DE10012824A1 - New 6-hydroxyhydrocarbyl or 6-thiohydrocarbyl-dihydropyrimidine-5-carboxylic acid derivatives, useful for the treatment of viral infections, especially hepatitis B infections - Google Patents

Abstract

6-(Hydroxy- or thio-hydrocarbyl)-dihydropyrimidine-5-carboxylic acid derivatives are new. They can be prepared via new 6-bromomethyl-dihydropyrimidine-5-carboxylic acid derivatives. 6-(Hydroxy- or thio-hydrocarbyl)-dihydropyrimidine-5-carboxylic acid derivatives of formula (I), their isomers of formula (Ia) and salts, are new. R<1> = phenyl, furyl or thienyl (each optionally substituted with 1 or more halo, NO2, CN, OH, alkyl, CF3, alkoxy or OCF3); R<2> = H, or aliphatic or cyclic, saturated or unsaturated hydrocarbyl optionally containing 1 or 2 O, CO, NH, N(1-4C alkyl), S or SO2 and optionally substituted with halo, NO2, CN, OH, aryl, aralkyl, heteroaryl or NR<6>R<7>; R<6>, R<7> = H, benzyl or alkyl; or NR<6>R<7> = 5-6 membered ring optionally containing O; R<3> = -CH2-R<8>m-X-R<9>; R<8> = divalent, aliphatic or cyclic, saturated or unsaturated hydrocarbyl optionally substituted with 1 or more halo, N3, CN, OH, CO, COOH, alkoxycarbonyl, alkoxy, alkylthio, or aryl or heteroaryl (each optionally substituted); R<9> = H, aryl or heteroaryl (each optionally substituted), or aliphatic or c yclic, saturated or unsaturated hydrocarbyl optionally interrupted with 1-3 O and optionally substituted with 1 or more aryl, aryloxy, N3, CN, OH, COOH, alkoxycarbonyl, heteroaryl, alkoxy or alkylthio and/or with 1 -CO-R<10> or -NR<11>R<12>; R<10> = benzyl, phenyl or alkyl; R<11>, R<12> = H, aryl, aralkyl or alkyl optionally substituted with alkoxycarbonyl, OH, -NHCOCH3, -NHCOCF3, or phenyl or benzyl (each optionally substituted with 1 or more OH, COOH, alkyl or alkoxy); or NR<11>R<12> = morpholino. piperidino or pyrrolidino; X = O or S; m = 0 or 1; R<4> = H, alkyl, alkenyl, benzoyl or acyl; R<5> = pyridyl, optionally substituted with 1-3 Q or thiazolyl, thienyl or furyl (each optionally substituted with 1 or 2 Q); and Q = halo, OH, CN, alkyl, CF3, alkoxy, alkylthio, carbalkoxy, acyloxy, NH2, NO2, HN(alkyl) or N(alkyl)2; provided that R<3> contains 1 OH and 1 ether oxygen or at least 2 ether oxygen atoms when X = O. Independent claims are also included for: (1) preparation of (I) and (Ia); (2) 6-bromomethyl-dihydropyrimidine-5-carboxylic acid intermediates of formula (VIII); and (3) combinations containing: (a) compound(s) (I) and/or (Ia); (b) hepatitis B virus (HBV) antiviral agent(s) other than compounds (I) and (Ia); and (c) immunomodulator(s).

Description

The present invention relates to new dihydropyrimidines, processes for their Production and pharmaceuticals containing these dihydropyrimidines, in particular for the treatment and prophylaxis of hepatitis B virus infections. The invention also affects combinations of these dihydropyrimidines with other antivirals Agents and, if appropriate, immunomodulators and medicaments containing them Combinations, especially for the treatment and prophylaxis of HBV infections like hepatitis B.

