7-membered ring compound and method of production and pharmaceutical application thereof
View Patent ↗A 7-membered heterocyclic compound having the formula (I), or its salt, or a solvate thereof with a chymase inhibitory action and useful for the prevention or treatment of various diseases, in which chymase is involved: a method for producing the same, and a pharmaceutical composition useful for the prevention or treatment of diseases, in which chymase is involved, including the compound of having the formula (I), or its pharmaceutically acceptable salt, or a solvate thereof are provided.
1. A method for producing a compound having the formula (R-Ia) or (S-Ia):
wherein R 2 and R 3 are independently (1) a hydrogen atom, (2) a halogen atom, or (3) C 1 to C 6 alkyl,
R 5 and R 6 are independently (1) a hydrogen atom or (2) C 1 to C 6 alkyl which may optionally be substituted with a group selected from the group consisting of (i) carboxyl, (ii) C 1 to C 6 alkoxy, (iii) C 1 to C 6 alkoxycarbonyl, (iv) C 6 to C 12 aryloxycarbonyl, (v) C 1 to C 10 heteroaryloxycarbonyl, and (vi) amino,
R 2 and R 3 and also R 5 and R 6 may independently form a 3-to 8-membered ring,
Ar′ is a C 6 to C 14 aromatic hydrocarbon group, and the Ar′ group may be substituted with 1 to 5 groups selected from the group consisting of (i) halogen atoms, (ii) nitro, (iii) cyano, (iv) C 1 to C 6 alkyl which may optionally be substituted with 1 to 3 halogen atoms and (v) C 1 to C 6 alkoxy which may optionally be substituted with 1 to 3 halogen atoms,
Xa is a linear or branched C 1 to C 6 alkylene,
R 7a is a C 1 to C 6 alkyl which may optionally be substituted with a group selected from the group consisting of (i) carboxyl, (ii) C 1 to C 6 alkoxycarbonyl, (iii) phenyl, (iv) hydroxyl, (v) C 1 to C 6 alkoxy and (vi) a halogen atom,
R 8a is a hydrogen atom,
R 26 , R 27 and R 28 may be the same or different and indicate (i) a hydrogen atom, (ii) a halogen atom, (iii) cyano, (iv) nitro, (v) C 1 to C 6 alkyl, (vi) C 1 to C 6 alkoxy, (vi) C 1 to C 6 alkoxycarbonyl, (viii) C 1 to C 6 alkylsulfonyl, (ix) carboxyl, (x) carboxy-C 1 to C 6 alkyl, (xi) hydroxyl
or (xii) amino,
or a salt thereof or solvate thereof,
the method comprising:
conversion of a compound having the formula (Vaa):
wherein R 7a and R 8a are as defined above and R 26a , R 27a , and R 28a may be the same or different and indicate (i) a hydrogen atom, (ii) a halogen atom, (iii) cyano, (iv) nitro, (v) C 1 to C 6 alkyl, (vi) C 1 to C 6 alkoxy, (vi) C 1 to C 6 alkoxycarbonyl, (viii) C 1 to C 6 alkylsulfonyl, (ix) carboxyl protected by t-butyl, benzyl, or 4-methoxybenzyl, (x) carboxy-C 1 to C 6 alkyl protected by t-butyl, benzyl, or 4-methoxybenzyl or (xi) hydroxyl protected by t-butyl, benzyl, or 4-methoxybenzyl, or a salt thereof into a compound having the formula (IXa):
wherein R 7a , R 8a , R 26a , R 27a and R 28a are as defined above,
subsequent coupling reaction of the obtained compound having the formula (IXa) and a compound having the formula (R-IIIa) or (S-IIIa):
wherein Ar′, Xa, R 2 , R 3 , R 5 and R 6 are as defined above, and Pa indicates benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl or 2,4,6-trimethoxybenzyl,
to produce a compound having the formula (R-Ib) or formula (S-Ib):
wherein Ar′, Xa, R 2 , R 3 , R 5 , R 6 , R 7a , R 8a , R 26a , R 27a , R 28a and Pa are as defined above,
and removal of Pa from the obtained compound having the formula (R-Ib) or formula (S-Ib), and, optionally, reduction and/or hydrolysis of the resultant compound simultaneously with or before and/or after the removal of Pa.
2. The method according to claim 1 wherein
Ar′ is a phenyl group, and may optionally be substituted with 1 to 5 groups selected from (i) halogen atom, (ii) nitro, (iii) cyano, (iv) C 1 to C 6 alkyl which may optionally be substituted with 1 to 3 halogen atoms, and (v) C 1 to C 6 alkoxy which may optionally be substituted with 1 to 3 halogen atoms, and
R 2 , R 3 , R 4 , R 5 , and R 6 are all hydrogen atoms.