IP Library › Granted Patent US 7,504,421
Granted Patent B2
US 7,504,421 · App. 11/359,927 · Granted Mar 17, 2009

Substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines and their use

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Quick Facts
Patent No.
US 7,504,421
App. No.
11/359,927
Granted
Mar 17, 2009
Kind
B2
Abstract

The invention relates to compounds of general formula (I), a method for the production thereof and the use thereof as pharmacologically effective substances for a broad medical indication spectrum. Furthermore, selective adenosine receptor ligands, preferably selective adenosine A1-, adenosine A2a- and/or adenosine A2b-receptor ligands are provided for the prophylaxis and/or the treatment of diseases, especially cardiovascular diseases, diseases of the urogenital region, diseases of the respiratory tract, inflammatory and neuroinflammatory diseases, diabetes, especially pancreatic diabetes, neurodegenerative diseases, pain states, cancer as well as liver fibrosis and liver cirrhosis.

Claims (514)

1. A compound of the formula (I)

wherein:

R 1 , R 2 , R 3 are identical or different and independently of one another are selected from the group consisting of the following substituents:

hydrogen;

hydroxyl;

optionally substituted (C 1 -C 8 )-alkyl;

optionally substituted (C 6 -C 10 )-aryl;

optionally substituted (C 1 -C 8 )-alkoxy, wherein none of R 1 , R 2 , and R 3 is ortho methoxy;

—O—(CH 2 ) n —CH═CH 2 where n=0, 1 or 2;

halogen;

nitro;

cyano;

—C(O)—R 5 ;

—C(O)—NR 6 R 7 ;

—NR 6 R 7 ;

—NR 6 —C(O)—R 8 ;

—O—C(O)—R 8 ;

—SO 2 —NR 6 R 7 ; and

—NR 6 —SO 2 R 8 ,

where:

R 5 denotes:

hydrogen;

hydroxyl;

optionally substituted (C 1 -C 8 )-alkyl;

optionally substituted (C 3 -C 7 )-cycloalkyl;

optionally substituted (C 1 -C 8 )-alkoxy;

optionally substituted (C 6 -C 10 )-aryl;

optionally substituted (C 6 -C 10 )-aryloxy; or

—O—(CH 2 )n-[(C 6 -C 10 )-aryl] where n=1, 2 or 3,

where the (C 6 -C 10 )-aryl group may be fused via two adjacent ring atoms to optionally substituted (C 4 -C 7 )-cycloalkyl,

or

R 5 represents a 5- to 7-membered saturated or unsaturated heterocycle which may be mono- or polysubstituted by

an oxo group (═O);

halogen;

optionally substituted (C 1 -C 8 )-alkyl;

nitro;

cyano;

hydroxyl;

optionally substituted (C 6 -C 10 )-aryl; or

by (C 1 -C 8 )-alkoxy,

or

R 5 represents optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S,

where the heterocycle and the heteroaryl ring may each optionally be fused via two adjacent ring atoms to optionally substituted (C 6 -C 10 )-aryl or optionally substituted (C 4 -C 7 )-cycloalkyl,

and

R 6 and R 7 are identical or different and represent

hydrogen;

optionally substituted (C 1 -C 8 )-alkyl;

optionally substituted (C 6 -C 10 )-aryl; or

represent optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S,

or

R 6 and R 7 together with the nitrogen atom to which they are optionally attached form a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N, O and S, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of

an oxo group (═O);

halogen;

(C 1 -C 8 )-alkyl;

nitro;

cyano;

hydroxyl;

(C 6 -C 10 )-aryl; and

(C 1 -C 8 )-alkoxy,

and

R 8 represents hydroxyl;

NR 6 R 7 where R 6 and R 7 are as defined above;

optionally substituted (C 1 -C 8 )-alkyl;

(C 1 -C 8 )-alkoxy;

optionally substituted (C 6 -C 10 )-aryl;

(C 6 -C 10 )-aryloxy; or

—O—(CH 2 ) n —[(C 6 -C 10 )-aryl] where n=1, 2 or 3,

and

R 4 represents straight-chain or branched (C 1 -C 8 )-alkyl or (C 2 -C 8 )-alkenyl which are optionally mono- or polysubstituted by

hydroxyl;

halogen;

cyano;

—C(O)—R 5 where R 5 is as defined above;

—C(O)—NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 —C(O)—R 8 where R 6 and R 8 are as defined above;

—SO 2 —NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 —SO 2 —R 8 where R 6 and R 8 are as defined above;

—C(O)—(CH 2 ) n —C(O)—R 8 where n=0 to 2 and R 8 is as defined above;

