WO2001068642A1

WO2001068642A1 - Dihydropyrimidines and the use thereof as medicaments for the treatment of hepatitis b

Info

Publication number: WO2001068642A1
Application number: PCT/EP2001/002444
Authority: WO
Inventors: Siegfried Goldmann; Jürgen Stoltefuss; Ulrich Niewöhner; Karl-Heinz Schlemmer; Thomas Krämer; Arnold Paessens; Erwin Graef; Olaf Weber; Karl Deres
Original assignee: Bayer Aktiengesellschaft
Priority date: 2000-03-16
Filing date: 2001-03-05
Publication date: 2001-09-20
Also published as: AU5618501A; DE10012824A1

Abstract

The invention relates to dihydropyrimidines of formula (I) and the isomeric form thereof (Ia), where R?1, R2, R3, R4 and R5¿ have the meanings given in the claims and combinations thereof with other antiviral agents, which are suitable for the treatment of HBV infections.

Description

DIH _x X _' R _O PYR'EMIDINE AND THEIR USE AS A MEDICINAL PRODUCT FOR TREATING HEPATITIS B

The present invention relates to new dihydropyrimidines, processes for their preparation and medicaments containing these dihydropyrimidines, in particular for the treatment and prophylaxis of hepatitis B virus infections. The invention also relates to combinations of these dihydropyrimidines with other antiviral agents and, if appropriate, immunomodulators and medicaments containing these combinations, in particular for the treatment and prophylaxis of HBV infections such as hepatitis B.

The hepatitis B virus belongs to the Hepadna virus family. It causes an acute and / or a persistent-progressive, chronic illness. A wide variety of other clinical manifestations in the clinical picture are also caused by the hepatitis B virus - in particular chronic inflammation of the liver, cirrhosis of the liver and hepatocellular carcinoma. Furthermore, coinfection with the hepatitis delta virus can have a negative impact on the course of the disease.

The only agents approved for the treatment of chronic hepatitis are interferon and lamivudine. However, interferon is only moderately effective and has undesirable side effects; Although lamivudine works well, resistance develops quickly during treatment, and rebound occurs in most cases after therapy is discontinued.

From EP-PS 103 796 dihydropyrimidines are known, to which an effect influencing the circulation is attributed. EP-A 169 712 describes substituted dihydropyrimidines as intermediates which can be oxidized to the corresponding pyrimidines. WO 99/1438 relates to dihydropyrimidines which are said to be suitable for the treatment of cerebrovascular ischemia and pain. WO 99/54312, 99/54326 and 99/54329 relate to dihydropyrimidines which are suitable for the treatment and prophylaxis of hepatitis. The present invention relates to dihydropyrimidines of the formula

or their isomeric form

Wonn

R phenyl, furyl or thienyl, where these ring systems can be substituted, independently of one another, one or more times by substituents selected from the group halogen, nitro, cyano, hydroxy, alkyl, trifluoromethyl, alkoxy, trifluoromethoxy,

R is hydrogen, a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical which optionally contains one or two identical or different hetero chain links from the group -O-, -CO-, -NH-, -N (CpC - alkyl) -, -S - or -SO ₂ - and which is optionally substituted by halogen, nitro, cyano, hydroxy, aryl, aralkyl, heteroaryl or the group -NR ⁶ R ⁷ ,

Wonn

R ⁶ and R ⁷ independently of one another are hydrogen, benzyl or alkyl or together with the nitrogen atom to which they are attached stand, form a 5- to 6-membered ring which optionally contains oxygen,

a group of the formula -CH ₂ -R ⁸ _m -XR

Wonn

R is a double-bonded linear, branched or cyclic, saturated or unsaturated hydrocarbon radical which is optionally mono- or polysubstituted, identically or differently by halogen, optionally substituted aryl, azido, cyano, hydroxy, carbonyl, carboxyl, alkoxycarbonyl, optionally substituted heteroaryl, alkoxy or alkylthio is substituted,

R ^{9 is} hydrogen, optionally substituted aryl, optionally substituted heteroaryl or a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical which is optionally interrupted one to three times by oxygen and which is optionally one or more times, identical or different, by aryl, aryloxy, Azido, cyano, hydroxy, carboxyl, alkoxycarbonyl,

Heteroaryl, alkoxy or alkylthio is substituted

and / or which can be substituted by a group of the formula -CO-R ¹⁰ or -NR ⁿ R ¹² ,

wherein

R, 1 ^I 0 ^U benzyl, phenyl or alkyl,

R ¹¹ and R ¹² independently of one another denote hydrogen, aryl, aralkyl or denote alkyl, which is optionally by Alkoxycarbonyl, hydroxyl, phenyl or benzyl is substituted, phenyl or benzyl optionally being substituted one or more times, identically or differently by hydroxy, carboxyl, alkyl or alkoxy, or alkyl optionally by -NH- CO-CH ₃ or -NH-CO -CF _{3 is} substituted,

or

R ¹¹ and R ¹² together with the nitrogen atom on which they are located form a morpholinyl, piperidinyl or pyrrolidinyl ring,

X oxygen or sulfur

and

m means zero or 1

and - if X = O - with the proviso that R ^{3 contains} either a) at least one hydroxyl group and at least one ether oxygen atom or b) at least two ether oxygen atoms,

R ^{4 is} hydrogen, alkyl, alkenyl, benzoyl or acyl,

R pyridyl, which is identical or different up to three times by halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy,

Amino, nitro, mono- or di alkylamino can be substituted, or thiazolyl, thienyl or furyl, which can be identical or different up to two times by halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy, amino, nitro, Mono- or dialkylamino can be substituted, mean and their salts.

Preferred compounds of the formulas (I) or (I a) according to the invention are those in which

R ^{1 is} phenyl, furyl or thienyl, it being possible for these ring systems to be substituted one or two times identically or differently by substituents from the group halogen, hydroxyl, methyl, C 1 -C 4 -alkoxy, trifluoromethoxy,

R ² is hydrogen, C ₃ -C ₄ alkenyl or C _ö alkyl optionally substituted by halogen, hydroxy, Cι-C ₂ - alkoxy, pyridyl, cyano, phenoxy or benzyl,

R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,

Wonn

R -C-C ₆ alkylene, which is optionally substituted by halogen, -C-C ₄ - (alkoxy) - carbonyl, hydroxy, phenyl or heteroaryl, which in turn is up to twice by halogen, hydroxy, -C-C ₂ alkyl, Ci - C ₂ alkoxy or -CC ₃ - (alkoxy) carbonyl may be substituted,

R ^{9 is} hydrogen, phenyl or heteroaryl or a -CC-alkyl radical, which is optionally interrupted one to three times by oxygen, phenyl or heteroaryl optionally by halogen, hydroxyl, -CC ₂ -alkyl, C 1 -C -alkoxy or Cι -C - (alkoxy) carbonyl are substituted and the Cι-Cιo-alkyl radical is optionally substituted by halogen, hydroxy, Cι-C - alkoxy, alkoxycarbonyl or by phenyl, which in turn is up to twice by halogen, Hydroxy, CrC ₂ - alkyl, C] -C ₄ alkoxy or -CC ₄ alkoxycarbonyl may be substituted,

X oxygen or sulfur

and

m means zero or 1

and - unless X = S - with the proviso that R contains either a) at least one hydroxyl group and 1 to 4 ether oxygen atoms or b) at least 2 to 4 ether oxygen atoms,

R> 4 hydrogen,

R ⁵ pyridyl or thiazolyl, which can be substituted up to twice in the same or different way by fluorine, chlorine, bromine, alkyl or alkoxy,

mean,

and their salts.

