Carbostyril derivatives and salts thereof, process for preparing them, and cardiotonic composition containing same

Claim 2

A carbostyril derivative or salt thereof represented by the general formula, wherein R is a group of the formula (wherein A is a group of the formula ((wherein B is a lower alkylene group)) or a group of the formula R I and R 2 are each the same or different and are each a lower alkyl group or a phenyl-lower alkyl group which may have lower alkoxy groups as the substituents on the phenyl ring; furthermore, R I and R 2 may form, together with the adjacent nitrogen atom being bonded thereto, a group of the formula ((wherein R 3 is a phenyl group which may have 1 to 2 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group and a lower alkylenedioxy group; Z is a group of the formula , a group of the formula wherein R 4 is a hydroxyl group, a lower alkanoyloxy group or a lower alkoxy group; or a group of the formula wherein B is the same as defined above, and R 5 is a cyano group, a halogen atom or a group of the formula wherein R 6 and R 7 are each the same or ditferent, and are each a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a benzoyl group or a lower alkanoyl group; further R 6 and R 7 may form, together with the adjacent nitrogen atom being bonded thereto, and further with or without an additional nitrogen atom or oxygen atom, a 5-or 6-membered saturated or unsaturated heterocyclic group)) ); or a group of the formula (wherein R 1' is a lower alkylenedioxy group, an oxo group, a hydroxylimino group, a lower alkanoylyimino group, a group of the formula = N-A' (( wherein A' is a lower alkyl group, a phenyl-lower alkyl gruop, a lower alkylsulfonyl group or a phenoxy-lower alkyl group)) or a group of the formula (( wherein R 4 ' and R 5 ' are each the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a phenyl-lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a benzoyl group which may have 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom on the phenyl ring, a phenyl-lower alkanoyl group, a phenyl-lower alkenylcarbonyl group which may have lower alkoxy groups as the substituents on the phenyl ring, or a phenoxy-lower alkyl group)), and ℓ is 0 or 1); or a group of the formula (wherein R 2' is a hydrogen atom or a lower alkyl group; R 3 is a hydrogen atom, a lower alkyl group, a lower. alkanoyl group, a phenyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group, further the alkyl moiety may be substituted with a halogen atom, a cyano group or a hydroxyl group; a benzoyl-lower alkyl group, a phenyl-lower alkenyl group, a lower alkenyl group, a phenoxy-lower alkyl group, a phenylthio-lower alkyl group or an anilino-Iower alkyl group in which the amino moiety may be substituted with a lower alkyl group); the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single or double bond; provided that, when R I and R 2 are each the same or different and are each a lower alkyl group or a phenyl-lower alkyl group which may have lower alkoxy groups as the substituents on the phenyl ring, and when R I and R 2 form, together with the adjacent nitorgen atom being bonded thereto, a group of the formula (wherein R 3 is the same as defined above; and Z is a group of the formula then A is a group of the formula (wherein B is the same as defined above); further provided that, when is 0, and R 4' is a hydrogen atom, a lower alkyl group or a phenyl-lower alkyl group, then R 5' should be neither a hydrogen atom, a lower alkyl group nor a phenyl-lower alkyl group.

Claim 3

The carbostyril derivative or salt thereof according to Claim 1, wherein said carbostyril derivative or salt thereof is represented by the general formula, wherein A is a group of the formula (wherein B is a C 1 -C 6 alkylene group) or a group of the formula R' and R 2 are each the same or different and are each a C 1 -C 6 alkyl group or a phenyl-C 1 -C 6 alkyl group which may have 1 to 3 C 1 -C 6 alkoxy groups as the substituents on the phenyl ring; furthermore R' and R 2 may form, together with the adjacent nitrogen atom being bonded thereto, a group of the formula (wherein R 3 is a phenyl group which may have 1 to 2 substituents selected from the group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylthio group ans a C 1 -C 4 alkylene dioxy group; Z is a group of the formula a group of the formula wherein R 4 is a hydroxyl group, a C 1 -C 6 alkanoyloxy group or a C 1 -C 6 alkoxy group, B is the same as defined above; or a group of the formula wherein B is the same as defiend above, and R 5 is a cyano group, a halogen atom or a group of the formula wherein R 6 and R 7 are each the same or different, and are each a hydrogen atom, a C l -C 6 alkyl group, a lower alkoxycarbonyl group in which the lower alkoxy moiety having 1 to 6 carbon atoms, a benzoyl group or a C 1 -C 6 alkanoyl group; further R 6 and R 7 may form, together with the adjacent nitrogen atom being bonded thereto, and further with or without an additional nitrogen atom or oxygen atom, a piperidino, piperazino, morpholino, imidazolyl, pyrrolyl or pyrrolidyl group); the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single or double bond; provided that, when R' and R 2 are each the same or different and are each a C 1 -C 6 alkyl group or a phenyl-C 1 -C 6 alkyl group which may have 1 to 3 C l -C 6 alkoxy groups as the substituents on the phenyl ring, and when R 1 and R 2 form, together with the adjacent nitrogen atom being bonded thereto, a group of the formula (wherein R 3 is the same as defined above; and Z is a group of the formula then A is a group of the formula (wherein B is the same as defined above).

