WO2001068641A1

WO2001068641A1 - 6-aminoalkyl-dihydropyrimidines and the use thereof as medicaments against viral diseases

Info

Publication number: WO2001068641A1
Application number: PCT/EP2001/002443
Authority: WO
Inventors: Siegfried Goldmann; Jürgen Stoltefuss; Ulrich Niewöhner; Karl-Heinz Schlemmer; Jörg Keldenich; Arnold Paessens; Erwin Graef; Olaf Weber; Karl Deres
Original assignee: Bayer Aktiengesellschaft
Priority date: 2000-03-17
Filing date: 2001-03-05
Publication date: 2001-09-20
Also published as: DE10013126A1; AU2001256184A1

Abstract

Novel dihydropyrimidines or the isomeric form thereof, wherein R1 = pyridyl, pyrimidinyl, thiazolyl or oxazolyl, wherein said radicals can be substituted up to three times by halogen and/or C¿1?-C6-alkyl, R?2= C¿6-C10-aryl or 5-10 membered heteroaryl, wherein said aryl or heteroaryl radicals can be respectively substituted by one to three substituents from the group of C1-C6alkyl, C1-C6-alkoxycarbonyl, halogen, nitro, polyfluoro-C1-C4-alkyl, R3 = C1-C14-alkyl, wherein one to two carbon atoms can be substituted in the chain thereof by oxygen or sulphur and/or the C1-C14 -alkyl radical can be substituted by one to three substitutents from the group of hydroxy, cyano, NR6R7, C1-C6- alkoxycarbonyl, C6-C10-aryl, 5-10 membered heteroaryl, wherein C6-C10-aryl and 5-10 membered heteroaryl can be substituted by one to three substituents from the group of hydroxy, C1-C6-alkoxycarbonyl, halogen, halogen- C1-C6-alkyl and X = C1-C3-alkylene which can be interrupted by oxygen and/or substituted by C1-C6 aryl. The invention also relates to combinations of novel dihydropyrimidines and combinations thereof with other antiviral agents, suitable for combating HBV infections.

Description

-AMI _N 0ALKYL-DIHYDR0PPYRIMIDINE AND THEIR USE AS A MEDICINE AGAINST VIRAL DISEASES

The present invention relates to new 6-aminoalkyl-dihydropyrimidines, processes for their preparation and their use as medicaments, in particular for the treatment and prophylaxis of hepatitis B virus infections. The invention also relates to combinations of these dihydropyrimidines with other antiviral agents and, if appropriate, immunomodulators and medicaments containing these combinations, in particular for the treatment and prophylaxis of HBV infections such as hepatitis B.

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

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

From EP-PS 103 796 dihydropyrimidines are known, to which an effect influencing the circulation is attributed. WO 99/1438 relates to dihydropyrimidines which are said to be suitable for the treatment of cerebrovascular ischemia and pain. WO 99/54312, 99/54326 and 99/54329 relate to dihydropyrimidines which are suitable for the treatment and prophylaxis of hepatitis.

The present invention relates to compounds of the formula

or their isomeric form

Wonn

R ¹ pyridyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl, where these radicals can be substituted up to three times by halogen and / or -CC ₆ alkyl,

R ² C ₆ -C ~ aryl or 5- to 10-membered heteroaryl, these aryl or heteroaryl radicals each having one to three substituents from the group d- C ₆ alkyl, -CC ₆ alkoxycarbonyl, halogen, nitro , Polyfluoro-C ₄ alkyl may be substituted,

R ³ C 1 -C ₁₄ alkyl, in the chain of which one or two carbon atoms can be replaced by oxygen or sulfur and / or the C 1 -C ₄ alkyl radical by one to three substituents from the group hydroxyl, cyano, NR ⁶ R ⁷ , CpC ₆ - alkoxycarbonyl, C ₆ -Cιo-aryl, 5- to 10-membered heteroaryl may be substituted, wherein C ₆ -Cιo-aryl and 5- to 10-membered heteroaryl in turn by one to three substituents from the group hydroxy C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxycarbonyl, halogen, halogen-C ₆ -C ₆ -alkyl may be substituted, Wonn

R ⁶ and R ⁷ independently of one another are hydrogen, C ₁ -C ₆ -alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated C ₁ -C 8 -hydrocarbon group which is optionally substituted by di- C] -C ₆ -alkylamino, or together with the nitrogen atom to which they are attached form a 3- to 8-membered ring which can be mono- to trisubstituted by C 1 -C ₆ -alkyl and can contain one or two further heteroatoms from the series nitrogen, oxygen, sulfur ;

R ⁴ -C-Cιo-alkyl, the halogen, hydroxy, aminocarbonyl, 5- to

10-membered heteroaryl and or 5- to 10-membered heterocyclyl may be substituted and the carbon chain of which may be interrupted by -O-, -S-, -SO ₂ - and / or - (-C-C ₆ -alkyl) N-, or C ₆ -Cιo aryl or 5- to 10-membered heteroaryl or 5- to 10- membered heterocyclyl, the halogen-Cι-C ₆ turn respectively - alkoxy and / or Cι-C ₆ - may be substituted alkyl,

