DE10129716A1 - Combination preparation useful as antiviral agent effective against herpes viruses, especially herpes simplex, contains acetylsalicylic acid and 5-sulfonyl-2-phenylacetamido-thiazole derivative - Google Patents

Abstract

Combination preparation (A) contains: (a) acetylsalicylic acid (ASA) and (b) 5-aminosulfonyl-2-phenylacetamido-thiazole derivatives (I) or 5-halosulfonyl-2-phenylacetamido-thiazole derivatives (IV). Combination preparation (A) contains: (a) acetylsalicylic acid (ASA) and (b) thiazole derivatives of formula (I) (or their salts) or (IV). R1 = H, halo, alkyl, alkoxy, aminoalkyl or haloalkyl; R2, R3 = H, alkoxy, cycloalkyl or biphenylaminocarbonyl, alkyl (optionally substituted (os) by 1-3 of 3-6C cycloalkyl, alkoxy, halo, OH, NH2, trialkylsilyloxy, 3,4-methylenedioxyphenyl, tetrahydrofuran-2-yl, N(R2a)COOtBu, Het1, Het2 or aryl (os by OH or alkoxy)), P(O)(OR8)(OR9), COCH(NH2)-R10, CHR11-OCOR12 or CH(NH2)-R10, or NR2R3 = 5- or 6-membered saturated heterocyclyl, optionally containing a further O heteroatom; R2a, R8, R9 = H or 1-4C alkyl; Het1 = C- or N-bonded 5- or 6-membered aromatic heterocyclyl containing 1-3 of S, N and/or O as heteroatom(s); Het2 = C- or N-bonded 3-8 membered, saturated or unsaturated, non-aromatic heterocyclyl containing 1-3 of S, N and/or O as heteroatom(s); R10 = side-chain of a naturally occurring aminoacid; R11 = 1-4C alkyl; R12 = H, 1-4C alkyl or CH(NH2)-R10; R4 = H, acyl, 2-6C alkenyl or cycloalkyl, or alkyl (os by 1-3 of halo, OH, cycloalkyl, acyl, alkoxy, COOH, NHCOOtBu, OEt, CH2CH2OEt, phenoxy, aryl or NR13R14), or alkyl substituted by optionally benzo-fused Het1, 2-(R16)-pyrrolidino, tetrahydrofuran-2-yl, benzo-1,4-dioxan-2-yl, 2-oxo-pyrrolidino or OCOR17R18; R13, R14 = H, acyl, alkyl, CONH2, mono- or dialkylaminoalkyl, mono- or dialkylaminocarbonyl, aryl or alkoxycarbonyl, or NR13R14 = 5- or 6-membered saturated heterocyclyl, optionally containing a further O, S or NR15 heteroatom and os by =O; R15 = H or 1-4C alkyl; R16 = H or alkyl; R17, R18 = H, or alkyl or aryl (both os by 1-3 of OH, alkoxy or halo); R5, R7 = H, alkyl, halo, NH2, mono- or di-alkylamino or alkanoylamino; R6 = phenyl (os by 1-3 groups R6a); R6a = halo, aryl (os by 1-3 of alkanoyl, alkoxy, alkyl, halo, alkoxycarbonyl, NO2, haloalkyl, haloalkoxy, NH2, alkylthio, OH, COOH, CONH2, mono- or di-alkylaminocarbonyl, mono- or di-alkanoylamino, alkoxycarbonylamino, alkylsulfoxy, alkylsulfonyl, trialkylsilyloxy, Het2 or CN), alkoxy (os by 1-6 F, but not perfluorinated), alkoxycarbonyl, alkylthio, OH, COOH, alkyl (os by tetrahydrofuran-2-yl), Het1 (os by 1-3 of alkanoyl, alkoxy, alkyl, halo, alkoxycarbonyl, NO2, haloalkyl, haloalkoxy, NH2, alkylthio, OH, COOH, CONH2, mono- or dialkylaminocarbonyl, mono- or di-alkanoylamino, alkoxycarbonylamino, alkylsulfoxy, alkylsulfonyl, Het2 (mono- or bi-cyclic) or CN), Het2 (mono- or bi-cyclic; and os by 1-3 of =O, halo, OH, alkoxycarbonyl, alkoxycarbonylamino, alkyl, haloalkyl or hydroxyalkyl), 2-6C alkenyl, OR19, NR20R21, CONR22R23, carbazole, dibenzofuran, dibenzothiophene, xanthene or 9,10-dihydroacridine; R19 = phenyl (os by NR24R25) or alkyl (os by 1-3 of OH or halo); R24, R25 = H, alkyl or acyl; R20, R21 = H, CONH2, mono- or di-alkylaminocarbonyl, phenyl, acyl or alkyl (os by alkoxy or acyl, or by phenyl or Het1 (both os by 1-3 of halo or OH)); R22, R23 = H or alkyl, and D = halogen; Alkyl moieties or acyl groups have 1-6C, cycloalkyl moieties 3-8C and aryl moieties 6-10C unless specified otherwise.

Description

The present invention relates to combination preparations of Thiazolyl sulfonamides with acetylsalicylic acid, their preparation and their use in Treatment of herpes infections.

Herpes infections are common; practically everyone is latent with the virus infected, although the disease does not always break out. The currently on most common drug for the treatment of herpes disease Acyclovir (Zovirax®), which has been on the market for around two decades. Since then there have been practically no new structural classes for herpes therapy on the Market launched.

US 4 987 127 describes the use of acetylsalicylic acid for Treatment of herpes diseases.

The object of the present invention is to combine preparations for treatment of herpes diseases.

• - Halogen,
• - (C₆-C₁₀)-Aryl, das gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)-Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkyl, Halogen, (C₁-C₆)-Alkoxycarbonyl, Nitro, Halogen-(C₁-C₆)-Ikyl, Halogen-(C₁-C₆)-Ikoxy, Amino, (C₁-C₆)-Alkylthio, Hydroxy, Carboxyl, Carbamoyl, Mono- oder Di-(C₁-C₆)-alkylaminocarbonyl, Mono- oder Di- (C₁-C₆)-alkanoylamino, (C₁-C₆)-Alkoxycarbonylamino, (C₁-C₆)- Alkylsulfoxy, (C₁-C₆)-Alkylsulfonyl, Tri-(C₁-C₆)-alkylsilyloxy, einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8- gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, und/oder Cyano substituiert sein kann,
• - (C₁-C₆)-Alkoxy,
• - (C₁-C₆)-Alkoxycarbonyl,
• - (C₁-C₆)-Alkylthio,
• - Hydroxy,
• - Carboxyl,
• - partiell fluoriertem (C₁-C₆)-Alkoxy mit bis zu 6 Fluoratomen,
• - (C₁-C₆)-Alkyl, das gegebenenfalls durch einen Rest der Formel
  
  
  substituiert ist,
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 5- bis 6- gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)-Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)- Alkyl, Halogen, (C₁-C₆)-Alkoxycarbonyl, Nitro, Halogen-(C₁-C₆)- alkyl, Halogen-(C₁-C₆)-alkoxy, Amino, (C₁-C₆)-Alkylthio, Hydroxy, Carboxyl, Carbamoyl, Aminocarbonyl, Mono- oder Di-(C₁-C₆ )-alkylaminocarbonyl, Mono- oder Di-(C₁-C₆)-alkanoylamino, (C₁-C₆)- Alkoxycarbonylamino, (C₁-C₆)-Alkylsulfoxy, (C₁-C₆)-Alkylsulfonyl, einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8- gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, und/oder Cyano substituiert sein kann,
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8- gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 3 Substituenten ausgewählt aus Oxo, Halogen, Hydroxy, (C₁-C₆)-Alkoxycarbonyl, (C₁-C₆)-Alkoxycarbonylamino, (C₁-C₆)-Alkyl, Halogen-(C₁-C₆)-alkyl und Hydroxy-(C₁-C₆)-alkyl substituiert sein kann,
• - (C₂-C₆)-Alkenyl

The present invention therefore relates to combination preparations containing acetylsalicylic acid and a compound of the general formula (I):


in which
R ^{1 is} hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino (C ₁ -C ₆ ) alkyl or halogen (C ₁ -C ₆ ) alkyl .
R ² and R ^{3 are the} same or different and stand for hydrogen, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl or biphenylaminocarbonyl, or
represent (C ₁ -C ₆ ) alkyl which is optionally substituted by 1 to 3 substituents selected from the group consisting of (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy , Halogen, hydroxy, amino, tri- (C ₁ -C ₆ ) alkylsilyloxy, radicals of the formula


wherein R ^{2 'represents} hydrogen or (C ₁ -C ₄ ) alkyl,
a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where a nitrogen-containing heterocycle can also be bonded via the nitrogen atom, a saturated 3- to 8-membered bond optionally bonded via a nitrogen atom or unsaturated, non-aromatic, heterocycle with up to 3 heteroatoms from the series S, N and / or O, and (C ₆ -C ₁₀ ) aryl, which in turn can be substituted by hydroxy or (C ₁ -C ₆ ) alkoxy can, exists, or
for a group of the formula


stand in which R ⁸ and R ^{9 are} identical or different from each other and represent hydrogen and (C ₁ -C ₄ ) alkyl, or
for a group of the formula


where R ^{10 represents} the side group of a naturally occurring α-amino acid, or
for a group of the formula


in which R ^{11 is} (C ₁ -C ₄ ) alkyl, and R ^{12 is} hydrogen, (C ₁ -C ₄ ) alkyl or a group of the formula


where R ^{10 'represents} the side group of a naturally occurring α-amino acid, or
R ² and R ³ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally also have an oxygen atom,
R ^{4 represents} hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkoxy, carboxyl,


where R ^{4 'represents} hydrogen,
- (OCH ₂ CH ₂ ) _n OCH ₂ CH ₃ , in which n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and -NR ¹³ R ¹⁴ ,
wherein R ¹³ and R ^{14 are the} same or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkoxycarbonyl, or
R ¹³ and R ¹⁴ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which can optionally contain a further hetero atom from the S or O series or a radical of the formula -NR ¹⁵ and can be substituted by oxo,
wherein
R ^{15 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, a nitrogen-containing heterocycle can also be bound via the nitrogen atom, or by residues of the formulas


or


is substituted,
wherein
R ¹⁶ denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ¹⁷ and R ^{18 are} identical or different and denote hydrogen, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, the aforementioned (C ₁ -C ₆ ) alkyl and (C ₆ -C ₁₀ ) -aryl may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ ) alkoxy and halogen,
R ^{5 represents} hydrogen, (C ₁ -C ₆ ) alkyl, halogen, amino, mono- or di (C ₁ -C ₆ ) alkylamino or represents (C ₁ -C ₆ ) alkanoylamino,
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of

