DE19962532A1 - New 2-acylamino-5-aminosulfonyl-1,3-thiazole derivatives, useful as antiviral agents, especially for treatment or prophylaxis of herpes simplex virus infections - Google Patents

Abstract

2-Acylamino-5-aminosulfonyl-1,3-thiazole derivatives (I) are new. Thiazole derivatives of formula (I) and their salts are new. 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(R'2)-COOCMe3, Het1, Het2 or aryl (itself os by OH or alkoxy); -COCH(R10)-NH2; or -CH(R11)-OCOR12; or NR2R3 = 5- or 6-membered saturated heterocycle optionally containing O; R'2, R8, R9 = H or 1-4C alkyl; Het1 = optionally N-bonded 5- or 6-membered aromatic heterocycle containing 1-3 of S, N and O as heteroatom(s); Het2 = optionally N-bonded 3-8 membered saturated or unsaturated non-aromatic heterocycle containing 1-3 of S, N and O as heteroatom(s); R10 = side-chain of a naturally occurring alpha -amino acid; R11 = 1-4C alkyl; R12 = H, 1-4C alkyl or -CHR10-NH2; R4 = H, 1-6C acyl, 2-6C alkenyl or cycloalkyl; or alkyl os by (i) 1-3 of halo, OH, cycloalkyl, 1-6C acyl, alkoxy, COOH, -NHCOOCMe3, -(OCH2CH2)nOEt, OPh, aryl or NR13R14 or (ii) Het1 (optionally fused with benzo), 1-(R16)-2-pyrrolidinyl, tetrahydrofuran-2-yl, benzo-1,4-dioxan-2-yl, 2-oxo-1-pyrrolidinyl or -OCONR17R18; n = 0 or 1; R13, R14 = H, 1-6C acyl, alkyl, CONH2, mono- or dialkylaminoalkyl, mono- or dialkylaminocarbonyl, aryl or alkoxycarbonyl; or NR13R14 = 5- or 6-membered saturated heterocycle optionally containing O, S or NR15 as additionally heteroatom and os by oxo; R15 = H or 1-4C alkyl; R17, R18 = H; or alkyl or aryl (both os by 1-3 of OH, alkoxy and halo); R5, R7 = H, alkyl, halo, NH2, mono- or dialkylamino or (1-6C) alkanoylamino; R6 = phenyl, os by 1-3 Q; Q = halo, aryl (os by 1-3 Q'), alkoxy (os by 1-6 F), alkoxycarbonyl, alkylthio, OH, COOH, alkyl (os by tetrahydrofuran-2-yl), Het1 (os by 1-3 Q'), mono- or bicyclic Het2 (os by 1-3 of oxo, halo, OH, alkoxycarbonyl, alkoxycarbonylamino, alkyl, haloalkyl and hydroxyalkyl), 2-6C alkenyl, OR19, NR20R21, CONR22R23, carbazole, dibenzofuran, dibenzothiepin, xanthene or 9,10-dihydroacridine; Q' = (1-6C) alkanoyl, alkoxy, alkyl, halo, alkoxycarbonyl, NO2, haloalkyl, haloalkoxy, NH2, alkylthio, OH, COOH, CONH2, mono- or dialkylaminocarbonyl, mono- or di-(1-6C alkanoyl)-amino, alkoxycarbonylamino, alkylsulfoxy, alkylsulfonyl, trialkylsilyloxy, CN or mono- or bicyclic Het2; R19 = phenyl (os by NR24R25) or alkyl (os by 1-3 of OH or halo); R24, R25 = H, alkyl or 1-6C acyl; R20, R21 = H, CONH2, mono- or dialkylaminocarbonyl, phenyl, 1-6C acyl or alkyl (where alkyl is os by alkoxy, 1-6C acyl, phenyl or Het1; and phenyl and Het1 are os by one or more of halo and/or OH); R22, R23 = H or alkyl; and D' = halogen. alkyl moieties have 1-6C, cycloalkyl moieties 3-8C and aryl moieties 6-10C unless specified otherwise. Independent claims are included for: (i) the preparation of (I); (ii) new sulfonyl halide intermediates of formula (IV); and (iii) the use of N-(5-(aminosulfonyl)-1,3-thiazol-2-yl)-acetamide, N-(5-(aminosulfonyl)-1,3-thiazol-2-yl)-2-phenylacetamide or N-(5-(aminosulfonyl)-1,3-thiazol-2-yl)-2-(1,1'-biphenyl)-4-ylacetamide derivatives for the preparation of medicaments.

