Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai

Meiji Seika Kaisha, Ltd.

Yamanouchi Pharmaceutical Company Ltd.

Kowa Company Limited

Meiji Seiki Kaisha, Ltd.

Zaidan Hojin Biselbutsu Kagaku Kenkyu Kai (Microbial Chemistry Research

Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai (Microbial Chemistry Research

Sumio Umezawa

Hamao Umezawa

Tsutomu Tsuchiya

Tomio Takeuchi

Shunzo Fukatsu

Yasushi Takagi

Shinichi Kondo

Shuichi Sakamoto

Akihiro Tanaka

Osamu Tsuchiya

Yoshiaki Takahashi

Kenji Maeda

Eiichi Akita

Shuntaro Yasuda

Toshiaki Miyake

Toshio Yoneta

Yukio Horiuchi

Shigeo Seki

Isamu Watanabe

Takeo Miyazawa

Tetsuo Shitara

Yoshihiko Kobayashi

Kuniaki Tatsuta

Shunji Kageyama

Tomo Jikihara

Takashi Yamaguchi

Masa Hamada

Takeo Yoshioka

Toshihito Mori

Tomohisa Takita

Kazuhiro Kamiya

Hidenori Iwamoto

Kazuo Umezawa

Takayuki Usui

Naoki Matsumoto

Hiroshi Tanaka

Tadashi Wakazawa

Kaichiro Kominato

Eijiro Umemura

Hiromi Sohtome

Masao Murase

Shunze Fukatsu

Tomo Jikahara

Yoshiharu Ishido

20,23-disubstituted mycaminosyltylonolide derivatives and use of the same in the field of the prophylaxis and treatment of pasteurellosis are disclosed. The di-substituents are peperidino optionally substituted with one or two methyl groups. The derivatives have selective antibacterial activity against Pasteurella.

Macrolide antibiotics and treatment and prophylaxis of pasteurellosis using the same

7-O-(4-Amino-2,4,6-trideoxy-2-fluoro-&agr;-L-talopyranosyl)-daunomycinone or -adriamycinone is now synthesized as a novel daunomycinone or adriamycinone derivative having the general formula

Anthracycline derivatives having 4-amino-2,4,6-trideoxy-2 fluoro-&agr;-L-talopyranosyl group

7-O-(4-Amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl)-daunomycinon e or -adriamycinone is now synthesized as a daunomycinone or adriamycinone derivative having the general formula ##STR1## wherein R is a hydrogen atom or hydroxyl group. These novel compounds according to this invention exhibit excellent antitumor activities and have a high solubility in water, and hence they are useful as an antitumor agent.

3,4-di-O,N-Protected-4-amino-2,4,6-trideoxy-2-fluoro-L-manno-pyranosyl

Anthracycline derivatives having

2'-Deoxy-2'-fluorocoformycin and 2'-deoxy-8-epi-2'-fluorocoformycin are synthesized in this invention through a multi-stage process via 3,5-di-O-benzoyl-2-deoxy-2-fluoro-.alpha.- and -.beta.-D-ribofuranosyl bromides. Further, according to this invention, 2'-deoxy-2'-epi-2'-fluorocoformycin and 2'-deoxy-8,2'-diepi-2'-fluorocoformycin are synthesized by a multi-stage process starting from 3,5-di-O-benzoyl-2-deoxy-2-fluoro-.alpha.-D-arabinofuranosyl bromide. These four 2'-fluoro derivatives of coformycin are novel compounds and have high enzyme-inhibitory activities against adenosine deaminase. In particular, these novel compounds are useful substances which exhibit therapeutic effects on acute lymphocytic leukemias due to their high enzyme-inhibitory activities above-mentioned. In addition, a variety of intermediates are obtained as novel compounds which are useful for the synthesis of the aforesaid novel 2'-fluoro derivatives of coformycin.

2'-deoxy-2'-epi-2'-fluorocoformycin

An object of this invention is to provide a novel process for the synthesis of a 2'-deoxy-2'-halocoformycin having an inhibitory activity against adenosine deaminase in a practically high yield. Thus, there is provided a process comprising multi-stage reactions with using as the starting intermediate a tert-butyl 1-(3,5-di-O-acyl-2-deoxy-2-halo-.beta.-D-ribofuranosyl or arabinofuranosyl)-5-aminoimidazole-4-carboxylate of formula (II) ##STR1## whereby there are produced a 2'-deoxy-2'-halocoformycin or a 2'-deoxy-2'-epi-2'-halocoformycin of formula (I-a) ##STR2## and also a 2'-deoxy-8-epi-2'-halocoformycin or a 2'-deoxy-8,2'-diepi-2'-halocoformycin of formula (I-b) ##STR3## It is expectable that a 2'-deoxy-2'-halocoformycin and epimers thereof are useful as a drug for lymphocytic leukemias and as drugs for various diseases attributable to the actions of adenosine deaminase.