(C 1 -C 8 )-alkoxy;

or

R 4 represents a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N, O and S, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of an oxo group (═O); halogen; (C 1 -C 8 )-alkyl; nitro; cyano; hydroxyl; (C 6 -C 10 )-aryl; or by (C 1 -C 8 )-alkoxy, and

which may optionally be fused via two adjacent ring atoms to optionally substituted (C 6 -C 10 )-aryl or optionally substituted (C 4 -C 7 )-cycloalkyl,

or a tautomer, salt, hydrate, or alkoxide thereof,

except for the following compounds of the formula (I), in which the radicals R 1 , R 2 , R 3 and R 4 are as defined below:

R 1 =R 2 =H; R 3 =para-OH; R 4 =—CH 2 -Z where Z=CN, C(O)—OC 2 H 5 , 4-Br—C 6 H 4 —CO, 4-n-butyl-C 6 H 4 —CO, H, C 6 H 5 , C(O)—O—CH 2 —C 6 H 5 , C(O)—OCH 3 , C(O)—OH, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO, 3-Br—C 6 H 4 —CO, 4-C 6 H 5 —C 6 H 4 —CO, 4—CH 3 —C 6 H 4 —CO, 3,4-Cl 2 -C 6 H 3 —CO;

R 1 =R 2 =H; R 3 =meta-OH; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —NH—CO, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO;

R 1 =R 2 =H; R 3 =para-O—C(O)—CH 3 ; R 4 =—CH 2 -Z where Z=4—CH 3 —C 6 H 4 —CO, H, 2-oxo-benzopyranyl-3-carbonyl, (CH 2 ) 3 —CH 3 , 4-C 6 H 5 —C 6 H 4 ;

R 1 =R 2 =R 3 =H; R 4 =—CH 2 -Z where Z=CH 3 , CN, 2-naphthyl;

R 1 =R 2 =H; R 3 =para-butoxy; R 4 =—CH 2 -Z where Z=4-Cl—C 6 H 5 , C(O)—OCH 3 , C(O)—C 6 H 5 , CH═CH 2 , C(O)—NH 2 , H, 4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—OC 2 H 5 , C(O)—O—CH 2 —C 6 H 5 , 2-oxo-benzopyranyl-3-carbonyl, C(O)—NH—C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =para-bromo; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—NH 2 , C(O)—OCH 3 , 4-Cl—C 6 H 5 , 4-Br—C 6 H 4 —NH—CO;

R 1 =R 2 =H; R 3 =meta-fluoro; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, C(O)—NH 2 , C(O)—O—CH 2 —C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =para-chloro; R 4 =—CH 2 -Z where Z=2-naphthyl, CH 3 ;

R 1 =R 2 =H; R 3 =para-OCH 3 ; R 4 =—CH 2 -Z where Z=2-naphthyl, CH 3 ;

R 1 =R 2 =H; R 3 =meta-NO 2 ; R 4 =—CH 2 -Z where Z=CH 3 .

2. The compound of the formula (I) as claimed in claim 1 , wherein:

R 1 , R 2 , R 3 are identical or different and independently of one another are selected from the group consisting of the following substituents:

hydrogen;

hydroxyl;

optionally substituted (C 1 -C 6 )-alkyl;

optionally substituted phenyl or naphthyl;

optionally substituted (C 1 -C 6 )-alkoxy, wherein none of R 1 , R 2 , and R 3 is ortho methoxy;

—O—(CH 2 ) n —CH═CH 2, where n=1 or 2;

fluorine, chlorine, bromine;

nitro;

cyano;

—C(O)—R 5 ;

—C(O)—NR 6 R 7 ;

—NR 6 R 7 ;

—NR 6 —C(O)—R 8 ;

—O—C(O)—R 8 ;

—SO 2 —NR 6 R 7 ; and

—NR 6 —SO 2 R 8 ,

where:

R 5 denotes:

hydrogen;

hydroxyl;

optionally substituted (C 1 -C 6 )-alkyl;

optionally substituted (C 3 -C 7 )-cycloalkyl;

optionally substituted (C 1 -C 6 )-alkoxy;

optionally substituted phenyl or naphthyl;

optionally substituted phenyloxy or naphthyloxy; or —O—(CH 2 ) n -phenyl where n=1, 2 or 3,

where the phenyl or naphthyl group may be fused via two adjacent ring atoms to optionally substituted (C 4 -C 7 )-cycloalkyl,

or

R 5 represents a 5- to 7-membered saturated or unsaturated heterocycle which may be mono- or polysubstituted by

an oxo group (═O);

fluorine, chlorine, bromine;

optionally substituted (C 1 -C 6 )-alkyl;

nitro;

cyano;

hydroxyl;

optionally substituted phenyl or naphthyl; or

by (C 1 -C 6 )-alkoxy,

or

R 5 represents optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S,

where the heterocycle and the heteroaryl ring may each optionally be fused via two adjacent ring atoms to optionally substituted phenyl or naphthyl or optionally substituted (C 4 -C 7 )-cycloalkyl,

and

R 6 and R 7 are identical or different and represent

hydrogen;

optionally substituted (C 1 -C 6 )-alkyl;

optionally substituted phenyl or naphthyl; or

represent optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S

or

R 6 and R 7 together with the nitrogen atom to which they are optionally attached form a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N, O and S, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of

an oxo group (═O);

fluorine, chlorine, bromine;

