2-heterocyclically substituted dihydropyrimidines

Details 2-heterocyclically substituted dihydropyrimidines 2-heterocyclically substituted dihydropyrimidines

2000-10-18

2003-01-07

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S333000, C544S327000, C544S328000

Reexamination Certificate

active

06503913

ABSTRACT:

The present invention relates to new 2-heterocyclically substituted dihydropyrimidines, processes for their preparation and their use as medicaments, in particular as medicaments for the treatment and prophylaxis of hepatitis B.
The publication EP 103 796 A2 has already disclosed dihydropyrimidines having an action affecting the circulation.
The present invention relates to new 2-heterocyclically substituted dihydropyrimidines of the general formula (I)
or its isomeric form (Ia)
in which
R
1
represents phenyl, furyl, thienyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or a radical of the formula
 where the abovementioned ring systems are optionally monosubstituted or polysubstituted in an identical or different manner by substituents selected from the group consisting of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, carboxyl, hydroxyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl and (C
1
-C
6
)-alkyl, which for its part can be substituted by aryl having 6 to 10 carbon atoms or halogen,
and/or the ring systems mentioned are optionally substituted by groups of the formula —S—R
6
, NR
7
R, CO—NR
9
R
10
, SO
2
—CF
3
and —A—CH
2
—R
11
,
 in which
R
6
denotes phenyl which is optionally substituted by halogen,
R
7
, R
8
, R
9
and R
10
are identical or different and denote hydrogen, phenyl, hydroxy-substituted phenyl, hydroxyl, (C
1
-C
6
)-acyl or (C
1
-C
6
)-alkyl, which for its part can be substituted by hydroxyl, (C
1
-C
6
)-alkoxycarbonyl, phenyl or hydroxy-substituted phenyl,
A denotes a radical O, S, SO or SO
2
,
R
11
denotes phenyl which is optionally mono- to polysubstituted, in an identical or different manner, by substituents selected from the group consisting of halogen, nitro, trifluoromethyl, (C
1
-C
6
)-alkyl and (C
1
-C
6
)-alkoxy,
R
2
represents a radical of the formula —OR
12
or —NR
13
R
14
,
 in which
R
12
denotes hydrogen, (C
1
-C
6
)-alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated (C
1
-C
8
)-hydrocarbon radical which optionally contains one or two identical or different hetero chain members from the group consisting of O, CO, NH, —N—(C
1
-C
4
)-alkyl, —N—((C
1
-C
4
)-alkyl)
2
, S and SO
2
and which is optionally substituted by halogen, nitro, cyano, hydroxyl, aryl having 6 to 10 carbon atoms or aralkyl having 6 to 10 carbon atoms, heteroaryl or a group of the formula —NR
15
R
16
,
 in which
R
15
and R
16
are identical or different and denote hydrogen, benzyl or (C
1
-C
6
)-alkyl,
R
13
and R
14
are identical or different and denote hydrogen, (C
1
-C
6
)-alkyl or cycloalkyl having 3 to 6 carbon atoms,
R
3
represents hydrogen, amino or
a radical of the formula
formyl, cyano or trifluoromethyl, or
a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms, which is optionally mono- or polysubstituted, in an identical or different manner, by aryloxy having 6 to 10 carbon atoms, azido, cyano, hydroxyl, carboxyl, (C
1
-C
6
)-alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, (C
1
-C
6
)-alkylthio, (C
1
-C
6
)-alkoxy, which for its part can be substituted by azido or amino,
and/or is substituted by triazolyl which for its part can be substituted up to 3 times by (C
1
-C
6
)-alkoxycarbonyl,
and/or can be substituted by groups of the formula —OSO
2
—CH
3
or (CO)
a
—NR
17
R
18
,
 in which
a denotes a number 0 or 1,
R
17
and R
18
are identical or different and denote hydrogen or aryl, aralkyl having 6 to 10 carbon atoms,
or denote (C
1
-C
6
)-alkyl which is optionally substituted by (C
1
-C
6
)-alkoxycarbonyl, hydroxyl, phenyl or benzyl, where phenyl or benzyl are optionally mono- or polysubstituted, in an identical or different manner, by hydroxyl, carboxyl (C
1
-C
6
)-alkyl or (C
1
-C
6
)-alkoxy, or (C
1
-C
6
)-alkyl is optionally substituted by groups of the formula NH—CO—CH
3
or NH—CO—CF
3
,
R