• - halogen,
• - (C ₆ -C ₁₀ ) aryl, optionally with 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl , Halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio , Hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) - alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, tri- (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle can be substituted with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
• - (C ₁ -C ₆ ) alkoxy,
• - (C ₁ -C ₆ ) alkoxycarbonyl,
• - (C ₁ -C ₆ ) alkylthio,
• - hydroxy,
• - carboxyl,
• partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms,
• - (C ₁ -C ₆ ) alkyl, optionally by a radical of the formula
  
  
  is substituted,
• - A 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally with 1 to 3 substituents, selected from (C ₁ -C ₆ ) alkanoyl , (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen ( C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, aminocarbonyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di- ( C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8- optionally bonded via a nitrogen atom membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
• - A 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally selected from 1 to 3 substituents Oxo, halogen, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl and hydroxy- (C ₁ -C ₆ ) alkyl may be substituted,
• - (C ₂ -C ₆ ) alkenyl

• - -OR¹⁹,
• - -NR²⁰R²¹ oder -CO-NR²²R²³,
• - Carbazol, Dibenzofuran oder Dibenzothiophen,
• - Xanthen oder 9,10-Dihydroacridin

besteht,
worin R¹⁹ Phenyl bedeutet, das seinerseits gegebenenfalls durch eine Gruppe der Formel -NR²⁴R²⁵ substituiert ist,
worin
R²⁴ und R²⁵ gleich oder verschieden sind und Wasserstoff, (C₁-C₆)- Alkyl oder (C₁-C₆)-Acyl bedeuten,
oder
R¹⁹ (C₁-C₆)-Alkyl bedeutet, das gegebenenfalls ein- bis dreifach durch Hydroxy und/oder Halogen substituiert ist,
R²⁰ und R²¹ gleich oder verschieden sind und Wasserstoff, Carbamoyl, Mono- oder Di-(C₁-C₆)-alkylaminocarbonyl, Phenyl, (C₁-C₆)-Acyl oder (C₁-C₆)-Alkyl bedeuten,
wobei zuvor genanntes (C₁-C₆)-Alkyl gegebenenfalls durch (C₁-C₆)- Alkoxy, (C₁-C₆)-Acyl, durch Phenyl oder durch einen 5- bis 6-gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O substituiert ist,
wobei zuvor genanntes Phenyl und zuvor genannter aromatischer Heterocyclus gegebenenfalls ein- bis dreifach gleich oder verschieden durch Halogen und/oder Hydroxy substituiert sind, und
R²² und R²³ gleich oder verschieden sind und Wasserstoff oder (C₁-C₆)-Alkyl bedeuten,
und R⁷ die Bedeutung von R⁵ aufweisen kann und mit dieser gleich oder verschieden sein kann,
und deren Salze. and groups of formulas

• - -OR ¹⁹ ,
• - -NR ²⁰ R ²¹ or -CO-NR ²² R ²³ ,
• - carbazole, dibenzofuran or dibenzothiophene,
• - xanthene or 9,10-dihydroacridine

consists,
in which R ^{19 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acyl,
or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are the} same or different and are hydrogen, carbamoyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl mean,
where the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and R ^{7 can have} the meaning of R ⁵ and can be the same or different with it,
and their salts.

Physiologically acceptable salts of the compounds according to the invention can for example salts of the substances according to the invention with mineral acids, carboxylic acids or Be sulfonic acids. Z are particularly preferred. B. salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, Acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or Benzoic acid. Surprisingly, there is a clear synergy of Effectiveness of acetylsalicylic acid formulations in the disease index, the mean survival and proportion of surviving animals. The Combination of oral administration of substituted thiazolylamides with topical Acetylsalicylic acid in the specified formulations in the treatment of So HSV infection shows next to the advantage of suppressing the herpetic Pain caused by acetylsalicylic acid (analgesic effect) surprisingly the advantage of a synergistic positive influence on the Disease events on.

Salts with customary bases can also be mentioned, such as for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth salts (e.g. Calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, Ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.

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

The scope of the invention also includes those compounds which are only in the Body to be converted to the actual active ingredients of formula (I) (so-called prodrugs).

(C ₁ -C ₆ ) -alkyl suitably represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is preferred. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 3 carbon atoms ((C ₁ -C ₃ ) -alkyl) is particularly preferred.

Halogen (C ₁ -C ₆ ) alkyl suitably represents a (C ₁ -C ₆ ) alkyl group, which can be as defined above, and which preferably has 1 to 3 halogen atoms, namely F, Cl, Br and / or I. Chlorine or fluorine, as substituents, for example, trifluoromethyl, fluoromethyl, etc.

Combination preparations stand for mixtures of substances, the acetylsalicylic acid and Contain compounds of the general formula (I). If desired, others can Substances can be added.

Hydroxy (C ₁ -C ₆ ) alkyl suitably represents a (C ₁ -C ₆ ) alkyl group which can be defined as above and which has 1 to 3 hydroxyl groups as substituents, for example hydroxymethyl etc.

In the context of the invention, (C ₂ -C ₆ ) alkenyl advantageously represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Examples include: ethenyl, n-prop-2-en-1-yl and n-but-2-en-1-yl. A straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred.

(C ₁ -C ₆ ) alkoxy expediently represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms (C ₁ -C ₃ ) is particularly preferred.

Halogen (C ₁ -C ₆ ) alkoxy expediently represents single or multiple halogen-substituted (C ₁ -C ₆ ) alkoxy. Regarding the (C ₁ -C ₆ ) alkoxy portion and the definition of halogen, reference is made to the above definition. For example, halogen (C ₁ -C ₆ ) alkoxy includes one or more partially chlorinated and / or fluorinated or perfluorinated (C ₁ -C ₆ ) alkoxy such as trifluoromethoxy, fluoromethoxy, chloromethoxy, pentafluoroethoxy, trifluoromethyl methoxy etc.

Partially fluorinated (C ₁ -C ₆ ) alkoxy having up to 6 fluorine atoms expediently represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, which can be substituted by 1 to 6, preferably 1 to 4, more preferably 1 to 3, fluorine atoms , A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms and 1 to 4 fluorine atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy, each of which has one to four fluorine atoms. (1,3-Difluoroprop-2-yl) -oxy and 1,1,2,2-tetrafluoroethoxy are particularly preferred.

(C ₁ -C ₆ ) -Alkylthio expediently represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms. A straight-chain or branched alkylthio radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is preferred. Examples include: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio. A straight-chain or branched alkylthio radical having 1 to 3 carbon atoms (C ₁ -C ₃ ) -alkylthio is particularly preferred.

(C ₁ -C ₆ ) -alkoxycarbonyl advantageously represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is particularly preferred.

Mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl expediently stands in the context of the invention for a carbamoyl group (H ₂ N-CO-) in which one or both hydrogen atoms are replaced by a (C ₁ -C ₆ ) alkyl group are replaced. With regard to the definition of the (C ₁ -C ₆ ) alkyl group, reference is made to the above explanation of (C ₁ -C ₆ ) alkyl. Examples include methylaminocarbonyl, dimethylaminocarbonyl, etc.

Mono- or di- (C ₁ -C ₆ ) acylamino in the context of the invention expediently represents an amino group (H ₂ N-) in which one or both hydrogen atoms are replaced by a (C ₁ -C ₆ ) acyl group. With regard to the definition of the (C ₁ -C ₆ ) acyl group, reference is made to the above explanation of (C ₁ -C ₆ ) acyl. Examples include (C ₁ -C ₆ ) alkanoyl, as mentioned in the definition of (C ₁ -C ₆ ) acyl.

(C ₁ -C ₆ ) Alkylsulfoxy expediently represents a (C ₁ -C ₆ ) alkyl-S (= O) group, reference being made to the above definition in relation to the (C ₁ -C ₆ ) alkyl group can.

(C ₁ -C ₆ ) -Alkylsulfonyl expediently represents a (C ₁ -C ₆ ) -alkyl-SO ₂ group, reference being made to the above definition in relation to the (C ₁ -C ₆ ) -alkyl group.

(C ₆ -C ₁₀ ) aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, (C ₁ -C ₆ ) -acyl is expediently a straight-chain or branched acyl radical having 1 to 6 carbon atoms. Examples include: formyl, acetyl, ethanoyl, propanoyl, isopropanoyl, butanoyl, isobutanoyl and pentanoyl. A straight-chain or branched acyl radical having 1 to 4 carbon atoms is preferred. Acetyl and ethanoyl are particularly preferred.

