2,3-Disubstituted pyridine derivative, process for the preparation thereof, pharmaceutical composition containing the same, and intermediate therefor

A compound of the formula (Ia):

• 23
• wherein A1 is an oxygen atom, a sulfur atom, CH2 or NH;
• X11 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, or a lower acyl group;
• X21 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group;
• Y1 is a hydrogen atom or a lower alkyl group;
• Z11 and Z21 are the same or different and each a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonyl-amino group, a lower alkylsulfonylamino group, a carbamoyl group, or a group which can be converted into a hydroxy group in vivo,
• or a pharmaceutically acceptable salt

A compound which is selected from the group consisting of the following compounds:

• 2-phenoxy-3-[3-(pyridin-4-yl)propoxy]pyridine;
• 2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;
• 2-(3-fluorophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;
• 2-(3-fluorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]-pyridine;
• 2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]-pyridine;
• 2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]-pyridine;
• 2-(3-chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine;
• 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;
• 2-phenoxy-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine;
• 2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]-pyridine;
• 2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridin-4-yl)-propoxy]pyridine;
• 2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-5-yl)propoxy]-pyridine;
• 2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridin-4-yl) -propoxy]pyridine;
• 2-(3-chlorophenoxy)-3-[3-(3-methylsulfonylaminopyridin-4-yl) -propoxy]pyridine;
• and
• 2-(3-bromophenylthio)-3-[3-(pyridin-4-yl)propoxy]pyridine,
• or a pharmaceutically acceptable salt thereof.

A process for preparing a compound of the formula (I):

• 24
• wherein A is an oxygen atom, a sulfur atom, or CHR1, R1 is a hydrogen atom or a lower alkyl group, X1 and X2 are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxy-carbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyl group, a lower acyloxy group, an amino group, a lower acylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be converted into a hydroxy group in vivo, Y1 is a hydrogen atom or a lower alkyl group, Z1 and Z2 are the same or different, and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be convereted into a hydroxy group in vivo, and n is an integer of 2 to 4, or a pharmaceutically acceptable salt thereof,
• which comprises condensing a compound of the formula (III):
• 25
• wherein A2 is an oxygen atom, a sulfur atom or CHR1, X12 and X22 are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkoxycarbonyl group, a lower acyl group, or a lower acyloxy group, and R1 and Y1 are as defined above, with a compound of the formula (IV):
• 26
• wherein Z12 and Z22 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkoxycarbonyl group, a lower acyloxy group, a benzyloxy group, a benzoyloxy group, a mono- or di-lower alkoxy-substituted benzoyl group, a mono- or di-lower alkoxy-substituted benzoyloxy group, an amino group, a lower alkoxycarbonyl-amino group, or a lower alkylsulfonylamino group, and n is as defined above.

A process for preparing a compound of the formula (I):

• 27
• wherein A is an oxygen atom, a sulfur atom, or NR2, R2 is a hydrogen atom or a lower alkyl group, X1 and X2 are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxy-carbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyl group, a lower acyloxy group, an amino group, a lower acylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be converted into a hydroxy group in vivo, Y1 is a hydrogen atom or a lower alkyl group, Z1 and Z2 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be convereted into a hydroxy group in vivo;
• and n is an integer of 2 to 4, or a pharmaceutically acceptable salt thereof,
• which comprises reacting a compound of the formula (V):
• 28
• wherein L is a halogen atom or a nitro group, Z13 and Z23 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, or a lower alkoxycarbonyl group, and Y1 and n are as defined above,
• with a compound of the formula (VI):
• 29
• wherein A3 is an oxygen atom, a sulfur atom or NR2, X12 and X22 are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkoxycarbonyl group, a lower acyl group, or a lower acyloxy group, and R2 is as defined above.