Substituted 2-carba-3,5-dicyano-4-aryl-6-aminopyridines and the use of the same as selective ligands of the adenosine receptor

1. A compound of the formula (I)

in which

R 1 , R 2 and R 3 independently of one another represent (C 1 –C 8 )-alkyl which may be substituted up to three times by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 2 –C 4 )-alkenyl, (C 2 –C 4 )-alkynyl, halogen or (C 6 –C 10 )-aryloxy, (C 6 –C 10 )-aryl which may be substituted up to three times by halogen, nitro, (C 1 –C 4 )-alkoxy, carboxyl, (C 1 –C 4 )-alkoxycarbonyl or mono- or di-(C 1 –C 4 )-alkylamino, (C 1 –C 8 )-alkoxy which may be substituted by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 2 –C 4 )-alkenyl, (C 6 –C 10 )-aryl, 5- or 6-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S, (C 6 –C 10 -aryloxy, halogen, cyano, (C 1 –C 4 )-alkoxycarbonyl, (C 1 –C 4 )-alkanoyloxy, amino or mono- or di-(C 1 –C 4 )-alkylamino, hydrogen, hydroxyl, halogen, nitro, cyano or —NH—C(O)—R 7 ,

in which

R 7 represents (C 1 –C 8 )-alkyl which may be substituted by hydroxyl or (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl or (C 6 –C 10 )-aryl which may be substituted up to three times by, independently of one another, by halogen, nitro, (C 1 –C 4 )-alkoxy, carboxyl, (C 1 –C 4 )-alkoxycarbonyl or mono- or di-(C 1 –C 4 )-alkylamino,

or

R 1 and R 2 are attached to adjacent phenyl ring atoms and, together with the two ring carbon atoms, form a 5- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms selected from the group consisting of N, O and S which may be substituted by (C 1 –C 4 )-alkyl or oxo,

R 4 represents hydrogen, (C 1 –C 8 )-alkyl which may be substituted by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 6 –C 10 )-aryl, 5- or 6-membered saturated or partially unsaturated heterocyclyl having up to three heteroatoms selected from the group consisting of N, O and S or 5- to 10-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S, or (C 3 –C 7 )-cycloalkyl which may be substituted by hydroxyl or (C 1 –C 8 )-alkyl,

R 5 represents (C 1 –C 4 )-alkyl or (C 1 –C 4 )-alkoxy which may be mono- or disubstituted, independently of one another, by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 6 –C 10 )-aryl or 5- to 10-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S, where aryl and heteroaryl for their part may be substituted by halogen, (C 1 –C 4 )-alkyl, (C 1 –C 4 )-alkoxy, amino, mono- or di-(C 1 –C 4 )-alkylamino, nitro, cyano, trifluoromethyl or hydroxyl, or (C 2 –C 4 )-alkenyl,

R 6 represents (C 1 –C 8 )-alkyl which may be substituted by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 2 –C 4 )-alkenyl, —CO—O—R 8 , (C 6 –C 10 )-aryl or 5- to 10-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S where aryl and heteroaryl for their part may be substituted by halogen, (C 1 –C 4 )-alkyl, (C 1 –C 4 )-alkoxy, amino, mono- or di-(C 1 –C 4 )-alkylamino, nitro, cyano, trifluoromethyl or hydroxyl, (C 3 –C 7 )-cycloalkyl or —CO—O—R 8 ,

in which

R 8 represents hydrogen, (C 1 –C 8 )-alkyl which may be substituted by hydroxyl or (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl or (C 6 –C 10 )-aryl which may be substituted up to three times, independently of one another, by halogen, nitro, (C 1 –C 4 )-alkoxy, carboxyl, (C 1 –C 4 )-alkoxycarbonyl or mono- or di-(C 1 –C 4 )-alkylamino,

or

R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated ring which may contain one or two heteroatoms selected from the group consisting of N, O and S in the ring and which may be mono- to trisubstituted, independently of one another, by oxo, fluorine, chlorine, bromine, hydroxyl, (C 1 –C 6 )-alkyl or (C 1 –C 6 )-alkoxy,

or a salt, a hydrate, a hydrate of a salt or a solvate thereof.

