Carbostyril compounds, compositions containing same and processes for preparing same

Claim 2

A carbostyril compound of the formaula (I): wherein R is a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenyl-lower alkyl group which has, on the phenyl ring thereof, at least one substitutent selected from among lower alkanoyloxy and hydroxy groups, a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, or a naphthoyl group, R 2 is a benzoyl group which may optionally have, on the phenyl ring thereof, at least one lower alkoxy group, and its pharmaceutically acceptable salt.

Claim 3

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 1, wherein R 2 is a benzoyl group which is substituted with 1 to 3 of a (C1-6)alkoxy group.

Claim 4

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 2, wherein R 1 a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with 1 to 3 substituents selected from the group consisting of nitro, unsubstituted or (C l-6 )alkyl-substituted amino, phenyl-(Cl-6)alkoxy, hydroxy, carboxy, phenyl-(C 1-6 )alkoxycarbonyl-(C 1-6 )alkoxy, (C l-6 )alkanoyloxy, carboxy-(C 1-6 )alkoxy, and (C 1-6 )alkyl-substituted amino-(C 1-6 )alkyl.

Claim 5

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 2, wherein R 1 is a (C 1-6 )alkanoyl group.

Claim 6

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 2, wherein R 1 is a (C 1-6 )alkoxycarbonyl group, a (C 1-6 )alkoxycarbonyl-(C 1-6 )alkyl group, a phenyl-(C 1-6 )alkyl group which has, on the phenyl ring thereof, at least one substitutent selected from among (C 1-6 )alkanoyloxy and hydroxy groups, or a naphthoyl group.

Claim 7

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 3, wherein R 1 is a benzoyl group which is substituted, on the phenyl ring thereof, with 1 to 3 substituents selected from the group consisting of hydroxy, carboxy, unsubstituted or (C 1-6 )alkyl-substituted amino, carboxy-(C 1-6 Dalkoxy, and (C l-6 )alkyl-substituted amino-(Cl-6)alkyl.

Claim 8

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 3, wherein R 1 is an unsubstituted benzoyl group.

Claim 9

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 6, wherein R 1 is a benzoyl group which is substituted, on the phenyl ring thereof, 1 to 2 substituents selected form the group consisting of unsubstituted or (C 1-6 )alkyl-substituted amino, hydroxy, and carboxy-(C 1-6 )alkoxy.

Claim 10

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 8, wherein R 2 is a 3,4-di(C 1-6 )alkokybenzoyl group.

Claim 11

A carbostyril compound or its pharmaceutically acceptable salt as claimed in Claim 9, wherein R 1 is a benzoyl group which is substituted, on the phenyl ring thereof, with one substituent selected form the group consisting of unsubstituted or (C 1-6 )alkyl-substituted amino, and hydroxy.

Claim 12

1-(4-Aminobenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril according to Claim 10.

Claim 13

1-(4-Hydroxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril according to Claim 10.

Claim 14

1-Benzoyl-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril according to Claim 7.

Claim 15

l-(4-Hydroxy-3-dimethylaminomethylbenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril according to Calim 9.

Claim 16

l-(4-Hydroxy-3-dimethylaminomethylbenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril according to Calim 9.

Claim 17

1-(3-Hydroxy-5-carboxymethoxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-l-piperazinyll-3,4-dihydrocarbostyril according to Claim 9.