(C 1 -C 6 )-alkyl;

nitro;

cyano;

hydroxyl;

phenyl or naphthyl; and

(C 1 -C 6 )-alkoxy,

and

R 8 represents NR 6 R 7 where R 6 and R 7 are as defined above;

optionally substituted (C 1 -C 6 )-alkyl;

(C 1 -C 6 )-alkoxy;

optionally substituted phenyl or naphthyl;

phenyloxy or naphthyloxy; or

—O—(CH 2 ) n ,-phenyl where n=1, 2 or 3,

and

R 4 represents straight-chain or branched (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl which are optionally mono- or polysubstituted by

hydroxyl;

fluoro, chloro, bromine;

cyano;

—C(O)—R 5 where R 5 is as defined above;

—C(O)—NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 —C(O)—R 8 where R 6 and R 8 are as defined above;

—SO 2 —NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 —SO 2 —R 8 where R 6 and R 8 are as defined above;

—C(O)—(CH 2 ) n —C(O)—R 8 where n=0 to 2 and R 8 is as defined above;

(C 1 -C 6 )-alkoxy;

or

R 4 represents a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N, O and S,

which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of an oxo group (═O); fluorine, chlorine, bromine; (C 1 -C 6 )-alkyl; nitro; cyano; hydroxyl; phenyl or naphthyl; or by(C 1 -C 6 )-alkoxy and

which may optionally be fused via two adjacent ring atoms to optionally substituted phenyl or naphthyl or optionally substituted (C 4 -C 7 )-cycloalkyl,

or a tautomer, salt hydrate, or alkoxide thereof,

except for the following compounds of the formula (I), in which the radicals R 1 , R 2 , R 3 and R 4 are as defined below:

R 1 =R 2 =H; R 3 =para-OH; R 4 =—CH 2 -Z where Z=CN, C(O)—OC 2 H 5 , 4-Br—C 6 H 4 —CO, 4-n-butyl-C 6 H 4 —CO, H, C 6 H 5 , C(O)—O—CH 2 —C 6 H 5 , C(O)—OCH 3 , C(O)—OH, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO, 3-Br—C 6 H 4 —CO, 4-C 6 H 5 —C 6 H 4 —CO, 4—CH 3 —C 6 H 4 —CO, 3,4-Cl 2 -C 6 H 3 —CO;

R 1 =R 2 =H; R 3 =meta-OH; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —NH—CO, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO;

R 1 =R 2 =H; R 3 =para-O—C(O)—CH 3 ; R 4 =—CH 2 -Z where Z=4—CH 3 —C 6 H 4 —CO, H, 2-oxo-benzopyranyl-3-carbonyl, (CH 2 ) 3 —CH 3 , 4-C 6 H 5 —C 6 H 4 ;

R 1 =R 2 =R 3 =H; R 4 =—CH 2 -Z where Z=CH 3 , CN, 2-naphthyl;

R 1 =R 2 =H; R 3 =para-butoxy; R 4 =—CH 2 -Z where Z=4-Cl—C 6 H 5 , C(O)—OCH 3 , C(O)—C 6 H 5 , CH═CH 2 , C(O)—NH 2 , H, 4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—OC 2 H 5 , C(O)—O—CH 2 —C 6 H 5 , 2-oxo-benzopyranyl-3-carbonyl, C(O) —NH—C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =para-bromo; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—NH 2 , C(O)—OCH 3 , 4-Cl—C 6 H 5 , 4-Br—C 6 H 4 —NH—CO;

R 1 =R 2 =H; R 3 =meta-fluoro; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, C(O)—NH 2 , C(O)—O—CH 2 —C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =para-chloro; R 4 =—CH 2 -Z where Z=2-naphthyl, CH 3 ;

R 1 =R 2 =H; R 3 =para-OCH 3 ; R 4 =—CH 2 -Z where Z=2-naphthyl, CH 3 ;

R 1 =R 2 =H; R 3 =meta-NO 2 ; R 4 =—CH 2 -Z where Z=CH 3 .

