DE10210319A1 - New thiazole-5-sulfonamide derivatives, useful for the treatment of viral infections in humans and animals, especially herpes simplex or human cytomegalovirus infections - Google Patents

Abstract

Thiazole-5-sulfonamide derivatives (I) are new. Thiazole-5-sulfonamide derivatives of formula (I) and their salts are new. R1 = H, halo, R, OR, 1-6C aminoalkyl or 1-6C haloalkyl; R = 1-6C alkyl; R2, R3 = H, 3-8C cycloalkyl or biphenylaminocarbonyl; 1-6C alkyl (substituted with 0-3 of 3-6C cycloalkyl, OR, halo, OH, NH2, OSiR3, 3,4-methylenedioxyphenyl, tetrahydro-2-furyl or N(R21)COOtBu), 5- or 6-membered heteroaryl, 3- to 8-membered heterocyclyl, 6-10C aryl (optionally substituted with OH or OR), PO(OR22)(OR23), COCH(NH)R24 or CH(R25)OCOR26; or NR2R3 = 5- or 6-membered saturated heterocycle optionally containing O; R21-R23 = H or 1-4C alkyl; R24 = the side chain of a natural alpha-amino acid; R25 = 1-4C alkyl; R26 = H, 1-4C alkyl or CH(NH2)R27; R27 = the side chain of a natural alpha-amino acid; R6 = phenyl (substituted with 0-3 of halo), Ar, OR, SR, SCF3, OH, COOH, 1-6C fluoroalkoxy, 1-6C alkyl (optionally substituted with tetrahydro-2-furyl), Het1, Het2, 2-6C alkenyl, OR61, NR62R3, CONR64R5, carbazole, dibenzofuran, dibenzothiophene, xanthene or 9,10-dihydroacridine; Ar = 6-10C aryl (substituted with 0-3 of 1-6C alkanoyl, OR, R, halo, COOR, NO2, CN, 1-6C haloalkyl, 1-6C haloalkoxy, NH2, SR, OH, COOH, CONH2, CONHR, CONRR, mono- or di(1-6C alkanoyl)amino, NHCOOR, SOR, SO2R, OSiR3) or 3- to 8-membered heterocyclyl; Het1 = 5- or 6-membered heteroaryl (optionally substituted as for Ar); Het2 = 3- to 8-membered heterocyclyl (substituted with 0-3 of oxo, halo, OH, COOR, NHCOOR, R, 1-6C haloalkyl and 1-6C hydroxyalkyl); R61 = phenyl optionally substituted with NR66R67; or 1-6C alkyl substituted with 0-3 of OH and/or halo; R66, R67 = H, R or 1-6C acyl; R62, R63 = H, CONH2, CONHR, CONRR, phenyl, 1-6C acyl, or 1-6C alkyl (optionally substituted with OR, 1-6C acyl, Ph or 5- to 6-membered heteroaryl, where phenyl and heteroaryl are substituted with 0-3 of halo and OH); R64, R65 = H or R; R7, R8 = H, R, halo or NH2; A = CR4'R5'-CO-CR4R5, CR4'R5'-CO-NR9, NR9-CO-CR4R5 or NR9'-CO-NR9; R4, R4' = H, 1-6C acyl, 2-6C alkenyl, 3-8C cycloalkyl, COOR, or 1-6C alkyl (substituted with 0-3 of halo, OH, 1-6C acyl, OR, ethoxyethoxy, OPh, 6-10C aryl or NR41R42); R41, R42 = H, 1-6C acyl, R, CONH2, mono- or di(1-6C alkyl)amino(1-6C)alkyl, CONHR, CONRR, 6-10C aryl or COOR, or NR41R42 = optionally oxo-substituted 5- or 6-membered heterocyclyl optionally N-substituted with 1-4C alkyl; R5, R5' = H, R or 1-6C alkanoyl; R9, R9' = H, 1-6C acyl, 2-6 alkenyl, 3-8C cycloalkyl, or 1-6C alkyl substituted with 0-3 of halo, OH, 3-8C cycloalkyl, 1-6C acyl, OR, COOH, NHCOOtBu, ethoxyethoxy, OPh, 6-10C aryl, NR92R93, optionally benzo-fused 5- or 6-membered heteroaryl, 2-pyrrolidyl, 1-R-2pyrrolidinyl, tetrahydro-2-furyl, benzo(1,4)dioxan-2-yl, 2-oxopyrrolidino or OCONR96R97; R92, R93 = groups as defined for R41 and R42; R94 = H or 1-4C alkyl; and R96, R97 = H, or 1-6C alkyl or 6-10C aryl substituted with 0-3 of OH, OR and halo.

Description

The present invention relates to new thiazolylcarbonyl derivatives, processes for their manufacture and their use as pharmaceuticals, in particular as antiviral drugs.

From the publications R. J. Cremlyn et al., J. Heterocycl. Chem .; 18; 1981; 997-1006 and R. Bellemin et al., J. Heterocycl. Chem .; 21; 1984; 1017-1021 and R.E. Olson et al .; J. Med. Chem .; 42; 7; 1999; 1178-1192 are 2-methyl-thiazole-5- known sulfonamides.

WO 97/24343, WO 99/42455, WO 00/29399 and WO 01/47904 relate Phenylthiazole derivatives with anti-herpes virus properties. WO 99/47507 Affects 1,3,4-thiadiazole derivatives with anti-herpes virus properties. WO 02/12211 concerns thiazole derivatives with anti-herpes virus properties.

The present invention relates to new compounds which are thiazolylcarbonyl derivatives 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 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 ^{2-1 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 can be substituted by hydroxy or (C ₁ -C ₆ ) alkoxy, or
for a group of the formula


wherein
R ^2-2 and R ^{2-3 are} identical or different from one another and represent hydrogen and (C ₁ -C ₄ ) -alkyl, or
for a group of the formula


wherein
R ^{2-4 represents} the side group of a naturally occurring α-amino acid, or
for a group of the formula


wherein
R ^{2-5 represents} (C ₁ -C ₄ ) alkyl, and
R ^{2-6 represents} hydrogen, (C ₁ -C ₄ ) alkyl or a group of the formula


wherein
R ^{2-7 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 ^{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, cyano, 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, 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;
(C ₁ -C ₆ ) alkoxy;
(C ₁ -C ₆ ) alkoxycarbonyl;
(C ₁ -C ₆ ) alkylthio;
trifluoromethylthio;
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


