Triazine derivatives, processes for preparation thereof and pharmaceutical compositions comprising the same

Claim 2

A compound of the formula wherein R is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroauinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, each of which may have one or more substituent(s) selected from lower alkyl, hydroxy(lower)alkyl, lower alkylamino, lower alkanoyl, cyclic lower alkanoyl, lower alkoxy(lower)alkyl, lower alkylamino(lower)alkanoyl, benzyl, benzyloxy(lower)-alkyl, lower alkoxycarbonyl(lower)alkyl and 4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl; R 2 is a hydrogen, lower alkenyl, benzyl, carboxy(lower)-alkyl or lower alkoxycarbonyl(lower)alkyl; R 3 and R 4 , which may be the same or different, are each hydrogen or lower alkyl or together represent a bond; provided that when R 1 is 2-oxo-l,2,3,4-tetrahydroquinolyl which is unsubstituted or substituted by a lower alkyl, then, R 4 is a hydrogen or R 2 is a lower alkenyl, benzyl, carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl; and pharmaceutically acceptable salt thereof.

Claim 3

A compound of claim 1, wherein R 1 is a 1,2,3,4-tetrahydroquinolyl which may have one or more substituent(s) selected from lower alkyl, lower alkanoyl, cyclic lower alkanoyl and lower alkylamino(lower)alkanoyl.

Claim 4

A compound of claim 1, wherein R 1 is a 2-oxo-1,2,3,4-tetrahydroquinolyl which is substituted with a lower alkyl; R 2 is a lower alkenyl, benzyl, carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl.

Claim 5

A compound of claim 1, wherein R 1 is a 2-oxo-l,2,3,4-tetrahydroquinolyl which is substituted with a lower alkyl and R 2 , R 3 and R are each hydrogen.

Claim 6

The compound according to claim 4, which is 6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-4,5-dihydro-1,2,4-triazin-3(2H)-one.

Claim 7

A compound of claim 1, wherein R 1 is a 2-oxo-1,2,3,4-tetrahydroquinolyl which is substituted with a hydroxy(lower)alkyl.

Claim 8

A compound of claim 1, wherein R 1 is a 2-oxo-1,2-dihydroquinolyl which may be substituted with a lower alkyl.

Claim 9

The compound according to claim 7, which is 6-(1-met) 1-2-oxo-1,2-dihydroquinolin-6-yl)-5-methyl-4 5-dihydro-1,2,4-triazin-3(2H)-one.

Claim 10

A compound of claim 1, wherein R 1 is a indolyl which may be substituted with one or more lower alkyl(s).

Claim 11

A compound of claim 1, wherein R 1 is a 2-oxoindolinyl which may be substituted with a lower alkyl.

Claim 12

A compound of claim 1, wherein R is a benzothiazolyl which may be substituted with a lower alkylamino.

Claim 13

A compound of claim 1, wherein R 1 is a 2-oxobenzothiazolinyl which may have one or more substituent(s) selected from lower alkyl, lower alkoxy(lower)alkyl, lower alkoxycarbonyl(lower)-alkyl and 4-(2-hydroxyethyl)piperazin-1-yl- carbonylmethyl.

Claim 14

A compound of claim 1, wherein R 1 is a 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized.

Claim 15

A compound of claim 1, wherein R 1 is a 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl which may be substituted with a lower alkyl.

