EP1286974A2

EP1286974A2 - Medicament for viral diseases

Info

Publication number: EP1286974A2
Application number: EP01909773A
Authority: EP
Inventors: Michael Brands; Susanne Nikolic; Peter Eckenberg; Marcus Bauser; Johannes Kaulen; Arnold Paessens; Erwin Graef; Olaf c/o Bayer Corp. WEBER; Stefan Lottmann; Karl-Heinz Schlemmer
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 2000-02-28
Filing date: 2001-02-19
Publication date: 2003-03-05
Also published as: BR0108723A; CA2401405A1; WO2001064755A3; KR20020079963A; MXPA02008418A; PL365124A1; WO2001064755A2; US20030187028A1; TR200201954T2; CN1406233A; IL151188A0; JP2003526639A; AU3739801A

Abstract

Isoxazoles are highly effective anti-viral agents. Combinations of isoxazoles, dihydropyrimidines and/or lamivudine and, optionally, interferon inhibit the proliferation of HBV viruses better than conventional agents. (I) R1, R2 = (halo)alkyl, X = a bivalent group, A = aryl or heteroaryl and R3 = H or (halo)alkyl.

Description

Medicines for viral diseases

The present invention relates to new isoxazoles and combinations of A) non-nucleoside inhibitors from the class of the isoxazoles, B) other antiviral agents such as (i) dihydropyrimidines and / or (ii) nucleoside analogs, such as e.g. Lamivudine, and optionally C) immunomodulators, e.g. Interferon (the combinations are two, three or fourfold combinations), a process for the preparation of the isoxazoles and combinations and their use as medicaments, in particular for the treatment and prophylaxis of HBV

Infections.

“Combinations” in the sense of the invention are understood not only to mean dosage forms which contain all components (so-called fixed combinations) and combination packs which contain the components separately from one another, but also components which are applied simultaneously or at different times, provided that they are used for treatment or prophylaxis of the same disease.

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

Several options have already been proposed for virus inhibition:

1. the inhibition of the virus by dihydropyrimidines, which bring about a strong reduction in the viral DNA and the viral core protein; 2. the inhibition of HBV polymerase by analogues of the substrates of this enzyme such as lamivudine, FTC, adefovir dipivoxil, abacavir, ß-L-FDDC, L-FMAU and BMS 200 475;

3. the inhibition of HBV by immunological principles such as the treatment of chronic hepatitis by interferon;

4. inhibition by other active substances, the mode of action of which is not known or is the subject of speculation, such as AT-61 = N - [(IE) -2- chloro-2-phenyl-1- (l-piperidinylcarbonyl) ethenyl] benzamide, which is apparently in the

The process of packaging the pre-genomic RNA intervenes in the unfinished core particles; see. King et al., Antimicrob. Agents and chemother. 42, 3179-3186 (1998);

5. stimulation of host immune defense, e.g. with thymosin-α.

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. Combinations of interferon with lamivudine are not synergistically effective.

Previous therapeutic agents for the treatment of HBV-infected patients, e.g. Interferon or lamivudine are used as monotherapy. It is known from clinical studies that combinations of both inhibitors have no advantage in combating HB V diseases.

For Adefovir Dipivoxil, BMS 200 475 and the other inhibitors mentioned above there is as yet no generally available clinical experience. New means for better and more effective therapy are therefore desirable.

WO 99/45908 describes unsubstituted isoxazoles, e.g. Leflunomide (= N- (4-trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide), with antiviral activity, among others against hepatitis viruses. However, our own studies with these compounds have shown no activity against the hepatitis B virus.

As described in WO 99/45908, leflunomide metabolizes rapidly in vivo by ring opening to N- (4-trifluoromethylphenyl) -2-cyano-4-oxobutyramide. This isomerization is only possible for isoxazoles which have a hydrogen atom on the carbon atom which is adjacent to the nitrogen atom of the isoxazole ring (3-position).

Surprisingly, it was found that isoxazoles substituted in the 3-position

Isoxazoles of WO 99/45908 clearly superior and are highly effective against hepatitis viruses. It has furthermore been found that combinations of A) isoxazoles, B) other HBV-antiviral active substances and, if appropriate, C) immunomodulators do not have the disadvantages of the prior art or only do so in part.

The invention thus relates to compounds of the formula

embedded image in which R ¹ and R ² independently of one another alkyl which is optionally substituted by one or more halogen atoms,

X is a double-bonded radical from the series consisting of OY, -N (R ⁴ ) -C (= Y) -, -CH ₂ - or a group of the formula

- (CH ₂ ) _n C (= Y) -,

n is an integer from 1 to 4,

R ³ and R ⁴ independently of one another are hydrogen or optionally halogen-substituted alkyl,

Y is an oxygen or sulfur atom and

A aryl or 6-membered hetaryl, which are optionally substituted by 1 to 3 radicals which independently of one another from the series halogen, alkyl, alkoxy, alkylthio, alkoxycarbonyl, aminocarbonylamino, mono- and di-alkylamino, cyano, amino, mono- and Dialkylaminocarbonyl - in the case of substitution in the o-position from the series halogen, alkyl, alkoxy, alkylthio - are selected,

mean.

The following applies to compounds I:

In the context of the invention, alkyl and the alkyl parts in mono- and dialkylamino and in mono- and dialkylaminocarbonyl stand for a linear or branched alkyl radical having 1 to 8, preferably 1 to 6, carbon atoms, such as methyl, ethyl, propyl, isopropyl, tert.- Butyl, n-pentyl, n-hexyl, 2-ethylhexyl or n-octyl. In the context of the invention, alkoxy represents a linear or branched alkoxy radical having 1 to 6, preferably 1 to 4, carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, alkylthio represents a linear or branched alkylthio radical having 1 to 6, preferably 1 to 4, carbon atoms, such as, for example, methylthio, ethylthio and propylthio.

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, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Halogen in the context of the invention represents fluorine, chlorine, bromine or iodine.

Preferred halogenated alkyl is trifluoromethyl.

Aryl generally represents an aromatic radical having 6 to 10 carbon atoms, preferably phenyl and naphthyl.

Hetaryl is preferably pyridyl or pyrimidyl in the context of the invention.

Preferred compounds of the formula (I) are those in which

R and R ^2, independently of one another, optionally halogen-substituted C] -C ₈

alkyl,

X is a double-bonded residue from the series C = Y and CH,

R and R ⁴ independently of one another are hydrogen or optionally halogen-substituted dC ₆ alkyl, Y is an oxygen or sulfur atom and

A phenyl, pyridyl or pyrimidyl, optionally with 1 to 3 radicals from the series halogen, -CC ₆ - alkyl, -C-C ₆ - alkoxy, QC ₆ - alkylthio, CC ₆ - alkoxycarbonyl, carbamoyl, mono-Ci-C _ό -alkylaminocarbonyl, Di-Cj-C ₆ - alkylaminocarbonyl, cyano - in the case of substitution in the o-position from the series halogen, dC ₆ - alkyl, -C-C ₆ - alkoxy, dC ₆ - alkylthio - are substituted,

mean.

