DE10012549A1 - New heterocyclic-substituted dihydropyrimidine derivatives useful for treatment of viral infections, especially hepatitis B infections - Google Patents

Abstract

Heterocyclic-substituted dihydropyrimidine derivatives are new. Heterocyclic-substituted dihydropyrimidine derivatives of formula (I), their isomers of formula (Ia) and salts are new. [Image] R1>-R3>H, halo, CN, 1-6C alkyl, 1-6C alkoxy or NO2; R4>aliphatic hydrocarbyl with up to 8C optionally containing 1 or 2 O, S and/or NR7> and optionally substituted with 1 or 2 OH, 1-6C alkoxy, imidazolyl, tetrazolyl and/or NR8>R9>; R7>H or 1-6C alkyl; R8>, R9>H, or 1-4C alkoxy or 1-6C alkyl (each optionally substituted with OH, CF3 or phenyl); or NR8>R9>mono- or bicyclic ring containing 2-10C (the hydrocarbyl chain is optionally interrupted with 1 or more O, NR1>0>, CO, S, SO or SO2 and optionally substituted with 1 or more OH, 1-6C alkyl, 1-6C hydroxyalkyl and/or halo); R1>0>H, or 1-6C alkyl or 3-8C cycloalkyl (each optionally substituted with OH or phenyl), 1-6C acyl, 1-6C alkoxycarbonyl, or 6-10C aryl or 5 or 6 membered heteroaryl (both optionally substituted with halo, 1-6C alkyl or 1-6C alkoxy); R5>pyridyl, thiazolyl, oxazolyl, furyl or thienyl (each optionally substituted with 1-3 halo, OH, CN, CF3, 1-6C alkoxy, 1-6C alkyl, 1-6C alkylthio, 1-6C acyloxy, NH2, NO2, HN(1-6C alkyl) and/or N(1-6C alkyl)2; R6>5-7 membered, aromatic or partly unsaturated heterocycle containing up to 4 N, O and/or S optionally carrying a fused benzene ring on 2 adjacent C atoms and optionally substituted with 1 or 2 NH2 and/or 1-6C alkyl. Independent claims are also included for: (1) preparation of compounds (I) and (Ia) by; (a) cyclization of a dihydropyrimidine carboxamide of formula (X) with a dehydrating agent; (b) reaction of an optionally substituted benzaldehyde of formula (II) with a beta -ketoester of formula (III), reaction of the resulting substituted beta -ketoester of formula (IV) with an amidine of formula R5>C(=NH)NH2 (V) or its salt, de-esterifying the dihydropyrimidine carboxylic acid ester obtained with a base or F ions, reacting the resulting dihydropyrimidine carboxylic acid of formula (VII) with N,N-carbonyldiimidazole, reacting the dihydropyrimidinyl imidazolyl ketone of formula (VIII) with an amine of formula Z-A-NH2 (IX) and cyclizing the dihydropyrimidine carboxamide (X) with a dehydrating agent; or (c) reaction of a heterocyclic-substituted methyl-dihydropyrimidine derivative of formula (XIII) with a brominating agent and reaction of the resulting heterocyclic-substituted bromomethyl-dihydropyrimidine derivative with an amine of formula HNR8>R9>. (2) heterocyclic-substituted bromomethyl-dihydropyridine derivatives of formula (XIV); and (3) combinations containing: (i) compound(s) (I) and/or (Ia); (ii) hepatitis B virus (HBV) antiviral agent(s) other than compounds (I) and (Ia); and (iii) immunomodulator(s). [Image] [Image] [Image] Z : OH or -C(L)-R1>1>; R1>1>H, NH2 or 1- 6C alkyl; L : O, S or NH; A : -NH-, -CH2CH2- or -CH2CH2-O-; and X : CN or (CH3)3Si. - ACTIVITY : Virucide. The activity of compounds (I) and (Ia) against hepatitis B virus was determined by the methods described in Proc. Natl. Acad. Sci. 84, 1005-1009 (1987) and Antiviral Research 19, 55-70 (1992). 4-(2-Chloro-4-fluorophenyl)-6-morpholino-5-(1,3,4-oxadiazol-2-yl)-2-( 1,3-thiazol-2-yl)-1,4-dihydropyrimidine (I) displayed an IC50 value of 100 nM. - MECHANISM OF ACTION : None given.

Description

The present invention relates to new heterocyclically substituted dihydro pyrimidines, processes for their preparation and medicaments containing them Dihydropyrimidines especially for the treatment and prophylaxis of hepatitis B Virus infections. The invention also relates to combinations of these dihydro pyrimidines with other antiviral agents and possibly immunomodulators as well as drugs containing these combinations, in particular for treatment and prophylaxis of HBV infections such as 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. WO 99/54312, 99/54326 and 99/54329 relate to dihydropyrimidines, which are useful for the treatment and prophylaxis of Hepatitis.

The present invention relates to new compounds of the formula

or their isomeric form

wherein
R ¹ to R ³ independently of one another are hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ - C ₄ -alkoxy or nitro,
R ^{4 is} a straight-chain or branched hydrocarbon radical having up to 8 carbon atoms, which may contain one or two identical or different hetero chain links from the groups O, S and NR ⁷ and which may be mono- or discrete, identical or different, by hydroxyl, C ₁ -C ₆ alkoxy, imidazolyl, tetrazolyl or a radical of the formula -NR ⁸ R ^{9 is} substituted,
wherein
R ^{7 represents} hydrogen or C ₁ -C ₆ alkyl and
R ⁸ and R ⁹ independently of one another denote hydrogen, C ₁ -C ₄ alkoxy or C ₁ -C ₆ alkyl, which in turn can be substituted by hydroxy, trifluoromethyl or phenyl,
or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a mono- or bicyclic ring with 2 to 10 carbon atoms, in which the carbon chain is one or more, identical or different, by -O-, -NR ¹⁰ -, -CO-, -S-, -SO- or -SO ₂ - may be interrupted and is optionally substituted singly or multiply, identically or differently, by hydroxy, C ₁ -C ₆ alkyl, hydroxy-substituted C ₁ -C ₆ alkyl or halogen is substituted,
in which
R ^{10 is} hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, which in turn can be substituted by hydroxy or phenyl,
or
C ₁ -C ₆ acyl or C ₁ -C ₆ alkoxycarbonyl or
C ₆ -C ₁₀ aryl or 5- to 6-membered heteroaryl, which in turn can be substituted by halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy,
R ⁵ pyridyl, thiazolyl, oxazolyl, furyl or thienyl, which are identical or different up to three times by halogen, hydroxy, cyano, trifluoromethyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ - Alkylthio, C ₁ -C ₆ acyloxy, amino, nitro, mono- or di-C ₁ -C ₆ alkylamino can be substituted, and
R ^{6 is} a 5- to 7-membered, partially unsaturated or aromatic heterocycle with up to 4 heteroatoms from the series N, O and / or S, in which a benzene ring can be fused onto two adjacent ring carbon atoms and which may be one to two times , identical or different, is substituted by amino or C ₁ -C ₆ alkyl,
mean,
as well as their salts.

