WO2000076966A2 - Indolinylamide derivatives and the use thereof as antiviral drugs - Google Patents

Abstract

The invention relates to compounds of general formula (I), to a method for the production thereof and to the use of said compounds as medicaments, particularly as antiviral drugs.

Description

Indolinylamide derivatives

The present invention relates to new compounds, a process for their preparation and their use as medicaments, in particular as antiviral medicaments.

The synthesis publication J. Org. Chem. 1988, 53, 2047-2052 discloses bromoindolinyl urea derivatives.

US-A-4,428,881 discloses indolyl (alkyl) urea derivatives as herbicides.

WO97 / 24343 relates to phenylthiazole derivatives with anti-Heφes virus properties.

WO99 / 42455 also relates to phenylthiazole derivatives with anti-Heφes virus

Characteristics.

WO 99/47507 relates to 1,3,4-thiadiazole derivatives with anti-Heφes virus properties.

The object of the present invention is to provide new compounds which can serve as medicaments, preferably as antiviral agents.

The present invention relates to compounds of the general formula (I)

woπn - is a single or a double bond,

D is N or CH,

R ^{1 is} hydrogen or (-CC ₆ ) alkyl,

R ^{2 is} hydrogen or (dC ₆ ) alkyl,

R ^{3 represents} phenyl, which may optionally be substituted by one to two substituents selected from the group consisting of halogen, (C ₆ -Cιo) aryl, which may optionally be substituted by one to three substituents, from be selected from the group consisting of (-C-C _ό ) alkoxy carbonyl, halogen, (Cι-C ₆ ) alkyl, (Cι-C ₆ ) alkoxy, nitro, halogen (Cι- C ₆ ) alkyl and cyano , _(Cι-C6) alkanoyl, (C, -C ₆₎ alkoxy, (C, -C ₆₎ oxycarbonyl alk-, _(Cι-C6) alkylthio, hydroxyl, carboxyl, partially fluorinated _(Ci-C6) alkoxy with up to 6 fluorine atoms, (-CC ₆ ) -alkyl, which can optionally be substituted by 1 to 3 halogen atoms, a 5- to 6-membered aromatic heterocycle with 1 to 4 heteroatoms from the series, optionally bonded via a nitrogen atom S, N and O, which can optionally be substituted by 1 to 3 halogen atoms, a 3- to 8-membered saturated or unsaturated bond which is optionally bonded via a nitrogen atom saturated non-aromatic heterocycle with up to three heteroatoms from the series S, N and O, optionally with 1 to 3 substituents selected from oxo, halogen, hydroxy, (-C-C ₆ ) alkoxycarbonyl,

(-C-C _ö ) alkyl, halogen (-C-C ₆ ) alkyl and hydroxy (-C-C ₆ ) alkyl may be substituted, and groups of the formulas -OR ⁶ , -NR ⁷ R ⁸ and -CO-NR ⁹ R ¹⁰ , in which R ^{6 is} phenyl, optionally with 1 to 3 substituents selected from the group consisting of halogen,

(-CC ₆ ) alkoxy and (-C-C _ö ) alkyl may be substituted. R 'and R ^{8 are the} same or different and are hydrogen, (-CC ₆ ) alkyl, (-C-C _ό ) alkanoyl, and

R ⁹ and R ^{10 are the} same or different and are hydrogen or (-CC ₆ ) - alkyl, or

R ³ is _(Cι-C6) alkyl, which is substituted by (C ₆ -Cι ₀₎ aryl, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, (C] -C ₆ ) alkoxy, trifluoromethyl and phenyl, or

R ^{3 is} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 heteroatoms from the series S, N and O, or

R is a group of the following formula,

R ^{4 is} hydrogen, (-C ₆ ) alkyl or (C ₆ -Cιo) aryl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen. Amino, mono- or di (-CC ₆ ) - alkylamino, (-C-C ₆ ) alkoxy, triazolyl, furyl, tetrahydrofuryl, (C ₃ -C ₆ ) cycloalkyl, pyrrolidino. optionally dinyl with _(Cι-C6) alkyl substituted pyrrolidine, Moφholino, pyridyl, trifluoromethyl, _(Cι-C6) alkoxy-carbonylamino and phenyl, or (C ₃ -C _ö) cycloalkyl,