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-membered group optionally bonded via a nitrogen atom 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 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;
(C ₂ -C ₆ ) alkenyl;
and groups of formulas;
-OR ^6-1 ;
-NR ^6-2 R ^6-3 or -CO-NR ^6-4 R ^6-5 ;
Carbazole, dibenzofuran or dibenzothiophene;
Xanthene or 9,10-dihydroacridine;
consists,
wherein
R ^{6-1 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ^6-6 R ^6-7 ,
wherein
R ^6-6 and R ^{6-7 are the} same or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acyl,
or
R ^6-1 denotes (C ₁ -C ₆ ) alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ^6-2 and R ^{6-3 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,
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 ^6-4 and R ^{6-5 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
R ⁷ and R ^{8 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) alkyl, halogen or amino,
A for a group of the formulas -CR ⁴ 'R ⁵ ' -C (O) -CR ⁴ R ⁵ -, -CR ⁴ 'R ⁵ ' -C (O) -NR ⁹ -, -NR ⁹ '-C (O ) -CR ⁴ R ⁵ - or -NR ⁹ '-C (O) -NR ⁹ -,
wherein
R ⁴ and R ⁴ 'are identical or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₆ ) Alkoxycarbonyl, or
represent (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 ^4-1 R ^4-2 ,
wherein
R ^4-1 and R ^{4-2 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 ^4-1 and R ^4-2 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further heteroatom from the series S or O or a radical of the formula -NR ^4-3 , and by Oxo may be substituted
wherein
R ^4-3 denotes hydrogen or (C ₁ -C ₄ ) alkyl,
R ⁵ and R ⁵ 'are identical or different and represent hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkanoyl,
R ⁹ and R ⁹ 'are identical or different and represent hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
represent (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,


wherein
R ^{9-1 represents} hydrogen,

- (OCH ₂ CH ₂ ) _n OCH ₂ CH ₃ ,

wherein
n is 0 or 1, there is phenoxy, (C ₆ -C ₁₀ ) aryl and NR ^9-2 R ^9-3 ,
wherein
R ^9-2 and R ^{9-3 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 ^9-2 and R ^9-3 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further heteroatom from the series S or O or a radical of the formula -NR ^9-4 , and by oxo can be substituted
wherein
R ^{9-4 denotes} hydrogen or (C ₁ -C ₄ ) alkyl,
or
R ⁹ and R ⁹ 'are the same or different and stand for (C ₁ -C ₆ ) alkyl, which is formed by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted, where a nitrogen-containing heterocycle can also be bonded via the nitrogen atom, or by
Remains of the formulas


wherein
R ^9-5 denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ^9-6 and R ^{9-7 are the} same 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,
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, Naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, Maleic 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, 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 which are not like image and mirror image (diastereomers) behave, exist. The invention relates to both the enantiomers or Diastereomers or their respective mixtures. The racemic shapes can be as well the diastereomers in a known manner into the stereoisomerically uniform constituents separate.

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 the 1 to 3 halogen atoms, namely F, Cl, Br and / or I, preferably chlorine or fluorine, as substituents, for example trifluoromethyl, fluoromethyl etc.

Hydroxy (C ₁ -C ₆ ) alkyl is expediently 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. 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 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 in the context of the invention expediently represents a carbamoyl group (H ₂ N-CO-) in which one or both hydrogen atoms are replaced by a (C ₁ -C ₆ ) alkyl group. 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 ) allcyl. 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.

(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 series S, O and / or N stand for example for 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, 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, optionally bonded via a nitrogen atom saturated or unsaturated, non-aromatic heterocycle with up to 3 Heteroatoms 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.

In a preferred embodiment, the invention relates to compounds of the general formula (I)
in which
R ^{1 is} hydrogen, (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 are hydrogen or (C ₃ -C ₈ ) cycloalkyl
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,
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 ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
(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 may be substituted;
a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series 5, 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 with up to 3 heteroatoms from the series S, N and / or O, and / or cyano;
a 5- to 6-membered saturated 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 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;
trifluoromethylthio;
consists,
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 ⁷ and R ^{8 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) -alkyl or halogen,
A represents a group of the formulas CR ⁴ 'R ⁵ ' -C (O) -NR ⁹ - or -NR ⁹ '-C (O) -NR ⁹ -,
wherein
R ⁴ 'for hydrogen or
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 ) alkoxy,
R ⁵ 'represents hydrogen or (C ₁ -C ₆ ) alkyl,
R ⁹ and R ⁹ 'are the same or different and are hydrogen or
represent (C ₁ -C ₆ ) alkyl, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy and (C ₃ -C ₈ ) cycloalkyl,
and their salts.

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

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 ⁹ and R ⁹ 'are hydrogen or (C ₁ -C ₆ ) -alkyl, in particular (C ₁ -C ₆ ) -alkyl.

In a further preferred embodiment, the invention relates to compounds of the general formula (I) in which R ⁷ and R ^{8 are} 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
Phenyl, which may optionally be substituted by 1 to 3 halogen;
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
consists.

In a further preferred embodiment, the invention relates to compounds of the general formula (I) in which R ^{6 is} m-biphenyl, which can optionally be substituted by 1 to 3 halogen.

In a further preferred embodiment, the invention relates to compounds of the general formula (I) in which R ⁴ , R ⁴ ', R ⁵ and R ⁵ ' are hydrogen.

• 1. [A1] Verbindungen der allgemeinen Formel (A1I)
  
  
  in welcher
  R¹, R², R³ und R⁹ die oben angegebene Bedeutung haben,
  und
  X¹ für Halogen, vorzugsweise für Chlor steht,
  mit Aminen der allgemeinen Formel (A1II)
  
  
  in welcher
  R⁶, R⁷ und R⁸ die oben angegebene Bedeutung haben,
  in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer Base und/oder Hilfsmittels umsetzt, oder
• 2. [A2] Isocyanate der allgemeinen Formel (A2I)
  
  R⁶-NCO (A2I)
  
  in welcher
  R⁶ die oben angegebene Bedeutung hat,
  mit Thiazolylaminen der allgemeinen Formel (A2II)
  
  
  in welcher
  R¹, R², R³ und R⁹ die oben angegebene Bedeutung haben,
  in inerten Lösemitteln umsetzt,
  oder
• 3. [B] Verbindungen der allgemeinen Formel (BI)
  
  
  in welcher
  R¹, R², R³, R⁶, R⁷ und R⁸ die oben angegebene Bedeutung haben,
  und
  R²⁶ gleich (C₁-C₆)-Alkyl bedeutet,
• 4. [B1] für den Fall dass R⁴ gleich Methyl sein soll, mit Lithiumaluminiumhydrid in inerten Lösungsmitteln zu Verbindungen der allgemeinen Formel (BI1)
  
  
  in welcher
  R¹, R², R³, R⁶, R⁷ und R⁸ die oben angegebene Bedeutung haben, umsetzt,
  oder
• 5. [B2] für den Fall dass R⁴ gleich Wasserstoff sein soll, mit Lithiumhydroxid in inerten Lösungsmitteln zu Verbindungen der allgemeinen Formel (B2I)
  
  
  in welcher
  R¹, R², R³, R⁶, R⁷ und R⁸ die oben angegebene Bedeutung haben umsetzt,
  oder
• 6. [B3] für den Fall, dass R⁴ ungleich Wasserstoff oder Methyl sein soll, mit Verbindungen der allgemeinen Formel (B3I)
  