The hepatitis B virus belongs to the Hepadna virus family. It causes an acute one and / or a persistent-progressive, chronic illness. Diverse others Clinical manifestations in the clinical picture are caused by the hepatitis B virus causes - especially chronic inflammation of the liver, cirrhosis and hepato cellular carcinoma. Furthermore, co-infection with the hepatitis delta virus negatively affect 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 none desired side effects; Lamivudine is effective, but under treatment Resistance develops rapidly and after therapy is discontinued in most cases there is a rebound effect.

From EP-PS 103 796 dihydropyrimidines are known, one of which is the circulation influencing effect is attributed. In EP-A 169 712 sub substituted dihydropyrimidines described as intermediates that lead to the ent speaking pyrimidines can be oxidized. WO 99/1438 relates to dihydro pyrimidine, which is used for the treatment of cerebrovascular ischemia and Pain should be suitable. WO 99/54312, 99/54326 and 99/54329 relate Dihydropyrimidines, which are suitable for the treatment and prophylaxis of hepatitis.  

The present invention relates to dihydropyrimidines of the formula

or their isomeric form

wherein
R ^{1 is} 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 ^{2 is} hydrogen, a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical, which optionally has one or two identical or different hetero chain links from the group -O-, -CO-, -NH-, -N (C ₁ -C ₄ 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 ,
wherein
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 optionally contains oxygen,
R ^{3 is} a group of the formula -CH ₂ -R ⁸ _m -XR ⁹ ,
wherein
R ^{8 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
and / or which can be substituted by a group of the formula -CO-R ¹⁰ or -NR ¹¹ R ¹² ,
wherein
R ¹⁰ benzyl, phenyl or alkyl,
R ¹¹ and R ¹² independently of one another are hydrogen, aryl, aralkyl or are alkyl which is optionally substituted by alkoxycarbonyl, hydroxyl, phenyl or benzyl, phenyl or benzyl optionally one or more times, identically or differently, by hydroxyl, carboxyl, alkyl or Alkoxy is substituted, or alkyl is optionally substituted by -NH- CO-CH ₃ or -NH-CO-CF ₃ ,
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 - 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 can be substituted up to three times the same or different by halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy, amino, nitro, mono- or dialkylamino, or thiazolyl, thienyl or furyl, which may be substituted up to twice the same or different by halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy, amino, nitro, mono- or dialkylamino,
and their salts.

Preferred compounds of the formulas (I) or (Ia) according to the invention are those in which
R ^{1 is} phenyl, furyl or thienyl, where these ring systems may be substituted one or two times, identically or differently, by substituents from the group halogen, hydroxy, methyl, C ₁ -C ₂ alkoxy, trifluoromethoxy,
R ^{2 is} hydrogen, C ₃ -C ₄ alkenyl or C ₁ -C ₆ alkyl, which is optionally substituted by halogen, hydroxy, C ₁ -C ₂ alkoxy, pyridyl, cyano, phenoxy or benzyl,
R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,
wherein
R ^{8 is} C ₁ -C ₆ alkylene, which is optionally substituted by halogen, C ₁ -C ₄ alkoxy carbonyl, hydroxy, phenyl or heteroaryl, which in turn is up to two times substituted by halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₃ alkoxycarbonyl may be substituted,
R ^{9 is} hydrogen, phenyl or heteroaryl or a C ₁ -C ₁₀ alkyl radical which is optionally interrupted one to three times by oxygen, phenyl or heteroaryl optionally being substituted by halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ -alkoxy or C ₁ -C ₂ -alkoxycarbonyl are substituted and the C ₁ -C ₁₀ -alkyl radical is optionally substituted by halogen, hydroxy, C ₁ -C ₄ -alkoxy, alkoxycarbonyl or by phenyl, which in turn is up to two times substituted by halogen , Hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkoxycarbonyl 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,
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 ₁ -C ₄ alkyl,
R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,
wherein
R ^{8 is} C ₁ -C ₄ alkylene which is optionally substituted by fluorine, chlorine, hydroxy, C ₁ -C ₂ alkoxy or by phenyl or heteroaryl, which in turn can be substituted by halogen, hydroxy, methyl or methoxy,
R ^{9 is} hydrogen, C ₁ -C ₈ -alkyl, which is optionally interrupted up to twice by oxygen, phenyl or 5- to 6-membered hetero aryl, alkyl, phenyl and heteroaryl optionally being substituted by halo, 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 ^{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 is} 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 C ₁ -C ₃ alkoxy,
mean,
and their salts.