Description

The present invention relates to new compounds, namely thiazolylamide Derivatives, processes for their preparation and their use as medicines, especially as antiviral drugs.

From the publication C. Ziegler et al., J. Org. Chem. 25, 1960, 1454-1455 2-aminothiazole-5-sulfonamides known. In addition, in the German Open legend 21 01 640 N-thiazol-2-yl amides and ureas with a herbicidal Effect described.

WO 97/24343 relates to phenylthiazole derivatives with anti-herpes virus properties ten.

WO 99/42455 also relates to phenylthiazole derivatives with anti-herpes virus Characteristics.

WO 99/47507 relates to 1,3,4-thiadiazole derivatives with their own anti-herpes virus create.

The present invention relates to new compounds which are thiazolylamide derivatives 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} identical or different and represent hydrogen, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₅ ) 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 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

stands in which 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

stands in which 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 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 ) alkyl amino ( 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} which 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 are 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 have 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, which is 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,

and groups of formulas

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

consists,
where R ¹⁹

Phenyl means, for its part, optionally by a group of the formula -NR ²⁴

R ²⁵

is substituted,
wherein
R ²⁴

and R ²⁵

are the same or different and are hydrogen, (C ₁

-C ₆

) Alkyl or (C1-C ₆

) -Acyl mean
or
R ¹⁹

(C ₁

-C ₆

) -Alkyl, which is optionally substituted one to three times 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,
the aforementioned (C ₁

-C ₆

) -Alkyl optionally by (C ₁

-C ₆

) Alkoxy, (C ₁

-C ₆

) -Acyl, is substituted by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, the aforementioned phenyl and the aforementioned aromatic heterocycle optionally being one to three times are identical or different substituted 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 chlorinated water Substance 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, malein acid or benzoic acid.

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, ethyldiisopro pylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephen amine or methylpiperidine.

The compounds of the invention can, depending on the substituent tion 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 forms can be just like the diastereo separate in a known manner into the stereoisomerically uniform constituents.

The scope of the invention also includes those compounds which are only in the Body to the actual active ingredients of formula (I) are converted (so-called 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 the 1 to 3 halogen atoms, namely F, Cl, Br and / or I, preferably chlorine or fluorine, as a substituent, for example trifluoromethyl, fluoromethyl, etc.

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 hydroxy 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. With regard to the (C ₁ -C ₆ ) alkoxy content 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 alkyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkylthio radical having 1 to 4 carbon atoms (C ₂ -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 suitably stands 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. Regarding 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, dimethylamino carbonyl 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, with respect to the (C ₁ -C ₆ ) alkyl group being able to be referred to the relevant definition above.

(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.

In the context of the invention, (C ₃ -C ₈ ) cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. May be mentioned:
Cyclopropyl, cyclopentyl and cyclohexyl. The meaning of (C ₃ -C ₆ ) cycloalkyl is appropriately for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl.

Halogen generally represents 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 can 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 optionally contains a further heteroatom from the S or O series or a radical of the Formula -NR ¹⁵ , in which R ^{15 is} as defined above, may in the context of the invention generally represent morpholinyl, piperidinyl, piperazinyl, methylpiperazinyl, thiomorpholinyl or pyrrolidinyl. Morpholinyl, piperidinyl, pyrrolidinyl and thiomorpholinyl are particularly preferred.