Compounds of the formula (I) in which

R ¹ and R ² independently of one another C ¹ -C ₆ alkyl or trifluoromethyl,

X C = Y,

R ³ and R ⁴ independently of one another are hydrogen or dC ₆ -alkyl, preferably hydrogen or methyl,

Y is an oxygen or sulfur atom and

A mono- to trisubstituted, preferably 3,4- or 3,5-disubstituted, phenyl or pyridyl, the substituents of which are independent of one another from the

Series alkyl, halogen, CF _{3 are} selected, in particular 3-methyl-4-fluoro- and 3-chloro-4-fluorophenyl,

mean. The isoxazoles according to the invention can be prepared from the corresponding acid chloride 2 by reaction with an amine HNAR ³ :

(Scheme 1)

The synthesis of the heterocyclic building block 2 can e.g. in analogy to G. Storck, J.E. McMurry, J. Am. Chem. Soc. 1967, 89, 5461 according to the following scheme:

(Scheme 2)

For this purpose, for example, ketoester 5 with pyrroldin 6 is converted into enaminoester 7 under dehydrating conditions, which reacts with an aliphatic nitro compound in the presence of base, such as triethylamine, and a dehydrating agent such as phenyl isocyanate or phosphorus oxychloride to give isoxazole 8. The ethyl ester can then be split, for example with aqueous sodium hydroxide solution, and the resulting acid 9 can be converted into the acid chloride, for example by treatment with thionyl chloride. For example, the preparation of 3- (3,5-dimethyl-4-isoxazolyl) acetyl chloride and propanoyl chloride can be carried out analogously to the literature (J. Org. Chem. 59, 2882-2884 (1994), Ann. Chim. 26 ( 7), 340 (1902)).

Commercial anilines or heterocyclic amines can be used as amine component 3.

Bases for the reactions of schemes 1 and 2 can generally be sodium or lithium bistrimethylsilylamide; Alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide; sodium hydrogencarbonate; sodium hydride; organic tri (-C ₆ ) alkylamines such as triethylamine or diisopropylethylamine; Heterocycles such as 1,4-diazabicyclo [5,4,0] -undec-7-ene (DBU), pyridine, diamino-pyridine, methylpiperidine or N-methylmorpholine can be used.

Preferred bases for the reactions of Scheme 1 include organic amines such as triethylamine, diisopropylethylamine or N-methylmorpholine, which can also be carrier bound, e.g. Morpholinomethyl-polystyrene.

Preferred bases for the reactions of Scheme 2 include lithium hydroxide, pyridine, diisopropylethylamine and triethylamine.

For the synthesis of the thioamides (formula I with Y = S), the amides 4 can be reacted with Lawesson's reagent (= 2,4-bis (4-methoxyphenyl) -l, 3,2,4-dithiaphosphetane-2,4-di- sulfide; see R. Shabana et al., Tetrahedron 1980 (36), 3047-3051); the reaction can take place in toluene at elevated temperature.

For the synthesis of the ureas [X = -N (R ⁴ ) -C (= Y) -], for example, 3-amino-2,5-dimethyl-isoxazole can be used as the starting material (A. Pascual, Helv. Chim. Acta 1989 ( 72), 556-569), which after conversion into the carbamoyl chloride is reacted in an analogous manner with amines HNAR ³ . The amines (X = CH ₂ ) can be obtained from the corresponding carboxamides described in Scheme 1 by reduction, for example with borane-dimethyl sulfide complex (J. March, Advanced Organic Chemistry, 4th edition, New York 1992, p. 1212) ,

The reactions of Schemes 1 and 2 can be carried out in inert organic solvents. These include saturated linear, branched and cyclic hydrocarbons such as hexane, cyclohexane or petroleum fractions, alcohols such as methanol, ethanol or isopropanol, ethers such as diethyl ether, 1,4-dioxane or tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2- Dichloroethane, trichloroethane or tetrachloroethane, aromatic hydrocarbons such as benzene, toluene or xylene, dipolar aprotic solvents such as nitromethane, dimethylformamide or acetonitrile, or mixtures thereof. Dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethanol and dimethylformamide are particularly preferred.

Preferred solvents for the reactions of Scheme 1 include chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloromethane and ethers such as tetrahydrofuran. The reactions of scheme 2 are preferably carried out in aromatic hydrocarbons such as toluene, chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, ethers such as tetrahydrofuran or alkanols such as ethanol.

The reactions of schemes 1 and 2 are generally carried out in a temperature range from 0 to 150, preferably from 0 to 90 ° C. The reactions can be carried out under normal, elevated or reduced pressure (e.g. 0.5 to 5 bar); generally one works at normal pressure.

The invention thus furthermore relates to a process for the preparation of compounds of the formula (I) in which R ¹ to R ³ and A have the meanings given above,

XC = Y or or a group of the formula - (CH ₂ ) _n C (= Y) -,

Y is an oxygen atom and

n is an integer from 1 to 4,

by reacting acid chlorides of the formula

embedded image in which

R ^! and R ² and X and Y have the meanings given above,

with amines of the formula NHAR ³ ,

wherein A and R ^{3 have} the meanings given above.

The invention further relates to a process for the preparation of compounds of the formula (I) in which

R ¹ to R ³ and A have the meanings given above and

X C = Y and

Y represents a sulfur atom, by treatment of compounds of formula (I), wherein

R to R and A have the meanings given above,

X C = Y and

Y represents an oxygen atom,

with Lawesson's reagent.

R ¹ to R ³ and A have the meanings given above and

X represents CH ₂ ,

by reduction of compounds of formula (I), wherein

R to R and A have the meanings given above and

X C = Y and

Y represents an oxygen atom.

R ¹ to R ⁴ and A have the meanings given in claim 1 and

X -N (R ⁴ ) -C (= Y) - and Y represents an oxygen atom,

by reacting compounds of the formula

embedded image in which

1 • R and R ^{~ have} the meanings given above,

with carbonyl group donors and amines of the formula NHAR ³ ,

wherein A and R ^{3 have} the meanings given above.

The term "carbonyl group donors" in the sense of the invention includes e.g. Trichloromethyl chloroformate, carbonyldiimidazole and phosgene.

R ¹ to R ⁴ and A have the meanings given above and

X -N (R ⁴ ) -C (= Y) - and

Y represents a sulfur atom,

by reacting compounds of the formula

embedded image in which

R> 1 u., N "d ,. R r> 2 have the meanings given above,

with thiocarbonyl group donors and amines of the formula NHAR,

wherein A and R ^{3 have} the meanings given above.

The term "thiocarbonyl group donors" in the sense of the invention includes e.g. N, N'-thiocarbonyldiimidazole and thiophosgene.

The invention further relates to combinations A) of at least one isoxazole, B) of at least one HBV-antiviral active substance different from A, preferably (i) an HBV-DNA or HBV-core protein inhibitor and or (ii) an HBV- Polymerase inhibitor, and optionally (C) at least one immunomodulator. The invention thus relates to combinations of nucleoside and non-nucleoside inhibitors and, if appropriate, immunomodulators for the treatment and prophylaxis of HBV infections and the use of these

Combinations for the treatment of HBV-induced diseases.

The compounds I described above are suitable as isoxazoles A.

HBV-DNA or HBV-core protein inhibitors B (i) are those non-nucleoside inhibitors that inhibit HBV-DNA intra- and extracellularly and at least halve the half-life of the HBV-core protein in the cell. Preferred HBV core protein inhibitors B (i) are, for example, dihydropyrimidines, as are preferred in DE-OS 198 17 264 (= WO 99/54 326), 198 17 265 (= WO 99/54 312) and 198 17 262 (= WO 99/54 329) are described.