(C ₃ -C ₈ ) Cycloalkyl in the context of the invention stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned: cyclopropyl, cyclopentyl and cyclohexyl. The meaning of (C ₃ -C ₆ ) cycloalkyl is appropriately for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl.

Halogen generally stands for fluorine, chlorine, bromine and Iodine. Fluorine, chlorine and bromine are preferred. Fluorine and Chlorine.

In the context of the invention, (C ₁ -C ₆ ) alkanoyl represents formyl and (C ₁ -C ₅ ) alkylcarbonyl groups, (C ₁ -C ₅ ) alkyl may be a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms, for example Acetyl, propionyl, butyryl, pentanoyl.

A 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the Row S, O and / or N stands for example for pyridyl, pyrimidyl, thienyl, furyl, Pyrrolyl, thiazolyl, N-triazolyl, oxazolyl or imidazolyl. Preferred are pyridyl, Furyl, thiazolyl and N-triazolyl.

A 5- to 6-membered aromatic benzocondensed heterocycle with up to 3 Heteroatoms from the S, O and / or N series represent, for example, benzimidazolyl.

A 5- to 6-membered saturated heterocycle bonded via a nitrogen atom, which can be formed from two substituent groups together with the nitrogen atom to which they are bonded, and which may optionally be a further heteroatom from the series S or O or a radical of the formula -NR ¹⁵ , in which R ^{15 is} as defined above, in the context of the invention generally represents morpholinyl, piperidinyl, piperazinyl, methylpiperazinyl, thiomorpholinyl or pyrrolidinyl. Morpholinyl, piperidinyl, pyrrolidinyl and thiomorpholinyl are particularly preferred.

A 3- to 8-membered saturated, optionally bonded via a nitrogen atom or unsaturated, non-aromatic heterocycle with up to 3 heteroatoms the series S, N and / or O includes z. B. the above 5- to 6-membered a saturated nitrogen-bonded heterocycle and 3-, 7- and 8-membered heterocycles, such as. B. aziridines (e.g. 1-azacyclopropan-1-yl), azetidines (e.g. 1-azacyclobutan-1-yl) and azepines (e.g. 1-azepan-1-yl). The unsaturated Representatives can contain 1 to 2 double bonds in the ring.

The side group of a naturally occurring α-amino acid with the meaning of R ¹⁰ includes, for example: hydrogen (glycine), methyl (alanine), propan-2-yl (valine), 2-methyl-propan-1-yl (leucine), 1-methyl-propan-1-yl (isoleucine), a propane-1,3-diyl group connected to the nitrogen atom of the amino group (proline), a 2-hydroxypropane-1,3-diyl group, the is connected to the nitrogen atom of the amino group (hydroxyproline), a group of the formula


(Tryptophan), a benzyl group (phenylalanine), a methylthioethyl group (methionine), hydroxymethyl (serine), p-hydroxybenzyl (tyrosine), 1-hydroxyethan-1-yl (threonine), mercaptomethyl (cysteine), carbamoylmethyl (asparagine) , Carbamoylethyl (glutamine), carboxymethyl (aspartic acid), carboxyethyl (glutamic acid), 4-aminobutan-1-yl (lysine), 3-guanidinopropan-1-yl (arginine), imidazol-4-ylmethyl (histidine), 3-ureidopropane -1-yl (citrulline), mercaptoethyl (homocysteine), hydroxyethyl (homoserine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine), 3-amino-propan-1-yl (ornithine), etc.

• - Halogen,
• - (C₆-C₁₀)-Aryl, das gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkyl, Halogen, (C₁-C₆)Alkoxycarbonyl, Nitro, Halogen(C₁-C₆)alkyl, Halogen(C₁-C₆)alkoxy, Amino, (C₁-C₆)Alkylthio, Hydroxy, Carboxyl, Carbamoyl, Mono- oder Di(C₁-C₆)alkylaminocarbonyl, Mono- oder Di(C₁-C₆)alkanoylamino, (C₁-C₆)Alkoxycarbonylamino, (C₁-C₆ )Alkylsulfoxy, (C₁-C₆)Alkylsulfonyl, Tri(C₁-C₆)alkylsilyloxy, einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8-gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, und/oder Cyano substituiert sein kann,
• - (C₁-C₆)-Alkoxy,
• - (C₁-C₆)-Alkoxycarbonyl,
• - (C₁-C₆)-Alkylthio,
• - Hydroxy,
• - Carboxyl,
• - partiell fluoriertem (C₁-C₆)-Alkoxy mit bis zu 6 Fluoratomen,
• - (C₁-C₆)-Alkyl, das gegebenenfalls durch einen Rest der Formel
  
  
  substituiert ist,
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 5- bis 6- gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)- Alkyl, Halogen, (C₁-C₆)Alkoxycarbonyl, Nitro, Halogen(C₁-C₆)alkyl, Halogen(C₁-C₆)alkoxy, Amino, (C₁-C₆)Alkylthio, Hydroxy, Carboxyl, Carbamoyl, Mono- oder Di(C₁-C₆)alkylaminocarbonyl, Mono- oder Di(C₁-C₆)alkanoylamino, (C₁-C₆)Alkoxycarbonylamino, (C₁-C₆)Alkylsulfoxy, (C₁-C₆)Alkylsulfonyl, einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8-gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, und/oder Cyano substituiert sein kann,
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8- gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 3 Substituenten ausgewählt aus Oxo, Halogen, Hydroxy, (C₁-C₆)-Alkoxycarbonyl, (C₁-C₆)-Alkoxycarbonylamino, (C₁-C₆)-Alkyl, Halogen(C₁-C₆)alkyl und Hydroxy(C₁-C₆)-alkyl substituiert sein kann,

In a further embodiment, the invention relates to combination preparations containing acetylsalicylic acid and compounds of the general formula (I):


in which
R ^{1 represents} hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino (C ₁ -C ₆ ) alkyl or halogen (C ₁ -C ₆ ) alkyl,
R ² and R ^{3 are the} same or different and stand for hydrogen, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl or biphenylaminocarbonyl, or
represent (C ₁ -C ₆ ) alkyl which is optionally substituted by 1 to 3 substituents selected from the group consisting of (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy , Halogen, hydroxy, amino, radicals of the formula


a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where a nitrogen-containing heterocycle can also be bonded via the nitrogen atom,
a 3- to 8-membered saturated or unsaturated, non-aromatic, heterocycle optionally having a nitrogen atom and having up to 3 heteroatoms from the series S, N and / or O, and
(C ₆ -C ₁₀ ) aryl, which in turn can be substituted by hydroxy or (C ₁ -C ₆ ) alkoxy, or
for a group of the formula


stand in which R ⁸ and R ^{9 are} identical or different from each other and represent hydrogen and (C ₁ -C ₄ ) alkyl, or
for a group of the formula


where R ^{10 represents} the side group of a naturally occurring α-amino acid, or
for a group of the formula


in which R ^{11 is} (C ₁ -C ₄ ) alkyl, and R ^{12 is} hydrogen, (C ₁ -C ₄ ) alkyl or a group of the formula


where R ^{10 'represents} the side group of a naturally occurring α-amino acid, or
R ² and R ³ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally also have an oxygen atom,
R ^{4 represents} hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl, which can optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkoxy,
- (OCH ₂ CH ₂ ) _n OCH ₂ CH ₃ , in which n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and -NR ¹⁴ R ¹⁴ ,
wherein R ¹³ and R ^{14 are the} same or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylamino- ( C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkoxycarbonyl, or
R ¹³ and R ¹⁴ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further hetero atom from the S or O series or a radical of the formula -NR ¹⁵ and may be substituted by oxo,
wherein R ^{15 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, a nitrogen-containing heterocycle can also be bound via the nitrogen atom, or by residues of the formulas


or


is substituted,
wherein
R ¹⁶ denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ¹⁷ and R ^{18 are} identical or different and denote hydrogen, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, the aforementioned (C ₁ -C ₆ ) alkyl and (C ₆ -C ₁₀ ) -aryl may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ ) alkoxy and halogen,
R ^{5 represents} hydrogen, (C ₁ -C ₆ ) alkyl, halogen, amino, mono- or di (C ₁ -C ₆ ) alkylamino or represents (C ₁ -C ₆ ) alkanoylamino,
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of

• - halogen,
• - (C ₆ -C ₁₀ ) aryl which may be substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, Halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, Mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) Alkylsulfonyl, tri (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, and / or cyano may be substituted,
• - (C ₁ -C ₆ ) alkoxy,
• - (C ₁ -C ₆ ) alkoxycarbonyl,
• - (C ₁ -C ₆ ) alkylthio,
• - hydroxy,
• - carboxyl,
• partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms,
• - (C ₁ -C ₆ ) alkyl, optionally by a radical of the formula
  
  
  is substituted,
• a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally with 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ - C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle optionally bonded via a nitrogen atom with up to 3 heteroatoms from the series S, N and / or O, and / or cyano can be substituted,
• - A 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally selected from 1 to 3 substituents Oxo, halogen, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl and hydroxy (C ₁ -C ₆ ) alkyl may be substituted,

