Carbostyril compounds, compositions containing same and processes for preparing same

Claim 2

A carbostyril compound of the formula (I) wherein R l represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl-lower alkyl group; R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a hydroxy group; R 3 represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitroso group, an amino group which may be substituted with a lower alkyl group, a lower alkanoylamino group, a N,N-di-lower alkylaminomethyl group, a carbamoylmethyl group, a cyanomethyl group, or a carboxymethyl group; R 4 and R 5 , which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, or a nitro group; the bonding between the 3- and 4-positions of the carbostyril nucleus is a single bond or a double bond; and the position at which the imidazopyridyl group of the formula is attached to the carbostyril nucleus is the 5- or 6-position; with the proviso that when the imidazopyridyl group is attached to the 5-position of the carbostyril nucleus, R 2 should not be a hydrogen atom, a lower alkyl group, or a halogen atom; or its pharmaceutically acceptable salt.

Claim 3

A compound or its pharmaceutically acceptable salt as claimed in Claim 1, wherein the substitutent of the formula is attached to the 5-position of the carbostyril nucleus.

Claim 4

A compound or its pharmaceutically acceptable salt as claimed in Claim 1, wherein the substituent of the formula is attached to the 6-position of the carbostyril nucleus.

Claim 5

A compound or its pharmaceutically acceptable salt as claimed in Claim 2 or 3, wherein R 1 represents a hydrogen atom.

Claim 6

A compound or its pharmaceutically acceptable salt as claimed in Claim 2 or 3, wherein R 1 represents a lower alkyl group, a phenyl-lower allkenyl group, a lower alkylthio group, or a lower alkynyl group.

Claim 7

5-(3,7-Dimethylimidazo[1,2-a]pyridine-2-yl)-8-methoxy- carbostyril or its pharmaceutically acceptable salt according to Claim 4.

Claim 8

5-(3-Methyl-6-nitroimidazo[1,2-a]pyridine-2-yl)-8-methoxycarbostyril or its pharmaceutically acceptable salt according to Claim 4.

Claim 9

5-(3-Ethylimidazo[1,2-a]pyridine-2-yl)-8-methoxycarbo- styril or its pharmaceutically acceptable salt according to Claim 4.

Claim 10

1-Allyl-5-(imidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4- - dihydrocarbostyril or its pharmaceutically acceptable salt according to Claim 5.

Claim 11

1-Propargyl-5-(imidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril or its pharmaceutically acceptable salt according to Claim 5.

Claim 12

6-(Imidazo[1,2-a]pyridine-2-yl)-3,4-dihydrocarbostyril or its pharmaceutically acceptable salt according to Claim 4.

Claim 13

8-Chloro-6-(3-methylimidazo[1,2-a]pyridine-2-yl)-3,4-dihydrocarbostyril or its pharmaceutically acceptable salt according to Claim 4.

Claim 14

8-Methoxy-6-(imidazo[1,2-a]pyridine-Z-yl)-3,4-dihydrocarbostyril or its pharmaceutically acceptable salt according to Claim 4.

Claim 15

5-(3-Methylimidazo[1,2-a]pyridine-2-yl)-8-methoxy- carbostyril or its pharmaceutically acceptable salt according to Claim 4.

Claim 16

8-Methyl-6-(3-methylimidazo[1,2-a]pyridine-2-yl)-3,4-dihydrocarbostyril or its pharmaceutically acceptable salt according to Claim 4.

Claim 17

8-Methoxy-5-(imidazo[1,2-a]pyridine-2-yl)carbostyril or its pharmaceutically acceptable salt according to Claim 4.

Claim 18

A process for preparing a carbostyril compound of the formula (I) wherein R 1 represents a hydrogen atom, a lower alkyl group, a lower aklenyl group, a lower alkynyl group, or a phenyl-lower alkyl group; R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a hydroxy group; R 3 represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitroso group, an amino group which may be substituted with a lower alkyl group, a lower alkanoylamino group, a N,N-di-lower alkylaminomethyl group, a carbamoylmethyl group, a cyanomethyl group, or a carboxymethyl group; R 4 and R 5 , which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, or a nitro group; the bonding between the 3- and 4-positions of the carbostyril nucleus is a single bond or a double bond; and the position at which the imidazopyridyl group of the formula is attached to the carbostyril nucleus is the 5- or 6-positions; with'the proviso that when the imidazopyridyl group is attached to the 5-position of the carbostyril nucleus, R 2 should not be a hydrogen atom, a lower alkyl group, or a halogen atom; or its pharmaceutically acceptable salt, which comprises; (a) reacting a compound of the formula (II) wherein X I represents a halogen atom and R 6 represents a hydrogen atom or a lower alkyl group and R 1 , R 2 , and the bonding between the 3- and 4-positions of the carbostyril nucleus have the same meanings as defined above, with a compound of the formula (III) wherein R 4 and R 5 have the same meanings as defined above; (b) halogenating a compound of the formula (Ie) wherein Rl, R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings is defined above; (c) nitrosylating a compound of the formula (Ie) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (d) reducing a compound of the formula (Ig) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (e) acylating a compound of the formula (Ii) wherein R l , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (f) reducing a compound of the formula (Ii) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (g) reacting a compound of the formula (Ii) wherein R 1 , R2, R 4 , R S and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; with a compound of the formula (XX) wherein X 2 represents halogen (h) reacting a compound of the formula (Ie) wherein R l , R 2 , R4, R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above, with a compound of the formula (XXI) wherein R 14 and R 15 , which may be the same or different, each represents a lower alkyl group; (i) reacting a compound of the formula (Im) wherein R 1 , R 2 , R 4 , R 5 , R 14 , R 15 and the bonding between the 3- and 4-positions of the carbostyril nucleus have the sane meanings as defined above, with a compound of the formula (XXII) wherein R 16 represents a lower alkyl group and X 2 represents halogen; (j) reacting a compound of the formula (In) wherein R 1 , R 2 , R 4 , R 5 , R 14 , R 15 , R 16 and the bonding between the 3- and 4-positions of the carbostyril nucleus have the same meanings as defined above, with a compound of the formula (XXIII) wherein M represents an alkali metal; (k) hydrolyzing a compound of the formula (Io) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (1) hydrolyzing a compound of the formula (Ip) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above, optionally converting the product according to one of the steps (a) to (1) above into its pharmaceutically acceptable salt.