Compounds according to the invention of the formulas (I) or (Ia) in which

R ¹ phenyl, which is optionally substituted up to twice, identically or differently, by substituents from the group fluorine, chlorine, bromine, iodine, hydroxyl, methyl, methoxy, trifluoromethoxy,

R ^{2 is} hydrogen or C _r C ₄ alkyl, R ³ the group -CH ₂ -R ⁸ _m -XR ⁹

Wonn

R C-C ₄ alkylene, optionally by fluorine, chlorine, hydroxy, Ci

C ₂ alkoxy or substituted by phenyl or heteroaryl, which in turn can be substituted by halogen, hydroxy, methyl or methoxy,

R ^{9 is} hydrogen, -CC ₈ - alkyl, optionally up to twice

Oxygen is interrupted, phenyl or 5- to 6-membered heteroaryl, alkyl, phenyl and heteroaryl optionally being substituted by halogen, hydroxy, methyl or -Cs-alkoxy,

X oxygen or sulfur

and

m means zero or 1

and - unless X = S - with the proviso that R ^{3 contains} either a) at least one hydroxyl group and 1 to 3 ether oxygen atoms or b) 2 to 3 ether oxygen atoms,

R> 4 hydrogen,

R ⁵ pyridyl or thiazolyl, which can be substituted up to twice the same or different by fluorine, chlorine, bromine, C ₁ -C ₃ -alkyl or -Cj- alkoxy,

mean, and their salts.

Compounds according to the invention of the formulas (I) or (Ia) in which

R phenyl, optionally up to twice the same or different

Fluorine, chlorine, bromine, iodine, methyl or methoxy is substituted,

R linear or branched C 1 -C 4 alkyl,

R ^{3 is} the group -CH ₂ -R ⁸ _m -XR ⁹ , wherein

R Cj-C -alkylene, which can be substituted by fluorine, chlorine, hydroxy or phenyl, where the phenyl radical is optionally substituted by fluorine, chlorine, hydroxy, methyl or methoxy,

R ⁹ is hydrogen, Ci-C _ö -alkyl which is optionally interrupted once by oxygen, fluorine, chlorine, hydroxyl or methoxy substituted phenyl or 5- to 6-membered heteroaryl, wherein alkyl, phenyl and heteroaryl are optionally substituted by;

X oxygen or sulfur

and

m means zero or 1

and - unless X = S - with the proviso that R ^{3 contains} either a) a hydroxyl group and one or two ether oxygen atoms or b) 2 ether oxygen atoms, R ^{4 is} hydrogen

and

R ⁵ pyridyl or thiazolyl, which can be substituted up to twice, identically or differently, by fluorine, chlorine or bromine,

mean,

and their salts.

Particularly preferred are compounds of the formula (I) or (I a), in which R ^{5 represents} 2-pyridyl, which can be substituted by 1 to 2 fluorine atoms, or represents thiazolyl.

In the context of the invention, acyl and the acyl part of acyloxy mean a linear or branched acyl radical having 1 to 6, preferably 1 to 4, carbon atoms, such as e.g. Acetyl and propionyl.

In the context of the invention, alkyl represents a linear or branched alkyl radical having 1 to 6 carbon atoms, e.g. Methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. A linear or branched alkyl radical having up to 4 carbon atoms is preferred.

"Cyclic saturated hydrocarbon radical" in the context of the invention stands for cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopentyl or cyclohexyl.

In the context of the invention, alkenyl represents a linear or branched alkenyl radical having 2 to 5, preferably 3 to 5, carbon atoms, such as, for example, ethenyl, propenyl, allyl and n-pentenyl. In the context of the invention, alkoxy represents a linear or branched alkoxy radical having 1 to 6, preferably 1 to 4, carbon atoms, such as, for example, methoxy, ethoxy and propoxy.

Alkoxycarbonyl stands for a linear or branched in the context of the invention

Alkoxycarbonyl radical having 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy radical, such as e.g. Methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

A linear, branched or cyclic, saturated or unsaturated hydrocarbon radical generally contains 1 to 12, preferably 1 to 10 and in particular 1 to

8 carbon atoms and includes, for example, the alkyl, alkenyl and cycloalkyl radicals described above, preferably C ₁ -C ₆ -alkyl radicals.

Aryl and the aryl part of aryloxy generally mean an aromatic radical having 6 to 10 carbon atoms, preferably phenyl and naphthyl.

In the context of the invention, aralkyl stands for aralkyl with preferably 6 to 10, in particular 6, carbon atoms in the aryl part (preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 4, in particular 1 or 2, carbon atoms in the alkyl part, the alkyl part being linear or branched can be. preferred

Aralkyl radicals are benzyl and phenethyl.

Heteroaryl in the context of the invention represents 5- to 7-membered rings with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms from the series oxygen, sulfur and nitrogen. Preferred examples include

Furyl, thienyl, pyrazolyl, imidazolyl, 1.2.3- and 1.2.4-triazolyl, oxazolyl, isoxazolyl, thi.azolyl, isothiazolyl, pyrrolyl, pyridyl, pyrimidinyl and pyrazinyl.

The compounds of the invention can be in stereoisomeric forms, which are either like image and mirror image (enantiomers), or which are not like image and

Mirror image (diastereomers) behave, exist. The invention relates to both Enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a manner known per se.

The compounds according to the invention include the isomers of the formulas (I) and (I a) and mixtures thereof. If R ^{4 is} hydrogen, the isomers (I) and (la) are in tautomeric equilibrium:

(I) (l a)

The compounds according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.

Physiologically acceptable salts can be salts of inorganic or organic acids. Salts of inorganic acids such as, for example, are preferred

Hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts of organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Z are particularly preferred. B. sodium, potassium, magnesium or calcium salts and ammonium salts of ammonia or organic amines, such as ethylamine, di- or triethyl amine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine are derived.