Compounds of the formula (I) are preferred
wherein
R ¹ to R ³ independently of one another are hydrogen, fluorine, chlorine, bromine, cyano, C ₁ -C ₄ -alkyl, methoxy, ethoxy or nitro,
R ^{4 is} a straight-chain or branched hydrocarbon radical having up to 6 carbon atoms, which optionally contains a hetero chain link from the series O, S and NR ⁷ and which is optionally substituted by hydroxyl, C ₁ -C ₄ alkoxy, imidazolyl or a radical of the formula -NR ⁸ R ^{9 is} substituted,
wherein
R ^{7 represents} hydrogen, methyl or ethyl and
R ⁸ and R ⁹ independently of one another denote hydrogen, C ₂ -C ₄ alkoxy or C ₁ -C ₄ alkyl, which in turn can be substituted by hydroxy or trifluoromethyl,
or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a mono- or bicyclic ring with 3 to 7 carbon atoms, in which the carbon chain is mono- or discrete, identical or different, by -O-, -NR ¹⁰ -, -CO- or -S- can be interrupted, and which is optionally substituted one or more times, identically or differently, by hydroxy, C ₁ -C ₄ alkyl or hydroxy-substituted C ₁ -C ₄ alkyl,
in which
R ^{10 is} hydrogen, C ₁ -C ₄ alkyl, which may be substituted by hydroxy or phenyl, or C ₃ -C ₆ cycloalkyl, formyl, acetyl or C ₁ -C ₄ alkoxycarbonyl or phenyl, pyridyl or pyrimidinyl, which in turn can be substituted by halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy,
R ⁵ pyridyl, which can be substituted up to twice the same or different by fluorine, chlorine, bromine, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkyl, or thiazolyl, which in turn by fluorine, chlorine, bromine or C ₁ -C ₄ alkyl may be substituted, and
R ^{6 is} a 5- to 6-membered, partially unsaturated or aromatic heterocycle having up to 3 heteroatoms from the series N, O and / or S, which is optionally substituted by amino or C ₁ -C ₄ -alkyl,
mean,
as well as their salts.

Compounds of the formula (I) are particularly preferred
wherein
R ¹ to R ³ independently of one another are hydrogen, fluorine or chlorine,
R ^{4 is} a straight-chain or branched hydrocarbon radical having up to 4 carbon atoms, which optionally contains an oxygen atom as a hetero chain link and / or is optionally substituted by hydroxy, C ₁ -C ₃ -alkoxy or a radical of the formula -NR ⁸ R ⁹ ,
wherein
R ⁸ and R ⁹ independently of one another are hydrogen, ethoxy, propoxy or C ₁ -C ₄ -alkyl, which in turn are optionally substituted by hydroxy or trifluoromethyl,
or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a radical of the formula

form,
wherein
a zero or 1 and
YO, S or NR ¹⁰ mean in which
R ^{10 represents} hydrogen or C ₁ -C ₄ alkyl,
R ⁵ pyridyl, which can be substituted up to twice the same or different by fluorine or chlorine, or thiazolyl,
R ^{6 is} a 5-membered aromatic heterocycle with up to 3 heteroatoms from the series N, O and / or S, which is optionally substituted by amino or C ₁ -C ₄ alkyl,
mean,
as well as their salts.

Compounds of the formula (I) are very particularly preferred
wherein
R ¹ to R ³ independently of one another are hydrogen, fluorine or chlorine,
R ^{4 is} methyl or ethyl, which are optionally substituted by hydroxy, methoxy, ethoxy, 2-methoxyethyl or a radical of the formula -NR ⁸ R ⁹ ,
wherein
R ⁸ and R ⁹ independently of one another are hydrogen, ethoxy, methyl or ethyl, which in turn are optionally substituted by hydroxy or trifluoromethyl, or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a radical of the formula

form,
wherein
YO or NR ¹⁰ and
R ^{10 is} hydrogen or methyl,
R ⁵ pyridyl, which is substituted up to twice the same or different by fluorine or chlorine, or thiazolyl, and
R ^{6 is} a 1,2,4-oxadiazole, 1,3,4-oxadiazole or 1,3,4-thiadiazole ring, which may each be substituted by amino or methyl,
mean,
as well as their salts.

Halogen generally represents fluorine, chlorine, bromine and Iodine, preferably fluorine, chlorine and bromine, especially fluorine and chlorine.

In the context of the invention, C ₁ -C ₆ alkyl and C ₁ -C ₄ alkyl represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, tert. -Butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred.

In the context of the invention, C ₁ -C ₆ alkoxy and C ₁ -C ₄ alkoxy represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, tert. -Butoxy, n-pentoxy and n-hexoxy. A straight-chain or branched alkoxy radical having 1 to 4, in particular 1 to 3, carbon atoms is preferred.

In the context of the invention, C ₁ -C ₆ -acyl represents a straight-chain or branched acyl radical having 1 to 6 carbon atoms, such as, for example, formyl, acetyl, propionyl, n-butyryl, isobutyryl and n-hexanoyl. Formyl and acetyl are preferred.

In the context of the invention, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₄ alkoxycarbonyl represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, which is linked via a carbonyl group, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and n-hexoxycarbonyl. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred.

In the context of the invention, C ₁ -C ₆ -acyloxy represents a straight-chain or branched acyl radical having 1 to 6 carbon atoms which is linked via an oxygen atom, such as, for example, acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy .

In the context of the invention, C ₁ -C ₆ -alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms, such as, for example, methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

In the context of the invention, mono- and di-C ₁ -C ₆ -alkylamino stand for an amino group with one straight-chain or branched or two identical or different straight-chain or branched alkyl substituents each having 1 to 6 carbon atoms, such as methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-tert.- Butyl-N-methylamino, N, N-diisopropylamino and N-ethyl-Nn-pentylamino.

In the context of the invention, C ₃ -C ₈ cycloalkyl and C ₃ -C ₆ cycloalkyl stand for a cycloalkyl radical having 3 to 8 or 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

In the context of the invention, C ₆ -C ₁₀ aryl represents an aromatic radical having 6 to 10 carbon atoms. Phenyl is preferred.

5- to 6-membered heteroaryl in the context of the invention represents a 5- to 6-membered group third aromatic ring containing 1 to 4 heteroatoms from the series N, O and / or S. contains. Examples include: pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, Thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl and Pyridazinyl. Pyridyl and pyrimidinyl are preferred.

A 5- to 7-membered, partially unsaturated or aromatic heterocycle with bis for 4 heteroatoms from the series N, O and / or S stands for in the context of the invention a 5- to 7-membered heterocycle which contains 1 to 4 heteroatoms selected from N, O and / or S contains, via a ring carbon atom (with the dihydropyrimidine ring) is linked and which is aromatic or one or more double bonds may contain. Examples include: pyridyl, furyl, thienyl, pyrrolyl, Pyrrolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, dihydro oxazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, dihydrooxazolyl, dihydro isoxazolyl, dihydrodioxazinyl, imidazolyl, imidazolinyl, triazolyl, tetrazolyl,  Oxadiazolyl, thiadiazolyl, dihydrothiazolyl, dihydropyridinyl, azepinyl, diazepinyl. Preferred are thienyl, pyridyl, triazolyl, 5,6-dihydro-1,4,2-dioxazinyl, oxadiazolyl, Thiadiazolyl, 4,5-dihydro-1,3-oxazolyl and 4,5-dihydro-1,3-thiazolyl.

