DE10054932A1 - Antiviral medicaments containing new or known chroman-4-one or chroman-4-one derivatives, especially effective against hepatitis B virus infections - Google Patents

Abstract

The use of new and known chroman-4-one or chroman-4-one derivatives (I) in antiviral medicaments is new. Most compounds (I) are new. The use of new and known chroman derivatives of formula (I) for the preparation of antiviral medicaments is new. R1 = Br, or phenyl, pyrrolyl, pyridyl, pyrimidinyl, piperazinyl or quinolyl (all optionally substituted (os) by 1-3 halo, alkyl, CF3, alkoxy, alkoxycarbonyl, alkylthio, NO2, CN, NH2, CONH2 or NHCOCH2Ph); R2 = H; or R1+R2 (on adjacent C atoms) = group completing a fused benzene ring; R3, R4 = alkyl (os by COOH, OT or COOT); or R3+R4 = 2-7C alkylene (os by COOT and optionally having one CH2 replaced by O or NR9) or a group completing a tetrahydro-2H-pyran ring; R5 = 2-6C alkyl (os by CN, COOT, COOH or CONH2); R6 = H or as R5; R7 = H; R8 = OH; or R7+R8 = O; R9 = H, COPh or COOPh; and T = 1-4C alkyl. Alkyl moieties have 1-6C unless specified otherwise. Independent claims are included for: (1) new compounds (I), excluding compounds (I; R1 = unsubstituted phenyl or R1+R2 = fused benzene ring); (2) preparation of the new compounds (I); (3) combinations of: (a) at least one chromanone and/or chromanol; (b) at least one anti-hepatitis B virus (HBV) agent other than (a); and optionally (c) at least one immunomodulator; and (4) preparation of the drug combinations (3), by combining or formulating (a), (b) and optionally (c) by conventional methods.

Description

The invention relates to combinations of A) non-nucleoside inhibitors from the class of chromanones or chromanols with B) other HBV antivirals Active ingredients such as (i) nucleoside analogs, such as. B. lamivudine, optionally (ii) HBV DNA or HBV core protein inhibitors such as dihydropyrimidines and / or (iii) Isoxazoles, and optionally C) immunomodulators, such as. B. Interferon, a ver drive to make these combinations and their use as medicines, especially for the treatment and prophylaxis of HBV infections. It is about ie combinations of at least two, three or four active ingredients Groups A and B.

"Combinations" in the sense of the invention are not only presentation shapes that contain all components (so-called fixed combinations), and Kombina tion packs that contain the components separately, understood, but also components applied at the same time or at different times, provided that they used to treat or prevent the same disease.

The hepatitis B virus belongs to the Hepadna virus family. It causes one acute and / or a persistent-progressive, chronic illness. diverse other clinical manifestations in the clinical picture are caused by the 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 is a strong reduction the viral DNA and the viral core protein;  
• 2. the inhibition of the polymerase of HBV by analogues of the substrates of this Enzyme 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 Treatment of chronic hepatitis by interferon;
• 4. the inhibition by other active substances, whose modes of action are not are known or the subject of speculation, e.g. 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 engages core particles; 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.

Lamivudine has recently been used to treat chronic HBV infection Patients. However, it shows a high after stopping therapy Rebound effect and leads to resistance during long-term therapy. For adefovir Dipivoxil, BMS 200 475 and the other inhibitors mentioned above are still lying no generally available clinical experience.

Interferon is only moderately effective and has undesirable side effects. station wagon Nations of interferon with lamivudine are not synergistically effective.

Previous therapeutic agents for the treatment of HBV-infected patients, such as B. Inter feron or lamivudine are used as monotherapy. From clinical studies it is known that combinations of both inhibitors have no advantage in Combat HBV diseases.

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

It has now surprisingly been found that combinations of A) are not nucleoside inhibitors from the class of chromanones or chromanols, B) of A different HBV antiviral active ingredients and optionally C) immune modulators such as B. interferon, the disadvantages of the prior art are not or only partially show.

The invention therefore relates to combinations

• A) at least one chromanone and / or chromanol,
• B) at least one HBV antiviral active substance different from A, preferably as (i) at least one HBV polymerase inhibitor, optionally in Combination with an HBV antiviral different from A and B (i) Active ingredient, in particular (ii) an HBV DNA or HBV core protein Inhibitor and / or (iii) an isoxazole, and optionally
• C) at least one immunomodulator.

The invention thus relates to combinations of nucleoside and non-nucleosi inhibitors and possibly immunomodulators for treatment and Prophylaxis of HBV infections and the use of these combinations for Treatment of HBV-induced diseases.

The combinations according to the invention inhibit the multiplication of the HBV virus unpredictably much better than those known from the prior art Means or their known combinations. The use of the invention Combinations offer valuable treatment for HBV-induced diseases Advantages compared to monotherapy with the individual compounds, namely at all Synergistic antiviral activity, but also well tolerated  speed of the combinations according to the invention in the area of toxicity at which 50% of cells survive ("Tox-50") - compared to Tox-50 of the individual components.

Preferred chromanones or chromanols A include compounds of the formula

wherein
R ¹ bromine, phenyl, pyrrolyl, pyridyl, pyrimidinyl, piperazinyl or quinolinyl, of which the cyclic substituents are each up to three times the same or different by halogen, C ₁ -C ₆ alkyl, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylthio, nitro, cyano, amino, aminocarbonyl or benzyloxycarbonylamino may be substituted,
R ^{2 is} hydrogen or
R ¹ and R ² together with two adjacent carbon atoms of ring A form a fused benzene ring,
R ³ and R ^{4 are,} independently of one another, linear or branched C ₁ -C ₆ alkyl which can be substituted by carboxyl, C ₁ -C ₄ alkoxy and / or C ₁ -C ₄ alkoxycarbonyl, or
R ³ and R ⁴ together form a C ₂ -C ₇ alkylene radical optionally substituted by C ₁ -C ₄ alkoxycarbonyl, in which a CH ₂ group is represented by an oxygen atom or by NR ⁹ (with R ⁹ = hydrogen, benzoyl or benzyloxycarbonyl) can be replaced, or together with the carbon atom on which they stand, a tetrahydro-2H-pyran ring,
R ^{5 is} linear or branched C ₂ -C ₆ alkyl which can be substituted by cyano, C ₁ -C ₄ alkoxy carbonyl, carboxyl or aminocarbonyl,
R ^{6 is} hydrogen or linear or branched C ₂ -C ₆ alkyl which can be substituted by cyano, C ₁ -C ₄ alkoxycarbonyl, carboxyl or aminocarbonyl,
R ^{7 is} hydrogen,
R ^{8 is} hydroxy or
R ⁷ and R ⁸ together represent an oxo group.

Particularly preferred chromanones / chromanols correspond to the formula I in which
R ^{1 is} phenyl, pyridyl or quinolinyl, each of which can be substituted up to three times by fluorine or chlorine or simply by methyl, trifluoromethyl, methoxy, methylthio, nitro, cyano or amino; Pyrrolyl, which can be substituted by tert-butoxycarbonyl;
R ^{2 is} hydrogen,
R ³ and R ^{4 are} each methyl or
R ³ and R ⁴ together form a C ₃ -C ₅ alkylene radical, in which a CH ₂ group can be replaced by an oxygen atom, or together with the carbon atom on which they are located, a tetrahydro-2H-pyran ring,
R ⁵ cyanoethyl,
R ^{6 is} hydrogen or cyanoethyl
mean and
R ⁷ and R ^{8 have} the meanings given above.

Particularly preferred chromanones / chromanols correspond to the formula I in which
R ¹ phenyl which can be substituted up to three times by fluorine, up to twice by chlorine or simply by methyl, trifluoromethyl, methoxy, methylthio, nitro, cyano or amino; pyridyl; Pyrrolyl, which can be substituted by tert-butoxy carbonyl;
R ^{2 is} hydrogen,
R ³ and R ^{4 are} each methyl or
R ³ and R ⁴ together form a C ₃ -C ₅ alkylene radical or, together with the carbon atom on which they are located, a tetrahydro-2H-pyran ring,
R ⁵ and R ⁶ cyanoethyl
mean and
R ⁷ and R ^{8 have} the meanings given above.

The most effective chromanones against HBV are those of Examples 76, 82, 97, 99, 116 and 132.  

In the context of the chromanone / chromanol definition, alkyl stands for a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4 carbon atoms, such as z. As methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy stands for a straight in the chromanon / chromanol definition chain or branched alkoxy radical with 1 to 6, preferably 1 to 4 carbon atoms, such as B. methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, n- Pentoxy and n-hexoxy.

Alkylthio stands for a straight in the chromanon / chromanol definition chain or branched alkylthio radical with 1 to 6, preferably 1 to 4, carbon atoms such as methylthio, ethylthio and propylthio.

Alkoxycarbonyl stands for one in the chromanone / chromanol definition straight-chain or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4 Carbon atoms such as B. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylene in the chromanone / chromanol definition for C ₂ -C ₇ -, preferably C ₃ -C ₅ alkylene such as. B. ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene and 1,7-heptylene.

Halogen in the chromanone / chromanol definition means fluorine, chlorine, Bromine or iodine.

The chromanone or chromanole A are largely from EP-A 4 624 (= US 4,261,988). There they became more hypocholesterolemic Activity and its growth-promoting effects recommended; an antiviral Effect is not described there.  

Many Chroman-4-ones are known; see. DE-OS 26 11 910 and in the series "Heterocyclic Compounds" by the band "Chromenes, Chromanones and Chromones", P. 207ff, ed. G. P. Ellis, New York, London, Sydney, Toronto 1977. You are accessible by the methods described there or by analogous methods.

For example, Chroman-4-one can

• a) condensation of o-hydroxyacetophenone with carbonyl compounds in Presence of basic condensing agents,
• b) Fries rearrangement of the phenol esters α, β-unsaturated carboxylic acids,
• c) Cyclization of β-phenoxypropionic acids with acidic condensing agents or
• d) Reduction of 4H-chromen-4-ones

getting produced; see. z. B. also H. J. Kabbe in Synthesis 1978, 886-889.

The substitution of ring A of the chroman-4-one base body can be done by Suzuki reaction (see Chem. Rev. 90, 879 (1990), Pure Appl. Chem. 63, 419 (1991) and Chem. Rev. 1995, 2457-2483) of the corresponding organic boron compound with ring halogen, pseudohalogen, aryldiazonium salt or trifluor methylsulfonate-substituted chromanones or by Stille- or Migita-Stille- Kosugi coupling received; see. z. B. Angew. Chem. Int. Ed. Engl. 25, 508 (1986), Pure appl. Chem. 57, 1771 (1985), Synthesis 1987, 693-696 and 1992, 803, Tetrahedron Lett. 27, 4407-4410 (1986). Conversely, you can also use chromanone Boron or chromanone-stannane compounds with halogen, pseudohalogen, aryl implement diazonium salt or trifluoromethyl sulfonate arylene or hetarylene.  

Of course, you can also directly from the appropriately substituted Phenols or phenol ethers or esters run out, d. H. the arylation already the Chromanon intermediate stage.

The amount of organic boron compound used for the Suzuki reaction can 1 to 10, preferably 1 to 2 mol, based on halogen, pseudohalogen, Aryl diazonium salt or trifluoromethyl sulfonate substituted chromanone.

For the Suzuki reaction and the Stille or Migita-Kosugi-Stille coupling, preferred catalysts include, for example, the following palladium compounds:
Palladium (II) acetate, tri- (dibenzylideneacetone) palladium (0), trip-tolylphosphine palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), tetrakis (triphenyl phosphine) palladium (II) chloride, Bis (triphenylphosphino) palladium (II) chloride and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride. The amount of catalysts used can vary within wide limits; In general, amounts of 1 to 10, preferably 1.5 to 8, mol%, based on halogen, pseudohalogen, aryldiazonium salt or trifluoromethylsulfonate-substituted chromanone, have proven useful.

Bases preferred for the Suzuki reaction include e.g. B. alkali metal hydroxides, carbo nates, bicarbonates and phosphates such as potassium and sodium hydroxide, Cesium fluoride, potassium, sodium, cesium and thallium carbonate, sodium hydro gene carbonate, potassium phosphate, tert-butylammonium fluoride, alkali alcoholates and -phenolates such as sodium ethylate (with or without tert-butylammonium fluoride and Crown ethers) and amines, preferably tertiary amines such as triethylamine. The amount the bases used can be varied within wide limits; usually are amounts of 1 to 2, preferably 1.1 to 1.8, in particular 1.1 to 1.6 mol per Mol of starting chromanone sufficient; Bases such as B. triethylamine can However, they also serve as solvents and are used to a high degree in this case Excess used.  

For the Suzuki reaction and the Stille or Migita-Kosugi-Stille clutch before Preferred solvents include aromatics such as benzene, toluene, halocarbons substances such as dichloromethane, aliphatic alcohols such as ethanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethylene glycol dimethyl ether, Nitriles such as acetonitrile, amides such as dimethylformamide, and water and their Mixtures such as B. toluene / ethanol, benzene / ethanol and acetonitrile / water.

The Suzuki and the Stille or Migita-Kosugi-Stille CC coupling can be carried out at temperatures of 20 to 150, preferably 40 to 120 ° C and in the presence of palladium (0). The reaction can, for example, by the scheme

X = halogen, pseudohalogen, aryldiazonium salt, trifluoromethyl sulfonate
Y = Stannan, Bororganyl
are explained. In this reaction scheme, X and Y can also be interchanged.

Often used as a ligand for palladium (0) is triphenylphosphine or its monosodium sulfonate derivative used. Per mole of halogen, pseudohalogen, aryldiazonium salt or trifluoromethylsulfonate-substituted chromanone are preferably 0.8 to 1.3 moles of stannane were used. For catalysis you can use the Palla mentioned above Use dium (0) catalysts.

The substituents in the 3-position can be α, β-ethylenically un by Michael addition saturated compounds on 3-position unsubstituted chromanones in the presence of bases are introduced, as is e.g. B. is known from EP-A 4 624. For the Michael addition particularly preferred α, β-ethylenically unsaturated compounds are acrylic acid alkyl esters and acrylonitrile. The amount of α, β-ethyl used Nisch unsaturated compound can 1 to 8, preferably 1 to 5 moles per mole Chromanon starting compound amount.

Bases preferred for Michael addition include sodium and potassium hydride, alkali C ₁ -C ₄ alcoholates (especially sodium alcoholates), bis (trimethylsilyl) lithium amide (Tetrahedron Lett. 35, 6347-6350 (1994)) and lithium-N , N-diiso propylamide (J. Chem. Soc. Perkin Trans. I 1995, 197-201, and J. Am. Chem. Soc. 113, 2071-2092 (1991)). The amount of base used can be 0.4 to 10, preferably 1 to 3, moles per mole of chromanone starting compound.