Compounds according to the invention of the formulas (I) or (Ia) in which
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 linear or branched C ₁ -C ₄ alkyl,
R ^{3 is} the group -CH ₂ -R ⁸ _m -XR ⁹ , wherein
R ^{8 is} C ₁ -C ₄ 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, C ₁ -C ₆ -alkyl, which is optionally interrupted once by oxygen, phenyl or 5- to 6-membered heteroaryl, alkyl, phenyl and heteroaryl optionally being 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 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.

Compounds of the formula (I) or (Ia) in which R ^{5 is} 2-pyridyl, which can be substituted by 1 to 2 fluorine atoms, or thiazolyl are particularly preferred.

Acyl and the acyl part of acyloxy mean one in the context of the invention linear or branched acyl radical with 1 to 6, preferably 1 to 4 carbon atoms, such as B. acetyl and propionyl.

In the context of the invention, alkyl represents a linear or branched alkyl radical with 1 to 6 carbon atoms, such as. B. methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. A linear or branched alkyl radical with up to is preferred 4 carbon atoms.

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

In the context of the invention, alkenyl stands for a linear or branched Alkenyl radical with 2 to 5, preferably 3 to 5 carbon atoms, such as. B. ethenyl, Propenyl, allyl, n-pentenyl and n-hexenyl.  

In the context of the invention, alkoxy represents a linear or branched alkoxy radical with 1 to 6, preferably 1 to 4 carbon atoms, such as. B. methoxy, ethoxy and Propoxy.

Alkoxycarbonyl stands for a linear or branched in the context of the invention Alkoxycarbonylrest with 1 to 6, preferably 1 to 4 carbon atoms, such as. B. 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 residues, a.

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

In the context of the invention, aralkyl stands for aralkyl with preferably 6 to 10, especially 6 carbon atoms in the aryl part (preferably phenyl or naphthyl, especially phenyl) and preferably 1 to 4, in particular 1 or 2 carbon atoms in the alkyl part, where the alkyl part can be linear or branched. Preferred Aralkyl radicals are benzyl and phenethyl.

In the context of the invention, heteroaryl also stands for 5- to 7-membered rings 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, Thiazolyl, isothiazolyl, pyrrolyl, pyridyl, pyrimidinyl and pyrazinyl.

The compounds according to the invention can exist in stereoisomeric forms 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. The Racemfor Like the diastereomers, they can be introduced into the ste in a manner known per se Separate the reoisomerically uniform constituents.

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

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

Physiologically acceptable salts can be salts of inorganic or organic Be acids. Salts of inorganic acids such as, for example, are preferred Hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts organic carboxylic or sulfonic acids such as 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 compounds of the invention. Z are particularly preferred. B. sodium, Potassium, magnesium or calcium salts and ammonium salts, which are available from Ammo niac or organic amines, such as ethylamine, di- or triethylamine,  Di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, Lysine, ethylenediamine or 2-phenylethylamine are derived.

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

• 1. [A] aldehydes of the formula
  R ¹ -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),
  in which R ² and R ^{3 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
• 2. [B] compounds of the formula
  in which R ¹ to R ^{3 have} the meanings given above,
  with amidines of the formula
  where R ^{5 has} the meaning given above,
  or with their salts (e.g. 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
• 3. [C] aldehydes of the formula
  R ¹ -CHO (II),
  where R ^{1 has} the meaning given above,
  with compounds of the formula
  in which R ² and R ^{3 have} the meanings given above,
  and amidines of the formula (III) or with their salts (such as, for example, hydrochlorides or acetates) with or without addition of base or acid, preferably at temperatures from 20 to 150 ° C., if appropriate in the presence of inert organic solvents, or
• 4. [D] aldehydes of the formula (II) with compounds of the formula (IV) and imino ethers of the formula (VII)
  wherein
  R ^{5 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
• 5. [E] if m in R ^{3 of} the formula (I) is zero, compounds of the formula
  

