Otsuka Pharmaceutical Company, Limited

Shigeharu Tamada

Kazuyuki Nakagawa

Shiro Yoshizaki

Kaoru Tanimura

Shuji Teramoto

Kazumi Kondo

Hidenori Ogawa

Takafumi Fujioka

Tatsuyoshi Tanaka

Kazuyoshi Nagami

Seiji Sato

Masahiro Murakami

Satoshi Hayakawa

Hitoshi Tone

Youichi Taniguchi

Yoshihiko Ito

Yoshimasa Nakano

Katsumi Tamura

Shinji Nishitani

Hideaki Sato

Tomoyuki Kawaguchi

Yasumitsu Tamura

Yasuyuki Kita

Shuji Akai

Hiromichi Fujioka

Katsuhide Matoba

Toshinori Kaneyasu

Eiyu Yo

Novel carbostyril derivatives and salts thereof having useful pharmacological activities such as myocardial contraction increasing activity (positive inotropic activity), coronary blood flow increasing activity, hypotensive activity, activity for inhibiting vasoconstriction induced by norepinephrine, and anti-inflammatory effect in one hand, while they do not possess activity for increasing heart beat at all substantially as well as show quite low toxicity and low side-effects in central nervous system activities.

Carbostyril derivatives and salts thereof

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

Dihydropyridine derivatives and salts thereof represented by the general formula, ##STR1## which possess excellent calcium antagonist effect, hypotensive effect, platelets aggregation inhibitory effect, phosphodiesterase inhibitory effect, calmodulin inhibitory effect and peroxidized lipid lowering effect, and thus dihydropyridine derivatives and salts thereof are useful as a coronary blood flow improving agent such as coronary vasodilator, hypotensive agent, prophylaxis and treating agents for thrombosis, phosphodiesterase inhibitory agent, peroxidized lipid metabolism lowering agent, anti-inflammatory agent and others.

Dihydropyridine derivatives and process for preparing the same

Dihydropyridine derivatives and salts thereof represented by the general formula, ##STR1## which possess excellent calcium antagonist effect, hypotensive effect, platelets aggregation inhibitory effect, phosphodiesterase inhibitory effect, calmodulin inhibitory effect and peroxidized lipid lowering effect, and thus dihydropyridine derivatives and salts thereof are useful as a coronary blood flow improving agent such as coronary vasodilator, hypotensive agent, prophylaxis and treating agents for thrombosis, phophodiesterase inhibitory agent, peroxidized lipid metabolism lowering agent, anti-inflammatory agent and others.

Novel dihydropyridine derivatives

Carbostyril derivative or a pharmaceutically acceptable acid addition salt thereof, having excellent platelate aggregation inhibitory effect, calcium antagonism, hypotensive effect and phosphodiesterase inhibitory effect are useful as prophylactic or treating agents for thrombosis, circulation improving agents for coronary blood flow such as coronary vasodilators, hypotensive agents and phosphodiesterase inhibitors. Furthermore, the carbostyril derivatives are weak in heart rate increasing activity and also in cardiac muscle contraction increasing activity, and the carbostyril derivatives are useful agents for curing and treating heart diseases such as cardiac angina and myocardial infarction caused by hypercoagulability of the platelets. Processes are disclosed for preparation of the carbostyril derivatives.

Carbostyril derivative

Carbostyril derivative represented by the formula (I): ##STR1## wherein R.sup.1 and R.sup.2, which may be the same or different, each represents a hydrogen atom, a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group; R.sup.4 represents a hydrogen atom or an alkyl group, R.sup.5 and R.sup.6, which may be the same or different, each represents a hydrogen atom, an alkyl group, a cycloalkyl group, or a phenylalkyl group, or R.sup.5 and R.sup.6 may, when taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen or oxygen atoms as hetero atoms; and the ring A has a partial structure: ##STR2## wherein R.sup.3 represents a hydrogen atom, a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group, with the proviso that at least one of R.sup.1, R.sup.2 and R.sup.3 when R.sub.3 is present, or at least one of R.sub.1 and R.sub.2 when R.sub.3 is absent, represents a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group; the pharmaceutically acceptable acid addition salts of the above carbostyril compounds represented by the formula (I), and processes for preparing the above carbostyril compounds represented by the formula (I).