Preferred solvents for the Michael addition include ethers such as tetrahydrofuran and dioxane and alcohols, with the corresponding alcohols being preferred as solvents when using alkali C ₁ -C ₄ -alcoholates as base.

The Michael addition can be carried out at temperatures of 20 to 100, preferably 40 to 80 ° C are carried out.

Instead of this Michael addition, the corresponding Mukaiyama reaction (with titanium compounds instead of base catalysis) can also be used; see. z. B. Chem. Lett. 1987, 743-746, Bull. Chem. Soc. Jpn. 49: 779-783 (1976) Angew. Chem. 111, 3574-3576 (1999), Synthesis 1977, 91-110. In addition, the substituents R ⁵ / R ^{6 can} also be prepared by reacting the 3-position unsubstituted chromanones with halogen compounds; see. also Tetrahedron Lett. 1978, 573-576, J. Org. Chem. 61, 2081-2084 (1996).

The chromanol compounds according to the invention can be obtained by hydrogenation chromanone, e.g. B. with complex hydrides such as sodium borohydride, accessible Lich.

HBV polymerase inhibitors B (i) in the sense of the invention are substances such as the endogenous polymerase assay, which was described by Ph. A. Furman et al. in Antimicrobial Agents and Chemotherapy, Vol. 36 (No. 12), 2688 (1992), lead to an inhibition of the formation of an HBV-DNA double strand in such a way that there is a maximum of 50% of the activity of the zero value:
Preferred HBV polymerase inhibitors B (i) include, for example
3TC = Lamivudine =
4-amino-1 - [(2R-cis) -2- (hydroxymethyl) -1,3-oxathiolan-5-yl] pyrimidin-2 (1H) -one, cf. EP-PS 382 526 (= US-PS 5 047 407) and WO 91/11186 (= US-PS S 204 466);
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 =
[1S- (1.α, 3.α, 4.β)] - 2-amino-1.9-dihydro-9- [4-hydroxy-3- (hydroxymethyl) -2-methylene-cyclopentyl] -6H-purine 6-one, cf. EP-PS 481 754 (= US-PS 5 206 244 and 5 340 816), WO 98/09964 and 99/41275;
Abacavir =
(-) - (1S-cis) -4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol, cf. EP-PS 349 242 (= US-PS 5 049 671) and EP-PS 434 450 (= US-PS 5 034 394);
FTC =
(2R-cis) -4-amino-5-fluoro-1- [2- (hydroxymethyl) -1.3-oxathiolan-5-yl] pyrimidine-2 (1H) -one, cf. WO 92/14743 (= US-PS 5 204 466, 5 210 085, 5 539 116, 5 700 937, 5 728 575, 5 814 639, 5 827 727, 5 852 027, 5 892 025, 5 914 331, 5 914 400) and WO 92/18517;
β-L-FDDC =
5- (6-Amino-2-fluoro-9H-purin-9-yl) tetrahydro-2-furanmethanol, cf. WO 94/27616 (= U.S. Patents 5,627,160, 5,561,120, 5,631,239 and 5,830,881);
L-FMAU = 1- (2-deoxy-2-fluoro-β-L-arabinofuranosyl) -5-methyl-pyrimidine-2.4 (1H, 3H) -dione, cf. WO 99/05157, WO 99/05158 and US Pat. No. 5,753,789.

HBV DNA or HBV core protein inhibitors B (ii) are such non-nucleosi inhibitors that inhibit HBV-DNA intra- and extracellularly and in the Cell half the half-life of the HBV core protein at least.

Preferred HBV DNA and HBV core protein inhibitors B (ii) are e.g. B. Dihydro pyrimidines, as are preferably described in DE-OS 198 17 264 (= WO 99/54 326), 198 17 265 (= WO 99/54 312) and 198 17 262 (= WO 99/54329) are described, to which reference is hereby made for the purpose of disclosure.

Preferred dihydropyrimidines B (ii) 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 radicals of the formulas

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, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ - Alkoxycarbonyl and C ₁ -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 the ring systems listed, if appropriate
-SR ⁶ , -NR ⁷ R ⁸ , -CO-NR ⁹ R ¹⁰ , -SO ₂ -CF ₃ and -A-CH ₂ -R ^{11 are} substituted,
wherein
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 C ₁ -C ₆ -alkyl, the alkyl radical in turn being hydroxyl, C ₁ -C ₆ -alkoxycarbonyl, Phenyl or hydroxy-substituted phenyl can be substituted,
A is a radical -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 halogen, nitro, trifluoromethyl, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy,
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-chain or branched C ₁ -C ₆ -alkoxycarbonyl, a straight-chain, branched or cyclic, saturated or unsaturated C ₁ -C ₈ -hydrocarbon radical, which may contain one or two identical or different hetero-chain links from the group -O-, -CO-, -NH-, -N- (C ₁ -C ₄ alkyl) -,
-S- or -SO ₂ - and which is optionally substituted by halogen, nitro, cyano, hydroxy, aryl having 6 to 10 carbon atoms, aralkyl having 6 to 10 carbon atoms, heteroaryl or a group of the formula -NR ¹⁵ R ¹⁶ ,
wherein R ¹⁵ and R ¹⁶ independently of one another are hydrogen, benzyl or C ₁ -C ₆ alkyl,
R ¹³ and R ¹⁴ independently of one another hydrogen, C ₁ -C ₆ alkyl or cyclo alkyl having 3 to 6 carbon atoms
mean,
R ^{3 is} hydrogen, amino or a radical of the formula

or
Formyl, cyano, hydroxy-substituted C ₁ -C 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, C ₁ - C ₆ - alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, C ₁ -C ₆ alkylthio or C ₁ -C ₆ alkoxy (where the alkylthio or alkoxy radical may in turn be substituted by azido, amino, hydroxyl) and / or is substituted by the group - (CO) _a -NR ¹⁷ R ¹⁸ ,
wherein
a means 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 C ₁ -C ₆ alkyl, which may be substituted by C ₁ -C ₆ alkoxycarbonyl, amino, hydroxyl, phenyl or Benzyl are substituted, phenyl and benzyl optionally substituted one or more times, identically or differently, by hydroxy, carboxyl, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy and / or C ₁ -C ₆ - Alkyl is 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,
or
R ³ optionally methoxy-substituted phenyl
or
R ² and R ³ together represent a radical of the formula

R ^{4 is} hydrogen, C ₁ -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, identically or differently, by halogen, hydroxy, cyano, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ - Alkylthio, carbalkoxy, C ₁ -C ₆ -acyloxy, amino, nitro, mono- or di-C ₁ -C ₆ -alkylamino can be substituted,
mean.

The following compounds are very particularly preferred dihydropyrimidines B (ii):

their isomeric forms and their salts.

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

The above dihydropyrimidines II and IIa and various processes for their Manufacture are from DE-OS 198 17 264 (= WO 99/54 326) and 198 17 265 (= WO 99/54 312), to which reference is hereby made for the purpose of disclosure is taken.

Further preferred dihydropyrimidines B (ii) correspond to the formula

or their isomeric form

and / or their salts, wherein
R ^{1 is} phenyl, furyl, thienyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or a radical of the formulas

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, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ - Alkoxycarbonyl and C ₁ -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 / or the ring systems listed are optionally substituted 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 ¹¹ ,
wherein
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 C ₁ -C ₆ -alkyl, the alkyl radical in turn being hydroxyl, C ₁ -C ₆ -alkoxycarbonyl, Phenyl or hydroxy-substituted phenyl can be substituted,
A is a radical -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, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy,
mean,
R ^{2 is} a radical of the formulas -OR ¹² or -NR ¹³ R ¹⁴ ,
wherein
R ^{12 is} hydrogen, C ₁ -C ₆ -alkoxycarbonyl or a straight-chain, ver branched or cyclic, saturated or unsaturated C ₁ -C ₈ -hydrocarbon radical, which optionally contains one or two identical or different hetero-chain links from the group -O-, - CO-, -NH-, -N- (C ₁ -C ₄ alkyl) -, -S- and -SO ₂ - and optionally by halogen, nitro, cyano, hydroxy, aryl with 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,
wherein R ¹⁵ and R ¹⁶ independently of one another are hydrogen, benzyl or C ₁ -C 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

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 times, identically or differently, by aryloxy having 6 to 10 carbon atoms, azido, cyano, hydroxy, carboxyl, C ₁ -C ₆ -Alkoxy carbonyl, a 5- to 7-membered heterocyclic ring, C ₁ -C ₆ -alkylthio or C ₁ -C ₆ -alkoxy (where the alkylthio or alkoxy radical in turn may be substituted by azido, amino or hydroxyl) and / or is substituted 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, aralkyl having 6 to 10 carbon atoms or C ₁ -C ₆ -alkyl, which are optionally substituted by C ₁ -C ₆ -alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, phenyl and benzyl are optionally substituted one or more times, identically or differently, by hydroxyl, carboxyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy and / or C ₁ -C 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,
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.

The compounds III and IIIa can be in stereoisomeric forms, which are either like image and mirror image (enantiomers) or which are not like image and mirror image (Diastereomers) behave, exist. The compounds III and IIIa thus include both the enantiomers and the diastereomers and their respective Mi mixtures. The racemic forms, like the diastereomers, can be known Separate into the stereoisomerically uniform components.

The dihydropyrimidines III and IIIa, which in the 2-position optionally contain substituted oxazolyl or thiazolyl radical, and various processes their manufacture are known from DE-OS 198 17 262 (= WO 99/54 329), to which reference is hereby made for the purpose of disclosure.

Alkyl per se and the alkyl parts in mono- and dialkylamino as well as in mono- and di alkylaminocarbonyl are part of the dihydropyrimidine definition 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.

Alkenyl stands for a straight-chain in the context of the dihydropyrimidine definition or branched alkenyl radical having 2 to 6, preferably 3 to 5 carbon atoms, such as z. B. ethenyl, propenyl, isopropenyl, tert-butenyl, n-pentenyl and n-hexenyl.

Cycloalkyl with 3 to 6 carbon atoms is part of the dihydropyrimidine Definition of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, preferably Cyclopentyl and cyclohexyl.

In the context of the definition of dihydropyrimidine, acyl stands for a straight-chain or branched acyl radical having 1 to 6, preferably 1 to 4 carbon atoms, such as. B. Acetyl and propionyl.  

Alkoxy stands for a linear or ver in the context of the dihydropyrimidine definition branched alkoxy radical having 1 to 6, preferably 1 to 4 carbon atoms, such as. B. Methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

In the context of the dihydropyrimidine definition, alkylthio stands for 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 dihydropyrimidine definition, alkoxycarbonyl stands for a linear one or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4 carbon atoms, such as B. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy carbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Aralkyl is preferred in the context of the dihydropyrimidine definition for aralkyl as 6 to 10, especially 6 carbon atoms in the aryl part (preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 4, in particular 1 or 2 Carbon atoms in the alkyl part, where the alkyl part can be linear or branched. Preferred aralkyl radicals are benzyl and phenethyl.

In the context of the dihydropyrimidine definition, aryl stands for an aromatic radical with 6 to 10 carbon atoms, preferably phenyl and naphthyl.

Heteroaryl stands for 5- to 7-membered in the context of the dihydropyrimidine definition 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.  

Halogen is fluorine, chlorine, bromine in the dihydropyrimidine definition or iodine.

Preferred halogenated alkyl is trifluoromethyl.

The compounds II or IIa and III or IIIa can also be present as salts. in the Physiologically acceptable salts are preferred within the scope of the invention.

Physiologically acceptable salts can be salts of the compounds II or IIa and III or IIIa with inorganic or organic acids. To be favoured Salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, Phosphoric acid or sulfuric acid, or salts of organic carbon or sulfone acids, such as acetic acid, maleic acid, fumaric acid, malic acid, Citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, Ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfone acid.

Physiologically acceptable salts can also be metal or ammonium salts Compounds II or IIa and III or IIIa. Z are particularly preferred. B. Sodium, potassium, magnesium or calcium salts as well as ammonium salts, which by Ammonia or organic amines, such as ethylamine, di- or Triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, Arginine, lysine, ethylenediamine or 2-phenylethylamine.

Preferred isoxazoles B (iii) include e.g. B. Compounds of formula

wherein
R ¹ and R ² independently of one another alkyl which is optionally substituted by one or more halogen atoms,
X is a divalent radical from the series C = Y, -N (R ⁴ ) -C (= Y) -, CH ₂ ,
R ³ and R ⁴ 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 selected independently of one another from the series halogen, alkyl, alkoxy, alkylthio, alkoxycarbonyl, aminocarbonylamino, mono- and dialkylamino, cyano, amino, mono- and dialkylaminocarbonyl,
mean.

Compounds of the formula (I) in which
R ¹ and R ² independently of one another optionally halogen-substituted C ₁ -C ₈ alkyl,
X is a double-bonded residue from the series C = Y and CH ₂ ,
R ³ and R ⁴ independently of one another are hydrogen or optionally halogen-substituted C ₁ -C 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, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkoxycarbonyl , Carbamoyl, mono-C ₁ -C ₆ -alkylaminocarbonyl, di-C ₁ -C ₆ -alkylaminocarbonyl, cyano,
mean.

Particularly preferred are compounds of formula (I), wherein
R ¹ and R ² independently of one another are C ₁ -C ₆ alkyl or trifluoromethyl,
XC = Y,
R ³ and R ⁴ independently of one another are hydrogen or C ₁ -C 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 selected independently of one another from the series alkyl, halogen, CF ₃ , in particular 3-methyl-4-fluoro- and 3 chloro-4-fluoro-phenyl,
mean.

The isoxazoles A can be prepared from the corresponding acid chloride 2 by reaction with an amine HNAR ³ :

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

For this, z. B. the ketoester 5 with pyrroldine 6 under dehydrating loading conditions in the enamino ester 7, which with an aliphatic nitro compound in the presence of base, such as. B. triethylamine, and a water Withdrawal agents such as phenyl isocyanate or phosphorus oxychloride for isoxazole 8 responding. Then the ethyl ester z. B. with aqueous sodium hydroxide solution split and the resulting acid 9 z. B. by treating with thionyl chloride in the Transfer acid chloride.

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

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 ₁ -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 are also carriers can be bound such. B. 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 used Lawesson reagent (= 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiaphosphetane-2,4- disulfide; see. R. Shabana et al., Tetrahedron 1980 (36), 3047-3051) become; the reaction can take place in toluene at elevated temperature.

For the synthesis of the ureas [X = -N (R ⁴ ) -C (= Y) -] z. B. 3-amino-2,5-dimethyl isoxazole can be used as 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 becomes.

The amines (X = CH ₂ ) are from the corresponding carboxamides described in Scheme 1 by reduction z. B. accessible with borane-dimethyl sulfide complex (J. March, Advanced Organic Chemistry, 4th ed., New York 1992, p. 1212).