The compounds (I) according to the invention can be prepared by

[A] aldehydes of the formula

R -CHO (II),

where R ^{1 has} the meaning given above,

with amidines of the formula

where R ^{5 has} the meaning given above,

or with their salts (such as hydrochlorides or acetates)

and compounds of the formula

R ³ -CO-CH ₂ -COOR ² (IV),

wherein R and R have the meanings given above,

with or without addition of base or acid, preferably at temperatures of 20 to 150 ° C, optionally in the presence of inert organic solvents or

[B] Compounds of the formula

wherein R ι l ι b-: i.s R have the meanings given above,

with amidines of the formula

where R ^{3 has} the meaning given above,

or with their salts (e.g. hydrochlorides or acetates)

[C] Aldehydes of the formula

R ^! -CHO (II),

where R ^{1 has} the meaning given above,

with compounds of the formula

R ³ - C = C COOR ²

H (VI),

NH, wherein R and R have the meanings given above,

and amidines of the formula (III) or with their salts (such as hydrochlorides or acetates) with or without addition of base or acid, preferably at temperatures of 20 to 150 ° C, optionally in the presence of inert organic solvents or

[D] aldehydes of the formula (II) with compounds of the formula (IV) and imino ethers of the formula (VII)

Wonn

R has the meaning given above and

R. 13 represents C 1 -C ₄ -alkyl,

in the presence of ammonium salts with or without addition of base or acid, preferably at temperatures from 20 to 150 ° C., optionally in the presence of inert organic solvents, or else

[E] if m in R ^{3 of} the formula (I) is zero, compounds of the formula

where R. 1, τ R2, τ R> 4 and R have the meanings given above,

with compounds of the formula

HXR ⁹ (LX),

wherein X and R ^{9 have} the meanings given above,

preferably in the presence of a strong base, preferably at temperatures of 20 to 150 ° C, optionally in the presence of inert organic solvents.

The process according to the invention can be illustrated by the following formula scheme:

[A]

For all process variants A, B, C, D and E, all inert organic solvents are suitable as solvents. These preferably include alcohols such as methanol, ethanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether, carboxylic acids such as glacial acetic acid, or Dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric triamide.

The reaction temperatures can be varied over a wide range. In general, temperatures from 20 to 150 ° C, but preferably at the boiling point of the solvent.

The reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works under normal pressure.

The reaction can be carried out with or without addition of base or acid; however, it is advisable to implement in the presence of weaker acids, such as. B. acetic acid or formic acid.

The aldehydes (II) used as starting materials are known or can be prepared by methods known from the literature [cf. T. D. Harris and G.P. Roth, J. Org. Chem. 44, 146 (1979), DE-OS 2 165 260, 2 401 665, Mijano et al., Chem. Abstr. 59, 13 929 c (1963), E. Adler and H.-D. Becker, Chem. Scand. 15, 849 (1961), E.P. Papadopoulos, M. Mardin and Ch. Issidoridis, J. Org. Chem. Soc. 78, 2543 (1956)].

The ylidene-β-keto esters (V) used as starting materials can be prepared by methods known from the literature [cf. G. Jones, "The Knoevenagel Condition" in Organic Reactions, Vol. XV, 204 ff. (1967)].

The enaminocarboxylic acid esters (VI) and the imino ethers (VII) used as starting materials are known or can be prepared by methods known from the literature [cf. S.A. Glickman and A.C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)].

The ß-ketocarboxylic acid esters (IV) used as starting materials are known or can be prepared by methods known from the literature [e.g. BD Borrmann, "Implementation of Diketene with Alcohols, Phenols and Mercaptans" in "Methods of Organic Chemistry" (Houben-Weyl), Vol. VII / 4, 230 ff (1968); Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].

Compounds of formula (VIII) are new; the invention therefore also relates

Compounds of formula (VIII).

The compounds according to the invention show a valuable, unforeseeable activity against viruses. Surprisingly, they are antiviral against hepatitis BV viruses (HBV) by causing an extremely strong reduction in the DNA of intra- and extracellular hepatitis B viruses. The compounds according to the invention are therefore suitable for the treatment of virus-induced diseases, in particular acute and chronic persistent viral infections of HBV. A chronic viral disease caused by HBV can lead to different severity of the clinical picture; As is well known, chronic hepatitis B virus infection in many cases leads to cirrhosis of the liver and / or hepatocellular carcinoma.

Examples of indications for the compounds according to the invention are:

The treatment of acute and chronic viral infections that can lead to infectious hepatitis, for example infections with hepatitis B viruses. The compounds according to the invention are particularly suitable for the treatment of chronic hepatitis B infections and the treatment of acute and chronic hepatitis B virus infections.

One embodiment of the invention relates to combinations of A) above dihydropyrimidines (I) or (Ia) and B) at least one HBV antiviral agent different from A. A particular embodiment of the invention relates to combinations of A) the above dihydropyrimidines (I) or (Ia), B) HBV polymerase inhibitors and, if appropriate, C) immunomodulators.

HBV polymerase inhibitors B for the purposes of the invention are substances which are described in the endogenous polymerase assay described below, which was described by Ph. A. Furman et al. in Antimicrobial Agents and Chemotherapy, Vol. 36 (No. 12), 2688 (1992) lead to an inhibition of the formation of an HBV-DNA double strand in such a way that a maximum of 50% of the activity of the zero value results:

HBV virions from culture supernatants incorporate nucleoside 5'-triphosphates into the plus strand of HBV DNA in vitro. Using agarose gel electrophoresis, the incorporation of [- P] deoxynucleoside 5'-triphosphate into the 3.2 kb viral DNA product in the presence and absence of a substance with potential HBV-

Polymerase inhibitory properties were observed. HBV virions are obtained from the cell culture supernatant of HepG2.2.15 cells by precipitation with polyethylene glycol and concentrated. 1 volume of clarified cell culture supernatant is mixed with V mit volume of an aqueous solution containing 50% by weight of 8000 polyethylene glycol and 0.6 M sodium chloride. The virions are centrifuged at

2,500 xg / 15 minutes sedimented. The sediments are resuspended in 2 ml of buffer containing 0.05 M Tris-HCl (P _H 7.5) and dialyzed against the same buffer containing 100 raM potassium chloride. The samples can be frozen at -80 ° C. Each reaction mixture (100 μl) contains at least 10 ⁵ HBV virions; 50 mM Tris-HCl (p _H 7.5); 300mM potassium chloride; 50mM magnesium chloride; 0.1% ®Nonident

P-40 (non-ionic detergent from Boehringer Mannheim); 10 μM each of dATP, dGTP and dTTP; 10 μCi [ ³² P] dCTP (3000 Ci / mmol; final concentration 33 nM) and 1 μM of the potential polymerase inhibitor in its triphosphorylated form. The samples are incubated at 37 ° C for one hour and then the reaction is stopped by adding 50 mM EDTA. A 10% weight volume SDS

Solution (containing 10 g SDS per 90 ml water) is made up to a final concentration of 1 vol .-% (based on total volume), and Proteinase K is added to a final concentration of 1 mg / ml. After incubation at 37 ° C for one hour, samples are extracted with the same volume of phenol / chloroform / isoamyl alcohol (volume ratio 25: 24: 1) and the DNA is precipitated from the aqueous phase with ethanol. The DNA pellet is dissolved in 10 μl gel buffer (solution of

10.8 g Tris, 5.5 g boric acid and 0.75 g EDTA in 1 liter water (= TBE buffer)) resuspended and separated by electrophoresis in an agarose gel. The gel is either dried or the nucleic acids contained therein are transferred to a membrane using Southern transfer technology. Then the amount of the DNA double strand formed and labeled in relation to the negative control

(= Endo-Pol reaction without substance or with control substance without effect) determined. An HBV polymerase inhibitor is present when a maximum of 50% of the activity of the negative control is present.

