Pyridine derivatives

1. A process for producing 2-amino-4,6-disubstituted nicotinic acid ester analogs and salts thereof, comprising reacting the compounds of formulae (I), (II), (III), and an ammonium salt in accordance with the following scheme:

wherein

Ar is an aryl or heteroaryl group, and optionally substituted by one or more substituents;

R 1 is hydrogen, halogen, or C 1-6 alkyl;

R 2 is optionally substituted aryl, heteroaryl, alkyl or alkenyl; and

R 3 is —CR 21 R 22 R 23 ,

wherein

R 21 , R 22 and R 23 are each independently C 1-6 alkyl or aryl.

2. The process as claimed in claim 1 , wherein:

Ar is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl and optionally substituted by one or more substituents,

wherein the optional substituents are each independently hydrogen, C 1-6 alkyl, halogen, C 1-12 alkoxy, cyano, nitro, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl, di C 1-6 alkylamino, C 1-6 alkylcarbonylamino, —S—(CH 2 ) n —R 11 or —O—(CH 2 ) n —R 11 ,

wherein

n represents an integer selected from 0 to 6, and

R 11 is C 2-6 alkenyl, benzoyl, diphenylmethyl, di(C 1-6 alkyl)amino, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, or an optionally substituted 3 to 10 membered saturated or unsaturated ring having 0 to 3 heteroatoms selected from the group consisting of S, O and N as heteroatoms;

R 1 is hydrogen, halogen, or C 1-6 alkyl;

R 2 is optionally substituted phenyl or styryl;

wherein the optional substituents are each independently hydrogen, halogen, C 1-6 alkoxy, di C 1-6 alkylamino, C 1-6 alkanoylamino, C 1-6 alkyl(hydroxy C 1-6 alkyl)amino, C 1-6 alkyl(benzyl)amino, morpholino, C 1-6 alkylsulfonylamino, optionally substituted piperidino, optionally substituted pyrrolidino, piperidino-C 1-6 alkylene-oxy, —CO—NHR 51 , or NH—COR 51 ,

wherein

R 51 represents piperidino-C 1-6 alkylene, carboxy-C 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene, oxotetrahydrofuryl, oxopyrrolidinyl, —CH(OH)R 51a , or —C 1-6 alkylene-R 51b ,

wherein

R 51 is carboxy-C 1-6 alkylene or C 1-6 alkoxycarbonyl-C 1-6 alkylene,

R 51b is optionally substituted piperidino, optionally substituted piperazino, optionally substituted amino, or —CH(NH 2 )— carboxy,

N-protected amino-C 1-6 alkylene, or 5 to 8 membered saturated ring having 0 to 3 N as heteroatoms and the N atom is protected;

—CR 31 R 32 R 33 ,

wherein R 31 is hydrogen or C 1-6 alkyl,

R 32 is hydrogen, a 5 to 8 membered saturated ring having 0 to 3 atoms selected from the group consisting of S, O and N as heteroatoms, or optionally substituted C 1-6 alkyl, and

R 33 is hydrogen, amino, C 1-6 alkoxycarbonylamino, C 2-6 alkenyl-oxycarbonylamino, benzyloxycarbonylamino or

R 32 and R 33 may form, together with the adjacent carbon atom, an optionally substituted or optionally benzene fused 5 to 8 membered saturated ring having 0 to 3 heteroatoms selected from the group consisting of N, O and S as heteroatoms; and

R 3 is a —CR 21 R 22 R 23 ,

wherein

R 21 , R 22 and R 23 are each independently C 1-6 alkyl or phenyl.

3. The process as claimed in claim 1 , wherein:

Ar is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl and optionally substituted by one or more substituents,

wherein the optional substituents are each independently hydrogen, C 1-6 alkyl, halogen, C 1-12 alkoxy, cyano, nitro, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl, di C 1-6 alkylamino, C 1-6 alkylcarbonylamino, —S—(CH 2 ) n —R 11 , or —O—(CH 2 ) n —R 11 ,

wherein

n represents an integer selected from 0 to 6, and

R 11 is C 2-6 alkenyl, benzoyl, diphenylmethyl, di (C 1-6 alkyl)amino, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, optionally substituted 3 to 10 membered saturated or unsaturated ring having 0 to 3 heteroatoms selected from the group consisting of S, O and N as heteroatoms, which ring is optionally substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, halogen substituted alkyl, nitro, cyano, hydroxy, phenyl, amino, C 1-6 alkylamino, C 3-8 cycloalkylamino, benzylamino, carbamoyl, —O— 1-6 alkylene-phenyl, and —O-phenyl;

R 1 is hydrogen, halogen, or C 1-6 alkyl;

R 2 is optionally substituted phenyl or styryl;

wherein the optional substituents are each independently hydrogen, halogen, amino, C 1-6 alkoxy, di C 1-6 alkylamino, C 1-6 alkanoylamino, C 1-6 alkyl(hydroxy C 1-6 alkyl)amino, C 1-6 alkyl(benzyl)amino, morpholino, C 1-6 alkylsulfonylamino, optionally substituted piperidino, optionally substituted pyrrolidino, piperidino-C 1-6 alkylene-oxy, —CO—NHR 51 , or —NH—COR 51 ,

wherein

R 51 represents piperidino-C 1-6 alkylene, carboxy-C 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene, oxotetrahydrofuryl, oxopyrrolidinyl, —CH(OH)R 51a , or —C 1-6 alkylene-R 51b ,

wherein

R 51a is carboxy-C 1-6 alkylene or C 1-6 alkoxycarbonyl-C 1-6 alkylene,

R 51b is —NHR 51b-1 (wherein R 51b-1 represents hydrogen, C 1-6 alkyl, —C 1-6 alkylene-O—C 1-6 alkyl, hydroxy-C 1-6 alkylene, or piperidino-C 1-6 alkylene), —CH(NH 2 )—COOH, pyrroline, or —N(C 1-6 alkyl)R 51b-2 (wherein R 51b-2 represents C 1-6 alkyl or ethylpyrrolidine),

piperidino optionally substituted by carboxy or C 1-6 alkoxycarbonyl, piperazino fused with cyclohexane,

piperazino optionally substituted by C 1-6 alkyl, benzyl, hydroxy-C 1-6 alkylene, C 1-6 alklyl-carbonyl, cyclohexane, benzodioxane-C 1-6 alkylene, or furyl-carbonyl,