  Y-R⁴ (B3I)
  
  in welcher Y für eine Abgangsgruppe, wie z. B. Triflat oder Halogen, vorzugsweise Chlor steht, und R⁴ die oben angegebene Bedeutung hat,
  in inerten Lösungsmitteln zu Verbindungen der allgemeinen Formel (B3II)
  
  
  in welcher
  R¹, R², R³, R⁴, R⁶, R⁷, R⁸ und R²⁶ die oben angegebene Bedeutung haben umsetzt,
  und diese dann zu Verbindungen der allgemeinen Formel (B3III)
  
  
  in welcher
  R¹, R², R³, R⁴, R⁶, R⁷ und R⁸ die oben angegebene Bedeutung haben,
  decarboxyliert,
  und für den Fall dass R⁵ ein Substituent anders als Wasserstoff ist,
  Verbindungen der allgemeinen Formel (B3III)
  mit Verbindungen der allgemeinen Formel (B3IV)
  
  X²-R⁵ (B3IV)
  
  in welcher
  X² für eine Abgangsgruppe, wie z. B. Triflat oder Halogen, vorzugsweise Chlor steht,
  und
  R⁵ die oben angegebene Bedeutung hat,
  in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer Base und/oder eines Hilfsmittels zu Verbindungen der Formel (I) umsetzt,
  oder
• 7. [C] Verbindungen der allgemeinen Formel (CI)
  
  
  in welcher
  R¹, R², R³ und R⁹ die oben angegebene Bedeutung haben,
  mit Verbindungen der allgemeinen Formel (CII)
  
  
  in welcher
  X³ für eine Abgangsgruppe, wie z. B. Halogen, vorzugsweise Chlor, oder Hydroxy steht,
  und
  R⁸, 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.

We have also found a process for the preparation of the compounds of the general formula (I) according to the invention, characterized in that

• 1. [A1] compounds of the general formula (A1I)
  
  
  in which
  R ¹ , R ² , R ³ and R ^{9 have} the meaning given above,
  and
  X ^{1 represents} halogen, preferably chlorine,
  with amines of the general formula (A1II)
  
  
  in which
  R ⁶ , R ⁷ and R ^{8 have} the meaning given above,
  in inert solvents, optionally in the presence of a base and / or auxiliary, or
• 2. [A2] isocyanates of the general formula (A2I)
  
  R ⁶ -NCO (A2I)
  
  in which
  R ^{6 has} the meaning given above,
  with thiazolylamines of the general formula (A2II)
  
  
  in which
  R ¹ , R ² , R ³ and R ^{9 have} the meaning given above,
  reacted in inert solvents,
  or
• 3. [B] compounds of the general formula (BI)
  
  
  in which
  R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ^{8 have} the meaning given above,
  and
  R ²⁶ is (C ₁ -C ₆ ) alkyl,
• 4. [B1] in the event that R ^{4 is} to be methyl, with lithium aluminum hydride in inert solvents to give compounds of the general formula (BI1)
  
  
  in which
  R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ^{8 have} the meaning given above,
  or
• 5. [B2] in the event that R ^{4 is} to be hydrogen, using lithium hydroxide in inert solvents to give compounds of the general formula (B2I)
  
  
  in which
  R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ^{8 have} the meaning given above,
  or
• 6. [B3] in the event that R ^{4 is} not to be hydrogen or methyl, with compounds of the general formula (B3I)
  
  YR ⁴ (B3I)
  
  in which Y for a leaving group, such as B. triflate or halogen, preferably chlorine, and R ^{4 has} the meaning given above,
  in inert solvents to give compounds of the general formula (B3II)
  
  
  in which
  R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and R ^{26 have} the meaning given above,
  and these then to compounds of the general formula (B3III)
  
  
  in which
  R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ^{8 have} the meaning given above,
  decarboxylated
  and in the event that R ^{5 is} a substituent other than hydrogen,
  Compounds of the general formula (B3III)
  with compounds of the general formula (B3IV)
  
  X ² -R ⁵ (B3IV)
  
  in which
  X ² for a leaving group, such as. B. triflate or halogen, preferably chlorine,
  and
  R ^{5 has} 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),
  or
• 7. [C] compounds of the general formula (CI)
  
  
  in which
  R ¹ , R ² , R ³ and R ^{9 have} the meaning given above,
  with compounds of the general formula (CII)
  
  
  in which
  X ³ for a leaving group, such as. B. halogen, preferably chlorine, or hydroxy,
  and
  R ⁸ , 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).

The methods according to the invention can be illustrated by the following formula schemes:

The methods [B1], [B2] and [B3] according to the invention can be illustrated by the following formula scheme:

The process [C] according to the invention can be explained by way of example using the following formula:

Here mean:
HOBt: 1-hydroxy-1H-benzotriazole
DIC: diisopropylcarbodiimide
DMF: N, N-dimethylformamide

The corresponding ketones can be produced by coupling reactions, which are known to the person skilled in the art (e.g. Houben-Weyl, methods of organic Chemistry, Georg Thieme Verlag, Stuttgart or Comprehensive Organic Synthesis, Ed. B. M. Trost, Pergamon Press, Oxford, 1991).

Conventional organic solvents are suitable as solvents for processes [A1] and [A2] Solvents that do not change under the reaction conditions. This includes preferably 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 or acetonitrile. It is also possible To use mixtures of the solvents mentioned. Dioxane is preferred.

In general, inorganic or organic bases can be used as bases for the process [A1] 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, 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 (A1I).

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 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 (A1I) are new and can be prepared be by

Compounds of the general formula (A1II)


in which
R ¹ , R ² and R ^{3 have} the meaning given above
and
D represents (C ₁ -C ₄ ) -alkyl, preferably methyl,
first by alkylation with compounds of the general formula (A1III)

R ⁴ '-I (A1III),

in which
R ⁴ 'has the meaning of R ⁴ given above but does not represent hydrogen,
in inert solvents and in the presence of a base in the compounds of the general formula (A1IV)


in which
R ¹ , R ² , R ³ , R ⁴ 'and D have the meaning given above,
convicted
in a further step by reaction with hydrochloric acid, the compounds of the general formula (A1V)


in which
R ¹ , R ² , R ³ and R ⁴ 'have the meaning given above,
produces and finally reacted with trichloromethyl chloroformate in ethers.

Conventional organic solvents which are suitable as solvents for the alkylation are do not change under the reaction conditions. These 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 or triethylamine, pyridine, Dimethyl sulfoxide, dimethylformamide, acetonitrile, acetone or nitromethane. As well it is possible to use mixtures of the solvents mentioned. Are preferred Dichloromethane, dimethyl sulfoxide and dimethylformamide.

In general, inorganic or organic bases can be used as bases for the process according to the invention. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates such as sodium or potassium methoxide, sodium or potassium tert-ethanolate or potassium , or 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, methylpiperidine or morpholine. It is also possible to use alkali metals such as sodium or their hydrides such as sodium hydride as bases. Sodium hydride is preferred.