Claim 4

The carbostyril derivative or salt thereof according to Claim 2, wherein A is a group of the formula, (wherein B is a C 1 -C 6 alkylene group), R 1 and R 2 are each the same or different, and are each a C 1 -C 6 alkyl group or a phenyl-C 1 -C 6 alkyl group which may have C 1 -C 6 alkoxy groups as the substituents on the phenyl ring.

Claim 5

The carbostyril derivative or salt thereof according to Claim 3, wherein R' is a C 1 -C 6 alkyl group, and R 2 is a phenyl-C 1 -C 6 alkyl group which may have C 1 -C 6 alkoxy groups as the substituents on the phenyl ring.

Claim 6

The carbostyril derivative or salt thereof accordig to Claim 4, wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a double bond.

Claim 7

The carbostyril derivative or salt thereof according to Claim 4, wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single bond.

Claim 8

The carbostyril derivative or salt thereof according to Claim 2, wherein R 1 and R 2 form, together with the adjacent nitrogen atom being bonded thereto, a group of the formula (wherein Z and R 3 are the same as defined above).

Claim 9

The carbostyril derivative or salt thereof according to Claim 7, wherein Z is a group of the formula (wherein B and R 4 are the same as defined above).

Claim 10

The carbostyril derivative or salt thereof according to Claim 8, wherein A is a group of the formula

Claim 11

The carbostyril derivative or salt thereof according to Claim 9, wherein R 4 is a hydroxyl group.

Claim 12

The carbostyril derivative or salt thereof according to Claim 10, wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single bond.

Claim 13

The carbostyril derivative or salt thereof according to Claim 7, wherein Z is a group of the formula (wherein B and R 5 are the same as defined above).

Claim 14

The carbostyril derivative or salt thereof according to Claim 8, wherein A is a group of the formula (wherein B is the same as defined above).

Claim 15

The carbostyril derivative or salt thereof according to Claim 1, wherein R is a group of the formula (wherein R 1' is a C l -C 4 alkylenedioxy group, an oxo group, a hydroxyimino group, a C 1 -C 6 alkanoyloxyimino group, a group of the formula = N-A' (( wherein A' is a C 1 -C 6 alkyl group, a phenyl-C 1 -C 6 alkyl group, a C 1 -C 6 alkylsulfonyl group or a phenoxy-C 1 -C 6 alkyl group)), or a group of the formula ((wherein R 4' and R 5' are each the same or different, and are each a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkanoyl group, a phenyl-C 1 -C 6 alkyl group, a C 1 -C 6 alkoxycarbonyl group, a C l -C 6 alkylsulfonyl group, a benzoyl group which may have 1 to 3 substituents, on the phenyl ring, selected from the group consisting og a C 1 -C 6 alkoxy group and a halogen atom, a phenyl-C 2 -C 6 alkanoyl group, a phenyl-C 3 -C 6 alkenylcarbonyl group which may have 1 to 3 C 1 -C 6 alkoxy groups as the substituents on the phenyl ring or a phenoxy-C 1 -C 6 alkyl group)); is 0 or 1; further the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single or double bond: provided that, when ℓ is 0 and R 4' is a hydrogen atom, a C 1 -C 6 alkyl group or a phenyl-C 1 -C 6 alkyl group, then R 5' should be neither a hydrogen atom, a C 1 -C 6 alkyl group nor a phenyl-C 1 -C 6 alkyl group).