The reactions of Schemes 1 and 2 can be carried out in inert organic solvents be performed. These include saturated linear, branched and cyclic  Hydrocarbons such as hexane, cyclohexane or petroleum fractions, alcohols such as Methanol, ethanol or iso-propanol, ethers such as diethyl ether, 1,4-dioxane or Tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, chloroform, tetra chloromethane, 1,2-dichloroethane, trichloroethane or tetrachloroethane, aromatic Hydrocarbons such as benzene, toluene or xylene, dipolar aprotic solution agents such as nitromethane, dimethylformamide or acetonitrile, or their Mi mixtures. Dichloromethane, chloroform, 1,2-dichloroethane are particularly preferred. Toluene, ethanol and dimethylformamide.

Preferred solvents for the reactions of Scheme 1 include chlorinated ones Hydrocarbons such as dichloromethane, chloroform, 1,2-dichloromethane and ether like tetrahydrofuran. The reactions of scheme 2 are preferred in aromati hydrocarbons such as toluene, chlorinated hydrocarbons such as Di chloromethane, chloroform, 1,2-dichloroethane, ethers such as tetrahydrofuran or alka noles like ethanol.

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

Combinations are also a subject of the invention

• A) at least one chromanone and / or chromanol,
• B) (i) an HBV polymerase inhibitor and / or (ii) a dihydropyrimidine and / or (iii) an isoxazole and optionally
• C) at least one immunomodulator.

A particularly preferred embodiment of the invention relates to combinations of A) above chromanones and / or chromanoles and B) (i) lamivudine.

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

wherein
R ¹ and R ² independently of one another are C ₁ -C ₄ -alkyl or, together with the nitrogen atom on which they are located, form a ring with 5 to 6 ring atoms which comprise carbon and / or oxygen,
R ³ -R ¹² independently of one another are hydrogen, halogen, C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, nitro, cyano or trifluoromethyl,
R ^{13 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₇ acyl or aralkyl and
X halogen or optionally substituted C ₁ -C ₄ alkyl
mean,
and their salts.

These phenylpropenamides and processes for their preparation are from the WO 98/33 501 known, to which reference is hereby made for the purpose of disclosure becomes. AT-61 is the compound of the above formula wherein X is chlorine, A 1-piperidinyl and Y and Z each represent phenyl.

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

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

The present invention includes pharmaceutical preparations which, in addition to non- toxic, inert pharmaceutically suitable excipients one or more inventions contain combinations according to the invention or from a com combination exist, as well as processes for the preparation of these preparations.

The quantitative ratio of components A, B and optionally C of the Invention appropriate combinations can fluctuate within wide limits; preferably be it carries 5 to 1000 mg A / 5 to 500 mg B, especially 10 to 500 mg A / 20 to 400 mg B and further 5 to 1000 mg A / 5 to 500 mg B and / or 1 to 10 million I.U. (international units) C.

Component C, which may also be used, may be present in quantities of in particular 2 to 7 million IU about three times a week over a period of time up to one year.  

The combinations according to the invention are intended in the pharma listed above general preparations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture is present.

The pharmaceutical preparations listed above can in addition to the Invention Combinations according to the invention also contain other active pharmaceutical ingredients.

The pharmaceutical preparations listed above can be prepared according to known methods take place, for. B. by mixing the active ingredient or ingredients with the carrier or carriers.

In general, it has been found in both human and veterinary medicine proved advantageous, the combinations according to the invention in total amounts of about 0.5 to about 500, preferably 1 to 100 mg / kg body weight per 24 hours, if necessary in the form of several individual doses to achieve the desired results nisse to administer. A single dose contains the active ingredient or ingredients preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg of body Weight. However, it may be necessary to deviate from the doses mentioned give way, depending on the type and body weight of the be object, the type and severity of the disease, the type of preparation and the application of the drug and the period or interval within which is administered.

The indication areas for the combinations according to the invention include:

• 1. the treatment of acute and chronic viral infections that lead to a infectious hepatitis, preferably the treatment of acute and chronic hepatitis B virus infections;
• 2. the treatment of acute and chronic HBV infections in Ko infection with the hepatitis delta virus;  
• 3. the treatment of acute and chronic HBV infections in Ko infection with other viruses such as B. HIV or HCV, and
• 4. the prophylactic / therapeutic treatment for transplants, such as z. B. Liver transplants.

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

The invention further relates to medicaments containing one of the above defined combinations and at least one further pharmaceutical active ingredient substance and / or at least one pharmaceutical excipient.

Another object of the invention is the use of the combination defined above nations for the manufacture of medicines for the treatment and prophylaxis of the above Diseases described, preferably viral diseases, in particular from hepatitis B.

The percentages in the following examples relate to the Weight; Parts are parts by weight. Mixing ratios of solvents mixtures refer to volume.  

Examples A. Chromanone / Chromanole List of solvents / conditions used for chromatography

I dichloromethane / methanol
II dichloromethane
III ethyl acetate
IV petroleum ether / ethyl acetate
V cyclohexane / ethyl acetate
VI dichloromethane / cyclohexane
VII cyclohexane
VIII acetonitrile / water / trifluoroacetic acid
IX acetonitrile
X water
XI Kromasil C18 column 125.2 mm, gradient acetonitrile + 0.01 molar H ₃

PO ₄

, 0-1 min 10% IX, 1-9 min gradient to 90% IX, 9-13 min 90% IX; UV detection 210 nm, flow rate 0.5 ml / min
XII Symmetry C18 2.1.150 mm, gradient acetonitrile + 0.6 g 30% HCl, 0 min 10% IX, 0.01-4 min gradient to 90% IX, 4-9 min 90% IX, UV detection 210 nm, flow rate 0.6 ml / min
XIII Kromasil C18 column 125.2 mm, gradient acetonitrile + 0.1% HClO ₄

, 0-0.5 min 2% IX, 0.51-4.5 min gradient to 90% IX, 4.5-6.5 min 90% IX; UV detection 210 nm, flow rate 0.75 ml / min
XIV Kromasil 100 C18 column 7 µm 250.20 mm, gradient acetonitrile + 0.2% tri fluoroacetic acid, 0-0.01 min 5% IX, 0.01-10 min gradient up to 95% IX, 10-15 min 95% IX; UV detection 210 nm, flow rate 25 ml / min.

Examples 1 to 43 are starting compounds; concern the other examples Chromanon or chromanol end products.  

example 1

Acetic acid-3-bromophenyl

A solution of 49.83 g (288 mmol) of 3-bromophenol in 94.09 g (921.67 mmol, 86.96 ml) of acetic anhydride is stirred in the presence of 1 ml of concentrated sulfuric acid until the exothermic reaction has subsided. This is followed by hydrolysis with 2% ice-cold hydrochloric acid, separation of the organic phase, extraction of the aqueous phase three times with diethyl ether, washing the combined organic phases twice with 2N sodium carbonate solution and washing once with water. After drying over sodium sulfate and distilling off the solvent, 46.36 g (73%) of the product are obtained in the form of a colorless oil.
¹ H-NMR (300 MHz, DMSO-D ₆ , δ / ppm):
2.25 (s, 3H), 7.15 (dd, 1H), 7.3-7.5 (m, 3H).
MS (EI POS): 214 [M] ⁺ .

Example 2

Acetic acid 3,4-difluorophenyl ester

In the reaction of 3,4-difluorophenol analogously to Example 1, the title compound is obtained.
Yield: quantitative
¹ H-NMR (400 MHz, DMSO-D ₆ , δ / ppm):
2.30 (s, 3H), 7.05 (m, 1H), 7.40 (m, 1H), 7.50 (dd, 1H).
MS (DCI): 173 [M + H] ⁺
R _f value: 0.76 (I, 10: 1).

Example 3

4-bromo-2-hydroxyacetophenone

122.77 g (920.74 mmol) of aluminum chloride are added in portions to 99.00 g (460.37 mmol) of the compound from Example 1 via a solids metering. The mixture is then heated to 140 ° C. for 4 h and then hydrolyzed with ice water. The brown solid is filtered off and dissolved in dichloromethane, the solution is washed three times with water. After the solvent has been distilled off, the crystals obtained are recrystallized from n-pentane.
Yield: 63 g (63.63%).
¹ H-NMR (300 MHz, DMSO-D ₆ ): 2.6 (s, 3H) ppm, 7.18 (dd, 1H) ppm, 7.2 (dd, 1H) ppm, 7.8 (dd, 1H) ppm, 11.99 (br.s, 1H) ppm.
MS (EI POS): 214 [M] ⁺ .

Example 4

4,5-difluoro-2-hydroxyacetophenone

Analogously to Example 3, the title compound is obtained by reacting the compound from Example 2.
Yield: 93%
Melting point: 50-52 ° C
MS (DCI): 173 [M + H] ⁺
R _f value: 0.16 (IV, 20: 1).

Example 5

3- (3-bromophenoxy) propionic acid

34.60 g (200 mmol) of 3-bromophenol are added to a solution of 8.00 g of sodium hydroxide (200 mmol) in 200 ml of water. After heating to boiling, 30.60 g (200 mmol) of 3-bromopropionic acid and 8.00 g (200 mmol) of sodium hydroxide, dissolved in 400 ml of water, are added dropwise over the course of 30 minutes. The mixture is then stirred under reflux for 2 h, cooled to 0 ° C. and brought to pH 1 with concentrated hydrochloric acid. The precipitated product is filtered off, washed with water and n-pentane and dried. 12.20 g (24.89%) of colorless crystals are obtained.
¹ H NMR (200 MHz, DMSO-D ₆ , δ / ppm): 2.65 (t, 2H), 4.15 (t, 2H), 6.95 (dd, 1H), 7.10-7 , 20 (m, 2H), 7.20-7.30 (m, 1H), 12.40 (br, s, 1H).
MS (EI POS): 244 [M ⁺ ].

Example 6

7-Bromo-spiro [2H-1-benzopyran-2,1'cyclobutan] -4 (3H) -one

50.00 g (232.51 mmol) of the compound from Example 3 are initially introduced into 400 ml of toluene. 24.45 g (348.76 mmol) of cyclobutanone and 4.96 g (5.82 ml, 69.75 mmol) of pyrrolidine are then added. The mixture is heated to boiling for 2 hours at room temperature and 1.5 hours on a water separator. For working up, 200 ml of 1N hydrochloric acid are added and the organic phase is separated off, washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over magnesium sulfate. After the solvent has been distilled off, the product is purified by column chromatography on silica gel (VI 1: 2). Subsequent crystallization from n-pentane gives 39.20 g (54.6%) of the target compound.
¹ H-NMR (300 MHz, DMSO-D ₆ , δ / ppm): 1.68-1.92 (m, 2H), 2.05-2.30 (m, 4H), 3.00 (s, 2H), 7.25 (dd, 1H), 7.35 (d, 1H), 7.65 (d, 1H).
MS (DCI / NH ₃ ): 284 [M + NH ₄ ⁺ ].

Example 7

The following compound was obtained analogously to Example 6

Mp 80-84 ° C; Yield 48%.  

Example 8

7-Bromo-spiro [2H-1-benzopyran-2,1'cyclopentan] -4 (3H) -one

13.00 g (60.45 mmol) of the compound from Example 3 are introduced into 60 ml of toluene. Then 6.61 g (6.95 ml, 78.59 mmol) of cyclopentanone and 1.29 g (1.51 ml, 18.14 mmol) of pyrrolidine are added. The mixture is stirred for one hour at room temperature and then boiled for 3 hours on a water separator. For working up, 20 ml of 1N hydrochloric acid are added and the organic phase is separated off, washed with 2N aqueous sodium carbonate solution and water. After drying over sodium sulfate and distilling off the solvent, 13.5 g (79.43%) of yellow crystals are obtained by column chromatography on silica gel (V 20: 1).
¹ H-NMR (400 MHz, CD ₂ Cl ₂ , δ / ppm):
1.60-1.70 (m, 2H), 1.70-1.80 (m, 2H), 1.80-1.92 (m, 2H), 2.00-2.11 (m, 2H) ), 2.80 (s, 2H), 7.11 (dd, 1H), 7.13 (dd, 1H), 7.69 (d, 1H).
MS (ESI; acetonitrile / water 70:30 + 0.1% acetic acid): 281 [M + H] ⁺ , 303 [M + Na] ⁺ .
The following compounds were prepared analogously to Example 8:

Example 9

Yield: 60%.
¹ H NMR (200 MHz, CDCl ₃ , δ / ppm): 1.25-2.2 (m, 10H), 2.70 (s, 1H), 2.85 (s, 1H), 7.15 -7.30 (m, 2H), 7.35-7.50 (m, 3H), 7.60-7.70 (m, 2H), 7.90-8.00 (dd, 1H).
MS (EI POS): 293 [M + H] ⁺ .

Example 10

Yield: 24%.
¹ H-NMR (200 MHz, CDCl ₃ , δ / ppm): 1.55-2.00 (m, 6H), 2.05-2.20 (m, 2H), 2.85 (s, 2H) , 7.15-7.30 (m, 2H), 7.35-7.55 (m, 3H), 7.60-7.70 (m, 2H), 7.95 (d, 1H).
MS (EI POS): 278 [M] ⁺ .

Example 11

Yield: 95%.
¹ H-NMR (400 MHz, DMSO-D ₆ , δ / ppm):
1.20-2.00 (m, 12H), 2.70 (s, 2H), 7.10 (dd, 1H), 7.20 (d, 1H), 7.70 (d, 1H).
R _f value: 0.62 (I, 100: 1)
MS (DCI): 295 [M + H] ⁺ .

Example 12

Yield: quantitative.
¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm):
1.25-2.00 (m, 10H), 2.70 (s, 2H), 7.20 (d, 1H), 7.40 (s, 1H), 7.55 (d, 1H).
R _f value: 0.6 (I, 100: 1)
MS (DCI): 295 [M + H] ⁺ .

Example 13

Yield: 68%.
¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm):
1.30-1.75 (m, 8H), 2.00 (m, 2H), 2.70 (s, 2H), 6.80 (dd, 1H), 7.65 (dd, 1H).
R _f value: 0.58 (II)
MS (DCI): 253 [M + H] ⁺ .

Example 14

Yield: 75%.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 1.25-2.00 (m, 10H), 2.35 (s, 3H), 2.55 (m, 4H), 2.65 (s, 2H), 3.25 (m, 4H), 6.40 (d, 1H), 7.40 (d, 1H).
R _f value: 0.64 (I, 10: 1)
MS (DCI): 333 [M + H] ⁺ .

Example 15 (Diastereomer A)

Yield: 89%.
¹ H-NMR (300 MHz, DMSO-D ₆ , δ / ppm): 1.20 (t, 3H), 1.59-1.92 (m, 8H), 2.50-2.62 (m, 1H), 2.85 (s, 2H), 4.08 (q, 2H), 7.23 (dd, 1H), 7.30 (dd, 1H), 7.63 (d, 1H).
MS (DCI / NH ₃ ): 384 [M + NH ₄ ⁺ ].