The alkylation generally takes place in one of the solvents listed above, preferably in dimethylformamide in a temperature range from 0 ° C to + 70 ° C, preferably from 0 ° C to + 30 ° C and normal pressure.

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 (A1II).

The compounds of the general formula (A1V) are prepared at Reflux temperature and normal pressure.

Suitable as a solvent for the reaction with chloroformic acid trichloromethyl ester are generally ethers such as diethyl ether, dioxane, tetrahydrofuran or Glycol. Dioxane is preferred.

The reaction of compounds of the general formula (A1V) with Trichloromethyl chloroformate is carried out 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 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 other connections are known per se [cf. DE 748 376 or can according to the methods published there.

The compounds of the general formula (A1V) are new and can for example, by making

Compounds of the general formula (A1VI)


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 (A1VII)


in which
R ^{1 has} the meaning given above,
transferred, then with amines of the general formula (A1VIII)

HNR ² R ³ (A1VIII),

in which
R ² and R ^{3 have} the meaning given above,
the compounds of the general formula (A1IX) in inert solvents


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 (A1X)

H ₂ NR ⁴ "(A1X),

in which
R ⁴ "has the meaning of R ⁴ 'given above and is the same or different with it,
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 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 (A1VIII) alcohols such as methanol, ethanol, propanol and Isopropanol. Methanol is preferred.

The reaction with the amines is initially carried out 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 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 (A1X) takes place in Ethers such as diethyl ether, dioxane, tetrahydrofuran or Glycol. Methanol is preferred.

In general, inorganic or organic bases can be used as bases. 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, 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 (A1X).

Conventional organic solvents are suitable as solvents for processes [B1], [B2] and [B3] Solvents that do not change under the reaction conditions. For this preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran (THF), 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. Likewise it is possible to use mixtures of the solvents mentioned. THF is preferred.

The methods [B1], [B2] and [B3] according to the invention are generally described in a temperature range from -50 ° C to + 100 ° C, preferably from -30 ° C to + 60 ° C, carried out.

The methods [B1], [B2] and [B3] according to the invention are generally described in Normal pressure carried out. However, it is also possible to use the overpressure method or to be carried out at negative pressure (e.g. in a range from 0.5 to 5 bar).

Conventional organic solvents which are suitable as solvents for process [C] are: do not change under the reaction conditions. These 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. DMF is preferred.

In general, inorganic or organic bases can be used as bases for process [C] 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 carbodiimides, such as diisopropylcarbodiimide (DIC), 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, phosphoric acid diphenyl ester azide, benzotriazolyl-N-oxy-tris (dimethylamino) - phosphonium hexafluorophosphate (BOP), or uronium compounds such as O-benzotriazol-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 (CI).

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 under positive pressure or under negative pressure to be carried out (e.g. in a range from 0.5 to 5 bar).

The invention further relates to the compounds of formula (I) for use as Drug.

The invention further relates to a pharmaceutical composition comprising a Compound of general formula (I) in admixture with at least one includes pharmaceutically acceptable carriers or excipients.

The invention further relates to the use of a compound of the general Formula (I) for the manufacture of a medicament, in particular a medicament for Treatment and / or prevention of viral infections, such as herpes viruses, in particular Herpes simplex virus or human cytomegalovirus (HCMV).

A. Assessment of physiological effectiveness

The in vitro activity of the compounds according to the invention against HSV can be seen in following assays are shown:

Determination of HSV inhibition

HSV (HSV-1 Walki, HSV-1F or HSV-2G) 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. 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 among the above Conditions incubated for 24 hours. 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 was 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 were coated 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 Overlay Eagle Medium with Earl's Salt) and incubate 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 demonstrated in a screening test system 96-well microtiter plates with the help of various cell lines neuronal, lymphoid and epithelial origin such as Vero (kidney cell line of the green Vervet monkey), 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 cytopathogenic effect was compared to the reference substance acyclovir sodium (Zovirax®), a clinically approved anti-herpes chemotherapy drug, certainly.

The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on microtiter plates (e.g. 96-well MTP) in final concentrations of 250-0.5 µM (micromolar) 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, for example, 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-1F or HSV- 2G with a mo i (multiplicity of infection) of 0.0025 for HELF, Vero and MEF cells and a mo i 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 optically evaluated 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 (preparation examples) in the following Table 1: Table 1

IC ₅₀ here means the half-maximum fluorescence intensity in relation to the non-infected cell control (100% value). The IC ₅₀ value can also be related to a suitable active ingredient control (see assay description: infected cells in the presence of a substance with an anti-herpes effect of a suitable concentration, for example Zovirax 20 μM). This active ingredient control achieves fluorescence intensities of 85% to 95% in relation to cell control.

Derivatives according to the invention are preferred whose IC ₅₀ (HSV-1F / 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 in vitro activity of the compounds according to the invention against HCMV can be seen in following assays are shown:

Determination of HCMV inhibition

Human cytomegalovirus (HCMV), strain Davis (ATCC-VR807), is in vitro grown on human embryonic fibroblasts (NHDF cells). After infection of the NHDF cells with an infection multiplicity (M.O.I) of 0.01 are the virus-infected cells harvested ~ 7 days later and in the presence of Minimal Essential Medium (MEM), 10% Fetal Calf Serum (FKS) with 10% DMSO Store at -80 ° C. After serial dilution of the virus infected cells in The titer is determined in steps of ten (HCMVDavis cell-associated) on 24-well Plates of confluent NHDF cells after incubation for several days and Vital staining with neutral red by counting the infectious centers (plaques).

The anti-HCMV effect is tested in a screening test system 96-well microtiter plates determined with the aid of NHDF cells. The influence of Substances on the spread of the cytopathogenic effect were compared to that Reference substance ganciclovir (Cymevene®), a clinically approved HCMV Therapeutic determined.

The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on microtiter plates (e.g. 96-well MTP) in final concentrations of 250-0.5 µM (micromolar) 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 NHDF cells (5 × 10 ³ cells per well) in MEM medium with 10% fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 ug / ml streptomycin were added to each well and the cells in the relevant wells were infected with a multiplicity of infection (moi) of 0.025 with HCMVDavis (cell-associated). The plates are then incubated at 37 ° C in a CO ₂ incubator (5% CO ₂ ) for 12-15 days. After this time, the cell lawn in the substance-free virus controls is completely destroyed by the cytopathogenic effect of the viruses (100% CPE). The plates are first optically evaluated 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 IC ₅₀ value can be determined by comparing the intensities. IC ₅₀ here means the half-maximum fluorescence intensity in relation to the non-infected cell control (100% value).

The results for some compounds (preparation examples) are summarized in the following Table 2: Table 2

Derivatives according to the invention are preferred, the IC ₅₀ (HCMV Davis) of which is preferably less than 50 μM, more preferably less than 25 μM and very particularly preferably less than 10 μM in the in vitro screening test system described above.

