DE10109856A1 - Use of N-phenyl arylamide for treating or preventing chronic or acute hepatitis B viral infections in humans or animals, including co-infections with hepatitis D virus - Google Patents

Abstract

Use of N-phenyl arylamides (I) to prepare a composition for treatment or prevention of hepatitis B virus (HBV) infection. Use of N-phenyl arylamides of formula (I) to prepare a composition for treatment or prevention of hepatitis B virus (HBV) infection. R = mono- or bi-cyclic, saturated or unsaturated ring that may contain up to three heteroatoms (oxygen, sulfur, nitrogen) and up to three substituents (cyano, halo, nitro, (fluoro)alkyl, alkoxy, aryl or aryloxy); R<6> and R<7> = H, halo, (fluoro)alkyl or alkoxy; and R<8>-R<10> = H, halo or fluoroalkyl. Independent claims are also included for: (1) New amides of formula (Ia) and N-(3-fluoro-5-methylphenyl)-2-methylbenzamide (Ib); and (2) Preparation of (I) and (Ia). R<1>, R<6>, R<7> = H, halo, alkyl, fluoroalkyl or alkoxy; R<2> = H, halo, alkyl, fluoroalkyl, alkoxy or NO2; and R<3>-R<5> and R<8>-R<10> = H, CN, halo or fluoroalkyl.

Description

The present invention relates to the use of anilides for the preparation of medicines for the treatment and prophylaxis of HBV infections as well as new ones Anilides and a process for their preparation.

The hepatitis B virus belongs to the Hepadna virus family. It causes one acute and / or a persistent-progressive, chronic illness. Diverse their clinical manifestations in the clinical picture are caused by hepatitis B Virus caused - especially chronic inflammation of the liver, cirrhosis and hepatocellular carcinoma. Furthermore, co-infection with the hepatitis Delta virus negatively affect the course of the disease.

Several options have already been proposed for virus inhibition:

• 1. the inhibition of the virus by dihydropyrimidines, which greatly reduce the cause viral DNA and the viral core protein;
• 2. the inhibition of the polymerase of HBV by analogues of the substrates of this ene enzymes such as lamivudine, FTC, adefovir dipivoxil, abacavir, β-L-FDDC, L-FMAU and BMS 200 475;
• 3. the inhibition of HBV by immunological principles, such as. B. the Be action of chronic hepatitis by interferon;
• 4. the inhibition by other active substances whose modes of action are not knows or is the subject of speculation, such as B. AT-61 = N - [(1E) -2- Chloro-2-phenyl-1- (1-piperidinylcarbonyl) ethenyl] benzamide, which apparently in the Process of packaging the pre-genomic RNA into the unfinished core parts kel intervenes; see. King et al., Antimicrob. Agents and chemother. 42, 3179-3186 (1998);  
• 5. the stimulation of host immune defense, such as. B. with thymosin-α.

The only agents approved for the treatment of chronic hepatitis are In terferon and lamivudine. However, interferon is only moderately effective and has none desired side effects; Lamivudine is effective, but under treatment resistance develops quickly and after stopping therapy in most cases there is a rebound effect.

For Adefovir Dipivoxil, BMS 200 475 and the other inhibitors mentioned above there is no generally available clinical experience.

New means for better and more effective therapy are therefore desirable.

Surprisingly, it was found that anilides acted against hepatitis viruses are highly effective.

The invention therefore relates to the use of compounds of the formula

wherein
R is a mono- or bicyclic saturated or unsaturated radical which contains up to three, preferably up to two heteroatoms (selected from the series of oxygen, nitrogen, sulfur) and up to three substituents (selected from the series cyano, halogen, nitro , Alkyl, fluoroalkyl, alkoxy, aryl, aryloxy) can carry,
R ⁶ and R ^{7 are} independently hydrogen, halogen, alkyl, fluoroalkyl or alkoxy and
R ⁸ to R ¹⁰ independently of one another are hydrogen, halogen or fluoroalkyl
mean,
for the manufacture of medicinal products for the treatment and prophylaxis of HBV infections.

Preferred radicals R include furanyl, quinolinyl, pyrazolyl, thiazolyl, dihydrooxathiinyl, dihydrooxazolyl (these radicals can be substituted), in particular substituted phenyl. Accordingly, preferred compounds to be used correspond to the formula

wherein
R ¹ , R ² , R ⁶ and R ⁷ independently of one another hydrogen, halogen, alkyl, fluoroalkyl or alkoxy and R ² also nitro and
R ³ to R ⁵ and R ⁸ to R ¹⁰ independently of one another are hydrogen, cyano, halogen or fluoroalkyl
mean.