R ^{5 is} hydrogen (-C-C _h ) alkyl. or R ⁴ and R ⁵ together form a (C ₂ -C) alkanedyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-ghedπgen ring, in which a methylene group can optionally be replaced by O or N - R ^u , woπn R ^{11 is} hydrogen, (C ₁ -C ₆ ) alkyl, which may optionally be substituted with ammo, mono (C ₆ C) alkylamιno or D (C ₆ C) alkylamιno, (C ₆ C) alkanoyl, (-C-C _ö ) alkoxycarbonyl, pyπdyl or pyπmidmyl,

and their pharmaceutically contractual salts

Physiologically acceptable, pharmaceutically acceptable salts of the compounds according to the invention can, depending on the functional group which they contain, be salts of the substances according to the invention with acids or bases

Salts of the substances according to the invention with acids can be salts with mineral acids,

Be carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, benzene acid, malic acid, malonic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid

Salts of the substances according to the invention with bases which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine ,

Tπethvlamin. Eihyldnsopropylamm, procaine, dibenzylamine, N-Methylmoφhohn, dihydroabietylamine, 1-Ephenamιn or methyl-pipeπdin

Depending on the substitution pattern, the compounds according to the invention can be converted into stereoisomeric forms which are either like images and mirror images

(Enantiomers), or which do not behave like image and mirror image (diastereomers) hold, exist. The invention relates both to the enantiomers or diastereomers or to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

The scope of the invention also includes those compounds which are only converted into the actual active compounds of the formula (I) in the body (so-called produgs).

The notation of formula (I) of the compounds of the invention

means in the context of the present description that the sulfonyl group binds to the 5- or 6-position, as indicated above.

(CrC ₆ ) -alkyl represents a straight-chain or branched alkyl radical with 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, tert-butyl, n-pentyl and n-hexyl. Particularly preferred is a straight-chain or branched alkyl radical having 1 to 3 carbon atoms ((C _\ - C ₃₎ alkyl).

Halogen (-C-C ₍ ,) - alkyl represents a (-C-C ₆ ) alkyl group, which can be as defined above, and which has 1 to 3 halogen atoms, namely F, Cl, Br and / or I, preferably chlorine or Fluorine, as a substituent, for example, trifluoromethyl, Fluoπnethvl etc. Hydroxy (-C-C ₆ ) alkyl represents a (-C-C ₆ ) alkyl group, which can be as defined above, and which has 1 to 3 hydroxyl groups as substituents, for example hydroxymethyl etc.

(-C-C ₆ ) alkoxy represents a straight-chain or branched alkoxy radical with 1 to

6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms (-C-C) 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-C) is particularly preferred.

Partially fluorinated (Ci-Cβ alkoxy with up to 6 fluorine atoms stands for a straight-chain or branched alkoxy radical with 1 to 6 carbon atoms, which can be substituted with 1 to 6, preferably 1 to 4, more preferably 1 to 3, fluorine atoms. A straight-chain is preferred or branched alkoxy radical having 1 to 4 carbon atoms and 1 to 4 fluorine atoms, for example: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy, each having one to 4 fluorine atoms, particularly preferred are (1,3-difluoroprop-2-yl) oxy and 1,1,2,2-tetrafluoroethoxy.

(CrC _ό VAlkylthio stands for a straight-chain or branched alkyl residue with 1 to 6 carbon atoms. A straight-chain or branched alkylthio residue with 1 to 4 carbon atoms (Cι-C) 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 ₆ ) alkoxycarbonyl stands for 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-C) is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso- propoxycarbonyl and tert.butoxycarbonyl. A straight-chain or branched alkoxycarbonyl radical having 1 to 3 carbon atoms (C 1 -C ₃ ) is particularly preferred.

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

(Ci-C _ά VAlkanoyl in the context of the invention represents a straight-chain or branched alkanoyl radical having 1 to 6 carbon atoms. Examples include: formyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. A straight-chain or is preferred branched acyl radical having 1 to 4 carbon atoms, particularly preferred are acetyl and ethylcarbonyl.

In the context of the invention, (C -C ₈ ) -cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. May be mentioned:

Cyclopropyl, cyclopentyl and cyclohexyl.

Halogen in the context of the invention generally represents fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.

A 5- to 6-membered aromatic heterocycle with up to 4 heteroatoms from the series S, O and / or N is, for example, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, N-triazolyl, tetrazolyl, oxazolyl or imidazolyl. Pyridyl, furyl and N-triazolyl are preferred. The heterocycle can optionally be bound via a nitrogen atom (for example in the case of pyrrole). In the meaning of R ^{3 it can} optionally be substituted by 1 to 3 halogen atoms.

