Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-18
2004-02-24
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S328000, C544S333000
Reexamination Certificate
active
06696451
ABSTRACT:
This application is a 371 of PCT/EP99/02344 filed Apr. 7, 1999.
The present invention relates to novel dihydropyrimidine compounds, to processes for their preparation and to their use as medicaments, in particular for the treatment and prophylaxis of hepatitis B.
Dihydropyrimidines having cardiovascular action are already known from the publication EP 103 796 A2.
The present invention now provides novel dihydropyrimidine compounds of the general formula (I)
or their isomeric form (Ia)
in which
R
1
represents phenyl, furyl, thienyl, triazolyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or represents radicals of the formulae
where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different 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 may 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 formulae —S—R
6
, NR
7
R
8
, CO—NR
9
R
10
, SO
2
—CF
3
, and —A—CH
2
—R
11
, in which
R
6
represents phenyl which is optionally substituted by halogen,
R
7
, R
8
, R
9
and R
10
are identical or different, and each represents hydrogen, phenyl, hydroxyl-substituted phenyl, hydroxyl, (C
1
-C
6
)-acyl or (C
1
-C
6
)-alkyl, which for its part may be substituted by hydroxyl, (C
1
-C
6
)-alkoxycarbonyl, phenyl or hydroxyl-substituted phenyl,
A represents a radical O, S, SO or SO
2
,
R
11
represents phenyl which is optionally mono- to polysubstituted by identical or different 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 —XR
12
or —NR
13
R
14
, in which
X represents a bond or oxygen,
R
12
represents hydrogen, straight-chain or branched (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, —NH—(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 each represents hydrogen, benzyl or (C
1
-C
6
)-alkyl,
R
13
and R
14
are identical or different, and each represents hydrogen, (C
1
-C
6
)-alkyl or cycloalkyl having 3 to 6 carbon atoms,
R
3
represents hydrogen, amino or represents a radical of the formula
or
represents formyl, cyano, trifluoromethyl or pyridyl, or
represents a straight-chain, branched or cyclic saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of 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 and (C
1
-C
6
)-alkoxy, which for its part may be substituted by azido or amino, and/or is substituted by triazolyl, which for its part may be substituted up to 3 times by (C
1
-C
6
)-alkoxycarbonyl, and/or may be substituted by groups of the formulae —OSO
2
—CH
3
or (CO)
a
—NR
17
R
18
, in which
a represents a number 0 or 1,
R
17
and R
18
are identical or different, and each represents hydrogen or aryl, aralkyl having 6 to 10 carbon atoms, or represents (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 by identical or different substituents from the group consisting of hydroxyl, carboxyl, (C
1
-C
6
)-alkyl and (C
1
-C
6
)-alkoxy, or (C
1
-C
6
)-alkyl is optionally substituted by groups of the formulae NH—CO—CH
3
or NH—CO—CF
3
, or
R
17
and R
18
together with the nitrogen atom form a morpholine, piperidinyl or pyrrolidinyl ring, or
R
3
represents phenyl which is optionally substituted by methoxy, or
R
2
and R
3
together form a radical of the formula
R
4
represents hydrogen, (C
1
-C
4
)-alkyl, (C
2
-C
4
)-alkenyl, benzoyl or represents acyl having 2 to 6 carbon atoms,
R
5
represents pyridyl which is substituted up to 3 times by identical or different substituents from the group consisting of halogen, hydroxyl, cyano, trifluoromethyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkylthio, carbalkoxy, (C
1
-C
6
)-acyloxy, amino, nitro, mono- and (C
1
-C
6
)-dialkylamino,
and salts thereof.
In the context of the invention, cycloalkyl having 3 to 6 carbon atoms or (C
3
-C
6
)-cycloalkyl represents cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl. Preference is given to cyclopentyl or cyclohexyl.
Aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
In the context of the invention, (C
1
-C
6
)-acyl represents a straight-chain or branched acyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched acyl radical having 1 to 4 carbon atoms. Particularly preferred acyl radicals are acetyl and propionyl.
In the context of the invention, (C
1
-C
6
)-alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
In the context of the invention, (C
2
-C
6
)-alkenyl represents a straight-chain or branched alkenyl radical having 2 to 5 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 3 to 5 carbon atoms. Examples which may be mentioned are: ethenyl, propenyl, alkyl, n-pentenyl and n-hexenyl.
In the context of the invention, (C
1
-C
6
)-alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy and propoxy.
In the context of the invention, (C
1
-C
6
)-alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methylthio, ethylthio and propylthio.
In the context of the invention, (C
1
-C
6
)-alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
A straight-chain, branched or cyclic, saturated or unsaturated (C
1
-C
8
)-hydrocarbon radical includes, for example, the above-described (C
1
-C
6
)-alkyl, (C
2
-C
6
)-alkenyl or (C
3
-C
6
)-cycloalkyl, preferably (C
1
-C
6
)-alkyl.
The compounds according to the invention may exist in stereoisomeric forms which are related either as image and mirror image (enantiomers), or which are not related as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic forms can, just like the diastereomers, be separated in a known manner into the stereoisomerically pure constituents.
The compounds of the present invention include the isomers of the general formulae (I) and (Ia) and mixtures thereof. If R
4
is hydrogen, the isomers (I) and (Ia) exist in a tautomeric equilibrium:
The substances according to the invention may also be present as salts. In the context of the invention, preference is given to physiologically acceptable salts.
Physiologically acceptable salts can be salts of the compound
Deres Karl
Goldmann Siegfired
Graef Erwin
Krämer Thomas
Lettmann Stefan
Bayer Aktiengesellschaft
Rao Deepak
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