Novel denzamide derivatives and process for production thereof
There are provided a novel process for the production of an isoquinoline derivative having an inhibitory action for I f current; a novel benzamide derivative or a salt thereof used for the production process; and a process for the production of the benzamide derivative or a salt thereof.
1 . A benzamide derivative represented by the formula (I) or a salt thereof.
[In the formula, R 1 is —H or an ester residue; R 2 is —H or a protective group of amino group; and Ar is an optionally substituted aryl.]
2 . The compound according to claim 1 , wherein R 1 is —H, lower alkyl or benzyl; and Ar is an optionally substituted phenyl.
3 . The compound according to claim, 1 , wherein R 1 is —H or lower alkyl; R 2 is —H; and Ar is 4-fluoropheny.
4 . A process for the production of the compound mentioned in claim 1 in which R 2 is —H comprising a reaction in which a dihydrooxazole derivative represented by the formula (II)
[In the formula, Ar is an optionally substituted aryl] with a nipecotic acid derivative represented by the formula (III)
[In the formula, R 1 is —H or an ester residue] under an acidic condition and, when R 1 is a group other than —H, R 1 is removed if necessary.
5 . A process for the production of the compound mentioned in claim 1 in which R 1 is —H or lower alkyl, R 2 is —H and Ar is 4-fluorophenyl comprising a reaction in which a compound represented by the formula (II) mentioned in claim 4 in which Ar is 4-fluorophenyl with a compound represented by the formula (III) mentioned in claim 4 in which R 1 is —H or lower alkyl under an acidic condition and, when R 1 is lower alkyl, R 1 is removed if necessary.
6 . A process for the production of an isoquinoline derivative represented by the formula (IV)
[In the formula, R 3 and R 4 are same or different and each is —H, lower alkyl or —O-lower alkyl; and Ar is an optionally substituted aryl], characterized in that, the compound mentioned in claim 1 is, if necessary, subjected to a reaction for removal of R 1 and/or R 2 in case R 1 and/or R 2 are/is groups other than —H, then condensed with a tetrahydroisoquinoline derivative represented by the formula (V) or a salt thereof
[In the formula, R 3 and R 4 are same or different and each is —H, lower alkyl or —O-lower alkyl] and, in case R 2 is a group other than —H, a reaction for removal of R 2 is conducted.
7 . A process for the production of a compound represented by the formula (IV) mentioned in claim 6 in which R 3 is 6-methoxy, R 4 is 7-methoxy and Ar is 4-fluorophenyl, characterized in that, a compound mentioned in claim 1 in which R 1 is —H or lower alkyl, R 2 is —H and Ar is 4-fluorophenyl is subjected, if necessary, to a-reaction for removal of R 1 in case R 1 is lower alkyl and then condensed with a compound represented by the formula (V) mentioned in claim 6 in which R 3 is 6-methoxy and R 4 is 7-methoxy.