Preferred dihydropyrimidines B (i) correspond, for example, to the formula

or their isomeric form

and their salts, in which

R ¹ phenyl, furyl, thienyl, triazolyl, pyridyl, cycloalkyl with 3 to 6 carbon atoms or residues of the formulas

or

means, the above-mentioned ring systems optionally one or more, identical or different by substituents selected from the group halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, carboxyl, hydroxyl, Ci-C _ό alkoxy, C ₁ -C ₆ alkoxycarbonyl and -C-C ₆ alkyl, are substituted, where the alkyl radical in turn can be substituted by aryl having 6 to 10 carbon atoms or halogen, and the ring systems listed optionally by -SR ⁶ , -NR ⁷ R ⁸ , -CO-NR ⁹ R ¹⁰ , -S0 ₂ -CF ₃ and -A-CH2-R ^1! are substituted,

embedded image in which

R> 6 optionally halogen-substituted phenyl,

R ⁷ to R ^{10 are} independently hydrogen, phenyl, hydroxy-substituted

Phenyl, hydroxy, C ₆ -C ₆ -acyl or C ₆ -C ₆ alkyl, where the alkyl radical in turn can be substituted by hydroxy, C ₆ -C ₆ alkoxycarbonyl, phenyl or hydroxy-substituted phenyl,

A is a radical -O-, -S-, -SO- or -S0 ₂ -,

R ^1] phenyl, which is optionally substituted one or more times, identically or differently, by substituents selected from the group consisting of halogen, nitro, trifluoromethyl, cid-alkyl and C ₁ -C ₆ -alkoxy,

mean,

R ^{2 is} a radical of the formulas -XR ¹² or -NR ¹³ R ¹⁴ , embedded image in which

X is a single bond or oxygen,

R is hydrogen, straight-chain or branched C ₁ -C ₆ -alkoxycarbonyl, a straight-chain, branched or cyclic, saturated or unsaturated C _j - C ₈ -hydrocarbon radical, which optionally has one or two identical or different hetero-chain links from the group -O-, -CO- , -NH-, -N- (d- C ₄ - alkyl) -, -S- or -SO ₂ - and optionally by halogen,

Nitro, cyano, hydroxy, aryl with 6 to 10 carbon atoms, aralkyl with 6 to 10 carbon atoms, heteroaryl or a group of the formula -NR R is substituted,

wherein

R ¹⁵ and R ¹⁶ independently of one another are hydrogen, benzyl or dC ₆ -alkyl,

R and R independently of one another hydrogen, -CC ₆ - alkyl or cycloalkyl with

3 to 6 carbon atoms,

R ^{3 is} hydrogen, amino or a radical of the formula

H ₃ CO

OCH, or

Formyl, cyano, hydroxy substituted CpC ₆ - alkylthio, trifluoromethyl or pyridyl or a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical with up to 8 carbon atoms, optionally one or more times, identically or differently, by aryloxy with 6 to 10 carbon atoms, azido, halogen, cyano, hydroxy, carboxyl, Cj-C ₆ - Alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, -CC ₆ -

Alkylthio or -CC ₆ - alkoxy (where the alkylthio or alkoxy radical in turn can be substituted by azido, amino, hydroxyl) and / or by the group - (CO) _a -NR ¹⁷ R ¹⁸ ,

where a is zero or 1,

R ¹⁷ and R ¹⁸ independently of one another are hydrogen or aryl having 6 to 10 carbon atoms, aralkyl having 6 to 10 carbon atoms or dC ₆ - alkyl, which are optionally substituted by C ₆ -C ₆ -alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, where Phenyl and benzyl are optionally substituted one or more times, identically or differently, by hydroxyl, carboxyl, CpC _ö alkyl or C ₁ -C ₆ alkoxy and / or dC ₆ alkyl optionally by -NH-CO-CH ₃ or -NH- CO-CF _{3 is} substituted,

or

R ¹⁷ and R ¹⁸ together with the nitrogen atom on which they stand mean a morpholinyl, piperidinyl or pyrrolidinyl ring,

or

R optionally methoxy-substituted phenyl

or

R and R together form a radical of the formula ^" ° s /

R are hydrogen, C ₄ - alkyl, C ₂ -C ₄ alkenyl, benzoyl or acyl having 2 to 6 carbon atoms, preferably hydrogen, methyl, benzoyl or C ₂ -C ₆ - acyl, and

R ⁵ pyridyl, pyrimidyl or pyrazinyl, each up to 3 times, identical or different, by halogen, hydroxy, cyano, trifluoromethyl, dC ₆ -alkoxy, d- C ₆ -alkyl, dC ₆ - alkylthio, carbalkoxy, dC ₆ - Acyloxy, amino, nitro, mono- or di-C ₆ -C ₆ alkylamino can be substituted,

mean.

The following compounds are very particularly preferred dihydropyrimidines B:

their isomeric forms and their salts.

The compounds II and Ila include the isomers of the formulas (II) and (Ila) and mixtures thereof. When R ^{4 is} hydrogen, the isomers (II) and (Ila) are in tautomeric equilibrium:

(l) (la)

The above dihydropyrimidines II and Ila and various processes for their preparation are known from DE-OS 198 17 264 (= WO 99/54 326) and 198 17 265 (= WO

99/54 312) known -

Further preferred dihydropyrimidines B (i) correspond to the formula

or their isomeric form

and / or their salts, wherein

R is phenyl, furyl, thienyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or a radical of the formulas

means, where the ring systems listed above, if appropriate, once or more, identically or differently, by substituents selected from the group halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, carboxyl, hydroxyl, d-

C ₆ -A_koxy, Cι-C ₆ alkoxycarbonyl and Cι-C ₆ alkyl, are substituted, wherein the alkyl radical in turn can be substituted by aryl with 6 to 10 carbon atoms or halogen, and or the ring systems listed optionally by groups of the formulas - SR ⁶ , -NR ⁷ R ⁸ , -CO-NR ⁹ R ¹⁰ , -SO ₂ -CF ₃ and -A-CH ₂ -R ^{U are} substituted,

embedded image in which

R ⁶ optionally halogen-substituted phenyl,

R ⁷ to R ¹⁰ independently of one another are hydrogen, phenyl, hydroxyl-substituted phenyl, hydroxyl, C ₁ -C ₆ -acyl or dC ₆ - alkyl, the alkyl radical of which - can be substituted by hydroxy, dC ₆ - alkoxycarbonyl, phenyl or hydroxy-substituted phenyl,

A is a radical -O-, -S-, -SO- or -S0 ₂ -,

R ^{11 is} phenyl, which may be one or more times, identical or different

Substituents selected from the group halogen, nitro, trifluoromethyl,

C ₁ -C ₆ alkyl and C ₆ -C ₆ alkoxy, is substituted,

mean,

R ^{2 is} a radical of the formulas -OR ¹² or -NR ¹³ R ¹⁴ ,

embedded image in which

R ^{12 is} hydrogen, C] -C ₆ - alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated C, -C ₈ -Kohlenwasserstoff_τest, which optionally one or two identical or different hetero chain links from the group -O-, -CO -, -NH-, -N- (C _r C ₄ - alkyl) -, -S- and -SO ₂ - and optionally by halogen, nitro, cyano, hydroxy, aryl with 6 to 10 carbon atoms or aralkyl with 6 up to 10 carbon atoms, heteroaryl or a group of the formula -NR ¹⁵ R ^{16 is} substituted,

embedded image in which

R, 15 and R, 16 independently of one another are hydrogen, benzyl or dC ₆ -alkyl,

R ¹³ and R ¹⁴ independently of one another are hydrogen, C ₁ -C ₆ -alkyl or cycloalkyl having 3 to 6 carbon atoms, R, 3 is hydrogen, amino or a radical of the formula

H ₃ CO

OCH,

or formyl, cyano, hydroxy-substituted C ₁ -C ₄ alkylthio, trifluoromethyl or a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms, optionally one or more, the same or different, by aryloxy having 6 to 10 carbon atoms, azido, cyano, hydroxy, carboxyl, dC ₆ - alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, dC ₆ - alkylthio or dC ₆ - alkoxy (the alkylthio or alkoxy radical in turn being azido, amino or hydroxyl may be substituted) and / or is substituted by the group - (CO) _a -NR ¹⁷ R ¹⁸ ,

embedded image in which

Means zero or 1

R ¹⁷ and R ¹⁸ independently of one another are hydrogen or aryl, aralkyl having 6 to 10 carbon atoms or dC ₆ -alkyl, which are optionally substituted by dC ₆ -alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, phenyl and benzyl optionally being mono- or are substituted several times, identically or differently by hydroxy, carboxyl, dC ₆ alkyl or dC ₆ alkoxy and / or C ₁ -C ₆ alkyl optionally substituted by -NH-CO-CH ₃ or -NH-CO-CF ₃ ,

or

R ¹⁷ and R ¹⁸ together with the nitrogen atom on which they stand mean a morpholinyl, piperidinyl or pyrrolidinyl ring, D is an oxygen or sulfur atom and

R ^{5 is} hydrogen, halogen or straight-chain or branched alkyl having up to 6 carbon atoms

mean.