Process for the preparation of 2'-deoxy-2'-halocoformycins or

Novel anthracycline derivatives have now been produced, which exhibit higher antitumor activities and lower toxicities than those of daunomycin, adriamycin etc. that have been clinically used as anticancer agents. That is, a daunomycinone or adriamycinone derivative represented by the general formula (I): ##STR1## wherein R is a hydrogen atom or a hydroxyl group, and 7-O-(2,6-dideoxy-6,6,6-trifluoro-.alpha.-L-lyxo-hexopyranosyl)adriamycinon e derivative which is an adriamycinone derivative represented by formula (II): ##STR2## have now been newly synthesized. The novel anthracycline derivatives having the general formula (I) and formula (II), respectively, show excellent anticancer or antitumor activities and are of low toxicities. These novel compounds are very useful as anticancer or antitumor agents and are expected to be useful for the therapeutic treatments of a variety of cancers and tumors, similarly to daunomycin or adriamycin.

Anthracycline derivative having a trifluoromethylated sugar

To provide novel fluorine-containing anthracycline derivatives having high antitumor activities and a solubility in water, there have now been synthesized a 7-O-(2,6-dideoxy-2-fluoro-3-O- or -4-O- or -3,4-di-O-aminoalkanoyl-.alpha.-L-talopyranosyl)daunomycinone or -adriamycinone of general formula (I) shown below, as well as a 7-O-(3-O- or -4-O- or -3,4-di-O-aminoalkanoyl-2,6-dideoxy-2,6,6,6-tetrafluoro-.alpha.-L-talopyra nosyl- or -2,6-dideoxy-6,6,6-trifluoro-.alpha.-L-lyxo-hexopyranosyl)adriamycinone of general formula (II) shown below: General formula (I) ##STR1## General formula (II) ##STR2## wherein either one or both of A.sup.1 and A.sup.2 is or are an .alpha.-amino acid residue or an .omega.-amino acid residue and T denotes a fluorine or hydrogen atom. The novel fluorine-containing anthracycline derivatives of general formulae (I) and (II) are highly active against tumors and soluble in water, and they are useful as antitumor agents administrable in the form of injectable solution.

Fluorine-containing anthracycline derivatives having hydroxyl groups(s)

Processes for preparing 2'-deoxy-2'-fluorocoformycin and stereoisomers

3,4'-dideoxymycaminosltylonolide derivative and process for producing

4-O-(aminoglycosyl)- or

Mycaminosyl tylonolide derivatives represented by the following general formula ##STR1## (wherein R.sup.1 denotes hydroxyl group, a lower alkanoyloxy group, benzoyloxy 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.

Mycaminosyl tylonolide derivatives

3-Deoxy mycaminosyl tylonolide derivatives represented by the following general formula and salts thereof: ##STR1## wherein X represents an oxygen atom or .dbd.N--OR.sup.4 (wherein R.sup.4 represents hydrogen or lower alkyl); R.sup.1 represents a hydrogen atom, an acyl group or an alkylsilyl group; R.sup.2 represents a hydrogen atom or an acyl group; and R.sup.3 represents a hydrogen atom or a hydroxyl group. The compounds of this invention of the formula (I) are novel compounds and have excellent antibacterial activity.

3-deoxy mycaminosyl tylonolide derivatives

2,6-Dideoxy-2-fluoro-L-talopyranose and 1-substituted derivatives thereof, including methyl 2,6-dideoxy-2-fluoro-L-talopyranoside and 3,4-di-O-protected-2,6-dideoxy-2-fluoro-L-talopyranosyl halides, are now provided and these new compounds are useful as intermediates for use in the synthesis of new compounds having antitumor activity, especially 7-O-(2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl) daunomycinone or -adriamycinone. 2,6-Dideoxy-2-fluoro-L-talopyranose shows antibacterial activity. 2,6-Dideoxy-fluoro-L-talopyranose and the 1-substituted derivatives thereof may be produced by a multi-stage process starting from L-fucose.

Process for producing 2,6-dideoxy-2-fluoro-L-talopyranose

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Tokyo, Japan

Sumio Umezawa