• 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 (HSV) or human cytomegalovirus (HCMV). 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)

• 1. Behandlung und Prophylaxe von HCMV-Infektionen bei AIDS-Patienten (Retinitis, Pneumonitis, gastrointestinale Infektionen).
• 2. Behandlung und Prophylaxe von Cytomegalievirus-In-fektionen bei Knochenmark- und Organtransplantationspatienten, die an einer HCMV- Pneumonitis, -Enzephalitis, sowie an gastrointestinalen und systemischen HCMV-Infektionen oft lebensbedrohlich erkranken.
• 3. Behandlung und Prophylaxe von HCMV-Infektionen bei Neugeborenen und Kleinkindern.
• 4. Behandlung einer akuten HCMV-Infektion bei Schwangeren.
• 5. Behandlung der HCMV-Infektion bei immunsupprimierten Patienten bei Krebs und Krebs-Therapie.

The following can also be mentioned as indication areas:

• 1. Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).
• 2. Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients who often develop life-threatening illnesses from HCMV pneumonitis, encephalitis, as well as gastrointestinal and systemic HCMV infections.
• 3. Treatment and prophylaxis of HCMV infections in newborns and young children.
• 4. Treatment of acute HCMV infection in pregnant women.
• 5. Treatment of HCMV infection in immunosuppressed patients with cancer and cancer therapy.

The new active ingredients can be used alone and, if necessary, in combination with other antiviral agents such as Gancyclovir or Acyclovir used become.

In vivo effect

The Suitability of the Compounds According to the Invention for the Treatment of HSV Infections can be shown in the following animal models:

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 μl of a dilution of the virus stock (infection dose 5 × 10 ⁴ Pfu) was introduced into the nose of the anesthetized animals using 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 mass 3 times a day at 7 a.m., 2 p.m. and 7 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 Times of death determined.

The suitability of the compounds according to the invention for the treatment of HCMV Infections can be shown in the following animal models:

HCMV Xenograft Gelfoam® model animals

3-4 week old female immunodeficient mice (16-18 g), Fox Chase SCID or Fox Chase SCID-NOD or SCID-beige are used by commercial breeders (Bomholtgaard, Jackson). The animals are under sterile conditions (including litter and feed) kept in isolators.

virus growing

Human cytomegalovirus (HCMV), strain DavisSmith, is raised in vitro human embryonic foreskin fibroblasts (NHDF cells). To Infection of the NHDF cells with an infection multiplicity (M.O.I) of 0.01 the virus-infected cells were harvested 5-7 days later and in the presence of minimal Essential Medium (MEM), 10% Fetal Calf Serum (FKS) with 10% DMSO Store at -40 ° C. After serial dilution of the virus infected cells in The titer is determined in steps of ten on 24-well plates of confluent NHDF cells after vital staining with neutral red.

Preparation of the sponges, transplantation, treatment and evaluation

1 × 1 × 1 cm collagen sponges (Gelfoam®; Peasel & Lorey, Order No. 407534; KT Chong et al., Abstracts of 39 ^th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1999, p. 439) first wetted with phosphate buffered saline (PBS), the enclosed air bubbles removed by degassing and then stored in MEM + 10% FCS. 1 × 10 ⁶ virus-infected NHDF cells (infection with HCMV-Davis MO I = 0.01) are detached 3 hours after infection and dropped onto a moist sponge in 20 μl MEM, 10% FCS. 12-13 hours later, the infected sponges are incubated with 25 μl PBS / 0.1% BSA / 1 mM DTT with 5 ng / μl basic fibroblast growth factor (bFGF). For the transplantation, the immunodeficient mice are anesthetized with avertine, the dorsal coat removed with the help of a dry razor, the epidermis opened 1-2 cm, relieved and the moist sponges transplanted under the dorsal skin. The surgical wound is closed with tissue glue. 24 hours after the transplant, the mice are treated orally with substance three times a day for 8 days (7 a.m. and 2 p.m. and 7 p.m.). The dose is 7 or 15 or 30 or 60 mg / kg body weight, the application volume 10 ml / kg body weight. The substances are formulated in the form of a 0.5% tylose suspension with 2% DMSO. 9 days after the transplant and 16 hours after the last substance application, the animals are killed painlessly and the sponge is removed. The virus-infected cells are released from the sponge by collagenase digestion (330 U / 1.5 ml) and stored in the presence of MEM, 10% fetal calf serum, 10% DMSO at -140 ° C. The evaluation is carried out after serial dilution of the virus-infected cells in steps of ten by titer determination on 24-well plates of confluent NHDF cells after vital staining with neutral red. The number of infectious virus particles after substance treatment is determined in comparison to the placebo-treated control group.

The active substance can act systemically and / or locally. For this purpose, he can be applied in a suitable manner, such as. B. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.

The active ingredient can be administered in suitable administration forms for these administration routes be administered.

Known active ingredients are quick and / or suitable for oral administration modified dispensing application forms, such as. B. tablets (non-coated as well as coated tablets, e.g. (Enteric coatings), capsules, coated tablets, Granules, pellets, powders, emulsions, suspensions and solutions.

Parenteral administration can be done by bypassing an absorption step happen (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneally). For parenteral administration are suitable as Application forms and. a. Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates and sterile powders.

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

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

In general, it has proven to be advantageous for parenteral administration Amounts of about 0.01 to 100 mg / kg, preferably about 0.1 to 10 mg / kg Give body weight for effective results. With oral application the amount is about 0.1 to 50 mg / kg, preferably about 0.5 to 5 mg / kg Body weight.

Nevertheless, it may be necessary from the amounts mentioned deviate, depending on body weight, application route, individual behavior towards the active ingredient, type of preparation and time or interval at which the application takes place.

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

B. Examples Analytical methods HPLC method MHZ2P

Instrument: Micromass Platform LCZ, HP1100; Column: Symmetry C18, 50 mm × 2.1 mm, 3.5 µm; Eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1% formic acid; Gradient: 0.0 min 10% A → 4.0 min 90% A → 6.0 min 90% A; Oven: 40 ° C, flow: 0.5 ml / min, UV detection: 208-400 nm.