where R ¹

, R ²

, R ⁴

and R ⁵

have the meanings given above,
with compounds of the formula

HXR ⁹ (IX),

wherein X and R ^{9 have} the meanings given above,
with or without addition of base or acid, 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 method according to the invention can be exemplified by the following formula scheme:

For all process variants A, B, C, D and E, all inert solvents are used organic solvents in question. 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 hexamethylphos phosphoric triamide.

The reaction temperatures can be varied over a wide range. in the generally one works at temperatures of 20 to 150 ° C, but preferably at the boiling point of the respective solvent.

The reaction can be carried out at normal pressure, but also at elevated pressure become. 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 e.g. B. acetic acid or formic acid.

The aldehydes (II) used as starting materials are known or can be based on methods known from the literature are produced [cf. T. D. Harris and G. P. Roth, J. Org. Chem. 44, 146 (1979), DE-OS 21 65 260, 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 found in the literature known methods are produced [cf. G. Jones, "The Knoevenagel Conden sation "in Organic Reactions, Vol. XV, 204 ff. (1967)].

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

The β-ketocarboxylic acid esters (IV) used as starting materials are known or can be prepared by methods known from the literature [e.g. B. D. Borrmann,  "Conversion of diketene with alcohols, phenols and mercaptans" into "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 of the invention show a valuable, unpredictable Effect against viruses. They are surprisingly antiviral to hepatitis B Viruses (HBV) take effect by causing an extraordinarily strong reduction in DNA of intra- and extracellular hepatitis B viruses. The fiction moderate connections are thus for the treatment of virus-induced crane kung, especially acute and chronic persistent viral infections of HBV suitable. Chronic viral disease caused by HBV can lead to differently severe clinical pictures; the chro is known to lead African hepatitis B virus infection in many cases for liver cirrhosis and / or hepatocellular carcinoma.

As indication areas for the compounds according to the invention, for example be called wise:

Treatment of acute and chronic viral infections that result in a infectious hepatitis, such as infections with hepatitis B Viruses. The compounds according to the invention are particularly suitable for treatment 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) Di above hydropyrimidines (I) or (Ia) and B) at least one HBV different from A antiviral agent.  

A particular embodiment of the invention relates to combinations of A) above dihydropyrimidines (I) and (Ia), B) HBV polymerase inhibitors and against also C) immunomodulators.

Such substances are HBV polymerase inhibitors B in the sense of the invention referred to in the endogenous polymerase assay described below, by Ph. A. Furman et al. in Antimicrobial Agents and Chemotherapy, Vol. 36 (No. 12), 2688 (1992) has been published to inhibit the formation of an HBV DNA Double strand lead such that there is a maximum of 50% of the activity of the zero value result in:

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 [α- ³² P] deoxynucleoside 5'-triphosphate into the 3.2 kb viral DNA product is observed in the presence and absence of a substance with potentially HBV polymerase inhibitory properties. 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 ¼ volume of an aqueous solution containing 50% by weight of 8000 polyethylene glycol and 0.6 M sodium chloride. The virions are sedimented by centrifugation at 2,500 x g / 15 minutes. The sediments are resuspended in 2 ml of buffer containing 0.05 M Tris-HCl (pH 7.5) and dialyzed against the same buffer containing 100 mM 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); 300 mM potassium chloride; 50 mM 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 added to a final concentration of 1% by volume (based on total volume) and Proteinase K is added to a final concentration of 1 mg / ml added. 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 resuspended in 10 ul gel buffer (solution of 10.8 g Tris, 5.5 g boric acid and 0.75 g EDTA in 1 liter water (= TBE buffer)) 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 the Southern transfer technique. Then the amount of the DNA double strand formed and labeled in relation to the negative control (= endo-pole reaction without substance or with control substance without effect) is 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-amino-1 - [(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 5 204 466);
Adefovir dipivoxil = 9- {2 - [[bis [(pivaloyloxy) methoxy] phosphinyl] methoxy] ethyl} adenine, cf. EP-PS 481 214 (= US-PS 5 663 159 and 5 792 756), US-PS 4 724 233 and 4 808 716;
BMS 200 475 = [1S- (1.α, 3.α, 4.β)] - 2-amino-1.9-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 = (-) - (1S-cis) -4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-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] pyrimidine-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;
β-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-β-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) above dihydropyrimidines (I) or (Ia) and B) lamivudine.