Claim 18

A process for preparing a carbostyril compound of the formula (I) : wherein R is a lower alkanoyl group, a lower alkoxy- carbonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenyl-lower alkyl group which has, on the phenyl ring thereof, at least one substitutent selected from among lower alkanoyloxy and hydroxy groups, a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, or a naphthoyl group, R is a benzoyl group which may optionally have, on the phenyl ring thereof, at least one lower alkoxy group, and its pharmaceutically acceptable salt, which comprises, reacting a compound of the formula (II): wherein R 2 is as defined above, with a compound of the formula (V) : wherein R' is a group of R 1 or R 1' , in which R 1 is a lower alkanoyl group, a lower alkoxy-carbonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenyl-lower alkyl group which has, on the phenyl ring thereof, at least one substitutent selected from among lower alkanoyloxy and hydroxy groups, a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, or a naphthoyl group, and R 1' is a lower alkanoyl group, a lower alkoxycarbonyl group or a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, W is a halogen atom or a group of the formula -O-R 1' in which R 11 is as defined above, provided that W is a halogen atom, when R' is the group R 1 , and that W is a group of the formula -O-R 1' , when R' is the group R , and optionally, i) when R is a phenyl-lower alkyl group which is substituted with at least one lower alkanoyloxy group on the phenyl ring thereof or a benzoyl group which is substituted with at least one phenyl-lower alkoxy group on the phenyl ring thereof, subjecting the resultant product to hydrolysis or catalytic reduction to provide a compound of the formula (I) in which R is a phenyl-lower alkyl group which is substituted with at least one hydroxy group on the phenyl ring thereof or a benzoyl group which is substituted with at least one hydroxy group on the phenyl ring thereof, ii) when R is a benzoyl group which is substituted with at least one nitro group on the phenyl ring therof, subjecting the resultant product to reduction to provide a compound of the formula (I) in which R is a benzoyl group which is substituted with at least one amino group on the phenyl ring thereof, iii) when R is a benzoyl group which is substituted with at least one hydroxy group on the phenyl ring thereof, reacting the resultant product with a monohalo-lower alkanoic acid or a monohalo-lower alkanoic acid phenyl-lower alkyl ester to provide a compound of the formula (I) in which R is a benzoyl group which is substituted with at least one carboxy-lower alkoxy or phenyl-lower alkoxycarbonyl-lower alkoxy group on the phenyl ring thereof, iv) when R is a benzoyl which is substituted with at least one phenyl-lower alkoxycarbonyl-lower alkoxy group on the phenyl ring thereof, subjecting the resultant product to hydrolysis or catalytic reduction to provide a compound of the formula (I) in which R is a benzoyl group which is substituted with at least one carboxy-lower alkoxy group on the phenyl ring thereof, v) when R is a benzoyl group which has at least one substituent selected from hydroxy and unsubstituted or lower alkyl-substituted amino groups on the phenyl ring thereof, reacting the resultant product with a compound of the formula : wherein R 3 is a hydrogen atom or a lower alkyl group, R 4 is a lower alkyl group and formaldehyde, or a compound of the formula : wherein R 3 and R 4 are each as defined above, and X is a halogen atom, to provide a compound of the formula (I) in whcih R is a benzoyl group which is substituted with at least one lower alkyl-substituted amino-lower alkyl gorup on the phenyl ring thereof, or vi) when R is a phenyl-lower alkyl gorup which is substituted with at least one hydroxy group on the phenyl ring thereof or a benzoyl group which is substituted with at least one hydroxy group on the phenyl ring thereof, subjecting the resultant product to acylation to provide a compound of the formula (I) in whcih R is a phenyl-lower alkyl group which is substituted with at least one lower alkanoyloxy group on the phenyl ring thereof or a benzoyl group which is substituted with at least one lower alkanoyloxy group on the phenyl ring thereof.

Claim 19

A process for preparing a carbostyril compound of the formula (I) : wherein R is a lower alkanoyl group, a lower alkoxy- carbonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenyl-lower alkyl group which has, on the phenyl ring thereof, at least one substitutent selected from among lower alkanoyloxy and hydroxy groups, a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, or a naphthoyl group, R is a benzoyl group which may optionally have, on the phenyl ring thereof, at least one lower alkoxy group, and its pharmaceutically acceptable salt, which comprises, reacting a compound of the formula (II): wherein R 2 is as defined above, with a compound of the formula (V) : wherein R' is a group of R 1 or R 1' , in which R 1 is a lower alkanoyl group, a lower alkoxy-carbonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenyl-lower alkyl group which has, on the phenyl ring thereof, at least one substitutent selected from among lower alkanoyloxy and hydroxy groups, a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, or a naphthoyl group, and R 1' is a lower alkanoyl group, a lower alkoxycarbonyl group or a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, W is a halogen atom or a group of the formula -O-R 1' in which R 11 is as defined above, provided that W is a halogen atom, when R' is the group R 1 , and that W is a group of the formula -O-R 1' , when R' is the group R , and optionally, i) when R is a phenyl-lower alkyl group which is substituted with at least one lower alkanoyloxy group on the phenyl ring thereof or a benzoyl group which is substituted with at least one phenyl-lower alkoxy group on the phenyl ring thereof, subjecting the resultant product to hydrolysis or catalytic reduction to provide a compound of the formula (I) in which R is a phenyl-lower alkyl group which is substituted with at least one hydroxy group on the phenyl ring thereof or a benzoyl group which is substituted with at least one hydroxy group on the phenyl ring thereof, ii) when R is a benzoyl group which is substituted with at least one nitro group on the phenyl ring therof, subjecting the resultant product to reduction to provide a compound of the formula (I) in which R is a benzoyl group which is substituted with at least one amino group on the phenyl ring thereof, iii) when R is a benzoyl group which is substituted with at least one hydroxy group on the phenyl ring thereof, reacting the resultant product with a monohalo-lower alkanoic acid or a monohalo-lower alkanoic acid phenyl-lower alkyl ester to provide a compound of the formula (I) in which R is a benzoyl group which is substituted with at least one carboxy-lower alkoxy or phenyl-lower alkoxycarbonyl-lower alkoxy group on the phenyl ring thereof, iv) when R is a benzoyl which is substituted with at least one phenyl-lower alkoxycarbonyl-lower alkoxy group on the phenyl ring thereof, subjecting the resultant product to hydrolysis or catalytic reduction to provide a compound of the formula (I) in which R is a benzoyl group which is substituted with at least one carboxy-lower alkoxy group on the phenyl ring thereof, v) when R is a benzoyl group which has at least one substituent selected from hydroxy and unsubstituted or lower alkyl-substituted amino groups on the phenyl ring thereof, reacting the resultant product with a compound of the formula : wherein R 3 is a hydrogen atom or a lower alkyl group, R 4 is a lower alkyl group and formaldehyde, or a compound of the formula : wherein R 3 and R 4 are each as defined above, and X is a halogen atom, to provide a compound of the formula (I) in whcih R is a benzoyl group which is substituted with at least one lower alkyl-substituted amino-lower alkyl gorup on the phenyl ring thereof, or vi) when R is a phenyl-lower alkyl gorup which is substituted with at least one hydroxy group on the phenyl ring thereof or a benzoyl group which is substituted with at least one hydroxy group on the phenyl ring thereof, subjecting the resultant product to acylation to provide a compound of the formula (I) in whcih R is a phenyl-lower alkyl group which is substituted with at least one lower alkanoyloxy group on the phenyl ring thereof or a benzoyl group which is substituted with at least one lower alkanoyloxy group on the phenyl ring thereof.