Physiologically acceptable salts of the compounds according to the invention can Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfone be acids. Z are particularly preferred. B. salts with hydrochloric acid, bromine hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfone acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, Propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or Benzoic acid.

The compounds of the invention can, depending on the substitution patterns in stereoisomeric forms that are either like image and mirror image (Enantiomers) or that do not behave like image and mirror image (diastereomers), exist. The invention relates to both the enantiomers and the diastereomes ren and their respective mixtures. The racemic shapes can be just like that Diastereomers in a known manner into the stereoisomerically uniform constituents separate.

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

• 1. [A] aldehydes of the formula
  wherein
  R ¹ to R ^{3 have} the meanings given above,
  with β-keto esters of the formula
  wherein
  R ^{4 has} the meaning given above and
  X represents a cyano or trimethylsilyl group,
  with or without addition of base or acid, optionally in the presence of inert organic solvents, to give compounds of the formula
  implements
  this then 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, if appropriate in the presence of inert organic solvents, to give compounds of the formula
  reacting
  then the ester grouping with a base or with fluoride ions, optionally in the presence of inert organic solvents, to give carboxylic acids of the formula
  splits,
  this then by means of N, N'-carbonyldiimidazole with or without base addition, if appropriate in the presence of inert organic solvents in imidazolides of the formula
  convicted,
  hereinafter with compounds of the formula
  ZA-NH ₂ (IX),
  wherein
  Z represents hydroxy or a radical of the formula
  stands,
  wherein
  R ^{11 is} hydrogen, amino or C ₁ -C ₆ alkyl and
  Mean LO, S or NH and
  A represents a group of the series -NH-, -CH ₂ CH ₂ - or -CH ₂ CH ₂ O-,
  with or without added base, optionally in the presence of inert organic solvents, preferably at temperatures from 0 ° C. to 120 ° C., to give compounds of the formula
  implements
  and finally cyclized them in the presence of a dehydrating agent, such as, for example, phosphorus oxychloride or phosphorus pentoxide, optionally in the presence of inert organic solvents, or
• 2. [B] compounds of the formula
  in which R ⁴ and R ^{6 have} the meanings given above,
  in a one-step process with aldehydes of the formula (II) and amidines of the formula (V) or their salts (such as, for example, hydrochlorides or acetates) with or without addition of base or acid, if appropriate in the presence of inert organic solvents, or
• 3. [C] compounds of the formula (XI) with aldehydes of the formula (II) in a two-stage process first, with or without addition of base or acid, optionally in the presence of inert organic solvents, in compounds of the formula
  in which R ¹ to R ⁴ and R ^{6 have} the meanings given above,
  transferred and then reacted with amidines of the formula (V) or their salts (such as, for example, hydrochlorides or acetates) with or without addition of base or acid, if appropriate in the presence of inert organic solvents, preferably at temperatures from 20 to 150 ° C. or
• 4. [D] if R ⁴ in formula (I) is a methyl group substituted by NR ⁸ R ⁹ , compounds of the formula
  (which can be produced using process variants [A], [B] or [C]),
  in which R ¹ to R ³ , R ⁵ and R ^{6 have} the meanings given above,
  with a brominating agent such as N-bromosuccinimide, optionally in the presence of inert solvents in compounds of the formula
  transferred and then with compounds of the formula
  in which R ⁸ and R ^{9 have} the meanings given above,
  with or without an auxiliary base, if appropriate in the presence of inert solvents.

The methods according to the invention can be exemplified by the following schemes are explained:  

Method A

DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene
TBAF = tetrabutylammonium fluoride
CDI = N, N'-carbonyldiimidazole

Method B

Method C

Method D

For all process variants [A], [B], [C] and [D] all come under Reaction conditions of inert organic solvents in question. This includes for example halogenated hydrocarbons such as dichloromethane, chloroform, Carbon tetrachloride, trichloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as Diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or Diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, Isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitro methane, glacial acetic acid, ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide, Acetonitrile, pyridine or hexamethylphosphoric triamide and mixtures thereof. Preferred for process variants [A] (II) - <(IV) - <(VI), [B] and [C] Alcohols such as methanol, ethanol, n-propanol or isopropanol. In the Process variant [D] are halogenated hydrocarbons such as dichloromethane, Chloroform, carbon tetrachloride or 1,2-dichloroethane are preferred.

The reaction temperatures can be varied within a wide range. In general, one works between 0 ° C and 150 ° C, but preferably in Range from room temperature to the boiling point of the respective solvent.

The reactions can be carried out at normal pressure, but also at elevated pressure be led; generally one works under normal pressure.

The reactions can be carried out with or without addition of base or acid become; However, in particular with the process variants [A] (II) - <(IV) - <(VI), [B] and [C] showed that implementations within the meaning of the invention preferably in the presence of weaker acids, such as. B. acetic acid or Formic acid, or in the presence of weaker bases, such as. B. sodium acetate, or with a combination of both, e.g. B. piperidine acetate take place.

The aldehydes (II) used as starting materials are known or can be based on methods known from the literature are produced [cf. T. D. Harns and G. P. Roth, J.  Org. Chem. 44, 146 (1979); DE-OS 21 65 260 and 24 01 665; Mijano et al., Chem. Abstr. 59, 13,929c (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 β-ketocarboxylic acid esters (III) 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", in "Methods of organic chemistry "(Houben-Weyl), Vol. VII / 4, 230ff (1968); Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].

Some of the compounds (V) are known or can be used as in WO-A-99/54326 and WO-A-99/54329.

The compounds (XI) used as starting materials are known or can are produced by methods known from the literature [e.g. B. Chem. Ber. 90, 2683 (1957); J. Org. Chem. 58, 4474 (1993)].

The compounds (IX) and (XV) are known or by customary methods producible.

One embodiment of the invention relates to combinations of A) above Dihydropyrimidines (I) or (Ia) and B) at least one different from A. HBV antiviral agent.

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

Areas of indication for the compounds according to the invention include:
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.

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 potential 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 (pH 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 admitted. 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% 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 the 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 results are as follows for some compounds of the invention Listed table as an example:

table

Treatment of the HepGits 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.

The compounds according to the invention show an unforeseeable effect against viruses. They are surprisingly antiviral against hepatitis B viruses (HBV) effective by having an extremely strong reduction intra- and / or cause extracellular HBV DNA. The compounds of the invention are thus for the treatment of virus-induced diseases, especially acute  and chronic persistent viral infections of HBV. A chronic one Viral disease caused by HBV can lead to different degrees of severity Cause clinical pictures; is known to cause chronic hepatitis B Virus infection in many cases to liver cirrhosis and / or hepatocellular Carcinoma.