3. The compound of the formula (I) as claimed in claim 1 , wherein:

R 1 , R 2 , R 3 are identical or different and independently of one another are selected from the group consisting of the following substituents:

hydrogen;

hydroxyl;

optionally substituted (C 1 -C 4 )-alkyl;

optionally substituted phenyl;

optionally substituted (C 1 -C 4 )-alkoxy, wherein none of R 1 , R 2 , and R 3 is ortho methoxy;

—O—(CH 2 ) n —CH═CH 2 where n=1;

fluorine, chlorine;

nitro;

cyano;

—C(O)—R 5 ;

—C(O)—NR 6 R 7 ;

—NR 6 R 7 ;

—NR 6 —C(O)—R 8 ;

—O—C(O)—R 8 ;

—SO 2 —NR 6 R 7 ; and

—NR 6 —SO 2 R 8 ,

where:

R 5 denotes:

hydrogen;

hydroxyl;

optionally substituted (C 1 -C 4 )-alkyl;

optionally substituted (C 3 -C 7 )-cycloalkyl;

optionally substituted (C 1 -C 4 )-alkoxy;

optionally substituted phenyl;

optionally substituted phenyloxy; or

—O—(CH 2 ) n -phenyl where n=1,

where the phenyl group may be fused via two adjacent ring atoms to optionally substituted (C 5 -C 6 )-cycloalkyl,

or

R 5 represents a 5- to 7-membered saturated or unsaturated heterocycle which may be mono- or polysubstituted by

an oxo group (═O);

fluorine, chlorine;

optionally substituted (C 1 -C 4 )-alkyl;

nitro;

cyano;

hydroxyl;

optionally substituted phenyl; or

by (C 1 -C 4 )-alkoxy,

or

R 5 represents optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S, selected from the group consisting of furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl and pyridazinyl,

where the heterocycle and the heteroaryl ring may each optionally be fused via two adjacent ring atoms to optionally substituted phenyl or optionally substituted (C 5 -C 6 )-cycloalkyl,

and

R 6 and R 7 are identical or different and represent

hydrogen;

optionally substituted (C 1 -C 4 )-alkyl;

optionally substituted phenyl; or

represent optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S selected from the group consisting of furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl and pyridazinyl,

or

R 6 and R 7 together with the nitrogen atom to which they are optionally attached form a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N, O and S which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of

an oxo group (═O);

fluorine, chlorine;

(C 1 -C 4 )-alkyl;

nitro;

cyano;

hydroxyl;

phenyl; and

(C 1 -C 4 )-alkoxy,

and

R 8 represents NR 6 R 7 where R 6 and R 7 are as defined above; optionally substituted (C 1 -C 4 )-alkyl;

(C 1 -C 4 )-alkoxy;

optionally substituted phenyl;

phenyloxy; or

—O—(CH 2 ) n -phenyl where n=1,

and

R 4 represents straight-chain or branched (C 1 -C 4 )-alkyl or (C 2 -C 4 )-alkenyl which are optionally mono- or polysubstituted by

hydroxyl;

fluorine, chlorine;

cyano;

—C(O)—R 5 where R 5 is as defined above;

—C(O)—NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 —C(O)—R 8 where R 6 and R 8 are as defined above;

—SO 2 —NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 —SO 2 —R 8 where R 6 and R 8 are as defined above;

—C(O)—(CH 2 ) n —C(O)—R 8 where n=0 to 2 and R 8 is as defined above;

(C 1 -C 4 )-alkoxy;

or

R 4 represents a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N, O and S,

which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of an oxo group (═O); fluorine, chlorine; (C 1 -C 4 )-alkyl; nitro; cyano; hydroxyl; phenyl; or by (C 1 -C 4 )-alkoxy and which may optionally be fused via two adjacent ring atoms to optionally substituted phenyl or optionally substituted (C 5 -C 6 )-cycloalkyl,

or a tautomer, salt, hydrate, or alkoxide thereof,

except for the following compounds of the formula (I), in which the radicals R 1 , R 2 , R 3 and R 4 are as defined below:

R 1 =R 2 =H; R 3 =para-OH; R 4 =—CH 2 -Z where Z=CN, C(O)—OC 2 H 5 , 4-Br—C 6 H 4 —CO, 4-n-butyl-C 6 H 4 —CO, H, C 6 H 5 , C(O)—O—CH 2 —C 6 H 5 , C(O)—OCH 3 , C(O)—OH, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO, 3-Br—C 6 H 4 —CO, 4-C 6 H 5 —C 6 H 4 —CO, 4—CH 3 —C 6 H 4 —CO, 3,4-Cl 2 -C 6 H 3 —CO;

R 1 =R 2 =H; R 3 =meta-OH; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —NH—CO, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO;

R 1 =R 2 =H; R 3 =para-O—C(O)—CH 3 ; R 4 =—CH 2 -Z where Z=4—CH 3 —C 6 H 4 —CO, H, 2-oxo-benzopyranyl-3-carbonyl, 4-C 6 H 5 —C 6 H 4 ;

R 1 =R 2 =R 3 =H; R 4 =—CH 2 -Z where Z=CH 3 , CN;

R 1 =R 2 =H; R 3 =para-butoxy; R 4 =—CH 2 -Z where Z=4-Cl—C 6 H 5 , C(O)—OCH 3 , C(O)—C 6 H 5 , CH═CH 2 , C(O)—NH 2 , H, 4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—OC 2 H 5 , C(O)—O—CH 2 —C 6 H 5 , 2-oxo-benzopyranyl-3-carbonyl, C(O)—NH—C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =meta-fluoro; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, C(O)—NH 2 , C(O)—O—CH 2 —C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =para-chloro; R 4 =—CH 2 -Z where Z=CH 3 ;

R 1 =R 2 =H; R 3 =para-OCH 3 ; R 4 =—CH 2 -Z where Z=CH 3 ;

R 1 =R 2 =H; R 3 =meta-NO 2 ; R 4 =—CH 2 -Z where Z=CH 3 .