A 3- to 8-membered ge optionally bonded via a nitrogen atom saturated or unsaturated, non-aromatic heterocycle with up to 3 hetero atoms from the series S, N and / or O include z. B. the above 5- to 6- incorporate saturated heterocycles bonded via a nitrogen atom 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 methyl thioethyl group (methionine), hydroxymethyl (serine), p-hydroxybenzyl (tyrosine), 1-hydroxy-ethan-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-ureidopropan-1-yl (citrulline), Mercaptoethyl (homocysteine), hydroxyethyl (homoserine), 4-amino-3-hydroxy butan-1-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine) etc.

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

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

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

In a further preferred embodiment, the invention relates to 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, optionally with 1 to 3 substituents, selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl , Halo gene, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halo gene (C ₁ -C ₆ ) alkoxy, amino, hydroxy, mono- or di (C ₁ -C ₆ ) alkyl amino, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxy carbonylamino, and / or cyano may be substituted, and
• - A 5- to 6- optionally bonded via a nitrogen atom link aromatic heterocycle with up to 3 heteroatoms the series S, N and / or O, optionally by 1 to 2 halo gene atoms can be substituted,

consists.  

In a further preferred embodiment, the invention relates to 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 ²⁷ R 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 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 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, the abovementioned phenyl and the abovementioned aromatic heterocycle optionally being 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 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, 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, 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 ) Alkoxy carbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono, optionally bonded via a nitrogen atom - or bicyclic heterocycle can be substituted with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
and their salts.

Z are particularly preferred. B. the compound N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -2- [1,1'-biphenyl] -4-yl-N-methylacetamide of the formula:

the compound N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -2- (2'-fluoro [1,1'-biphenyl] -4-yl) -N- methylacetamide of the formula:

as well as the compound N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridinyl) phenyl] acetamide of the formula:

and pharmaceutically acceptable salts thereof.

The invention further relates to 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.

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

HNR ² R ³ (V)

in which R ² and R ^{3 have} the meaning given above, in inert solvents to give compounds of the formula (I),
[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 can be, 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
[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).

Process [A] according to the invention can be exemplified by the following formula scheme:

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 exemplified by the following formula scheme:

Herein means:
DMF: N, N-dimethylformamide.

Process [D] according to the invention can be exemplified by the following formula scheme:

Herein means:
DMF: N, N-dimethylformamide.

Conventional orga are suitable as solvents for processes [A], [B], [C] and [D] African solvents that do not change under the reaction conditions. For this preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol di methyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclo hexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, Trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorine benzene, or ethyl acetate, dimethyl sulfoxide, dimethylformamide (DMF) or aceto nitrile. It is also possible to use mixtures of the solvents mentioned. DMF is preferred.

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-ene (DBU), pyridine, diaminopyridine, N-methylmorpholine or N-methylpiperidine or morpholine. Triethylamine is preferred.

Suitable aids are known dehydration or coupling reagents, such as carbodiimides, such as diisopropylcarbodiimide, dicyclo hexylcarbodiimide (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-oxa zolium-3-sulfonate, or phosphorus compounds such as propanephosphonic anhydride, Phosphoric acid diphenyl ester azide, benzotriazolyl-N-oxy-tris (dimethylamino) phospho nium hexafluorophosphate (BOP), or uronium compounds such as O-benzotriazole 1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), or methane sulfonic acid chloride, optionally in the presence of auxiliaries such as N-hydroxy succinimide or N-hydroxybenzotriazole.

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

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

The processes according to the invention are generally carried out at normal pressure guided. However, it is also possible to use the process under positive pressure or under negative pressure to be carried out (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. It is also possible to carry out the process at overpressure or underpressure (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 isopropa are suitable nol. Methanol is preferred.

The reaction with the amines of the general formula (V) is carried out first Room temperature and then below the reflux temperature of the respective Ethers.

The reaction is generally carried out at normal pressure. It is also possible to carry out the process at overpressure or underpressure (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 before added from 1 mole to 2 moles based on 1 mole of the compound of formula (VIII).