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

wherein
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 to R ¹² independently of one another are hydrogen, halogen, C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, nitro, cyano or trifluoromethyl,
R ^{13 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₇ acyl or aralkyl and
X halogen or optionally substituted C ₁ -C ₄ alkyl
mean,
and their salts.

These phenylpropenamides and processes for their preparation are from WO 98/33501 known, to which reference is hereby made for the purpose of disclosure becomes. AT-61 is the compound of the above formula wherein X is chlorine, A 1-piperidinyl and Y and Z each represent 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) the 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. Sci. 84, 1005-1009 (1987) and B.E. Korba et al., Antiviral Research 19, 55-70 (1992) described methods examined.

The antiviral tests were carried out in 96-well microtiter plates. The first vertical row of plate received only growth medium and HepG2.2.15 cells. she 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 pipetted into a test concentration of 100 μM (1st test concentration) in each case in the second vertical test series of the microtiter plate and then diluted 2 ¹⁰ -fold in growth medium plus 2% by weight 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 (5 × 10 ⁴ cells / ml) in growth medium plus 2% by weight of fetal 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 were given 225 µl freshly prepared growth medium. The verb according to the invention Each was again made up as a 10-fold concentrated solution in one volume of 25 µl added. The batches were incubated for a further 4 days.

Before harvesting the supernatants to determine the antiviral effect, the HepG2.2.15 cells under light microscopy or by means of biochemical detection drive (e.g. Alamar blue staining or trypan blue staining) to cytotoxic ver changes examined.  

The supernatants and / or cells were then harvested and by means of vacuum on 96-well dot-blot chambers covered with nylon membrane (corresponding to the Manufacturer information) sucked.

Determination of cytotoxicity

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

The tolerance of some of the compounds of the invention has become additional on other host cells such as B. HeLa cells, primary peripheral blood cells of the Human or transformed cell lines such as H-9 cells.

There were no cytotoxic changes at concentrations of the inventions compounds of <10 µM according to the invention can be determined.

Determination of the antiviral effect

After transfer of the supernatants or lysed cells to the nylon membrane of the Blot apparatus (see above) were the intra- or extracellular supernatants of the HepG2.2.15 cells denatured (1.5 M NaCl / 0.5 N NaOH), neutralized (3 M NaCl / 0.5 M Tris HCl, pH 7.5) and washed (2 × SSC). Then the Baked DNA to the membrane by incubating the filters at 120 ° C for 2-4 hours.

Hybridization of the DNA

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 are performed, each by manufacturer was marked with digoxigenin, purified and used for hybridization the.

Prehybridization and hybridization were carried out in 5 × SSC, 1 × blocking rea genz, 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 one 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 Manufacturer information:

The filters were washed and in a blocking reagent (by manufacturer information) pre-hybridized. Subsequently, an anti-DIG antibody, the was coupled with alkaline phosphatase, hybridized for 30 minutes. After one The alkaline phosphatase substrate, CSPD, was added to the washing step, 5 Incubated for minutes with the filters, then wrapped in plastic wrap and white Incubated for 15 minutes at 37 ° C. The chemiluminescence of hepatitis B specific DNA signals were obtained by exposing the filter to an X-ray film made visible (incubation depending on signal strength: 10 minutes to 2 hours).

