Takeda Chemical Industries, Inc.

Shoji Kishimoto

Michihiko Ochiai

Takeshi Fujita

Taisuke Matsuo, Deceased

Kiminori Tomimatsu

Michiyuki Sendai

Taisuke Matsuo

Kohei Nishikawa

Akio Miyake

Yoshiyasu Furukawa

Yoshinobu Yoshimura

Shogo Marui

Donald Elliot Ingber

Hiroaki Okada

Moses J Folkman

Tetsuya Aono

Tsuneo Kanamaru

Shigeru Kamei

Naoto Hashimoto

Katsuichi Sudo

Seiji Kuzuna

O-substituted fumagillol derivatives and its salts have an angiogenesis inhibiting activity and are useful for prophylaxis and treatment of diseases induced by abnormally stimulated neovascularization.

Angiogenesis inhibitory agent

The present invention relates to a compound of the formula: ##STR1## wherein R.sup.1 is 2-methyl-1-propenyl group or isobutyl group; R.sup.2 and R.sup.3 are each hydrogen atom, an optionally substituted hydrocarbon residue or an optionally substituted acyl group or R.sup.2 and R.sup.3 may form a ring together with the adjacent nitrogen atom; and the bonding mark .about. represents an .alpha.-linkage or .beta.-linkage, or a salt thereof. The compound (I) of the present invention has, among others, angiogenesis inhibiting activity, cell-growth inhibiting activity and immune reaction inhibiting activity, thus being useful as medicines, etc.

6-amino-6-desoxyfumagillols, production and use thereof

The present invention relates to a compound of the formula: ##STR1## wherein R.sup.1 is 2-methyl-1-propenyl group or isobutyl group; R.sup.2 is hydrogen atom, an optionally substituted aliphatic hydrocarbon residue or an optionally substituted acyl group, or a salt thereof. The compound (I) of the invention has, among others, angiogenesis inhibiting activity, cell-proliferation inhibiting activity and immune reaction inhibiting activity, thus being useful as medicines, etc.

6-epifumagillols and the pharmaceutical use thereof

A complex of a fumagillin derivative represented by the general formula: ##STR1## wherein R.sup.1 is hydrogen; R.sup.2 is halogen, N(O)mR.sup.5 R.sup.6, N.sup.+ R.sup.5 R.sup.6 R.sup.7.X.sup.-, S(O)nR.sup.5 or S.sup.+ R.sup.5 R.sup.6.X.sup.- (wherein R.sup.5, R.sup.6 and R.sup.7 are independently an optionally substituted hydrocarbon or heterocyclic group; X.sup.- is a counter anion; m is an integer of 0 or 1; n is an integer from 0 to 2; and R.sup.5 and R.sup.6 together with the adjacent nitrogen or sulfur atom may form a nitrogen- or sulfur-containing heterocyclic group which may be substituted and form a condensed ring); or R.sup.1 and R.sup.2 together represent a bond; R.sup.3 is 2-methyl-1-propenyl group or isobutyl group; A is O or NR.sup.8 (wherein R.sup.8 is hydrogen or an optionally substituted lower alkyl or aryl group); R.sup.4 is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted acyl group); or a salt thereof, with an optionally etherified cyclodextrin is disclosed. The present invention also provides an antineoplastic agent containing the complex.

Cyclodextrin complex of fumagillin derivative

The present invention relates to a compound of the formula: ##STR1## wherein A is halogen, N(O)mR.sup.1 R.sup.2, N.sup..sym. R.sup.1 R.sup.2 R.sup.3 .multidot.X.sup..crclbar., S(O)nR.sup.1 or S.sup..sym. (O)mR.sup.1 R.sup.2 .multidot.X.sup..crclbar. where R.sup.1, R.sup.2 and R.sup.3 are each optionally substituted hydrocarbon or heterocyclic group, X.sup..crclbar. is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R.sup.1 and R.sup.2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, Z is O or NR.sup.4 where R.sup.4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group; provided that, when A is chlorine, E is an optionally substituted hydrocarbon or acyl excepting dinitrobenzoyl, a salt thereof, production and use thereof. The novel cyclohexanol derivatives of the present invention have angiogenesis inhibiting activity and anti-tumor activity, and they are used as antirheumatic agents, therapeutic agents of psoriasis, therapeutic agents of diabetic retinopathy and anti-tumor agents.

Cyclohexanol derivatives, production and use thereof

The present invention is related to a compound of the formula ##STR1## wherein R.sup.1 is a 2-methyl-1-propenyl or isobutyl group which may be substituted and R.sup.2 is (1) a substituted alkanoyl group, (2) a substituted aroyl group having at least one substituent selected from the group consisting of C.sub.2-6 alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, carbamoyl and carboxyl, (3) an aromatic heterocycle-carbonyl, which may optionally be substituted, (4) a carbamoyl group, which may optionally be substituted, (5) an alkyl group, which may optionally be substituted, (6) a benzenesulfonyl group, which may optionally be substituted, (7) an alkylsulfonyl group, which may optionally be substituted, (8) a sulfamoyl group, which may optionally be substituted, (9) an alkoxycarbonyl group, which may optionally be substituted or (10) a phenoxycarbonyl group, which may optionally be substituted; or a salt thereof. The compound (I) has a strong angiogenesis inhibitory activity.

