydroxyl-protecting group such as an acyl group, for example, an alkanoyl group of 2-6 carbon atoms (e.g., acetyl, propionyl or butyryl), an aminoalkanoyl group of 2-6 carbon atoms (e.g., .beta.-hydroxyl-.gamma.-amino-n-butyryl), benzoyl, benzyl, methoxycyclohexyl or cyclohexylidene; and R.sub.1 and R.sub.2 may be the same or different and each is independently a hydrogen atom or a known amino-protecting group selected from an acyl group such as an alkanoyl group of 2-6 carbon atoms (e.g., acetyl, propionyl or butyryl), an alkoxycarbonyl group such as an alkoxycarbonyl group of 2-5 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), an aralkyloxycarbonyl group such as phenylalkyloxycarbonyl group containing the alkyl group of 1-4 carbon atoms (e.g., benzyloxycarbonyl) or an aryloxycarbonyl group (e.g., phenyloxycarbonyl or naphthyloxycarbonyl); or R.sub.1 and R.sub.2 taken together forms a phthaloyl group; and n is a whole number of 1 to 4, to the action of a basic medium to produce an acyl-migration product of the formula (IV): ##SPC8## wherein R', R.sub.1, R.sub.2 and n have the same meanings as defined above, and if at least one of the amino-protecting and hydroxyl-protecting groups remain in the acyl-migration product removing the amino-protecting group and the hydroxyl-protecting group from the acyl-migration product (IV), to give the desired product (II).In carrying out the process of this invention, the starting compound 6-0-((S)-.alpha.-hydroxyl-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin (III) may be subjected to the action of the basic or alkaline medium by treating the starting compound in solution in water or an organic solvent under basic or alkaline conditions which are provided by the presence of an organic base such as tertiary amine, for example, triethylamine or hydrazine or an inorganic base such as an alkali metal hydroxide, for example, sodium or potassium hydroxide or carbonate or a basic anion-exchange resin in such a quantity enough to give the basicity or alkalinity to the solution of the starting compound. This basic treatment may be done simply by dissolving the starting compound in a solvent therefore but containing a base in an amount sufficient to make the solution basic or by adding to a solution of the starting compound a base in an amount sufficient to make the solution basic, and then by heating the basic solution of the starting compound at an elevated temperature, preferably at a temperature of 50.degree.-100.degree.C. As the organic solvent which may be used as the reaction medium for the basic treatment of the present process, there may be mentioned a lower alkanol of 1-4 carbon atoms, for example, methanol, ethanol, butanol and propanol, either aqueous or anhydrous. When the starting compound of the formula (III) is subjected to the action of the basic medium in this way, there takes place such a reaction of rearrangement wherein the group --COCH(OH)(CH.sub.2).sub.n NR.sub.1 R.sub.2 bonded through the ester-linkage to the hydroxyl group in the 6-position of the 3', 4'-dideoxyneamine or 3',4'-dideoxyribostamycin molecule of the starting compound is liberated therefrom and transferred to the amino group in the adjacent 1-position of said molecule, producing the acyl-migration product of the formula (IV).This reaction of rearrangement, that is, the reaction in which such an acyl group having been bonded through the ester-linkage to a hydroxyl substituent on a carbon atom of an organic compound molecule is caused to transfer from said hydroxyl group to such an amino substituent which is existing on a carbon atom adjacent to the first-mentioned carbon atom and in the "trans"-position in relation to said hydroxyl group, by making alkaline or basic the conditions of the environment medium wherein the organic compound molecule is present, is the new reaction which was previously discovered by the present inventors (see co-pending U.S. patent application Ser. No. 390,217; British patent application No. 39735/73; German patent application No.P 23 42946.1 and French patent application No. 73 30875, as well as the "Journal of Antibiotics" Vol. 26, pages 365-367 (1973)). This new reaction which was discovered by the present inventors is utilized in the process of this invention.It is known that, in general, an acyl group is likely to be bonded to a hydroxyl group under acidic conditions but is likely to be bonded to an amino group under basic conditions, so that the acyl group migrates from the hydroxyl group to the amino group when the nature of the environment medium containing the aforesaid different groups is reversed from acidicity to basicity, and vice versa. This phenomena is known as "acyl migration" (see "Organic Reactions" Vol. 12, page 173, published from John Wiley & Sons, 1962). However, the acyl migration has never been utilized before the process of this invention for the purpose of introducing the acyl group in to an amino group existing in a particular position of a molecule when said molecule bears many amino groups.In carrying out the process of this invention, the migration of the (S)-.alpha.