The half-maximum inhibitory concentration (IC ₅₀ , 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, besides not toxic, inert pharmaceutically suitable excipients one or more verbin extensions (I) or (Ia) or a combination according to the invention. included or the from  one or more active ingredients (I) or (Ia) or from an inventive Combination exist.

The active ingredients (I) and (Ia) should be in the pharmaceutical preparations listed above tions in a concentration of about 0.1 to 99.5 wt .-%, preferably of about 0.5 to 95 wt .-% of the total mixture may be present.

The pharmaceutical preparations listed above can be used in addition to the verbin dungen (I) or (Ia) also contain other active pharmaceutical ingredients.

The quantitative ratio of components A, B and optionally C of the Invention appropriate combinations can fluctuate 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 may also be used, may be present in quantities of wise 1 to 10 million, especially 2 to 7 million IU (international units), about three times a week for up to a year.

The compounds or combinations according to the invention are shown in the above pharmaceutical preparations in general in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture be there.

The preparation of the pharmaceutical preparations listed above can be based on usual way by known methods, e.g. B. by mixing the active ingredient (s) with the carrier or carriers.

In general, it has been found in both human and veterinary medicine proven advantageous, the active ingredient (s) according to the invention in total amounts from about 0.5 to about 500, preferably from 1 to 100 mg / kg body weight per 24th  Hours, if necessary in the form of several individual doses, to achieve the ge to deliver the desired results. A single dose contains the effect substances preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg Body weight. However, it may be necessary from the dosages mentioned deviate, 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 the application of the drug, as well as 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 several other pharmaceutical active ingredient (s).

Another object of the invention is the use of the verb defined above and combinations in the manufacture of a medicament for treatment and prophylaxis of the diseases described above, preferably virus viruses diseases, especially hepatitis B.

The percentages in the examples below relate, unless otherwise stated specified, each by weight. The ratios of solvents to solvents 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 concentration with a water jet pump, the mixture 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 of methanol is mixed with a sodium methylate solution of 0.40 g (17.391 mmol) of sodium and 65 ml of 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-1-oxide (Johnson et al., J. Chem. Soc. B, 1967, 1211) in 80 ml of dichloromethane is successively mixed with 21.8 ml ( 0.174 mol) of trimethylsilyl cyanide and 14.6 ml (0.158 mol) of dimethylcarbamic acid chloride were added and the mixture was stirred at room temperature for 48 hours. 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 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 combined under nitrogen and stirred for 24 hours at reflux. 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 and then with an 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) of potassium fluoride and 10 g of polyethylene glycol 8000 are mixed with 125 ml of DMSO and at 160 ° C. for 30 minutes heated. 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.
R _f 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 the solvent has been stripped off, 23.6 g (39.1%) of 3,5-difluoro-2-pyridinecarboximidamide hydrochloride (mp: 183 ° C.) remain.
¹ H-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-fluorobenzaldehyde and 36.6 g (315 mmol) methyl acetoacetate in 150 ml isopropanol is mixed with 1.7 ml Piperidine acetate added. After stirring overnight at room temperature Diluted dichloromethane, shaken with water and the organic phase over Dried sodium sulfate and concentrated. The product is raw as a cis / trans mixture implemented further.

Example VIII

Methyl isopropoxyacetoacetate

8 g (200 mmol) of 60% sodium hydride in mineral oil are placed under argon in 150 ml THF suspended and with a solution of 6.01 g (100 mmol) of isopropanol in 50 ml THF added dropwise with gentle cooling. After stirring for 1 hour  becomes a solution of 15.06 g (100 mmol) methyl chloroacetoacetate in 50 ml THF added dropwise, the temperature being allowed to rise to 45 ° C. It gets over night stirred, mixed dropwise with ice cooling with 100 ml of 10% acetic acid and freed from THF under reduced pressure. The residue is in dichloromethane added, the resulting solution with saturated aqueous sodium chloride Solution shaken out, the organic phase dried and concentrated. The Reini Solution is carried out on a silica gel column with toluene / ethyl acetate mixtures. You get 10.2 g (58.6%) colorless oil.