R ^{5 is} hydrogen or Cj-do-alkyl, which may be substituted by halogen, hydroxy or phenyl and the carbon chain of which may be interrupted by -O-, -S-, -SO - and / or - (-C-C ₆ -alkyl) N- can, or C ₆ -C] o-aryl or 5- to 10-membered heteroaryl, which in turn can be substituted by halogen, dC ₆ alkoxy and / or C ₁ -C ₆ alkyl,

with the proviso (1) that R ⁴ and R ^{5 are} not simultaneously unsubstituted alkyl,

or R ⁵ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated mono- or bicyclic ring with up to 10 carbon atoms, of which up to 3 carbon ring members are identical or different by -O-, -NR ⁸ -, -S- can be replaced, where in the case of a monocyclic ring it contains at least one substituent which, if it is on a C or an N atom, from the series hydroxyl, halogen, = O, Ci-Cio-alkyl, -C-Cιo-alkoxy, C ₃ -C ₆ cycloalkyl, hydroxy-Ci-C _ö -alkyl, mono- and di-Ci-C _ό -alkylamino-Ci-C _ö -alkyl, Cι-C ₆ - alkoxycarbonylamino, C ₆ -Cιo-aralkyl or C ₆ -Cιo-aryl, where aryl or

Aralkyl can be substituted by halogen, cyano, nitro, carboxyl, amino, Ci-Cö-alkoxy and / or C - C ₆ - alkyl, and -CO-R ^{y is} selected with R ^y = Ci-Cio-alkyl, halogen -C, -Cιo-alkyl, C, -C ₁₀ - alkoxy, optionally C, -C _{] 0} - alkyl or Cι-Cιo alkoxy-substituted C ₆ -Cι ₀ aryl, optionally dC ₁₀ alkyl- or Crdo-alkoxy-substituted Cö-Cio-aryloxy, C ₆ -Cιo-aralkyloxy, optionally

Halogen-substituted C _ö -Cio-aryloxy-Ci-Cio-alkyl or a 5- to 10-membered heterocycle, which heterocycle can be substituted by halogen, -C-C ₆ - alkoxy and / or C] -C ₆ - alkyl .

- and if the substituent is on an S atom, one or two oxygen atoms are selected,

and where in the case of a bicyclic ring system the linkage can take place via the same carbon atom (spiro), via two directly adjacent carbon atoms (fused) or via two non-adjacent carbon atoms (bridged) and the bicyclus optionally comprises up to 3 identical or different substituents in the row above,

R Ci-Cio-alkyl or C ₃ -Cιo-cycloalkyl, which can each be substituted by hydroxy and / or phenyl, or C] -C ₆ -acyl, benzoyl, C ₆ -Cιo-aryl or 5- to 10-membered heteroaryl, where the aryl and heteroaryl radicals are each halogen, -C-C ₆ alkoxy and / or Ci-C _ö -Alkyl can be substituted, and

X -C-C ₃ alkylene, which can be interrupted by oxygen and / or substituted by Ci-C _ö - alkyl, with the proviso (2) that X is not -CH ₂ -Y- (CH ₂ ) _Z - means with Y = O, S or NR ', z = an integer from 2 to 4,

R '= hydrogen or C, -C ₆ alkyl,

mean,

and their salts.

Preferred compounds (I) and (Ia) are those in which

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated mono- or bicyclic ring with bis

Form 10 carbon atoms, of whose carbon ring members up to 3 may be replaced identically or differently by -O-, -NR ⁸ -, -S-, and in the case of a monocyclic ring this contains at least one substituent which, if attached to a C -Atom is out of line

Hydroxy, halogen, = O, Ci-Cio-alkyl, Ci-Cio-alkoxy, hydroxy-dC ₆ -alkyl, mono- and di-Cι-C ₆ -alkylamino-Cι-C ₆ -alkyl, Ci-C _ö - Alkoxycarbonylamino is selected

and if the substituent is on an N atom, from the series -C-Cιo-alkyl, C, -Cιo-alkoxy, C ₃ -C ₆ cycloalkyl, hydroxy-dC ₆ -alkyl, C ₆ - Cio-aralkyl, C _ό -Cio-aryl or a 5- to 10-membered heterocycle wherein aryl, aralkyl or heterocyclic substituted by halogen, cyano, nitro, carboxyl, amino, Cι-C ₆ -alkoxy and alkyl or CpC _ö may be substituted, and - CO-R ^y is selected by R ^y = Ci Cio-alkyl, halogen-C, -Cιo-alkyl, C, -Cι ₀ -alkoxy, optionally d-do- alkyl or Ci-Cio- alkoxy-substituted C _ό -Cio-aryl, optionally d-Cι ₀ alkyl or Cι-Cιo-alkoxy-substituted C _ό -Cio-aryloxy, C _ό -Cio-aralkyloxy, optionally halogen-substituted C _ö -Cιo-aryloxy-Cι-Cιo-alkyl or a 5- to 10-membered Heterocycle, this heterocycle by halogen, -CC ₆ -

Alkoxy and / or -CC ₆ - alkyl can be substituted,

and if the substituent is on an S atom, is selected from one or two oxygen atoms,

where, in the case of a bicyclic ring system, the linkage can take place via the same carbon atom (spiro), via two directly adjacent carbon atoms (fused) or via two non-adjacent carbon atoms (bridged) and the bicyclus can optionally contain up to 3 identical or different substituents from the above Row carries,

and where the above provisions (1) and (2) apply.