Preferred HBV polymerase inhibitors B) include, for example

3TC = Lamivudine =

= 4-arnino-l - [(2R-cis) -2- (hydroxymethyl) -1.3-oxathiolan-5-yl] pyrimidin-2 (1H) -one, cf. EP-PS 382 526 (= US-PS 5 047 407) and WO 91/11186 (= US-PS 5 204466);

Adefovir Dipivoxil logo CNRS logo INIST

9- {2 - [[bis [(pivaloyloxy) methoxy] phosphinyl] methoxy] ethyl} adenine, cf. EP-PS

481,214 (= U.S. Patents 5,663,159 and 5,792,756), U.S. Patents 4,724,233 and 4,808,716;

BMS 200 475 =

[1 S- (l .α, 3.α, 4.ß)] - 2-amino-l .9-dihydro-9- [4-hydroxy-3- (hydroxymethyl) -2-methylene-cyclopentyl] -6H -purin-6-one, cf. EP-PS 481 754 (= US-PS 5 206 244 and 5 340 816), WO 98/09964 and 99/41275; Abacavir =

(-) - (IS-cis) -4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol, cf. EP-PS 349 242 (= US-PS 5 049 671) and EP-PS 434 450 (= US-PS 5 034 394);

FTC =

(2R-cis) -4-Amino-5-fluoro-1 - [2- (hydroxymethyl) - 1,3-oxathiolan-5-yl] -p> τimidin-2 (1H) -one, cf. WO 92/14743 (= US-PS 5 204 466, 5 210 085, 5 539 116, 5 700 937, 5 728 575, 5 814 639, 5 827 727, 5 852 027, 5 892 025, 5 914 331, 5 914 400) and WO 92/18517;

ß-L-FDDC =

5- (6-Amino-2-fluoro-9H-purin-9-yl) tetrahydro-2-furanmethanol, cf. WO 94/27616

(= U.S. Patents 5,627,160, 5,561,120.5,631,239 and 5,830,881);

L-FMAU = 1- (2-deoxy-2-fluoro-ß-L-arabinofuranosyl) -5-methyl-pyrimidine-2.4 (1H, 3H) -dione, cf. WO 99/05157, WO 99/05158 and US Pat. No. 5,753,789.

Another preferred embodiment of the invention relates to combinations of A) the above dihydropyrimidines (I) or (Ia) and B) lamivudine.

Other preferred HBV antiviral agents B include e.g. Phenylpropenamides of the formula

Wonn

R ¹ and R ² independently of one another are C - alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms which comprise carbon and / or oxygen,

R ³ to R ¹² independently of one another are hydrogen, halogen, -CC alkyl, optionally substituted C] -C - alkoxy, nitro, cyano or trifluoromethyl,

R ^{13 is} hydrogen, -CC ₄ alkyl, C, -C ₇ -acyl or aralkyl and

X halogen or optionally substituted -CC ₄ - alkyl

mean,

and their salts.

These phenylpropenamides and processes for their preparation are known from WO 98/33501, to which reference is hereby made for the purposes of the disclosure. AT-61 is the compound of the above formula wherein X is chlorine, A 1-piperidinyl and Y and Z are each phenyl.

Preferred immunomodulators C) include, for example, all interferons such as α, β and γ interferons, in particular also α-2a and α-2b interferons, interleukins such as interleukin-2, polypeptides such as thymosin-α-1 and thymoctonan, imidazoquinoline, derivatives such as ®Levamisole, immunoglobulins and therapeutic vaccines.

Another preferred embodiment of the invention relates to combinations of A) above dihydropyrimidines (I) or (Ia), B) lamivudine and optionally C) interferon. test Description

The antiviral activity of the compounds according to the invention against the hepatitis B virus was based on that of M.A. Seils et al., Proc. Natl. Acad. Be. 84, 1005-1009 (1987) and B.E. Korba et al., Antiviral Research 19, 55-70 (1992).

The antiviral tests were carried out in 96-well microtiter plates. The first vertical row of the plate received only growth medium and HepG2.2.15 cells. It served as a virus control.

Stock solutions of the test compounds (50 mM) were first dissolved in DMSO, further dilutions were made in the growth medium of HepG2.2.15. The compounds according to the invention were generally in a test concentration of 100 μM (1st test concentration) in each case in the second vertical test series of the

Pipetted the microtiter plate and then diluted 2 ¹⁰ -fold in growth medium plus 2% by weight of fetal calf serum in two steps (volume 25 μl).

Each well of the microtiter plate then received 225 μl of a HepG2.2.15 cell suspension ((55 xx 1100 ⁴⁴ ZZeelllleenn // mmll)) iinn WWaacchhssttuummssmmeeddiiuumm pplluuss 22 GGeeww ..-- %% föföttaalles calf serum. The test mixture was incubated for 4 days at 37 ° C. and 5% CO ₂ (v / v).

The supernatant was then aspirated and discarded, and the wells received 225 μl of freshly prepared growth medium. The compounds according to the invention were each added again as a 10-fold concentrated solution in a volume of 25 μl. The batches were incubated for a further 4 days.

Before harvesting the supernatants to determine the antiviral effect, the HepG2.2.15 cells were examined for cytotoxic changes by light microscopy or by means of biochemical detection methods (eg Alamar blue staining or trypan blue staining). The supernatants and or cells were then harvested and sucked by means of vacuum onto 96-well dot-blot chambers covered with nylon membrane (according to the manufacturer's instructions).

cytotoxicity

Substance-induced cytotoxic or cytostatic changes in the HepG2.2.15 cells were e.g. determined as changes in cell morphology by light microscopy. Such substance-induced changes in the HepG2.2.15 cells compared to untreated cells were e.g. visible as cell lysis, vacuolization or altered cell morphology. 50% cytotoxicity (Tox.-50) means that 50% of the cells have a morphology comparable to the corresponding cell control.

The tolerance of some of the compounds according to the invention was additionally tested on other host cells such as e.g. HeLa cells, human primary peripheral blood cells or transformed cell lines such as H-9 cells.