-hydroxy-.omega.-aminoacyl group --COCH(OH)(CH.sub.2).sub.n NR.sub.1 R.sub.2 takes place from the 6-hydroxyl group to the 1-amino group of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin molecule of the starting compound (III) under the basic conditions. When the amino-protecting groups R.sub.1 and R.sub.2 as well as the hydroxyl-protecting group Y which are possibly present in the starting compound (III) are such ones which are cleavable under the basic conditions, for example, an acyl group, a partial or complete removal of such kind of the amino-protecting group and the hydroxyl-protecting group would occur concurrently with the reaction of migrating the (S)-.alpha.-hydroxy-.omega.-aminoacyl substituent from the 6-hydroxyl group to the 1-amino group takes place during the basic treatment step of the present process. A typical example of the acyl type of the amino-protecting group R.sub.1, R.sub.2 which is cleavable under the basic conditions is phthaloyl group. A typical example of the acyl type of the hydroxyl-protecting group Y which is cleavable under the basic conditions and which is suitable for the present process is an aminoalkanoyl group of the formula --COCH(OH)(CH.sub.2).sub.n NR.sub.1 R.sub.2 where R.sub.1 and R.sub.2 taken together form a phthaloyl group and n is a whole number of 1 to 4. If the acyl-migration product (IV) so formed still contains the amino-protecting group and/or the hydroxyl-protecting group, such as an acyl group, which are in its nature cleavable under the basic conditions but which are remaining in the acyl-migration product (IV), further heating of the reaction mixture will ensure the complete removal of the residual amino- and hydroxyl-protecting groups from the acyl-migration product (IV) present therein, finally affording the desired product (II).When the starting compound (III) contains a hydroxyl-protecting group Y of the other nature than the acyl or aminoacyl group as well as an amino-protecting group R.sub.1, R.sub.2 of the other nature than the acyl group, such hydroxyl-protecting group and amino-protecting group cannot be removed during the basic treatment step of the process, and it is necessary to further treat the acyl-migration product (IV) in a known manner so as to remove the hydroxyl-protecting group Y and the amino-protecting groups R.sub.1, R.sub.2 remaining in the acyl-migration product (IV). By the removal of the hydroxyl-protecting group or the amino-protecting group is herein meant the conversion of the hydroxyl-protecting group or the amino-protecting group into a hydrogen atom to regenerate the original, free hydroxyl or amino group. For instance, when the hydroxyl-protecting group Y is benzyl group and the amino-masking group R.sub.1 and/or R.sub.2 are or is such as alkyloxycarbonyl, aralkyloxycarbonyl or aryloxycarbonyl, particularly carbobenzoxy group in the starting compound (III), the acyl-migration product (IV) obtained still contains these hydroxyl-protecting group and amino-protecting groups remaining therein and must be further treated so as to remove the hydroxyl-protecting group and amino-protecting groups of these kinds. Procedures for the removal of these hydroxyl-protecting group and amino-protecting group are well known to the skilled in the art. Thus, when the amino-masking group is of an alkyloxycarbonyl group such as t-butoxycarbonyl, a cycloalkyloxycarbonyl group, or aryloxycarbonyl group or an arylidene group such as salicylidene group, the removal of this kind of the amino-masking group may be effected by subjecting to a moderate hydrolysis treatment with a weak acid such as aqueous trifluoro-acetic acid, aqueous acetic acid and diluted aqueous hydrochloric acid. When the amino-masking groups is of an aralkyloxycarbonyl group such as benzyloxycarbonyl, the removal of this sort of the amino-masking group may be effected by subjecting to a hydrogenolysis treatment in the presence of a