• - -OR¹⁹
• - -NR²⁰R²¹ oder -CO-NR²²R²³

besteht,
worin R¹⁹ Phenyl bedeutet, das seinerseits gegebenenfalls durch eine Gruppe der Formel -NR²⁴R²² substituiert ist,
worin
R²⁴ und R²⁵ gleich oder verschieden sind und Wasserstoff, (C₁-C₆)- Alkyl oder (C₁-C₆)-Acyl bedeuten,
oder
R¹⁹ (C₁-C₆)-Alkyl bedeutet, das gegebenenfalls ein- bis dreifach durch Hydroxy und/oder Halogen substituiert ist,
R²⁰ und R²¹ gleich oder verschieden sind und Wasserstoff, Carbamoyl, Mono- oder Di(C₁-C₆)alkylaminocarbonyl, Phenyl, (C₁-C₆)-Acyl oder (C₁-C₆)-Alkyl bedeuten,
wobei zuvor genanntes (C₁-C₆)-Alkyl gegebenenfalls durch (C₁-C₆)- Alkoxy, (C₁-C₆)-Acyl, durch Phenyl oder durch einen 5- bis 6-gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O substituiert ist,
wobei zuvor genanntes Phenyl und zuvor genannter aromatischer Heterocyclus gegebenenfalls ein- bis dreifach gleich oder verschieden durch Halogen und/oder Hydroxy substituiert sind, und
R²² und R²³ gleich oder verschieden sind und Wasserstoff oder (C₁-C₆)-Alkyl bedeuten,
und R⁷ die Bedeutung von R⁵ aufweisen kann und mit dieser gleich oder verschieden sein kann,
und deren Salze. and groups of formulas

• - -OR ¹⁹
• - -NR ²⁰ R ²¹ or -CO-NR ²² R ²³

consists,
in which R ^{19 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²² ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acyl,
or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are} identical or different and are hydrogen, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl,
where the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and R ^{7 can have} the meaning of R ⁵ and can be the same or different with it,
and their salts.

In a preferred embodiment, the invention relates to combination preparations containing acetylsalicylic acid and compounds of the general formula (I), in which R ^{1 is} hydrogen or (C ₁ -C ₆ ) -alkyl.

In a further preferred embodiment, the invention relates to combination preparations containing acetylsalicylic acid and compounds of the general formula (I), in which R ² and R ³ each independently represent hydrogen or (C ₁ -C ₆ ) alkyl.

In a further preferred embodiment, the invention relates to combination preparations containing acetylsalicylic acid and compounds of the general formula (I), in which R ^{4 represents} hydrogen or (C ₁ -C ₆ ) -alkyl.

In a further preferred embodiment, the invention relates to combination preparations containing acetylsalicylic acid and compounds of the general formula (I) according to claim, in which R ^{5 is} hydrogen.

• - Halogen,
• - (C₆-C₁₀)-Aryl, das gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkyl, Halogen, (C₁-C₆ )Alkoxycarbonyl, Nitro, Halogen(C₁-C₆)alkyl, Halogen(C₁-C₆)alkoxy, Amino, Hydroxy, Mono- oder Di(C₁-C₆)alkylamino, Mono- oder Di(C₁-C₆)- Alkanoylamino, (C₁-C₆)Alkoxycarbonylamino, und/oder Cyano substituiert sein kann, und
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 5- bis 6-gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 2 Halogenatome substituiert sein kann,

besteht. In a further preferred embodiment, the invention relates to combination preparations containing acetylsalicylic acid and compounds of the general formula (I), in which
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of

• - halogen,
• - (C ₆ -C ₁₀ ) aryl which may be substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, Halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, hydroxy, mono- or di (C ₁ -C ₆ ) alkylamino, Mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, and / or cyano can be substituted, and
• a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which can optionally be substituted by 1 or 2 halogen atoms,

consists.

In a further preferred embodiment, the invention relates to combination preparations containing acetylsalicylic acid and compounds which have the following formula:


wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{7 are} as defined in claim 1, R ²⁶ and R ^{27 are the} same or different and are hydrogen, halogen, (C ₁ -C ₆ ) alkoxy, ( C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms, (C ₁ -C ₆ ) alkyl, are a group of the formulas -OR ¹⁹ , -NR ²⁰ R ²¹ or -CO-NR ²² R ²³ , wherein
R ¹⁹ denotes phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl, or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are} identical or different and are hydrogen, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl,
wherein the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 Heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
R ^{28 represents} (C ₆ -C ₁₀ ) aryl, which is optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) Alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) -Alkyl thio, hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, tri- (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, optionally bonded via a nitrogen atom , mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano may be substituted, or
R ^{28 represents} a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which is optionally selected from 1 to 3 substituents selected from (C ₁ -C ₆ ) Alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, Halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3 to 8 bonded via a nitrogen atom, if appropriate -membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
and their salts.

The invention further relates to combination preparations containing acetylsalicylic acid and compounds of the general formula (IV)


wherein
R ¹ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given for the formula (I), and D is a halogen atom.

• 1. [A] Verbindungen der allgemeinen Formel (II)
  
  
  in welcher
  R¹, R², R³ und R⁴ die oben angegebene Bedeutung haben,
  mit Verbindungen der allgemeinen Formel (III)
  
  
  in welcher
  A für eine Abgangsgruppe, wie z. B. Halogen, vorzugsweise Chlor, oder Hydroxy steht, und R⁵, R⁶ und R⁷ die oben angegebene Bedeutung haben, in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer Base und/oder eines Hilfsmittels zu Verbindungen der Formel (I) umsetzt,
• 2. [B] Verbindungen der allgemeinen Formel (IV)
  
  
  worin
  R¹, R⁴, R⁵, R⁶ und R⁷ die oben angegebene Bedeutung haben, und D ein Halogenatom, vorzugsweise Chlor ist, mit Aminen der allgemeinen Formel (V):
  
  HN²R³ (V)
  
  worin
  R² und R³ die oben angegebene Bedeutung haben, in inerten Lösemitteln zu Verbindungen der Formel (I) umsetzt,
• 3. [C] Verbindungen der allgemeinen Formel (X)
  
  
  worin
  R¹, R², R³, R⁴, R⁵, R⁷, R²⁶ und R²⁷ die oben angegebene Bedeutung haben, und E Trifluormethansulfonat oder Halogen, vorzugsweise Brom oder Iod ist,
  mit Boronsäuren oder Stannanen der allgemeinen Formel (XI):
  
  R²⁸M (XI)
  
  worin
  R²⁸ die oben angegebene Bedeutung hat und M beispielsweise eine Tri(C₁-C₆)alkylstannylgruppe, wie eine Trimethylstannylgruppe oder eine Boronsäuregruppe sein kann, in inerten Lösemitteln in Gegenwart von Palladiumkatalysatoren, z. B. Tetrakis(triphenylphosphan)palladium (0), ggf. in Anwesenheit von Base, z. B. Kaliumphosphat bei Temperaturen von 50-140°C zu Verbindungen der Formel (XIV)
  
  
  umsetzt, und
• 4. [D] Verbindungen der allgemeinen Formel (XII)
  
  
  worin
  R¹, R², R³, R⁴, R⁵, R⁷, R²⁶ und R²⁷ die oben angegebene Bedeutung haben, und M die oben angegebene Bedeutung besitzt, mit Trifluormethansulfonaten oder Halogeniden der allgemeinen Formel (XIII):
  
  R²⁸E (XIII)
  
  worin
  R²⁸ die oben angegebene Bedeutung hat und E die oben angegebene Bedeutung besitzt, in inerten Lösemitteln in Gegenwart von Palladiumkatalysatoren, z. B. Tetrakis(triphenylphosphan)palladium (0), ggf. in Anwesenheit von Base, z. B. Kaliumphosphat bei Temperaturen von 50-140°C zu Verbindungen der Formel (XIV) umsetzt.

The invention further relates to processes for the preparation of the compounds of general formula (I), characterized in that

• 1. [A] compounds of the general formula (II)
  
  
  in which
  R ¹ , R ² , R ³ and R ^{4 have} the meaning given above,
  with compounds of the general formula (III)
  
  
  in which
  A for a leaving group, such as B. halogen, preferably chlorine, or hydroxy, and R ⁵ , R ⁶ and R ^{7 have} the meaning given above, in inert solvents, optionally in the presence of a base and / or an auxiliary, to give compounds of the formula (I),
• 2. [B] compounds of the general formula (IV)
  
  
  wherein
  R ¹ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given above, and D is a halogen atom, preferably chlorine, with amines of the general formula (V):
  
  HN ² R ³ (V)
  
  wherein
  R ² and R ^{3 have} the meaning given above and are converted into compounds of the formula (I) in inert solvents,
• 3. [C] compounds of the general formula (X)
  
  
  wherein
  R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ²⁶ and R ^{27 have} the meaning given above, and E is trifluoromethanesulfonate or halogen, preferably bromine or iodine,
  with boronic acids or stannanes of the general formula (XI):
  
  R ²⁸ M (XI)
  
  wherein
  R ^{28 has} the meaning given above and M for example a tri (C ₁ -C ₆ ) alkylstannyl group, such as a trimethylstannyl group or a boronic acid group, in inert solvents in the presence of palladium catalysts, e.g. B. tetrakis (triphenylphosphine) palladium (0), optionally in the presence of base, e.g. B. Potassium phosphate at temperatures of 50-140 ° C to compounds of formula (XIV)
  
  
  implements, and
• 4. [D] compounds of the general formula (XII)
  
  
  wherein
  R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ²⁶ and R ^{27 have} the meaning given above, and M has the meaning given above, with trifluoromethanesulfonates or halides of the general formula (XIII):
  
  R ²⁸ E (XIII)
  
  wherein
  R ^{28 has} the meaning given above and E has the meaning given above, in inert solvents in the presence of palladium catalysts, for. B. tetrakis (triphenylphosphine) palladium (0), optionally in the presence of base, e.g. B. Potassium phosphate at temperatures of 50-140 ° C to compounds of formula (XIV).