No cytotoxic changes were found at concentrations of the compounds according to the invention of> 10 μM.

Determination of the antiviral effect

After transfer of the supernatants or lysed cells to the nylon membrane of the blot apparatus (see above), the intra- or extracellular supernatants of the HepG2.2.15 cells were denatured (1.5 M NaCl / 0.5 N NaOH), neutralized (3 M

NaCl / 0.5 M Tris HCl, pH 7.5) and washed (2 x SSC). The DNA was then baked on the membrane by incubating the filters at 120 ° C. for 2-4 hours.

Hybridization of the DNA The detection of the viral DNA from the treated HepG2.2.15 cells on the

Nylon filters were typically labeled with non-radioactive, digoxigenin Hepatitis B-specific DNA probes carried out, which were labeled with digoxigenin, purified and used for hybridization according to the manufacturer's instructions.

The prehybridization and hybridization took place in 5 x SSC, 1 x blocking reagent, 0.1% by weight N-lauroylsarcosine, 0.02% by weight SDS and 100 μg sperm DNA of the herring. The pre-hybridization took place at 60 ° C for 30 minutes, the specific hybridization with 20 to 40 ng / ml of the digoxigenized, denatured HBV-specific DNA (14 hours, 60 ° C). The filters were then washed.

Detection of HBV DNA by digoxigenin antibodies

The immunological detection of the digoxigenin-labeled DNA was carried out after

Product Information:

The filters were washed and prehybridized in a blocking reagent (according to the manufacturer's instructions). The mixture was then hybridized for 30 minutes with an anti-DIG antibody which was coupled with alkaline phosphatase. After a washing step, the substrate of the alkaline phosphatase, CSPD, was added, incubated with the filters for 5 minutes, then wrapped in plastic wrap and incubated at 37 ° C. for a further 15 minutes. The chemiluminescence of the hepatitis B-specific DNA signals was visualized by exposing the filters to an X-ray film (incubation depending on signal strength: 10 minutes to 2 hours).

The half-maximum inhibitory concentration (IC ₀ , inhibitory concentration 50%) was determined as the concentration at which the intra- or extracellular hepatitis B -specific band was reduced by 50% compared to an untreated sample by the compound according to the invention.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds (I) or (Ia) or a combination according to the invention, or which consist of one or more active ingredients (I) or (Ia) or consist of a combination according to the invention.

The active ingredients (I) or (Ia) in the pharmaceutical preparations listed above should be in a concentration of about 0.1 to 99.5% by weight, preferably about

0.5 to 95 wt .-% of the total mixture may be present.

In addition to the compounds (I) or (Ia), the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

The quantitative ratio of components A, B and optionally C of the combinations according to the invention can vary within wide limits; preferably it is 5 to 500 mg A / 10 to 1000 mg B, in particular 10 to 200 mg A / 20 to 400 mg B.

Component C, which is optionally to be used, can be used in amounts of preferably 1 to 10 million, in particular 2 to 7 million I.U. (international units), applied approximately three times a week over a period of up to one year.

The compounds or combinations according to the invention should generally be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95,% by weight of the total mixture.

The preparation of the pharmaceutical preparations listed above can be carried out in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

In general, it has proven to be advantageous in both human and veterinary medicine to add the active ingredient (s) according to the invention in a total amount of from about 0.5 to about 500, preferably from 1 to 100 mg / kg of body weight per 24 Hours, if necessary in the form of several single doses, to achieve the desired results. A single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place.

The invention therefore furthermore relates to the compounds and

Combinations to fight diseases.

The invention further relates to medicaments containing at least one of the compounds or combinations defined above and optionally one or more further pharmaceutical active ingredient (s).

The invention furthermore relates to the use of the compounds and combinations defined above in the manufacture of a medicament for the treatment and prophylaxis of the diseases described above, preferably viral diseases, in particular hepatitis B.

Unless stated otherwise, the percentages in the examples below relate to the weight. The ratios of solvents in solvent mixtures each relate to the volume.

Examples

A. Starting compounds

Example I 3-fluoropyridine N-oxide

22.20 ml of H ₂ O ₂ (30%) are added to a solution of 11.10 g (114.324 mmol) of 3-fluoropyridine in 74.00 ml of acetic acid and the mixture is stirred at a bath temperature of 100 ° C. for 7 hours. The mixture is then concentrated to 30 ml, 30 ml of water are added and the mixture is again concentrated to 30 ml. The solution is stirred with dichloromethane, made basic by adding K ₂ CO ₃ , separated, the aqueous phase is extracted twice with dichloromethane, dried and concentrated. Yield: 11.5 g (88.9%)

Mp .: 66-68 ° C

Example II 2-Cyano-3-fluoropyridine

5.20 g (45.980 mmol) of the compound from Example I are dissolved in 50 ml of acetonitrile. 13.70 g (138.092 mmol) of trimethylsilyl nitrile are added under argon and 12.80 ml of triethylamine are slowly run in. The solution is stirred under reflux for 7 hours and then at room temperature overnight. After this

Concentration with a water jet pump is taken up in dichloromethane, shaken twice with 50 ml of 2N aqueous sodium carbonate solution, washed with water, dried and concentrated.

Yield (crude): 5.3 g (oil)

Column chromatography: methylene chloride to methylene chloride / ethyl acetate (10: 1)

Example III 2-Amidino-3-fluoropyridine hydrochloride

A solution of 10.30 g (84.355 mmol) of the compound from Example II in 30 ml

Methanol is mixed with a sodium methylate solution consisting of 0.40 g (17.391 mmol) sodium and 65 ml methanol and stirred at 20 ° C. for 72 hours. 5.44 g (101.682 mmol) ammonium chloride (powdered) and 17.39 mmol (1.04 ml) acetic acid are added, the mixture is stirred at 40 ° C. for 28 hours and cooled. It is suctioned off from the insoluble salt (1.78 g), concentrated, concentrated with acetone, then stirred with acetone, suction filtered and washed. Yield: 10.6 g Mp .: «150 ° C dec.

Example IV 2-Cyano-3,5-dichloropyridine

Method 1:

A solution of 26 g (0.158 mol) of 3,5-dichloropyridine-l-oxide (Johnson et al., J.Chem.Soc.B, 1967, 1211) in 80 ml of dichloromethane is added successively with 21.8 ml (0.174 mol) trimethylsilyl cyanide and 14.6 ml (0.158 mol) dimethylcarbamic acid chloride were added and the mixture was stirred for 48 hours at room temperature. 100 ml of a 10% aqueous sodium hydrogen carbonate solution are added and the mixture is stirred intensively for 10 minutes. After the phases have been separated, the mixture is shaken once with dichloromethane; the combined organic phases are dried and concentrated. The

The residue is chromatographed on silica gel with dichloromethane and recrystallized from a little methanol. 11 g (40.2%) of 2-cyano-3,5-dichloropyridine (mp: 102 ° C.) are obtained.