Claim 20

A cardiotonic composition comprising a cardiotonically effective amount of a compound of the formula (I) : wherein R 1 is a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenyl-lower alkyl group which has, on the phenyl ring thereof, at least one substitutent selected from among lower alkanoyloxy and hydroxy groups, a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, or a naphthoyl group, R 2 is a benzoyl group which may optionally have, on the phenyl ring thereof, at least one lower alkoxy group, and its pharmaceutically acceptable salt.

Claim 21

A cardiotonic composition comprising a cardiotonically effective amount of a compound of the formula (I) : wherein R 1 is a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenyl-lower alkyl group which has, on the phenyl ring thereof, at least one substitutent selected from among lower alkanoyloxy and hydroxy groups, a benzoyl group which may optionally be substituted, on the phenyl ring thereof, with at least one substituent selected from the group consisting of nitro, unsubstituted or lower alkyl-substituted amino, phenyl-lower alkoxy, hydroxy, carboxy, phenyl-lower alkoxycarbonyl-lower alkoxy, lower alkanoyloxy, carboxy-lower alkoxy, and lower alkyl-substituted amino-lower alkyl, or a naphthoyl group, R 2 is a benzoyl group which may optionally have, on the phenyl ring thereof, at least one lower alkoxy group, and its pharmaceutically acceptable salt.

Claim 22

We hereby respectfully request the following corrections under Rule 88 EPC: 1) page 18, line 6 "atomospheres" should read "atmospheres" 2) page 18, line 19 "8the" should read "the" 3) page 31, line 4 "(0.43 g)" should read "(0.43 ml)" 4) page 39, line 6 "4.18" should read "4.68" 5) page 41, line 5 "sodium" should read "potassium" 6) page 46, line 5 "(24 ul)" should read "(24 1)" 7) page 46, line 5 "(16 ul)" should read "(16 1)" 8) page 51, line 10 "10-30 ul" should read "10-30 1".

Claim 23

We hereby respectfully request the following corrections under Rule 88 EPC: 1) page 18, line 6 "atomospheres" should read "atmospheres" 2) page 18, line 19 "8the" should read "the" 3) page 31, line 4 "(0.43 g)" should read "(0.43 ml)" 4) page 39, line 6 "4.18" should read "4.68" 5) page 41, line 5 "sodium" should read "potassium" 6) page 46, line 5 "(24 ul)" should read "(24 1)" 7) page 46, line 5 "(16 ul)" should read "(16 1)" 8) page 51, line 10 "10-30 ul" should read "10-30 1".

Claim 24

It is believed, that the corrections 1, 2 and 6 to 8 are obvious clerical errors. Corrections 3 to 5 are also thought to be acceptable since they do not extend the scope of protection sought for the present application. Furthermore, the corrected values for the amendments 3 to 5 are to be found in the translation of the priority document (Japanese Patent Appln. No. 268189/1984) page 16, line 6, and in the translation of the priority document (Japanese Patent Appln. No. 272086/1985) on page 34, line 6 and page 36, line 5 respectively.

Claim 25

It is believed, that the corrections 1, 2 and 6 to 8 are obvious clerical errors. Corrections 3 to 5 are also thought to be acceptable since they do not extend the scope of protection sought for the present application. Furthermore, the corrected values for the amendments 3 to 5 are to be found in the translation of the priority document (Japanese Patent Appln. No. 268189/1984) page 16, line 6, and in the translation of the priority document (Japanese Patent Appln. No. 272086/1985) on page 34, line 6 and page 36, line 5 respectively.

Claim 26

Copies of the appropriately amended pages are enclosed.

Claim 27

Copies of the appropriately amended pages are enclosed.