US 7,459,465 B2 · Isoquinoline compound and pharmaceutical use thereof

Abstract

The present invention relates to an isoquinoline compound represented by the following formula (I), an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof, as well as an agent for the prophylaxis and/or treatment of a disease caused by hyperreactivity of poly(ADP-ribose)polymerase, containing the compound, and a poly(ADP-ribose)polymerase inhibitor containing the compound. In addition, this compound is useful as an agent for the prophylaxis and/or treatment of cerebral infarction, particularly as an agent for the prophylaxis and/or treatment of acute cerebral infarction. Furthermore, this compound is useful as a prophylactic and/or therapeutic agent that improves neurological symptoms associated with cerebral infarction, particularly acute cerebral infarction. wherein the symbols are the same as defined in the description.

Claims36

Dependent claims

An isoquinoline compound represented by the following formula (I):

R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy;
Y is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group;
and
R is represented by the following formula (II):
X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), then X should be CH;
W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom;
s is an integer of 1 to 5;
t is an integer of 1 to 5;
when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 is a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl and R2′ is a hydroxyl group, hydroxyalkyl or alkoxyalkyl;
and
when R3 is hydroxyalkyl, R2 and R2′ are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2′ are taken together to form ketone,
an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof.

9 more elements

A method for producing a compound of the following formula (I):

wherein
R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy;
Y is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group;
and
R is represented by the following formula (II):
wherein
X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), then X should be CH;
W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom;
s is an integer of 1 to 5;
t is an integer of 1 to 5;
when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R is a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl and R2′ is a hydroxyl group, hydroxyalkyl or alkoxyalkyl;
and
when R3 is hydroxyalkyl, R2 and R2′ are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2′ are taken together to form ketone,
which comprises using a compound of the following formula (16):
R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy;
Y is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group;
and
R is represented by the following formula (II):
wherein
X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), then X should be CH;
W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom;
s is an integer of 1 to 5;
t is an integer of 1 to 5;
when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 is a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl and R2′ is a hydroxyl group, hydroxyalkyl or alkoxyalkyl;
and
when R2 is hydroxyalkyl, R2 and R2′ are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2′ are taken together to form ketone.

23 more elements

A method for producing the isoquinoline compound represented by the following formula (I):

wherein
R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl. N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy;
Y is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group;
and
R is represented by the following formula (II):
wherein
X is CH or a nitrogen atom, provided that when Y is absent in the formula (I) then X should be CH;
W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom;
s is an integer of 1 to 5;
t is an integer of 1 to 5;
when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 is a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl and R2′ is a hydroxyl group, hydroxyalkyl or alkoxyalkyl and
when R3 is hydroxyalkyl, R2 and R2′ are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2′ are taken together to form ketone,
an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof, which comprises the steps of any of the following (a), (b), or (c):
(a) reacting a compound of the following formula (11′):
wherein R1 is as defined above and J2 is dialkylamino, with a compound of the following formula (14):
wherein Y and R are as defined above and J3 is N-alkyl-N-alkoxyamino, to produce a compound of the following formula (15):
wherein each symbol is as defined above;
(b) using a compound of the following formula (15):
wherein each symbol is as defined above, to produce a compound of the following formula (16):
wherein each symbol is as defined above;
and
(c) using a compound of the following formula (16):
wherein each symbol is as defined above, to produce a compound of the following formula (I):
wherein each symbol is as defined above.

21 more elements

A method for producing the isoquinoline compound represented by the following formula (I):

wherein
R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy;
Y is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group;
and
R is represented by the following formula (II):
wherein
X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), then X should be CH;
W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom;
s is an integer of 1 to 5;
t is an integer of 1 to 5;
when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 is a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl and R2′ is a hydroxyl group, hydroxyalkyl or alkoxyalkyl;
and
when R3 is hydroxyalkyl, R2 and R2′ are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2′ are taken together to form ketone,
an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof, which comprises the steps (a), (b), and (c):
(a) reacting a compound of the following formula (11′):
wherein R1 is as defined above and J2 is dialkylamino, with a compound of the following formula (14):
wherein Y and R are as defined above and J3 is N-alkyl-N-alkoxyamino, to produce a compound of the following formula (15):
wherein each symbol is as defined above;
(b) using a compound of the following formula (15):
wherein each symbol is as defined above, to produce a compound of the following formula (16):
wherein each symbol is as defined above;
and
(c) using a compound of the following formula (16):
wherein each symbol is as defined above, to produce a compound of the following formula (I):
wherein each symbol is as defined above.

22 more elements

Dependencies are inferred from the claim text.

Isoquinoline compound and pharmaceutical use thereof

Life of this patent

Isoquinoline compound and pharmaceutical use thereof

Life of this patent

Abstract

Claims36