A 3- to 8-membered or unsaturated, non-aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the S, N and / or O series includes, for example, 5- to 5 within the scope of the invention 6-membered saturated heterocycles bonded via a nitrogen atom, such as Moφholinyl, Piperidinyl, Piperazinyl, Methylpiperazinyl, Thiomoφholinyl or Pyrrolidinyl. Moφholinyl, piperidinyl, pyrrolidinyl and Thiomoφholinyl are particularly preferred. In addition, 3-, 7- and 8-membered heterocycles, such as, for example, aziridines (for example 1-azacyclopropan-l-yl), azetidines (for example 1-azacyclobutan-l-yl) and

Azepines (e.g. 1-azepan-l-yl) included. The unsaturated representatives can contain 1 to 2 double bonds in the ring. The ring can be substituted as indicated above.

A (C ₂ -C) alkanediyl group with the meaning of R and R, which with the

Nitrogen atom to which it is bound forms a 3- to 8-membered ring, in which a methylene group can optionally be replaced by O or NR ¹ ', where R ¹ ' is hydrogen, (-C ₆ ) alkyl, optionally with Amino, mono (-C-C6) alkylamino or di (-C-C ₆ ) alkylamino can be substituted, (Cι-C6) alkanoyl, (Cι-C ₆ ) alkoxycarbonyl, pyridyl or pyrimidinyl, for example, includes the above a nitrogen atom-bound 3- to 8-membered saturated heterocycles, which may be substituted on the nitrogen.

Preferred compounds of the general formula (I) are those in which

D is equal to N.

Compounds of the general formula (F) are also preferred:

woπn DN is

R ^{1 is} hydrogen or (-CC ₆ ) alkyl,

R ^{2 is} hydrogen or (C, -C ₆ ) alkyl,

R ^{3 represents} phenyl, which can optionally be substituted by one or two substituents selected from the group consisting of halogen, (C ₆ -Cιo) aryl, which can optionally be substituted by one to three substituents, which are selected from the group consisting of (C 1 -C ₆ ) alkoxycarbonyl, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, nitro, halogen (C 1 -C ₆ ) alkyl and cyano exists, (-C-C ₆ ) alkanoyl, (dC ₆ ) alkoxy, (C _: -C ₆ ) alkoxycarbonyl, (Cι-C _ö ) alkylthio, hydroxy, carboxy, partially fluorinated (Q- C ₆ ) alkoxy with up to 6 fluorine atoms, (-CC ₆ ) -alkyl, which may optionally be substituted by 1 to 3 halogen atoms, a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 heteroatoms from the series S, N and O, which can optionally be substituted by 1 to 3 halogen atoms, a 3- to 8-membered saturated or unsubstituted or bonded via a nitrogen atom saturated non-aromatic heterocycle with up to three heteroatoms from the series S, N and O, optionally with 1 to 3 substituents selected from oxo, halogen, hydroxy, (-C-C ₆ ) alkoxycarbonyl, (Ci-C ₆ ) alkyl, halo _(Cι-C6) alkyl and hydroxy _(Cι-C6) alkyl may be substituted, and groups of the formulas -OR ^6, -NR ⁷ R ⁸ and -CO-NR ⁹ R ^10, where R ⁶ represents phenyl , which may be optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, _(Cι-C6) alkoxy and (Ci-C _ö lAlkyl,

R ⁷ and R ^{8 are the} same or different and are hydrogen, (C | -C (,) alkyl, (Ci- C _ό ) alkanoyl, and R and R, 10 are identical or different and are hydrogen or (-CC ₆ ) alkyl,

or

R3 ^is (Cι-C _ό) alkyl, which is substituted by (C ₆ -Cιo) -aryl which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, (Cι-C ₆₎ Alkoxy, trifluoromethyl and phenyl,

or

R ^{3 is} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 hetero atoms from the series S, N and O,

or

R is a group of the following formula,

R ^{4 is} hydrogen, (-CC ₆ ) alkyl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of ammo, mono- or di (-CC ₆ ) alkylamιno, (-C-C ₆ ) alkoxy, tπazolyl, furyl, (Ci-C ₆ ) cycloalkyl, pyrrolidino, optionally substituted with (C] -C ₆ ) alkyl substituted pyrrolidinyl, Moφholino, pyridyl, trifluoromethyl, (dC ₆ ) alkoxy-carbonylamino and phenyl, or (C ₃ -C ₆ ) cycloalkyl,