Preferred substituents for the heterocyclic radicals R include halogen (before preferably bromine), methyl, trifluoromethyl and phenyl; two adjacent substitutes ten can mean 2-oxa-propane-1,3-diyl, propane-1,3-diyl or butane-1,4-diyl.

Compounds to be used with particular preference correspond to formula II,
wherein
R ^{1 is} hydrogen, halogen (preferably fluorine or chlorine), alkyl (preferably methyl) or alkoxy (preferably methoxy),
R ^{2 is} hydrogen, halogen (preferably fluorine, chlorine or bromine), nitro, or alkoxy (preferably methoxy),
R ^{6 is} hydrogen or alkyl, preferably hydrogen or methyl,
R ⁷ halogen (preferably fluorine or chlorine) or alkyl (preferably methyl or ethyl),
R ^{8 is} hydrogen, halogen (preferably fluorine or chlorine) or trifluoromethyl and
R ³ to R ⁵ , R ⁹ and R ¹⁰ independently of one another are hydrogen or halogen, preferably hydrogen or fluorine,
mean.

Examples of compounds I to be used with particular preference are shown in Table 1.  

Table 1

Some of the compounds I are known; see. u. a. DE-OS 22 46 308, 26 35 818, 27 19 828, DD 151 447, EP-A 661 266, FR 8 118, BE 672 361, GB 1 436 306, 1 484 855, US 3 981 814, 3 988 364, 4 123 554, 5 631 280, 5 728 835, WO 96 / 30014,98 / 9630, JP-A2 01 071 843, 08 048 663, 51 076 425, 51 086 134, 51 095 131, 52 003 823, 52 110 826, 53 072 823, 53 105 444, 55 031 048, JP-B4 53 041 208, 54 002 252, 54 002 255, 55 038 923, 60 021 135, 61 011 201, 61 015 843, 61 021 444, 63 038 966.

The invention further relates to the new compounds 1 to 9 and 11 to 15 of Table 3 in the test section of the examples. The new connections can be analog known methods can be produced. Usually you become the acid chloride convert with the aniline to anilide.

The acid chlorides required as starting material are either known or they are can be prepared analogously to known processes. The manufacture of the case games 10-12 used acid chlorides can, for example, analogous to the previous writings in the literature (Il Farmaco 41 (6), 440-453 (1986); J. Org. Chem. 62, 5908-5919 (1997); J. Heterocyclic Chem. 23, 173-176 (1986)). The required carboxylic acids can, for example, analogously to a regulation in J. Org. Chem. 48, 366-372 (1983).

The anilines required as starting material are either known or they can be NEN can be prepared analogously to known processes (literature: US Pat. No. 4,326,081; J. Org. Chem 47 (15), 3018 (1982); Tetrahedron Lett. 29: 5545 (1988); Chem. Lett. 1991, 195; J. Mol. Catal. 60: 155 (1990); Chem. Pharm. Bull. 38 (8), 2097-2101 (1990); Bull. Chem. Soc. Jpn. 64: 602-612 (1991); Bull. Chem. Soc. Jpn. 65, 831-836 (1992); Synth. Commun. 27: 1059-1063 (1997); Synth. Commun. 25 3799-3803 (1995); Synth. Commun. 26, 973-980 (1996)).

Alkyl per se and the alkyl parts in fluoroalkyl stand for egg in the context of the invention NEN linear or branched alkyl radical having 1 to 8, preferably 1 to 6 carbon  atoms, such as B. methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl, n-hexyl, 2-ethylhexyl or n-octyl. Preferred fluoroalkyl is trifluoromethyl.

In the context of the invention, alkoxy represents a linear or branched alkoxy radical with 1 to 6, preferably 1 to 4 carbon atoms, such as. B. Methoxy, Ethoxy, Pro poxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Aryl per se and the aryl parts in aryloxy stand for one in the context of the invention aromatic radical with 6 to 10 carbon atoms, preferably phenyl and Naphthyl.

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

The present invention includes drugs for HBV infections, i.e. H. pharmaceutical preparations in addition to non-toxic, inert pharmaceutical suitable carriers one or more Ver to be used according to the invention contain bond or from a compound to be used according to the invention consist.