Example IX

4- (2-Bromo-4-fluorophenyl) -6-bromomethyl-2- (3,5-difluoropyridin-2-yl) -1,4-dihydropyrimidine-5-carboxylic acid methyl ester

A solution of 1.8 g (4.089 mmol) of 4- (2-bromo-4-fluorophenyl) -2- (3,5-difluoro pyridin-2-yl) -1,4-dihydro-6-methyl-pyrimidin-5-carboxylic acid methyl ester in 50 ml Dichloromethane is mixed with 0.8 g (4.5 mmol) of N-bromosuccinimide for 2 hours Heated to a gentle boil, cooled and concentrated. After rough cleaning a silica gel column gives 1.4 g (66%) of slightly yellow crystals of melting point 115-116 ° C.

B. Production examples

example 1

4- (2-Chloro-4-fluorophenyl) -2- (3-fluoropyridin-2-yl) -6-methoxy-ethoxymethyl-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

A mixture of 317 mg (2 mmol) 2-chloro-4-fluorobenzaldehyde, 20 ml Isopro panol, 380 mg (2 mmol) methyl 4-methoxyethoxyacetoacetate, 351 mg (2 mmol) 2-amidino-3-fluoropyridine hydrochloride and 164 mg (82 mmol) sodium acetate is stirred for 16 hours with gentle boiling, then cooled and constricted. The residue is dissolved in ethyl acetate; the solution becomes more aqueous Washed 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) from the melting point 122 ° C.  

Example 2

Methyl 4- (2,4-dichlorophenyl) -2- (3,5-difluoropyridin-2-yl) -1,4-dihydro-6- (4-pyridylthiomethyl) pyrimidine-5-carboxylic acid

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

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

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

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

Claims (24)

1. Dihydropyrimidines of the formula
or their isomeric form
wherein
R ^{1 is} 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 ^{2 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 ₁ -C ₄ -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 ,
wherein
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 optionally contains oxygen,
R ^{3 is} a group of the formula -CH ₂ -R ⁸ _m -XR ⁹ ,
wherein
R ^{8 is} a double-bonded linear, branched or cyclic, saturated or unsaturated hydrocarbon radical, optionally one or more times, 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
and / or which can be substituted by a group of the formula -CO-R ¹⁰ or -NR ¹¹ R ¹² ,
wherein
R ¹⁰ benzyl, phenyl or alkyl,
R ¹¹ and R ¹² independently of one another denote hydrogen, aryl, aralkyl or alkyl, which is optionally substituted by alkoxycarbonyl, hydroxyl, phenyl or benzyl, phenyl or benzyl optionally one or more times, identically or differently by hydroxyl, carboxyl, Alkyl or alkoxy is substituted, or alkyl is optionally substituted by -NH- CO-CH ₃ or -NH-CO-CF ₃ ,
or
R ¹¹ and R ¹² together with the nitrogen atom on which they stand form a morpholinyl, 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 can be up to three times the same or different from halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy, amino, nitro, mono- or di-alkylamino substituted,
or thiazolyl, thienyl or furyl, which can be substituted up to twice the same or different by halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy, amino, nitro, mono- or dialkylamino,
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 halogen, hydroxy, methyl, C ₁ -C ₂ -alkoxy, trifluoromethoxy,
R ^{2 is} hydrogen, C ₃ -C ₄ alkenyl or C ₁ -C ₆ alkyl, which is optionally substituted by halogen, hydroxy, C ₁ -C ₂ alkoxy, pyridyl, cyano, phenoxy or benzyl,
R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,
wherein
R ^{8 is} C ₁ -C ₆ alkylene, which is optionally substituted by halogen, C ₁ -C ₄ alkoxycarbonyl, hydroxy, phenyl or heteroaryl, which in turn is up to two times substituted by halogen, hydroxy, C ₁ - C ₂ alkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₃ alkoxycarbonyl may be substituted,
R ^{9 is} hydrogen, phenyl or heteroaryl or a C ₂ -C ₁₀ alkyl radical which is optionally interrupted one to three times by oxygen, phenyl or heteroaryl optionally being halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ -alkoxy or C ₁ - C ₂ -alkoxycarbonyl are substituted and the C ₁ -C ₁₀ -alkyl radical is optionally substituted by halogen, hydroxy, C ₁ -C ₄ -alkoxy, alkoxycarbonyl or by phenyl, which in turn is substituted up to twice by Halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkoxycarbonyl 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,
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. 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 ₁ -C ₄ alkyl,
R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,
wherein
R ^{8 is} C ₁ -C ₄ alkylene which is optionally substituted by fluorine, chlorine, hydroxy, C ₁ -C ₂ alkoxy or by phenyl or heteroaryl, which in turn can be substituted by halogen, hydroxy, methyl or methoxy,
R ^{9 is} hydrogen, C ₁ -C 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 ^{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 is} 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 C ₁ -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 linear or branched C ₁ -C ₄ alkyl,
R ³ the group -CH ₂ -R ⁸ _m -XR ⁹ ,
wherein
R ^{8 is} C ₁ -C ₄ 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, C ₁ -C ₆ -alkyl, which is optionally interrupted once by oxygen, phenyl or 5- to 6-membered heteroaryl, alkyl, phenyl and heteroaryl optionally being 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 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. 5. Dihydropyrimidines according to Claims 1 to 4, in which 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