2. The compound as claimed in claim 1

in which

R 1 and R 2 independently of one another represent hydrogen, (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkoxy which may be substituted by hydroxyl, (C 1 –C 4 )-alkoxy, (C 1 –C 4 )-alkanoyloxy or cyclopropyl, hydrogen, hydroxyl, fluorine, chlorine, nitro or —NH—C(O)—CH 3

or

R 1 and R 2 are attached to adjacent phenyl ring atoms and represent a group —O—CH 2 —O—or —O—CH 2 —CH 2 —O—,

R 3 represents hydrogen,

R 4 represents hydrogen, (C 1 –C 4 -alkyl which is substituted by hydroxyl, (C 1 –C 4 )-alkoxy or cyclopropyl, or represents cyclopropyl,

R 5 represents (C 1 –C 4 )-alkyl which may be mono- or disubstituted, independently of one another, by (C 3 –C 6 )-cycloalkyl, phenyl, which for its part may be substituted by fluorine, trifluoromethyl or (C 1 –C 4 )-alkoxy, pyridyl, furyl or thienyl, or (C 2 –C 4 )-alkenyl,

and

R 6 represents (C 1 –C 4 )-alkyl or —CO—O—R 8 wherein R 8 is (C 1 –C 4 )-alkyl

or

R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated ring which may contain a heteroatom selected from the group consisting of N, O and S in the ring

or a salt, a hydrate, a hydrate of a salt or a solvate thereof.

3. The compound as claimed in claim 1 or 2

in which

R 1 represents hydrogen, chlorine, nitro, methyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, where the alkoxy radicals for their part may be substituted by hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, —O—C(O)—CH 3 or cyclopropyl, or —NH—C(O)—CH 3 ,

R 2 represents hydrogen

or

R 1 and R 2 are attached to adjacent phenyl ring atoms and represent a group —O—CH 2 —O—,

R 3 represents hydrogen,

R 4 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, where the alkyl radicals for their part may be substituted by hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or cyclopropyl, or cyclopropyl,

R 5 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, where the alkyl radicals for their part may be mono- or disubstituted, independently of one another, by cyclopropyl, phenyl, which for its pan may be substituted by fluorine, trifluoromethyl or methoxy, pyridyl, furyl or thienyl, ethenyl, propenyl or butenyl

and

R 6 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl or isobutoxycarbonyl

or

R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring

or a salt, a hydrate, a hydrate of a salt or a solvate thereof.

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

(A) a compound of the formula (II)

in which

R 1 , R 2 and R 3 are as defined in claim 1 and X represents a leaving group,

is initially reacted with ethyl malonamide (III)

H 2 N—C(O)—CH 2 —C(O)—O—C 2 H 5   (III)

to give a compound of the formula (IV)

in which

R 1, R 2 and R 3 are as defined in claim 1 ,

and then reacted with a compound of the formula (V)

R 5 —Y  (V)

in which

R 5 is as defined in claim 1 and Y represents a leaving group

to give a compound of the formula (I)

in which

R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1 and R 6 represents a radical —C(O)—O—C 2 H 5 ,

and, if appropriate, subsequently reacted with a compound of the formula (VI)

R 8 —-OH  (VI)

in which R 8 is as defined in claim 1

to give a compound of the formula (I)

in which

R 6 represents a radical —C(O)—O—R 8 and R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are as defined in claim 1 ,

or

(B) a compound of the formula (II)

is reacted with a Grignard compound of the formula (VII)

in which

R 5 and R 6 are as defined in claim 1

to give a compound of the formula (I)

in which

R 1 , R 2 , R 3 , R 5 and R 6 are as defined in claim 1 and R 4 represents hydrogen,

and, if appropriate, subsequently reacted wit a compound of the formula (VIII)

R 4 —Y′  (VIII)

in which

R 4 is as defined in claim 1 and Y′ represents a leaving group.

5. A pharmaceutical composition, comprising at least one compound of the formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier.

6. A method for the treatment of disorders of the cardiovascular system (cardiovascular disorders) comprising administering an effective amount of a compound of the formula (I) as defined in claim 1 .