4. The compound of the formula (I) as claimed in any of claims 1 to 3 , wherein

R 1 , R 2 , R 3 are identical or different and independently of one another are selected from the group consisting of the following substituents:

hydrogen;

hydroxyl;

methyl;

trifluoromethyl;

methoxy;

radicals of the formulae —O—CH 2 —CH 2 —OH, —O—CH 2 —COOH or —O—CH 2 —CH═CH 2 ;

fluorine, chlorine or bromine;

nitro;

cyano;

—C(O)OH or —C(O)OCH 3 ;

—C(O)NH 2 ;

—NH 2 ;

—NH—C(O)—CH 3 ;

—O—C(O)—CH 3 or —O—C(O)—C 2 H 5 ;

radicals of the formulae

and

—NH—SO 2 CH 3 or —NH—SO 2 C 6 H 5 ,

and

R 4 represents straight-chain or branched (C 1 -C 4 )-alkyl which is optionally mono- or polysubstituted by

hydroxyl;

amino;

—C(O)—OCH 3 ;

—C(O)—NH 2 , —C(O)—HNCH 3 , —C(O)—HNC 2 H 5 , or —C(O)—HNC 6 H 5 ;

—NHC(O)NH 2 , —NHC(O)NHCH 3 , —NHC(O)NHC 2 H 5 , —NHC(O)OCH 3 or —NHC(O)OC 2 H 5 ;

—SO 2 —NH 2 ;

—NH—SO 2 —CH 3 or —NH—SO 2 —C 2 H 5 ;

—OCH 3 ;

or

R 4 represents allyl or 3,3-dimethylallyl,

or a tautomer, salt, hydrate, or alkoxide thereof,

except for the following compounds of the formula (I), in which the radicals R 1 ,

R 2 , R 3 and R 4 as defined below:

R 1 =R 2 =H; R 3 =para-OH; R 4 =—CH 2 -Z where Z=H, C 6 H 5 , C(O)—OCH 3 ;

R 1 =R 2 =H; R 3 =para-O—C(O)—CH 3 ; R 4 =—CH 2 -Z where Z=H;

R 1 =R 2 =R 3 =H; R 4 =—CH 2 -Z where Z=CH 3 ;

R 1 =R 2 =H; R 3 =meta-fluoro; R 4 =—CH 2 -Z where Z=C(O)—NH 2 ;

R 1 =R 2 =H; R 3 =para-chloro; R 4 =—CH 2 -Z where Z=CH 3 ;

R 1 =R 2 =H; R 3 =para-OCH 3 ; R 4 =—CH 2 -Z where Z=CH 3 ;

R 1 =R 2 =H; R 3 =meta-NO 2 ; R 4 =—CH 2 -Z where Z=CH 3 .

5. The compound of the formula (I) as claimed in any of claims 1 to 3 , wherein

R 1 , R 2 , R 3 are identical or different and independently of one another are selected from the group consisting of the following substituents:

hydrogen;

hydroxyl;

methyl;

methoxy;

radicals of the formulae —O—CH 2 —CH 2 —OH, —O—CH 2 —COOH or —O—CH 2 —CH═CH 2 ;

fluorine or chlorine;

nitro;

cyano;

—C(O)OH or —C(O)OCH 3 ;

—C(O)NH 2 ;

—NH 2 ;

—NH—C(O)CH 3 ;

—O—C(O)—CH 3 or —O—C(O)—C 2 H 5 ;

radicals of the formulae

and

—NH—SO 2 CH 3 or —NH—SO 2 C 6 H 5 ,

and

R 4 represents straight-chain or branched (C 1 -C 4 )-alkyl which is optionally mono- or polysubstituted by

hydroxyl;

amino;

—C(O)—OCH 3 ;

—C(O)—NH 2 , —C(O)—HNCH 3 , —C(O)—HNC 2 H 5 , or —C(O)—HNC 6 H 5 ;

—NHC(O)NH 2 , —NHC(O)NHCH 3 , —NHC(O)NHC 2 H 5 , —NHC(O)OCH 3 or —NHC(O)OC 2 H 5 ;

—SO 2 —NH 2 ;

—NH—SO 2 —CH 3 or —NH—SO 2 —C 2 H 5 ;