The compounds of general formula (VI) are known in some cases or according to methods can be produced [cf. Hantzsch, Chem. Ber. 1927, 60, 2544].  

The compounds of general formula (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 produce methods 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 or can be prepared by processes known per se. The following reaction schemes A, B, C and D illustrate the synthesis of biphenylacetic acid derivatives from the corresponding boronic acids as well as 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 compounds of formula (I) claim 1 for ver use as a medicine.

The invention further relates to a pharmaceutical composition comprising a ver Binding of the general formula (I) in a mixture with at least one pharma includes compatible carriers or excipients.

The invention further relates to the use of a compound of the general Formula (I) 1 for the manufacture of a medicament, in particular a medicament for the treatment and / or prevention of viral infections, such as herpes viruses, ins special herpes simplex viruses.

The invention further relates to the use of N- [5- (aminosulfonyl) -1,3-thiazole- 2-yl] acetamide derivatives, preferably of N- [5- (aminosulfonyl) -1,3-thiazol-2-yl] -2- phenylacetamide derivatives, more preferably N- [5- (aminosulfonyl) -1,3-thiazole- 2-yl] -2- [1,1'-biphenyl] -4-ylacetamide derivatives for the manufacture of medicaments, in particular the use of the derivatives mentioned for the preparation of agents for the treatment and / or prevention of viral infections in humans or  Animals, such as herpes viruses, especially herpes simplex viruses. N- [5- (Aminosulfonyl) -1,3-thiazol-2-yl] acetamide derivatives, N- (5- (aminosulfonyl) -1,3-thia zol-2-yl] -2-phenylacetamide derivatives or N- [5- (aminosulfonyl) -1,3-thiazol-2-yl] -2- [1,1'-biphenyl] -4-ylacetamide derivatives here means those compounds which result from the Substitution of one or more hydrogen atoms from N- [5- (aminosulfonyl) -1,3- thiazol-2-yl] acetamide, N- [5- (aminosulfonyl) -1,3-thiazol-2-yl] -2-phenylacetamide or N- [5- (aminosulfonyl) -1,3-thiazol-2-yl] -2- [1,1'-biphenyl] -4-ylacetamide ten.

The compounds 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 Er diseases caused by herpes viruses, especially diseases caused by herpes Simplex viruses are caused.

In vitro activity Viruses and cells

HSV (HSV-1 Walki, HSV-1F or HSV-2 G) was grown on Vero cells (ATCC CCL-81) under the following conditions: The cells were grown in M199 medium (5% fetal calf serum, 2 mM glutamine, 100 IU / ml penicillin, 100 µg / ml streptomycin) grown in cell culture flasks at 37 ° C and 5% CO ₂ . The cells were split 1: 4 twice a week. For the infection, the medium was removed, the cells were washed with "Hank's solution", detached with 0.05% trypsin, 0.02% EDTA (Seromed L2143) and incubated at a density of 4 × 105 cells per ml under the above-mentioned conditions for 24 hours . The medium was then removed and the virus solution with a moi of <0.05 in a volume of 2 ml per 175 cm 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 stocks used for the experiments had a titer of 1 × 10 ⁶ / ml - 1 × 10 ⁸ / ml.

The anti-HSV effect was determined in a screening test system in 96-well micro titre plates with the help of various cell lines neuronal, lymphoid and epithelial origin such as Vero (kidney cell line of the green sea cat), MEF (murine embryonic fibroblasts), HELP (human embryonic Fibroblasts), NT2 (human neuronal cell line) or Jurkat (human lymphoid T- Cell line). The influence of substances on the spread of the cyto pathogenic effect was compared to the reference substance acyclovir Sodium (ZoviraxR), a clinically approved anti-herpes chemotherapy drug, certainly.