• 1. [A] aldehydes of the formula
  R ¹ -CHO (II),
  wherein R ^{1 has} the meaning given in claims 1 to 5,
  with amidines of the formula
  wherein R ^{5 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),
  in which R ² and R ^{3 have} the meanings given in claims 1 to 6,
  implements or
• 2. [B] compounds of the formula
  wherein R ¹ to R ^{3 have} the meanings given 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
• 3. [C] aldehydes of the formula
  R ¹ -CHO (II),
  wherein R ^{1 has} the meaning given in claims 1 to 6,
  with compounds of the formula
  in which R ² and R ^{3 have} the meanings given in claims 1 to 6,
  and reacting amidines of the formula (III) or with their salts or
• 4. [D] aldehydes of the formula (II) with compounds of the formula (IV) and imino ethers of the formula (VII)
  wherein
  R ^{5 has} the meaning given in Claims 1 to 6 and
  R ^{13 represents} C ₁ -C ₄ alkyl,
  in the presence of ammonium salts or
• 5. [E] if m in R ³ in formula (I) is zero, compounds of the formula
  wherein
  R ¹ , R ² , R ⁴ and R ^{5 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 be implemented.

8. Compounds of the formula
wherein
R ¹ , R ² , R ⁴ and R ^{5 have} the meanings given 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 other 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 is. 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
wherein
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 -R ¹² independently of one another are hydrogen, halogen, C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, nitro, cyano or trifluoromethyl,
R ^{13 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₇ acyl or aralkyl and
X halogen or optionally substituted C ₁ -C 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 mean. 18. Combinations according to claims 13 to 17, wherein the immunomodulator C interferons contains.   19. Combinations of A) dihydropyrimidines according to Claims 1 to 5, B) lamivudine and C) Interferon. 20. A method for producing the combinations according to claims 13 to 19, characterized characterized in that components A and B are combined in a suitable manner or prepares. 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 other active pharmaceutical ingredients. 23. Use of combinations of claims 13 to 19 for producing a Medicinal product for the treatment and prophylaxis of viral diseases. 24. Use of combinations of claims 13 to 19 for the manufacture of a Medicinal product for the treatment and prophylaxis of hepatitis B infections.