Method 2:

Analog Troschuetz, R. et al., J. Heterocycl. Chem. 33, 1815-1821 (1996) 150 ml of diethylene glycol dimethyl ether, 47.68 g (0.261 mol) of 2,3,5-trichloropyridine, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) are finely powdered Potassium iodide and 75.0 g (0.838 mol) of copper (I) cyanide were combined under nitrogen and stirred at reflux for 24 hours. Then another 100 ml of diethylene glycol dimethyl ether, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75 g (0.838 mol) of copper (I) cyanide were added, and the mixture was stirred for a further 89 hours at the reflux temperature. After cooling to room temperature, the product is filtered off with suction and the filtrate is largely freed from diethylene glycol dimethyl ether by distillation. The residue is taken up in toluene and washed with an aqueous solution of Mohr's salt solution and then with aqueous sodium hydrogen carbonate solution (peroxide test). Then it is washed free of diethylene glycol dimethyl ether with water. It is filtered through ®Cellit, the filtrate is dried over magnesium sulfate and the solution is concentrated.

18.0 g (40.0%) of 2-cyano-3,5-dichloropyridine are obtained. Example V 2-Cyano-3,5-difluoropyridine

50 g (0.29 mol) of 2-cyano-3,5-dichloropyridine from Example IV, 33.6 g (0.58 mol)

Potassium fluoride and 10 g of polyethylene glycol 8000 are mixed with 125 ml of DMSO and heated to 160 ° C. for 30 minutes. After cooling, the product is distilled off together with the DMSO under high vacuum, the distillate is added to water, extracted with toluene and dried over sodium sulfate. The product is further implemented as a toluene solution.

Rf value: 0.43 (cyclohexane / ethyl acetate = 7: 3)

Example VI 3,5-difluoro-2-pyridinecarboximidamide hydrochloride

328 ml of trimethylaluminum (2 M in hexane, 0.624 mol) are added dropwise to a suspension of 33.4 g (0.624 mol) of ammonium chloride in 1 l of toluene, cooled to 0 to 5 ° C .; the mixture is stirred at room temperature until methane evolution has ceased. The toluene solution of 2-cyano-3,5-dichloropyridine from Example V is then added dropwise and the mixture is subsequently stirred at 80 ° C. overnight. After cooling to 0 to -5 ° C., methanol is added dropwise until the evolution of gas has ended, the salts are suctioned off and washed twice with a little methanol. The solvent is drawn off, the residue is dissolved in 500 ml of dichloromethane / methanol (9: 1) and suctioned off again from inorganic salts. After subtracting the Solvents remain 23.6 g (39.1%) of 3,5-difluoro-2-pyridinecarboximidamide hydrochloride (mp: 183 ° C).

1H-NMR (DMSO-D ₆ ):

8.3-8.45 (m, 1H) ppm; 8.8 (d, J = 2 Hz, 1H) ppm; 9.7 (s, broad, 4H) ppm.

Example VII 2-Acetyl-3- (2-chloro-4-fluorophenyl) acrylic acid methyl ester

A solution of 50 g (315 mmol) of 2-chloro-4-fluoro-benzaldehyde and 36.6 g (315 mmol) of methyl acetoacetate in 150 ml of isopropanol is mixed with 1.7 ml of piperidine acetate. After stirring overnight at room temperature, the mixture is diluted with dichloromethane, extracted with water and the organic phase is dried over sodium sulfate and concentrated. The product is further converted raw as a cis / trans mixture.

Example VIII

2-Acetyl-3- (2-bromo-4-fluorophenyl) -acrylic acid methyl ester

This compound was prepared in analogy to Example VII starting from 2-bromo-4-fluoro-benzaldehyde and methyl acetoacetate.

Example IX Methyl Isopropoxyethoxyacetoacetate

8 g (200 mmol) of 60% sodium hydride in mineral oil are suspended in 200 ml of THF under argon and a solution of 10.42 g (100 mmol) of isopropoxyethanol in 50 ml of THF is added dropwise with gentle cooling. After stirring for 1 hour, a solution of 15.06 g (100 mmol) methyl chloroacetoacetate in 50 ml THF is added dropwise, the temperature being allowed to rise to 45 ° C. The mixture is stirred overnight, 100 ml of 10% acetic acid are added dropwise while cooling with ice and the THF is removed under reduced pressure. The residue is taken up in dichloromethane, the resulting solution is shaken with saturated aqueous sodium chloride solution, the organic phase is dried and concentrated. The purification is carried out on a silica gel column with toluene / ethyl acetate mixtures. 13.9 g (63.69%) of colorless oil are obtained. Example X

4- (2-bromo-4-fluorophene) -2- (3,5-difluoropyridin-2-yl) -1, 4-dihydro-6-methyl-pyrimidine-5-carboxylic acid methyl ester

A solution of 6.02 g (20 mmol) of 2-acetyl-3- (2-bromo-4-fluorophene) -acrylic acid methyl ester (Example VIII), 3.87 g (20 mmol) of 3,5-difluoro-2 pyridine carboximide amide hydrochloride (Example VI) and 1.64 g (20 mmol) sodium acetate in 120 ml isopropanol is heated under gentle reflux for 6 hours. After cooling, the mixture is concentrated, the residue is dissolved in 100 ml of 1N hydrochloric acid and diethyl ether, the phases are separated and the organic phase is extracted twice with 30 ml of 1N hydrochloric acid each. The combined aqueous phases are made basic with aqueous ammonia, extracted twice with ethyl acetate, the organic phase over

Dried sodium sulfate and concentrated. The residue is chromatographed on a silica gel column using dichloromethane / ethyl acetate (10: 1) as the eluent and further purified by crystallization from diethyl ether. Yield: 5.92 g (67.2% of theory) mp: 123-126 ° C

Example XI

4- (2-Bromo-4-fluoφhenyl) -6-bromomethyl-2- (3,5-difluoφyridin-2-yl) -l, 4-dihydropyrimidine-5-carboxylic acid methyl ester

1.8 g (4.089 mmol) 4- (2-bromo-4-fluoro-phenyl) -2- (3,5-difluoro-pyridin-2-yl) -l, 4-di-hydro-6-methyl-pyrimidin- 5-carboxylic acid methyl ester (Example X) are dissolved in 50 ml dichloromethane and mixed with 0.8 g (4.5 mmol) N-bromosuccinimide, heated to gentle boiling for 2 hours, cooled and concentrated. After rough cleaning on a silica gel column, 1.4 g (66%) of slightly yellow crystals with a melting point of 115-116 ° C. are obtained.