R ^{5 is} hydrogen, (-CC ₆ ) alkyl, or R ⁴ and R ⁵ together form a (C ₂ -C ₇ ) alkanediyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-membered ring in which a methylene group can optionally be replaced by O or NR ^{1 1} , in which R ^{u is} hydrogen, (-CC ₆ ) alkyl, which may optionally be substituted with amino, mono (-C ₆ ) alkylamino or di (dC ₆ ) alkylamino, (C] -C6) alkanoyl, (-C ₆ ) alkoxycarbonyl, pyridyl or pyrimidinyl,

and their pharmaceutically acceptable salts.

Compounds of the general formula (I) are also preferred,

woπn

- ~ is a single or a double bond,

D is CH

R ^{1 is} hydrogen or (-CC ₆ ) alkyl,

R ^{2 is} hydrogen or (C, -C ₆ ) alkyl,

R ³ represents phenyl which may be optionally substituted with one to two substituents selected from the group consisting of halogen, (C ₆ -C _ö) aryl which may be optionally substituted by one to three substituents can be selected from the group consisting of (-C ₆ ) alkoxycarbonyl, halogen, (C ₆ ) alkyl, (C ₆ ) alkoxy. Nitro, halogen, alkyl and cyano (Cι-C _{6), (Cι-C6)} alkanoyl, (C) -C ₆₎ alkoxy, (Ci- C ₆₎ alkoxycarbonyl, _(Cι-C6) alkylthio, hydroxy, Carboxy, partially fluorinated (-C-C _ö ) alkoxy with up to 6 fluorine atoms, (-C-C ₆ ) alkyl, which can optionally be substituted by 1 to 3 halogen atoms, a given If necessary, a 5- to 6-membered aromatic heterocycle with 1 to 4 heteroatoms from the series S, N and O which is bonded via a nitrogen atom and which can optionally be substituted by 1 to 3 halogen atoms, and a 3- to 8-membered bond which is optionally bonded via a nitrogen atom saturated or unsaturated non-aromatic heterocycle with up to three heteroatoms from the series S, N and O, optionally with 1 to 3 substituents selected from oxo, halogen, hydroxy, (-C-C ₆ ) -alkoxycarbonyl, (Cι-C ₆ ) alkyl, halo _(Cι-C6) alkyl and hydroxy _(Cι-C6) alkyl may be substituted, and groups of the formulas -OR ^6, -NR ⁷ R ⁸ and -CO-NR ⁹ R ^10, where R ⁶ Phenyl means, which can optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, (-C-C _ό ) alkoxy and (Cι-C ₆ ) alkyl,

R ⁷ and R ^{8 are the} same or different and are hydrogen, (-CC ₆ ) alkyl, (Q-

C ₆ ) are alkanoyl, and

R ⁹ and R ^{10 are the} same or different and are hydrogen or (-CC ₆ ) alkyl,

or

R3 ^is (Cι-C _ö) alkyl, which is substituted by (C ₆ -Cι ₀₎ aryl, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, (Cι-C ₆ ) There is alkoxy, trifluoromethyl and phenyl,

or

R ^{3 is} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 hetero atoms from the series S, N and O, or

R is a group of the following formula,

R is hydrogen, (-CC ₆ ) alkyl or (C ₆ -C -o) aryl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, ammo, mono- or di (Cι -C ₆ ) alkylamιno, (Cι-C _ö ) alkoxy, Tπazolyl, furyl, tetrahydrofuryl, (C ₃ -C ₆ ) cycloalkyl, pyrrodmo, optionally substituted with (Cι-C ₆ ) alkyl pyrrolidinyl, Moφholomo, Pyπdyl , _(Cι-C6) Alkoxycarbonylamιno and phenyl, trifluoromethyl, or (C ₃ -C ₆₎ cycloalkyl,

R ^{5 is} hydrogen, (-CC ₆ ) alkyl, or

R ⁴ and R ⁵ together form a (C ₂ -C ₇ ) alkanedyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-ghedπgen ring, in which a methylene group can optionally be replaced by O or N. - R ¹¹ , where R ^{1 1 is} hydrogen, (C ¹ -C ₆ ) alkyl, which can optionally be substituted with amino, mono (C ₁ -C ₆ ) alkylamιno or D (C ₁ -C ₆ ) alkylammo,

(-C ₆ ) alkanoyl, (-C ₆ ) alkoxycarbonyl, pyπdyl or pyπmidinyl,

and their pharmaceutically contractual salts

Compounds of the general formula (I) are also preferred,

woπn

- is a single bond. D is CH

R ^{1 is} (C, -C ₆ ) alkyl.