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) are intended in the pharmaceuticals listed above Preparations in a concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight of the total mixture.

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 and B of the combination according to the invention nations 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 1 to 10 million, in particular 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 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.  

Examples

Abbreviations: DMSO = dimethyl sulfoxide, THF = tetrahydrofuran

The percentages in the following examples relate unless otherwise stated specified, each by weight. The mixing ratios of solvents in solvent mixtures refer to volume.

A. Starting compounds

example 1

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 2

2-cyano-3-fluoropyridine

5.20 g (45.980 mmol) of the compound from Example 1 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; solidifies on standing).
Column chromatography: methylene chloride to methylene chloride / ethyl acetate (10: 1).

Example 3

2-amidino-3-fluoropyridine hydrochloride

A solution of 10.30 g (84.355 mmol) of the compound from Example 2 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 (pulverized) 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, taken up with acetone and concentrated again, then stirred with acetone, suction filtered and washed.
Yield: 10.6 g.
Mp .: ≈ 150 ° C (decomposition).

Example 4

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 NaHCO ₃ 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 R. Troschuetz 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 added together under nitrogen and stirred under reflux for 24 hours. A further 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 are then added, and the mixture is stirred at reflux for a further 89 hours 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 aqueous NaHCO ₃ 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 5

2-cyano-3,5-difluoropyridine

50 g (0.29 mol) of 2-cyano-3,5-dichloropyridine from Example 4, 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 the organic phase is dried over sodium sulfate. The product is further implemented in the form of the toluene solution.
R _f value: 0.43 (cyclohexane / ethyl acetate = 7: 3).

Example 6

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 5 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 7

2-thiazole carboximidamide hydrochloride

To a methanolate solution prepared from 4.5 g of sodium (0.2 mol) and 220 ml of methanol, 22.9 g (0.21 mol) of 2-cyanothiazole (J. Chem. Soc. C, 1967, p 17) and stirred for two days at room temperature. It is suctioned off from inorganic salts, concentrated, crystallized with a little acetone and the product is suctioned off. 17.4 g (51%) of 2-amidino-thiazole hydrochloride are obtained.
Mp: 188 ° C (decomposed).
R _f value: 0.26 (ethyl acetate / methanol / water / concentrated ammonia = 6: 3: 0.5: 0.05).

Example 8

2-cyanoethyl (E / Z) -2-acetyl-3- (2-chloro-4-fluorophenyl) -2-propenoate

A solution of 30 g (189.2 mmol) of 2-chloro-4-fluoro-benzaldehyde and 29.36 g (189.2 mmol) of 2-cyanoethyl-3-oxobutanoate in 50 ml of isopropanol is mixed with 1.3 ml of piperidine and 1.2 ml glacial acetic acid added. After stirring overnight at room temperature, the solvent is stripped off and the residue is chromatographed on silica gel with cyclohexane / ethyl acetate as the eluent (50: 1; 30: 1; 2: 1). The product is used as a cis / trans mixture.
Yield: 38 g (67.9%).
R _f value = 0.18 (cyclohexane / ethyl acetate 4: 1).

Example 9

2- (trimethylsilyl) ethyl (E / Z) -2-acetyl-3- (2-chloro-4-fluorophenyl) -2-propenoate

Preparation analogous to Example 8 from 13.5 g (66.7 mmol) of 2- (trimethylsilyl) ethyl 3-oxobutanoate and 10.58 g (66.7 mmol) of 2-chloro-4-fluoro-benzaldehyde.
Yield 20.4 g (89.2%).
R _f value = 0.35 (cyclohexane / ethyl acetate = 4: 1).

Example 10

2- (trimethylsilyl) ethyl (E / Z) -3- (3-chloro-4-fluorophenyl) -2- (3-methoxypropanoyl) -2-propenoate

Preparation analogous to Example 8 from 11.3 g (46 mmol) of 2- (trimethylsilyl) ethyl-5- methoxy-3-oxo-pentanoate and 7.29 g (46 mmol) of 3-chloro-4-fluoro-benzaldehyde.

Yield: 11.6 g (65.2%).
R _f value = 0.31 (cyclohexane / ethyl acetate = 4: 1).

Example 11

(E / Z) -3- (1,3-benzothiazol-2-yl) -4- (2-chloro-4-fluorophenyl) -3-buten-2-one

Preparation analogous to Example 8 from 1.21 g (6.3 mmol) of 1-benzothiazol-2-yl-propan-2-one (Lit .: Chem. Ber. 90 (1957), 2683-2687) and 1.0 g (6.3 mmol) 2-chloro-4-fluorobenzaldehyde.
Yield: 1.23 g (58.84%).
R _f value = 0.57 (cyclohexane / ethyl acetate = 4: 1).
Mp .: 90 ° C.

Example 12

(E / Z) -4- (2-chloro-4-fluorophenyl) -3- (2-thienyl) -3-buten-2-one

Representation analogous to Example 8 from 500 mg (3.6 mmol) of 1-thiophen-2-yl-propan-2-one and 570 mg (3.6 mmol) of 2-chloro-4-fluorobenzaldehyde.
Yield: 260 mg (25.74%).
R _f value = 0.6 (cyclohexane / ethyl acetate = 4: 1).

Example 13

2- (trimethylsilyl) -ethyl-4- (2-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6-methyl-1,4-dihydro-5-pyrimidinecarboxylate

5 g (14.6 mmol) of the benzylidene compound from Example 9 and 2.82 g (14.6 mmol) of 3,5-difluoro-2-pyridinecarboximidamide hydrochloride from Example 6 are combined with 1.44 g (17.5 mmol) sodium acetate boiled under reflux in 100 ml of isopropanol for 3 hours. It is evaporated, the residue is taken up in ethyl acetate and washed with water. The organic phase is evaporated and the residue is purified by chromatography on silica gel with cyclohexane / ethyl acetate (4: 1; 2: 1).
Yield: 3.98 g (56.6%).
Mp .: 116 ° C.

Example 14

2-Cyanoethyl-4- (2-chloro-4-fluorophenyl) -2- (3-fluoro-2-pyridinyl) -6-methyl-1,4-dihydro-5-pyrimidinecarboxylate

Representation analogous to Example 13 from 12.3 g (41.7 mmol) of the benzylidene compound from Example 8 and 7.32 g (41.7 mmol) of 3-fluoro-2-pyridineimidamide hydrochloride from Example 3.
Yield: 2.2 g (12.7%).
Mp: 208 ° C.

Example 15

2-Cyanoethyl 4- (2-chloro-4-fluorophenyl) -2- (2-thiazolyl) -6-methyl-1,4-dihydro-5-pyrimidinecarboxylate

Representation analogous to Example 13 from 12.42 (42 mmol) of the benzylidene compound from Example 8 and 6.87 g (42 mmol) of 2-thiazolecarboximdamide hydrochloride from Example 7.
Yield: 5.2 g (30.6%).
R _f value = 0.28 (cyclohexane / ethyl acetate 1: 1).