Example 16 (Diastereomer B)

Yield: 55%.
¹ H NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.18 (t, 3H), 1.45-1.80 (m, 6H), 1.94-2.14 (m, 2H), 2.25-2.41 (m, 1H), 2.77 (s, 2H), 4.07 (q, 2H), 7.22 (dd, 1H), 7.34 ( d, 1H), 7.65 (d, 1H).
MS (DCI / NH ₃ ): 384 [M + NH ₄ ⁺ ].

Example 17

Mp 90-97 ° C; Yield 75%.

Example 18

Yield: 97%.
¹ H NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.60-2.10 (m, 4H), 2.90 (s, 2H), 3.10-3.60 (m, 4H), 7.25 (dd, 1H), 7.37-7.50 (m, 6H), 7.65 (d, 1H).
MS (EI POS): 399 [M] ⁺ .

Example 19

Yield: 35%.
¹ H-NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.60-1.90 (m, 4H), 2.90 (s, 2H), 3.60-3.80 (m, 4H), 7.25 (dd, 1H), 7.38 (dd, 1H), 7.65 (d, 1H).
MS (EI POS): 296 [M] ⁺ .

Example 20

Yield: 38%.
¹ H-NMR (300 MHz, DMSO-D ₆ , δ / ppm): 1.34-1.80 (m, 10H), 1.90-2.05 (m, 2H), 2.82 (s, 2H), 7.20 (dd, 1H), 7.28 (d, 1H), 7.62 (d, 1H).
MS (EI POS): 308 [M + H] ⁺ .

Example 21

Yield: 51%.
¹ H NMR (200 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.60-2.15 (m, 8H), 2.99 (s, 2H), 7.18 (d, 1H ), 7.38-7.50 (m, 1H), 7.53-7.70 (m, 1H), 7.90 (d, 1H), 8.10 (d, 1H), 9.32 ( d, 1H).
MS (DCI / NH ₃ ): 253 [M + H ⁺ ], 270 [M + NH ₄ ⁺ ].

Example 22

Mp 43-50 ° C; Yield: 51%.

Example 23

Yield: 25%.
¹ H NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm): 0.90 (t, 3H), 1.20-1.90 (m, 12H), 2.85 (s, 2H) ), 3.35 (t, 2H), 3.50-3.60 (m, 1H), 7.20 (d, 1H), 7.40-7.45 (m, 1H), 7.60- 7.65 (m, 1H), 7.90 (d, 1H), 8.10 (d, 1H), 9.30 (d, 1H).
MS (ESI POS): 339 [M + H] ⁺ .

Example 24

Mp 81-85 ° C; Yield: 70%.

Example 25

7-Bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one

7.02 g (8.89 ml, 120.90 mmol) of acetone and 1.98 g (2.33 ml) are added to a solution of 20.00 g (93.00 mmol) of the compound from Example 3 in 100 ml of toluene , 27.90 mmol) of pyrrolidine. It is boiled for 20 hours on a water separator. The solvent is distilled off and the product is isolated by chromatography on silica gel (cyclohexane / ethyl acetate 20: 1). Recovered starting material is stirred under reflux in 100 ml of benzene and 50 ml of acetone in the presence of 5.00 ml of piperidine for 16 h. After the solvent has been distilled off, the product is purified by column chromatography on silica gel (V 20: 1). From the combined oils, yellow crystals are obtained from ethyl acetate / petroleum ether, which are filtered off with suction and washed with diethyl ether.
Yield: 5.95 g (25.08%).
¹ H-NMR (200 MHz, CDCl ₃ , δ / ppm):
1.45 (s, 6H), 2.70 (s, 2H), 7.10 (dd, 1H), 7.25 (s, 1H), 7.70 (d, 1H).
MS (DCI / NH ₃ ): 255 [M + H] ⁺ , 272 [M + NH ₄ ] ⁺ .
Analogous to example 25

Example 26

Yield: 43%.
¹ H NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm): 0.80-0.96 (m, 6H), 1.50-1.80 (m, 4H), 2.80 (s, 2H), 7.20 (dd, 1H), 7.27 (d, 1H), 7.62 (dd, 1H).
MS (EI POS): 282 [M] ⁺ .

Example 27

Yield: 43%.
MS (LC-MS): 4.74 (RT / min), 427 [M + H] ⁺ .

Example 28

Yield: 29%.
¹ H-NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm):
0.90 (t, 6H), 1.65-1.90 (m, 4H), 2.85 (s, 2H), 7.15 (d, 1H), 7.42 (t, 1H), 7 , 60 (t, 1H), 7.85 (d, 1H), 8.10 (d, 1H), 9.30 (d, 1H).
MS (ESI POS): 255 [M + H] ⁺ .

Example 29

Yield: 7.25%.
MS (DCI / NH ₃ ): 285 [M + H] ⁺ , 302 [M + NH ₄ ] ⁺ .
HPLC (XI): RT = 8.00.

Example 30

7-Bromo-2,3-dihydro-4H-chromen-4-one

2.45 g (10 mmol) of the compound from Example 5 are added to 3.12 g (15.00 mmol) of phosphorus pentachloride at room temperature. The mixture is stirred at room temperature for 10 min, a clear solution being obtained. After adding 2.67 g (20 mmol) of aluminum chloride, the reaction mixture becomes solid. The mixture is heated to 130 ° C. for 30 minutes, added to ice after cooling and extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and, after distilling off the solvent, purified by column chromatography on silica gel (V 8: 2). Recrystallization from cyclohexane / pentane gives 0.78 g (34%) of colorless crystals.
¹ H NMR (200 MHz, CDCl ₃ , δ / ppm): 2.80 (t, 2H), 4.55 (t, 2H), 7.15 (dd, 1H), 7.25 (s; 1H ), 7.71 (t, 1H).
MS (EI POS): 226 [M ⁺ ].

Example 31

7- (3-pyridyl) -spiro [2H-1-benzopyran-2,1'cyclohexan] -4 (3H) -one

A solution of 1.00 g (3.39 mmol) of the compound from Example 11 in 20 ml Dioxane is mixed with 0.85 g (5.76 mmol) of diethyl (3-pyridyl) borane and 0.11 g (0.09 mmol) of tetrakis triphenylphosphine palladium. It gets under an hour Heated to reflux after cooling with 2.4 ml of aqueous 2 M sodium carbonate solution added and stirred under reflux for a further 15 hours.

All volatile components are removed under reduced pressure. The residue is taken up in dichloromethane / methanol, the solution is dried over sodium sulfate and the solvent is stripped off. The residue is chromatographed on silica gel (mobile solvent: II: I 20: 1).
Yield: 555 mg (56%)
¹ H-NMR (400 MHz, DMSO-D ₆ , δ / ppm):
1.20-1.70 (m, 8H), 1.90 (br. D, 2H), 2.80 (s, 2H), 7.40 (m, 2H), 7.50 (dd, 1H) , 7.80 (d, 1H), 8.20 (d, 1H), 8.65 (d, 1H), 8.95 (s, 1H).
MS (DCI): 294 [M + H] ⁺
R _f value: 0.29 (I, 50: 1)
The following compounds were obtained analogously to Example 31

Example 32

Yield: 51%
R _f value: = 0.52 (I, 20.1)
¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm):
1.30-1.80 (m, 6H), 2.05 (br. D, 2H), 2.75 (s, 2H), 7.10 (d, 1H), 7.35 (dd, 1H) , 7.75 (dd, 1H), 7.85 (dd, 1H), 8.10 (d, 1H), 8.60 (d, 1H), 8.85 (brs, 1H).
MS (DCI): 294 [M + H] ⁺ .

Example 33

Yield: 72%.
¹ H-NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm):
1.60-1.80 (m, 2H), 1.90-2.10 (m, 2H), 2.90 (s, 2H), 3.10-3.40 (m, 2H), 3, 80-3.90 (m, 2H), 5.10 (s, 2H), 7.28-7.41 (m, 5H), 7.50-7.78 (m, 4H), 7.79- 7.90 (m, 2H), 8.10 (d, 1H), 8.30 (dd, 1H), 8.90-9.00 (m, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 479 [M + H] ⁺ .

Example 34

Yield: 28%
MS (DCI / NH ₃ ): 407 [M + NH ₄ ] ^+
1 H-NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm):
1.20 (t, 3H), 1.55-2.00 (m, 8H), 2.55-2.65 (m, 1H), 2.88 (s, 2H), 4.02-4, 15 (m, 2H), 7.40-7.50 (m, 2H), 7.62-7.75 (m, 1H), 7.75-7.85 (m, 1H), 7.85- 7.95 (m, 1H), 8.05-8.15 (m, 1H), 8.25-8.35 (m, 1H).

Example 35

Yield: 87%.
¹ H NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm): 2.60-2.80 (m, 2H), 2.90 (s, 2H), 2.90-3.00 (m, 2H), 3.10-3.40 (m, 2H), 3.75-3.90 (m, 2H), 5.10 (s, 2H), 7.25-7.40 (m , 5H), 7.45 (dd, 1H), 7.48-7.53 (m, 1H), 7.85 (d, 1H), 7.96 (s, 4H).
MS (DCI / NH ₃ ): 470 [M + NH ₄ ] ⁺ .

Example 36

Yield: 63%.
¹ H-NMR (400 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.60-1.78 (m, 2H), 1.90-2.00 (m, 2H), 2.85 (s, 2H), 3.79-3.88 (m, 2H), 5.10 (s, 2H), 5.20 (s, 2H), 7.29-7.50 (m, 12H), 7.50-7.68 (m, 2H), 7.70 (d, 2H), 7.80 (d, 1H), 10.00 (s, 1H).
MS (ESI POS): 577 [M + H] ⁺ .

Example 37

Yield: 96%.
¹ H NMR (400 MHz, 300 K, DMSO-D ₆ , δ / ppm): 0.89 (t, 6H), 1.64-1.81 (m, 4H), 2.82 (s, 2H) ), 7.39-7.44 (m, 2H), 7.65-7.71 (m, 1H), 7.80 (d, 1H), 7.88 (d, 1H), 8.09 ( d, 1H), 8.24-8.27 (m, 1H).
MS (DCI / NH ₃ ): 323 [M + NH ₄ ] ⁺ , 306 [M + H] ⁺ .

Example 38

Mp 108-110 ° C; Yield: 67%.

Example 39

Yield: 50%.
¹ H NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.38-1.72 (m, 8H), 1.74-1.87 (m, 2H), 1.98 -2.10 (m, 2H), 2.85 (s, 2H), 7.25-7.35 (m, 2H), 7.55-7.63 (m, 1H), 7.64-7 , 82 (m, 3H), 8.05 (d, 1H), 8.46 (d, 1H), 8.90-8.95 (m, 1H).
MS (DCI / NH ₃ ) = 358 [M + H] ⁺ .

Example 40

Yield: 58%.
¹ H-NMR (300 MHz, 300 K, DMSO-D6, δ / ppm):
1.30-1.80 (m, 10H), 1.90-2.05 (m, 2H), 2.80 (s, 2H), 5.20 (s, 2H), 7.20-7, 50 (m, 7H), 7.58 (d, 2H), 7.66-7.78 (m, 3H), 9.80 (s, 1H).
MS (EI POS): 455 [M] ⁺ .

Example 41

Yield: 52%.
¹ H-NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm):
1.50-1.80 (m, 2H), 1.80-2.05 (m, 2H), 2.90 (s, 2H), 3.10-3.40 (m, 2H), 3, 70-3.90 (m, 2H), 5.10 (s, 2H), 7.20-7.55 (m, 10H), 7.70-7.90 (m, 3H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 428 [M + H] ⁺ .

Example 42

Mp 108-112 ° C; Yield: 20%.

Example 43

Yield: 88%.
¹ H-NMR (200 MHz, 300 K, CDCl ₃ , δ / ppm): 1.59-2.00 (m, 6H), 2.00-2.21 (m, 2H), 2.85 (s , 2H), 7.05-7.50 (m, 5H), 7.92 (d, 1H).
MS (DCI / NH ₃ ): 315 [M + H] ⁺ .

Example 44

7-bromo-3- (2-cyanoethyl) spiro [2H-1-benzopyran-2,1'-cyclobutane] -4 (3H) -one

Under argon, 2.00 g (7.49 mmol) of the compound from Example 6 are placed in 200 ml of tetrahydrofuran, and 0.18 g (7.49 mmol) of sodium hydride are added. Then, 0.60 g (11.23 mmol, 0.74 ml) of acrylonitrile are slowly added dropwise and the reaction mixture is heated to boiling for 2 hours. After cooling, 100 ml of water are added and it is extracted with ethyl acetate. The organic phase is separated off, dried over sodium sulfate and the solvent is distilled off. After chromatography on silica gel (1. VII, 2. VI (1: 1), 3. V (5: 1)) and subsequent recrystallization from ethyl acetate / n-pentane, 0.60 g (25.03%) of colorless crystals are obtained ,
¹ H-NMR (300 MHz, CDCl ₃ , δ / ppm):
1.70-1.92 (m, 2H), 1.92-2.12 (m, 2H), 2.12-2.20 (m, 2H), 2.21-2.55 (m, 4H) ), 2.69 (dd, 1H), 7.10-7.22 (m, 2H), 7.69 (d, 1H).
MS (ESI, acetonitrile / water 7: 3+ 1% acetic acid): 320 [M + H] ⁺ , 342 [M + Na] ⁺ .

Example 45

7-bromo-3,3-bis (2-cyanoethyl) spiro [2H-1-benzopyran-2,1'-cyclobutane] -4 (3H) -one

2.50 g (9.36 mmol) of the compound from Example 6 are placed in 20 ml of dioxane under argon, and 0.45 g (18.72 mmol) of sodium hydride are added. After stirring for 30 min at room temperature, 1.69 g (31.82 mmol) of acrylonitrile are added dropwise and the reaction mixture is heated under reflux for 4 h. The solvent is distilled off. Chromatography on silica gel (V (4: 1)) gives 0.34 g (11.34%) of the desired compound.
¹ H-NMR (300 MHz, DMSO-D ₆ , δ / ppm): 1.90-2.15 (m, 8H), 2.35-2.45 (m, 1H), 2.52-2, 80 (m, 5H), 7.30 (dd, 1H), 7.40 (d, 1H), 7.60 (d, 1H).
MS (DCI / NH ₃ ): 373 [M + H] ⁺ , 390 [M + NH ₄ ] ⁺ .

Analogously to Example 44, the reactions with acrylic acid derivatives monoalkylated compounds listed below:  

Example 46

Yield: 9%
Mp 75-78 ° C
R _f 0.52 (I, 100: 1)
MS (DCI): 294 [M + H] ⁺ .