HPLC method SMKL 03042001-sauer-210

Instrument: Finnigan MAT 9005, TSP: P4000, AS3000, UV300OHR; Column: Symmetry C 18, 150 mm × 2.1 mm, 5.0 µm; Eluent C: water, eluent B: water + 0.3 g of 35% HCl, eluent A: acetonitrile; Gradient: 00 min 2% A → 2.5 min 95% A → 5 min 95% A; Oven: 70 ° C, flow: 1.2 ml / min. UV detection: 210 nm. LC-MS method SMKL-N1-1Low Vol HCl

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

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, 117.7 g (1.8 mol) of a 26th % aqueous ammonia solution added dropwise at -10C °. The mixture is left 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 5- [sulfonyl] -4-methyl-1,3-thiazol-2-yl (methyl) carbamic acid chloride

1.767 g (15 mmol) of chloroformic acid trichloromethyl ester ("diphosgene") were added at room temperature to a solution of 3 g (15 mmol) of 4-methyl-2- (methylamino) -1,3-thiazole-5-sulfonamide in 45 ml of dioxane and the mixture was heated to reflux until a homogeneous solution was obtained and according to the DC no starting material was available. After the solvent has been suctioned off, the residue is mixed with 100 ml of abs. Toluene and recrystallization from ethyl acetate (addition of hexane until cloudy) gave 1.4 g of the product in the form of white crystals. (Yield 37.5%, Mp. Dec.). Example V 2-chloro-N, 4-dimethyl-1,3-thiazole-5-sulfonamide

177 ml of a solution of methylamine in methanol (2 M, 0.354 mol) at 0 ° to a solution of 41 g (0.177 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride in 360 ml of dichloromethane C. added. The mixture is stirred at 0 ° C. for 30 min, 1.8 l of water are added and the mixture is extracted 5 times with 400 ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate and the solvent is distilled off. 39.93 g of an oil are obtained, which solidifies on standing (Rf = 0.43 (toluene / ethyl acetate = 2/1), yield 99.7%). Example VI N- {5 - [(dimethylamino) sulfonyl] -4 methyl-1,3-thiazol-2-yl} -N-methylacetamide

6.0 g of sodium hydride (60% dispersion in mineral oil, 0.151 mol) were added in small portions at 0 ° C. to a solution of 36.2 g (0.137 mol) of N- {5 - [(dimethylamino) sulfonyl] -4-methyl- 1,3-thiazol-2-yl} acetamide added dropwise in dimethylformamide. Then 21.4 g (0.151 mol) of methyl iodide are added dropwise via a syringe. After complete conversion by TLC, the mixture was quenched by adding a saturated ammonium chloride solution. The mixture was evaporated to dryness, the residue was taken up in water, stirred for 16 h and filtered off. After drying the residue in vacuo, it was further purified by chromatography on silica gel with toluene / ethyl acetate (15-66% ethyl acetate) as the eluent. 31.0 g of a white powder were obtained. (Rf = 0.43 (toluene / ethyl acetate = 1/2), yield 74%). Example VII N, N, 4-trimethyl-2- (methylamino) -1,3-thiazole-5-sulfonamide

31 g (0.111 mol) of N- {5 - [(dimethylamino) sulfonyl] -4-methyl-1,3-thiazol-2-yl} -N-methylacetamide were suspended in 500 ml of 4 N hydrochloric acid and heated to reflux until the Reaction according to TLC (toluene / ethyl acetate 1/2) was complete. The mixture was washed with dichloromethane, made basic by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic phase was then dried over sodium sulfate and concentrated. The crude product was further purified by chromatography on silica gel with toluene / ethyl acetate (50-85% ethyl acetate) as the eluent. After the solvent was distilled off, 22.9 g of a solid was obtained. (Rf = 0.37 (toluene / ethyl acetate = 1/2), yield 87.7%) Example VIII 5 - [(Dimethylamino) sulfonyl] -4-methyl-1,3-thiazol-2-yl (methyl) carbamic acid chloride

15.4 g (78 mmol) of trichloromethyl chloroformate ("diphosgene") became at room temperature a solution of 22.9 g (97 mmol) of N, N, 4-trimethyl-2- (methylamino) -1,3-thiazole-5-sulfonamide added to 360 ml of dioxane and the mixture was heated to reflux until a homogeneous solution was obtained and according to the DC no starting material was available. After removing the solvent in vacuo, 29.0 g of the product were obtained in the form of an oil. (Yield 100%, NMR (CDCl ₃ ): 3.89 (3H), 2.81 (6H), 2.62 (3H) ppm). Example IX 2 - {[2- (Dimethylamino) ethyl] amino} -N, 4-dimethyl-1,3-thiazole-5-sulfonamide

A solution of 5.0 g (22.1 mmol) of 2-chloro-N, 4-dimethyl-1,3-thiazole-5-sulfonamide, 2.92 g (33.1 mmol) of 2-N, N-dimethylaminoethylamine and 6, 10 ml of triethylamine in 6.65 ml of dioxane is stirred at 100 ° C. for 16 h. 20 ml of water are then added and the mixture is extracted with 3 × 100 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated. After chromatography of the crude product on silica gel with a mixture of chloroform and methanol as the eluent (0-30% methanol), 3.05 g of an oil are obtained. (Rf = 0.4 (chloroform / 5% methanol), yield 49.7%). Production Examples Example 1

1.25 g (6, .82 mmol) of 3-phenylbenzylamine is introduced with 1.38 g (13.64 mmol) of triethylamine in 25 ml of DMF. 1.84 g (6.82 mmol) of 5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl (methyl) carbamic acid chloride are added and the mixture is stirred at RT. After complete conversion according to TLC (CH ₂ Cl ₂ / CH ₃ OH 100: 5), the DMF is removed and the resulting residue is taken up in dichloromethane, which is washed several times with water. The organic phase is dried over MgSO ₄ and concentrated.

The crude product obtained is purified by chromatography on silica gel. (Mobile phase CH ₂ Cl ₂ / CH ₃ OH 100: 2)
1.15 g of a white solid are obtained.
R _f = 0.36 (CH ₂ Cl ₂ / CH ₃ OH 100: 5);
Yield 40.5%;
Mp: 152 ° C.
¹ H NMR (300 MHz, DMSO): δ = 8.25 (1H); 7.60 - 7.70 (3H); 7.30 - 7.60 (8H); 4.45 (2H); 3.55 (3H); 2.40 (3H).

The following compounds are prepared in analogy to the instructions in Example 1 or Example 3: Example 2

Retention time LC / MS (SMKL-N1-1Low Vol HCl) 5.08 min. Example 3 N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -3- ^{(1,1'-biphenyl-3-yl)} -N- methylpropanamide

48.4 mg (0.23 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 58.1 mg (0.26 mmol) [ 1,1'-biphenyl] -3-propanoic acid, 34.7 mg (0.26 mmol) of 1-hydroxy-1H-benzotriazole and 32.4 mg (0.26 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 washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated. The crude product is finely cleaned on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient). 31.2 mg (31%) of product are obtained.
LC-MS (method: SMKL-N1-1Low Vol HCl): retention time: 4.76;
MS (ESI): 831 (2 Mz + H), 416 (Mz + H).
1H NMR (DMSO): 7.68-7.27 (m, 11H), 3.62 (s, 3H), 3.15 (t, J = 7 Hz, 2H), 3.00 (t, J = 7 Hz, 2H), 2.45 (s, 3H).