The compounds to be used according to the invention can be found in the above led pharmaceutical preparations in general in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the preparations be that.

The pharmaceutical preparations listed above can in addition to the inventions compounds to be used in accordance with the invention also have further pharmaceutical activity substances included.

The preparation of the pharmaceutical preparations listed above can be carried out in practice Licher done by known methods, for. B. by mixing the active ingredient or the active ingredients with the carrier or carriers.  

The active substance can act systemically and / or locally. For this purpose he can be applied in a suitable manner, such as. B. oral, parenteral, pulmonary, nasal, sublin gual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant. For the active ingredient can administer these administration routes in suitable administration forms be enough.

The active ingredient is suitable for oral administration quickly and / or modified giving application forms, such as. B. tablets without or with (e.g. gastric juice resistant) coating, capsules, dragees, granules, pellets, powders, emulsions, Suspensions and solutions.

The parenteral application can be bypassing a resorption step happen (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneally). For parenteral administration are suitable as application shape u. a. Injection and infusion preparations in the form of solutions, suspensions sions, emulsions, lyophilisates and sterile powders.

For the other application routes, z. B. Inhalation Drugs (et al. Powder inhalers, nebulizers), nose drops / solutions, sprays; lingual, sublingual or buccal tablets or capsules, suppositories, ear and Eye preparations, vaginal capsules, aqueous suspensions (lotions, shakes mixtures), lipophilic suspensions, ointments, creams, milk, pastes, powder or Implants.

The active substances can be added to the applications listed in a manner known per se forms are transferred. This is done using inert non-toxic, pharmaceutically suitable excipients. These include a. Carriers (e.g. micro crystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersant (e.g. polyvinylpyrrolidone), synthetic  table and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidant such as ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) or taste and / or smell.

In general, it has been found in both human and veterinary medicine proven to be advantageous in the compounds (I) to be used according to the invention in Total amounts from about 0.5 to about 500, preferably 1 to 100 mg / kg body weight each 24 hours, if necessary in the form of several single doses, to achieve to deliver the desired results. A single dose contains the active ingredient or the active compounds preferably in amounts from about 1 to about 80, in particular 1 up to 30 mg / kg body weight. However, it may be necessary from the above Dosages vary depending on the type and body weight of the object to be treated, the type and severity of the disease, the Type of preparation and application of the drug as well as the period or Interval within which the administration takes place.

The indication areas for the compounds to be used according to the invention include:

• 1. the treatment of acute and chronic viral infections that lead to a infectious hepatitis, such as infection with He patitis B viruses; the treatment of chronic He is particularly preferred patits-B infections and the treatment of acute hepatitis-B virus infections tion;
• 2. the treatment of acute and chronic HBV infections in Koinfek tion with the hepatitis delta virus.

The invention therefore furthermore relates to medicaments for HBV infections, containing at least one compound to be used according to the invention and ge if necessary, further active pharmaceutical ingredients.  

Examples Working procedure for the automated synthesis of benzanilides

A solution of 10 µmol amine in 50 µl dioxane is mixed with 4 µl triethylamine and with a solution of 10 µmol of the respective acid chloride in 50 µl dioxane. After the addition has ended, the mixture is shaken for 12 hours, filtered and washed with 100 μl of dioxane.
LC-MS method:
Column Symmetry C18 2.1.150 mm, column oven 50 ° C, flow rate 0.6 ml / min. UV detection 210 nm, gradient acetonitrile + 0.6 g 30% hydrochloric acid, 0 min 10% acetonitrile, 0.01-4 min gradient to 90% acetonitrile, 4-9 min 90% acetonitrile.

example 1

4-fluoro-N- (4-fluoro-3-methylphenyl) -benzamide

To a solution of 2.90 g (34.49 mmol) of sodium hydrogen carbonate in 50 ml of water, both a solution of 3.70 g (29.56 mmol) of 4-fluoro-3-methylaniline in 25 ml of tetrahydrofuran and a solution from 3.12 g (19.71 mmol) of 4-fluorobenzoyl chloride in 40 ml of tetrahydrofuran. After stirring for 1 hour at room temperature, 600 ml of ethyl acetate are added to the reaction mixture, and the organic phase is washed with 1 N hydrochloric acid. After drying over magnesium sulfate and removal of the solvent, the target compound is obtained in a yield of 98% (4.80 g).
¹ H NMR (300 MHz, DMSO-D ₆ , δ / ppm): 2.25 (s, 3H), 7.10 (t, 1H), 7.35 (t, 2H), 7.50-7 , 60 (m, 1H), 7.61-7.70 (dd, 1H), 7.98-8.10 (m, 2H), 10.2 (broad s, 1H).
MS (DCI / NII ₃ ): 248 [M + H] ⁺ , 265 [M + NH ₄ ] ⁺ .