Claim 16

The carbostyril derivative or salt thereof according to Claim 14, wherein ℓ is 0.

Claim 17

The carbostyril derivative or salt thereof according to CLaim 14, wherein ℓ is 1.

Claim 18

The carbostyril derivative or salt thereof according to Claim 1, wherein R is a group of the formula (wherein R 2' is a hydrogen atom, or a C 1 -C 6 alkyl group, and R 3' is a hydrogen atom, a C 1 -C 6 alkyl group, a Ci-C 6 alkanoyl group, a phenyl-Ci-C 6 alkyl group which may have 1 to 3 substituents, on the phenyl irng, selected from the group consisting of a C 1 -C 6 alkoxy group, a halogen atom and a nitro geoup, further the alkyl moiety in the phenylalkyl group may have the substituents selected from the group consisting of a halogen atom, a cyano group and a hydroxyl group, a benzoyl-C 1 -C 6 alkyl group, a phenyl-CrC 6 alkenyl group, a C Z -C 12 alkenyl group having 1 to 3 double bonds therein, a phenoxy-C 1 -C 6 alkyl group, a phenylthio-C 1 -C 6 alkyl group or an anilino-C 1 -C 6 alkyl group which may have C 1 -C 6 alkyl groups as the substituents in the amino moiety); and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single or double bond.

Claim 19

The carbostyril derivative or salt thereof according to Claim 17, wherein R is a C 1 -C 6 alkyl group.

Claim 20

The carbostyril derivative or salt thereof according to Claim 18, wherein R 3' is a phenyl-C 1 -C 6 alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a C 1 -C 6 alkoxy group, a halogen atom and a nitro group, further the C 1 -C 6 alkyl moiety in the phenylalkyl group may have the substituents selected from the group consisting of a halogen atom, a cyano group and a hydroxyl group.

Claim 21

The carbostyril derivative or salt thereof according to Claim 19, wherein R 3' is an unsubstituted phenylalkyl group in which the alkyl moiety contains 1 to 6 carbon atoms.

Claim 22

The carbostyril derivative or salt thereof according to Claim 20, wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single bond.

Claim 23

6-{1-Hydroxyimino-2-[N-methyl-N-(4-methoxybenzyl)amino]butyl}carbostyril.

Claim 24

6-{1-Hydroxyimino-2-[N-methyl-N-(4-methoxybenzyl)amino]butyl}carbostyril.

Claim 25

6-[4-(3-Phenyl-3-hydroxyiminopropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.

Claim 26

6-[4-(3-Phenyl-3-hydroxyiminopropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.

Claim 27

6-[4-(4-Phenyl-4-hydroxyiminobutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.

Claim 28

6-[4-(4-Phenyl-4-hydroxyiminobutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.

Claim 29

6-[N-(1-Benzyl-4-piperidyl)-N-methylamido]-3,4-dihydrocarbosytril.

Claim 30

6-[N-(1-Benzyl-4-piperidyl)-N-methylamido]-3,4-dihydrocarbosytril.