The compounds III and IIla can exist in stereoisomeric forms which either behave like images and mirror images (enantiomers) or which do not behave like images and mirror images (diastereomers). The compounds III and IIla thus include both the enantiomers and the diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

The dihydropyrimidines III and Illa, which contain an optionally substituted oxazolyl or thiazolyl radical in the 2-position, and various processes for their preparation are known from DE-OS 198 17 262 (= WO 99/54 329).

The following applies to the compounds II, Ila, III and purple:

In the context of the invention, alkyl per se and the alkyl parts in mono- and dialkylamino and in mono- and dialkylaminocarbonyl represent a linear or branched alkyl radical having 1 to 8, preferably 1 to 6, carbon atoms, such as e.g. Methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl, n-hexyl, 2-ethylhexyl or n-octyl.

In the context of the invention, alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6, preferably 3 to 5, carbon atoms, such as, for example, ethenyl, propenyl, isopropenyl, tert-butyl, n-pentenyl and n-hexenyl. Cycloalkyl having 3 to 6 carbon atoms in the context of the invention stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, preferably cyclopentyl and cyclohexyl.

In the context of the invention, acyl stands for a straight-chain or branched

Acyl radical having 1 to 6, preferably 1 to 4 carbon atoms, e.g. Acetyl and propionyl.

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

Propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

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, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

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

Aralkyl radicals are benzyl and phenethyl.

Aryl generally represents an aromatic radical having 6 to 10 carbon atoms, preferably phenyl and naphthyl. 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, thiophenyl, pyrazolyl, imidazolyl, 1.2.3- and 1.2.4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1.2.3-, 1.3.4-, 1.2.4- and 1.2.5-oxadiazolyl , Pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, 1.3.5-, 1.2.4- and 1.2.3-triazinyl, 1.2.4-, 1.3.2-, 1.3.6- and 1.2.6-oxazinyl, especially pyridyl and pyrimidyl ,

Preferred halogenated alkyl is trifluoromethyl.

The compounds II or Ila and III or Illa can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.

Physiologically acceptable salts can be salts of the compounds II or Ila and III or Illa with inorganic or organic acids. Salts of inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts of organic carboxylic or sulfonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid are preferred , Phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds II or Ila and III or Illa. For example, particular preference is given to Sodium, potassium, magnesium or calcium salts and ammonium salts derived from ammonia or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine, are derived.

Combinations are also a subject of the invention A) at least one isoxazole,

B) at least (i) a dihydropyrimidine and / or (ii) an HBV polymerase

Inhibitors and if necessary

C) at least one immunomodulator.

HBV polymerase inhibitors B (ii) in the context of the invention are substances such as the endogenous polymerase assay, which was described by Ph. A. Furman et al. in Anti-microbial 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:

Preferred HBV polymerase inhibitors B (ii) include, for example

3TC = lamivudine = = 4-amino-l - [(2R-cis) -2- (hydroxymethyl) -l .3-oxathiolan-5-yl] -pyrimidin-2 (lH) -one, cf. EP-PS 382 526 (= US-PS 5 047 407) and WO 91/11186 (= US-PS 5 204466);

Adefovir Dipivoxil logo CNRS logo INIST

9- {2 - [[bis [(pivaloyloxy) methoxy] phosphinyl] methoxy] ethyl} adenine, cf. EP-PS 481 214 (= US-PS 5 663 159 and 5 792 756), US-PS 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 isoxazoles (I) and B) (ii) lamivudine.

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

embedded image in which

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, dC ₄ -alkyl, optionally substituted dC ₄ -alkoxy, nitro, cyano or trifluoromethyl,

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

X halogen or optionally substituted d-C alkyl

mean,

and their salts.

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

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

Another preferred embodiment of the invention relates to combinations A) of at least one isoxazole, B) (i) at least one dihydropyrimidine, (ii) lamivudine and optionally C) interferon.

The combinations according to the invention unpredictably inhibit the multiplication of the HBV virus significantly better than the agents known from the prior art or their known combinations. The use of the combinations according to the invention offers valuable treatments for HBV-induced diseases

Advantages 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.

In general, it has proven to be advantageous both in human and in veterinary medicine for the compounds (I) according to the invention or the combinations according to the invention in total amounts of about 0.5 to about 500, preferably 1 to 100 mg / kg of body weight each 24 hours, if necessary in the form of several single doses, to achieve the desired results. A single dose contains the active ingredient or active ingredients 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 medicament, and the

Period or interval within which the administration takes place.

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 1000 mg A / 5 to 500 mg B, in particular 10 to 500 mg A / 20 to

400 mg B and 5 to 1000 mg A / 5 to 500 mg B and / or 1 to 10 million IU (international units) C.

Component C, which may also be used, can be used in amounts of preferably in particular 2 to 7 million IU. about three times a week for up to a year.

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

Combinations exist, as well as processes for the preparation of these preparations.

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

The pharmaceutical preparations listed above can be prepared in a customary manner by known methods, e.g. by mixing the active ingredient or ingredients with the carrier (s).

The active substances can act systemically and / or locally. For this purpose they can be applied in a suitable way, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant. The active ingredients can be administered in suitable application forms for these application routes.

For oral administration, the active ingredient or ingredients are suitable for rapid and / or modified delivery forms, e.g. Tablets with or without (e.g. enteric coating), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.

Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration, the following are suitable shape injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes, e.g. Inhaled drug forms (e.g. powder inhalers, nebulizers), nasal drops solutions, sprays; Tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include Carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), dyes (e.g. inorganic pigments) such as iron oxides) or taste and / or smell.

The indication areas for the compounds (I) and combinations according to the invention include:

1. the treatment of acute and chronic viral infections which can lead to infectious hepatitis, for example infections with hepatitis B viruses; the treatment of chronic is particularly preferred

Hepatitis B infections and the treatment of acute hepatitis B virus infection;

2. the treatment of acute and chronic HBV infections when co-infected with the hepatitis delta virus; and 3. the treatment of infections during organ transplants, especially liver transplants.

The invention therefore furthermore relates to the compounds (I) for combating diseases.

The invention further relates to medicaments containing at least one compound (I) and, if appropriate, further active pharmaceutical ingredients.

The invention further relates to the use of the compounds (I) in

Production of a medicament for the treatment and prophylaxis of viral diseases, in particular hepatitis B.

The invention therefore also relates to the combinations defined above for combating diseases.

The invention further relates to medicaments containing at least one of the combinations defined above and optionally further pharmaceutical active ingredients.

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

The percentages in the following examples relate to the weight, unless stated otherwise. Examples

1. Manufacturing examples

example 1

5-isopropyl-3-methylisoxazole-4-carboxylic acid N- (4-fluoro-3-methylphenyl) -amide

A solution of 10.97 g (69.3 mmol) of ethyl isobutyryl acetate and 4.93 g

(69.3 mmol) pyrrolidine in 50 ml of toluene is heated to reflux in a water separator for 3 hours. The toluene is then removed under reduced pressure and the residue is dissolved in a mixture of 5.73 g (76.3 mmol) of nitroethane, 28 ml (201 mmol) of triethylamine and 120 ml of chloroform. This solution is cooled to 5 ° C and added dropwise with a solution of 11.7 g (76.3 mmol)

Phosphorus oxychloride in 20 ml of chloroform. After the addition has ended, the mixture is stirred at room temperature for 15 hours and poured onto 100 ml of ice water. The organic phase is separated off, washed successively with 6 M hydrochloric acid, 5% sodium hydroxide solution, water and saturated aqueous NaCl solution and dried over sodium sulfate. Distill off the solvent and chromatography on

Silica gel (mobile phase dichloromethane) gives 7.52 g (55%) of 5-isopropyl-3-methyl-isoxazole-4-carboxylic acid ethyl ester as a colorless oil. 1H-NMR (300 MHz, DMSO-D ₆ ): δ = 1.28 (d, 6H) ppm, 1.31 (t, 3H) ppm, 2.35 (s, 3H) ppm, 3.71 (quint ., 1H) ppm, 4.27 (q, 2H) ppm.