Example 16

2- (trimethylsilyl) ethyl-4- (3-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6- (2-methoxyethyl) -1,4-dihydro-5- pyrimidine carboxylate

Representation analogous to Example 13 from 2.0 g (5.17 mmol) of the benzylidene compound from Example 10 and 1.0 g (5.17 mmol) of 3,5-difluoro-2-pyridinecarboximidamide hydrochloride from Example 6.
Yield: 1.46 g (53.7%).
R _f value = 0.77 (cyclohexane / ethyl acetate = 1: 1).

Example 17

4- (2-chloro-4-fluorophenyl) -2- (2-thiazolyl) -6-methyl-1,4-dihydro-5-pyrimidinecarboxylic acid

6.7 g (16.55 mmol) of the cyanoethyl ester from Example 15 and 33.1 ml (33.1 mmol) of 1N sodium hydroxide solution are stirred in 300 ml of THF for 1 hour at room temperature. The mixture is evaporated and the residue is partitioned between ethyl acetate and water. The aqueous phase is separated off, neutralized with 2N hydrochloric acid and extracted twice with ethyl acetate. After drying over sodium sulfate, the mixture is evaporated and the residue is reacted without further purification.
Yield: 4.8 g (82.44%).
R _f value = 0.27 (petroleum ether / ethyl acetate = 1: 1).

Example 18

4- (2-chloro-4-fluorophenyl) -2- (3-fluoro-2-pyridinyl) -6-methyl-1,4-dihydro-5-pyrimidinecarboxylic acid

Representation analogous to Example 17 from 3.25 g (7.8 mmol) of the cyanoethyl ester from Example 14.
Yield: 1.78 g (62.84%).
Mp .: 180 ° C (decomposition).

Example 19

4- (2-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6-methyl-1,4-dihydro-5-pyrimidinecarboxylic acid

8.2 g (17 mmol) of the trimethylsilylethyl ester from Example 13 and 4.89 g (18.7 mmol) of tetrabutylammonium fluoride are stirred in 210 ml of THF overnight at room temperature. The approach is evaporated. Flash chromatography on silica gel with cyclohexane / ethyl acetate (20: 1; 10: 1) first elutes 1.8 g of the starting substance and then with methylene chloride / methanol (30: 1) the product.
Yield: 5 g (7.7%).
R _f value = 0.31 (dichloromethane / methanol = 10: 1).

Example 20

4- (3-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6- (2-methoxy-ethyl) -1,4-dihydro-5-pyrimidinecarboxylic acid

Representation analogous to Example 19 from 8.35 g (15.87 mmol) of the trimethylsilyl ethyl ester from Example 16 and 4.56 g (17.4 mmol) of tetrabutylammonium fluoride.
Yield: 4.3 g (63, 64).

Example 21

[4- (2-chloro-4-fluorophenyl) -2- (2-thiazolyl) -6-methyl-1,4-dihydro-5-pyrimidinyl] - (1H-imidazol-1-yl) methanone

2.3 g (6.5 mmol) of the carboxylic acid from Example 17 and 1.27 g (7.85 mmol) of carbonyl diimidazole are stirred in 100 ml of THF at room temperature overnight. The batch is evaporated, the residue is taken up in ethyl acetate and washed three times with water and once with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the mixture is evaporated and reacted further without further purification.
Yield: 2.5 g (95.2%).
Mp .: 110 ° C.

Example 22

[4- (2-chloro-4-fluorophenyl) -2- (3-fluoro-2-pyridinyl) -6-methyl-1,4-dihydro-5-pyrimidinyl] - (1H-imidazol-1-yl) - methanone

Representation analogous to Example 21 from 1.78 g (4.9 mmol) of the carboxylic acid from Example 18 and 0.95 g (5.87 mmol) of carbonyldiimidazole.
Yield: 1.44 g (71.14%).
R _f value = 0.44 (dichloromethane / methanol = 10: 1).

Example 23

[4- (2-Chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6-methyl-1,4-dihydro-5-pyrimidinyl] - (1H-imidazol-1-yl ) -methanone

Representation analogous to Example 21 from 1.35 g (3.5 mmol) of the carboxylic acid from Example 19 and 0.69 g (4.2 mmol) of carbonyldiimidazole.
Yield: 0.85 g (55.7%).
R _f value = 0.38 (methylene chloride / methanol = 10: 1).

Example 24

[4- (3-Chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6- (2-methoxyethyl) -1,4-dihydro-5-pyrimidinyl] - (1H -imidazol-1-yl) methanone

Representation analogous to Example 21 from 4.8 g (11.2 mmol) of the carboxylic acid from Example 20 and 2.19 g (13.5 mmol) carbonyldiimidazole.

Yield: 4.68 g (87.2%).

R _f value = 0.4 (dichloromethane / methanol = 10: 1).

Example 25

4- (2-chloro-4-fluorophenyl) -2- (2-thiazolyl) -6-methyl-1,4-dihydro-5-pyrimidinecarbohydrazide

0.25 g (0.62 mmol) of the imidazolide from Example 21 and 0.31 g (6.2 mmol) of hydrazine hydrate are refluxed in 20 ml of acetonitrile overnight. After cooling, 20 ml of dichloromethane and 20 ml of dilute hydrochloric acid are added and the mixture is stirred for 10 minutes. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with petroleum ether / ethyl acetate (4: 1) (removal of a by-product), then dichloromethane / methanol (30: 1) (product).
Yield: 128 mg (56.2%).
R _f value = 0.35 (dichloromethane / methanol = 10: 1).
Mp .: 100 ° C.

The carboxylic acid compiled in Table 1 is analogous to Example 25 hydrazides or amides from the corresponding imidazolides from Examples 21 to 24 and the corresponding hydrazines or amines.

Table 1

B. Production examples

Example I

3- [4- (2-chloro-4-fluorophenyl) -6-methyl-2- (1,3-thiazol-2-yl) -1,4-dihydro-5-pyrimidinyl] -5,6-dihydro- 1,4,2-dioxazine

50 mg (0.12 mmol) of the carboxamide from Example 27 and 1 ml of phosphorus oxychloride are stirred at 50 ° C. for 5 hours. Saturated aqueous NaHCO ₃ solution is added and the mixture is extracted twice with ethyl acetate. The organic phase is dried with sodium sulfate and evaporated. The product is purified by flash chromatography on silica gel with dichloromethane / methanol (100: 1) as the eluent.
Yield: 20 mg (41.8%).
Mp: 195 ° C.

The dioxazines in Table 2 are prepared in an analogous manner.  

Table 2

Example V

4- (2-chloro-4-fluorophenyl) -6-methyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) - 2- (1,3-thiazol-2-yl) - 1,4-dihydropyrimidine

100 mg (0.273 mmol) of the carboxylic acid hydazide from Example 28 and 40 mg (0.3 mmol) of ethyl acetimidate hydrochloride are refluxed in 5 ml of pyridine for 4 hours. It is evaporated, the residue is taken up in ethyl acetate and washed with 1N hydrochloric acid and then with saturated aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated.
Yield: 100 mg (93.8%).
R _f = 0.7 (dichloromethane / methanol = 10: 1).