R ^{2 is} hydrogen

R ^{3 represents} phenyl, which may optionally be substituted by a substituent selected from the group consisting of (C ₆ -Cιo) aryl and (Ci- C ₆ ) alkoxycarbonyl,

R ⁴ is hydrogen, _(Cι-C6) alkyl or (C ₆ -Cι ₀₎ aryl, which may be optionally substituted by a substituent which is selected from the group consisting of _(Cι-C6) alkoxy, and tetrahydrofuryl , or (C ₃ - C ₆ ) cycloalkyl,

R ^{5 is} hydrogen, or

R ⁴ and R ⁵ together form a (C ₂ -C ₇ ) alkanedyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-ghedπgen ring in which a methylene group is replaced by NR ¹ ' , where R is hydrogen or (-CC ₆ ) alkyl,

and their pharmaceutically contractual salts

Compounds of the general formula (I) or (F) which have the following structure are also preferred

wherein the substituents have the meaning given above, and their pharmaceutically acceptable salts.

Also preferred are the general formula (I) or (F), which have the following structure:

wherein the substituents have the meaning given above, and their pharmaceutically acceptable salts.

In a further preferred embodiment, the compounds of the general formula (I) for R ^{1 are} hydrogen or methyl.

In a further preferred embodiment, the compounds of the general formula (I) according to claim for R ^{3 have} hydrogen or methyl. In a further preferred embodiment, the compounds of the formula (I) for R ^{4 have} methyl, methoxyethyl, triazolylethyl, benzyl, cyclopropyl, furylmethyl, cyclopropylmethyl or sec-butyl.

In a further preferred embodiment, the compounds of the general formula (I) according to claim for R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded have Moφholino.

Also preferred are compounds of the above general formula (I), wherein

D is N or CH,

R ^{1 is} hydrogen or (-CC ₃ ) alkyl,

R ^{2 is} hydrogen or (C, -C ₃ ) alkyl,

R ^{3 represents} phenyl which may optionally be substituted with one to two substituents selected from the group consisting of halogen, phenyl which may optionally be substituted with one to three substituents selected from the group consisting of (-C-C ₄ ) alkoxycarbonyl, halogen, (-C-C ₃ ) -alkyl, (dC ₃ ) alkoxy, nitro, halogen (Cι-C ₃ ) alkyl and cyano, (Cι-C ₃ ) alkanoyl, ( dC ₄ ) alkoxy, (Cι-C) alkoxycarbonyl, (Cι-C ₃ ) alkylfhio, hydroxy, carboxy, partially fluorinated (C _\ - C ₃ ) alkoxy with up to 6 fluorine atoms, (Cι-C ₃ ) alkyl, if necessary by

1 to 3 halogen atoms can be substituted, a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with 1 to 4 heteroatoms from the series S, N and O, which can optionally be substituted by 1 to 3 halogen atoms, optionally via one a nitrogen atom-bound 3- to 8-membered saturated or unsaturated non-aromatic heterocycle with up to three heteroatoms from the series S, N and O, optionally by 1 to 3 substituents, selected from oxo, halogen, hydroxy, (-C-C ₄ ) alkoxycarbonyl, (-C-C ₃ ) alkyl, halogen (-C-C ₃ ) alkyl and hydroxy (Cj-C ₃ ) alkyl may be substituted, and groups of the formulas -OR ⁶ , -NR ⁷ R ⁸ and -CO-NR ⁹ R ¹⁰ , wherein R ^{6 is} phenyl, optionally selected from 1 to 3 substituents the group consisting of halogen, (C ₁ -C ₃ ) alkoxy and (C ₁ -C ₃ ) alkyl may be substituted,

R ⁷ and R ^{8 are the} same or different and are hydrogen, (-CC ₃ ) alkyl, (-C-C ₃ ) alkanoyl, and

