Otsuka Pharmaceutical Company, Limited

Hitoshi Tone

Hisashi Miyamoto

Hiraki Ueda

Hiroshi Yamashita

Kazuyuki Nakagawa

Michiaki Tominaga

Yoshimasa Nakano

Katsumi Tamura

Seiji Sato

Hideaki Sato

Toshiki Miyazaki

Kazumi Kondo

Takao Nishi

Masahiro Murakami

Kuninori Tai

Satoshi Hayakawa

Shigeharu Tamada

Youichi Taniguchi

Yoshihiko Ito

Shinji Nishitani

Satoshi Matsuda

Tomoyuki Kawaguchi

Yasumitsu Tamura

Yasuyuki Kita

Shuji Akai

Hiromichi Fujioka

Jun-ichi Minamikawa

Katsuhide Matoba

Akihiro Hashimoto

Toshinori Kaneyasu

Masatoshi Morisue

An object of the present invention is to provide a commercially advantageous process for preparing a fluoro benzoic acid. The process according to the present invention comprises either alkylating a fluoro benzoic acid of the formula

Processes for the preparation of fluorinated benzoic acids

Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R.sup.1 is cyclopropyl which may have 1 to 3 substituents of alkyl and halogen; phenyl which may be substituted by 1 to 3 substituents of alkoxy, halogen and OH; alkyl which may be substituted by halogen, alkanoyloxy or OH; alkenyl; or thienyl, R.sup.2 is 5- to 9-membered saturated or unsaturated heterocyclic ring which may be substituted, R.sup.3 is alkyl, R is H or alkyl, and X is halogen, and pharmaceutically acceptable salts thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.

Intermediates for anti-microbial quinolone carboxylic acids

Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R.sup.1 is cyclopropyl which may have 1 to 3 substituents of alkyl and halogen; phenyl which may be substituted by 1 to 3 substituents of alkoxy, halogen and OH; alkyl which may be substituted by halogen, alkanoyloxy or OH; alkenyl; or thienyl, R.sup.2 is 5- to 9-membered saturated or unsaturated heterocyclic ring which may be sustituted, R.sup.3 is alkyl, R is H or alkyl, and X is halogen, and pharmaceutically acceptable salts thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.

Intermediates for anti-microbial benzoheterocyclic compounds

Piperazine derivatives and salts thereof

Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R.sup.1 is cyclopropyl which may have 1 to 3 substituents of alkyl and halogen; phenyl which may be substituted by 1 to 3 substituents of alkoxy, halogen and OH; alkyl which may be substituted by halogen, alkanoyloxy or OH; alkenyl; or thienyl, R.sup.2 is 5- to 9-membered saturated or unsaturated heterocyclic ring which may be sustituted, R.sup.3 is alkyl or halogen, R.sup.4 is alkyl or halogen, R is H or alkyl, R.sup.1 and R.sup.3 may be taken together to form ##STR2## wherein R.sup.31 is H or alkyl, and X is halogen, provided that R.sup.3 and R.sup.4 are not simultaneously halogen, and salts thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.

Benzoheterocyclic compounds

Useful as intermediates for antimicrobacterial agents are compounds of the formulas ##STR1## wherein R.sup.1A is a cyclopropyl which may be substituted by 1 to 3 substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkyl and a halogen atom; a phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkoxy, a halogen atom and hydroxy on the phenyl group; a C.sub.1 -C.sub.6 alkyl which may be substituted by a halogen atom, a C.sub.1 -C.sub.6 alkanoyloxy or hydroxy; a C.sub.2 -C.sub.6 alkenyl; or thienyl, R.sup.3A is a C.sub.1 -C.sub.6 alkyl group, or a halogen atom, R.sup.4 is a C.sub.1 -C.sub.6 alkyl group, R.sup.14 is a hydrogen atom, a lower alkyl group, or a group of the formula ##STR2## R.sup.31 is hydrogen or a C.sub.1 -C.sub.6 alkyl group, and X and X.sup.4 are halogen atoms, and salts thereof.