A mixture of 7.5 g (38.0 mmol) of the ester, 70 ml of ethanol, 20 ml of water and 3.04 g (76.1 mmol) of sodium hydroxide is heated to reflux for 2 hours. After cooling, the majority of the ethanol is distilled off under reduced pressure. The aqueous phase is acidified with concentrated hydrochloric acid and then extracted several times with dichloromethane. The combined extracts are dried over sodium sulfate and freed from the solvent. The residue is stirred with petroleum ether. By filtration and drying under reduced pressure, 5.13 g (80%) of 5-isopropyl-3-methylisoxazole-4-carboxylic acid are isolated as a colorless solid.

1H-NMR (200 MHz, DMSO-D ₆ ): δ = 1.25 (d, 6H) ppm, 2.60 (s, 3H) ppm, 3.39 (quint., 1H) ppm. MS (DCI / NH3): 170 [M + H] ⁺ .

7.03 g (59.1 mmol) of thionyl chloride are added to 2 g (11.8 mmol) of the acid described. The mixture is heated to reflux with stirring until the gas evolution ceases (about 1 hour). The thionyl chloride is removed under reduced pressure and the resulting acid chloride (brown oil) is reacted further without purification.

A mixture of 56.3 mg (0.3 mmol) of the acid chloride, 37.5 mg (0.3 mmol) of 4-fluoro-3-methylanillin and 2.4 ml of 1,2-dichloroethane is mixed with 124 mg of morpholino-methyl Polystyrene (occupancy 3.69 mmol / g) was added and the mixture was stirred at room temperature for 16 hours. The resin is filtered off and washed with dichloromethane. Removal of volatiles under reduced pressure gives 80 mg (96%)

5-isopropyl-3-methylisoxazole-4-carboxylic acid N- (4-fluoro-3-methylphenyl) -amide as a colorless solid.

LC-MS (C18 column, 50x2.1 mm, 3.5 μm; gradient acetonitrile + 0.1% formic acid [A], water + 0.1% formic acid [B]: up to 4 min A / B = 1: 9 , 4-6 min A / B = 9: l; flow rate 0.5 ml / min; ionization ESI positive): Rt 4.3 min, m / z 276 [M] ⁺ . Example 2

3,5-dimethylisoxazole-4-carboxylic acid N- (4-fluoro-3-methylphenyl) -amide

A solution of 2.53 g (18.8 mmol) of 4-fluoro-3-methylaniline and 2.88 ml (20.7 mmol) of triethylamine in 30 ml of dichloromethane is cooled to 0 ° C. and added dropwise with a solution of 3 0 g (18.8 mmol) of 3,5-dimethylisoxazole carboxylic acid chloride in 10 ml of dichloromethane. The solution is stirred for 1 hour at 0 ° C. and then washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous NaCl solution. The organic phase is dried over sodium sulfate and the volatile constituents are removed under reduced pressure. The remaining residue is chromatographed on silica gel (dichloromethane / ethyl acetate gradient). 3,5-Dimethylisoxazole-4-carboxylic acid N- (4-fluoro-3-methylphenyl) -amide results as a colorless solid (4.0 g, 86%).

1H-NMR (200 MHz, CDC1 ₃ ): δ = 2.30 (s, 3H) ppm, 2.51 (s, 3H) ppm, 2.67 (s, 3H) ppm, 6.97 (t, 1H) ) ppm, 7.23 (m, 1H) ppm, 7.41 (m, 1H) ppm. MS (DCI / NH ₃ ): 249 (M + H) ⁺ .

Example 3

3,5-dimethylisoxazole-4-carboxylic acid N- (4-fluoro-3-methylphenyl) -thioamid

A mixture of 100 mg (0.40 mmol) of 3,5-dimethylisoxazole-4-carboxylic acid N- (4-fluoro-3-methylphenyl) amide, 80 mg (0.20 mmol) of Lawesson's reagent and 5 ml of toluene is heated to 90 ° C for 1 hour. After the toluene has been distilled off under reduced pressure, it is chromatographed on silica gel (dichloromethane / ethyl acetate gradient). 3,5-Dimethylisoxazole-4-carboxylic acid N- (4-fluoro-3-methylphenyl) thioamide results as a colorless solid (106 mg, 100%).

1H-NMR (200 MHz, DMSO-D ₆ ): δ = 2.26 (s, 3H) ppm, 2.32 (s, 3H) ppm, 2.52 (s, 3H) ppm, 7.22 (t , 1H) ppm, 7.67 (m, 2H) ppm, 11.65 (s, br, 1H) ppm. MS (DCI / NH ₃ ): 265 (M + H) ⁺ .

The compounds of the examples below were synthesized analogously to Examples 1 to 3.

LCMS-methods:

Method A:

C18 column, 150x2.1 mm, 5 µm; Gradient acetonitrile + 0.1% formic acid [A], water + 0.1% formic acid [B]: up to 9 min A / B = T: 9, 9-10.1 min A / B = 9: 1; Flow rate 0.5 ml / min; Oven temperature 40 ° C, UV detection 210-350 nm, ionization ESI positive

Method B:

C18 column, 50x2.1 mm, 3.5 µm; Gradient acetonitrile + 0.1% formic acid [A], water + 0.1% formic acid [B]: up to 4 min A / B = 1: 9, 4-6 min A / B = 9: 1; Flow rate 0.5 ml / min; Oven temperature 40 ° C, UV detection 208-400 nm, ionization ESI positive

Method C:

C18 column, 150x2.1 mm, 5 µm; Gradient acetonitrile [A], 0.01 N hydrochloric acid [B], water [C]: up to 4 min A / B / C = l 0:45:45, 4-9 min A / B / C = 90: 5: 5; flow rate

0.6 ml / min; Oven temperature 40 ° C, UV detection 210 nm, ionization ESI positive Example 32

N - [(3,5-dimethyl-4-isoxazolyl) methyl] -4-fluoro-3-methylaniline

500 mg (2.01 mmol) of the compound from Example 2 are dissolved in 30 ml of tetrahydrofuran under argon, and 0.65 g (8.56 mmol, 4.28 ml) of borane-dimethyl sulfide complex is added at 0 ° C. The mixture is then heated to boiling for 2 h. 4.13 ml of 1N hydrochloric acid are added and the mixture is stirred under reflux for a further hour. After cooling to room temperature and addition of 12.5 ml of 0.5 M sodium hydroxide solution, the mixture is extracted with ethyl acetate and the organic phase is washed with saturated sodium chloride solution. It is dried over magnesium sulfate and the solvent is distilled off. The residue is then purified by chromatography on silica gel (1st dichloromethane, 2nd cyclohexane: ethyl acetate 6: 1) and recrystallized. The target compound is obtained in a yield of 54% (0.253 g). MS (EI / POS): 234 [M + H] ⁺

1H-NMR (200 MHz, CDC1 ₃ ): δ = 2.22 (d, 3H) ppm; 2.27 (s, 3H) ppm; 2.38 (s, 3H) ppm; 3.30 (broad s, IH) ppm; 3.95 (s, 2H) ppm; 6.35 - 6.50 (m, 2H) ppm; 6.85 (t, IH) ppm.