The 5-methyl-oxadiazoles listed in Table 3 are prepared in an analogous manner manufactured. The enantiomers are separated by chromatographic separation Racemates on chiral stationary polyamide-silica gel phases, as described in EP-A 379 917 are obtained with n-heptane / toluene mixtures as the eluent.  

Table 3

Example VIII

4- (2-chloro-4-fluorophenyl) -6-methyl-5- (1,3,4-oxadiazol-2-yl) -2- (1,3-thiazol-2-yl) -1,4- dihydropyrimidine

20 mg (0.051 mmol) of the carboxylic acid hydrazide from Example 29 and 28.8 mg (0.2 mmol) of phosphorus pentoxide are stirred for 48 hours at room temperature in 5 ml of dichloromethane. It is shaken out with water and the organic phase is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with dichloromethane / methanol (50: 1).
Yield: 12 mg (62.9%).
R _f value = 0.61 (dichloromethane / methanol = 20: 1).

Example IX

4- (2-chloro-4-fluorophenyl) -6-methyl-5- (1,3,4-thiadiazol-2-yl) -2- (1,3-thiazol-2-yl) -1,4- dihydropyrimidine

Preparation from the carboxylic acid hydrazide from Example 29 and phosphorus pentasulfide in an analogous manner to Example VIII.
Yield: 77.6%.
R _f value = 0.52 (dichloromethane / methanol = 10: 1).

Example X

5- [4- (2-chloro-4-fluorophenyl) -6-methyl-2- (1,3-thiazol-2-yl) -1,4-dihydro-5-pyrimidinyl] -1,3,4- oxadiazol-2-amine

45 mg (0.11 mmol) of the carboxylic acid hydrazide from Example 31 and 169 mg (1.1 mmol) of phosphorus oxytrichloride are stirred at 60 ° C. overnight. The mixture is poured onto ice water, made slightly alkaline with 1N sodium hydroxide solution and extracted twice with dichloromethane. After drying with sodium sulfate, the organic phase is evaporated and the residue is purified by flash chromatography on silica gel with dichloromethane / methanol (100: 1, then 50: 1).
Yield: 6 mg (14%).
R _f value = 0.48 (dichloromethane / methanol = 10: 1).

The oxa and thia diazole manufactured. The enantiomers are separated by chromatographic separation on chiral stationary polyamide-silica gel phases, as described in EP-A 379 917 are obtained with n-heptane / toluene mixtures as the eluent.  

Table 4

Example XVI

4- (2-chloro-4-fluorophenyl) -5- (4,5-dihydro-1,3-oxazol-2-yl) -6-methyl-2- (1,3-thiazol-2-yl) - 1,4-dihydropyrimidine

100 mg (0.253 mmol) of the carboxamide from Example 33 and 1.94 g (12.7 mmol) of phosphorus oxytrichloride are stirred in 10 ml of 1,2-dichloroethane at 60 ° C. overnight. The mixture is evaporated, the residue is taken up in dichloromethane, shaken with saturated aqueous sodium hydrogen carbonate solution, and the organic phase is evaporated. The residue is purified by flash chromatography on silica gel with dichloromethane / methanol (50: 1) as the eluent.
Yield: 85 mg (89.0%).
Mp: 203 ° C.

Example XVII

4- (2-chloro-4-fluorophenyl) -5- (4,5-dihydro-1,3-oxazol-2-yl) -6-methyl-2- (3,5-difluoropyridin-2-yl) - 1,4-dihydropyrimidine

Preparation from the carboxamide from Example 44 as in Example XVI.
Yield: 29.0%.
R _f value = 0.69 (dichloromethane / methanol = 10: 1).

Example XVIII

4- (2-chloro-4-fluorophenyl) -6-methyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -2- (3-fluoropyridin-2-yl) -1, 4-dihydropyrimidine

1.5 g (10.7 mmol) of 1- (3-methyl-1,2,4-oxadiazol-5-yl) propan-2-one [Lit .: Monthly Journal Chemie 113 (1982), 781-792] , 1.7 g (10.7 mmol) of 2-chloro-4-fluorobenzaldehyde and 1.88 g (10.7 mmol) of 3-fluoro-2-pyridinecarboximidamide hydrochloride from Example 3 are combined with 0.88 g (10th , 7 mmol) boiled for 5 hours in 60 ml of iso propanol under reflux. 17 ml of 1N hydrochloric acid and 100 ml of ethyl acetate are then added to the batch, and the organic phase is separated off. The organic phase is extracted again with 17 ml of 1N hydrochloric acid. The combined aqueous phases are washed twice with 30 ml of diethyl ether, made alkaline with 40% sodium hydroxide solution and extracted with 50 ml of ethyl acetate. After drying the ethyl acetate phase with sodium sulfate, the mixture is evaporated and the residue is purified by chromatography on silica gel with cyclohexane / ethyl acetate (1: 1).
Yield: 400 mg (9.3%).
R _f value = 0.20 (cyclohexane / ethyl acetate = 1: 1).

The oxadiazoles listed in Table 5 are obtained in an analogous manner from the corresponding carboximidamides of Examples 6 and 7.  

Table 5

Example XXI

4- (2-chloro-4-fluorophenyl) -2- (3-fluoro-2-pyridinyl) -6-methyl-5- (5-methyl-1,2,4-oxadiazol-3-yl) -1, 4-dihydropyrimidine

Preparation analogous to Example XVIII from 1- (5-methyl-1,2,4-oxadiazol-3-yl) propan-2-one (Lit .: Monthly Bulletin Chemistry 113 (1982), 793-804), 2-chloro 4-fluorobenzaldehyde and 3-fluoro-2-pyridinecarboximidamide hydrochloride from Example 3.
Yield: 11.6%.
R _f value = 0.16 (cyclohexane / ethyl acetate = 1: 1).

Example XXII

4- (2-chloro-4-fluorophenyl) -2- (1,3-thiazol-2-yl) -6-methyl-5- (5-methyl-1,2,4-oxadiazol-3-yl) - 1,4-dihydropyrimidine

Preparation analogous to Example XXI with 2-thiazolecarboximidamide from Example 7.
Yield: 17.9%.
R _f value = 0.38 (cyclohexane / ethyl acetate = 1: 1).

Example XXIII

2- [4- (2-Chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6-methyl-1,4-dihydro-5-pyrimidinyl] -1,3-benzothiazole

100 mg (0.3 mmol) of the benzylidene compound from Example 11, 88 mg (0.45 mmol) of 3,5-difluoropyridinecarboximidamide hydrochloride from Example 6 and 30 mg (0.36 mmol) of sodium acetate are mixed in 10 ml for 5 hours Boiled isopropanol under reflux. It is evaporated and the residue is purified by flash chromatography on silica gel with cyclohexane / ethyl acetate (10: 1; 4: 1).
Yield: 100 mg (70.4%).
R _f value = 0.46 (cyclohexane / ethyl acetate = 2: 1).