The following compounds were obtained analogously to Example 1:

Example 2

3-bromo-4-fluoro-N- (4-fluoro-3-methylphenyl) -benzamide

Yield: 87%.
¹ H NMR (300 MHz, DMSO-D ₆ , δ / ppm): 2.25 (s, 3H), 7.15 (t, 1H), 7.50-7.60 (m, 2H), 7 , 65 (dd, 1H), 7.95-8.05 (m, 1H), 8.30 (dd, 1H), 10.28 (broad s, 1H).
MS (DCI / NH ₃ ): 343 [M + NH ₄ ] ⁺ .

Example 3

N- (4-fluoro-3-methylphenyl) -2-phenyl-4-quinoline-carboxamide

Yield: 56%.
¹ H NMR (300 MHz, DMSO-D ₆ , δ / ppm): 2.28 (s, 3H), 7.20 (t, 1H), 7.50-7.70 (m, 5H), 7 , 75 (dd, 1H), 7.85 (t, 1H), 8.19 (d, 2H), 8.30-8.40 (m, 3H), 10.39 (broad s, 1H).
MS (ESI POS): 357 [M + H] ⁺ .

Example 4

N- (4-fluoro-3-methylphenyl) -2-methyl-4- (trifluoromethyl) -1,3-thiazol-5-carboxamide

A suspension of 0.13 g (0.46 mmol) of morpholinomethyl polystyrene resin and 0.05 g (0.22 mmol) of 2-methyl-4- (trifluoromethyl) -1,3-thiazole-5-carbonyl chloride in 1 ml of 1,2-dichloroethane is mixed with a solution of 0.03 g (0.22 mmol) of 4-fluoro-3-methylaniline in 1 ml of 1,2-dichloroethane. After 18 hours, the mixture is filtered through a filter cartridge (1.8 g of silica gel, 1.8 g of Extrelut) and washed with 15 ml of 1,2-di chloroethane. After removal of the solvent, the target compound is obtained in a yield of 68% (0.056 g).
¹ H NMR (200 MHz, DMSO-D ₆ , δ / ppm): 2.20-2.30 (m, 3H), 2.80 (s, 3H), 7.15 (t, 1H), 7 , 38-7.50 (m, 1H), 7.55 (dd, 1H), 10.85 (broad s, 1H).
MS (ESI POS): 360 [M + H + CH3CN] ⁺ .

The following compounds are obtained analogously to Example 4:

Example 5

N- (4-fluoro-3-methylphenyl) -5-methyl-1-phenyl-1H-pyrazole-3-carboxamide

Yield: 23%
¹ H NMR (200 MHz, DMSO-D ₆ , δ / ppm): 2.20 (m, 3H), 2.30 (s, 3H), 6.82 (s, 1H), 7.10 (t , 1H), 7.30-7.50 (m, 6H), 7.60 (dd, 1H).
MS (ESI POS): 310 [M + H] ⁺ .

Example 6

5-bromo-N- (4-fluoro-3-methylphenyl) -2-furamide

Yield: 16%
¹ H NMR (300 MHz, DMSO-D ₆ , δ / ppm): 2.20-2.25 (m, 3H), 6.82 (d, 1H), 7.11 (t, 1H), 7 , 34 (d, 1H), 7.49-7.57 (m, 1H), 7.61 (dd, 1H), 10.1 S (broad s, 1H).

Example 7

N- (4-fluoro-3-methylphenyl) -2-methyl-5,6-dihydro-1,4-oxathiin-3-carboxamide

Yield: 93%
¹ H-NMR (200 MHz, DMSO-D ₆ , δ / ppm): 2.00 (s, 3H), 2.15-2.25 (m, 3H), 3.00-3.10 (m, 2H), 4.20-4.33 (m, 2H), 7.08 (t, 1H), 7.35-7.50 (m, 1H), 7.55 (dd, 1H), 9.85 (broad s, 1H).
MS (ESI POS): 268 [M] ⁺ , 269 [M + H] ⁺ , 309 [M + H + CH3CN] ⁺ .