Example 47

Yield: 31%
R _f 0.48 (I, 100: 1)
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 1.25 (t, 3H), 1.40-2.40 (m, 15H), 4.15 (q, 2H), 7.20 (s, 1H), 7.25 (d, 1H), 7.35-7.50 (m, 3H), 7.65 (m, 2H), 7.9 (d, 1H).
MS (DCI): 393 [M + H] ⁺ .

Example 48

Yield: 12%
R _f 0.57 (I, 100: 1)
¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm): 1.25-1.40 (m, 3H), 1.55-1.80 (m, 5H), 2.00 (m, 4H) , 2.40-2.65 (m, 3H), 7.15 (dd, 1H), 7.20 (d, 1H), 7.70 (d, 1H).
MS (DCI): 348 [M + H] ⁺ .

Example 49

Yield: 22%
R _f 0.5 (I, 20: 1)
¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm):
1.30 (m, 3H), 1.55-1.75 (m, 5H), 2.05 (m, 4H), 2.40-2.70 (m, 3H), 7.00-7, 40 (m, 4H), 7.90 (s, 1H), 7.95 (d, 1H), 8.65 (br. S, 1H), 8.85 (br. S, 1H).
MS (DCI): 347 [M + H] ⁺ .

Example 50

Yield: 2%
R _f 0.51 (I, 20: 1)
¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm): 1.15-1.30 (m, 3H), 1.40-1.65 (m, 5H), 1.95 (m, 4H) , 2.30-2.55 (m, 3H), 7.00 (d, 1H), 7.35 (br. S, 1H), 7.65 (dd, 1H), 7.85 (d, 1H) ), 7.95 (s, 1H), 8.50 (br. S, 1H), 8.75 (br. S, 1H).
MS (DCI): 347 [M + H] ⁺ .

Example 51

Yield: 24%
Mp 80 ° C; R _f 0.36 (II)
MS (DCI): 306 [M + H] ⁺ .

Example 52

Yield: 19%.
R _f value: 0.29 (V, 4: 1)
¹ H NMR (300 MHz, 300 K, CD ₂ Cl ₂ ): 1.70-2.30 (m, 10H), 2.45-2.65 (m, 2H), 2.70 (dd, 1H ), 7.30-7.35 (m, 2H), 7.80-7.88 (m, 1H).
MS (DCI / NH ₃ ): 351 [M + NH ₄ ] ⁺ .

Example 53

Yield: 6.5%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ ): 1.30 (s, 3H), 1.52 (s, 3H), 1.80-1.90 (m, 1H), 1, 91-2.08 (m, 1H), 2.43-2.52 (m, 1H), 2.60-2.69 (m, 1H), 2.70 (dd, 1H), 7.11- 7.16 (m, 2H), 7.66 (d, 1H).
MS (DCI / NH ₃ ): 325 [M + NH ₄ ] ⁺ .

Example 54

Mp 72-82 ° C; Yield: 59%.

Example 55

Mp 107-111 ° C; Yield: 25%.

Example 56

Yield: 24%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.16 (t, 3H), 1.58-1.68 (m, 1H), 1.70-1.90 (m, 9H), 2.25-2.45 (m, 2H), 2, 50-2.58 (m, 2H), 4.04 (q, 2H), 7.07 (dd, 1H), 7.12 (d, 1H), 7.58 (d, 1H).
MS (DCI / NH ₃ ): 437 [M + NH ₄ ] ⁺ .

Example 57

Mp 89-94 ° C; Yield: 18%.

Example 58

Yield: 5%.
MS (ESI POS) = 506 [M + H] ⁺ .
LC-MS (XII): 5.13 (RT / min).

Example 59

Yield: 39%.
MS (DCI / NH ₃ ): 460 [M + NH ₄ ] ⁺ .

Example 60

Mp 64-69 ° C; Yield: 32%.

Example 61

Yield: 48%.
¹ H-NMR (400 MHz, DMSO-D ₆ , δ / ppm):
1.60-1.70 (m, 1H), 1.80-1.90 (m, 2H), 1.90-2.10 (m, 2H), 2.38-2.60 (m, 2H) ), 2.80 (dd, 1H), 3.10-3.25 (m, 2H), 3.90 (m, 2H), 5.10 (s, 2H), 7.28 (d, 1H) , 7.30-7.42 (m, 5H), 7.46 (t, 1H), 7.65 (dt, 1H), 7.92 (d, 1H), 8.18 (d, 1H), 9.22 (d. 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 455 [M + H] ⁺ .

Example 62

Yield: 26%.
¹ H-NMR (300 MHz, DMSO-D ₆ , δ / ppm):
1.58-2.10 (m, 12H), 2.70 (dd, 1H), 7.18 (d, 1H), 7.46 (dt, 1H), 7.64 (dt, 1H), 7 , 90 (d, 1H), 8.12 (d, 1H), 9.27 (d, 1H).
MS (EI POS) = 305 [M] ⁺ .

Analogously to Example 45, the following were the reactions with acrylic acid derivatives Dialkylated compounds obtained:

Example 63

Yield: 15%.
R _f value: 0.43 (I, 100: 1)
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 1.30-2.60 (m, 16H), 7.20 (s, 1H), 7.25 (d, 1H), 7.35 -7.50 (m, 3H), 7.65 (m, 2H), 7.9 (d, 1H).
MS (DCI): 385 [M + H] ⁺ .

Example 64

Yield: 10%.
R _f value: 0.41 (I, 100: 1)
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 1.25 (m, 6H), 1.50-2.50 (m, 18H), 4.15 (q, 4H), 7.20 (s, 1H), 7.25 (d, 1H), 7.35-7.50 (m, 3H), 7.60 (m, 2H), 7.85 (dd, 1H).
MS (DCI): 493 [M + H] ⁺ .

Example 65

Yield: 14%
Mp 145-149 ° C; R _f value: 0.36 (I, 100: 1)
MS (DCI): 403 [M + H] ⁺ .

Example 66

Yield: 38%
Mp 190-195 ° C; R _f value: 0.34 (I, 20: 1)
MS (DCI): 400 [M + H] ⁺ .

Example 67

Yield: 61%
52312 00070 552 001000280000000200012000285915220100040 0002010054932 00004 52193 ¹ H-NMR (200 MHz, 300 K, DMSO-D ₆ ): 1.65-1.88 (m, 1H), 1.90-2.22 (m, 7H), 2.40-2.55 (m, 1H), 2.55-2.90 (m, 5H), 7.45-7.55 (m, 2H), 7.80 (d, 1H), 7, 90-8.05 (m, 4H).
MS (DCI / NH ₃ ): 413 [M + NH ₄ ] ⁺ .

Example 68

Yield: 7.50%.
¹ H NMR (400 MHz, 300 K, DMSO-D ₆ ): 1.18 (t, 3H), 1.50-2.30 (m, 13H), 2.50-2.70 (m, 3H) ), 4.05 (q, 2H), 7.45 (s, 1H), 7.46-7.55 (m, 1H), 7.82 (d, 1H), 8.20 (td, 1H) , 8.62 (d, 1H), 8.99 (d, 1H).
MS (DCI / NH ₃ ): 472 [M + H] ⁺ .

Example 69

Mp 148-151 ° C; Yield: 39%.

Example 70

Yield: 44%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.75-1.91 (m, 1H), 2.10-2.30 (m, 7H), 2.30-2.40 (m, 2H), 2.42-2.54 (m, 2H) ), 2.58-2.72 (m, 2H), 7.25-7.30 (m, 1H), 7.32 (dd, 1H), 7.35-7.42 (m, 1H), 7.50-7.60 (m, 1H), 7.68 (dd, 1H), 7.75 (d, 1H), 7.84 (dd, 1H), 8.18 (dd, 1H), 8 , 84 (dd, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 422 [M + H] ⁺ .

Example 71

Mp 187-193 ° C; Yield: 74%.

Example 72

Yield: 90%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
2.00-2.24 (m, 8H), 2.28-2.38 (m, 2H), 2.41-2.51 (m, 2H), 2.58-2.70 (m, 2H) ), 7.20 (d, 1H), 7.24 (dd, 1H), 7.79 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 439 [M + H] ⁺ .

Example 73

Yield: 20%
¹ H-NMR (400 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.50-1.80 (m, 2H), 1.80-1.90 (m, 2H), 1.90 -2.13 (m, 4H), 2.15-2.30 (m, 2H), 2.30-2.70 (m, 2H), 3.00-3.30 (m, 2H), 3 , 70-4.00 (m, 2H), 5.05-5, 18 (m, 2H), 7.20-7.42 (m, 6H), 7.50 (t, 1H), 7.60 -7.70 (m, 1H), 7.90-7.99 (m, 1H), 8.10-8.20 (m, 1H).
MS (DCI / NH ₃ ): 525 [M + NH ₄ ] ⁺ .

Example 74

3- (2-cyanoethyl) -7- (3-cyanophenyl) spiro [2H-1-benzopyran-2,1'-cyclobutane] -4 (3H) -one

A solution of 0.05 g (0.16 mmol) of the compound from Example 44 and 0.03 g (0.23 mmol) of 3-cyanophenylboronic acid in 10 ml of dioxane is added under argon with 2 ml of 2N aqueous sodium carbonate solution and 0 .01 g (0.01 mmol) of tetrakis (triphenylphosphine palladium (II) are added and the mixture is stirred under reflux overnight. After the solvent has been distilled off, the residue is taken up in dichloromethane / methanol, dried over sodium sulfate and purified by flash chromatography on silica gel ( V 4: 1), giving 36.5 mg (62%) of the target compound.
¹ H-NMR (200 MHz, 300 K, DMSO-D ₆ , δ / ppm):
1.63-2.60 (m, 10H), 2.80 (dd, 1H), 7.42-7.55 (m, 2H), 7.62-7.75 (m, 1H), 7, 81 (d, 1H), 7.90 (d, 1H), 8.10 (d, 1H), 8.21-8.30 (m, 1H).
MS (DCI / NH ₃ ): 360 [M + NH ₄ ] ⁺ .

The following compounds were obtained analogously to Example 74:

Example 75

Yield: 38%
Mp 61-63 ° C; R _f value: 0.33 (I, 100: 1)
MS (DCI): 364 [M + H] ⁺ .

Example 76

Yield: 42%
Mp 86-90 ° C; R _f value: 0.28 (II)
MS (DCI): 360 [M + H] ⁺ .

Example 77

Yield: 34%
R _f value: 0.52 (I, 50: 1)
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 1.30-1.45 (m, 4H), 1.60 (m, 2H), 1.80 (m, 2H), 2.05 (m, 4H), 2.45-2.55 (m, 3H), 3.75 (br. s, 2H), 6.80 (d, 1H), 7.00 (s, 1H), 7, 10 (d, 1H), 7.20-7.45 (m, 3H), 7.85 (d, 1H).
MS (DCI): 361 [M + H] ⁺ .

Example 78

Yield: 58%
R _f value: 0.3 (II)
¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm): 1.25-2.10 (m, 12H), 2.45-2.75 (m, 3H), 7.45 (d, 1H) , 7.75 (dd, 1H), 7.80 (m, 2H), 8.05 (m, 2H).
MS (DCI): 414 [M + H] ⁺ .

Example 79

4.50 ml of aqueous 2 M sodium carbonate solution are added to a solution of 2.01 g (6.00 mmol) of the compound from Example 52 and 1.11 g (9.00 mmol) of 4-pyridylborononic acid in 30 ml of dimethoxyethane and 0.21 g (0.30 mmol) of bis (triphenyl phosphine) palladium (II) chloride. After 2 hours under reflux, a further 1.11 g (9.00 mmol) of 4-pyridylboronic acid and 0.21 g (0.30 mmol) of bis (triphenylphosphine) palladium (II) chloride are added, and another 2 h heated under reflux. 100 ml of dimethylformamide, 300 mg of [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride and 300 mg of triphenylphosphine are added to the reaction mixture. The mixture is stirred at 90 ° C for 20 h. After cooling, ethyl acetate and 5% aqueous NaH ₂ PO ₄ solution are added, the mixture is filtered through Celite and the organic phase is separated off. After extraction of the aqueous phase with ethyl acetate, the organic phases are washed with 5% aqueous NaH ₂ PO ₄ solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, the solvent is distilled off and the residue is purified by chromatography on silica gel (V 2: 1). Subsequent normal phase HPLC purification (V 35: 65) and recrystallization from diethyl ether give 0.805 g (40.36%) of the target compound in the form of colorless crystals.
¹ H-NMR (200 MHz, DMSO-D ₆ , δ / ppm): 1.55-2.20 (m, 10H), 2.45-2.55 (m, 2H), 2.60 (dd, 1H), 7.15 (d, 1H), 7.25 (d, 1H), 7.50 (dd, 2H), 7.92 (d, 1H), 8.60-8.80 (m, 2H) ).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 333 [M + H] ⁺ .

Example 80

Yield: 75%.
¹ H-NMR (200 MHz, 300 K, DMSO-D ₆ , δ / ppm):
1.62-2.20 (m, 6H), 2.20-2.42 (m, 2H), 2.52-2.60 (m, 2H), 2.80 (dd, 1H), 7, 40-7.51 (m, 2H), 7.80-7.91 (m, 3H), 7.91-8.05 (m, 2H).
MS (DCI / NH ₃ ): 403 [M + NH ₄ ] ⁺ .

Example 81

Yield: 60%.
¹ H-NMR (200 MHz, 300 K, DMSO-D ₆ , δ / ppm):
1.64-2.24 (m, 6H), 2.25-2.42 (m, 2H), 2.50-2.60 (m, 2H), 2.80 (dd, 1H), 7, 42-7.51 (m, 2H), 7.80-7.88 (m, 1H), 7.95 (s, 4H).
MS (DCI / NH ₃ ): 360 [M + NH ₄ ] ⁺ .

Example 82

A solution of 4.70 g (14.06 mmol) of the compound from Example 52 and 2.66 g (16.88 mmol) of 3,4-difluorophenylboronic acid in 85 ml of dimethoxyethane is mixed with 8.44 ml of 2 M aqueous sodium carbonate solution and 0.49 g (0.70 mmol) of bis (triphenyl phosphine) palladium (II) chloride were added. After stirring under reflux for 2 hours, ethyl acetate is added, the mixture is washed with 5% aqueous sodium dihydrogen phosphate solution and dried over magnesium sulfate. The solvent is distilled off and the residue is purified by chromatography on silica gel (VI 1: 1, V 10: 1) and recrystallized from diethyl ether and diethyl ether / n-pentane. The product is in the form of colorless crystals in a yield of 4.52 g (87%).
¹ H-NMR (200 MHz, CDCl ₃ , δ / ppm): 1.55-2.25 (m, 10H), 2.45-2.50 (m, 2H), 2.55 (dd, 1H) , 7.05 (d, 1H), 7.10-7.50 (m, 4H), 7.90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 368 [M + H] ⁺ .
R _f value: 0.48 (cyclohexane / ethyl acetate 2: 1).