palladium-carbon catalyst or to a treatment with hydrobromic acid and acetic acid. The o-nitrophenoxyacetyl group as the amino-masking group may be removed by a reductive treatment. When the amino-masking group is phthaloyl group, the removal of phthaloyl group may efficiently be achieved by treating hydrolytically with hydrazine hydrate in solution in ethanol under heating.When the hydroxyl-masking groups is of the acyl type such as alkanoyl and aroyl or ally, isopropylidene, cyclohexylidene, benzylidene, tetrahydropyranyl or methoxycyclohexyl, the removal of this acyl type of the hydroxyl-masking group may be accomplished by mild hydrolysis using diluted hydrochloric acid or aqueous acetic acid. When the hydroxyl-masking group is of such type as benzyl, the removal of this type of the hydroxyl-masking group may be achieved by catalytic hydrogenolysis in the presence of palladium on carbon.The 6-0-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (III) which is used as the starting compound in the process of this invention may be prepared from 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin as the initial material in various ways. Thus, 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin is at first reacted with such a reagent which is commonly used in the prior art of peptide synthesis to introduce a known amino-protecting group into the four amino groups of the initial 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin. The protection or masking of the amino groups of the neamine or ribostamycin may conveniently be effected in a known manner, either by reacting an aldehyde such as acetaldehyde or benzaldehyde with the amino group to convert the latter into Schiff's base type of the group, or by an acylating, carboalkoxylating or carbobenzoxylating the amino groups of the initial material. To this end, for example, 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin may be reacted with acetyl chloride, ethyl chloroformate or benzyl chloroformate to prepare the tetra-N-acetyl derivative, the tetra-N-ethoxycarbonyl derivative or the tetra-N-carbobenzoxy derivative of the neamine or ribostamycin, respectively.The tetra-N-acetyl derivative, tetra-N-ethoxycarbonyl derivative or tetra-N-carbobenzoxy derivative of 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin so prepared may subsequently be treated in a known manner so as to block all or parts of the hydroxyl groups other than the 6-hydroxyl group of said derivative with a known hydroxyl-protecting group such as an acyl, isopropylidene, cyclohexylidene, benzylidene or benzyl. The introduction of the hydroxyl-protecting group into all the hydroxyl groups other than the 6-hydroxyl group of said derivative may be achieved in a similar way to the preparation of tetra-N-carbobenzoxy-3', 4': 2",3"-dicyclohexylidene-5"-O-(1-methoxycyclohexyl)-ribostamycin, as is described in the "Journal of Antibiotics" Vol. 25, No. 10, pages 613-616 (1972). The derivative having the protected hydroxyl groups so formed is then esterified by reacting with an (S)-.alpha.-hydroxy-.omega.-amino acid of the formula (V) ##EQU2## wherein R.sub.1, R.sub.2 are n are as defined in the above or a functional derivative of this amino acid (V) in an anhydrous organic solvent in the presence of a dehydrating agent, to prepare 6-O-((S)-.alpha.-hydroxy-.omega.-aminoacyl derivative of 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin in which the neamine or ribostamycin molecule the four amino groups have been masked by the amino-protecting group and the hydroxyl groups also have been protected by the hydroxyl-protecting groups. When this 6-O-((S)-.alpha.-hydroxy-.omega.-aminoacyl derivative so prepared is then treated in a known manner so as to remove all the amino-protecting groups and, if desired, also all of the hydroxyl-protecting groups, there may be prepared the 6-O-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the above formula (III) where R.sub.1, R.sub.2 and Y each is a hydrogen atom.When an organic compound containing both amino group and hydroxyl group in the molecule thereof is intended to be acetylated preferentially at the hydroxyl group, it has been proposed that the protection of the amino group is done by protonating such amino group with a strong organic acid such as trifluoroacetic acid so as to protect said amino group, and then the hydroxyl group may be acetylated preferentially using a usual acetylation reagent such as acetyl chloride or acetic anhydride or mixed anhydrides (see J. Bello & J. R. Vinograd; "Journal of American Chemical Society" Vol. 78, page 1369 (1956)). Using this known method of protonating the amino group with a strong organic acid such as trifluoroacetic acid for the purpose of protecting the amino groups of the initial 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin, the 6-O-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3',4'-dideoxyribostamycin of the formula (III) may also be prepared in the following way: The 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin (the free base form) is dissolved in trifluoroacetic acid under ice-cooling and the resulting solution is admixed with ethyl ether to precipitate such a trifluoroacetic acid salt of 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin in which the four amino groups of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin molecule have each been protected with the trifluoroacetic acid molecule. This 3', 4' -dideoxyneamine or 3', 4'-dideoxyribostamycin trifluoroacetate so formed is then esterified or condensed with an (S)-.alpha.-hydroxy-.omega.-amino acid of the formula (V) in solution in an organic solvent such as dimethylformamide (DMF), acetone or tetrahydrofuran under ice-cooling and in the presence of a strong acid or a dehydrating agent such as dicyclohexylcarbodiimide. The acid of the formula (V) may conveniently be its functional derivative such as acid halide, azide derivative, active ester or mixed acid anhydride. In the reaction (esterification) of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin trifluoroacetate with the acid of the formula (V), all the hydroxyl groups, including the 6-hydroxyl group, of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin molecule are unblocked and are O-amino-acylated at random by the acid of the formula (V), so that there is formed a mixture of mono-O-aminoacylated and di-O-aminoacylated 3', 4'-dideoxyneamines (in the form of their trifluoroacetate) or a mixture of mono-O-aminoacylated to tetra-O-aminoacylated 3', 4'-dideoxyribostamycins (in the form of their trifluoroacetate). When this mixture of the O-aminoacylated 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin trifluoroacetates is neutralized with a base, there is given the mixed O-aminoacylated 3', 4'-dideoxyneamines or 3', 4'-dideoxyribostamycins which contain a 6-O-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin of the formula (III). From the above-mentioned mixed O-aminoacylated 3', 4'-dideoxyneamines or 3', 4'-dideoxyribostamycins may be isolated the 6-O-((S)-.alpha.-hydroxy-.omega. -aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (III) by a chromatographic method using, for example, cellulose powder, silica gel or a molecular sieve consisting of a three dimensional dextran network (commercially available under a trade name "Sephadex G-15", a product of Pharmacia Co., Sweden). However, the above-mentioned mixed O-aminoacylated 3', 4'-dideoxyneamines or 3', 4'-dideoxyribostamycins containing the 6-O-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycins as such may be immediately employed as the starting material for the process of this invention, before or after the trifluoroacetic acid is liberated therefrom by neutralizing with a base, as stated above. This is because the (S)-.alpha.-hydroxy-.gamma.-aminoacyl substituent(s) on the other hydroxyl group(s) than the 6-hydroxyl group in these mixed O-aminoacylated product may be regarded as one of the hydroxyl-protecting group Y of the acyl type as stated before. When said mixed O-aminoacylated 3', 4'-dideoxyneamines or 3', 4'-dideoxyribostamycins are subjected to the action of the basic medium in the process of this invention, there is formed the desired 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (II) as the sole acyl-migration product, because the migration of the (S)-.alpha.-hydroxy-.omega.-aminoacyl substituent from the hydroxyl group to the amino group cannot take place except that from the 6-hydroxyl group to the 1-amino group as long as the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin (III) is concerned with as the starting compound in the present process. The N-aminoacylation product may be precipitated from the reaction mixture by concentration of the latter and filtered out and dissolved in water to prepare an aqueous solution of them at pH of about 8. This solution may then be subjected to a chromatographic separation in a column of CM-Sephadex C-25 (ammonium form) to isolate the desired 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (II). Active fractions of the eluate issued from the column and containing the 1-N-((S)-.alpha.