Claim 31

Process for preparing a carbostyril derivative represented by the general formula, (wherein A, R, R 2 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (a) by reacting a carbostyril derivative represented by the general formula, (wherein A, B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, NH2 - R8 (wherein R 8 is a hydrogen atom or a lower alkoxy group), to obtain a carbostyril derivative represented by the general formula, (wherein A, B , R 3 , R 8 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (b) by reacting a carbostyril derivative represented by the general formula, (wherein A, B , R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 9 -X or (R 9 ) 2 O (wherein R 9 is a lower alkanoyl group; and X is a halogen atom), to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 , R 9 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (c) by reacting a carbostyril derivative represented by the general formula, (wherein A , B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a halogenating agent to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and X is a halogen atom), (d) by reacting a carbostyril derivative represented by the general formula, (wherein A, B, R 3 , X and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 9 and R 10 are each the same or different, and are each a hydrogen atom or a lower alkyl group; further R 9 and R 10 may form, together with the adjacent nitrogen atom being bonded thereto, further with or without additional oxygen atom or nitrogen atom, a 5-or 6-membered saturated or unsaturated heterocyclic group), to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 , R 9 , R 10 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (e) by reducing a carbostyril derivative represented by the general formula, (wherein A, B, R 3 , R 4 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (f) by reacting a carbostyril derivative represented by the general formula, (wherein A, B , R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 11 -X (wherein R" is a lower alkoxycarbonyl group, a benzoyl group or a lower alkanoyl group; X is a halogen atom), to obtain a carbostyril derivative represented by the general formula, 11 (wherein A, B, R 3 , R" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (g) by reacting a carbostyril derivative represented by the general formula, (wherein R 1 , R 2 , B and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with hydroxylamine of the formula, NH 2 0H to obtain a carbostyril derivative of the general formula, (wherein R 1 , R 2 , B , and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (h) by reacting a carbostyril derivative of the formula, (wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single or double bond), with a compound of the general formula, (wherein R I and R 2 are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein R', R 2 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (i) by reacting a carbostyril derivative represented by the general formula, (wherein A and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound of the general formula, (wherein R 3 is the same as defined above; and X 1 is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group), to obtain a carbostyril derivative represented by the general formula, (wherein R 3 , A, and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (j) by reacting a carbostyril derivative represented by the general formula, (wherein A , B, R 3 , X and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound of the formula, M-CN (wherein M is a metallic atom), to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (k) by reacting a carbostyril derivative represented by the general formula, (wherein A and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, X 1 -Z' -R3 (wherein X 1 and R 3 are the same as defined above; and Z' is a group of the formula or a group of the formula wherein R 4 , R5 and B are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein A, R 3 , Z' and the carbon-carbon bond between 3-4-positions in the carbostyril skeleton are the same as defined above),

Claim 32

Process for preparing a carbostyril derivative represented by the general formula, (wherein A, R, R 2 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (a) by reacting a carbostyril derivative represented by the general formula, (wherein A, B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, NH2 - R8 (wherein R 8 is a hydrogen atom or a lower alkoxy group), to obtain a carbostyril derivative represented by the general formula, (wherein A, B , R 3 , R 8 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (b) by reacting a carbostyril derivative represented by the general formula, (wherein A, B , R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 9 -X or (R 9 ) 2 O (wherein R 9 is a lower alkanoyl group; and X is a halogen atom), to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 , R 9 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (c) by reacting a carbostyril derivative represented by the general formula, (wherein A , B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a halogenating agent to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and X is a halogen atom), (d) by reacting a carbostyril derivative represented by the general formula, (wherein A, B, R 3 , X and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 9 and R 10 are each the same or different, and are each a hydrogen atom or a lower alkyl group; further R 9 and R 10 may form, together with the adjacent nitrogen atom being bonded thereto, further with or without additional oxygen atom or nitrogen atom, a 5-or 6-membered saturated or unsaturated heterocyclic group), to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 , R 9 , R 10 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (e) by reducing a carbostyril derivative represented by the general formula, (wherein A, B, R 3 , R 4 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (f) by reacting a carbostyril derivative represented by the general formula, (wherein A, B , R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 11 -X (wherein R" is a lower alkoxycarbonyl group, a benzoyl group or a lower alkanoyl group; X is a halogen atom), to obtain a carbostyril derivative represented by the general formula, 11 (wherein A, B, R 3 , R" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (g) by reacting a carbostyril derivative represented by the general formula, (wherein R 1 , R 2 , B and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with hydroxylamine of the formula, NH 2 0H to obtain a carbostyril derivative of the general formula, (wherein R 1 , R 2 , B , and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (h) by reacting a carbostyril derivative of the formula, (wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single or double bond), with a compound of the general formula, (wherein R I and R 2 are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein R', R 2 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (i) by reacting a carbostyril derivative represented by the general formula, (wherein A and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound of the general formula, (wherein R 3 is the same as defined above; and X 1 is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group), to obtain a carbostyril derivative represented by the general formula, (wherein R 3 , A, and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (j) by reacting a carbostyril derivative represented by the general formula, (wherein A , B, R 3 , X and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound of the formula, M-CN (wherein M is a metallic atom), to obtain a carbostyril derivative represented by the general formula, (wherein A, B, R 3 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (k) by reacting a carbostyril derivative represented by the general formula, (wherein A and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, X 1 -Z' -R3 (wherein X 1 and R 3 are the same as defined above; and Z' is a group of the formula or a group of the formula wherein R 4 , R5 and B are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein A, R 3 , Z' and the carbon-carbon bond between 3-4-positions in the carbostyril skeleton are the same as defined above),