The process [A] according to the invention can be illustrated by way of example using the following formula schemes:

Here mean:
HOBt: 1-hydroxy-1H-benzotriazole
EDC: N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide × HCl
DMF: N, N dimethylformamide

The process [C] according to the invention can be illustrated by the following formula schemes:

Herein means:
DMF: N, N-dimethylformamide

The process [D] according to the invention can be illustrated by way of example using the following formula schemes:

Herein means:
DMF: N, N-dimethylformamide

Customary solvents are suitable for processes [A], [B], [C] and [D] organic solvents that do not change under the reaction conditions. For this preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, Cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, Trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or Chlorobenzene, or ethyl acetate, dimethyl sulfoxide, dimethylformamide (DMF) or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Prefers is DMF.

In general, inorganic or organic bases can be used as bases for process [A] according to the invention. These preferably include organic amines (trialkyl (C ₁ -C ₆ ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7 -en (DBU), pyridine, diaminopyridine, N-methylmorpholine or N-methylpiperidine or morpholine. Triethylamine is preferred.

Known dehydration or Coupling reagents, such as, for example, carbodiimides, such as diisopropylcarbodiimide, Dicyclohexylcarbodiimide (DCC) or N (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC), or carbonyl compounds such as carbonyldiimidazole (CDI) or Isobutyl chloroformate, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfonate, or phosphorus compounds such as propanephosphonic anhydride, Phosphorsäurediphenylesterazid, Benzotriazolyl-N-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), or uronium compounds such as O-benzotriazole 1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), or Methanesulfonic acid chloride, optionally in the presence of auxiliaries such as N-hydroxysuccinimide or N-hydroxybenzotriazole.

In general, the base is used in an amount of 0.05 mol to 10 mol, preferably from 1 mol to 2 mol based on 1 mol of the compound of the formula (III) on.

The methods of the invention are generally in one Temperature range from -50 ° C to + 100 ° C, preferably from -30 ° C to + 60 ° C, performed.

The methods of the invention are generally at normal pressure carried out. However, it is also possible to use the process at overpressure or at Perform negative pressure (e.g. in a range from 0.5 to 5 bar).

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


in which
R ^{1 has} the meaning given above,
by reaction with the chlorosulfonic acid / SOCl _{2 system} in the compounds of the general formula (VII)


in which
R ^{1 has} the meaning given above,
transferred, then with amines of the general formula (V)

HNR ² R ³ (V)

in which
R ² and R ^{3 have} the meaning given above,
in inert solvents, the compounds of the general formula (VIII)


in which
R ¹ , R ² and R ^{3 have} the meaning given above,
produces, and in a last step a reaction with amines of the general formula (IX)

H ₂ NR ^{4 '} (IX)

in which
R ^{4 'has} the meaning of R ⁴ given above and is the same or different with it, but is not hydrogen,
in inert solvents and in the presence of a base.

The reaction with chlorosulfonic acid / SO ₂ Cl takes place first at room temperature and then below the reflux temperature of the respective ether.

The reaction is generally carried out at normal pressure. But it is also possible to carry out the process under positive pressure or under negative pressure (e.g. in a range from 0.5 to 5 bar).

As a solvent for the reaction with the amines of the general formula (V) alcohols such as methanol, ethanol, propanol and Isopropanol. Methanol is preferred.

The reaction with the amines of the general formula (V) initially takes place in Room temperature and then below the reflux temperature of the respective Ether.

The reaction is generally carried out at normal pressure. But it is also possible to carry out the process under positive pressure or under negative pressure (e.g. in a range from 0.5 to 5 bar).

The reaction with the compounds of the general formula (IX) takes place in ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether. Methanol is preferred.

In general, inorganic or organic bases can be used as bases. These preferably include organic amines (tri (C ₁ -C ₆ ) alkylamines, such as triethylamine), or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec- 7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Triethylamine is preferred.

In general, the base is used in an amount of 0.05 mol to 10 mol, preferably from 1 mol to 2 mol based on 1 mol of the compound of the formula (VIII) on.

Some of the compounds of the general formula (VI) are known or according to customary methods can be produced [cf. Hantzsch, Chem. Ber. 1927, 60, 2544].

The compounds of general formulas (VII) and (VIII) are new and can be as are produced as described above.

Amines of the general formulas (V) and (IX) are known.

Compounds of the general formulas (III) are known or can be subtracted Manufacture processes known from the literature.

Biphenylmethylcarboxylic acid or biphenylacetic acid derivatives of the formula (III) can be prepared in a manner known per se by transition metal-catalyzed, for example palladium-catalyzed, coupling reactions, such as, for example, B. the Suzuki or Stille clutch. The pyridylphenylmethylcarboxylic acid derivatives of the formula (III) are known from the literature (see, for example, BM Artico et al. In Eur. J. Med. Chem. (1992) 27, 219-228) or can be prepared by processes known per se. The following reaction schemes A, B, C and D exemplify the synthesis of biphenylacetic acid derivatives from the corresponding boronic acids and the synthesis of pyridylphenylacetic acid derivatives from the corresponding stannyl compounds:

Compounds of the formula (III) in which R ⁵ and R ^{7 are,} for example, fluorine can be prepared by the process shown in the following reaction scheme:

The fluorination with DAST (N, N-diethylaminosulfur trifluoride) takes place according to J. Fluor. Chem. 61, 1993, 117.

The invention further relates to the combination of acetylsalicylic acid with Compounds of formula (I) for use as medicaments, or combinations of Acetylsalicylic acid with inhibitors of HSV primase helicase or with inhibitors DNA synthesis or herpes virus replication.

The invention further relates to a pharmaceutical composition comprising a Compound of general formula (I) in a mixture with acetylsalicylic acid and comprises at least one pharmaceutically acceptable carrier or excipient.

The invention further relates to the use of a combination of a compound of the general formula (I) and acetylsalicylic acid for the preparation of a Medicinal product, in particular a medicinal product for treatment and / or prevention viral infections, such as herpes viruses, in particular herpes simplex viruses, especially herpes simplex 1 viruses.

In the context of the present invention, acetylsalicylic acid and Compounds of the general formula (I) are taken at the same time or with a time delay, as long as the time frame is chosen in such a way that the synergistic effect occurs. For the purposes of good patient compliance, it is desirable that Acetylsalicylic acid and the compounds of the general formula (I) at the same time administer.

The combinations according to the invention can be used both orally and topically be administered. It is also possible to take the acetylsalicylic acid orally and the compound of the general formula (I) to be administered topically, or vice versa. includes also become kit-of-parts.

The combinations of the general formulas (I) according to the invention do not show one predictable surprising spectrum of action. They have an antiviral effect to representatives of the group Herpes viridae, especially to herpes Simplex viruses (HSV). They are therefore for the treatment and prophylaxis of Diseases caused by herpes viruses, especially disorders caused by herpes Simplex viruses are caused.

• 1. Behandlung und Prophylaxe von Herpes-Infektionen, insbesondere Herpes Simplex-Infektionen bei Patienten mit Krankheitsbildern wie Herpes labialis, Herpes genitalis, und HSV bedingter Keratitis, Enzephalitis, Pneumonie, Hepatitis etc.
• 2. Behandlung und Prophylaxe von Herpes-Infektionen, insbesondere Herpes Simplex-Infektionen bei immunsupprimierten Patienten (z. B. AIDS-Patienten, Krebspatienten, Patienten mit genetisch bedingter Immundefiziens, Transplantationspatienten)
• 3. Behandlung und Prophylaxe von Herpes-Infektionen, insbesondere Herpes Simplex-Infektionen bei Neugeborenen und Kleinkindern
• 4. Behandlung und Prophylaxe von Herpes-Infektionen, insbesondere Herpes Simplex-Infektionen und Herpes-, insbesondere Herpes Simplex-positiven Patienten zur Unterdrückung der Rekurrenz (Suppressionstherapie)

The compounds according to the invention are therefore valuable active substances for the treatment and prophylaxis of diseases which are triggered by herpes viruses, in particular herpes simplex viruses. The following areas of indication can be mentioned, for example:

• 1. Treatment and prophylaxis of herpes infections, especially herpes simplex infections in patients with clinical pictures such as herpes labialis, genital herpes, and HSV-related keratitis, encephalitis, pneumonia, hepatitis etc.
• 2. Treatment and prophylaxis of herpes infections, in particular herpes simplex infections in immunosuppressed patients (e.g. AIDS patients, cancer patients, patients with genetic immunodeficiencies, transplant patients)
• 3. Treatment and prophylaxis of herpes infections, especially herpes simplex infections in newborns and young children
• 4. Treatment and prophylaxis of herpes infections, in particular herpes simplex infections and herpes, in particular herpes simplex-positive patients to suppress recurrence (suppression therapy)

Viruses and cells

HSV-2G was grown on Vero cells (ATCC CCL-81) under the following conditions: The cells were added to M199 medium (5% fetal calf serum, 2 mM glutamine, 100 IU / ml penicillin, 100 µg / ml streptomycin) in cell culture bottles 37 ° C and 5% CO ₂ grown. The cells were split 1: 4 twice a week. The medium was removed for the infection, the cells were washed with "Hank's solution", detached with 0.05% trypsin, 0.02% EDTA (Seromed L2143) and with a density of 4 × 10 ⁵ cells per ml under the above-mentioned conditions for 24 hours incubated. The medium was then removed and the virus solution with a mo i of <0.05 in a volume of 2 ml per 175 cm ² surface was added. After incubation for one hour under the conditions mentioned, the medium was made up to a volume of 50 ml per 175 cm ² bottle. 3 days after infection, the cultures showed clear signs of a cytopathic effect. The virus was released by freezing twice (-80 ° C) and thawing (37 ° C). The cell debris was separated by centrifugation (300 g, 10 min, 4 ° C) and the supernatant frozen in aliquots at -80 ° C.