The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on micro titer plates (e.g. 96-well MTP) in final concentrations of 250-0.5 µM (micro molar) in duplicate determinations (4 substances / plate). In the case of potent substances, the dilutions are continued over several plates up to 0.5 pM (picomolar). Toxic and cytostatic substance effects are also included. After the corresponding substance dilutions (1: 2) on the microtiter plate in medium, a suspension of cells (1 × 10 ⁴ cells per well) such as Vero cells in M199 (Medium 199) with 5% fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 µg / ml streptomycin or MEF cells in EMEM (Eagle's Minimum Essential Medium) with 10% fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 µg / ml streptomycin, or HELF Cells in EMEM with 10% fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 µg / ml streptomycin, or NT2 and Jurkat cells in DMEM (4.5 mg / l glucose plus pyridoxine) with 10% fetal calf serum 2 mM glutamine, 1 mM sodium pyruvate, non-essential amino acids and optionally 100 IU / ml penicillin and 100 µg / ml streptomycin were added to each well and the cells in the relevant wells were infected with an appropriate amount of virus (HSV-1 F or HSV-2 G with a mo i (multiplicity of infection) of 0.0025 for HELF, Vero and MEF cells and a moi of 0.1 for NT2 and Jurkat cells). The plates are then incubated at 37 ° C in a CO ₂ incubator (5% CO ₂ ) for several days. After this time the cell lawn of z. B. Vero cells in the substance-free virus controls, starting from 25 infectious centers, completely lysed or destroyed by the cytophatogenic effect of the HSV viruses (100% CPE). The plates are first evaluated optically using a microscope and then analyzed using a fluorescent dye. For this purpose, the cell culture supernatant from all the wells of the MTP is suctioned off and filled with 200 μl PBS washing solution. The PBS is suctioned off again and all wells are filled with 200 μl fluorescent dye solution (fluorescein diacetate, 10 μg / ml in PBS). After an incubation period of 30-90 min, the test plates are measured in a fluorescence measuring device at an excitation wavelength of 485 nm and an emission wavelength of 538 nm.

The results are summarized for some compounds in the table below composed.  

table

IC ₅₀ here means the half-maximum fluorescence intensity in relation to the non-infected cell control.

Preferred are N- [5- (aminosulfonyl) -1,3-thiazol-2-yl] acetamide derivatives according to the invention whose IC ₅₀ (HSV-1 F / Vero) in the in vitro screening test system described above is preferably less than 50 µM, more preferably less than 25 µM and very particularly preferably less than 10 µM.

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

• 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, especially herpes Simplex infections in immunosuppressed patients (e.g. AIDS patients, Cancer patients, patients with genetic immunodeficiency, 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, especially herpes Simplex infections and herpes, especially herpes simplex positive Patients to suppress recurrence (suppression therapy).

In vivo effect Animals

6 week old female mice, strain BALB / cABom, were from one commercial breeders (Bomholtgard Breeding and Research Center Ltd.).

infection

The animals were anesthetized in a tight glass jar with diethyl ether (Merck). 50 .mu.l of a dilution of the virus stock (infection dose 5 × 10 ⁴ Pfu) was introduced into the nose of the anesthetized animals with an Eppendorf pipette. This infection dose leads to death in 90-100% of the animals from a generalized infection with prominent respiratory and central nervous symptoms on average between 5 and 8 days.

Treatment and evaluation

6 hours after infection, the animals were dosed at 0.1-100 mg / kg body measure 3 times a day at 7:00 a.m., 2:00 p.m. and 7:00 p.m. over a period of Treated 5 days. The substances were pre-dissolved in DMSO and in  Tylose / PBS (Hoechst) resuspended (final concentration 1.5% DMSO, 0.5% tylose in PBS).

After the last application, the animals were observed and the time of death points determined.

A comparison of the survival curves yielded z. B. an ED ₅₀ of about 0.7 mg / kg for HSV-2, ED ₅₀ means that 50% of the animals survive at this dose.

The new active ingredients can be introduced into the usual formulations in a known manner are transferred, such as tablets, dragees, pills, granules, aerosols, syrups, emuls ions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers and solvents. This is where the therapeu Table active compound in a concentration of about 0.5 to 90% by weight of the total mixture is present, d. H. in amounts that are sufficient are in order to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the active ingredients substances with solvents and / or carriers, optionally using Emulsifiers and / or dispersants, z. B. in the case of using Water as a diluent, optionally organic solvents as auxiliary solvents means can be used.