Claim 33

Process for preparing a carbostyril derivative representeed by the general formula, (wherein R' is a group of the formula or a group of the formula (( wherein R 1' , R 2' R 3' are the same as defined above)); ℓ and the carbon-carbon bond between 3-and 4- positions in the carbostyril skeleton are the same as defined above), (a) by reacting a carbostyril derivative of the general formula, (wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single or double bond), with a compound represented by the general formula, (wherein R 6' is a group of the formula ((wherein R1' is the same as defined above)), or a group of the formula (( wherein R 2' and R 3' are the same as defined above)) ), to obtain a carbostyril derivative represented by the general formula, (wherein R6 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (b) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with hydroxylamine of the formula NH 2 -OH, to obtain a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (c) by reducing a carbostyril derivative represented by the general formula, wherein and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same s defined above), to btain a carbostyril derivative represented by the general formula, (wherein 1 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (d) by reducing a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and R 7' is a lower alkanoyloxy group), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (e) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 8' -OH (wherein R 8' is a lower alkanoyl group, a lower alkoxycarbonyl gorup, a benzoyl group which may have 1 to 3 substituents, on the phenyl ring, selected from the group consisting of a lower alkoxy group and a halogen atom, a phenyl-lower alkanoyl group or a phenyl-lower alkenylcarbonyl gorup which may have a lower alkoxy groups as the substituents on the phenyl ring), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ , R8 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (f) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ , and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 9' -X 1' (wherein R 9' is a lower alkyl group, a phenyl-lower alkyl group, a lower alkylsulfonyl group or a phenoxy-lower alkyl group; and X" is a halogen atom, a lower alkanesulfonyloxy group, a arylsulfonyloxy group or a aralkylsulfonyloxy group), to obtain a carbostyril derivative represented by the general formula, (wehrein ℓ , R 9' and the carbon-carbon bond between 3-and 4-positions in the carbpstyril skeleton are the same as defined above; and R 9" is the same as defined in R 9' or a hydrogen atom), (g) by reacting a carbostyril derivative represented by the general formula, (wherein t , R 9' , R 9" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 8' -OH (wherein R 8' is the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein i , R 8' , R 9' and the carbon-carbon bond between 3-and 4-positions in the carbstyril skeleton are the same as defined above), (h) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ, and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 10' and R 11' are each a hydrogen atom or a lower alkyl group), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ, R 10' , R 11' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (i) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ , R 10' , R 11' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 10' and R 11' are the same as defined above), to obtian a carbostyril derivative represented by the general formula, (wherein ℓ , R 10' , R 11' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (j) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ , and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 9' and R 9" are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ , R 9' , R" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (k) by reducing a carbostyril derivative represented by the general formula, (wherein ℓ , R 9' , R 9" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above) to obtain a carbostyril derivative represented by the general formula, (wherein ℓ, R 9' , R 9" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (I) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ , and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 9' -NH 2 (wherein R 9 is the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ , R 9' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above) and/or a carbostyril derivative represented by the general formula, (wherein ℓ , R 9' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above) (m) by reacting a carbostyril derivative represented by the general formula, (wherein R 2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 12' -OH (wherein R 12 ' is a lower alkanoyl group), to obtain a carbostyril derivative represented by the general formula, (wherein R 2' , R 12' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (n) by reacting a carbostyril derivative represented by the general formula, (wherein R 2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 13' -X 1' (wherein X 1' is the same as defined above; and R 13' is a lower alkanoyl group or the same definition for the above-mentioned symbol R 3 excluding a hydrogen atom), to obtain a carbostyril derivative represented by the general formula, (wherein R 2' , R 13' and the carbon-carbon bond between 3-and 4-positions in tt same as defined above), (o) by ring-closing a compound represented by the general formula, (wherein R' is the same as defined above; and R 14' is a halogen atom), to obtain a carbostyril derivative represented by the general formula, (wherein R' is the same as defined above), (p) by ring-closing a compound represented by the general formula, (wherein R' is the same as defined above; and R 15' is a hydroxyl group or a lower alkoxy group; the carbon-carbon bond being shown by a group of the formula -CH---CH-is a single or double bond), or by ring-closing a compound represented by the general formula, (wherein R ' , R 12' , R 15' and a group of the formula -CH--CH-are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein R' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (q) by reacting a carbostyril derivative represented by the general formula, (wherein R2' and the carbon-carbon bond between 3-and 4-position in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 16' is a phenyl group which may have 1 to 3 substituents, on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group; or a phneyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group; R 17' is a hydrogen atom or the same meaning in the above-mentioned R1 16' ; and R 18' and R 19' are each the same or different, and are each a hydrogen atom or a lower alkyl group), to obtain a carbostyril derivative represented by the general formula, (wherein R2', R 16' , R 17' , R 18' , R 19' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (r) by reducing a carbostyril derivative represented by the general formula, (wherein R 2' , B' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and B' is a lower alkylene group), to obtain a carbostyril derivative represented by the general formula, (wherein R 2 , B' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above) (s) by halogenating a carbostyril derivative represented by the general formula, (wherein R 2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and R 22' is a phenyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group, further the alkyl moiety in the phenylalkyl group may have hydroxyl groups as the substituents), to obtain a carbostyril derivative represented by the general formula, (wherein R2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and R 23 is a phenyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group, further the alkyl moiety in the phenylalkyl group may have halogen atoms as the substituents), (t) by reacting a carbostyril derivative represented by the general formula, (wherein R 2' , R 23 and the carbon-carbon-bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound of the general formula, M-CN (wherein M is a metallic atom), to obtian a carbostyril derivative represented by the general formula, (wherein R 2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and R 24' is a phenyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group, further the alkyl moiety in the phenylalkyl gorup having cyano groups as the substituents), (u) by ring-closing a compound represented by the general formula, (wherein R' is the same as defined above; and B' is a group of the formula R 25' -CH = CH-(( wherein R 25' is a lower alkoxy group or a halogen atom)), a group of the formula ((wherein R26 and R 27' are each a lower alkyl group)) or group of the formula CH-C-), to obtain a carbostyril derivative represented by the general formula, (wherein R' is the same as defined above), (v) by reacting a compound represented by the general formula, (wherein R 14' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R' is the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein R' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above).