Fumagillol derivatives and pharmaceutical compositions thereof

The present invention is related to a compound of the formula ##STR1## wherein R.sup.1 is a 2-methyl-1-propenyl or isobutyl group which may be substituted and R.sup.2 is (1) a substituted alkanoyl group, (2) a substituted aroyl group having at least one substituent selected from the group consisting of C.sub.2-6 alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, carbamoyl and carboxyl, (3) an aromatic heterocycle-carbonyl, which may optionally be substituted, (4) a carbamoyl group, which may optionally be substituted, (5) an alkyl group, which may optionally be substituted, (6) a benzenesulfonyl group, which may optionally be substituted, (7) an alkylsulfonyl group, which may optionally be substituted, (8) a sulfamoyl group, which may optionally be substituted, (9) an alkoxycarbonyl group, which may optionally be substituted or (10) a phenoxycarabonyl group, which may optionally be substituted; or a salt thereof. The compound (I) has a strong angiogenesis inhibitory activity.

An antibacterial agent is provided which is a cephem compound of the formula: ##STR1## wherein R.sup.1 is an acyl group; R.sup.2 is a carboxy group which may be esterified; R.sup.3 is a hydrogen atom, a lower alkyl group or cyano group; R.sup.4 is a hydrogen atom or a lower alkyl group, or R.sup.4 together with R.sup.3 is a methylene chain having 2 or 3 carbon atoms; R.sup.5 is a hydrogen atom or a lower alkyl group; A is an optionally substituted bivalent aromatic heterocyclic group which is bonded to a ring-constituting carbon atom with the adjacent sulfur atom; Y is a binding arm, sulfur or oxygen atom, --NH--, --CONH-- or --NHCO--; Z is a binding bond or --NH--; m is an integer of 0 to 4 and n is an integer of 0 to 6, or a pharmacologically acceptable salt thereof.

Cephem compounds, and use

Novel cephem compounds of the general formula: ##STR1## wherein R.sup.1 is a lower alkyl group, and salts and esters thereof, showing excellent and balanced antibacterial activity against a broad spectrum of bacteria, especially by rectal administration, and their production and use as antimicrobial agents are described.

Cephem compounds, their production and use

This invention relates to a compound of the formula: ##STR1## wherein Q is nitrogen or CH; R.sup.1 is hydrogen or a lower alkyl group which may be substituted; and ring A is a pyridine or pyridazine ring which is substituted at the ring-constituting carbon atom by a group of the formula:

Cephem compounds of the formula: ##STR1## wherein Q stands for a nitrogen atom or CH, R.sup.1 stands for a hydrogen atom or an optionally substituted lower alkyl group, R.sup.2 stands for a hydrogen atom or a lower alkyl group, A stands for a sulfur atom or NH, and n denotes an integral number ranging from 2 to 4, or salts thereof, and processes for producing them. The compounds (I) or salts thereof show not only excellent antibacterial activities against a wide range of pathogenic bacteria from gram-positive to gram-negative ones, including a variety of strains isolated clinically but also hydrophilic properties, and therefore they are excellent antibiotic substances having desirable water-solubility when used as injections.

Cephem compounds

A compound having the general formula ##STR1## wherein, R.sup.0 is a hydrogen atom, a nitrogen-containing heterocyclic group, an acyl group or an amino-protective group; Z is S, S.fwdarw.O,O or CH.sub.2 ; R.sup.4 is a hydrogen atom, a methoxy group, or a formamide group; R.sup.13 is a hydrogen atom, a methyl group, a hydroxyl group, or a halogen atom; A.sym. is a condensed triazolio group which may be substituted, or a pharmaceutically acceptable salt or ester thereof is novel and has an excellent antibacterial activity.

Disclosed are compounds of the general formula: ##STR1## wherein R.sub.1 is amino, an acylated amino or a protected amino group, X is hydrogen or methoxy, and R' is hydrogen, R or R.sup.4 wherein R is an organic residue attached to the azetidine ring through a carbon atom therein and R.sub.4 is azido, a halogen, an amino group which may optionally be acylated or a group of the formula ##STR2## wherein R.sub.5 is an organic residue and n is 0, 1 or 2, and pharmeceutically acceptable salts and esters thereof. The compounds have antimicrobial and/or .beta.-lactamase-inhibitory activity and are of value as drugs for human beings and domesticated animals.

1-sulfo-2-oxozetidine derivatives and their product ion

A 2-azetidinone derivative having a group of the formula ##STR1## wherein R.sup.1 and R.sup.2 are the same or different and each represents a hydrogen atom, alkyl, aryl or arylalkyl which may have a substituent at the 1-position and an amino group, at the 3-position, which may be acylated or protected, its salt or ester, and methods of producing the same, (1) a method comprising subjecting a 2-azetidinone derivative having a group of the formula ##STR2## wherein the symbols are as defined above at the 1-position and an amino group at the 3-position, its salt or ester to an acylation or protective-group introduction reaction, and (2) a method comprising reacting a 2-azetidinone derivative having a hydroxy group at the 1-position and an amino group, at the 3-position, which may be acylated or protected, or its salt with a compound of the formula ##STR3## wherein W is a halogen atom; other symbols are as defined above, its salt or ester. The above objective compounds are utilizable as excellent antimicrobial agents or as valuable intermediates for the synthesis of the same.

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Takarazuka, Japan

Shoji Kishimoto