The following examples are presented using analog methods: Example 4

Retention time LC / MS (SMKL-N1-1Low Vol HCl) 4.54 min. Example 5

Retention time LC / MS (SMKL-N1-1Low Vol HCl) 4.31 min. Example 6

R _f values, eluent CH ₂ Cl ₂ / MeOH 100: 5 = 0.97;
Mp: 159 ° C.
¹ H-NMR (400 MHz, CD ₂ Cl ₂ )
8.32 (t, 1H); 7.57-7.35 (m, 8H); 4.60 (d. 2H); 3.48 (s, 3H); 2.79 (s, 6H); 2.52 (s, 3H)
MS (ESI): m / z 479 [M + H] ⁺ . Example 7

R _f values, eluent CH ₂ Cl ₂ / MeOH 100: 5 = 0.93;
Mp: 173 ° C.
¹ H-NMR (400 MHz, CD ₂ Cl ₂ )
8.30 (t, 1H); 7.60-7.11 (m, 8H); 4.61 (d, 2H); 3.49 (s, 3H); 2.78 (s, 6H); 2.51 (s, 3H)
MS (ESI): m / z 463 [M + H] ⁺ . Example 8

R _f values, eluent CH ₂ Cl ₂ / MeOH 100: 5 = 0.60;
Mp: 152 ° C;
¹ H-NMR (400 MHz, CD ₂ Cl ₂ ),
8.26 (t, 1H); 7.52-7.13 (m, 9H); 4.61 (d, 2H); 3.48 (s, 3H); 2.72 (d, 3H); 2.49 (s, 3H)
MS (DCI): m / z 449 [M + H] ⁺ . Example 9

R _f values, eluent CH ₂ Cl ₂ / MeOH 100: 5 = 0.56;
Mp: 112 ° C.
¹ H-NMR (400 MHz, CD ₂ Cl ₂ )
8.42 (t, 1H); 7.67-7.12 (m, 9H); 4.72 (d. 2H); 3.56 (s. 3H); 2.81 (d, 3H); 2.59 (s, 3H)
MS (DCI): m / z 449 [M + H] ⁺ . Example 10

R _f values, eluent CH ₂ Cl ₂ / MeOH 100: 5 = 0.53
Mp .: 160 ° C
¹ H-NMR (200 MHz, d ₆ -DMSO)
8.28 (t, 1H); 7.75-7.26 (m, 9H); 4.47 (d. 2H); 3.57 (s, 3H); 2.45 (d. 3H); 2.09 (s, 3H)
MS (ESI): m / z 449 [M + H] ⁺ Example 11

R _f values, eluent CH ₂ Cl ₂ / MeOH 100: 5 = 0.90;
Mp: 168 ° C.
¹ H-NMR (300 MHz, d ₆ -DMSO)
8.34 (t, 1H); 7.67-7.32 (m, 9H); 4.47 (d. 2H); 3.58 (s. 3H); 2.67 (s, 6H); 2.47 (s, 3H). Example 12

R _f values, eluent CH ₂ Cl ₂ / MeOH 100: 5 = 0.77;
Mp 158 ° C.
¹ H-NMR (300 MHz, d ₆ -DMSO)
8.30 (t, 1H); 7.68 (s, 1H); 7.67-7.33 (m, 9H); 4.46 (d. 2H); 3.58 (s. 3H); 2.47 (d. 3H);
2.42 (s, 3H);
MS (DCI): m / z 451 [M + H] ⁺ . Example 13

R _f values, eluent CH ₂ Cl ₂ / MeOH 100: 5 = 0.39;
Mp: 17 ° C;
¹ H NMR (200 MHz, d ₆ -DMSO).
8.24 (t, 1H); 7.71-7.32 (m, 10H); 4.47 (d. 2H); 3.56 (s. 3H); 2.42 (s, 3H)
MS (DCI): m / z 451 [M + H] ⁺ . Example 14

Example 15

Example 16

Example 17 2 - [({[2- (tert-Butylsulfanyl) benzyl] amino} carbonyl) (methyl) amino] -N-cyclopropyl-4-methyl-1,3-thiazole-5-sulfonamide

R _f : 0.57 (dichloromethane: methanol 100: 5);
LC-MS (method: MHZ 2P): retention time 4.70 min;
MS (ESI): 469 (Mz + H).
¹ H NMR (300 MHz, DMSO): δ = 8.22 (t, 1H); 8.02 (d, 1H); 7.25-7.56 (m, 4H); 4.66 (d. 2H); 3.60 (s, 3H); 2.45 (s, 3H); 2.20 ("sextet", 1H); 1.29 (s, 9H); 0.37-0.58 (m, 4H). Example 18 N-Cyclopropyl-4-methyl-2- {methyl [({4 - [(trifluoromethyl) sulfanyl] benzyl} amino) carbonyl] amino} -1,3-thiazole-5-sulfonamide

MS (ESI): 481 (Mz + H);
LC-MS method SMKL-N1-1Low Vol HCl. Example 19 2 - [{[(2-anilinobenzyl) amino] carbonyl} (methyl) amino] -N-cyclopropyl-4-methyl-1,3-thiazole-5-sulfonamide

80.0 mg (0.26 mmol) 5 - [(Cyclopropylamino) sulfonyl] -4-methyl-1,3-thiazol-2-yl- (methyl) carbamoyl chloride (prepared from the compound from Example I by reaction with cyclopropylamine and Subsequent analogous reaction with methylamine and carbamoylation with diphosgene according to Example VIII) is placed in 3 ml dichloromethane. 53.9 mg (0.27 mmol) of 2-anilinobenzylamine are added and the mixture is stirred at RT. After complete conversion according to the DC control, the dichloromethane is removed and the resulting residue is finely cleaned on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient). 103 mg (80%) of product are obtained.
LC-MS (method: MHZ 2P): retention time 4.54;
MS (ESI): 943 (2 Mz + H), 472 (Mz + H).
¹ H NMR (300 MHz, DMSO): δ = 8.25 (t, 1H); 8.05 (d, 1H); 7.12-7.35 (m, 5H); 6.88-7.01 (m, 3H); 6.79 (t, 1H); 4.38 (d. 2H); 3.56 (s. 3H); 2.85 (s, 1H); 2.44 (s, 3H); 2.21 ("sextet", 1H); 0.37-0.58 (m, 4H). Example 20 N-Cyclopropyl-2 - [{[(2-isopropoxybenzyl) amino] carbonyl} (methyl) amino] -4-methyl-1,3-thiazole-5-sulfonamide

R _f : 0.59 (dichloromethane: methanol 100: 5);
LC-MS (method: MHZ 2P): retention time 4.38 mm;
MS (ESI): 439 (Mz + H).
¹ H NMR (300 MHz, DMSO): δ = 7.98-8.08 (m, 2H); 6.84-7.27 (m, 4H); 4.65 ("heptette", 1H); 4.35 (d. 2H); 3.58 (s. 3H); 2.43 (s, 3H); 2.20 ("sextet", 1H); 1.29 (d, 6H); 0.37-0.58 (m, 4H).

In analogy to the regulation of example 19, the following connection manufactured.