The virus titer was determined using a plaque assay. For this Vero cells were seeded in a density of 4 × 10 ⁵ cells per well in 24 well plates and after 24 hours incubation (37 ° C, 5% CO ₂ ) with dilutions of the virus stock from 10 ^-2 to 10 ^-12 (100 ul inoculum ) infected. The medium was removed 1 hour after infection and the cells with 1 ml overlay medium (0.5% methyl cellulose, 0.225 sodium bicarbonate, 2 mM glutamine, 100 IU / ml penicillin, 100 μg / ml streptomycin, 5% fetal calf serum in MEM-Eagle medium layered with Earl's salt) and incubated for 3 days. The cells were then fixed with 4% formalin for 1 hour, washed with water, stained with Giemsa (Merck) for 30 min and then washed and dried. The virus titer was determined using a plaque viewer. The virus stock used for the experiments had a titer of 2 × 10 ⁸ / ml.

Formulation of the active substances Oral treatment

N- [S- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridinyl) phenyl] acetamide was in 0.5% tylose in PBS resuspended. The infected animals were with 2 mg / kg t. i. d. Orally treated in 200 µl volume using a pharyngeal tube.

Topical treatment Formulation 1

Diethyl ether 60% by weight
Isopropanol 30% by weight
Water 6% by weight
Acetylsalicylic acid 4% by weight

A standard spraying device from Pfeiffer, Germany was used to spray the H ₅ V-2G infected areas of the animals.

Plastibase

Is a polyethylene with a molecular weight of about 21000 under special If conditions are dissolved in paraffin oil, an ointment base is obtained. The mixture is dissolved at 130 ° C, after 3 hours it is allowed to cool to 100 ° C. Has the Mixture reaches the temperature of 100 ° C, is quickly cooled, namely such that the mass is poured into a thin layer on cooled metal plates.

If this condition is not met, it will not be a gel, but a practical one unusable, crystalline mixture obtained. The gel P. is between -15 and 60 ° C resistant; the ointment base can be emulsified by adding monoglycerides be made.

Formulation 2

Slurry of acetylsalicylic acid in plastibase, concentration of the active ingredient 2% by weight.

In vivo effect Zosteriform spread model

6 week old female hairless mice (C3H / TifBom-hr) were purchased from a commercial breeder (M&B AIS, Denmark) and infected with HSV-2G a week later. The animals were anesthetized in a tight glass jar with diethyl ether (Merck). For dermal infection, the skin on the right flank of the animal was scratched 10 × crosswise with a sterile cannula (0.6 × 25 mm). The skin pretreated in this way was inoculated with 10 μl of virus suspension (2 × 10 ⁶ pfu HSV-2G). The animals were inspected daily and the disease index determined on the following scale: 0: no signs of infection visible, 1: blistering, 2: slight spread in the dermatome (zoster), 3: large areas affected (zoster), 4: confluent zoster band, 5: paralysis of the extremities, 6: death. The respective disease index of the group on the respective day was calculated by averaging all animals in the group. The cumulative disease index is calculated by adding up the disease indices of individual days. The infection usually leads to death in 100% of the untreated animals from a generalized infection with prominent central nervous symptoms between 5 and 7 days. The treatment was started 6 hours after the infection 3 times a day for 5 days by rubbing or spraying the infected body region with an active ingredient-containing formulation.

The topical treatment of percutaneously on the right flank with HSV-2G infected animals showed a weak effectiveness of the acetylsalicylic acid formulations in the mean survival time of the animals, but not in the disease index and in the proportion of surviving animals. Table 1

Topical treatment of percutaneously on the right flank infected with HSV-2G Animals that are used simultaneously with a substituted thiazolylamide (here the representative N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2- pyridinyl) phenyl] acetamide.

The following table shows some action data of Example 38: Table 2

Starting compounds EXAMPLE I 2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride

150 g (1.12 mol) of 2-chloro-4-methyl-1,3-thiazole are added dropwise at room temperature to a solution of 331 g (2.81 mmol) of thionyl chloride in 653 g (5.61 mmol) of chlorosulfonic acid. The solution is heated to reflux for 48 hours. The mixture is then poured into 3 l of ice water and extracted with 4 × 400 ml of dichloromethane. The combined organic phases are washed with 2.5 l of water, dried over sodium sulfate and concentrated. After the crude product has been distilled, 233.7 g of product are obtained in the form of an oil. (Bp 87-96 ° C, 0.7 mbar, GC 98.1%, yield 89.6%). Example II 2-chloro-4-methyl-1,3-thiazole-5-sulfonamide

117.7 g (1.8 mol) of a 26% solution are added to a solution of 208 g (95%, 0.9 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride in 1000 ml of tetrahydrofuran aqueous ammonia solution added dropwise at -10C °. The mixture is allowed to stir for 2 hours without further cooling and the reaction mixture is then concentrated on a rotary evaporator. The raw product is used in the next stage without further purification. Example III 4-Methyl-2- (methylamino) -1,3-thiazole-5-sulfonamide

144 g (0.576 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulfonamide are placed in 600 ml of acetonitrile at room temperature and 147 g (1.9 mol) of a 40% aqueous methylamine solution at room temperature added. The reaction mixture is stirred for 6 h at 50 ° C and then concentrated on a rotary evaporator. The residue is mixed with water, suction filtered and dried.
Yield: 78 g (66%)
Mp: 194 ° C. Example IV 2-fluorophenylboronic acid

155 g (0.86 mol) of 2-fluorobromobenzene are placed under argon in 732 ml of absolute tetrahydrofuran, and 600 ml of 1.6 M n-butyllithium in hexane are slowly added at -78 ° C. The mixture is then stirred at -78 ° C for 2 h. 298 ml (1.28 mol) of trimethyl borate are then added dropwise at -78 ° C. After 1 h the cooling is removed and the reaction mixture is stirred overnight and warmed to room temperature. For working up, the batch is mixed with 346 ml of saturated ammonium chloride solution at 0 ° C., the pH is adjusted to 6 with 1N HCl and the aqueous phase is extracted 3 times with 250 ml of methylene chloride. The combined organic phases are washed with saturated sodium chloride solution and dried with magnesium sulfate. Example IV is obtained in the form of a beige solid.
Yield: 60.0 g (48%)
MS (EI, m / z): 140 (80%, [M] ⁺ ), 96 (100%, [C ₆ H ₅ F] ⁺ ) Example V (2'-fluorine [1,1'-biphenyl] - 4-yl) methyl acetate

47.6 g (0.21 mol) of methyl 4-bromophenylacetate are placed under argon in 400 ml of absolute tetrahydrofuran, and 320 ml of 1 M sodium carbonate solution and 40 g (0.28 mol) of 2-fluorophenylboronic acid are added at room temperature. After adding 7.0 g (0.01 mol) of bis (triphenylphosphine) palladium (II) chloride, the mixture is heated under reflux for 18 h. After cooling, the mixture is diluted with 500 ml of water and extracted three times with 300 ml of ethyl acetate each time. The combined organic phases are washed with 400 ml of saturated ammonium chloride solution, water and saturated sodium chloride solution, dried over magnesium sulfate and freed from the solvent in vacuo. Example V is obtained after silica gel filtration (petroleum ether / ethyl acetate 10: 1) as a colorless oil.
Yield: 46.0 g (94%)
¹ H-NMR (500 MHz, CDCl ₃ , δ / ppm): 3.71 (s, 2H), 3.76 (s, 3H), 7.18-7.46 (m, 4H), 7.40 (d, J = 8.3 Hz; 2H) , 7.56 (dd, J ₁ = 8.3 Hz, J ₂ = 1.7 Hz; 2H). Example VI (2'-fluoro [1,1'-biphenyl] -4-yl) acetic acid

26.5 g (0.11 mol) (2'-fluoro [1,1'-biphenyl] -4-yl) methyl acetate are placed in 50 ml ethanol and at room temperature with a solution of 12.8 g (0.19 mol) Potassium hydroxide cookies added to 25 ml of water. The mixture is then heated under reflux for 4 h. After cooling, the crude mixture is concentrated in vacuo, the residue is dissolved in 100 ml of water and concentrated. Hydrochloric acid made acidic. The precipitate is filtered off, washed several times with water and the solid is dried. Example VI is obtained in the form of white crystals.
Yield: 22.7 g (91%)
Mp .: 102 ° C
¹ H-NMR (500 MHz, CDCl ₃ , δ / ppm): 3.74 (s, 2H), 7.18-7.47 (m, 4H), 7.41 (d, J = 8.2 Hz; 2H), 7.57 (dd, J ₁ = 8.2 Hz, J ₂ = 1.6 Hz; 2H). Example VII [4- (2-pyridinyl) phenyl] methyl acetate