The application takes place in the usual way, preferably orally, parenterally or topically, especially perlingually or intravenously.

In the case of parenteral use, solutions of the active ingredients can be found below Use of suitable liquid carrier materials can be used.  

In general, it has proven to be advantageous for intravenous administration Amounts from about 0.001 to 20 mg / kg, preferably about 0.01 to 10 mg / kg body weight to give effective results, and oral appli cation is about 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg Body weight.

Nevertheless, it may be necessary from the amounts mentioned deviate, depending on the body weight or the type of Appli cation path, from individual behavior towards the drug, the type of its formulation and the time or interval at which the administration is done. So in some cases it may be sufficient to use less than that the aforementioned minimum quantity, while in other cases the aforementioned upper limit must be exceeded. In the case of application of larger quantities it may be advisable to mix these in several single doses throughout the day divide.

It may make sense to use the compounds of the invention to combine other active substances, in particular antiviral active substances.  

Output connections

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

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 are 117.7 g (1.8 mol) of a 26% aqueous ammonia solution added dropwise at -10 ° C. It is left for 2 hours without further Stir cooling and then narrow the reaction mixture on the rotation  vaporizer one. The crude product goes to the next stage without further purification used.

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% strength aqueous methylamine solution are metered in at room temperature . 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 each time. 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'-Fluoro [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 the addition of 7.0 g (0.01 mol) of bis (triphenylphosphine) palladium (II) chloride, the mixture is heated under reflux for 18 h. After cooling, it 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 a solution of 12.8 g (0.19 mol) potassium hydroxide biscuits in 25 ml water is added at room temperature . 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 acidified. 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 diisopropyl ethylamine, 9.50 g (37.7 mmol) of 2-trimethylstannylpyridine and 0.4 g (0.3 mmol) of tetrakis (triphenylphosphine) palladium (0) 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 after silica gel chromatography (toluene / ethyl acetate gradient 5: 1-1: 1) as a colorless oil.
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; 2H), 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 mixed with 6.2 ml of a 1M potassium hydroxide solution in water 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).

Manufacturing 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 are added and the mixture is 72 hours stirred at room temperature. The reaction mixture is then filtered off with suction 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 is stirred for 18 h stirred at room temperature. 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 is 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 placed in 600 ml 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 18 h stirred at room temperature. 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).

The connections listed in the following table are produced analogously to the regulations listed above:

In the table above, the Rf value means the retention index in thin-layer chromatography on silica gel.
SMKL-N1-1 denotes the following LC-MS method.

method SMKL-N1

Device type MS: Finnigan MAT 900S
Ionization: ESI positive

Device type HPLC: TSP: P4000, AS3000, UV3000HR
Pump head normal

Column: Symmetry C 18
150 mm × 2.1 mm 5 μm
Delivery company: Waters

A: CH ₃ CN
B: HCl 0.01 n
C: H ₂ O
D: -

Claims (25)

1. 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 halo (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, residues 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
stands in which 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
stands in which 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 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 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 , where 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 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 ) alkoxy carbonyl, 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} which may be substituted by oxo,
where 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, one containing nitrogen 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 halo gene,
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 ) alkyl aminocarbonyl, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ - C ₆ ) alkyl sulfonyl, tri (C ₁ -C ₆ ) alkylsilyloxy, 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 from the S series , 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, optionally 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,
• - 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 from the series S, N and / or O, optionally selected by 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 ,
• - -R 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 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 identically or differently 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. Compounds of general formula (I) according to claim 1, wherein R ^{1 is} hydrogen or (C ₁ -C ₆ ) alkyl. 3. Compounds of general formula (I) according to claim 1 or 2, wherein R ² and R ³ each independently represent hydrogen or (C ₁ -C ₆ ) alkyl. 4. Compounds of general formula (I) according to claim 1, 2 or 3 wherein R ^{4 is} hydrogen or (C ₁ -C ₆ ) alkyl. 5. Compounds of general formula (I) according to claim 1, 2, 3 or 4 wherein R ^{5 is} hydrogen. 6. Compounds of general formula (I) according to claim 1, 2, 3, 4 or 5 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 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 ) alkanoyl amino, (C ₁ -C ₆ ) alkoxycarbonylamino, and / or cyano can be 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.