C. Embodiments of pharmaceutical compositions

The compounds of the invention can be pharmaceutical as follows Preparations are transferred:

tablet composition

100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg Corn starch (native), 10 mg polyvinyl pyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

manufacturing

The mixture of active ingredient, lactose and starch is made with a 5% solution (m / m) of the PVP granulated in water. After drying, the granules are mixed with the magnesium stearate for 5 min. mixed. This mixture comes with a usual Tablet press pressed (for tablet format see above). As a guide for the Pressing a pressure force of 15 kN is used.

Oral suspension composition

1000 mg of the compound from Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (Xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

10 ml correspond to a single dose of 100 mg of the compound according to the invention oral suspension.

manufacturing

The Rhodigel is suspended in ethanol, the active ingredient becomes the suspension added. The water is added with stirring. Until the completion of the Swelling of the Rhodigel is stirred for about 6 h.

Claims (15)

1. Compounds 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 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 ^{2-1 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 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 may be substituted by hydroxy or (C ₁ -C ₆ ) alkoxy, or
for a group of the formula


wherein
R ^2-2 and R ^{2-3 are} identical or different from one another and represent hydrogen and (C ₁ -C ₄ ) -alkyl, or
for a group of the formula


wherein
R ^{2-4 represents} the side group of a naturally occurring α-amino acid, or
for a group of the formula


wherein R ^{2-5 represents} (C ₁ -C ₄ ) alkyl, and R ^{2-6 represents} hydrogen, (C ₁ -C ₄ ) alkyl or a group of the formula


wherein
R ^{2-7 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 ^{6 is} 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, cyano, 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, 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,
(C ₁ -C ₆ ) alkoxy,
(C ₁ -C ₆ ) alkoxycarbonyl,
- (C ₁ -C ₆ ) alkylthio,
trifluoromethylthio,
hydroxy,
carboxyl,
partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms, (C ₁ -C ₆ ) alkyl, which may be replaced by a radical of the formula


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 ^6-1 ,
-NR ^6-2 R ^6-3 or -CO-NR ^6-4 R ^6-5 ,
Carbazole, dibenzofuran or dibenzothiophene,
Xanthene or 9,10-dihydroacridine
consists,
wherein
R ^{6-1 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ^6-6 R ^6-7 ,
wherein
R ^6-6 and R ^{6-7 are the} same or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acyl,
or
R ^6-1 denotes (C ₁ -C ₆ ) alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ^6-2 and R ^{6-3 are the} same or different and are hydrogen, carbamoyl, mono- or di- (C ₁ -C ₆ ) -allcylaminocarbonyl, 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 ^6-4 and R ^{6-5 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
R ⁷ and R ^{8 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) alkyl, halogen or amino,
A for a group of the formulas -CR ⁴ 'R ⁵ ' -C (O) -CR ⁴ R ⁵ -, -CR ⁴ 'R ⁵ ' -C (O) -NR ⁹ -, NR ^{9 '} -C (O) -CR ⁴ R ⁵ - or -NR ⁹ '-C (O) -NR ⁹ -,
wherein
R ^{4 and} R ⁴ 'are the same or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₆ ) - Alkoxycarbonyl stand, or
represent (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 , where n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and NR ^4-1 R ^4-2 ,
wherein
R ^4-1 and R ^{4-2 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 ^4-1 and R ^4-2 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further heteroatom from the series S or O or a radical of the formula -NR ^4-3 , and by Oxo may be substituted
wherein
R ^4-3 denotes hydrogen or (C ₁ -C ₄ ) alkyl,
R ⁵ and R ⁵ 'are identical or different and represent hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkanoyl,
R ⁹ and R ⁹ 'are identical or different and represent hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
represent (C ₁ -C ₆ ) alkyl, which may 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,


wherein
R ^{9-1 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 ^9-2 R ^9-3 ,
wherein
R ^9-2 and R ^{9-3 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 ^9-2 and R ^9-3 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further heteroatom from the series S or O or a radical of the formula -NR ^9-4 , and by oxo can be substituted, wherein
R ^{9-4 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ⁹ and R ⁹ 'are the same or different and stand for (C ₁ -C ₆ ) alkyl, which is formed by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted, where a nitrogen-containing heterocycle can also be bonded via the nitrogen atom, or by
Remains of the formulas


wherein
R ^9-5 denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ^9-6 and R ^{9-7 are the} same 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,
and their salts. 2. Compounds of general formula (I) according to claim 1, in which
R ^{1 represents} hydrogen, (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 are hydrogen or (C ₃ -C ₈ ) - cycloalkyl 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, 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 ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
(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, halo (C ₁ - C ₆₎ alkyl, halo (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 may be 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 with up to 3 heteroatoms from the series S, N and / or O, and / or cyano;
a 5- to 6-membered saturated 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 halogen, hydroxy, (C ₁ -C ₆ ) Alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl and hydroxy- (C ₁ -C ₆ ) alkyl may be substituted;
trifluoromethylthio,
consists,
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 ⁷ and R ^{8 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) -alkyl or halogen,
A represents a group of the formulas -CR ⁴ 'R ⁵ ' -C (O) -NR ⁹ - or NR ⁹ '-C (O) - NR ⁹ -,
R ⁴ 'for hydrogen or
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 ) alkoxy,
R ⁵ 'represents hydrogen or (C ₁ -C ₆ ) alkyl,
R ⁹ and R ⁹ 'are the same or different and are hydrogen or
represent (C ₁ -C ₆ ) alkyl, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy and (C ₃ -C ₈ ) cycloalkyl,
and their salts. 3. Compounds of general formula (I) according to claim 1 or 2, wherein R ^{1 is} (C ₁ -C ₆ ) alkyl. 4. Compounds of general formula (I) according to claim 1, 2 or 3, wherein R ² and R ³ each independently represent hydrogen or (C ₁ -C ₆ ) alkyl. 5. Compounds of general formula (I) according to claim 1, 2, 3 or 4 wherein R ⁹ and R ⁹ 'are (C ₁ -C ₆ ) alkyl. 6. Compounds of general formula (I) according to claim 1, 2, 3, 4 or 5 wherein R ⁷ and R ^{8 are} hydrogen. 7. Compounds of general formula (I) according to any one of claims 1 to 6, wherein
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
Phenyl, which may optionally be substituted by 1 to 3 halogen;
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. 8. Compounds according to any one of claims 1 to 7, wherein R ^{6 is} m-biphenyl, which may optionally be substituted by 1 to 3 halogen. 9. Compounds according to any one of claims 1 to 7, wherein R ⁴ , R ⁴ ', R ⁵ and R ⁵ ' are hydrogen. 10. Compounds according to claim 1 for use as a medicament. 11. Pharmaceutical composition, which is a compound of general Formula (I) according to claim 1 in admixture with a pharmaceutical compatible carriers or excipients. 12. Use of a compound of general formula (I) according to claim 1 for the manufacture of a drug. 13. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections. 14. A pharmaceutical composition according to claim 11 for treatment and / or prophylaxis of viral infections. 15. Methods for combating viral infections in humans and animals by administration of an antivirally effective amount of at least one Connection according to one of Claims 1 to 3.