7.85 g (34.3 mmol) of methyl 4-bromophenylacetate are placed under argon in 95 ml of toluene and at room temperature with 7.97 g (61.7 mmol) of diisopropylethylamine, 9.50 g (37.7 mmol) of 2-trimethylstannylpyridine and 0.4 g (0.3 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. The mixture is then heated under reflux for 18 h. After cooling, it is washed with 100 ml of 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic phase was discarded. The acidic and basic water phases were neutralized, extracted with 100 ml of dichloromethane each time, and the combined organic phases were dried over magnesium sulfate and freed from the solvent in vacuo. Example VII is obtained as a colorless oil after silica gel chromatography (toluene / ethyl acetate gradient 5: 1-1: 1).
Yield: 1.6 g (19%)
¹ H NMR (400 MHz, d ⁶ -DMSO, δ / ppm): 3.64 (s, 3H), 3.76 (s, 2H), 7.33-7.40 (m, 1H), 7.39 (d, J = 8.2 Hz; 2 H), 7.86-7.90 (m, 1H), 7.96 (d, J = 8.0 Hz; 1H), 8.05 (d, J = 8.2 Hz; 2H), 8.67 (d, J = 4.2 Hz, broad; 1H). Example VIII [4- (2-pyridinyl) phenyl] acetic acid

700 mg (3.11 mol) of methyl [4- (2-pyridinyl) phenyl] acetate are placed in 5 ml of tetrahydrofuran, and 6.2 ml of a 1 M potassium hydroxide solution in water are added at room temperature. The mixture is then stirred at room temperature for 18 h, then the solvent is largely removed in vacuo, the residue is taken up in 10 ml of water and the pH is brought to about 5 using 2N hydrochloric acid. Extraction of the aqueous phase twice with 10 ml of dichloromethane each gave, after drying the combined organic phases over magnesium sulfate and removing the solvent in vacuo, the compound of Example VIII in the form of a solid.
Yield: 300 mg (46%)
¹ H-NMR (400 MHz, d ⁶ -DMSO, δ / ppm): 3.76 (s, 2H), 7.45-7.51 (m, 1H), 7.50 (d, J = 8.3 Hz; 2H), 8.00 (td, J ₁ = 7.7 Hz, J ₂ = 1.9 Hz; 1H), 8.07 (d, J = 7.9 Hz; 1 H), 8.15 (d, J = 8.3 Hz; 2H), 8.78 (dt, J ₁ = 4.0 Hz, J ₂ = 0.9 Hz; 1H). Preparation Examples Example 15 N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -2- [1,1'-biphenyl] -4-yl-N-methylacetamide

138.2 mg (0.65 mmol) of 4-biphenylacetic acid and 99.7 mg (0.65 mmol) of 1-hydroxy-1H-benzotriazole hydrate are placed in 5 ml of dimethylformamide at room temperature. 150 mg (0.72 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 138.7 mg (0.72 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride added and the mixture stirred for 72 h at room temperature. The reaction mixture is then suctioned off and the residue is recrystallized from 2-propanol. A white solid is obtained.
Yield: 240 mg (83.0%)
Mp: 191 ° C
¹ H-NMR (300 MHz, d ⁶ -DMSO, δ / ppm): 2.47 (s, 3H; partly under DMSO signal), 3.71 (s, 3H), 4.20 (s, 2H), 7.32-7.70 (m, 11H). Example 38 N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridinyl) phenyl] acetamide

300 mg (1.41 mmol) of [4- (2-pyridinyl) phenyl] acetic acid and 190 mg (1.41 mmol) of 1-hydroxy-1H-benzotriazole hydrate are placed in 4 ml of dimethylformamide at room temperature. 307 mg (1.48 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 284 mg (1.48 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride are added and the mixture was stirred at room temperature for 18 h. The solvent is then removed in vacuo, the residue is taken up in toluene and the solvent is removed again in vacuo. The residue is stirred with 15 ml of water and 3 ml of methanol, then filtered off and the filtrate extracted with 20 ml of dichloromethane. Solid and dichloromethane phase are combined and the solvent removed in vacuo. The compound of Example 38 is obtained in the form of a white solid.
Yield: 440 mg (74.0%)
Mp: 188-192 ° C
MS (ESI, m / z): 403 (100%, [M + H] ⁺ )
¹ H-NMR (400 MHz, d ⁶ -DMSO, δ / ppm): 2.38 (s, 3H; under DMSO signal), 3.64 (s, 3H), 4.15 (s, 2H), 7.28-7.26 (m, 1H ), 7.32 (d, J = 8 Hz; 2H), 7.58 (s, 2H), 7.82-7.96 (m, 2H), 7.98 (d, J = 8.0 Hz; 2H), 8.61 (m; 1H) , Example 57 N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -2- (2'-fluoro [1,1'-biphenyl] -4-yl) - N-methylacetamide

17.33 g (73.3 mmol) (2'-fluoro [1,1'-biphenyl] -4-yl) acetic acid and 9.9 g (73.3 mmol) 1-hydroxy-1H-benzotriazole hydrate are dissolved in 600 ml of dimethylformamide at room temperature. 16.84 g (81.4 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 15.58 g (81.4 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide Hydrochloride are added and the mixture is stirred at room temperature for 18 h. The dimethylformamide is largely removed in a high vacuum at 50 ° C., the residue is taken up in 400 ml of dichloromethane and then washed with 350 ml of water and 10% citric acid solution. After drying over magnesium sulfate and removal of the solvent in vacuo, the compound of Example 57 is obtained in the form of a white solid.
Yield: 23.2 g (76.0%)
Mp: 211 ° C
¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm): 2.58 (s, 3H), 3.73 (s, 3H), 4.07 (s, 2H), 5.91 (s, 2H), 7.13-7.46 ( m, 4H), 7.34 (d, J = 8.1 Hz; 2H), 7.56 (d, broad, J = 8.1 Hz; 2H). Example 87 N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -2- (2 ', 5'-difluoro-1,1'-biphenyl-4-yl) -N -methylacetamid

1.00 g (4.0 mmol) (2 ', 5'-difluoro [1,1'-biphenyl] -4-yl) acetic acid and 0.54 g (4.0 mmol) 1-hydroxy-1H-benzotriazole hydrate are dissolved in 15 ml of dimethylformamide at room temperature. 0.84 g (4.0 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 0.77 g (4.0 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride are added and the mixture was stirred at room temperature for 18 h. The dimethylformamide is largely removed in a high vacuum at 50 ° C., the residue is stirred 3 times with 50 ml of water each time, filtered off, stirred with 50 ml of isopropanol and filtered off again. After removal of the solvent in vacuo, the compound of Example 87 is obtained in the form of a pale yellow solid.
Yield: 0.83 g (47.3%)
Mp: 184 ° C
¹ H NMR (400 MHz, DMSO, δ / ppm): 2.49 (s, 3H), 3.71 (s, 3H), 4.24 (s, 2H), 7.22-7.46 (m, 3H), 7.38 (d, J = 8.2 Hz; 2H), 7.56 (d, J = 8.2 Hz; 2H), 7.65 (s, 2H). Example 126 N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (1H-pyrazol-1-yl) phenyl] acetamide

0.100 g (0.48 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide are dissolved in 10 ml of N, N-dimethylformamide and at room temperature with 0.110 g (0.53 mmol) [4- (1H-Pyrazol-1-yl) phenyl] acetic acid, 0.070 g (0.53 mmol) of 1-hydroxy-1H-benzotriazole and 0.070 g (0.53 mmol) of N, N'-diisopropylcarbodiimide. The solution is stirred at room temperature overnight. The mixture is then poured onto water and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate and concentrated. The crude product is finely cleaned on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient).
Yield: 0.11 g (59%)
LC-MS (method: SMKL-N1-1Low Vol HCl): retention time: 3.65
MS (ESI): 783 (2Mz + H), 392 (Mz + H).
¹ H-NMR (300 MHz, DMSO, δ / ppm): 2.48 (s, 3H), 3.72 (s, 3H), 4.20 (s, 2H), 6.55 (t, J = 2 Hz; 1H), 7.38 ( d, J = 7 Hz; 2H), 7.65 (s, 2H), 7.75 (d, J = 2 Hz; 1H), 7.82 (d, J = 7 Hz; 2H), 8.49 (d, J = 2 Hz; 1H). SMKL-N1 method

Claims (17)

1. Combination preparations containing acetylsalicylic acid and a compound of the general formula (I):


in which
R ^{1 is} hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino (C ₁ -C ₆ ) alkyl or halogen (C ₁ -C ₆ ) alkyl stands,
R ² and R ^{3 are the} same or different and represent hydrogen, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl or biphenylaminocarbonyl, or
represent (C ₁ -C ₆ ) alkyl which is optionally substituted by 1 to 3 substituents selected from the group consisting of (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy , Halogen, hydroxy, amino, tri- (C ₁ -C ₆ ) alkylsilyloxy, radicals of the formula


wherein R ^{2 'represents} hydrogen or (C ₁ -C ₄ ) alkyl,
a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where a nitrogen-containing heterocycle can also be bonded via the nitrogen atom,
a 3- to 8-membered saturated or unsaturated, non-aromatic, heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, and (C ₆ -C ₁₀ ) -aryl, which in turn by Hydroxy or (C ₁ -C ₆ ) alkoxy may be substituted, or
for a group of the formula


stand in which R ⁸ and R ^{9 are} identical or different from each other and represent hydrogen and (C ₁ -C ₄ ) alkyl, or
for a group of the formula


where R ^{10 represents} the side group of a naturally occurring α-amino acid, or
for a group of the formula


in which R ^{11 is} (C ₁ -C ₄ ) alkyl, and R ^{12 is} hydrogen, (C ₁ -C ₄ ) alkyl or a group of the formula


where R ^{10 'represents} the side group of a naturally occurring α-amino acid, or
R ² and R ³ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally also have an oxygen atom,
R ^{4 represents} hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkoxy, carboxyl,