Example XII 4- (2-bromo-4-fluoro-phenyl) -6-bromomethyl-2- (3,5-difluoro-pyridin-2-yl) -1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester

A solution of 1.8 g (4.089 mmol) of 4- (2-bromo-4-fluoφhenyl) -2- (3,5-difluoropyridin-2-yl) -1, 4-dihydro-6-methyl-pyrimidine Methyl -5-carboxylate in 50 ml dichloromethane is mixed with 0.8 g (4.5 mmol) N-bromosuccinimide for 2 hours Heated to a gentle boil, cooled and concentrated. After rough cleaning on a silica gel column, 1.4 g (66%) of slightly yellow crystals with a melting point of 115-116 ° C. are obtained.

B. Production examples

example 1

4- (2-Chloro-4-fluoφhenyl) -2- (3-fluoφyridin-2-yl) -6-methoxyethoxymethyl-l, 4-dihydropyrimidine-5-carboxylic acid methyl ester

A mixture of 317 mg (2 mmol) of 2-chloro-4-fluorobenzaldehyde, 20 ml of isopropanol, 380 mg (2 mmol) of 4-methoxyethoxyacetoacetic acid, 351 mg

(2 mmol) 2-Amidino-3-fluoφyridin hydrochloride and 164 mg (82 mmol) sodium acetate is stirred for 16 hours with gentle boiling, then cooled and concentrated. The residue is dissolved in ethyl acetate; the solution is washed with aqueous sodium bicarbonate solution and water, dried and concentrated. After purification by column chromatography, 296 mg (32.8% of theory

Theory) colorless crystals (by crystallization with ether) of melting point 122 ° C.

Example 2

4- (2,4-Dichlθφhenyl) -2- (3,5-difluoφyridin-2-yl) -l, 4-dihydro-6- (4-pyridylthiomethyl) pyrimidine-5-carboxylic acid methyl ester

A solution of 49 mg of 6-bromomethyl-4- (2,4-dichlorothenyl) -2- (3,5-difluoro-pyridin-2-yl) -l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester and 13.3 mg (0.1 mmol) of 4-mercaptopyridine-Na salt in 1 ml of methanol is stirred for 24 hours, concentrated and purified on a silica gel column. 28 mg (53.7% of theory) of a yellow-colored substance are obtained.

The compounds listed in the following table were prepared in an analogous manner.

The active data of some compounds according to the invention are listed below.

Treatment of the hepatitis B virus-producing HepG2.2.15 cells with the compounds according to the invention surprisingly led to a reduction in intra- and / or extracellular viral DNA.

Claims

claims

Dihydropyrimidines of the formula

or their isomeric form

Wonn

R is hydrogen, a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical, which optionally contains one or two identical or different hetero chain links from the group - O-, -CO-, -NH-, -N (-C-C ₄ - alkyl) - , -S- or -SO ₂ - and which is optionally substituted by halogen, nitro, cyano, hydroxy, aryl, aralkyl, heteroaryl or the group -NR R,

Wonn R ⁶ and R ⁷ independently of one another are hydrogen, benzyl or alkyl or, together with the nitrogen atom on which they are located, form a 5- to 6-membered ring which may contain oxygen,

SO is a group of the formula -CH ₂ -R _m -XR,

Wonn

R is a double-bonded linear, branched or cyclic, saturated or unsaturated hydrocarbon radical which may be mono- or polysubstituted, identically or differently, by halogen, optionally substituted aryl, azido, cyano, hydroxy, carbonyl, carboxyl, alkoxycarbonyl, optionally substituted heteroaryl, alkoxy or alkylthio is substituted,

R ^{9 is} hydrogen, optionally substituted aryl, optionally substituted heteroaryl or a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical which is optionally interrupted one to three times by oxygen and which is optionally one or more times, identical or different, by aryl, aryloxy, Azido, cyano, hydroxy, carboxyl, alkoxycarbonyl, heteroaryl, alkoxy or

Alkylthio is substituted and / or which can be substituted by a group of the formula -CO-R ¹⁰ or -NR ⁿ R ¹² ,

wherein R ¹⁰ benzyl, phenyl or alkyl,

R ¹¹ and R ¹² independently of one another are hydrogen, aryl,

Aralkyl or alkyl, optionally by alkoxycarbonyl, hydroxyl, phenyl or

Benzyl is substituted, where phenyl or benzyl is optionally substituted one or more times, identically or differently, by hydroxyl, carboxyl, alkyl or alkoxy, or alkyl is optionally substituted by -NH- CO-CH ₃ or -NH-CO-CF ₃ ,

or

R and R together with the nitrogen atom on which they stand form a Moφholinyl-, Piperidinyl- or Pyrrolidinyl ring,

X oxygen or sulfur

and

m means zero or 1

and - unless X = S - with the proviso that R ^{3 contains} either a) at least one hydroxyl group and at least one ether oxygen atom or b) at least two ether oxygen atoms,

R ^{4 is} hydrogen, alkyl, alkenyl, benzoyl or acyl,

R ⁵ pyridyl which is identical or different up to three times by halogen,

Hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbo- alkoxy, acyloxy, amino, nitro, mono- or di alkylamino, or thiazolyl, thienyl or furyl, which can be identical or different up to two times by halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy, Amino, nitro, mono- or dialkylamino can be substituted,

mean,

and their salts.

2. Dihydropyrimidines according to claim 1, wherein

R ^{1 is} phenyl, furyl or thienyl, it being possible for these ring systems to be substituted one or two times, identically or differently, by substituents from the group consisting of halogen, hydroxy, methyl, d-C ₂ alkoxy, trifluoromethoxy

R ^{2 is} hydrogen, C ₃ -C ₄ alkenyl or -CC ₆ alkyl, which is optionally substituted by halogen, hydroxy, -C-C ₂ alkoxy, pyridyl, cyano, phenoxy or benzyl,

R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,

wherein

R ⁸ Ci-C _ö alkylene, which is optionally substituted by halogen, -CC-alkoxycarbonyl, hydroxy, phenyl or heteroaryl, which in turn up to twice by halogen, hydroxy, Ci-C ₂ alkyl, Cj-C ₂ - Alkoxy or -CC ₃ - (alkoxy) carbonyl may be substituted, R ^{9 is} hydrogen, phenyl or heteroaryl or a Ci-Cjo

Alkyl radical which is optionally interrupted one to three times by oxygen, phenyl or heteroaryl optionally by halogen, hydroxyl, C ₁ -C ₂ -alkyl, C] -C - alkoxy or d-

C ₂ -alkoxycarbonyl are substituted and the Ci-Cio- alkyl radical is optionally substituted by halogen, hydroxy, -C-C ₄ - alkoxy, alkoxycarbonyl or by phenyl, which in turn is up to twice by halogen, hydroxy, Cι-C ₂ - alkyl, C 1 -C ₄ - alkoxy or C 1 -C ₄ - (alkoxy) carbonyl may be substituted,

X oxygen or sulfur

and

m means zero or 1

and - unless X = S - with the proviso that R ^{3 contains} either a) at least one hydroxyl group and 1 to 4 ether oxygen atoms or b) at least 2 to 4 ether oxygen atoms,

R ^{4 is} hydrogen,

mean,

and their salts.

