Use of dihydropyrimidines as medicaments, and novel substances

Details Use of dihydropyrimidines as medicaments, and novel substances Use of dihydropyrimidines as medicaments, and novel substances

2000-10-18

2002-08-20

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...

C514S211080, C514S211100, C514S211150, C514S212080, C514S217060, C514S235800, C514S233800, C514S255050, C514S269000, C514S258100

Reexamination Certificate

active

06436943

ABSTRACT:

The present invention relates to the use of dihydropyrimidines as medicaments, to novel substances, to processes for their preparation, in particular as medicaments for the treatment and prophylaxis of hepatitis B.
The publication EP 103 796 A2 already discloses dihydropyrimidines having a circulation-influencing effect.
Surprisingly, it has now been found that dihydropyrimidines of the general formula (I)
or their mesomeric form (Ia)
in which
R
1
is phenyl, furyl, thienyl, triazolyl, pyridyl, cycloalkyl having from 3 to 6 carbon atoms or is a radical of the formula
where the abovementioned ring systems are optionally mono- or polysubstituted, identically or differently, by substituents chosen 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 in turn can be substituted by aryl having from 6 to 10 carbon atoms or halogen,
and/or the above ring systems 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
,
wherein
R
6
is phenyl, which is optionally substituted by halogen,
R
7
, R
8
, R
9
and R
10
are identical or different and are hydrogen, phenyl, hydroxy-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 hydroxy-substituted phenyl,
A is a radical O, S, SO or SO
2
,
R
11
is phenyl, which is optionally mono- or polysubstituted, identically or differently, by substituents chosen from the group consisting of halogen, nitro, trifluoromethyl, (C
1
-C
6
)-alkyl and (C
1
-C
6
)-alkoxy,
R
2
is a radical of the formula —XR
12
or —NR
13
R
14
,
wherein
X is a bond or oxygen,
R
12
is 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 from 6 to 10 carbon atoms or aralkyl having from 6 to 10 carbon atoms, heteroaryl or a group of the formula —NR
15
R
16
,
wherein
R
15
and R
16
are identical or different and are hydrogen, benzyl or (C
1
-C
6
)-alkyl,
R
13
and R
14
are identical or different and are hydrogen, (C
1
-C
6
)-alkyl or cycloalkyl having from 3 to 6 carbon atoms,
R
3
is hydrogen, amino or is a radical of the formula
is formyl, cyano, hydroxy-substituted (C
1
-C
6
)-alkylthio, trifluoromethyl or pyridyl, or
is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms, which is optionally mono- or polysubstituted, identically or differently, by aryloxy having from 6 to 10 carbon atoms, azido, halogen, cyano, hydroxyl, carboxyl, (C
1
-C
6
)-alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, (C
1
-C
6
)-alkylthio or (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
,
wherein
a is a number 0 or 1,
R
17
and R
18
are identical or different and are hydrogen or aryl, aralkyl having from 6 to 10 carbon atoms,
or are (C
1
-C
6
)-alkyl, which is optionally substituted by (C
1
-C
6
)-alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, where phenyl or benzyl are optionally mono- or polysubstituted, identically or differently, 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
,
or
R
17
and R
18
together with the nitrogen atom form a morpholine, piperidinyl or pyrrolidinyl ring,
or
R
3
is phenyl, which is optionally substituted by methoxy,
or
R
2
and R
3
together form a radical of the formula
R
4
is hydrogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkenyl, benzoyl or is acyl having from 2 to 6 carbon atoms,
R
4
is hydrogen, methyl, benzoyl or is (C
2
-C
6
)-acyl,
R
5
is pyridyl, pyrimidyl or pyrazinyl,
and their salts,
surprisingly have an antiviral action against hepatitis B (HBV) and are therefore suitable for the prophylaxis and control of virus-induced illnesses, in particular of acutely and chronically persistent HBV virus infections.
For the purposes of the invention, cycloalkyl having from 3 to 6 carbon atoms is cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl. The following may be mentioned in preference: cyclopentyl or cyclohexyl.
Aryl is generally an aromatic radical having from 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
For the purposes of the invention, (C
1
-C
6
)-acyl is a straight-chain or branched acyl radical having from 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.
For the purposes of the invention, (C
1
-C
6
)-alkyl is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be given are: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. Preference is given to a straight-chain or branched alkyl radical having from 1 to 4 carbon atoms.
For the purposes of the invention, (C
2
-C
6
)-alkenyl is a straight-chain or branched alkenyl radical having from 2 to 6 carbon atoms. Examples which may be given are: ethenyl, propenyl, isopropenyl, tert-butenyl, n-pentenyl and n-hexenyl. Preference is given to a straight-chain or branched lower alkenyl radical having from 3 to 5 carbon atoms.
For the purposes of the invention, (C
1
-C
6
)-alkoxy is a straight-chain or branched alkoxy radical having from 1 to 6 carbon atoms. Examples which may be given are: methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Preference is given to a straight-chain or branched alkoxy radical having from 1 to 4 carbon atoms.
For the purposes of the invention, (C
1
-C
6
)-alkoxycarbonyl is a straight-chain or branched alkoxycarbonyl radical having from 1 to 6 carbon atoms. Examples which may be given are: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl. Preference is given to a straight-chain or branched alkoxycarbonyl radical having from 1 to 4 carbon atoms.
Preference is given to using compounds of the general formula (I) or (Ia)
in which
R
1
is phenyl, furyl, thienyl, triazolyl, pyridyl, cyclopentyl or cyclohexyl or is a radical of the formula
where the abovementioned ring systems are optionally mono- or disubstituted, identically or differently, by substituents chosen from the group consisting of halogen, trifluoromethyl, nitro, SO
2
—F
3
, methyl, cyano, trifluoromethoxy, hydroxyl, carboxyl, methoxycarbonyl or radicals of the formula —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
is a radical of the formula —XR
12
or —NR
13
R
14
,
wherein
X is a bond or an oxygen atom,
R
12
is hydrogen, (C
1
-C
4
)-alkenyl, (C
1
-C
4
)-alkoxycarbonyl or (C
1
-C
4
)-alkyl which are optionally substituted by pyridyl, cyano, phenoxy, benzyl or by a radical of the formula —NR
15
R
16
,
wherein
R
15
and R
16
are identical or different and are hydrogen, benzyl or (C
1
-C
4
)-alkyl,
R
13
and R
14
are identical or different and are hydrogen, (C
1
-C
4
)-alkyl or cyclopropyl,
R
3
is hydrogen, amino or a radical of the formula
or
is formyl, cyano, hydroxy-substituted (C
1
-C
4
)-alkylthio, trifluoromethyl, cyclopropyl or pyridyl, or
is (C
1
-C
4
)-alkyl, which is optionally substituted by halogen, (C
1
-C
4
)-alkoxycarbonyl, hydroxyl or by triazolyl, which for its part can be substituted up to 3 times by (C
1
-C
4
)-alkoxycarbonyl,
a

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