The following compounds were obtained analogously to Example 82:

Example 83

Yield: 88%.
¹ H-NMR (400 MHz, 300 K, CDCl ₃ , δ / ppm): 1.60-2.20 (m, 10H), 2.35-2.53 (m, 2H), 2.55 (dd , 1H), 6.80-6.90 (m, 1H), 7.06-7.15 (m, 3H), 7.20 (dd, 1H), 7.90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 368 [M + H] ⁺ , 390 [M + Na] ⁺ .

Example 84

Yield: 33%.
¹ H NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.50-2.20 (m, 6H), 2.40-2.70 (m, 6H), 3.00 -3.60 (m, 3H), 4.40-4.70 (m, 1H), 7.11-7.19 (m, 3H), 7.22-7.31 (m, 7H), 7 , 33-7.37 (m, 1H), 7.74 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 497 [M + H] ⁺ .

Example 85

Yield: 72%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.50-2.30 (m, 6H), 2.40-2.70 (m, 3H), 3.10-3.70 (m, 3H), 4.40-4.70 (m, 1H) ), 7.00-7.30 (m, 4H), 7.38-7.48 (m, 5H), 7.91 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 505 [M + H] ⁺ .

Example 86

Mp 89-93 ° C; Yield: 67%.

Example 87

Mp 120-128 ° C; Yield: 57%.

Example 88

Mp 91-99 ° C; Yield: 58%.

Example 89

Yield: 68%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.40-2.10 (m, 7H), 2.20-2.50 (m, 3H), 2.90-3.60 (m, 3H), 7.10-7.15 (m, 2H) ), 7.18-7.26 (m, 5H), 7.57 (s, 4H), 7.74 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 519 [M + H] ⁺ .

Example 90

Mp 88-92 ° C; Yield: 74%.

Example 91

Yield: 68%.
¹ H NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.60-2.20 (m, 10H), 2.34-2.53 (m, 2H), 2.55 (dd, 1H), 7.05-7.25 (m, 4H), 7.90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 386 [M + H] ⁺ , 408 [M + Na] ⁺ .

Example 92

Yield: 83%.
¹ H NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.60-1.95 (m, 6H), 1.95-2.20 (m, 4H), 2.35 -2.55 (m, 2H), 2.60 (dd, 1H), 7.10 (s, 1H), 7.15-7.30 (m, 5H), 7.90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 368 [M + H] ⁺ , 390 [M + Na] ⁺ .

Example 93

Yield: 17%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 4.20-4.70 (m, 6H), 4.90 (s, 3H), 5.00-5.10 (m, 1H), 5.10-5.22 (m, 2H), 5.30-5.38 (m, 2H), 5.50-5.80 (m, 1H), 6.00-6 , 20 (m, 1H), 9.55-9.65 (m, 2H), 9.67-9.75 (m, 2H), 9.83-9.97 (m, 6H), 10.28 (d, 1H), 10.45 (s, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 497 [M + H] ⁺ .

Example 94

Yield: 29%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.70-1.90 (m, 2H), 1.90-2.30 (m, 4H), 2.40 -2.61 (m, 2H), 2.61-2.70 (m, 1H), 3.10-3.30 (m, 3H), 7.15-7.30 (m, 4H), 7 , 30-7.52 (m, 7H), 7.90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 469 [M + H] ⁺ , 491 [M + Na] ⁺ .

Example 95

Yield: 45%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.40-2.20 (m, 7H), 2.30-2.62 (m, 3H), 3.00-3.20 (m, 1H), 3.30-3.70 (m, 2H) ), 6.98-7.20 (m, 5H), 7.28-7.39 (m, 5H), 7.82 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 487 [M + H] ⁺ .

Example 96

Yield: 71%.
¹ H NMR (300 MHz, 300 K, CDCl ₃ , δ / ppm): 1.55-2.20 (m, 10H), 2.35-2.50 (m, 2H), 2.55 (dd , 1H), 7.10-7.20 (m, 4H), 7.53-7.62 (m, 2H), 7.90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 350 [M + H] ⁺ , 372 [M + Na] ⁺ .

Example 97

Yield: 70%.
¹ H-NMR (300 MHz, 300 K, CDCl ₃ , δ / ppm):
1.60-2.20 (m, 10H), 2.36-2.55 (m, 2H), 2.60 (dd, 1H), 7.11 (d, 1H), 7.20 (d, 1H), 7.53-7.62 (m, 1H), 7.68 (dd, 1H), 7.81 (dd, 1H), 7.88 (m, 1H), 7.95 (d, 1H) ).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 357 [M + H] ⁺ , 379 [M + Na] ⁺ .

Example 98

Yield: 69%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.61-1.99 (m, 6H), 2.01-2.20 (m, 4H), 2.38 -2.61 (m, 3H), 7.25 (d, 1H), 7.35 (dd, 1H), 7.42-7.50 (m, 1H), 7.60-7.65 (m , 1H), 7.75 (dd, 1H), 7.85-7.95 (m, 2H), 8.25 (dd, 1H), 8.90 (dd, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 383 [M + H] ⁺ .

Example 99

Yield: 81%.
¹ H-NMR (300 MHz, 300 K, CDCl ₃ , δ / ppm): 1.70-2.58 (m, 10H), 2.71 (dd, 1H), 7.12 (d, 1H), 7.18 (dd, 1H), 7.20-7.29 (m, 1H), 7.29-7.35 (m, 1H), 7.35-7.45 (m, 1H), 7, 90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 354 [M + H] ⁺ , 376 [M + Na] ⁺ .

Example 100

Yield: 65%.
¹ H-NMR (300 MHz, 300 K, CDCl ₃ , δ / ppm): 1.35 (s, 3H), 1.55 (s, 3H), 1.82-1.95 (m, 1H), 1.98-2.12 (m, 1H), 2.50-2.70 (m, 2H), 2.71 (dd, 1H), 7.05 (d, 1H), 7.15 (dd, 1H), 7.20-7.45 (m, 3H), 7.88 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 342 [M + H] ⁺ , 683 [2M + H] ⁺ .

Example 101

Yield: 78%.
¹ H-NMR (300 MHz, 300 K, CDCl ₃ , δ / ppm): 1.72-2.57 (m, 10H), 2.72 (dd, 1H), 6.82-6.90 (m , 1H), 7.05-7.13 (m, 2H), 7.15 (d, 1H), 7.20 (dd, 1H), 7.90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 354 [M + H] ⁺ , 376 [M + Na] ⁺ .

Example 102

Yield: 70%.
¹ H-NMR (200 MHz, 300 K, CDCl ₃ , δ / ppm): 1.38 (s, 3H), 1.60 (s, 3H), 1.80-2.20 (m, 2H), 1.95-2.70 (m, 2H), 2.75 (dd, 1H), 6.78-6.95 (m, 1H), 7.02-7.20 (m, 4H), 7, 90 (d, 1H).
MS (DCI / NH ₃ ): 341 [M] ⁺ , 359 [M + NH ₄ ] ⁺ .

Example 103

Yield: 83%.
¹ H-NMR (200 MHz, 300 K, CDCl ₃ , δ / ppm): 1.35 (s, 3H), 1.58 (s, 3H), 1.80-2.18 (m, 2H), 2.54-2.69 (m, 2H), 2.72 (dd, 1H), 7.10 (d, 1H), 7.18 (dd, 1H), 7.38-7.46 (m, 1H), 7.70 (d, 1H), 7.89 (d, 1H).
MS (DCI / NH ₃ ): 391 [M + NH ₄ ] ⁺ .

Example 104

Yield: 79%.
¹ H NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.60-2.20 (m, 10H), 2.35-2.55 (m, 2H), 2.55 (dd, 1H), 7.05-7.15 (m, 2H), 7.22 (dd, 1H), 7.31 (dd, 1H), 7.40-7.50 (m, 2H), 7.85-7.95 (m, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 350 [M + H] ⁺ , 372 [M + Na] ⁺ .

Example 105

Yield: 43%.
¹ H NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.60-1.95 (m, 6H), 1.95-2.20 (m, 4H), 2.35 -2.55 (m, 2H), 2.60 (dd, 1H), 6.92-7.05 (m, 1H), 7.05 (s, 1H), 7.10 (dd, 1H), 7.15-7.30 (m, 1H), 7.90 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 386 [M + H] ⁺ , 408 [M + Na] ⁺ .

Example 106

Yield: 56%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.15 (t, 3H), 1.60-1.70 (m, 1H), 1.75-1.95 (m, 9H), 2.25-2.45 (m, 2H), 2, 50-2.58 (m, 2H), 4.04 (q, 2H), 7.07 (d, 1H), 7.11 (dd, 1H), 7.16-7.24 (m, 1H) , 7.26-7.32 (m, 1H), 7.33-7.41 (m, 1H), 7.78 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 454 [M + H] ⁺ .

Example 107

Yield: 76%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.50 (t, 3H), 1.94-2.05 (m, 1H), 2.08-2.30 (m, 9H), 2.60-2.80 (m, 2H), 2, 85-2.92 (m, 2H), 4.38 (q, 2H), 7.09-7.17 (m, 1H), 7.38-7.49 (m, 4H), 8.13 ( d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 454 [M + H] ⁺ .

Example 108

Yield: 31%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.25 (t, 3H), 1.70-1.80 (m, 1H), 1.80-2.05 (m, 9H), 2.38-2.58 (m, 2H), 2, 60-2.68 (m, 2H), 4.15 (q, 2H), 7.20 (d, 1H), 7.22 (dd, 1H), 7.49 (dd, 1H), 7.57 (d, 1H), 7.75 (d, 1H), 7.88 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 486 [M + H] ⁺ .

Example 109

Mp 71-73 ° C; Yield: 14%.

Example 110

Yield: 11%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.18 (t, 3H), 1.62-1.70 (m, 1H), 1.75-1.98 (m, 9H), 2.28-2.45 (m, 2H), 2, 53-2.59 (m, 2H), 4.05 (q, 2H), 7.05-7.17 (m, 4H), 7.51-7.57 (m, 2H), 7.77 ( d, 1H).
MS (DCI / NH ₃ ): 453 [M + NH ₄ ] ⁺ .

Example 111

Yield: 33%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.27 (t, 3H), 1.70-1.80 (m, 1H), 1.83-2.05 (m, 9H), 2.38-2.52 (m, 2H), 2, 62-2.68 (m, 2H), 4.15 (q, 2H), 7.21 (d, 1H), 7.26 (dd, 1H), 7.28-7.34 (m, 1H) , 7.37-7.42 (m, 2H), 7.49-7.52 (m, 1H), 7.87 (d, 1H).
MS (DCI / NH ₃ ): 481 [M + NH ₄ ] ⁺ .

Example 112

Yield: 24%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.35 (t, 3H), 1.80-1.88 (m, 1H), 1.90-2.12 (m, 9H), 2.43-2.63 (m, 2H), 2, 63-2.76 (m, 2H), 4.22 (q, 2H), 6.80-6.85 (m, 1H), 7.00-7.05 (m, 1H), 7.05- 7.11 (m, 2H), 7.26 (s, 1H), 7.31 (d, 2H), 7.91 (d, 1H).
MS (DCI / NH ₃ ): 450 [M + NH ₄ ] ⁺ .

Example 113

Yield: 47%.
¹ H-NMR (400 MHz, 300 K, CDCl ₃ , δ / ppm): 1.65-1.80 (m, 1H), 1.84-2.12 (m, 5H), 2.43-2 , 59 (m, 2H), 2.60-2.67 (m, 1H), 3.75-3.90 (m, 4H), 6.82-6.92 (m, 1H), 7.10 -7.16 (m, 2H), 7.21-7.25 (m, 2H), 7.92 (d, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 384 [M + H] ⁺ .

Example 114

Yield: 52%.
¹ H NMR (300 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.65-1.95 (m, 4H), 2.00-2.13 (m, 1H), 2.35 -2.65 (m, 3H), 2.70 (dd, 1H), 3.60-3.80 (m, 4H), 7.40-7.56 (m, 4H), 7.70-7 , 75 (m, 1H), 7.76-7.88 (m, 2H).
MS (EI POS): 381 [M] ⁺ .

Example 115

Yield: 60%.
¹ H NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.38 (s, 3H), 1.58 (s, 3H), 1.85-1.95 (m, 1H ), 1.96-2.10 (m, 1H), 2.50-2.60 (m, 1H), 2.61-2.70 (m, 1H), 2.72 (dd, 1H), 7.07 (d, 1H), 7.14 (dd, 1H), 7.51 (t, 1H), 7.62 (td, 1H), 7.75-7.84 (m, 3H).
MS (DCI / NH ₃ ): 348 [M + NH ₄ ] ⁺ .

Example 116

Yield: 83%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.53-2.11 (m, 10H), 2.30-2.47 (m, 2H), 2.52 (dd, 1H), 7.16 (s, 1H), 7.22 (d, 1H), 7.59 (t, 1H), 7.83-7.91 (m, 2H), 8.17 (d, 1H), 8.36-8.42 (m, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 377 [M + H] ⁺ .

Example 117

Yield: 51%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.52-2.08 (m, 11H), 2.26-2.50 (m, 5H), 7.07 (d, 1H), 7.16 (dd, 1H), 7.19-7, 24 (m, 1H), 7.27-7.32 (m, 2H), 7.39-7.42 (m, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 378 [M + H] ⁺ .

Example 118

Mp 104.8 ° C; Yield: 56%.

Example 119

Yield: 59%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.60-2.19 (m, 10H), 2.35-2.58 (m, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 6.97 (d, 1H), 7.15 (t, 2H), 7.20-7.27 (m, 2H), 7.86 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 392 [M + H] ⁺ .

Example 120

Yield: 61%.
¹ H-NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm):
1.52-2.08 (m, 10H), 2.27-2.50 (m, 3H), 3.78 (s, 3H), 6.87 (ddd, 1H), 7.06 (t, 1H), 7.08 (d, 1H), 7.10-7.15 (m, 1H), 7.17 (dd, 1H), 7.30 (t, 1H), 7.79 (d, 1H) ).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 362 [M + H] ⁺ .

Example 121

Mp 72 ° C; Yield: 23%.

Example 122

Mp 97.7 ° C; Yield: 71%.

Example 123

Mp 112 ° C; Yield: 28%.

Example 124

Mp 138.8 ° C; Yield: 30%.