Claim 34

Process for preparing a carbostyril derivative representeed by the general formula, (wherein R' is a group of the formula or a group of the formula (( wherein R 1' , R 2' R 3' are the same as defined above)); ℓ and the carbon-carbon bond between 3-and 4- positions in the carbostyril skeleton are the same as defined above), (a) by reacting a carbostyril derivative of the general formula, (wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single or double bond), with a compound represented by the general formula, (wherein R 6' is a group of the formula ((wherein R1' is the same as defined above)), or a group of the formula (( wherein R 2' and R 3' are the same as defined above)) ), to obtain a carbostyril derivative represented by the general formula, (wherein R6 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (b) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with hydroxylamine of the formula NH 2 -OH, to obtain a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (c) by reducing a carbostyril derivative represented by the general formula, wherein and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same s defined above), to btain a carbostyril derivative represented by the general formula, (wherein 1 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (d) by reducing a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and R 7' is a lower alkanoyloxy group), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (e) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 8' -OH (wherein R 8' is a lower alkanoyl group, a lower alkoxycarbonyl gorup, a benzoyl group which may have 1 to 3 substituents, on the phenyl ring, selected from the group consisting of a lower alkoxy group and a halogen atom, a phenyl-lower alkanoyl group or a phenyl-lower alkenylcarbonyl gorup which may have a lower alkoxy groups as the substituents on the phenyl ring), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ , R8 and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (f) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ , and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 9' -X 1' (wherein R 9' is a lower alkyl group, a phenyl-lower alkyl group, a lower alkylsulfonyl group or a phenoxy-lower alkyl group; and X" is a halogen atom, a lower alkanesulfonyloxy group, a arylsulfonyloxy group or a aralkylsulfonyloxy group), to obtain a carbostyril derivative represented by the general formula, (wehrein ℓ , R 9' and the carbon-carbon bond between 3-and 4-positions in the carbpstyril skeleton are the same as defined above; and R 9" is the same as defined in R 9' or a hydrogen atom), (g) by reacting a carbostyril derivative represented by the general formula, (wherein t , R 9' , R 9" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 8' -OH (wherein R 8' is the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein i , R 8' , R 9' and the carbon-carbon bond between 3-and 4-positions in the carbstyril skeleton are the same as defined above), (h) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ, and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 10' and R 11' are each a hydrogen atom or a lower alkyl group), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ, R 10' , R 11' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (i) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ , R 10' , R 11' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 10' and R 11' are the same as defined above), to obtian a carbostyril derivative represented by the general formula, (wherein ℓ , R 10' , R 11' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (j) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ , and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 9' and R 9" are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ , R 9' , R" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (k) by reducing a carbostyril derivative represented by the general formula, (wherein ℓ , R 9' , R 9" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above) to obtain a carbostyril derivative represented by the general formula, (wherein ℓ, R 9' , R 9" and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (I) by reacting a carbostyril derivative represented by the general formula, (wherein ℓ , and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 9' -NH 2 (wherein R 9 is the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein ℓ , R 9' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above) and/or a carbostyril derivative represented by the general formula, (wherein ℓ , R 9' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above) (m) by reacting a carbostyril derivative represented by the general formula, (wherein R 2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 12' -OH (wherein R 12 ' is a lower