-hydroxy-.omega.-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin can be detected by an oxidation test with periodic acid, as the presence of an 1-N-acyl substituent is detectable by said test (see "Tetrahedron Letters", Vol. 28, pages 2624-2628 (1971)).when the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin trifluoroacetate is esterified by reacting with an (S)-.alpha.-hydroxy-.omega.-amino acid derivative of the formula (V), it has been found preferable that 1 molar proportion of the former is brought about into contact with 3-7 molar proportions of the latter at a temperature of 50.degree.-100.degree.C. When the compound of the formula (III) in its trifluoroacetate form is directly subjected to the action of the basic medium which may be a solution of hydrazine in an aqueous ethanol, the migration of the 6-O-(S)-.alpha.-hydroxy-.omega.-aminoacyl substituent from the 6-hydroxyl group to the 1-amino group takes place concurrently with or after the liberation of the trifluoroacetic acid from the starting compound (III) trifluoroacetate occurs. In this case when the compound (III) trifluoroacetate is directly subjected to the action of the basic medium, therefore, it is virtual that the formation of the product (IV) from the compound (III) trifluoroacetate takes place again via the compound (III) itself formed in site of the reaction mixture.The principal route of producing the final product of the formula (II) starting from 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin (I) according to the present invention may be represented schematically by the following equation: ##SPC9##if the reactions for introducing the amino-protecting groups and the hydroxyl-protecting groups into the initial 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin, the presence of the amino-protecting and hydroxyl-protecting groups in the reagents and in the intermediate products, and the reactions for removing the amino-protecting groups and hydroxyl-protecting groups from the product are omitted from the representation.Among the amino acid of the formula (V) which is used in the process, an (S)-.alpha.-hydroxy-.omega.-amino acid of the formula (V) where R.sub.1 and R.sub.2 each is not the hydrogen atom may conveniently be an (S)-.alpha.-hydroxy-.omega.-N-phthalimido acid or (S)-.alpha.-hydroxy-.omega.-N-carbobenzoxyamino acid. An (S)-.alpha.-hydroxy-.omega.-N-phthalimido acid of the formula ##SPC10##may be prepared by reacting a hydrochloride of an (S)-.alpha.-,.omega.-diamino acid of the formula ##EQU3## wherein m is a whole number of 1 or 2, with a basic copper carbonate in an alkaline aqueous solution to form the copper carboxylate, reacting this copper carboxylate with N-carboethoxyphthalimide to form a copper salt of (S)-.alpha.-amino-.omega.-N-phthalimido acid of the formula ##SPC11##treating this copper salt with diluted hydrochloric acid in methanol to give the corresponding (S)-.alpha.-amino-.omega.-N-phthalimido acid hydrochloride and then reacting this hydrochloride with sodium nitrite in aqueous acetic acid to produce the desired (S)-.alpha.-hydroxy-.omega.-N-phthalimido acid.As the amino acid of the formula (V), it is, of course, possible to use such an (S)-.alpha.-hydroxy-.omega.-amino acid (V) where R.sub.1 and R.sub.2 each is a hydrogen atom or a known amino-protecting group other than the aforesaid phthaloyl group. For preparation of an (S)-.alpha.-hydroxy-.omega.-amino acid (V) in which R.sub.1 is a hydrogen atom and R.sub.2 is independently an acyl group, alkyloxycarbonyl group, aralkyloxycarbonyl or aryloxycarbonyl group, for example, by reacting an .alpha.-hydroxy-.omega.-amino acid of the formula ##EQU4## wherein n is a whole number of 1 to 4, with an acyl chloride of the formulaR.sub.3 COClwherein R.sub.3 is a group such that the R.sub.3 CO group forms the group R.sub.2 which is an acyl group such as acetyl or benzoyl, in a dry organic solvent such as methanol, or with an alkyloxycarbonyl, aralkyloxycarbonyl or aryloxycarbonyl chloride of the formulaR.sub.4 O--CO--Clwherein R.sub.4 is a group such that the R.sub.4 O--CO-- group forms the R.sub.2 group which is an alkyloxycarbonyl, aralkyloxycarbonyl or aryloxycarbonyl group such as butoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl, in a suitable solvent such as ethyl alcohol or acetone under neutral or basic conditions in a way well known in the prior art of peptide synthesis.