Carbostyril derivatives and process for preparing the same

5-�1-Hydroxy-2-(heterocyclic-amino)!alkyl-8-hydroxy-3,4-dihydrocarbostyril derivatives having the formula (I) ##STR1## wherein R.sup.1 represents an alkyl group having 1 to 4 carbon atoms and A, when taken together with the nitrogen atom to which it is attached, form a 5- or 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen, or oxygen atoms as hetero atoms, the pharmaceutically acceptable acid addition salts thereof, and a process for preparing the same.

5-�1-Hydroxy-2-(heterocyclic-amino)!alkyl-8-hydroxy-3,4-dihydrocarb

5-[1-HYDROXY-2-(HETEROCYCLIC AMINO)]ETHYL-8-HYDROXY-3,4-DIHYDROCARBOSTYRIL DERIVATIVES REPRESENTED BY THE FORMULA (I) wherein A, when taken together with the nitrogen atom to which it is attached, forms a 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen, or oxygen atoms as hetero atoms, the pharmaceutically acceptable acid addition salts thereof, and a process for preparing the above compounds.

5-(1-Hydroxy-2-(heterocyclic

5-[1-Hydroxy-2-(substituted-amino)]alkyl -8-hydroxy-carbostyril derivatives represented by the formula (I) ##STR1## wherein R.sup.1 represents an alkyl group having 1 to 4 carbon atoms and R.sup.2 and R.sup.3, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group containing a straight or branched chain alkyl moiety having 1 to 4 carbon atoms or a cycloalkyl group having 4 to 6 carbon atoms, or R.sup.2 and R.sup.3 may, when taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen, oxygen or sulfur atoms as hetero atoms, the pharmaceutically acceptable acid addition salts thereof, and a process for preparing the same.

5-[1-Hydroxy-2-(substituted-amino)]alkyl-8-hydroxycarbostyril derivatives

5-[Hydroxy-2-(substituted-amino)]ethyl-8-hydroxy-carbostyril derivatives represented by the formula (I) ##STR1## wherein R.sup.1 and R.sup.2, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group containing a straight or branched chain alkyl moiety having 1 to 4 carbon atoms or a cycloalkyl group having 4 to 6 carbon atoms, or R.sup.1 and R.sup.2 may, when taken together with the nitrogen atom to which they are attached, form a 5 or 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen, oxygen or sulfur atoms as hetero atoms, the pharmaceutically acceptable acid addition salts thereof and a process for preparing the above compounds.

5-[1-Hydroxy-2-(substituted-amino)]ethyl-8-hydroxycarbostyril derivatives

5-[1-Hydroxy-2-(substituted-amino)]alkyl-8-hydroxy-3,4-dihydrocarbostyril derivatives having the formula (I) ##SPC1## wherein R.sup.1 represents an alkyl group having 1 to 4 carbon atoms, and R.sup.2 and R.sup.3, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group containing a straight or branched chain alkyl moiety having 1 to 4 carbon atoms or a cycloalkyl group having 4 to 6 carbon atoms, or R.sup.2 and R.sup.3 may, when taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen, oxygen or sulfur atoms as hetero atoms, the pharmaceutically acceptable acid addition salts thereof, and a process for preparing the same. These compounds posess a .beta.-adreno-receptor stimulating activity.

5-[1-Hydroxy-2-(s

5-[1-HYDROXY-2-SUBSTITUTED-AMINO)]ETHYL-8-HYDROXY-3,4-DIHYDROCARBOSTYRIL DERIVATIVES REPRESENTED BY THE FORMULA (I) ##SPC1## wherein R.sup.1 and R.sup.2, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group containing a straight or branched chain alkyl moiety having 1 to 4 carbon atoms or a cycloalkyl group having 4 to 6 carbon atoms, or R.sup.1 and R.sup.2 may, when taken together with the nitrogen atom to which they are attached, form a 5 or 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen, oxygen or sulfur atoms as hetero atoms, the pharmaceutically acceptable acid addition salts thereof, and a process for preparing the above compounds.

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Tokushima, Japan

Shigeharu Tamada