7. Compounds according to claim 1, 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 identical or different and represent hydrogen, halogen, (C ₁ - C ₆₎ alkoxy, (C ₁ -C ₆₎ -alkoxycarbonyl, (C ₁ -C ₆₎ -alkylthio, hydroxyl, carboxyl, partially fluorinated (C ₁ -C ₆ ) alkoxy with 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 , wherein
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 the} same or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acyl be, 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, halo gene (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-glazed 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, 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-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle which is optionally bonded via a nitrogen atom can be substituted with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
and their salts. 8. A compound according to claim 1 of the formula:
and pharmaceutically acceptable salts thereof. 9. A compound according to claim 1 of the formula:
and pharmaceutically acceptable salts thereof. 10. A compound according to claim 1 of the formula:
and pharmaceutically acceptable salts thereof. 11. Compounds of the general formula (IV)
wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given in claim 1, and D is a halogen atom. 12. A process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that
[A] compounds of the general formula (II)
in which
R ¹ , R ² , R ³ and R ^{4 have} the meaning given in claim 1, with compounds of the general formula (III)
in which
A stands for a leaving group, and
R ⁵ , R ⁶ and R ^{7 have} the meaning given in claim 1, in inert solvents, if appropriate in the presence of a base and / or an auxiliary,
or
[B] Compounds of the general formula (IV)
wherein
R ¹ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given in claim 1, and D is a halogen atom, preferably chlorine,
with amines of the general formula (V):
HNR ² R ³
wherein R ² and R ^{3 have} the meaning given in claim 1,
reacted in inert solvents,
[C] compounds of the general formula (X)
wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ²⁶ and R ^{27 have} the meaning given above, and E is trifluoromethanesulfonate or halogen, with boronic acids or stannanes of the general formula (XI):
R ²⁸ M (XI)
wherein R ^{28 has} the meaning given above and M can be, for example, a tri (C ₁ -C ₆ ) alkylstannyl group or a boronic acid group, in inert solvents in the presence of palladium catalysts, optionally in the presence of base at temperatures of 50-140 ° C to compounds of the formula (XIV)
implements, and
[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, optionally in the presence of base, at temperatures of 50-140 ° C. to give compounds of the formula (XIV). 13. Compounds according to claim 1 for use as a medicament. 14. Pharmaceutical composition containing a compound of general Formula (I) according to claim 1 in admixture with a pharmaceutically acceptable Lichen carrier or excipient includes. 15. Use of a compound of general formula (I) according to claim 1 for the manufacture of a drug. 16. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections. 17. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections Herpes viruses. 18. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections Herpes simplex virus.   19. Use of N- [5- (aminosulfonyl) -1,3-thiazol-2-yl] acetamide derivatives for the manufacture of pharmaceuticals. 20. Use of N- [5- (aminosulfonyl) -1,3-thiazol-2-yl] -2-phenylacetamide- Derivatives for the manufacture of medicines. 21. Use of N- [5- (aminosulfonyl) -1,3-thiazol-2-yl] -2- [1,1'-biphenyl] -4- ylacetamide derivatives for the manufacture of pharmaceuticals. 22. Use according to claim 19, 20 or 21 for the preparation of agents for Treatment and / or prevention of viral infections in humans or Animals. 23. Use according to claim 19, 20 or 21 for the production of agents for Treatment and / or prevention of viral infections in humans or Animals by herpes viruses. 24. Use according to claim 19, 20 or 21 for the preparation of agents for Treatment and / or prevention of viral infections in humans or Animals caused by herpes simplex viruses.