Example 8

N- (4-fluoro-3-methylphenyl) -1-methyl-3- (trifluoromethyl) -1H pyrazole-4-carboxamide

Yield: 91%
¹ H-NMR (200 MHz, DMSO-D ₆ , δ / ppm): 2.15-2.30 (m, 3H), 3.95 (s, 3H), 7.10 (t, 1 H), 7.40-7.55 (m, 1H), 7.62 (dd, 1H), 8.50 (s, 1H), 11.00 (broad s, 1H).
MS (ESI POS): 302 [M + H] ⁺ , 343 [M + H + CH3CN] ⁺ .

Example 9

N- (4-fluoro-3-methylphenyl) -3-methyl-2-nitrobenzamide

Yield: 26%
LC-MS: RT = 4.457 min. 289 [M + H] ⁺ , 330 [M + H + CH3CN] ⁺ .

Example 10

N- (4-fluoro-3-methylphenyl) -3a, 4,6,6a-tetrahydrofuro [3,4-d] isoxazole-3-carboxamide

Yield: 77%
¹ H-NMR (200 MHz, DMSO-D ₆ , δ / ppm): 2.18-2.30 (m, 3H), 3.55-3.78 (m, 2H), 4.05-4, 20 (m, 2H), 4.20-4.35 (m, 1H), 5.45 (dd, 1H), 7.10 (t, 1H), 7.45-7.60 (m, 1H) , 7.65 (dd, 1H).
LC-MS: 265 [M + H] ⁺ , 306 [M + H + CH3CN] ⁺ .

Example 11

N- (4-Fluoro-3-methylphenyl) -4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole-3-carboxamide

Yield: 73%
¹ H-NMR (200 MHz, DMSO-D ₆ , δ / ppm): 1.10-1.50 (m, 1H), 1.60-2.10 (m, 5H), 2.15-2, 28 (m, 3H), 3.90-4.05 (m, 1H), 5.15-5.30 (m, 1H), 7.10 (t, 1H), 7.45-7.60 (m, 1H), 7.69 (dd, 1H).
LC-MS: 263 [M + H] ⁺ , 304 [M + H + CH3CN] ⁺ .

Example 12

N- (4-fluoro-3-methylphenyl) -3a, 4,5,6,7,7a-hexahydro-1,2-benzisoxazole-3-carboxa mid

Yield: 71%
¹ H-NMR (200 MHz, DMSO-D ₆ , δ / ppm): 1.10-1.65 (m, 5H), 1.66-2.08 (m, 3H), 2.18-2, 24 (m, 3H), 3.25-3.41 (m, 1H), 4.45-4.62 (m, 1H), 7.10 (t, 1H), 7.48-7.60 ( m, 1H), 7.70 (dd, 1H), 10.40 (broad s, 1H).
LC-MS: 277 [M + H] ⁺ , 318 [M + H + CH3CN] ⁺ .

The benzanilides produced by automated synthesis are worked up with preparative LC-MS, the product being obtained with the expected molar mass becomes.

Table 2

test Description

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

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

Stock solutions of the test compounds (50 mM) were first dissolved in DMSO, further dilutions were made in the growth medium of HepG2.2.15. The compounds according to the invention were generally pipetted into a test concentration of 100 μM (1st test concentration) in each case in the second vertical test series of the microtiter plate and then diluted 2 ¹⁰ -fold in growth medium plus 2% by weight fetal calf serum in two steps (volume 25 µl).

Each well of the microtiter plate then received 225 μl of a HepG2.2.15 cell suspension (5 × 10 ⁴ cells / ml) in growth medium plus 2% by weight of fetal calf serum. The test mixture was incubated for 4 days at 37 ° C. and 5% CO ₂ (v / v).

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

Before harvesting the supernatants and or cells to determine the antiviral Ef the HepG2.2.15 cells were light microscopically or by means of biochemical Detection method (e.g. Alamar blue staining or trypan blue staining) on zyto toxic changes examined.  

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

cytotoxicity

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

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

There were no cytotoxic changes in the antiviral test con concentrations of the compounds to be used according to the invention who found the. As a rule, the compounds to be used according to the invention were up to 5 µM - sometimes up to 25 µM - compatible.

Determination of the antiviral effect

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

Hybridization of the DNA

Detection of the viral DNA from the treated HepG2.2.15 cells on the Nylon filters were usually made with non-radioactive, digoxigenin-labeled He Patitis B-specific DNA probes are carried out, each according to the manufacturer's instructions marked with digoxigenin, purified and used for hybridization.