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

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

4 carbon atoms. Cycloalkyl in the context of the invention stands for cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopentyl or cyclohexyl.

In the context of the invention, alkenyl represents a linear or branched alkenyl radical having 2 to 5, preferably 3 to 5, carbon atoms, such as, for example, Ethenyl, propenyl, allyl, n-pentenyl and n-hexenyl.

In the context of the invention, alkoxy represents a linear or branched alkoxy radical having 1 to 6, preferably 1 to 4, carbon atoms, such as e.g. Methoxy, ethoxy and

Propoxy.

In the context of the invention, alkoxycarbonyl represents a linear or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4, carbon atoms, such as e.g. Methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

A linear, branched or cyclic, saturated or unsaturated hydrocarbon radical generally contains 1 to 12, preferably 1 to 10 and in particular 1 to 8 carbon atoms and includes, for example, the alkyl, alkynyl and cycloalkyl radicals described above, preferably dC ₆ -alkyl radicals, on.

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

In the context of the invention, aralkyl stands for aralkyl with preferably 6 to 10, in particular 6, carbon atoms in the aryl part (preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 4, in particular 1 or 2, carbon atoms in the alkyl part, where the alkyl part can be linear or branched , Preferred aralkyl radicals are benzyl and phenethyl. Heteroaryl in the context of the invention represents 5- to 7-membered rings with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms from the series oxygen, sulfur and nitrogen. Preferred examples include furyl, thienyl, pyrazolyl, imidazolyl, 1.2.3- and 1.2.4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pynolyl, pyridyl, pyrimidinyl and pyrazinyl.

In the context of the invention, 5- to 10-membered heterocycle stands for 5- to 10-membered rings, preferably bonded via a nitrogen atom, with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms from the series oxygen, sulfur, nitrogen. Preferred examples include, for example

Morpholine, piperidine and tetrahydrofuran.

The compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both

Enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a manner known per se.

The compounds according to the invention include the isomers of the formulas (I) and (I a) and mixtures thereof. The compounds according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.

Physiologically acceptable salts can be salts of inorganic or organic

Be acids. Salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts of 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 toluenesulfonic acid or toluenesulfonic acid

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

The compounds according to the invention can be produced by:

[A] aldehydes of the formula

R -CHO (II)

where R ^{2 has} the meaning given above,

initially with ß-keto esters of the formula

wherein R .3 ι b_i-s R and X have the meanings given above,

with or without addition of base or acid, if appropriate in the presence of inert organic solvents in compounds of the formula

transferred and then with amidines of the formula

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

or their salts (such as hydrochlorides or acetates) with or without addition of base or acid, if appropriate in the presence of inert organic solvents or

[B] Compounds of the formula (III) are reacted in a one-step process with aldehydes (II) and amidines (V) or their salts (such as hydrochlorides or acetates) with or without addition of base or acid, if appropriate in the presence of inert organic solvents or

[C] if X in formula (I) represents a methylene group, compounds of the formula

wherein R to R have the meanings given above and

Y represents a nucleophilically exchangeable group such as chloride, bromide, iodide, mesylate or tosylate, with compounds of the formula

wherein R and R have the meanings given above,

with or without the addition of an auxiliary base, if appropriate, in inert solvents.

The compounds (VI) can be prepared, for example, by using compounds of the formula

in which R ¹ to R ^{3 have} the meanings given above,

with a brominating agent, e.g. N-bromosuccinimide, preferably in the presence of inert solvents in compounds of the formula

transferred. These can then be reacted with compounds (VII) directly or after further transformation of the nucleophile-exchangeable group customary in the literature.

[D] If X in formula (I) represents an ethylene group, compounds of the formula can also be used

in which R ² and R ^{3 have} the meanings given above,

with immonium salts of the formula

in which R ⁴ and R ^{5 have} the meanings given above,

with or without the addition of an auxiliary base, optionally in inert solvents in compounds of the formula

transfer and then react them with amidines (V) or their salts (such as hydrochlorides or acetates) with or without the addition of bases or acids, if appropriate in the presence of inert organic solvents.

The aldehydes (II) used as starting materials are known or can be prepared by methods known from the literature [cf. T. D. Harris and G.P. Roth, J. Org. Chem. 44, 146 (1979); DE-OS 2 165 260 and 2 401 665 ,; 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 ß-ketocarboxylic acid esters (III) used as starting materials are known in some cases or can be prepared analogously to methods known from the literature [e.g. B. D. Borrmann, "Reaction of Diketene with Alcohols, Phenols and Mercaptans", in "Methods of Organic Chemistry" (Houben-Weyl), Vol. VIL / 4, 230 ff (1968);

Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].