In analogy to the specification of example 32, the following example 33 is prepared starting from the compound from example 30: Example 33

4-fluoro-N - [(5-isopropyl-3-propyl-4-isoxazolyl) methyl] -3-methylaniline

Yield: 13%

MS (DCI / NH ₃ ) = 291 [M + H] ⁺ , 308 [M + NH ₄ ] ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 0.95 (t, 3H) ppm; 1.33 (d, 6H) ppm; 1.60 - 1.80

(m, 2H) ppm; 2.21 (d, 3H) ppm; 2.70 (t, 2H) ppm; 2.95 - 3.11 (m, IH) ppm; 3.22

(broad s, IH) ppm; 3.95 (s, 2H) ppm; 6.37 - 6.50 (m, 2H) ppm; 6.86 (t, IH) ppm.

Example 34

Level A:

3,5-dimethyl-4-isoxazolamine

12.00 g (84.44 mmol) of 3,5-dimethyl-4-nitro-isoxazole are placed in 430 ml of water, and 106.15 g (1.984 mol) of ammonium chloride are added. At 4 ° C, 46.93 g (7.17 mol) of zinc are added within 2 h, the reaction solution is mixed with

Ethyl acetate and the organic phase filtered through Celite. After drying over magnesium sulfate, the solvent is distilled off and the target compound is obtained in a yield of 86% (8.10 g). 1H-NMR (300 MHz, CDCI ₃ ): δ = 2.20 (s, 3H) ppm; 2.28 (s, 3H) ppm; 2.51 (broad s, 2H) ppm. Level B:

N- (3,5-dimethyl-4-isoxazolyl) -N '- (4-fluoro-3-methylphenyl) urea

1.25 g (10.00 mmol) of 3-methyl-4-fluoroaniline are dissolved in 40 ml of dichloromethane and 4.29 g (20.00 mmol) of 1,8-bis (dimethylamino) naphthalene are added. 0.72 ml (6.00 mmol) of trichloromethyl chloroformate in 10 ml of dimethyl methane are added dropwise at 0 ° C. and the mixture is stirred at room temperature for 1 h. The mixture is then diluted with 50 ml of dichloromethane and washed with ice water, 1 N hydrochloric acid and saturated sodium bicarbonate solution. After drying over magnesium sulfate, the filtrate is mixed with 1.12 g (10.00 mmol) of the amine from stage A and heated to boiling for 4 h. The precipitate is filtered off, washed with dichloromethane and recrystallized from ethanol. The target compound is obtained in a yield of 27% (0.71 g). MS (DCI / NH3): 264 [M + H] ⁺

1H-NMR (200 MHz, D ₆ -DMSO): δ = 2.10 (s, 3H) ppm; 2.20 (d, 3H) ppm; 2.26 (s, 3H) ppm; 7.00 (t, IH) ppm; 7.28 - 7.30 (m, IH) ppm; 7.34 (dd, IH) ppm; 7.68 (broad s, IH) ppm; 8.72 (broad s, IH) ppm.

Example 35

N- (3,5-dimethyl-4-isoxazolyl) -N '- (4-fluoro-3-methylphenyl) thiourea

1.25 g (10.00 mmol) of 3-methyl-4-fluoroaniline are dissolved in 50 ml of toluene, and 2.18 g (11.00 mmol) of N, N'-thiocarbonyldiimidazole are added. The mixture is then heated to boiling for 45 minutes. After cooling to 50 ° C., 1.12 g (10.00 mmol) of the compound from Example 34 (stage A) are added and the reaction solution is stirred at 70 ° C. for 4 h. After the solvent has been distilled off, the residue is stirred with ethyl acetate, the crystals are filtered off with suction and recrystallized from ethanol. The target compound is obtained in a yield of 54% (1.50 g). MS (DCI / NH3): 280 [M + H] ⁺ 1H-NMR (200 MHz, D ₆ -DMSO): δ = 2.10 (s, 3H) ppm; 2.20 (d, 3H) ppm; 2.25 (s,

3H) ppm; 7.05 - 7.18 (m, IH) ppm; 7.18 - 7.38 (m, 2H) ppm; 8.95 (broad s, IH) ppm; 9.80 (broad s, IH) ppm.

Example 36

3- (3,5-dimethyl-4-isoxazolyl) -N- (4-fluoro-3-methylphenyl) propanamide

1.00 g (7.99 mmol) of 4-fluoro-3-methylaniline are dissolved in 20 ml of dichloromethane, and 1.21 g (11.99 mmol) of triethylamine are added. A solution is formed at 0 ° C 1.50 g (7.99 mmol) of 3- (3,5-dimethyl-4-isoxazolyl) propanoyl chloride in 10 ml of dichloromethane were added. The mixture is stirred at 0 ° C. for 1 hour and then washed with water, 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solution. After drying over magnesium sulfate, the mixture is filtered through silica gel, the filtrate is concentrated, the residue is separated off and recrystallized from ethyl acetate / n-pentane. The target compound is obtained in a yield of 54% (1.19 g). Mp: 136-137 ° C.

Example 37

N- [3- (3,5-dimethyl-4-isoxazolyl) propyl] -N- (4-fluoro-3-methylphenyl) -amine

0.50 g (1.81 mmol) of the compound from Example 3 are dissolved in 30 ml of tetrahydrofuran, and 0.58 g (7.69 mmol) of borane dimethyl sulfide complex are added at 0 ° C.

After stirring under reflux for 2 hours, the mixture is cooled again to 0 ° C., 3.71 ml of 1N hydrochloric acid are added and the mixture is heated to boiling for 1 hour. 11 ml of 1N sodium hydroxide solution are added at room temperature, extracted with ethyl acetate and then washed with saturated sodium chloride solution. After drying over magnesium sulfate and distilling off the solvent, the target compound is purified by flash chromatography on silica gel (1st cyclohexane, 2nd cyclohexane / ethyl acetate 5: 1, 2: 1) and recrystallization from ethyl acetate / n-pentane in a yield of 58% (0.273 g) received. Mp .: 74-76 ° C 2. Examples of use

The antiviral activity of the compounds according to the invention 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

Pipette the microtiter plate and then dilute it in two steps 2 ¹⁰ -fold in growth medium plus 2% fetal calf serum (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% 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 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 or cells to determine the antiviral effect, the HepG2.2.15 cells were examined by light microscopy or by means of biochemical tests. procedures (eg Alamar blue staining or trypan blue staining) examined for cytotoxic changes.

The supernatants 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 HepG2.2.15-

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

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

The compounds according to the invention were generally cell-compatible up to concentrations of 10 μM (Tox-50).

Determination of the antiviral effect

After transfer of the supernatants or cells to the nylon membrane of the blot apparatus (see above), the 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 HC1, pH 7.5) and washed (2 x SSC). The DNA was then added by incubating the filter

Baked 120 ° C to the membrane within 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% N-lauroylsarcosine, 0.02% SDS and 100 μg sperm DNA of the herring.

The prehybridization 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:

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 hepatitis B-specific band was reduced by 50% by the compound according to the invention.

The treatment of the HepGits.2 virus-producing HepG2.2.15 cells with the compounds according to the invention surprisingly led to a reduction in viral DNA in the cell culture supernatant, which is discharged into the cell culture supernatant in the form of virions, or to a reduction in intracellular viral DNA.

More information:

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

Claims

Patentansprtiche

1. Compounds of the formula

embedded image in which

R ¹ and R ² independently of one another alkyl which is optionally substituted by one or more halogen atoms,

X is a double-bonded residue from the series consisting of

C = Y, -N (R ⁴ ) -C (= Y) -, -CH ₂ - or a group of the formula - (CH ₂ ) _n C (= Y) -

n is an integer from 1 to 4,

Y is an oxygen or sulfur atom and

A aryl or 6-membered hetaryl, which are optionally substituted by 1 to 3 radicals which are independently of one another from the halogen series,

Alkyl, alkoxy, alkylthio, alkoxycarbonyl, aminocarbonylamino, mono- and dialkylamino, cyano, amino, mono- and dialkylamino-carbonyl - in the case of substitution in the o-position from the series halogen, alkyl, alkoxy, alkylthio - are selected, mean.