where R ^{4 'represents} hydrogen,
- (OCH ₂ CH ₂ ) _n OCH ₂ CH ₃ , in which n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and -NR ¹³ R ¹⁴ ,
wherein R ¹³ and R ^{14 are the} same or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkoxycarbonyl, or
R ¹³ and R ¹⁴ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further hetero atom from the S or O series or a radical of the formula -NR ¹⁵ and may be substituted by oxo,
wherein
R ^{15 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, a nitrogen-containing heterocycle can also be bound via the nitrogen atom, or by residues of the formulas


or


is substituted,
wherein
R ¹⁶ denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ¹⁷ and R ^{18 are} identical or different and denote hydrogen, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, the aforementioned (C ₁ -C ₆ ) alkyl and (C ₆ -C ₁₀ ) -aryl may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ ) alkoxy and halogen,
R ^{5 represents} hydrogen, (C ₁ -C ₆ ) alkyl, halogen, amino, mono- or di (C ₁ -C ₆ ) alkylamino or represents (C ₁ -C ₆ ) alkanoylamino,
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
Halogen,
(C ₆ -C ₁₀ ) aryl optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, Halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, Hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ - C ₆₎ alkylsulfoxy, (C ₁ -C ₆₎ - alkylsulfonyl, tri- (C ₁ -C ₆₎ alkylsilyloxy, a bound optionally via a nitrogen atom 3- to 8-membered saturated or unsaturated, nonaromatic, mono- or bicyclic heterocycle can be substituted with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
(C ₁ -C ₆ ) alkoxy,
(C ₁ -C ₆ ) alkoxycarbonyl,
(C ₁ -C ₆ ) alkylthio,
hydroxy,
carboxyl,
partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms,
(C ₁ -C ₆ ) alkyl, optionally by a radical of the formula


is substituted,
an optionally bound via a nitrogen atom 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, optionally with 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, aminocarbonyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) -alkylsulfoxy, (C ₁ -C ₆ ) -alkylsulfonyl, a 3- to 8-membered group optionally bonded via a nitrogen atom saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle can be substituted with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which is optionally selected from 1 to 3 substituents from oxo , Halogen, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl and hydroxy- ( C ₁ -C ₆ ) alkyl can be substituted,
(C ₂ -C ₆ ) alkenyl
and groups of formulas
-OR ¹⁹ ,
-NR ²⁰ R ²¹ or -CO-NR ²² R ²³ ,
Carbazole, dibenzofuran or dibenzothiophene,
Xanthene or 9,10-dihydroacridine
consists,
in which R ^{19 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl,
or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are the} same or different and are hydrogen, carbamoyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl mean,
wherein the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and R ^{7 can have} the meaning of R ⁵ and can be the same or different with it,
and their salts. 2. Combination preparations containing acetylsalicylic acid and compounds of the general formula (I) according to Claim 1:


in which
R ^{1 represents} hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino (C ₁ -C ₆ ) alkyl or halogen (C ₁ -C ₆ ) alkyl,
R ² and R ^{3 are the} same or different and stand for hydrogen, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl or biphenylaminocarbonyl, or
represent (C ₁ -C ₆ ) alkyl which is optionally substituted by 1 to 3 substituents selected from the group consisting of (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy , Halogen, hydroxy, amino, radicals of the formula


a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where a nitrogen-containing heterocycle can also be bonded via the nitrogen atom,
a 3- to 8-membered saturated or unsaturated, non-aromatic, heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, and (C ₆ -C ₁₀ ) -aryl, which in turn by Hydroxy or (C ₁ -C ₆ ) alkoxy may be substituted, or
for a group of the formula


stand in which R ⁸ and R ^{9 are} identical or different from each other and represent hydrogen and (C ₁ -C ₄ ) alkyl, or
for a group of the formula


where R ^{10 represents} the side group of a naturally occurring α-amino acid, or
for a group of the formula


in which R ^{11 is} (C ₁ -C ₄ ) alkyl, and R ^{12 is} hydrogen, (C ₁ -C ₄ ) alkyl or a group of the formula


where R ^{10 'represents} the side group of a naturally occurring α-amino acid, or
R ² and R ³ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally also have an oxygen atom,
R ^{4 represents} hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl, which can optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkoxy,
- (OCH ₂ CH ₂ ) _n OCH ₂ CH ₃ , in which n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and -NR ¹³ R ¹⁴ ,
wherein R ¹³ and R ^{14 are the} same or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkoxycarbonyl, or
R ¹³ and R ¹⁴ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further hetero atom from the S or O series or a radical of the formula -NR ¹⁵ and may be substituted by oxo,
wherein R ^{15 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, a nitrogen-containing heterocycle can also be bound via the nitrogen atom, or by the rest of the formulas


or


is substituted,
wherein
R ¹⁶ denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ¹⁷ and R ^{18 are} identical or different and denote hydrogen, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, the aforementioned (C ₁ -C ₆ ) alkyl and (C ₆ - C ₁₀ ) aryl may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ ) alkoxy and halogen,
R ^{5 represents} hydrogen, (C ₁ -C ₆ ) alkyl, halogen, amino, mono- or di (C ₁ -C ₆ ) alkylamino or represents (C ₁ -C ₆ ) alkanoylamino,
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
Halogen,
(C ₆ -C ₁₀ ) aryl optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen , (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, mono - or di (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) Alkylsulfonyl, tri (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, and / or cyano may be substituted,
(C ₁ -C ₆ ) alkoxy,
(C ₁ -C ₆ ) alkoxycarbonyl,
(C ₁ -C ₆ ) alkylthio,
hydroxy,
carboxyl,
partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms,
(C ₁ -C ₆ ) alkyl, optionally by a radical of the formula


is substituted,
an optionally bound via a nitrogen atom 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, optionally with 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, ( C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di (C ₁ -C6) alkanoylamino, (C ₁ -C ₆ ) Alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle optionally having a nitrogen atom and having up to 3 heteroatoms can be substituted from the series S, N and / or O, and / or cyano,
a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which is optionally selected from 1 to 3 substituents from oxo , Halogen, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl and hydroxy (C ₁ - C ₆ ) alkyl may be substituted,
and groups of formulas
-OR ¹⁹ ,
-NR ²⁰ R ²¹ or -CO-NR ²² R ²³
consists,
in which R ^{19 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl,
or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are} identical or different and denote hydrogen, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl,
wherein the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and R ^{7 can have} the meaning of R ⁵ and can be the same or different with it,
and their salts. 3. Combination preparations according to claim 1, containing acetylsalicylic acid and compounds of the general formula (I), wherein R ^{1 is} hydrogen or (C ₁ -C ₆ ) alkyl. 4. Combination preparations according to claim 1, containing acetylsalicylic acid and compounds of the general formula (I), in which R ² and R ³ each independently represent hydrogen or (C ₁ -C ₆ ) alkyl. 5. Combination preparations according to claim 1, containing acetylsalicylic acid and compounds of general formula (I), wherein R ^{4 is} hydrogen or (C ₁ -C ₆ ) alkyl. 6. Combination preparations according to claim 1, containing acetylsalicylic acid and compounds of the general formula (I), in which R ^{5 is} hydrogen. 7. Combination preparations according to claim 1, containing acetylsalicylic acid and compounds of general formula (I), wherein
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
Halogen,
(C ₆ -C ₁₀ ) aryl optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen , (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, hydroxy, mono- or di (C ₁ -C ₆ ) alkylamino, mono - Or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, and / or cyano may be substituted, and
an optionally bound via a nitrogen atom 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which can optionally be substituted by 1 or 2 halogen atoms,
consists. 8. Combination preparations according to claim 1, containing acetylsalicylic acid and compounds which have the following formula:


wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{7 are} as defined in claim 1,
R ²⁶ and R ^{27 are the} same or different and are partial for hydrogen, halogen, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl fluorinated (C ₁ -C ₆ ) alkoxy having up to 6 fluorine atoms, (C ₁ -C ₆ ) alkyl, a group of the formulas -OR ¹⁹ , -NR ²⁰ R ²¹ or -CO-NR ²² R ²³ , in which
R ¹⁹ denotes phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl, or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are} identical or different and denote hydrogen, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl,
where the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 Heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) alkyl,
R ^{28 represents} (C ₆ -C ₁₀ ) aryl, which is optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) Alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) - alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, tri- (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, optionally bonded via a nitrogen atom , mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano may be substituted, or
R ^{28 represents} a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which is optionally selected from 1 to 3 substituents selected from (C ₁ -C ₆ ) Alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, Halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3 to 8 bonded via a nitrogen atom, if appropriate -membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
and their salts. 9. Combination preparations according to claim 1, containing acetylsalicylic acid and compounds of the general formula (IV)


wherein
R ¹ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given for the formula (I), and D is a halogen atom. 10. Combination of acetylsalicylic acid with compounds of formula (I) for Use as a medicine. 11. Pharmaceutical composition containing acetylsalicylic acid and a Compound of general formula (I) and at least one pharmaceutical compatible carrier or excipient. 12. Use of a combination of a compound of general formula (I) and acetylsalicylic acid for the manufacture of a medicament, in particular a medicine to treat and / or prevent viral infections. 13. Use of a combination according to claim 12, characterized characterized in that the administration of acetylsalicylic acid and the compound of the general formula (I) takes place simultaneously. 14. Use according to claim 12, characterized in that the Oral acetylsalicylic acid, and the compound of general formula (I) topically is administered. 15. Use according to claim 12, characterized in that the Acetylsalicylic acid and the active ingredient of the general formula (I) administered topically become. 16. Use according to claim 12, characterized in that the Acetylsalicylic acid topically and the active ingredient of the general formula (I) orally is administered. 17. Use according to claim 12, characterized in that the Acetylsalicylic acid and the active ingredient of the general formula (I) orally be administered.