Claim 16

A process for preparing a compound of the formula wherein R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2,3,4-tetrahydroquinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-lH-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl, each of which may have one or more substituent(s) selected from lower alkyl, hydroxy(lower)alkyl, lower alkylamino, lower alkanoyl, cyclic lower alkanoyl, lower alkoxy(lower)alkyl, lower alkylamino(lower)alkyanoyl, benzyl benzyloxy(lower)alkyl, lower alkoxycarbonyl-(lower)alkyl and 4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl; R 2 is a hydrogen, lower alkenyl, benzyl, carboxy(lower)-alkyl or lower alkoxycarbonyl(lower)alkyl; R 3 and R 4 , which may be the same or different, are each hydrogen or lower alkyl or together represent a bond; provided that when R 1 is 2-oxo-1,2,3,4-tetrahydroquinolyl which is unsubstituted or substituted by a lower alkyl, then, R 4 is a hydrogen or R 2 is a lower alkenyl, benzyl, carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl; and pharmaceutically acceptable salt thereof, which comprises (1) by reacting a compound of the formula [II] (wherein R 1 is as defined above; and is a hydrogen or lower alkyl) or its salt with a compound of the formula [III] (wherein R 2 is a lower alkenyl, benzyl, carboxy(lower)- alkyl or lower alkoxycarbonyl(lower)-alkyl; and Y is an acid residue) or its salt to provide a compound of the formula [Ia] (wherein R 1 , and are each as defined above) or its salt, or (2) by reducing a compound of the formula [Ia] (wherein R 1 , and are each as defined above) or its salt to provide a compound of the formula [Ib] (wherein R 1 , R 2 and R 4 are each as defined above), or (3) by treating a compound of the formula [IV] (wherein R 1 and are each as defined above; and Z is a leaving group) with a base and then by reducing to provide a compound of the formula (wherein R 1 and are each as defined above) or its salt, or (4) by solvolysis of a compound of the formula [Id] (wherein R 1 , R 3 and are each as defined above; and is a lower alkoxycarbonyl(lower)alkyl) or its salt to provide a compound of the formula [Ie] (wherein R 1 , R 3 and R 4 are each as defined above; and is a carboxy(lower)alkyl) or its salt, or (5) by alkylation of a compound of the formula [If] (wherein R 1 , R 2 and are each as defined above) or its salt to provide a compound of the formula [Ig] (wherein R 1 , R 2 and are each as defined above; and is a lower alkyl) or its salt, or (6) by subjecting a compound of the formula [Ih] (wherein R 2 , R 3 and R 4 are each as defined above; and R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tezrahydroquinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-lH-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, and each of which has at least one substituent selected from lower alkanoyl, cyclic lower alkanoyl and benzyloxy(lower)alkyl) or its salt to an elimination reaction of the protective group to provide a compound of the formula [Ii] (wherein R 2 , R 3 and R 4 are each as defined above; and is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl, and each of which may be substituted with a hydroxy(lower)alkyl) or its salt, or (7) by subjecting a compound of the formula (wherein R 2 , R 3 and R 4 are each as defined above; R S is a hydrogen or lower alkyl; and R 6 is a hydrogen or lower alkyl) or its salt to a Fischer Irdole Synthesis or chemically equivalent thereto to provide a compound of the formula [Ij] (wherein R 2 , R 3 , R 4 , R 5 and R 6 are each as'defined above) or its salt, or (8) by a cyclization of a compound of the formula [VI] (wherein R 2 , R 3 and R 4 are each as defined above; and R 7 is a lower alkylamino) or its salt to provide a compound of the formula [Ik] (wherein R 2 , R 3 , R 4 and R 7 are each as defined above) or its salt, or (9) by subjecting a compound of the formula [VII] (wherein R 1 and R 3 are each as defined above) a or its salt with hydrazine hydrate to provide a compound of the formula [Iℓ] (wherein R 1 is as defined above) or its salt, or (10) by acylation of a compound of the formula [Im] (wherein R 2 , R 3 and R 4 are each as defined above, and R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2,3,4-tetrahydroquinolyl, 2-oxo-1,2-dihydroauinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-lH-2,l-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl) or its salt to provide a compound of the formula [In] (wherein R 2 , R 3 and R 4 are each as defined above; and is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 2-oxe-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, and each of which has at least one substituent selected from lower alkanoyl, cyclic lower alkanoyl, and lower alkylamino-(lower)alkanoyl) or its salt, or (11) by alkylating a compound of the formula [Im] (wherein , R 2 , R 3 and R 4 are each as defined above) or its salt to provide a compound of the formula [Ip] (wherein R 2 , R 3 and R 4 are each as defined above; and R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl, and each of which is substituted with a lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, benzyl, benzyloxy-(lower)alkyl, lower alkoxycarbonyl-(lower)alkyl and 4-(2-hydroxyethyl)piperazin-1-yl- carbonylmethyl) or its salt, or (12) by reacting a compound of the formula [Iq] (wherein R 2 , R 3 and R 4 are each as defined above; and is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-lH-2,l-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, and each of which is substituted with a lower alkoxycarbonyl(lower)alkyl) or its salt with 1-(2-hydroxyethyl)piperazine to provide a compound of the formula (wherein R 2 , R 3 and R 4 are each as defined above; and R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2,3,4-tetrahydroquinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, and each of which is substituted with a 4-(2-hydroxyethyl)piperazin-l-yl- carbonylmethyl) or its salt.