3. Dihydropyrimidines according to claim 1, wherein R ¹ phenyl, which is optionally substituted up to twice, identically or differently, by substituents from the group fluorine, chlorine, bromine, iodine, hydroxyl, methyl, methoxy, trifluoromethoxy,

R ^{2 is} hydrogen or C _r C ₄ alkyl,

R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,

wherein

R ⁸ -CC alkylene, which is optionally substituted by fluorine, chlorine, hydroxy, CrC - alkoxy or by phenyl or heteroaryl, which in turn can be substituted by halogen, hydroxy, methyl or methoxy,

R ^{9 is} hydrogen, -CC ₈ alkyl, which is optionally interrupted up to twice by oxygen, phenyl or 5- to 6-membered heteroaryl, alkyl, phenyl and heteroaryl optionally being halogen, hydroxy, methyl or C ₁ -C ₃ -

Alkoxy are substituted,

X oxygen or sulfur

and

m means zero or 1

and - unless X = S - with the proviso that R contains either a) at least one hydroxyl group and 1 to 3 ether oxygen atoms or b) 2 to 3 ether oxygen atoms, R ^{4 is} hydrogen,

R ⁵ pyridyl or thiazolyl, which can be substituted up to twice the same or different by fluorine, chlorine, bromine, C] -C ₃ alkyl or Cι-C ₃ alkoxy,

mean,

and their salts.

4. Dihydropyrimidines according to claim 1, wherein

R ^{1 is} phenyl, which is optionally substituted up to twice the same or different by fluorine, chlorine, bromine, iodine, methyl or methoxy,

R ^{2 is} linear or branched -C ^ alkyl,

R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,

Wonn

R -CC ₄ alkylene, which by fluorine, chlorine, hydroxy or

Phenyl can be substituted, where the phenyl radical is optionally substituted by fluorine, chlorine, hydroxy, methyl or methoxy,

R ^{9 is} hydrogen, -CC ₆ - alkyl, which if necessary once

Oxygen is interrupted, phenyl or 5- to 6-membered heteroaryl, alkyl, phenyl and heteroaryl being are optionally substituted by fluorine, chlorine, hydroxyl or methoxy,

X oxygen or sulfur

and

m means zero or 1

and - unless X = S - with the proviso that R ^{3 is} either a) a

Contains hydroxyl group and one or two ether oxygen atoms or b) 2 ether oxygen atoms,

R, 4 hydrogen

and

mean,

and their salts.

5. Dihydropyrimidines according to claims 1 to 4, wherein R ^{5 represents} 2-pyridyl, which can be substituted by 1 to 2 fluorine atoms, or represents thiazolyl.

6. Dihydropyrimidines of Examples 8, 11, 24, 27, 33 and 38.

7. A process for the preparation of the dihydropyrimidines according to claims 1 to 6, after which [A] aldehydes of the formula

R -CHO (II),

wherein R ^{1 has} the meaning given in claims 1 to 5,

with amidines of the formula

wherein R has the meaning given in claims 1 to 6,

or with their salts

and compounds of the formula

R ³ -CO-CH ₂ -COOR ² (IV),

wherein R and R have the meanings given in claims 1 to 6,

implements or

[B] Compounds of the formula

COR ³

R, 1 ¹ _ _C - = C - / "(V),

^H \

COOR ² wherein R ¹ to R ^{3 have} the conditions specified in claims 1 to 6,

with amidines of the formula

wherein R ^{5 has} the meaning given in claims 1 to 6,

or with their salts or

[C] Aldehydes of the formula

R'-CHO (II),

wherein R ^{1 has} the meaning given in claims 1 to 6,

with compounds of the formula

R - C = C - COOR ²

I H (VI),

NH,

wherein R and R have the meanings given in claims 1 to 6,

and amidines of the formula (III) or with their salts or [D] aldehydes of the formula (II) with compounds of the formula (TV) and imino ethers of the formula (VII)

Wonn

R »5 has the meaning given in claims 1 to 6 and

R, 1 ^I 3 ^J represents C 1 -C ₄ alkyl,

in the presence of ammonium salts or

[E] if m in R ³ in formula (I) is zero, compounds of the formula

Wonn

R, R, R and R have the meanings given in claims 1 to 6, with compounds of the formula

HXR ⁹ (IX),

wherein X and R ^{9 have} the meanings given in claims 1 to 6, implemented.

8. Compounds of the formula

Wonn

R, R, R and R have the conditions specified in claims 1 to 6.

9. Compounds according to claims 1 to 6 for combating diseases.

10. Medicament containing at least one compound according to claims 1 to 6 and optionally further active pharmaceutical ingredients.

11. Use of compounds of claims 1 to 6 for the manufacture of a medicament for the treatment and prophylaxis of viral diseases.

12. Use of compounds of claims 1 to 6 for the manufacture of a medicament for the treatment and prophylaxis of hepatitis B infections.

13. Combinations

A) at least one dihydropyrimidine according to claims 1 to 6,

B) at least one HBV antiviral agent different from A and optionally

C) at least one immunomodulator.

14. Combinations according to claim 13, wherein component B is an HBV polymerase inhibitor.

15. Combinations according to claim 13, wherein component B is lamivudine.

16. Combinations according to claim 13, wherein component B consists of the compounds of the formula

Wonn

R ¹ and R ² independently of one another are C ¹ -C ₄ -alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms which comprise carbon and / or oxygen,

R> 3 - _π R12 are independently hydrogen, halogen, Cι-C ₄ - alkyl, optionally substituted CpC ₄ - alkoxy, nitro, cyano or trifluoromethyl,

R, 1 ¹ 3 ^J hydrogen, dC ₄ alkyl, -CC ₇ -acyl or aralkyl and

X halogen or optionally substituted -CC ₄ - alkyl

mean,

and whose salts are selected.

17. Combinations according to claim 16, wherein X is chlorine, A 1-piperidinyl and Y and Z are each phenyl.

18. Combinations according to claims 13 to 17, wherein the immunomodulator C contains interferons.

19. Combinations of A) dihydropyrimidines according to Claims 1 to 5, B) lamivudine and C) interferon.

20. A process for the preparation of the combinations according to claims 13 to 19, characterized in that components A and B are combined or prepared in a suitable manner.

21. Combinations according to claims 13 to 19 for combating diseases.

22. Medicament containing at least one combination according to claims 13 to 19 and optionally further active pharmaceutical ingredients.

23. Use of combinations of claims 13 to 19 for the manufacture of a medicament for the treatment and prophylaxis of viral diseases.

24. Use of combinations of claims 13 to 19 for the manufacture of a medicament for the treatment and prophylaxis of hepatitis B infections.