公开(公告)号：US07142787B2

公开(公告)日：2006-11-28

申请号：US09885498

申请日：2001-06-19

申请人： Yukio Horiuchi ,  Shu Yamamoto

发明人： Yukio Horiuchi ,  Shu Yamamoto

IPC分类号： H04B10/00

CPC分类号： H04L7/0075 ,  H04B10/503 ,  H04B10/5161 ,  H04B10/5561 ,  H04J14/08

摘要： This invention discloses a method to easily extract a header from an optical packet. An optical data transmission method to transmit an optical packet composed of a header and data containing steps of generating a second clock which has a frequency equal to one integer of that of a first clock carrying the data and synchronizes with the first clock, and carrying the header information on the second clock.

摘要翻译： 本发明公开了一种从光分组容易地提取报头的方法。 一种光数据传输方法，用于发送由报头组成的光分组和包含生成第二时钟的步骤的数据，所述第二时钟具有等于携带数据的第一时钟的一个整数的频率，并与第一时钟同步，并携带 第二个时钟的头信息。

公开(公告)号：US06201599B1

公开(公告)日：2001-03-13

申请号：US09109483

申请日：1998-07-02

申请人： Shiro Ryu ,  Yukio Horiuchi

发明人： Shiro Ryu ,  Yukio Horiuchi

IPC分类号： G01N2100

CPC分类号： H04B10/071 ,  H04B10/272

摘要： An apparatus for monitoring and measuring condition of a plurality of optical transmission lines individually according to this invention comprises at least one reflecting means having a predetermined reflection bandwidth arranged on each of said optical transmission lines; an optical pulse tester for outputting probe pulse light having predetermined wavelength in the reflection bandwidth of said reflecting means, and analyzing the reflected light of said probe pulse light in a time domain; optical coupling means for adding said probe pulse light from said optical pulse tester and a signal light, and coupling it to each of optical transmission lines through optical dividing means, along with coupling the reflected light of said probe pulse light to said optical pulse tester; and a plurality of optical filters arranged on the input end of each of said optical transmission lines for transmitting wavelength of signal light to be transmitted on their respective optical transmission lines and the predetermined wavelengths to be reflected on the reflection means on corresponding optical transmission lines. The predetermined wavelengths of a plurality of optical filters are different from each other.

摘要翻译： 根据本发明的用于监视和测量多个光传输线的状态的装置包括至少一个具有布置在每个所述光传输线上的预定反射带宽的反射装置; 一个光脉冲测试器，用于输出具有预定波长的探测脉冲光在所述反射装置的反射带宽中，并在时域中分析所述探针脉冲光的反射光; 光耦合装置，用于将来自所述光脉冲测试仪的所述探针脉冲光和信号光相加，并通过光分离装置将其耦合到每个光传输线，以及将所述探针脉冲光的反射光耦合到所述光脉冲测试仪; 以及多个光滤波器，布置在每个所述光传输线的输入端上，用于传输要在其各自的光传输线上传输的信号光的波长和预定波长，以在相应的光传输线上反射在反射装置上。 多个滤光器的预定波长彼此不同。

公开(公告)号：US5726789A

公开(公告)日：1998-03-10

申请号：US617614

申请日：1996-03-19

申请人： Yukio Horiuchi ,  Masatoshi Suzuki

发明人： Yukio Horiuchi ,  Masatoshi Suzuki

IPC分类号： H04B10/516 ,  G02F1/01 ,  G02F1/03 ,  H04B10/07 ,  H04B10/2507 ,  H04B10/508 ,  H04B10/524 ,  H04B10/54 ,  H04B10/61 ,  H04B10/04

CPC分类号： G02F1/0121 ,  G02F1/0327 ,  G02F2203/26

摘要： A device for modulating optical short pulses, while preventing a pulse compression optical fiber from degradation of the transmission characteristics even if the length of the pulse compression optical fiber varies, utilizes an optical short pulse generator 1, a pulse compression optical fiber 2, an optical divider 3, a photodetector 6, an amplifier 7, a band pass filter 8, a phase comparator 9, a loop filter 11, and a driving signal generator 12. The loop which comprises loop filter 11 and driving signal generator 12 controls an oscillation frequency in a VCO 12-1 so that the phase of a compressed optical pulse fed to an optical intensity modulator 4 is identical to the phase of a data signal that is synchronized with a reference clock and used to modulate the compressed optical pulse. In this manner, the extinction ratio of the modulation output is not degraded even if the length of the pulse compression optical fiber 2 varies due to ambient temperature variations.

摘要翻译： 一种用于调制光学短脉冲的装置，即使脉冲压缩光纤的长度变化也能防止脉冲压缩光纤降低传输特性，利用光学短脉冲发生器1，脉冲压缩光纤2，光学 分频器3，光电检测器6，放大器7，带通滤波器8，相位比较器9，环路滤波器11和驱动信号发生器12.包括环路滤波器11和驱动信号发生器12的环路控制振荡频率 在VCO 12-1中，使得馈送到光强度调制器4的压缩光脉冲的相位与与参考时钟同步并用于调制压缩的光脉冲的数据信号的相位相同。 以这种方式，即使脉冲压缩光纤2的长度由于环境温度变化而变化，调制输出的消光比也不会降低。