alkanoyl group), to obtain a carbostyril derivative represented by the general formula, (wherein R 2' , R 12' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (n) by reacting a carbostyril derivative represented by the general formula, (wherein R 2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, R 13' -X 1' (wherein X 1' is the same as defined above; and R 13' is a lower alkanoyl group or the same definition for the above-mentioned symbol R 3 excluding a hydrogen atom), to obtain a carbostyril derivative represented by the general formula, (wherein R 2' , R 13' and the carbon-carbon bond between 3-and 4-positions in tt same as defined above), (o) by ring-closing a compound represented by the general formula, (wherein R' is the same as defined above; and R 14' is a halogen atom), to obtain a carbostyril derivative represented by the general formula, (wherein R' is the same as defined above), (p) by ring-closing a compound represented by the general formula, (wherein R' is the same as defined above; and R 15' is a hydroxyl group or a lower alkoxy group; the carbon-carbon bond being shown by a group of the formula -CH---CH-is a single or double bond), or by ring-closing a compound represented by the general formula, (wherein R ' , R 12' , R 15' and a group of the formula -CH--CH-are the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein R' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (q) by reacting a carbostyril derivative represented by the general formula, (wherein R2' and the carbon-carbon bond between 3-and 4-position in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R 16' is a phenyl group which may have 1 to 3 substituents, on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group; or a phneyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group; R 17' is a hydrogen atom or the same meaning in the above-mentioned R1 16' ; and R 18' and R 19' are each the same or different, and are each a hydrogen atom or a lower alkyl group), to obtain a carbostyril derivative represented by the general formula, (wherein R2', R 16' , R 17' , R 18' , R 19' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), (r) by reducing a carbostyril derivative represented by the general formula, (wherein R 2' , B' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and B' is a lower alkylene group), to obtain a carbostyril derivative represented by the general formula, (wherein R 2 , B' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above) (s) by halogenating a carbostyril derivative represented by the general formula, (wherein R 2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and R 22' is a phenyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group, further the alkyl moiety in the phenylalkyl group may have hydroxyl groups as the substituents), to obtain a carbostyril derivative represented by the general formula, (wherein R2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and R 23 is a phenyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group, further the alkyl moiety in the phenylalkyl group may have halogen atoms as the substituents), (t) by reacting a carbostyril derivative represented by the general formula, (wherein R 2' , R 23 and the carbon-carbon-bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound of the general formula, M-CN (wherein M is a metallic atom), to obtian a carbostyril derivative represented by the general formula, (wherein R 2' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above; and R 24' is a phenyl-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of a lower alkoxy group, a halogen atom and a nitro group, further the alkyl moiety in the phenylalkyl gorup having cyano groups as the substituents), (u) by ring-closing a compound represented by the general formula, (wherein R' is the same as defined above; and B' is a group of the formula R 25' -CH = CH-(( wherein R 25' is a lower alkoxy group or a halogen atom)), a group of the formula ((wherein R26 and R 27' are each a lower alkyl group)) or group of the formula CH-C-), to obtain a carbostyril derivative represented by the general formula, (wherein R' is the same as defined above), (v) by reacting a compound represented by the general formula, (wherein R 14' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above), with a compound represented by the general formula, (wherein R' is the same as defined above), to obtain a carbostyril derivative represented by the general formula, (wherein R' and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined above).

Claim 35

A cardiotonic composition, containing as the active ingredient, a carbostyril derivative represented by the general formula, (wherein R and the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton are the same as defined in Claim 1.).