Claim 19

A process for preparing a carbostyril compound of the formula (I) wherein R 1 represents a hydrogen atom, a lower alkyl group, a lower aklenyl group, a lower alkynyl group, or a phenyl-lower alkyl group; R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a hydroxy group; R 3 represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitroso group, an amino group which may be substituted with a lower alkyl group, a lower alkanoylamino group, a N,N-di-lower alkylaminomethyl group, a carbamoylmethyl group, a cyanomethyl group, or a carboxymethyl group; R 4 and R 5 , which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, or a nitro group; the bonding between the 3- and 4-positions of the carbostyril nucleus is a single bond or a double bond; and the position at which the imidazopyridyl group of the formula is attached to the carbostyril nucleus is the 5- or 6-positions; with'the proviso that when the imidazopyridyl group is attached to the 5-position of the carbostyril nucleus, R 2 should not be a hydrogen atom, a lower alkyl group, or a halogen atom; or its pharmaceutically acceptable salt, which comprises; (a) reacting a compound of the formula (II) wherein X I represents a halogen atom and R 6 represents a hydrogen atom or a lower alkyl group and R 1 , R 2 , and the bonding between the 3- and 4-positions of the carbostyril nucleus have the same meanings as defined above, with a compound of the formula (III) wherein R 4 and R 5 have the same meanings as defined above; (b) halogenating a compound of the formula (Ie) wherein Rl, R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings is defined above; (c) nitrosylating a compound of the formula (Ie) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (d) reducing a compound of the formula (Ig) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (e) acylating a compound of the formula (Ii) wherein R l , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (f) reducing a compound of the formula (Ii) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (g) reacting a compound of the formula (Ii) wherein R 1 , R2, R 4 , R S and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; with a compound of the formula (XX) wherein X 2 represents halogen (h) reacting a compound of the formula (Ie) wherein R l , R 2 , R4, R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above, with a compound of the formula (XXI) wherein R 14 and R 15 , which may be the same or different, each represents a lower alkyl group; (i) reacting a compound of the formula (Im) wherein R 1 , R 2 , R 4 , R 5 , R 14 , R 15 and the bonding between the 3- and 4-positions of the carbostyril nucleus have the sane meanings as defined above, with a compound of the formula (XXII) wherein R 16 represents a lower alkyl group and X 2 represents halogen; (j) reacting a compound of the formula (In) wherein R 1 , R 2 , R 4 , R 5 , R 14 , R 15 , R 16 and the bonding between the 3- and 4-positions of the carbostyril nucleus have the same meanings as defined above, with a compound of the formula (XXIII) wherein M represents an alkali metal; (k) hydrolyzing a compound of the formula (Io) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above; (1) hydrolyzing a compound of the formula (Ip) wherein R 1 , R 2 , R 4 , R 5 and the bonding between the 3- and 4- positions of the carbostyril nucleus have the same meanings as defined above, optionally converting the product according to one of the steps (a) to (1) above into its pharmaceutically acceptable salt.

Claim 20

A cardiotonic composition comprising a cardiotonically effective amount of a compound of the formula (I) wherein R represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl-lower alkyl group; R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a hydroxy group; R 3 represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitroso group, an amino group which may be substituted with a lower alkyl group, a lower alkanoylamino group, a N,N-di-lower alkylaminomethyl group, a carbamoylmethyl group, a cyanomethyl group, or a carboxymethyl group; R 4 and R S , which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, or a nitro group; the bonding between the 3- and 4-positions of the carbostyril nucleus is a single bond or a double bond; and the position at which the imidazopyridyl group of the formula is attached to the carbostyril nucleus is the 5- or 6-position; with the proviso that when the imidazopyridyl group is attached to the 5-position of the carbostyril nucleus, R 2 should not be a hydrogen atom, a lower alkyl group, or a halogen atom; or its pharmaceutically acceptable salt as active ingredient and a pharmaceutically acceptable carrier.

Claim 21

A cardiotonic composition comprising a cardiotonically effective amount of a compound of the formula (I) wherein R represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl-lower alkyl group; R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a hydroxy group; R 3 represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitroso group, an amino group which may be substituted with a lower alkyl group, a lower alkanoylamino group, a N,N-di-lower alkylaminomethyl group, a carbamoylmethyl group, a cyanomethyl group, or a carboxymethyl group; R 4 and R S , which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, or a nitro group; the bonding between the 3- and 4-positions of the carbostyril nucleus is a single bond or a double bond; and the position at which the imidazopyridyl group of the formula is attached to the carbostyril nucleus is the 5- or 6-position; with the proviso that when the imidazopyridyl group is attached to the 5-position of the carbostyril nucleus, R 2 should not be a hydrogen atom, a lower alkyl group, or a halogen atom; or its pharmaceutically acceptable salt as active ingredient and a pharmaceutically acceptable carrier.