Example 125

Yield: 12.63%.
¹ H NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.40-1.62 (m, 2H), 2.00-2.12 (m, 2H), 2.12 -2.30 (m, 2H), 2.35-2.45 (m, 2H), 3.40-3.62 (m, 2H), 3.95-4.00 (m, 2H), 4 , 22-4.30 (m, 1H), 5.08 (s, 2H), 7.12-7.45 (m, 8H), 7.95 (d, 2H), 8.60-8.65 (m, 1H), 8.82-8.90 (m, 1H).
MS (DCI / NH ₃ ): 482 [M + H] ⁺ .

Example 126

Yield: 28.41%.
¹ H NMR (400 MHz, 300 K, CD ₂ Cl ₂ , δ / ppm): 1.70-2.52 (m, 12H), 2.75 (dd, 1H), 7.25-7.30 (m, 2H), 7.58-7.70 (m, 1H), 7.95 (d, 1H), 8.10-8.21 (m, 1H), 8.60-8.72 (m , 1H), 8.85-8.95 (m, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 319 [M + H] ⁺ , 341 [M + Na] ⁺ .

Example 127

Mp 145-149 ° C; Yield: 32%.

Example 128

Mp 103-105 ° C; Yield: 45%.

Example 129

Yield: 57%.
¹ H-NMR (200 MHz, 300 K, CDCl ₃ , δ / ppm):
1.60-2.10 (m, 6H), 2.45-2.65 (m, 3H), 3.76-3.92 (m, 4H), 3.94 (s, 3H), 3, 97 (s, 3H), 6.91-7.00 (d, 1H), 7.12 (d, 1H), 7.16-7.29 (m, 3H), 7.88 (d, 1H) ,
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 408 [M + H] ⁺ .

Example 129A

Yield: 26%.
¹ H NMR (200 MHz, 300 K, CDCl ₃ , δ / ppm): 1.40 (s, 9H), 1.60-2.10 (m, 6H), 2.45-2.65 (m , 3H), 3.70-3.90 (m, 4H), 6.20-6.35 (m, 2H), 6.95-7.05 (m, 2H), 7.35-7.40 (m, 1H), 7.81 (d, 1H).
MS (ESI, acetonitrile / water 7: 3 + 0.1% acetic acid): 437 [M + H] ⁺ , 459 [M + Na] ⁺ .

Example 130

3- (2-Carboxy) -7-phenyl-spiro [2H-1-benzopyran-2,1'-cyclohexane] -4 (3H) -one

A mixture of 100 mg (0.25 mmol) of the compound from Example 47, 0.35 ml of 1N sodium hydroxide solution, 2 ml of ethanol and 2 ml of water is stirred at 50 ° C. for two hours. The mixture is brought to pH 7 with dilute hydrochloric acid and evaporated to dryness. The residue is stirred with isopropanol, suction filtered and dried.
Yield: 58 mg (63%)
Melting point: 196 ° C
MS (DCI): 365 [M + H] ⁺
R _f value: 0.32 (I, 20: 1).

Example 131

3- (2-cyanoethyl) -7- (3-pyridyl) spiro [2H-1-benzopyran-2,1'-cyclohexane] -4 (3H) -one hydrochloride

20 mg of the compound from Example 49 in 5 ml of a 4 M hydrochloric acid solution in dioxane are stirred overnight at room temperature. All volatile components are removed under reduced pressure and the residue is stirred with isopropanol, suction filtered and dried.
Yield: 14 mg (64%).

Example 132

3- (2-cyanoethyl) -7- (3-aminophenyl) spiro [2H-1-benzopyran-2,1'-cyclohexane] -4 (3H) -one hydrochloride

Analogously to Example 131, the title compound is obtained in the reaction of the compound from Example 77 with dioxane / hydrochloric acid.
Yield: 60%.

Example 133

3- (2-cyanoethyl) -6-fluoro-7- (4-phenyl-piperazin-1-yl) spiro [2H-1-benzopyran-2,1'-cyclohexane] -4 (3H) -one

A solution of 100 mg (0.33 mmol) of the compound from Example 51 and 160 mg (0.99 mmol) of phenylpiperazine in 3 ml of DMSO is kept at 100 ° C. for 3 hours. The solvent is distilled off, the residue is mixed with water and extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed. The crude product is stirred with petroleum ether and isolated.
Yield: 110 mg (75%)
Melting point: 163-168 ° C
MS (DCI): 448 [M + H] ⁺
R _f value: 0.5 (I, 100: 1).

Example 134

3- [7- (4-aminocarbonylphenyl) spiro [2H-1-benzopyran-2,1'-cyclobutane] -4 (3H) -one-3-yl] -propionamide

While cooling with ice, 18.20 mg (0.05 mmol) of the compound from Example 81 are mixed with 14.69 mg (0.11 mmol) of potassium carbonate and 24.11 mg (0.02 ml, 0.21 mmol) of hydrogen peroxide in 2 , 00 ml of DMSO and stirred for 3 hours at room temperature. Then the same amounts of hydrogen peroxide and potassium carbonate are added again with ice cooling. After stirring for 2 hours at room temperature, water and ethyl acetate are added, the organic phase is separated off, washed with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. Chromatographic purification on silica gel (I 10: 1) gives 15.1 mg (75%) colorless crystals.
¹ H-NMR (400 MHz, DMSO-D ₆ , δ / ppm): 1.50-1.54 (m, 1H), 1.70-1.82 (m, 1H), 1.85-2, 25 (m, 6H), 2.30-2.45 (m, 2H), 2.65 (dd, 1H), 6.72 (br.s, 1H), 7.25 (br.s, 1H) , 7.40-7.50 (m, 2H), 7.75-7.90 (m, 2H), 7.95 (d, 2H), 8.05 (s, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 379 [M + H] ⁺ , 401 [M + Na] ⁺ , 779 [2M + Na] ⁺ .

The following compounds were obtained analogously to Example 134:  

Example 135

Yield: 31%
MS (DCI / NH ₃ ): 404 [M + H] ⁺ .
HPLC (XIII): RT = 4.98.

Example 136

Yield: 50%.
¹ H NMR (200 MHz, 300 K, DMSO-D ₆ , δ / ppm): 1.20-2.20 (m, 8H), 2.30-2.45 (m, 2H), 2.65 (dd, 1H), 6.75 (br. s, 2H), 7.30 (br.s, 2H), 7.40-7.50 (m, 2H), 7.51-7.62 (m , 1H), 7.75-7.85 (m, 1H), 7.85-7.95 (m, 1H), 8.10-8.20 (m, 1H), 8.20-8.30 (m, 1H).
MS (DCI / NH ₃ ): 379 [M + H] ⁺ .

Example 137

¹ H-NMR (200 MHz, 300 K, DMSO-D ₆ , δ / ppm) = 1.35-2.15 (m, 15H), 6.78 (br.s 1H), 7.27 (br. s, 1H), 7.31 (s, 1H), 7.36 (d, 1H), 7.48 (m, 3H), 7.77 (m, 3H).
MS (DCI / NH ₃ ): 364 [M + H] ⁺ .

Example 138

Yield: 36%.
¹ H-NMR (400 MHz, 300 K, DMSO-D ₆ , δ / ppm):
1.78-1.90 (m, 3H), 1.95-2.27 (m, 9H), 2.39-2.48 (m, 2H), 6.77 (br. S, 2H), 7.38 (br. S, 2H), 7.43-7.50 (m, 3H), 7.58 (t, 1H), 7.79 (d, 1H), 7.90-7.95 ( m, 2H), 8.18 (brs, 1H), 8.24 (brs, 1H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 450 [M + H] ⁺ , 472 [M + Na] ⁺ .

Example 139

Yield: 84%.
¹ H-NMR (200 MHz, 300 K, DMSO-D ₆ , δ / ppm):
1.70-2.30 (m, 11H), 2.34-2.50 (m, 3H), 6.80 (br. S, 2H), 7.34 (br. S, 2H), 7, 40-7.50 (m, 2H), 7.75-7.90 (m, 3H), 7.98 (d, 2H), 8.07 (brs, 2H).
MS (ESI, acetonitrile / water 7: 3 + 1% acetic acid): 450 [M + H] ⁺ .

Example 140

3- (2-cyanoethyl) -7- (4-aminophenyl) spiro [2H-1-benzopyran-2,1'-4-azacyclohexane] -4 (3H) -one

0.03 g (0.05 mmol) of the compound from Example 57 is dissolved in 2 ml of a mixture of ethyl acetate / methanol (1: 1) and 0.12 ml of water and 0.02 ml of concentrated hydrochloric acid are added. The mixture is then hydrogenated under normal pressure in the presence of 0.061 g of palladium on activated carbon (Pd / C 10%). After separating the catalyst and distilling off the solvent, the residue is purified using HPLC (XIV). The target compound is obtained in a yield of 3.8 mg (21.34%).
¹ H-NMR (400 MHz, DMSO-D ₆ , δ / ppm): 1.65-2.10 (m, 6H), 2.30-2.45 (m, 1H), 2.50-2, 60 (m, 1H), 2.65 (dd, 1H), 3.00-3.22 (m, 4H), 6.60 (d, 2H), 7.20-7.30 (m, 2H) , 7.40 (d, 2H), 7.65 (d, 1H), 8, 10-8.30 (m, 1H), 8.50-8.65 (m, 1H).
MS (ESI acetonitrile / water 7: 3 + 0.1% acetic acid): 362 [M + H] ⁺ , 384 [M + Na] ⁺ .

Example 141

5.5 mg (0.14 mmol) of sodium borohydride are added to a solution of 50 mg (0.14 mmol) of the compound from Example 40 of EP-A 4 624 in 2 ml of methanol at -78 ° C., and the reaction mixture is Stirred for 2 hours at this temperature. After adding a further 0.28 mmol of sodium borohydride, the mixture is stirred at room temperature until the starting material has reacted completely. Then water is added, the crystals are suction filtered and dried. The target compound is obtained in a yield of 33.8 mg (67.21%).
¹ H-NMR (200 MHz, DMSO-D ₆ , δ / ppm):
1.3-1.85 (m, 12H), 2.09 (m, 1H), 2.6-2.78 (m, 2H), 4.75 (dd, 1H), 5.60 (d, 1H, OH), 7.04 (s, 1H), 7.21 (d, 1H), 7.37 (dd, 1H), 7.43 (m, 3H), 7.63 (d, 2H).
MS (DCI, NH ₃ ): 365 [M + NH ₄ ] ⁺ .

B (iii), isoxazoles

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 isobutyryl acetate and 4.93 g (69.3 mmol) of pyrrolidine in 50 ml of toluene is refluxed 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 a solution of 11.7 g (76.3 mmol) of phosphorus oxychloride in 20 ml of chloroform is added dropwise. When the addition is complete, 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. Distilling off the solvent and chromatography on silica gel (mobile phase dichloromethane) give 7.52 g (55%) of 5-isopropyl-3-methylisoxazole-4-carboxylic acid ethyl ester as a colorless oil.
¹ H-NMR (300 MHz, DMSO-D ₆ ): 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.
¹ H NMR (200 MHz, DMSO-D ₆ ): 1.25 (d, 6H) ppm, 2.60 (s, 3H) ppm, 3.39 (quint., 1H) ppm.
MS (DCI / NH ₃ ): 170 [M + H] ⁺ .

7.03 g (59.1 mmol) of thionyl are added to 2 g (11.8 mmol) of the acid described given chloride. It is heated to reflux while stirring until the gas development stops (approx. 1 hour). The thionyl chloride is reduced Pressure is removed and the resulting acid chloride (brown oil) without purification implemented further.

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. Removing the volatile constituents under reduced pressure gives 80 mg (96%) of 5-isopropyl-3-methylisoxazole-4-carboxylic acid N- (4-fluoro-3-methylphenyl) -amide as a colorless solid.
LC-MS (C18 column, 50 × 2.1 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; 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 freed of the volatile constituents 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%).
¹ H-NMR (200 MHz, CDCl ₃ ): 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%).
¹ H-NMR (200 MHz, DMSO-D ₆ ): 2.26 (s, 3H) ppm, 2.32 (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 analogous to Examples 1 to 3 synthesized.

LCMS methods Method A

C18 column, 150 x 2.1 mm, 5 µm; Gradient acetonitrile + 0.1% formic acid [A], Water + 0.1% formic acid [B]: up to 9 min A / B = 1: 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, 50 x 2.1 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, 150 x 2.1 mm, 5 µm; Gradient acetonitrile [A], 0.01 N hydrochloric acid [B], water [C]: up to 4 min A / B / C = 10: 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 adding 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] ^+
1 H NMR (200 MHz, CDCl ₃ ): δ = 2.22 (d, 3H); 2.27 (s, 3H); 2.38 (s, 3H); 3.30 (broad s, 1H); 3.95 (s, 2H); 6.35-6.50 (m, 2H); 6.85 (t, 1H).

In analogy to the rule of Example 32, starting from the connection Example 30 produced the following example 33:  

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 ] ^+
1 H NMR (300 MHz, CDCl ₃ ): δ = 0.95 (t, 3H); 1.33 (d, 6H); 1.60-1.80 (m, 2H); 2.21 (d, 3H); 2.70 (t, 2H); 2.95-3.11 (m, 1H); 3.22 (broad s, 1H); 3.95 (s, 2H); 6.37-6.50 (m, 2H); 6.86 (t, 1H).

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 is 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).
¹ H NMR (300 MHz, CDCl ₃ ): δ = 2.20 (s, 3H); 2.28 (s, 3H); 2.51 (broad s, 2H).

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. At 0 ° C, 0.72 ml (6.00 mmol) of chloroformic acid trichloromethyl ester in 10 ml of dimethyl methane are added dropwise and the mixture is stirred at room temperature for 1 h. It 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 / NH ₃ ): 264 [M + H] ^+
1 H NMR (200 MHz, D ₆ -DMSO): δ = 2.10 (s, 3H); 2.20 (d, 3H); 2.26 (s, 3H); 7.00 (t, 1H); 7.28-7.30 (m, 1H); 7.34 (dd, 1H); 7.68 (broad s, 1H); 8.72 (broad s, 1H).

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 / NH ₃ ): 280 [M + H] ^+
1 H NMR (200 MHz, D ₆ -DMSO): δ = 2.10 (s, 3H); 2.20 (d, 3H); 2.25 (s, 3H); 7.05-7.18 (m, 1H); 7.18-7.38 (m, 2H); 8.95 (broad s, 1H); 9.80 (broad s, 1H).

HBV in cell culture; Testing for combinatorial effectiveness

The antiviral effect of the combinations according to the invention was based on to those of M. A. Sells et al., Proc. Natl. Acad. Sci. 84, 1005-1009 (1987) and B.E. Korba et al., Antiviral Research 19, 55-70 (1992) examined.

The tests of the combinatorial test of the test substances were carried out using Checkerboard titration performed.

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

Stock solutions of the test compounds (50 mM) were first dissolved in DMSO; further dilutions were made in growth medium. The rest of the bowls contained the combinations according to the invention or their individual components in the test concentrations of e.g. B. 5 uM to 0.01 uM, starting from A2 to H11 96-well microtiter plate.