—OCH 3 ;

or

R 4 represents allyl,

or a tautomer, salt, hydrate, or alkoxide thereof,

except for the following compounds of the formula (I), in which the radicals R 1 , R 2 , R 3 and R 4 are as defined below:

R 1 =R 2 =H; R 3 =para-OH; R 4 =—CH 2 -Z where Z=H, C 6 H 5 , C(O)—OCH 3 ;

R 1 =R 2 =H; R 3 =para-O—C(O)—CH 3 ; R 4 =—CH 2 -Z where Z=H;

R 1 =R 2 =R 3 =H; R 4 =—CH 2 -Z where Z=CH 3 ;

R 1 =R 2 =H; R 3 =meta-fluoro; R 4 =—CH 2 -Z where Z=C(O)—NH 2 ;

R 1 =R 2 =H; R 3 =para-chloro; R 4 =—CH 2 -Z where Z=CH 3 ;

R 1 =R 2 =H; R 3 =para-OCH 3 ; R 4 =—CH 2 -Z where Z=CH 3 ;

R 1 =R 2 =H; R 3 =meta-NO 2 ; R 4 =—CH 2 -Z where Z=CH 3 .

6. A process for preparing the compounds of the formula (I) as defined in claim 1 ,

wherein:

a compound of the formula (II)

wherein:

R 1 , R 2 , R 3 are identical or different and independently of one another are selected from the group consisting of the following substituents:

hydrogen;

hydroxyl;

optionally substituted (C 1 -C 8 )-alkyl;

optionally substituted (C 6 -C 10 )-aryl;

optionally substituted (C 1 -C 8 )-alkoxy;

—O—(CH 2 ) n -CH=CH 2 where n =0, 1 or 2;

halogen;

nitro;

cyano;

—c(O)—R 5 ;

—C(O)—NR 6 R 7 ;

—NR 6 R 7 ;

—NR 6 —C(O)—R 8 ;

—O—C(O)—R 8 ;

—SO 2 —NR 6 R 7 ; and

—NR 6 —SO 2 R 8 ;

where:

R 5 denotes:

hydrogen;

hydroxyl;

optionally substituted (C 1 -C 8 )-alkyl;

optionally substituted (C 3 -C 7 )-cycloalkyl;

optionally substituted (C 1 -C 8 )-alkoxy;

optionally substituted (C 6 -C 10 )-aryl;

optionally substituted (C 6 -C 10 )-aryloxy; or

—O—(CH 2 ) n —[(C 6 -C 10 )-aryl]where n=1, 2 or 3,

where the (C 6 -C 10 )-aryl group may be fused via two adjacent ring atoms to optionally substituted (C 4 -C 7 )-cycloalkyl,

or

R 5 represents a 5- to 7-membered saturated or unsaturated heterocycle which may be mono- or polysubstituted by

an oxo group (═O);

halogen;

optionally substituted (C 1 -C 8 )-alkyl;

nitro;

cyano;

hydroxyl;

optionally substituted (C 6 -C 10 )-aryl; or

by (C 1 -C 8 )-alkoxy,

or

R 5 represents optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S,

where the heterocycle and the heteroaryl ring may each optionally be fused via two adjacent ring atoms to optionally substituted (C 6 -C 10 )-aryl or optionally substituted (C 4 -C 7 )-cycloalkyl,

and

R 6 and R 7 are identical or different and represent

hydrogen;

optionally substituted (C 1 -C 8 )-alkyl;

optionally substituted (C 6 -C 10 )-aryl; or

represent optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S

or

R 6 and R 7 together with the nitrogen atom to which they are optionally attached form a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N,O and S, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of

an oxo group (═O);

halogen;

(C 1 -C 8 )-alkyl;

nitro;

cyano;

hydroxyl;

(C 6 -C 10 )-aryl; and

(C 1 -C 8 )-alkoxy,

and

R 8 represents hydroxyl;

NR 6 R 7 where R 6 and R 7 are as defined above;

optionally substituted (C 1 -C 8 )-alkyl;

(C 1 -C 8 )-alkoxy;

optionally substituted (C 6 -C 10 )-aryl;

(C 6 -C 10 )-aryloxy; or

—O—(CH 2 ) n -[(C 6 -C 10 )-aryl]where n =1, 2 or 3, is reacted with a compound of the formula (III)

R 4 —X  (III),

wherein

R 4 represents straight-chain or branched (C 1 -C 8 )-alkyl or (C 2 -C 8 )-alkenyl which are optionally mono- or polysubstituted by

hydroxyl;

halogen;

cyano;

—C(O)—R 5 where R 5 as defined above;

—C(O)—NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 —C(O)—R 8 where R 6 and R 8 are as defined above;

—SO 02 —NR 6 R 7 where R 6 and R 7 are as defined above;

—NR 6 —SO 02 —R 8 where R 6 and R 8 are as defined above;