Claim 17

A process for preparing a compound of the formula wherein R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2,3,4-tetrahydroquinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-lH-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl, each of which may have one or more substituent(s) selected from lower alkyl, hydroxy(lower)alkyl, lower alkylamino, lower alkanoyl, cyclic lower alkanoyl, lower alkoxy(lower)alkyl, lower alkylamino(lower)alkyanoyl, benzyl benzyloxy(lower)alkyl, lower alkoxycarbonyl-(lower)alkyl and 4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl; R 2 is a hydrogen, lower alkenyl, benzyl, carboxy(lower)-alkyl or lower alkoxycarbonyl(lower)alkyl; R 3 and R 4 , which may be the same or different, are each hydrogen or lower alkyl or together represent a bond; provided that when R 1 is 2-oxo-1,2,3,4-tetrahydroquinolyl which is unsubstituted or substituted by a lower alkyl, then, R 4 is a hydrogen or R 2 is a lower alkenyl, benzyl, carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl; and pharmaceutically acceptable salt thereof, which comprises (1) by reacting a compound of the formula [II] (wherein R 1 is as defined above; and is a hydrogen or lower alkyl) or its salt with a compound of the formula [III] (wherein R 2 is a lower alkenyl, benzyl, carboxy(lower)- alkyl or lower alkoxycarbonyl(lower)-alkyl; and Y is an acid residue) or its salt to provide a compound of the formula [Ia] (wherein R 1 , and are each as defined above) or its salt, or (2) by reducing a compound of the formula [Ia] (wherein R 1 , and are each as defined above) or its salt to provide a compound of the formula [Ib] (wherein R 1 , R 2 and R 4 are each as defined above), or (3) by treating a compound of the formula [IV] (wherein R 1 and are each as defined above; and Z is a leaving group) with a base and then by reducing to provide a compound of the formula (wherein R 1 and are each as defined above) or its salt, or (4) by solvolysis of a compound of the formula [Id] (wherein R 1 , R 3 and are each as defined above; and is a lower alkoxycarbonyl(lower)alkyl) or its salt to provide a compound of the formula [Ie] (wherein R 1 , R 3 and R 4 are each as defined above; and is a carboxy(lower)alkyl) or its salt, or (5) by alkylation of a compound of the formula [If] (wherein R 1 , R 2 and are each as defined above) or its salt to provide a compound of the formula [Ig] (wherein R 1 , R 2 and are each as defined above; and is a lower alkyl) or its salt, or (6) by subjecting a compound of the formula [Ih] (wherein R 2 , R 3 and R 4 are each as defined above; and R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tezrahydroquinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-lH-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, and each of which has at least one substituent selected from lower alkanoyl, cyclic lower alkanoyl and benzyloxy(lower)alkyl) or its salt to an elimination reaction of the protective group to provide a compound of the formula [Ii] (wherein R 2 , R 3 and R 4 are each as defined above; and is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl, and each of which may be substituted with a hydroxy(lower)alkyl) or its salt, or (7) by subjecting a compound of the formula (wherein R 2 , R 3 and R 4 are each as defined above; R S is a hydrogen or lower alkyl; and R 6 is a hydrogen or lower alkyl) or its salt to a Fischer Irdole Synthesis or chemically equivalent thereto to provide a compound of the formula [Ij] (wherein R 2 , R 3 , R 4 , R 5 and R 6 are each as'defined above) or its salt, or (8) by a cyclization of a compound of the formula [VI] (wherein R 2 , R 3 and R 4 are each as defined above; and R 7 is a lower alkylamino) or its salt to provide a compound of the formula [Ik] (wherein R 2 , R 3 , R 4 and R 7 are each as defined above) or its salt, or (9) by subjecting a compound of the formula [VII] (wherein R 1 and R 3 are each as defined above) a or its salt with hydrazine hydrate to provide a compound of the formula [Iℓ] (wherein R 1 is as defined above) or its salt, or (10) by acylation of a compound of the formula [Im] (wherein R 2 , R 3 and R 4 are each as defined above, and R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2,3,4-tetrahydroquinolyl, 2-oxo-1,2-dihydroauinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-lH-2,l-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl) or its salt to provide a compound of the formula [In] (wherein R 2 , R 3 and R 4 are each as defined above; and is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 2-oxe-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, and each of which has at least one substituent selected from lower alkanoyl, cyclic lower alkanoyl, and lower alkylamino-(lower)alkanoyl) or its salt, or (11) by alkylating a compound of the formula [Im] (wherein , R 2 , R 3 and R 4 are each as defined above) or its salt to provide a compound of the formula [Ip] (wherein R 2 , R 3 and R 4 are each as defined above; and R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl, and each of which is substituted with a lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, benzyl, benzyloxy-(lower)alkyl, lower alkoxycarbonyl-(lower)alkyl and 4-(2-hydroxyethyl)piperazin-1-yl- carbonylmethyl) or its salt, or (12) by reacting a compound of the formula [Iq] (wherein R 2 , R 3 and R 4 are each as defined above; and is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-lH-2,l-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, and each of which is substituted with a lower alkoxycarbonyl(lower)alkyl) or its salt with 1-(2-hydroxyethyl)piperazine to provide a compound of the formula (wherein R 2 , R 3 and R 4 are each as defined above; and R 1 is a 1,2,3,4-tetrahydroquinolyl, 2-oxo-l,2,3,4-tetrahydroquinolyl, 2-oxo-1,2-dihydroquinolyl, indolyl, 2-oxoindolinyl, benzothiazolyl, 2-oxobenzothiazolinyl, 3,4-dihydro-1H-2,1-benzothiazinyl in which the S atom being optionally oxidized, or 3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, and each of which is substituted with a 4-(2-hydroxyethyl)piperazin-l-yl- carbonylmethyl) or its salt.

Claim 18

A pharmaceutical composition comprising a compound of claim 1 for treating hypertension, thrombosis and(or) ulcer.

Claim 19

A method for treating hypertension, thrombosis and (or) ulcer which comprises administering a pharmaceutically effective amount of a compound of claim 1.