Example XXIV

4- (2-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6-methyl-5- (2-thienyl) -1,4-dihydropyrimidine

Preparation analogous to Example XXIII from the benzylidene compound from Example 12 and 3,5-difluoropyridinecarboximidamide hydrochloride from Example 6.
Yield: 28.1%.
R _f value = 0.5 (cyclohexane / ethyl acetate = 2: 1).

Example XXV

4- (2-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6-methyl-5- (2-pyridinyl) -1,4-dihydropyrimidine

Preparation analogous to Example XVIII from 2-pyridylacetone (Lit .: J. Org. Chem. 58, 16 (1993), 4474-4478), 2-chloro-4-fluorobenzaldehyde and 3,5-difluoropyridineimidamide. Hydrochloride from example 6.

Example XXVI

6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -5- (1,3,4-oxadiazol-2-yl) -1, 4-dihydropyrimidine

0.5 g (1.23 mmol) of the oxadiazole from Example XII are boiled in 10 ml of dichloromethane under reflux, and 0.24 g (1.35 mmol) of N-bromosuccinimide are added at the boiling point. After 30 minutes, the mixture is cooled to room temperature, filtered and evaporated. The residue is purified by flash chromatography on silica gel with cyclohexane / ethyl acetate (9: 1, 4: 1, 1: 1) as the eluent.
Yield: 306 mg (51.2%).
R _f value = 0.5 (cyclohexane / ethyl acetate = 1: 1).

Example XXVII

6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (1,3-thiazol-2-yl) -5- (1,3,4-oxadiazol-2-yl) -1, 4-dihydropyrimidine

Preparation analogous to Example XXVI from the oxadiazole of Example VIII.
Yield: 42.5%.
R _f value = 0.59 (cyclohexane / ethyl acetate = 1: 1).

Example XXVIII

4- (2-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6 - [(4-methylpiperazino) methyl] -5- (1,3,4-oxadiazole-2 -yl) -1,4-dihydropyrimidine

20 mg (0.041 mmol) of the bromomethyl compound XXVI and 9 mg (0.092 mmol) of 1-methylpiperazine are stirred in 5 ml of dichloromethane overnight at room temperature. It is shaken out with 10 ml of saturated aqueous sodium hydrogen carbonate solution, the organic phase is dried with sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with dichloromethane / methanol (5: 1) as the eluent.
Yield: 17 mg (53.1%).

R _f = 0.45 (dichloromethane / methanol = 10: 1).

The compounds listed in Table 6 are obtained in an analogous manner the two bromomethyl compounds XXVI and XXVII and the corresponding Amines made.

Table 6

Claims (24)

1. Compounds of the formula
or their isomeric form
wherein
R ¹ to R ³ independently of one another are hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy or nitro,
R ^{4 is} a straight-chain or branched hydrocarbon radical with up to. 8 carbon atoms, which optionally contains one or two identical or different hetero chain links from the group O, S and NR ⁷ and which optionally one or two times, the same or different, by hydroxy, C ₁ -C ₆ alkoxy, imidazolyl, tetrazolyl or a radical of the formula -NR ⁸ R ^{9 is} substituted,
wherein
R ^{7 represents} hydrogen or C ₁ -C ₆ alkyl and
R ⁸ and R ⁹ independently of one another are hydrogen, C ₁ -C ₄ alkoxy or C ₁ - C ₆ alkyl, which in turn can be substituted by hydroxy, trifluoromethyl or phenyl,
or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a mono- or bicyclic ring with 2 to 10 carbon atoms in which the carbon chain is one or more, identical or different, by -O-, -NR ¹⁰ -, -CO-, -S-, -SO- or -SO ₂ - can be interrupted and optionally one or more times, the same or different, by hydroxy, C ₁ -C ₆ alkyl, hydroxy-substituted C ₁ -C ₆ alkyl or halogen is substituted,
in which
R ^{10 is} hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, which in turn can be substituted by hydroxy or phenyl,
or
C ₁ -C ₆ acyl or C ₁ -C ₆ alkoxycarbonyl or
C ₆ -C ₁₀ aryl or 5- to 6-membered heteroaryl, which in turn can be substituted by halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy,
R ⁵ pyridyl, thiazolyl, oxazolyl, furyl or thienyl, which are up to three times the same or different by halogen, hydroxy, cyano, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ -Alkylthio, C ₁ -C ₆ -acyloxy, amino, nitro, mono- or di-C ₁ -C ₆ -alkylamino can be substituted, and
R ^{6 is} a 5- to 7-membered, partially unsaturated or aromatic heterocycle with up to 4 heteroatoms from the N, O and / or S series, in which a benzene ring can be fused on via two adjacent ring carbon atoms and which may be mono- or disubstituted, identical or different, is substituted by amino or C ₁ -C ₆ alkyl,
mean,
as well as their salts. 2. Compounds according to claim 1, wherein
R ¹ to R ³ independently of one another are hydrogen, fluorine, chlorine, bromine, cyano, C ₁ -C ₄ -alkyl, methoxy, ethoxy or nitro,
R ^{4 is} a straight-chain or branched hydrocarbon radical having up to 6 carbon atoms, which optionally contains a hetero chain link from the series O, S and NR ⁷ and which is optionally substituted by hydroxyl, C ₁ -C ₄ alkoxy, imidazolyl or a radical of the formula -NR ⁸ R ^{9 is} substituted,
wherein
R ^{7 represents} hydrogen, methyl or ethyl and
R ⁸ and R ⁹ independently of one another are hydrogen, C ₂ -C ₄ alkoxy or C ₁ -C ₄ alkyl, which in turn can be substituted by hydroxy or trifluoromethyl,
or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a mono- or bicyclic ring with 3 to 7 carbon atoms, in which the carbon chain is one or two, identical or different, by -O-, -NR ¹⁰ -, -CO- or -S- may be interrupted and, by hydroxy, C ₁ optionally mono- or polysubstituted by identical or different - C ₄ alkyl or hydroxy-substituted C ₁ -C ₄ alkyl,
in which
R ^{10 is} hydrogen, C ₁ -C ₄ alkyl, which may be substituted by hydroxy or phenyl, or C ₃ -C ₆ cycloalkyl, formyl, acetyl or C ₁ -C ₄ alkoxycarbonyl or phenyl, pyridyl or pyrimidinyl, which in turn can be substituted by halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy,
R ⁵ pyridyl, which can be substituted up to twice the same or different by fluorine, chlorine, bromine, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkyl, or thiazolyl, which in turn by fluorine, chlorine, bromine or C ₁ -C ₄ alkyl may be substituted, and
R ^{6 is} a 5- to 6-membered, partially unsaturated or aromatic heterocycle with up to 3 heteroatoms from the series N, O and / or S, which is optionally substituted by amino or C ₁ -C ₄ -alkyl,
mean,
as well as their salts. 3. Compounds according to claim 1, wherein
R ¹ to R ³ independently of one another are hydrogen, fluorine or chlorine,
R ^{4 is} a straight-chain or branched hydrocarbon radical having up to 4 carbon atoms, which optionally contains an oxygen atom as a hetero chain link and / or is optionally substituted by hydroxy, C ₁ -C ₃ alkoxy or a radical of the formula -NR ⁸ R ⁹ ,
wherein
R ⁸ and R ⁹ independently of one another are hydrogen, ethoxy, propoxy or C ₁ -C ₄ -alkyl, which in turn are optionally substituted by hydroxy or trifluoromethyl,
or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a radical of the formula
form,
wherein
a zero or 1 and
YO, S or NR ¹⁰ mean in which
R ^{10 represents} hydrogen or C ₁ -C ₄ alkyl,
R ⁵ pyridyl, which can be substituted up to twice the same or different by fluorine or chlorine, or thiazolyl,
R ^{6 is} a 5-membered aromatic heterocycle with up to 3 hetero atoms from the series N, O and / or S, which is optionally substituted by amino or C ₁ -C ₄ alkyl,
mean,
as well as their salts. 4. Compounds according to claim 1,
wherein
R ¹ to R ³ independently of one another are hydrogen, fluorine or chlorine,
R ^{4 is} methyl or ethyl, which are optionally substituted by hydroxy, methoxy, ethoxy, 2-methoxyethyl or a radical of the formula -NR ⁸ R ⁹ ,
wherein
R ⁸ and R ⁹ independently of one another are hydrogen, ethoxy, methyl or ethyl, which in turn are optionally substituted by hydroxy or trifluoromethyl, or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a radical of the formula
form,
wherein
YO or NR ¹⁰ and
R ^{10 is} hydrogen or methyl,
R ⁵ pyridyl, which is substituted up to twice the same or different by fluorine or chlorine, or thiazolyl, and
R ^{6 is} a 1,2,4-oxadiazole, 1,3,4-oxadiazole or 1,3,4-thiadiazole ring, which can each be substituted by amino or methyl,
mean,
as well as their salts. 5. Compounds of Examples VI, XIIa, XV, XIX, XX and XXXIII. 6. A process for preparing the compounds according to claims 1 to 5, after which