公开(公告)号：US5539557A

公开(公告)日：1996-07-23

申请号：US343528

申请日：1994-11-17

申请人： Yukio Horiuchi ,  Hiroharu Wakabayashi ,  Shigeyuki Akiba ,  Shu Yamamoto

发明人： Yukio Horiuchi ,  Hiroharu Wakabayashi ,  Shigeyuki Akiba ,  Shu Yamamoto

IPC分类号： H04J14/00 ,  H04B10/07 ,  H04B10/077 ,  H04B10/2507 ,  H04B10/29 ,  H04J14/04 ,  H04J14/06 ,  H04B10/08

CPC分类号： H04B10/0777 ,  H04B2210/074 ,  H04B2210/078

摘要： At the time of receiving a repeater supervisory signal superimposed on or combined by wavelength multiplexing with a main optical signal in an optical amplifier repeater system, the received optical signal is subjected to a photoelectric conversion by a photodetector and then branched into two electric signals, the one of which is subjected to equalizing amplification, timing extraction and discrimination and regeneration to extract only the main signal component. The main signal component thus extracted and the main signal contained in the other electric signal, which is not regenerated, are respectively subjected to required equalization, delay adjustment and amplitude adjustment so that they match with one another in waveform, phase and amplitude. In addition, the amplitude adjustment of the main signal is automatically controlled. By differentially combining these signals to remove only the main signal component to minimize its residual value, thereby extracting the supervisory signal to be obtained.

摘要翻译： PCT No.PCT / JP94 / 00653 Sec。 371日期：1994年11月17日 102（e）1994年11月17日PCT PCT 1994年4月20日PCT公布。 公开号WO94 / 24779 日期1994年10月27日在光学放大器中继器系统中接收到与主光信号叠加或组合在一起的中继器监视信号的时间，接收的光信号经受光电检测器的光电转换，然后分支成 两个电信号，其中一个经受均衡放大，定时提取和鉴别和再生以仅提取主信号分量。 如此提取的主信号分量和未再生的另一电信号中所包含的主信号分别经受所需的均衡，延迟调整和振幅调整，使得它们在波形，相位和幅度上彼此匹配。 另外，主信号的幅度调整也被自动控制。 通过差分地组合这些信号以仅去除主信号分量以最小化其残留值，从而提取要获得的监控信号。

公开(公告)号：US07158728B2

公开(公告)日：2007-01-02

申请号：US10191319

申请日：2002-07-10

申请人： Yasunori Kasahara ,  Hideki Goto ,  Takashi Mizuochi ,  Kenkichi Shimomura ,  Yukio Horiuchi ,  Masatoshi Suzuki ,  Daishi Ishii ,  Toshio Kawazawa

发明人： Yasunori Kasahara ,  Hideki Goto ,  Takashi Mizuochi ,  Kenkichi Shimomura ,  Yukio Horiuchi ,  Masatoshi Suzuki ,  Daishi Ishii ,  Toshio Kawazawa

IPC分类号： H04B10/02

CPC分类号： H04B10/2918 ,  H04B10/0777 ,  H04B2210/074

摘要： An optical repeating system includes an optical transmitter and a plurality of optical amplifying repeaters. The optical transmitter specifies a part or all of the optical amplifying repeaters, and transmits a supervisory command to the specified optical amplifying repeaters as a first sub-signal via an uplink or downlink optical transmission line. The supervisory command is a command to supervise internal circuits of the optical amplifying repeaters. Receiving the supervisory command addressed thereto via the uplink or downlink optical transmission line, the optical amplifying repeaters each transmit a supervisory signal indicating a supervisory result corresponding to the supervisory command to optical receivers via the uplink and downlink optical transmission lines as a second sub-signal. The optical system can reduce the time take to acquire the supervisory information about the plurality of the optical amplifying repeaters.

摘要翻译： 光学重复系统包括光发射机和多个光放大中继器。 光发射机规定了一部分或全部光放大中继器，并经由上行或下行光传输线路将指示的光放大中继器的监控命令作为第一子信号发送。 监控命令是监控光放大中继器内部电路的命令。 通过上行链路或下行链路光传输线路接收到该监控命令，光放大中继器将经过上行和下行光传输线路的指示对应于监控命令的监控结果的监控信号发送给光接收机作为第二子信号 。 光学系统可以减少获取关于多个光学放大转发器的监控信息的时间。