4
represents hydrogen, (C
1
-C
4
)-alkyl, acetyl or benzoyl,
D represents an oxygen or sulphur atom,
R
5
represents hydrogen, halogen or straight-chain or branched alkyl having up to 6 carbon atoms,
and their salts.
Compounds of the general formulae (I) and (Ia) according to the invention are preferred
in which
R
1
represents phenyl, furyl, thienyl, pyridyl, cyclopentyl or cyclohexyl, where the abovementioned ring systems are optionally substituted one or 2 times, in an identical or different manner, by substituents selected from the group consisting of halogen, trifluoromethyl, nitro, SO
2
—CF
3
, methyl, cyano, trifluoromethoxy, carboxyl, methoxycarbonyl or radicals of the formulae —CO—NH—CH
2
—C(CH
3
)
3
, —CO—NH(CH
2
)
2
OH, —CO—NH—CH
2
—C
6
H
5
, —CO—NH—C
6
H
5
, —CO—NH—(pOH)—C
6
H
4
, —O—CH
2
—C
6
H
5
or —S—pCl—C
6
H
4
,
R
2
represents a radical of the formula —OR
2
or —NR
13
R
14
,
 in which
R
12
denotes hydrogen, (C
1
-C
4
)-alkenyl or (C
1
-C
4
)-alkyl, which is optionally substituted by pyridyl, cyano, phenoxy, benzyl or by a radical of the formula —NR
15
R
16
,
 in which
R
15
and R
16
are identical or different and denote hydrogen, methyl or ethyl,
R
13
and R
14
are identical or different and denote hydrogen, methyl, ethyl or cyclopropyl,
R
3
represents hydrogen or a radical of the formula
represents formyl, cyano, trifluoromethyl or cyclopropyl, or
represents (C
1
-C
4
)-alkyl which is optionally substituted by radicals of the formula —SO
2
CH
3
, —NH—CO—CH
3
, —NH—CO—CF
3
, fluorine, chlorine, (C
1
-C
3
)-alkoxycarbonyl or hydroxyl,
O and/or alkyl is optionally substituted by groups of the formula —OSO
2
—CH
3
or (CO)
a
—NR
17
R
18
,
 in which
a denotes a number 0 or 1,
R
17
and R
18
are identical or different and denote hydrogen, phenyl or benzyl, or
denote C
1
-C
4
-alkyl which is optionally substituted by (C
1
-C
4
)-alkoxycarbonyl, hydroxyl, phenyl or benzyl, where phenyl or benzyl are optionally mono- or polysubstituted, in an identical or different manner, by hydroxyl, carboxyl, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy, and/or (C
1
-C
4
)-alkyl is optionally substituted by radicals of the formula —NH—CO—CH
3
or —NH—CO—CF
3
, or
R
4
represents hydrogen, methyl, ethyl or acetyl,
D represents an oxygen or sulphur atom,
R
5
represents hydrogen, halogen or (C
1
-C
4
)-alkyl,
and their salts.
Compounds of the general formulae (I) and (Ia) according to the invention are particularly preferred
in which
R
1
represents phenyl or thienyl, where the abovementioned ring systems are optionally substituted up to 2 times, in an identical or different manner, by substituents selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl or nitro,
R
2
represents a radical of the formula —OR
12
or —NR
13
R
14
,
 in which
R
12
represents hydrogen or (C
1
-C
4
)-alkyl,
R
13
and R
14
are identical or different and denote hydrogen or methyl
R
3
represents hydrogen or formyl, cyano, trifluoromethyl or cyclopropyl, or represents (C
1
-C
3
)-alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, which for its part can be substituted up to 3 times by C
1
-C
3
-alkoxycarbonyl,
R
4
represents hydrogen or methyl,
D represents an oxygen or sulphur atom,
R
5
represents hydrogen, fluorine, chlorine or (C
1
-C
3
)-alkyl,
and their salts.
Compounds of the general formulae (I) and (Ia) according to the invention are very particularly preferred
in which
R
1
represents phenyl or thienyl, each of which is optionally substituted up to 2 times, in an identical or different manner, by fluorine or chlorine,
R
2
represents methoxy, ethoxy or n-propoxy,
R
3
represents hydrogen, methyl or cylcopropyl,
R
4
represents hydrogen,
D represents an oxygen or sulphur atom,
R
5
represents hydrogen, fluorine or chlorine,
and their salts.
In the context of the invention, cycloalkyl having 3 to 6 carbon atoms represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl. The following may be preferably mentioned: cyclopentyl or cyclohexyl.
Aryl in general represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
In the context of the

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