—C(O)—(CH 2 ) n —C(O)—R 8 where n =0 to 2 and R8 is as defined above;

(C 1 -C 8 )-alkoxy; or

R 4 represents a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N, O and S, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of an oxo group (═O); halogen; (C 1 -C 8 )-alkyl; nitro; cyano; hydroxyl; (C 6 -C 10 )-aryl; or by (C1-C8)-alkoxy, and

which may optionally be fused via two adjacent ring atoms to optionally substituted (C 6 -C 10 )-aryl or optionally substituted (C 4 -C 7 )-cycloalkyl,

or a tautomer, salt, hydrate, or alkoxide thereof;

and

X represents a nucleofugic group

in an inert solvents solvent, if appropriate in the presence of a base; to thereby produce a compound of formula (I),

except for the following compounds of the formula (I), in which the radicals R 1 , R 2 , R 3 and R 4 as defined below:

R 1 =R 2 =H; R 3 =para-OH; R 4 =—CH 2 -Z where Z=CN, C(O)—OC 2 H 5 , 4-Br—C 6 H 4 —CO, 4-n-butyl-C 6 H 4 —CO, H, C 6 H 5 , C(O)—O—CH 2 —C 6 H 5 , C(O)—OCH 3 , C(O)—OH, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO, 3 -Br—C 6 H 4 —CO, 4-C 6 H 5 —C 6 H 4 —CO, 4—CH 3 —C 6 H 4 —CO, 3,4-Cl 2 -C 6 H 3 —CO;

R 1 =R 2 =H; R 3 =meta-OH; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —NH—CO, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO;

R 1 =R 2 =H; R 3 =para-O—C(O)—CH 3 , R 4 =—CH2-Z where Z=4—CH 3 —C 6 H 4 —CO, H, 2oxo-benzopyranyl-3-carbonyl, (CH 2 ) 3 —CH 3 , 4-C 6 H 5 —C 6 H 4 ;

R 1 =R 2 =R 3 =H; R 4 =—CH 2 -Z where Z=CH 3 , CN 2-naphthyl;

R 1 =R 2 =H; R 3 =para-butoxy; R 4 =—CH 2 -Z where Z=4-Cl—C 6 H 5 , C(O)—OCH 3 , C(O)—C 6 H 5 , CH═CH 2 , C(O)—NH 2 , H, 4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—OC 2 H 5 , C(O)—O—CH 2 —C 6 H 5 , 2-oxo-benzopyranyl-3-carbonyl, C(O)—NH—C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =para-bromo; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—NH 2 , C(O)—OCH 3 , 4-Cl—C 6 H 5 , 4-Br—C 6 H 4 —NH—CO;

R 1 =R 2 =H; R 3 =meta-fluoro; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, C(O)—NH 2 , C(O)—O—CH 2 —C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =para-chloro; R 4 =—CH 2 -Z where Z=2-naphthyl, CH3;

R 1 =R 2 =H; R 3 =para-OCH 3 ; R 4 =—CH 2 -Z where Z=2-naphthyl, CH3;

R 1 =R 2 =H; R 3 =meta-NO 2 ; R 4 =—CH 2 -Z where Z=CH 3 .

7. A process for preparing the compounds of the formula (I) as defined in claim 1 in the case that in the formula (I) the radical R 4 has the meaning of

alkyl, substituted by the radicals —NR 6 —C(O)—R 8 , —NR 6 —C(O)—NR 6 R 7 , —NR 6 —SO 2 —R 8

wherein

R 6 R 7 and R are identical or different and represent

hydrogen;

optionally substituted (C 1 -C 8 )-alkyl;

optionally substituted (C 6 -C 10 )-aryl; or

represent optionally substituted 5- to 6-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S

or

R 6 and R 7 together with the nitrogen atom to which they are optionally attached form a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of N, O and S, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of

an oxo group (═O);

halogen;

(C 1 -C 8 )-alkyl;

nitro;

cyano;

hydroxyl;

(C 6 -C 10 )-aryl; and

(C 1 -C 8 )-alkoxy,

and

R 8 represents hydroxyl;

NR 6 R 7 where R 6 and R 7 are as defined above;

optionally substituted (C 1 -C 8 )-alkyl;

(C 1 -C 8 )-alkoxy;

optionally substituted (C 6 -C 10 )-aryl;

(C 6 -C 10 )-aryloxy; or

—O—(CH 2 ) n -[(C 6 -C 10 )-aryl]where n=1, 2 or 3,

wherein:

initially the compound of the above formula (II) as defined in claim 6 is reacted with 2-bromoethylamine to give the compound of the formula (IV)

which is then reacted with a compound of the formula

R 9 —Y  (V),

in which

R 9 has the meaning —C(O)—R 8 , —C(O)—O—R 8 , —C(O)—NR 6 R 7 , —SO 2 —R 8

and

Y represents a nucleofugic group,

or

R 9 has the meaning R 6

and

Y represents the group O═C═N—,

in an inert solvent, if appropriate in the presence of a base; to thereby produce a compound of formula (I),

except for the following compounds of the formula (I), in which the radicals R 1 , R 2 ,R 3 and R 4 as defined below:

R 1 =R 2 =H; R 3 =para-OH; R 4 =—CH 2 -Z where Z=CN, C(O)—OC 2 H 5 , 4-Br—C 6 H 4 —CO, 4-n-butyl-C 6 H 4 —CO, H, C 6 H 5 , C(O) —O—CH 2 —C 6 H 5 , C(O)—OCH 3 , C(O) —OH, 2-oxo-benzo-pyranyl-3 -carbonyl, 4-Cl—C 6 H 4 —CO, 3-Br—C 6 H 4 —CO, 4-C 6 H 5 —C 6 H 4 —CO, 4—CH 3 —C 6 H 4 —CO, 3,4-Cl 2 -C 6 H 3 —CO;

R 1 =R 2 =H; R 3 =meta-OH; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —NH—CO, 2-oxo- benzo-pyranyl-3-carbonyl, 4-Cl—C 6 H 4 —CO;

R 1 =R 2 =H; R 3 =para-O—C(O)—CH 3 ; R 4 =—CH 2 -Z where Z=4—CH 3 —C 6 H 4 —CO, H, 2-oxo-benzopyranyl-3-carbonyl, (CH 2 ) 3 —CH 3 , 4C 6 H 5 —C 6 H 4 ;

R 1 =R 2 =R 3 =H; R 4 =—CH 2 -Z where Z=CH 3 , CN, 2-naphthyl;

R 1 =R 2 =H; R 3 =para-butoxy; R 4 =—CH 2 -Z where Z=4-Cl—C 6 H 5 , C(O)—OCH 3 , C(O)—C 6 H 5 , CH═CH 2 , C(O)—NH 2 , H, 4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—OC 2 H 5 , C(O)—O—CH 2 —C 6 H 5, 2-oxo-benzopyranyl-3-carbonyl, C(O)—NH—C 6 H 5 , CN;

R 1 =R 2 =H; R 3 = para-bromo; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, 4-Cl—C 6 H 4 —CO, C(O)—NH 2 , C(O)—OCH 3 , 4-Cl—C 6 H 5 , 4-Br—C 6 H 4 —NH—CO;

R 1 =R 2 =H; R 3 =meta-fluoro; R 4 =—CH 2 -Z where Z=4-Br—C 6 H 4 —CO, C(O)—NH 2 , C(O)—O—CH 2 —C 6 H 5 , CN;

R 1 =R 2 =H; R 3 =para-chloro; R 4 =—CH 2 -Z where Z =2-naphthyl, CH 3 ;

R 1 =R 2 =H; R 3 =para-OCH 3 ; R 4 =—CH 2 -Z where Z=2-naphthyl, CH 3 ; R 1 =R 2 =H; R 3 =meta-NO 2 ; R l =—CH 2 -Z where Z=CH 3 .

8. A pharmaceutical composition, comprising at least one compound of the formula (I) as defined in claim 1 , plus at least one pharmaceutically acceptable carrier or excipient.

9. A pharmaceutical composition, comprising at least one selective adenosine receptor ligand of claim 1 , selected from the group consisting of Adenosine A 1 receptor ligands, Adenosine A 2 a receptor ligands and Adenosine A 2 b receptor ligands, plus at least one pharmaceutically acceptable carrier or excipient.

10. The process of claim 6 wherein the nucleofugic group X in formula (III) is halogen, mesylate, tosylate, triflate or 1-imidazolyl.

11. The process of claim 10 wherein said halogen is chlorine, bromine or iodine.

12. The process of claim 7 wherein the nucleofugic group Y in formula (V) represents halogen, mesylate, tosylate, triflate or 1-imidazolyl.

13. The process of claim 12 wherein said halogen is chlorine, bromine or iodine.

Assignments (2)
MERGER Recorded Jan 12, 2010
From: BAYER HEALTHCARE AG
To: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT
Reel/Frame 023769/0122 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 3, 2009
From: ROSENTRETER, ULRICH; HENNING, ROLF; BAUSER, MARCUS; KRAMER, THOMAS; VAUPEL, ANDREA; HUBSCH, WALTER; DEMBOWSKY, KLAUS; SALCHER-SCHRAUFSTATTER, OLGA; STASCH, JOHANNES-PETER; KRAHN, THOMAS; PERZBORN, ELISABETH
To: BAYER AKTIENGESELLSCHAFT
Reel/Frame 023465/0942 →
Priority Claims (1)
DE 199 47 154 · Oct 1, 1999 · national
Continuity (2)
Division 1011028400
Related Publication 20060264432A1 · Nov 23, 2006