In the case of the compounds of the formula (I) according to the invention, in which X represents a methylene group, the corresponding β-ketocarboxylic acid esters (III) can also be obtained by reacting chloroacetoacetic esters of the formula

where R has the meaning given above,

can be obtained with compounds of the formula (VII).

Some of the compounds (V) are known or can be prepared as described in WO-A-99/54326 and WO-A-99/54329. The compounds (VIII) and (X) can be prepared in accordance with process variants [A] or [B] as described in WO-A-99/54326.

The compounds (VII) and (XI) are known or can be prepared by customary methods.

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

Dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and hexamethyl phosphoric acid triamide.

The reaction temperatures can be varied over a wide range. In general, you work between 20 and 150 ° C, but preferably at

Boiling temperature of the respective solvent.

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

The reaction can be carried out with or without addition of base or acid; however, it is advisable to carry out the reaction in the presence of weaker acids, e.g. Acetic acid or formic acid.

Compounds of formula (IX) are new; the invention therefore also relates to compounds of the formula (IX).

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.

An embodiment of the invention relates to combinations of A) at least one of the dihydropyrimidines defined above (without taking into account the provisions (1) and (2)), B) at least one other antiviral agent other than A.

A particular embodiment of the invention relates to combinations A) of the above dihydropyrimidines (without taking into account the provisions (1) and (2)), B) HBV polymerase inhibitors and, if appropriate, C) immunomodulators.

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.

The invention therefore also relates to these combinations for the treatment and prophylaxis of HBV infections and their use for the treatment of HBV-induced diseases.

The use of the combinations according to the invention offers valuable advantages in the treatment of HBV-induced diseases compared to monotherapy with the individual compounds, namely mainly a synergistic antiviral activity, but also a good tolerance of the combinations according to the invention in the area of toxicity, in which 50% of the cells survive ("Tox-50") - compared to the Tox-50 of the individual components. HBV polymerase inhibitors B for the purposes of the invention are substances which are described in the endogenous polymerase assay described below, which was described by Ph. A. Furman et al. in Antimicrobial Agents and Chemotherapy, Vol. 36 (No. 12), 2688 (1992), lead to an inhibition of the formation of an HBV-DNA double strand in such a way that there is a maximum of 50% of the activity of the zero value:

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- P] deoxynucleoside 5'-tnphosphate in the viral

3.2-kb DNA product 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 part by volume of clarified cell culture is obtained with part by volume of an aqueous solution containing 50% by weight of polyethylene glycol

8000 and 0.6 M sodium chloride mixed. The virions are sedimented by centrifugation at 2,500 xg / 15 minutes. The sediments are resuspended in 2 ml of buffer containing 0.05 M Tris-HCl (P _H 7.5) and dialyzed against the same buffer containing 100 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); 300mM potassium chloride; 50mM magnesium chloride; 0.1% ®Nonident P-40 (non-ionic detergent from Boehringer Mannheim); 10 μM each of dATP, dGTP and dTTP; 10 μCi [ ³² P] dCTP (3000 Ci / mmol; final concentration 33 nM) and 1 μM of the potential polymerase inhibitor in its triphosphorylated form. The samples are incubated at 37 ° C for one hour and then the reaction is stopped by adding 50 mM EDTA. A 10% weight volume SDS solution (containing 10 g SDS per 90 ml water) is 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 aqueous phase is the DNA precipitated with ethanol. The DNA pellet is resuspended in 10 μl gel buffer (solution of 10.8 g Tris, 5.5 g boric acid and 0.75 g EDTA in 1 liter water (= TBE buffer)) 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 logo CNRS logo INIST

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

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

BMS 200 475 =

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

Abacavir =

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

(2R-cis) -4-amino-5-fluoro-l- [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;

ß-L-FDDC =

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

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

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

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

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

Wonn R ¹ and R ² independently of one another are C 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, -C ₄ alkyl, -C-C ₇ acyl or aralkyl and

X halogen or optionally substituted -CC ₄ - alkyl

mean,

and their salts.

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

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

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

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

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

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

Each well of the microtiter plate then received 225 μl of a HepG2.2.15 cell suspension (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 (v / v).

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

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

cytotoxicity

Substance-induced cytotoxic or cytostatic changes in the HepG2.2.15 cells were e.g. determined by means of light microscopy as changes in cell morphology. Such substance-induced changes in the HepG2.2.15 cells in the

Comparison to untreated cells was e.g. visible as cell lysis, vacuolization or altered cell morphology. 50% cytotoxicity (Tox.-50) means that 50% of the cells have a morphology comparable to the corresponding cell control.