N-protected amino-C 1-6 alkylene, N-protected 2-piperidyl, N-protected 3-piperidyl or N-protected 4-piperidyl;

—CR 31 R 32 R 33 ,

wherein

R 31 is hydrogen or C 1-6 alkyl,

R 32 is hydrogen; C 1-6 alkyl optionally substituted by hydroxy, amino, phenyl, C 1-6 alkoxyphenyl, halophenyl or aminophenyl; or a 5 to 8 membered saturated ring having 0 to 3 atoms selected from the group consisting of S, O and N as heteroatoms, and

R 33 is hydrogen, amino, C 1-6 alkoxycarbonylamino, C 2-6 alkenyloxy-carbonylamino, or benzyloxycarbonylamino or

R 32 and R 33 may form, together with the adjacent carbon atom, an optionally substituted 5 to 8 membered saturated ring having 0 to 3 heteroatoms selected from the group consisting of N, O and S as heteroatoms, which ring is optionally be substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, halogen substituted alkyl, nitro, cyano, hydroxy, phenyl, amino, C 1-6 alkylamino, C 3-8 cycloalkylamino, benzylamino, carbamoyl, —O—C 1-6 alkylene-phenyl, —O-phenyl, phenyl-C 1-6 alkyl, di C 1-6 alkylamino, and piperidino-C 1-6 alkylcarbonyl, or said ring may be fused with a benzene ring; and

R 3 is t-butyl, 1,1-dimetlylpropyl or trityl group.

4. The process as claimed in claim 1 , wherein:

Ar is phenyl, and optionally substituted by one substituent,

wherein the optional substituent is hydrogen, C 1-2 alkoxy, or —O—C 1-6 alkylene-R 11 ,

wherein

R 11 is vinyl, diphenylmethyl, C 1-6 alkanoyl, optionally substituted C 5-10 aryl, or optionally substituted 5 to 10 membered heteroaryl, optionally substituted 3 to 8 membered cycloalkyl optionally interrupted by O atom, or a 5 to 8 membered saturated heterocyclic ring interrupted by NH and/or O;

R 1 is hydrogen;

R 2 is optionally substituted phenyl or styryl;

wherein the optional substituents are each independently hydrogen, halogen, amino, C 1-6 alkoxy, di C 1-6 alkylamino, C 1-6 alkanoylamino, C 1-6 alkyl(hydroxy C 1-6 alkyl)amino, C 1-6 alkyl(benzyl)amino, morpholino, C 1-6 alkylsulfonylamino, optionally substituted piperidino, optionally substituted pyrrolidino, piperidino-C 1-6 alkylene-oxy, —CO—NHR 51 , or —NH—COR 51 ,

wherein

R 51 represents piperidino-C 1-6 alkylene, carboxy-C 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene, oxotetrahydrofuryl, oxopyrrolidinyl, —CH(OH)R 51a , or —C 1-6 alkylene-R 51b ,

wherein

R 51a is carboxy-C 1-6 alkylene or C 1-6 alkoxycarbonyl-C 1-6 alkylene,

R 51b is —NHR 51b-1 (wherein R 51b-1 represents hydrogen, C 1-6 alkyl, —C 1-6 alkylene-O—C 1-6 alkyl, hydroxy-C 1-6 alkylene, piperidino-C 1-6 alkylene), —CH(NH 2 )—COOH, pyrroline, —N(C 1-6 alkyl)R 51b-2 (wherein R 51b-2 represents C 1-6 alkyl or ethylpyrrolidine),

piperidino optionally substituted by carboxy or C 1-6 alkoxycarbonyl, piperazino fused with cyclohexane, or piperazino optionally substituted by C 1-6 alkyl, benzyl, hydroxy-C 1-6 alkylene, C 1-6 alkyl-carbonyl, cyclohexane, benzodioxane-C 1-6 alkylene, or furyl-carbonyl,

N-protected amino-C 1-6 alkylene, N-protected 2-piperidyl, N-protected 3-piperidyl or N-protected 4-piperidyl;

—CR 31 R 32 R 33 ,

wherein

R 31 is hydrogen or C 1-6 alkyl,

R 32 is hydrogen, or C 1-6 alkyl optionally substituted by hydroxy, amino, phenyl, C 1-6 alkoxyphenyl, halophenyl, or aminophenyl, and

R 33 is hydrogen, amino, or benzyloxycarbonylamino; or R 32 and R 33 may form optionally substituted C 5-8 cycloalkyl optionally interrupted by NH, wherein said substituent is C 1-6 alkyl, phenyl-C 1-6 alkyl, amino, C 1-6 alkylamino, benzylamino, di C 1-6 alkylamino, carbamoyl, C 1-6 alkoxy-carbonyl, piperidino-C 1-6 alkylcarbonyl, or C 1-6 alkylsulfonyl, and said ring may be fused with a benzene ring;

R 3 is t-butyl group.

5. The process as claimed in claim 1 , wherein the ammonium salt is ammonium acetate.