Novel pyrazine derivatives represented by the formula (1) and salts thereof which possess inhibitory effect against superoxide radicals (O.sub.2.sup.-) released from the macrophage cells of guinea pig by stimulation, and also possess anti-albuminuria activity in Masugi nephritis. ##STR1## The pyrazine derivatives (1) and salts thereof are useful agents for preventing and treating of various diseases caused by the superoxide radicals, for example, diseases of autoimmune such as rheumatoid arthritis, arteriosclerosis, ischemic heart disease, transient cerebral ischematic attack, hepatic insufficiency, renal insufficiency and the like, as well as they are useful agents for preventing and treating the nephritis in various clinical fields.

Pyrazinyl and piperazinyl substituted pyrazine compounds

The novel indole derivatives and salts thereof represented by the general formula (1) ##STR1## possess, for example, an inhibitory effect against superoxide (O.sub.2.sup.-) released from the macrophage cells of guinea pig by stimulation and an anti-albuminuria activity against Masugi nephritis, and are useful in various clinical fields as an agent for preventing and treating diseases and cases associated with the above superoxide radical, for example, autoimmune diseases (e.g. rheumatism), arteriosclerosis, ischemic disease, ischemic encephalopathia, hepatic insufficiency and renal insufficiency, and also as an agent for preventing and treating nephritis.

Indole derivatives

Novel 1-substituted phenyl-4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R.sup.1 is hydrogen atom or an alkyl having 1 to 2 carbon atoms, R.sup.2 is hydrogen atom or fluorine atom, and R.sup.3 is hydroxy, fluorine atom or an alkanoyloxy having 1 to 6 carbon atoms, and a pharmaceutically acceptable salt thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition comprising as an active ingredient said 1-substituted phenyl-4-oxoquinoline-3-carboxylic acid compounds or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

Antimicrobial 1-substituted phenyl-4-oxoquinoline-3-carboxylic acid

Novel 1-substituted phenyl-4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R is hydrogen atom or fluorine atom, R.degree. is hydroxy, fluorine atom or an alkanoyloxy having 1 to 6 carbon atoms, and X.sup.1 is hydrogen atom or fluorine atom, and a pharmaceutically acceptable salt thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition comprising as an active ingredient said 1-substituted phenyl-4-oxoquinoline-3-carboxylic acid compounds or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

Carbostyril compounds represented by the formula (I): ##STR1## wherein R.sub.1 represents a hydrogen atom or an alkyl group; R.sub.2 represents a hydrogen atom, an alkyl group or a phenylalkyl group; R.sub.3 represents a hydrogen atom and R.sub.4 represents a phenylalkyl group or a phenoxyalkyl group; the 3,4-bond of the carbostyril nucleus represents a single or double bond, pharmaceutically acceptable acid addition salts thereof, and process for preparing the same.

Carbostyril compounds

Carbostyril compounds represented by the formula (I) ##STR1## wherein R.sub.1 represents a hydrogen atom, an alkyl group or a phenylalkyl group, R.sub.2 represents an alkenyl group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyalkyl group, an alkylcarbonyl group, a cycloalkylcarbonyl group, an alkylcarbonylalkyl group, an alkoxycarbonylalkyl group, an alkynyl group or a carbamoylalkyl group, R.sub.3 and R.sub.4, which may be the same or different, each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxyalkyl group, an alkenyl group, a phenylalkyl group, a phenoxyalkyl group or a phenyl group, and the 3,4-bond of the carbostyril nucleus represents a single or double bond, pharmaceutically acceptable salts thereof, and a process for preparing the same.

Carbostyril compounds represented by the formula (I): ##STR1## wherein R.sub.1 represents a hydrogen atom, R.sub.2 represents a hydrogen atom, a phenylalkyl group, an alkoxyalkyl group, a hydroxyalkyl group, an alkylcarbonyl group, an alkynyl group, R.sub.3 and R.sub.4 each represents a hydrogen atom, a heterocyclic alkyl group or R.sub.3 and R.sub.4 can form, when taken together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic ring which may contain a nitrogen atom or an oxygen atom as an additional hetero atom, the 3,4-bond of the carbostyril nucleus represents a single or double bond, pharmaceutically acceptable acid addition salts thereof, and process for preparing the same.

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Itano, Japan

Hitoshi Tone