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

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

Determination of the antiviral effect

After transfer of the supernatants or lysed cells to the nylon membrane of the

Blot apparatus (see above), the intra- or extracellular supernatants of the HepG2.2.15 cells were denatured (1.5 M NaCl / 0.5 N NaOH), neutralized (3 M NaCl / 0.5 M Tris HCl, pH 7.5) and washed (2 x SSC ). The DNA was then baked on the membrane by incubating the filters at 120 ° C. for 2-4 hours. Hybridization of the DNA

The detection of the viral DNA from the treated HepG2.2.15 cells on the nylon filters was generally carried out using non-radioactive, digoxigenin-labeled hepatitis B-specific DNA probes, which were labeled with digoxigenin according to the manufacturer's instructions, purified and used for hybridization ,

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

Detection of HBV DNA by digoxigenin antibodies

The immunological detection of the digoxigenin-labeled DNA was carried out according to the manufacturer's instructions:

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

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

The compounds according to the invention show an unforeseeable and valuable activity against viruses. They are surprisingly antiviral to hepatitis B

Viruses (HBV) are effective by causing an extremely large reduction in intra- and / or extracellular HBV DNA. The compounds according to the invention are therefore suitable for the treatment of virus-induced diseases, in particular acute and chronic persistent viral infections of HBV. A chronic viral disease caused by HBV can lead to different severity of the clinical picture; As is well known, chronic hepatitis B virus infection in many cases leads to liver zinosis and / or hepatocellular carcinoma.

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

The active ingredients (I) or (Ia) should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, of the total mixture his.

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

The quantitative ratio of components A, B and optionally C of the combinations according to the invention can vary within wide limits; it is preferably 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, can be used in amounts of preferably 1 to 10 million, in particular 2 to 7 million IU (international units), about three times a week over a period of up to one year.

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

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

In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of from about 0.5 to about 500, preferably from 1 to 100 mg / kg of body weight per 24 hours, if appropriate in Form of multiple doses to be administered to achieve the desired results. A single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg

Body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place.

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

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

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

Examples

A. Starting compounds

Example I 3-fluoropyridine N-oxide

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

Mp .: 66-68 ° C

Example II 2-Cyano-3-fluoropyridine

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

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

Yield (crude): 5.3 g (oil)

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

Example III 2-Amidino-3-fluoro yridine hydrochloride

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

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

Example IV 2-Cyano-3,5-dichloropyridine

Method 1:

A solution of 26 g (0.158 mol) of 3,5-dichloropyridine-l-oxide (Johnson et al., J.Chem.Soc.B, 1967, 1211) in 80 ml of dichloromethane is added successively with 21.8 ml (0.174 mol) trimethylsilyl cyanide and 14.6 ml (0.158 mol) dimethylcarbamide 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 vigorously 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 under reflux for 24 hours. Then another 100 ml of diethylene glycol dimethyl ether, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75 g (0.838 mol) of copper (I) cyanide were added, and the mixture was stirred for a further 89 hours at the reflux temperature. After cooling to room temperature, the product is filtered off with suction and the filtrate is largely freed from diethylene glycol dimethyl ether by distillation. The residue is taken up in toluene and washed with an aqueous solution of Mohr's salt solution and then with an aqueous sodium hydrogen carbonate solution (peroxide test). Then it is washed free of diethylene glycol dimethyl ether with water. It is filtered through cellite, 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-dichloφyridine from Example IV, 33.6 g (0.58 mol)

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

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

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

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

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

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

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

Example VIII 4- (2-Chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridinyl) -6-methyl-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

4.5 g (23.2 mmol) of 3,5-difluoro-2-pyridinecarboximidamide hydrochloride from Example VI are mixed with 7.7 g (30 mmol) of 2-acetyl-3- (2-chloro-4-fluorophenyl) - Methyl 2-propenate from Example VII and 2.3 g (27.9 mmol) of sodium acetate dissolved or suspended in 120 ml of isopropanol and boiled under reflux for 4 hours. After cooling to room temperature, it is suctioned off from inorganic salts and concentrated. The residue is taken up in 30 ml of 1N hydrochloric acid and 35 ml of ethyl acetate and the phases are separated. The ethyl acetate phase is extracted once with 30 ml of 1 N hydrochloric acid. The combined aqueous phases are extracted three times with 10 ml of diethyl ether. The aqueous phase is made alkaline with sodium hydroxide solution and extracted with ethyl acetate. The organic phases are dried over sodium sulfate and concentrated. 7.4 g (80%) of product, mp: 126 ° C., are obtained

1H-NMR (DMSO-D ₆ ): 2.4 (s, 3H) ppm, 3.5 (s, 3H) ppm, 6.0 (s, 1H) ppm, 7.2 (m,

1H) ppm, 7.4 (m, 2H) ppm, 8.0 (m, 1H) ppm, 8.55 (d, J = 2 Hz, 1H) ppm, 9.75 (s, NH) ppm. After separation of the enantiomers on chiral columns (Chiralpak AS from Baker, running average n-heptane / ethanol = 8: 2), the (-) - enantiomer is obtained. Mp .: 117 ° C (from ethanol) [α] _D ²⁰ : - 62.8 ° (methanol)

Example IX (R) -6-Bromomethyl-4- (2-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester

2 g (5.05 mmol) (-) - 4- (2-chloro-4-fluorophenyl) -2- (3,5-difluoro-2-pyridyl) -6-methyl-l, 4-dihydropyrimidine-5- carboxylic acid methyl esters from Example VIII are heated in 30 ml of carbon tetrachloride under argon to 50 ° C., a clear solution being formed. At this temperature, 0.99 g (5.56 mmol) of N-bromosuccinimide are added and the mixture is kept at this temperature for 10 minutes. It is immediately cooled, suction filtered and concentrated at room temperature under reduced pressure. According to HPLC, the product is> 90% pure and is used as raw material. R _f = 0.33 (cyclohexane / ethyl acetate = 7: 3)

The following were produced analogously:

Example X 6-Bromomethyl-4- (2,4-dichloro-henyl) -2- (3,5-difluoro-2-pyridyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester Example XI 6-Bromomethyl-4- (2-chloro-phenyl) -2- (3,5-difluoro-2-pyridyl) -l, 4-dihydropyrimidine-5-carboxylic acid, methyl ester

Example XII 6-Bromomethyl-4- (2,4-difluoro-phenyl) -2- (3,5-difluoro-2-pyridyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester

Example XIII 6-Bromomethyl-4- (2-chloro-4-fluoφhenyl) -2- (2-thiazolyl) -l, 4-dihydropyrimidine-5-carboxylic acid methyl ester

Example XIV 6-bromomethyl-4- (2-bromo-4-fluoφhenyl) -2- (2-thiazolyl) -l, 4-dihydropyrimidine-5-carboxylic acid methyl ester

Preparation Examples

Example 1 (R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(4-cyclopropyl-l-piperazinyl) methyl] -2- (3,5-difluoro-2-pyridinyl) -l, Methyl 4-dihydropyrimidine-5-carbonate

A solution of 25 mg (0.05 mmol) of freshly prepared (R) -6-bromomethyl-4- (2-chloro-4-fluorophene) -2- (3,5-difluoro-2-pyridinyl) -l, 4th Dihydropyrimidine-5-carboxylic acid methyl ester from Example IX in 0.3 ml of methanol is mixed with 14 mg (0.13 mmol) of sodium carbonate and 26.2 mg (0.13 mmol) of 1-cyclopropylpiperazine dihydrochloride and 2 hours at room temperature touched. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated. Yield: 24 mg (87.6% of theory) R _r value = 0.26 (dichloromethane / methanol = 95: 5)

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

Solvent abbreviation

Cyclohexane / ethyl acetate = 7: 3 A

Cyclohexane / ethyl acetate = 8: 2 B

Cyclohexane / ethyl acetate = 1: 1 C

Cyclohexane / ethyl acetate = 7: 3 + drops of NH ₃ D

Methylene chloride / methanol = 95: 5 U

Methylene chloride / methanol = 9: 1 F

Toluene / acetone = 1: 1 G

Toluene / methanol = 10: 1 H

Toluene / ethyl acetate = 4: 1 l

Methylene chloride / methanol = 10: 1 J

Methylene chloride / methanol = 95: 5 + drops of NH ₃ K.

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

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

Claims

claims

1. Compounds of the formula

or their isomeric form

wherein

R ¹ pyridyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl, where these radicals can be substituted up to three times by halogen and / or Ci-C _ό - alkyl,

R ² C _ό -Cio-aryl or 5- to 10-membered heteroaryl, these aryl or heteroaryl radicals each having one to three substituents from the group -C-C ₆ alkyl, CC ₆ alkoxycarbonyl, halogen, nitro, poly fluoro-C) -C -alkyl can be substituted,

R ³ -C ₄ alkyl, in the chain of which one or two carbon atoms can be replaced by oxygen or sulfur and / or the C 1 -C ₄ alkyl radical by one to three substituents from the group hydroxyl, Cyano, NR ⁶ R ^7, CC ₆ - alkoxycarbonyl, C ₆ -Cι ₀ aryl, 5- to 10-membered heteroaryl may be substituted with C _ö -Cio-aryl and 5- to 10-membered heteroaryl in turn by one to three substituents from the group hydroxy, Cι-C ₆ - alkyl, Ci-C _ό - alkoxy, Ci-C _ό - alkoxycarbonyl, halogen, halogen-Ci-C _ό may be substituted alkyl,

Wonn

R and R independently of one another are hydrogen, C ₁ -C ₆ -alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated C ₁ -C 8 -hydrocarbon group which is optionally substituted by di-C] -C ₆ -alkylamino, or together with the nitrogen atom to which they are attached form a 3- to 8-membered ring which can be substituted one to three times by C ₁ -C ₆ -alkyl and / or one or two further heteroatoms from the series nitrogen, oxygen, Can contain sulfur;

R ⁴ Ci-Cio-alkyl, which are substituted by halogen, hydroxy, aminocarbonyl, 5- to 10-membered heteroaryl and / or 5- to 10-membered heterocyclyl and whose carbon chain by -O-, -S-, -SO - and / or - (-C ₆ -alkyl) N- may be interrupted, or C ₆ -Cιo-aryl or 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl, each of which in turn by halogen Cι-C ₆ - alkoxy and or dC _ό -alkyl may be substituted,