2. Compounds of formula (I) according to claim 1, wherein

R ¹ and R ² independently of one another optionally halogen-substituted d-Cs-alkyl,

X is a double-bonded residue from the series C = Y and CH,

R ³ and R ⁴ independently of one another are hydrogen or optionally halogen-substituted dC ₆ alkyl,

Y is an oxygen or sulfur atom and

A phenyl, pyridyl or pyrimidyl, optionally substituted by 1 to 3

Radicals from the series halogen, dC ₆ -alkyl, dC ₆ -alkoxy, dC ₆ -alkylthio, -C-C ₆ -alkoxycarbonyl, carbamoyl, mono-Cι-C ₆ -alkyl-aminocarbonyl, di-Cι-C ₆ -alkylaminocarbonyl, Cyano - in the case of substitution in the o-position from the series halogen, C] -C ₆ alkyl, dC ₆ - alkoxy, Cι-C ₆ - alkylthio - are substituted,

mean.

3. Compounds of formula (I) according to claim 1, wherein

R ¹ and R ² independently of one another dC ₆ - alkyl or trifluoromethyl,

X C = Y,

R ³ and R ⁴ independently of one another are hydrogen or C ₁ -C ₆ -alkyl, Y is an oxygen or sulfur atom and

A mono- to trisubstituted phenyl or pyridyl, the substituents of which are selected independently of one another from the series alkyl, halogen, CF ₃ ,

mean.

4. Compounds of formula (I) according to claim 1, wherein

X C = Y,

R ³ and R ⁴ are independently hydrogen or C _\ -C ₆ - alkyl,

Y is an oxygen or sulfur atom and

A disubstituted phenyl or pyridyl, the substituents of which are selected independently of one another from the series alkyl, halogen, CF ₃ and phenyl,

mean.

5. Compounds of formula (I) according to claim 1, wherein

R ¹ and R ² independently of one another dC ₆ - alkyl or trifluoromethyl,

X C = Y,

R> 3. and independently of one another hydrogen or methyl, Y is an oxygen atom and

A is 3-methyl-4-fluorophenyl or 3-chloro-4-fluorophenyl.

6. Compound selected from the compounds of Examples 1, 2 and 4 to 9.

7. A process for the preparation of compounds of formula (I) according to claims 1 to 6, wherein

R ¹ to R ³ and A have the meanings given in Claims 1 to 6,

XC = Y or a group of the formula - (CH ₂ ) _n C (= Y) -,

Y is an oxygen atom and

n is an integer from 1 to 4,

by reacting acid chlorides of the formula

embedded image in which

1 9

R and R have the meanings given in Claims 1 to 6 and

X and Y have the meanings given above, with amines of the formula NHAR ³ ,

wherein A and R have the meanings given above.

8. A process for the preparation of compounds of formula (I), wherein

R ¹ to R ³ and A have the meanings given in claims 1 to 4 and

X C = Y and

Y represents a sulfur atom,

by treatment of compounds of formula (I), wherein

R ¹ to R ³ and A have the meanings given above,

X C = Y and

Y represents an oxygen atom,

with Lawesson's reagent.

9. A process for the preparation of compounds of formula (I), wherein

R ¹ to R ³ and A have the meanings given in claims 1 and 2 and

X represents CH ₂ , by reduction of compounds of formula (I), wherein

1 ^

R to R and A have the meanings given above and

X C = Y and

Y represents an oxygen atom.

10. A process for the preparation of compounds of formula (I), wherein

R ¹ to R ⁴ and A have the meanings given in claim 1 and

X -N (R ⁴ ) -C (= Y) - and

Y represents an oxygen atom,

by reacting compounds of the formula

wherein

R, 1 and, r R> 2 have the meanings given above,

with carbonyl group donors and amines of the formula NHAR,

wherein A and R have the meanings given above.

11. A process for the preparation of compounds of formula (I), wherein R ¹ to R ⁴ and A have the meanings given in claim 1 and

X -N (R ⁴ ) -C (= Y) - and

Y represents a sulfur atom,

by reacting compounds of the formula

embedded image in which

R and R have the meanings given above,

with thiocarbonyl group donors and amines of the formula NHAR,

where A and R have the meanings given above.

12. Combinations

A) at least one isoxazole,

B) at least one HBV antiviral active substance different from A and optionally C) at least one immunomodulator.

13. Combinations according to claim 12, the isoxazole A of the formula

corresponds to what

X is a divalent radical from the series C = Y, -N (R ⁴ ) -C (= Y) -, CH ₂ ,

R and R independently of one another are hydrogen or alkyl,

Y is an oxygen or sulfur atom and

A aryl or hetaryl, which are optionally substituted by 1 to 3 radicals which are independently selected from the group consisting of halogen, alkyl,

Alkoxy, alkylthio, alkoxycarbonyl, aminocarbonylamino, mono- and dialkylamino, cyano, amino, mono- and dialkylaminocarbonyl are selected,

mean.

14. Combinations according to claims 12 and 13, whose component B at least one dihydropyrimidine of the formula

or their isomeric form

and / or their salts,

embedded image in which

R ¹ phenyl, furyl, thienyl, triazolyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or radicals of the formulas

or

means

wherein the ring systems are optionally mono- or polysubstituted by identical or different substituents selected from the group comprising halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, carboxyl, hydroxyl, Cι-C ₆ alkoxy listed above, Cι-C ₆ - alkoxycarbonyl and _C. -C _Ö - alkyl, are substituted, where the alkyl radical in turn can be substituted by aryl having 6 to 10 carbon atoms or halogen, and the ring systems listed optionally by -SR ⁶ , -NR ⁷ R ⁸ , -CO-NR ⁹ R ¹⁰ , -SO ₂ -CF ₃ and -A -CH ₂ -R ^{n are} substituted,

Wonn

R ⁶ optionally halogen-substituted phenyl,

R to R independently of one another are hydrogen, phenyl, hydroxyl-substituted phenyl, hydroxy, C] -C ₆ -acyl or C ₁ -C ₆ -alkyl, the alkyl radical in turn being substituted by hydroxy, C ₁ -C ₆ -alkoxycarbonyl, phenyl or hydroxyl-substituted Phenyl may be substituted

A is a radical -O-, -S-, -SO- or -SO ₂ -,

R ¹ 'phenyl which is optionally substituted one or more times, identically or differently, by substituents selected from the group consisting of halogen, nitro, trifluoromethyl, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy,

mean,

R ^{2 is} a radical of the formulas -XR ¹² or -NR ¹³ R ¹⁴ ,

wherein

X is a single bond or oxygen,

R ¹² is hydrogen, straight or branched _C. -C _ö alkoxycarbonyl, a straight-chain, branched or cyclic, saturated or unsaturated C.-C ₈ -hydrocarbon radical, which may be one or contains two identical or different hetero chain links from the group -O-, -CO-, -NH-, -N- (-C-C ₄ alkyl) -, -S- or -SO ₂ - and optionally by halogen, nitro, Cyano, hydroxy, aryl with 6 to 10 carbon atoms, aralkyl with 6 to 10 carbon atoms, heteroaryl or a group of the formula -NR ¹⁵ R ^{16 is} substituted,

wherein

R ¹³ and R ¹⁴ independently of one another are hydrogen, dC ₆ -alkyl or cycloalkyl having 3 to 6 carbon atoms,