Stock solutions of the substances to be tested were placed on separate 96-well plates prepared and then put together on the test plate with HepG2.2.15 cells Pipette. This means that test concentrations in the range of approx. 10-50 times and covered below the IC-50 concentrations.

The test mixture was incubated for 8 days at 37 ° C. and 5% CO ₂ (v / v). On day 4, the medium was replaced by fresh inhibitor-containing medium.

cytotoxicity

Before harvesting the supernatants / cell lysates to determine the antiviral effect the HepG2.2.15 cells were light microscopic or by means of biochemical Detection methods (e.g. Alamar blue staining or trypan blue staining) cytotoxic changes examined.

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

The compatibility of some combinations according to the invention has also been improved other host cells, such as. B. HeLa cells, primary peripheral blood cells of the Humans or transformed cell lines such as H-9 cells.

There were no cell-cytotoxic changes in the test concentration range be determined.

Determination of the antiviral effect

The supernatants / cell lysates were then harvested and reduced by means of Pressure on 96-well dot-blot chambers covered with nylon membrane (corresponding the manufacturer's instructions).

In brief: after transfer of the supernatants or total cell lysates to the nylon The nucleic acids contained therein became the membrane of the blot apparatus (see above) denatured (1.5 M NaCU 0.5 N NaOH), neutralized (3 M NaCl / 0.5 M Tris Hcl, pH  7.5) and washed (2 × SSC). The DNA was then incubated Filters at 120 ° C, 2-4 hours, baked on the membrane.

Hybridization of the DNA

Detection of the viral DNA from the treated HepG2.2.15 cells on the Nylon filters were typically labeled with non-radioactive, digoxigenin Hepatitis B-specific DNA probes, each according to the manufacturer were marked with digoxigenin, cleaned and used for hybidization.

In short: the prehybidization and hybidization were carried out in 5 × SSC, 1 × blockie reagent, 0.1% N-lauroylsarcosine, 0.02% SDS and 100 µg sperm DNA from Hering. The pre-hybridization took place at 60 ° C for 30 minutes, the specific one Hybridization with 20-40 ng / ml of the digoxigenized, denatured HBV-specific DNA (14 hours, 60 ° C). The filters were then washed.

Detection of HBV DNA by digoxigenin antibodies

The immunological detection of the digoxigenin-labeled DNA was carried out after Manufacturer's instructions.

In short: the filters were washed and placed in a blocking reagent (after Manufacturer information) pre-hybridized. Then an anti-DIG Antibody coupled to alkaline phosphatase hybridized for 30 minutes. After a washing step, the substrate of alkaline phosphatase, CSPD, added, incubated for 5 minutes with the filters, then wrapped in plastic wrap packs and incubated for a further 15 minutes at 37 ° C. The chemiluminescence of the Hepatitis B-specific DNA signals were determined by exposure of the filter Bioluminescence visible on an X-ray film or with a Lumi imager made (incubation depending on signal strength: approx. 2 minutes to approx. 2 hours) and the Measure degree of blackening.  

The inhibition values were calculated according to the cut-off values from the internal test controls converted into% inhibition values. To analyze the synergistic effect The combinations of the difference values of calculated and ge measured inhibition values of each combination; see. Prichard et al., Antimicrob. Agents chemother. 37: 540-545 (1993).

The treatment of HBV with the combinations according to the invention works antiviral better than single treatment; the treatment of the hepatits B virus producing HepG2.2.15 cells with the combinations according to the invention led to a greater reduction in intracellular viral DNA; the Kombina tion treatment is synergistically effective.

Claims (22)

1. Combinations

• A) at least one chromanone and / or chromanol,
• B) at least one HBV antiviral active ingredient different from A and, if appropriate
• C) at least one immunomodulator.

2. Combinations according to claim 1

• A) at least one chromanone and / or chromanol,
• B) (i) at least one HBV polymerase inhibitor, optionally in combination with an HBV anti-viral active ingredient different from A and B (i), and if appropriate
• C) at least one immunomodulator.

3. Combinations according to claims 1 and 2, the component B at least contains an HBV DNA or HBV core protein inhibitor. 4. Combinations according to claims 1 to 3, whose component A at least one compound of the formula
contains what
R ¹ bromine, phenyl, pyrrolyl, pyridyl, pyrimidinyl, piperazinyl or quinolinyl, of which the cyclic substituents are each up to three times the same or different by halogen, C ₁ -C ₆ alkyl, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylthio, nitro, cyano, amino, aminocarbonyl or benzyloxycarbonylamino may be substituted,
R ^{2 is} hydrogen or
R ¹ and R ² together with two adjacent carbon atoms of ring A form a fused benzene ring,
R ³ and R ^{4 are,} independently of one another, linear or branched C ₁ -C ₆ alkyl which can be substituted by carboxyl, C ₁ -C ₄ alkoxy and / or C ₁ -C ₄ alkoxycarbonyl, or
R ³ and R ⁴ together represent a C ₂ -C ₇ alkylene radical optionally substituted by C ₁ -C ₄ alkoxycarbonyl, in which a CH ₂ group is replaced by an oxygen atom or by NR ⁹ (with R ⁹ = hydrogen, benzoyl or benzyloxycarbonyl) can be, or together with the carbon atom on which they are, a tetrahydro-2H-pyran ring,
R ^{5 is} linear or branched C ₂ -C ₆ alkyl which can be substituted by cyano, C ₁ -C ₄ alkoxycarbonyl, carboxyl or aminocarbonyl,
R ^{6 is} hydrogen or linear or branched C ₂ -C ₆ alkyl which can be substituted by cyano, C ₁ -C ₄ alkoxycarbonyl, carboxyl or aminocarbonyl,
R ^{7 is} hydrogen,
R ^{8 is} hydroxy or
R ⁷ and R ⁸ together represent an oxo group. 5. Combinations according to claims 1 to 4, whose component A contains at least one compound of formula I in claim 4, wherein
R ^{1 is} phenyl, pyridyl or quinolinyl, each of which can be substituted up to three times by fluorine or chlorine or simply by methyl, trifluoromethyl, methoxy, methylthio, nitro, cyano or amino; Pyrrolyl, which can be substituted by tert-butoxycarbonyl;
R ^{2 is} hydrogen,
R ³ and R ^{4 are} each methyl or
R ³ and R ⁴ together are a C ₃ -C ₅ alkylene radical, in which a CH ₂ group can be replaced by an oxygen atom, or together with the carbon atom on which they are located, a tetrahydro-2H-pyran ring,
R ⁵ cyanoethyl,
R ^{6 is} hydrogen or cyanoethyl
mean and
R ⁷ and R ^{8 have} the meanings given above. 6. Combinations according to claims 1 to 5, whose component A contains at least one compound of formula I in claim 4, wherein
R ¹ phenyl which can be substituted up to three times by fluorine, up to twice by chlorine or simply by methyl, trifluoromethyl, methoxy, methylthio, nitro, cyano or amino; pyridyl; Pyrrolyl, which can be substituted by tert-butoxycarbonyl;
R ^{2 is} hydrogen,
R ³ and R ^{4 are} each methyl or
R ³ and R ⁴ together form a C ₃ -C ₅ alkylene radical or, together with the carbon atom on which they are located, a tetrahydro-2H-pyran ring,
R ⁵ and R ⁶ cyanoethyl
mean and
R ⁷ and R ^{8 have} the meanings given above. 7. Combinations according to claims 1 to 6, the component A at least contains a chromanol of Examples 76, 82, 97, 99, 116, 132.   8. Combinations according to claims 1 to 7, the component B (i) lamivudine contains. 9. Combinations according to claims 1 to 8, whose component B (ii) min least a dihydropyrimidine of the formula
or their isomeric form
and / or their salts, wherein
R ¹ phenyl, furyl, thienyl, triazolyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or radicals of the formulas
or
means, the above-mentioned ring systems optionally one or more times, identically or differently, by substituents selected from the group halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, carboxyl, hydroxyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ - Alkoxycarbonyl and C ₁ -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 , -SO ₂ -CF ₃ and -A-CH ₂ -R ^{11 are} substituted,
wherein
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 C ₁ -C ₆ -alkyl, the alkyl radical in turn being hydroxyl, C ₁ -C ₆ -alkoxycarbonyl, Phenyl or hydroxy-substituted phenyl can be substituted,
A is a radical -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 halogen, nitro, trifluoromethyl, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy,
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-chain or branched C ₁ -C ₆ -alkoxy carbonyl, a straight-chain, branched or cyclic, saturated or unsaturated C ₁ -C ₈ -hydrocarbon radical, which may contain one or two identical or different hetero-chain links from the group -O-, -CO-, -NH-, -N- (C ₁ -C ₄ alkyl) -, -S- or -SO ₂ - and optionally by halogen, nitro, cyano, hydroxy, aryl with 6 to 10 carbon atoms, Aralkyl having 6 to 10 carbon atoms, heteroaryl or a group of the formula -NR ¹⁵ R ^{16 is} substituted,
wherein R ¹⁵ and R ¹⁶ independently of one another are hydrogen, benzyl or C ₁ -C 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
or
Formyl, cyano, hydroxy-substituted C ₁ -C ₆ alkylthio, trifluoromethyl or pyridyl or
a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms, optionally one or more times, identically or differently, by aryloxy having 6 to 10 carbon atoms, azido, halogen, cyano, hydroxy, carboxyl, C ₁ -C ₆ Alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, C ₁ -C ₆ -alkylthio or C ₁ -C ₆ -alkoxy (where the alkylthio or alkoxy radical in turn can be substituted by azido, amino, hydroxyl) and / or is substituted 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 C ₁ -C ₆ -alkyl, which may be replaced by C ₁ -C ₆ -alkoxycarbonyl, amino, hydroxyl, phenyl or Benzyl are substituted, phenyl and benzyl optionally being substituted one or more times, identically or differently, by hydroxyl, carboxyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy and / or C ₁ -C ₆ alkyl optionally is 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,
or
R ³ optionally methoxy-substituted phenyl
or
R ² and R ³ together represent a radical of the formula
R ^{4 is} hydrogen, C ₁ -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, identically or differently, by halogen, hydroxy, cyano, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ - Alkylthio, carbalkoxy, C ₁ -C ₆ -acyloxy, amino, nitro, mono- or di-C ₁ -C ₆ -alkylamino can be substituted,
mean. 10. Combinations according to claims 1 to 9, whose component B (ii) at least one compound of the formulas
contains their isomeric forms and / or their salts. 11. Combinations according to claims 1 to 10, whose component B (ii) at least one compound of the formula
or their isomeric form
and / or their salts, wherein
R ^{1 is} phenyl, furyl, thienyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or a radical of the formulas
means, the above-mentioned ring systems optionally one or more times, identically or differently, by substituents selected from the group halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, carboxyl, hydroxyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ - Alkoxycarbonyl and C ₁ -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 / or the ring systems listed are optionally substituted 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 ¹¹ ,
wherein
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 C ₁ -C ₆ -alkyl, the alkyl radical in turn being hydroxyl, C ₁ -C ₆ -alkoxy carbonyl, Phenyl or hydroxy-substituted phenyl can be substituted,
A is a radical -O-, -S-, -SO- or -SO ₂ -,
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 -OR ¹² or -NR ¹³ R ¹⁴ ,
wherein
R ^{12 is} hydrogen, C ₁ -C ₆ -alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated C ₁ - C ₈ -hydrocarbon radical, which optionally contains one or two identical or different hetero-chain links from the group -O-, -CO-, -NH-, -N- (C ₁ -C ₄ alkyl) -, -S- and -SO ₂ - and optionally by halogen, nitro, cyano, hydroxy, aryl with 6 to 10 carbon atoms or aralkyl with 6 to 10 carbon atoms, heteroaryl or a group of the formula -NR ¹⁵ R ^{16 is} substituted,
wherein R ¹⁵ and R ¹⁶ independently of one another are hydrogen, benzyl or C ₁ -C 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
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 times, identically or differently, by aryloxy having 6 to 10 carbon atoms, azido, cyano, hydroxy, carboxyl, C ₁ -C ₆ alkoxycarbonyl , a 5- to 7-membered heterocyclic ring, C ₁ -C ₆ alkylthio or C ₁ -C ₆ alkoxy (where the alkylthio or alkoxy radical may in turn be substituted by azido, amino or hydroxyl) and / or by the group - (CO) _a -NR ₁₇ R _{18 is} substituted,
where a is zero or 1,
R ¹⁷ and R ¹⁸ independently of one another are hydrogen or aryl, aralkyl having 6 to 10 carbon atoms or C ₁ -C ₆ -alkyl, which are optionally substituted by C ₁ -C ₆ -alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, phenyl and benzyl are optionally substituted one or more times, identically or differently, by hydroxyl, carboxyl, C ₁ -C ₆ -alkyl or C ₁ - C ₆ -alkoxy and / or C ₁ -C ₆ -alkyl where appropriate 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,
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. 12. Combinations according to claims 1 to 11, whose component B (iii) at least one compound of the formula
contains what
R ¹ and R ² independently of one another alkyl which is optionally substituted by one or more halogen atoms,
X is a divalent radical from the series C = Y, -N (R ⁴ ) -C (= Y) -, CH ₂ ,
R ³ and R ⁴ 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 selected independently of one another from the series halogen, alkyl, alkoxy, alkylthio, alkoxycarbonyl, aminocarbonylamino, mono- and dialkylamino, cyano, amino, mono- and dialkylaminocarbonyl,
mean. 13. Combinations according to claims 1 to 12, the component B (i) one HBV polymerase inhibitor and / or (ii) contains a dihydropyrimidine. 14. Combinations according to claims 1 to 13, 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, C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, nitro, cyano or trifluoromethyl,
R ^{13 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₇ acyl or aralkyl and
X halogen or optionally substituted C ₁ -C ₄ alkyl
mean. 15. Combinations according to claim 14, wherein X is chlorine, A 1-piperidinyl and Y and Z are each phenyl. 16. Combinations according to claims 1 to 15, the immunomodulator C Contains interferons. 17. Combinations of A) at least one chromanone and / or chromanol, B) (i) lamivudine, (ii) at least one dihydropyrimidine, (iii) at least an isoxazole and optionally C) at least one interferon. 18. A method for producing the combinations according to claims 1 to 17, characterized in that components A, B and given if C is suitably combined or prepared. 19. Combinations according to claims 1 to 17 for combating Er diseases. 20. Medicament containing a combination according to claims 1 to 17 and at least one further pharmaceutical active ingredient and / or one pharmaceutical excipient. 21. Use of combinations of claims 1 to 17 for the production a medicine for the treatment and prophylaxis of viral diseases. 22. Use of combinations of claims 1 to 17 for the production a medicine to treat and prevent hepatitis B infection tions.