R ^{5 is} hydrogen or Ci-Cio-alkyl, which may be substituted by halogen, hydroxy or phenyl and the carbon chain of which is interrupted by -O-, -S-, -SO - and / or - (C] -C ₆ -alkyl) N- can be, or C ₆ -C -o-aryl or 5- to 10-membered heteroaryl, which in turn can be substituted by halogen, -C-C ₆ alkoxy and / or C] -C ₆ alkyl,

R ^{5 is} hydrogen or Ci-Cio-alkyl by halogen, hydroxy or

Be substituted phenyl and its carbon chain can be interrupted by -O-, -S-, -SO ₂ - and / or - (-C-C ₆ -alkyl) N-, or C ₆ -Cιo-aryl or 5- to 10- membered heteroaryl, which in turn can be substituted by halogen, C - C ₆ alkoxy and / or C ₁ -C ₆ alkyl,

or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated mono- or bicyclic

Form a ring with up to 10 carbon atoms, of which up to 3 carbon ring members can be replaced identically or differently by -O-, -NR ^X -, -S-,

where in the case of a monocyclic ring this contains at least one substituent which

if it is on a C or an N atom, from the series

Hydroxy, halogen, cyano, nitro, carboxyl, amino, = O, Ci-Cio-

Alkyl, Ci-Cio-alkoxy, C ₃ -C ₆ cycloalkyl, hydroxy-Ci-Cβ-alkyl, mono- and di-C ₆ -C ₆ alkylamino-CrC ₆ alkyl, C ₁ -C ₆ alkoxy carbonylamino, C ₆ -Cιo aralkyl or C ₆ -Cιo aryl, where aryl or Aralkyl can be substituted by halogen, cyano, nitro, carboxyl, amino, C ₁ -C ₆ alkoxy and / or C ₁ -C ₆ alkyl, and -CO-R ^{y is} selected with R ^y = Ci-Cio-alkyl, halogen -Cι-Cιo-alkyl, Cj-Cio- alkoxy, optionally C _t -do- alkyl or Ci-Cio-alkoxy-substituted C ₆ -Cιo-aryl, optionally Cp

C _ΪO - alkyl or Ci-Cio-alkoxy-substituted C ₆ -C] ₀ -aryloxy, C ₆ -Cιo- aralkyloxy, optionally halogen-substituted Ce-Cio-aryloxy-Ci-Cio-alkyl or a 5- bis 10 membered heterocycle, wherein said heterocycle by halogen, Cι-C ₆ - alkoxy and / or C - C _ö - alkyl may be substituted,

and where in the case of a bicyclic ring system the linkage can take place via the same carbon atom (spiro), via two directly adjacent carbon atoms (fused) or via two non-directly adjacent carbon atoms (bridged) and the bicyclus can optionally have up to 3 identical or different substituents from the series given above,

R ⁸ Ci-Cio-alkyl or Crdo-cycloalkyl, which can each be substituted by hydroxy and / or phenyl, or -CC ₆ -acyl, benzoyl, C ₆ -Cιo-aryl or 5- to 10-membered heteroaryl, where the aryl and heteroaryl radicals can each be substituted by halogen, -CC ₆ -alkoxy and or -C-C _ö alkyl, and

dC ₃ alkylene, which can be interrupted by oxygen and or can be substituted by - C ₆ - alkyl, with the proviso (2) that X is not -CH ₂ -Y- (CH ₂ ) _Z - with Y = O, S or NR ', z = an integer from 2 to 4,

R '= hydrogen or CC ₆ alkyl,

mean,

and their salts.

2. Compounds according to claim 1, wherein

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated mono- or bicyclic ring with up to 10 carbon atoms, of which carbon ring members up to 3 are identical or different by -O-, -NR ⁸ -, -S- can be replaced, in the case of a monocyclic ring this at least one

Contains substituents, if it is on a C atom, from the series

Hydroxy, halogen, = O, Cj-Cio-alkyl, Ci-Cio-alkoxy, hydroxy-Ci-C ₆ -alkyl, mono- and di-C _r C ₆ -alkylamino-dC ₆ -alkyl, dC ₆ -alk- oxycarbonylamino is selected

and if the substituent is on an N atom, from the series d-Cio-alkyl, dC ₁₀ alkoxy, C ₃ -C ₆ cycloalkyl, hydroxy-Cι-C ₆ - alkyl, C ₆ -Cιo-aralkyl, C _ό -Cio aryl or a 5- to 10-membered

Heterocycle, where aryl, aralkyl or the heterocycle can be substituted by halogen, cyano, nitro, carboxyl, amino, Ci-C _ό -alkoxy and or Ci-C ₆ - alkyl, and -CO-R ^{y is} selected with R ^y = Ci-Cio-alkyl, halogen-Cι-Cιo-alkyl, Ci-Cio-alkoxy, optionally Ci-Cio-alkyl or Ci-do-alkoxy-substituted C _ö -Cio-aryl, optionally d-

Cio-alkyl- or Ci-Cio-alkoxy-substituted C _ö -Cio-aryloxy, C _ό -do- Aralkyloxy, optionally halogen-substituted C _ό -Cιo-aryloxy-Cι-Cιo-alkyl or a 5- to 10-membered heterocycle, this heterocycle by halogen, Cj-C ₆ - alkoxy and / or Cι-C ₆ - alkyl can be substituted

in the case of a bicyclic ring system, the linkage via the same carbon atom (spiro), via two directly adjacent

Carbon atoms (fused) or via two non-directly adjacent carbon atoms (bridged) and the bicyclus optionally carries up to 3 identical or different substituents from the series given above,

mean and the provisions (1) and (2) of claim 1 apply,

and their salts.