Prehybridization and hybridization were done in 5 × SSC, 1 × blocking reagent, 0.1% by weight N-lauroylsarcosine, 0.02% by weight SDS and 100 µg sperm DNA of the herring. The prehybridization took place at 60 ° C for 30 minutes, the speci fish 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 Her manufacturers specified.

The filters were washed and placed in a blocking reagent (manufacturer's gabe) pre-hybridized. Subsequently, an anti-DIG antibody, which was used with alkaline phosphatase was coupled, hybridized for 30 minutes. After a wash step, the substrate of alkaline phosphatase, CSPD, was added, 5 minutes incubated with the filters, then wrapped in plastic wrap and another 15 mi grooves incubated at 37 ° C. The chemiluminescence of hepatitis B-specific DNA Signals were visible through exposure of the filters to an X-ray film makes (incubation depending on signal strength: 10 minutes to 2 hours).

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

Table 3 shows the data for some compounds.  

Table 3

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

The compounds according to the invention show an unforeseeable effect against viruses. Surprisingly, they are antiviral against hepatitis B (HBV) sam and are therefore for the treatment of virus-induced diseases, in particular suitable for acute and chronic persistent viral infections of HBV. A chronic viral disease caused by HBV can be too different cause severe clinical pictures; is known to cause chronic hepatitis B virus infection in many cases for liver cirrhosis and / or hepatocellular Carcinoma.

Claims (9)

1. Use of compounds of the formula
wherein
R is a mono- or bicyclic saturated or unsaturated radical which contains up to three heteroatoms (selected from the series oxygen, nitrogen, sulfur) and up to three substituents (selected from the series cyano, halogen, nitro, alkyl, fluoroalkyl, alkoxy , Aryl, aryloxy) can carry
R ⁶ and R ^{7 are} independently hydrogen, halogen, alkyl, fluoroalkyl or alkoxy and
R ⁸ to R ¹⁰ independently of one another are hydrogen, halogen or fluoroalkyl
mean,
for the manufacture of medicines for the treatment and prophylaxis of HBV infections. 2. Use according to claim 1, wherein the compounds of the formula to be used
correspond,
wherein
R ¹ , R ² , R ⁶ and R ⁷ independently of one another hydrogen, halogen, alkyl, fluoroalkyl or alkoxy and R ² also nitro and
R ³ to R ⁵ and R ⁸ to R ¹⁰ independently of one another are hydrogen, cyano, halogen or fluoroalkyl
mean. 3. Use according to claim 1, according to which the radical R is furanyl, quinolinyl, Pyrazolyl, thiazolyl, dihydro-oxathiinyl or dihydro-oxazolyl, where these residues are substituted by halogen, methyl, trifluoromethyl and phenyl and two adjacent substituents can be 2-oxa-propane-1,3-diyl, Pro can mean pan-1,3-diyl or butane-1,4-diyl. 4. Use according to claim 2, wherein in formula II
R ^{1 is} hydrogen, halogen, alkyl or alkoxy,
R ^{2 is} hydrogen, halogen, nitro, or alkoxy,
R ^{6 is} hydrogen or alkyl,
R ⁷ halogen or alkyl,
R ^{8 is} hydrogen, halogen or trifluoromethyl and
R ³ to R ⁵ , R ⁹ and R ¹⁰ independently of one another are hydrogen or halogen
mean. 5. Use according to claim 2, wherein in formula II
R ^{1 is} hydrogen, fluorine, chlorine, methyl or methoxy,
R ^{2 is} hydrogen, fluorine, chlorine, bromine, nitro or methoxy,
R ^{6 is} hydrogen or methyl,
R ⁷ fluorine, chlorine, methyl or ethyl,
R ^{8 is} hydrogen, fluorine, chlorine or trifluoromethyl and
R ³ to R ⁵ , R ⁹ and R ¹⁰ independently of one another are hydrogen or fluorine
mean. 6. Use according to claim 1, wherein the compounds to be used are selected from the series of compounds in Table 1.   7. Medicines for HBV infections containing at least one verb extension of the type defined in claims 1 to 6 and optionally further active pharmaceutical ingredients. 8. Compounds selected from compounds 1 to 9 and 11 to 15 of the Table 3 in the test section of the examples. 9. A method for producing the compounds according to claim 7 by implementation of the corresponding acid chloride with the corresponding aniline.