• 1. [A] compounds of the formula
  wherein
  R ¹ to R ^{5 have} the meanings given in claims 1 to 5,
  Z represents hydroxy or a radical of the formula
  stands,
  wherein
  R ^{11 is} hydrogen, amino or C ₁ -C ₆ alkyl and
  Mean LO, S or NH and
  A represents a group of the series -NH-, -CH ₂ CH ₂ - or -CH ₂ CH ₂ O-,

cyclized in the presence of a dehydrating agent or

• 1. [B] compounds of the formula
  in which R ⁴ and R ^{6 have} the meanings given in Claims 1 to 5,
  in a one-step process with aldehydes of the formula
  wherein
  R ¹ to R ^{3 have} the meanings given in claims 1 to 5,
  and amidines of the formula
  wherein R ^{5 has} the meaning given in claims 1 to 5,
  or their salts or
• 2. [C] compounds of the formula
  in which R ¹ to R ⁴ and R ^{6 have} the meanings given in Claims 1 to 5,
  with amidines of the formula
  wherein R ^{5 has} the meaning given in claims 1 to 5,
  or their salts or
• 3. [D] if R ^{4 is} an NR ⁸ R ⁹ -substituted methyl group, in which R ⁸ and R ^{9 have} the meanings given in claims 1 to 5,
  Compounds of the formula
  in which R ¹ to R ³ and R ⁵ and R ^{6 have} the meanings given in Claims 1 to 5,
  with compounds of the formula
  in which R ⁸ and R ^{9 have} the meanings given in Claims 1 to 5,

implements. 7. A process for the preparation of the compounds according to claims 1 to 5, after which

• 1. [A] aldehydes of the formula
  in which R ¹ to R ^{3 have} the meanings given in claims 1 to 5,
  with β-keto esters of the formula
  wherein
  R ^{4 has} the meaning given in claims 1 to 5 and
  X represents a cyano or trimethylsilyl group,
  to compounds of the formula
  implements
  this then with amidines of the formula
  wherein R ^{5 has} the meaning given in claims 1 to 5,
  or their salts to give compounds of the formula
  reacting
  then the ester grouping with a base or with fluoride ions to give carboxylic acids of the formula
  splits,
  this then by means of N, N'-carbonyldiimidazole in imidazolides of the formula
  convicted,
  hereinafter with compounds of the formula
  ZA-NH ₂ (IX),
  wherein
  Z represents hydroxy or a radical of the formula
  stands,
  wherein
  R ^{11 is} hydrogen, amino or C ₁ -C ₆ alkyl and
  Mean LO, S or NH and
  A represents a group of the series -NH-, -CH ₂ CH ₂ - or -CH ₂ CH ₂ O-,
  to compounds of the formula
  implemented and finally cyclized in the presence of a dehydrating agent or
• 2. [B] compounds of the formula
  in which R ⁴ and R ^{6 have} the meanings given in Claims 1 to 5,
  in a one-step process with aldehydes of the formula (II) and amidines of the formula (V) or their salts or
• 3. [C] compounds of the formula (XI) with aldehydes of the formula (II) in a two-stage process, first in compounds of the formula
  in which R ¹ to R ⁴ and R ^{6 have} the meanings given in Claims 1 to 5,
  transferred and then reacted with amidines of the formula (V) or their salts or else
• 4. [D] if R ^{4 is} an NR ⁸ R ⁹ -substituted methyl group, in which R ⁸ and R ^{9 have} the meanings given in claims 1 to 5,
  Compounds of the formula
  wherein R ¹ to R ³ , R ⁵ and R ^{6 have} the meanings given in claims 1 to 5,
  with a brominating agent in compounds of the formula
  transferred and then with compounds of the formula
  in which R ⁸ and R ^{9 have} the meanings given in Claims 1 to 5,

implements. 8. Compounds of the formula
wherein R ¹ to R ³ , R ⁵ and R ^{6 have} the meanings given in claims 1 to 5. 9. Compounds according to claims 1 to 5 for combating diseases. 10. Medicament containing at least one compound according to claims 1 to 5 and optionally one or more other active pharmaceutical ingredients. 11. Use of compounds of claims 1 to 5 for the preparation of a Medicinal product for the treatment and prophylaxis of viral diseases. 12. Use of compounds of claims 1 to 5 for the preparation of a Medicinal product for the treatment and prophylaxis of hepatitis B infections. 13. Combinations

• A) at least one dihydropyrimidine according to claims 1 to 5.
• 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 Is 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
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. 18. Combinations according to claims 13 to 17, wherein the immunomodulator C Contains interferons. 19. Combinations of A) dihydropyrimidine according to Claims 1 to 5, B) Lamivudine and optionally C) interferon. 20. A method for producing the combinations according to claims 13 to 19, characterized in that components A, B and optionally C combined or prepared in a suitable manner. 21. Combinations according to claims 13 to 19 for combating Er diseases. 22. Medicament containing at least one combination according to claims 13 to 19 and optionally one or more other pharmaceutical agents fabrics. 23. Use of combinations of claims 13 to 19 for the manufacture a medicine for the treatment and prophylaxis of viral diseases. 24. Use of combinations of claims 13 to 19 for the manufacture a medicine for the treatment and prophylaxis of hepatitis B Infections.