3. Compounds of Examples 37, 38, 44, 45, 70-72, 77, 78, 80, 83-85.

4. A process for the preparation of the compounds according to claims 1 to 3, after which

[A] aldehydes of the formula

R ² -CHO (π)

wherein R ^{2 has} the meaning given in claims 1 to 3,

initially with ß-keto esters of the formula

in which R ³ to R ⁵ and X have the meanings given in Claims 1 to 3,

in compounds of the formula

transferred and then with amidines of the formula

wherein R has the meaning given in claims 1 to 3, or its salts or

[B] Reacts compounds of the formula (III) in a one-step process with aldehydes (II) and amidines (V) or their salts or else

[C] if X in formula (I) represents a methylene group, compounds of the formula

Wonn

R to R have the meanings given in claims 1 to 3 and

Y represents a nucleophilically exchangeable group,

with compounds of the formula

wherein R ⁴ and R ^{5 have} the meanings given in claims 1 to 3, or implement

[D] if X in formula (I) represents an ethylene group, compounds of the formula

in which R ² and R ^{3 have} the meanings given in claims 1 to 3, with immonium salts of the formula

in which R ⁴ and R ^{5 have} the meanings given in Claims 1 to 3,

in compounds of the formula

transferred and then reacted with amidines (V) or their salts.

5. A process for the preparation of the compounds according to claims 1 to 3, after which

[A] Compounds of the formula

wherein R ² to R ⁵ and X have the meanings given in claims 1 to 3, with amidines of the formula

NH

R NH,

(V)

wherein R ^{1 has} the meaning given in claims 1 to 3, or its salts or

[B] Compounds of the formula

in which R ³ to R ⁵ and X have the meanings given in Claims 1 to 3,

in a one-step process with aldehydes of the formula

R ² -CHO (II)

wherein R ^{2 has} the meaning given in Claims 1 to 3,

and amidines (V) or their salts

[C] if X in formula (I) represents a methylene group, compounds of the formula

Wonn

R ¹ to R ^{3 have} the meanings given in claims 1 to 3 and

Y represents a member of the group chloride, bromide, iodide, mesylate, tosylate,

with compounds of the formula

wherein R and R ^{3 have} the meanings given in Claims 1 to 3, or implement

[D] if X in formula (I) represents an ethylene group, compounds of the formula

with amidines (V) or their salts.

6. Compounds of the formula

Wonn

R ¹ , R ² , R and R ^{5 have} the meanings given in Claims 1 to 3.

7. Compounds according to claims 1 to 3 for combating diseases.

8. Medicament containing at least one compound according to claims 1 to 3 and optionally further active pharmaceutical ingredients.

9. Use of compounds of claims 1 to 3 (without taking into account the provisions (1) and (2)) for the manufacture of a medicament for the treatment and prophylaxis of viral diseases.

10. Use of compounds of claims 1 to 3 (without taking into account the provisions (1) and (2)) for the manufacture of a medicament for the treatment and prophylaxis of hepatitis B infections.

11. Combinations

A) at least one dihydropyrimidine according to claims 1 to 3 (without

Taking into account the provisions (1) and (2)), B) at least one HBV antiviral agent different from A and, if appropriate C) at least one immunomodulator.

12. Combinations according to claim 11, wherein component B is an HBV polymerase inhibitor.

13. Combinations according to claim 12, wherein component B is lamivudine.

14. Combinations according to claim 11, wherein component B consists of the compounds of the formula

Wonn

R ¹ and R ² independently of one another are C] -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 - -Rr. 12 independently of one another hydrogen, halogen, C 1 -C ₄ -alkyl, optionally substituted dC ₄ -alkoxy, nitro, cyano or trifluoromethyl,

R, 1 "3 is hydrogen, _CC. ₄ - alkyl, C -C ₇ -acyl or aralkyl and

X halogen or optionally substituted dC ₄ alkyl mean,

and whose salts are selected.

15. Combinations according to claim 14, wherein

X is chlorine, A 1-piperidinyl and Y and Z are each phenyl.

16. A process for the preparation of the combinations according to claims 11 to 15, characterized in that components A and B are combined or prepared in a suitable manner.

17. Combinations according to claims 11 to 15 for combating diseases.

18. Medicament containing at least one combination according to claims 11 to 15 and optionally further active pharmaceutical ingredients.

19. Use of combinations of claims 11 to 15 for the manufacture of a medicament for the treatment and prophylaxis of viral diseases.

20. Use of combinations of claims 11 to 15 for the manufacture of a medicament for the treatment and prophylaxis of hepatitis B infections.