R ^{3 is} hydrogen, amino or a radical of the formula

H ₃ CO

OCH, or

Formyl, cyano, hydroxy-substituted -CC ₆ - alkylthio, trifluoromethyl or pyridyl or a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical with up to 8 carbon atoms, optionally one or more, the same or different, by aryloxy with 6 to 10 carbon atoms, azido, halogen, cyano, hydroxy, carboxyl, dC ₆ -

Alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, d- C ₆ alkylthio or C ₆ -C alkoxy (where the alkylthio or alkoxy radical may in turn be substituted by azido, amino, hydroxyl) and / or by the group - (CO) _a -NR ¹⁷ R ^{18 is} substituted, embedded image in which

a means zero or 1,

R ¹⁷ and R ¹⁸ independently of one another are hydrogen or aryl with 6 to

10 carbon atoms, aralkyl having 6 to 10 carbon atoms or -CC ₆ - alkyl, which are optionally substituted by dC ₆ - alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, phenyl and benzyl optionally one or more times, identically or differently hydroxy,

Carboxyl, Cj-Cό- alkyl or Cι-C ₆ - alkoxy are substituted and / or C _r C ₆ alkyl is optionally substituted by -NH-CO-CH ₃ or -NH-CO-CF ₃ ,

or

R and R together with the nitrogen atom on which they stand represent a morpholinyl, piperidinyl or pyrrolidinyl ring,

or

R, 3 optionally methoxy-substituted phenyl

or

R and R together represent a radical of the formula - C / R ^{4 is} hydrogen, dC ₄ alkyl, C ₂ -C ₄ alkenyl, benzoyl or acyl having 2 to 6 carbon atoms, preferably hydrogen, methyl, benzoyl or C ₂ -C ₆ acyl, and

R ⁵ pyridyl, pyrimidyl or pyrazinyl, each up to 3 times, the same or different, by halogen, hydroxy, cyano, trifluoromethyl, Ci-C _ö alkoxy, dC ₆ alkyl, dC ₆ - alkylthio, carbalkoxy, CC ₆ - Acyloxy, amino, nitro, mono- or di-C ₆ -C ₆ alkylamino can be substituted,

mean.

15. Combinations according to claim 14, whose component B at least one compound of the formulas

contains their isomeric forms and / or their salts.

16. Combinations according to claim 14, whose component B at least one compound of the formula

or their isomeric form

and or contains their salts,

embedded image in which

means

where the ring systems listed above may be mono- or polysubstituted, identically or differently, by substituents selected from the group halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, carboxyl, hydroxyl, C ₁ -C ₆ -alkoxy, dC ₆ -alkoxycarbonyl and -C _ö - Alkyl, are substituted, where the alkyl radical in turn can be substituted by aryl having 6 to 10 carbon atoms or halogen, and / or the ring systems listed optionally by groups of the formulas -SR ⁶ , -NR ⁷ R ⁸ , -CO-NR ⁹ R ¹⁰ , -SO ₂ -CF ₃ and -A-CH ₂ -R ^{n are} substituted,

embedded image in which

R optionally halogen-substituted phenyl,

R ⁷ to R ¹⁰ are independently hydrogen, phenyl, hydroxy-substituted phenyl, hydroxy, dC ₆ acyl or _C. -C ₆ alkyl, where the alkyl radical in turn can be substituted by hydroxy, dC _ö - alkoxycarbonyl, phenyl or hydroxy-substituted phenyl,

A a residue -O-, -S-, -SO- or -SO ₂ - R ^{11 is} phenyl which is optionally substituted one or more times, identically or differently, by substituents selected from the group consisting of halogen, nitro, trifluoromethyl, dC ₆ alkyl and dC ₆ alkoxy,

mean,

R ^{2 is} a radical of the formulas -OR ¹² or -NR ¹³ R ¹⁴ ,

wherein

R ^{12 is} hydrogen, -CC ₆ - alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated C.-C ₈ - hydrocarbon radical, which optionally contains one or two identical or different hetero chain links from the group -O-, -CO-, - NH,

-N- (C] -C ₄ - alkyl) -, -S- and -SO - and optionally by halogen, nitro, cyano, hydroxy, aryl having 6 to 10 carbon atoms or aralkyl having 6 to 10 carbon atoms, heteroaryl or a group of the formula -NR ¹⁵ R ^{16 is} substituted,

embedded image in which

R and R independently of one another are hydrogen, C ₁ -C ₆ -alkyl or cycloalkyl having 3 to 6 carbon atoms,

R ^{3 is} hydrogen, amino or a radical of the formula H ₃ CO

OCH,

or formyl, cyano, hydroxy-substituted C.-C ₄ -alkylthio, trifluoromethyl or a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical with up to 8 carbon atoms, optionally with one or more, the same or different, by aryloxy 6 to 10 carbon atoms, azido, cyano, hydroxy, carboxyl, dC ₆ -alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, -C-C ₆ - alkylthio or dC ₆ - alkoxy (the alkylthio or alkoxy radical in turn may be substituted by azido, amino or hydroxyl) and / or by the

Group - (CO) _a -NR ^I7 R ^{18 is} substituted,

Wonn

a means zero or 1,

17 1 row

R and R independently of one another are hydrogen or aryl, aralkyl having 6 to

10 carbon atoms or dC ₆ -alkyl, which are optionally substituted by dC ₆ -alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, phenyl and benzyl optionally one or more times, identically or differently, by hydroxyl, carboxyl, dC ₆ -alkyl or dC ₆ -alkoxy are substituted and / or dC ₆ -alkyl is optionally substituted by -NH-CO-CH ₃ or -NH-CO-CF ₃ ,

or

D is an oxygen or sulfur atom and R ^{5 is} hydrogen, halogen or straight-chain or branched alkyl having up to 6 carbon atoms

mean.

17. Combinations according to claims 12 to 16, whose component B contains at least one HB V polymerase inhibitor.

18. Combinations according to claims 12 to 16, whose component B contains lamivudine.

19. Combinations according to claims 12 to 16, whose component B at least one compound of the formula

and / or their salts, wherein

R and R independently of one another denote dC-alkyl or together with the nitrogen atom on which they are located form a ring with 5 to 6 ring atoms which comprise carbon and / or oxygen, R -R independently of one another hydrogen, halogen, dC ₄ - alkyl, optionally substituted dC ₄ - alkoxy, nitro, cyano or trifluoromethyl,

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

X halogen or optionally substituted dC ₄ alkyl

mean.

20. Combinations according to claims 12 to 19, whose component B (i) contains a dihydropyrimidine and / or (ii) an HBV polymerase inhibitor.

21. Combinations according to claims 12 to 19, whose component B at least one compound of the formula

and / or their salt (s), 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, dC ₄ alkyl, optionally substituted dC ₄ alkoxy, nitro, cyano or trifluoromethyl,

R ^{13 is} hydrogen, dC ₄ alkyl, C 1 -C ₇ acyl or aralkyl and

X halogen or optionally substituted -CC ₄ - alkyl

mean.

22. Combinations according to claim 21,

wherein

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

23. Combinations according to claims 12 to 22, whose immunomodulator C contains interferons.

24. Combinations of A) at least one isoxazole, B) (i) at least one

Dihydropyrimidins, (ii) lamivudine and optionally C) at least one interferon.

25. A process for the preparation of the combinations according to claims 12 to 24, characterized in that components A, B and optionally C are combined or prepared in a suitable manner.

26. Compounds according to claims 1 to 6 and combinations according to claims 12 to 24 for combating diseases.

27. Medicament containing at least one compound according to claims 1 to 6 or at least one combination according to claims 12 to 24 and optionally further active pharmaceutical ingredients.

28. Use of compounds of claims 1 to 6 or combinations of claims 12 to 24 in the manufacture of a medicament for the treatment and prophylaxis of viral diseases.

29. Use according to claim 28 in the manufacture of a medicament for the treatment and prophylaxis of hepatitis B.