R ⁹ and R ^{10 are the} same or different and are hydrogen or (d-C ₃ ) alkyl, or

R ^{3 is} (C ₁ -C ₃ ) alkyl which is substituted by phenyl, which may optionally be substituted by 1 to 3 substituents, selected from the group consisting of halogen, (C 1 -C) alkoxy, trifluoromethyl and phenyl, or

R ^{3 is} (C ₁ -C ₃ ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 heteroatoms from the series S, N and O, or

R ^{J is} a group of the following formula

R ^{4 is} hydrogen, (-CC) alkyl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of amino, Mono- or di (-C-C ₃ ) alkylamino, (Cι-C ₃ ) alkoxy, triazolyl, furyl, (C ₃ - C _ö ) cycloalkyl, pyrrolidino, optionally substituted with (Cι-C) alkyl pyrrolidinyl, Moφholino, pyridyl, Trifluoromethyl, (-CC ₄ ) alkoxy-carbonylamino and phenyl, or (C ₃ -C ₆ ) cycloalkyl,

R ^{5 is} hydrogen, (-CC ₃ ) alkyl, or

R ⁴ and R ⁵ together form a (C ₂ -C 7) alkanediyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-membered ring in which a methylene group can optionally be replaced by O or N -

R ¹¹ , in which R ^{1 1 is} hydrogen, (C ¹ -C ₃ ) alkyl, which may optionally be substituted by amino, mono (C ₁ -C ₃ ) alkylamino or di (C ₁ -C ₃ ) alkylamino, (C] -C ₃ ) Alkanoyl, (-C-C ₃ ) alkoxycarbonyl, pyridyl or pyrimidinyl,

and their pharmaceutically acceptable salts.

The invention further relates to processes for the preparation of the compounds of formula (I).

In process (A), compounds of the general formula (II) are used

wherein ---, R ¹ , R ⁴ and R ^{5 have} the meaning given above,

with compounds of the general formula (III)

R -NCO (III) in which R ^{3 has} the meaning given above, to give compounds of the general formula (Ia):

wherein ~, R, R, R and R have the meaning given above.

The reaction is preferably carried out in a solvent such as e.g. Ethyl acetate, dioxane, dichloroethane performed.

The reaction is preferably in a temperature range from room temperature to

Reflux of the solvent was carried out at normal pressure.

The reaction is preferably carried out at normal pressure.

For working up the reaction mixtures, aminomethylpolystyrene resins are preferably used as scavenger reagents to trap the excess reactants.

In process (B), compounds of the general formula (IV) are used

wherein ---, R, R and R ^{3 have} the meaning given above, and X is halogen, such as chlorine. with compounds of the general formula (V) HNR ² R ³ (V)

to compounds of the general formula (I), where D is equal to N.

The reaction is preferably carried out in a solvent such as, for example, dioxane, tetrahydrofuran

The reaction is preferably carried out in a temperature range from room temperature to reflux of the solvents at normal pressure

The reaction is preferably carried out at normal pressure

The reaction is preferably carried out in the presence of a base such as, for example, Tπ (C ₆ -C ₆ ) alkylamine, such as Tπethylamine

For working up the reaction mixtures, ammomethylpolystyrene resins and / or methylsocyanate polystyrene resins are preferably used as scavenger reagents to trap the excess reactants

In process (C), compounds of the general formula (II) are used

wherein ™, R ¹ , R ⁴ and R ^{5 have} the meaning given above,

with compounds of the general formula (VI)

R ² R ³ CHCOY (VI) where Y is an electronegative group such as halogen, for example chlorine, or the free acid is used in the presence of a coupling reagent, for example HOBt (N-hydroxybenzotriazole) and EDCI (l-ethyl-3- (3'-dimethylaminopropyl) carbodiimideΗCl), and in which R ² and R ^{3 have} the meaning given above, to give compounds of the general formula (Ia):

wherein -, R, R ² , R, R and R ^{D have} the meaning given above.

The reaction is preferably carried out in a solvent such as e.g. Tetrahydrofuran, dioxane, dichloroethane performed.

The reaction is preferably carried out in a temperature range from room temperature to reflux of the solvents at atmospheric pressure.

The reaction is preferably carried out at normal pressure.

The reaction is preferably carried out in the presence of a base, e.g. N, N-diisopropylethylamine.

The invention further relates to intermediates of formula (IV):

which are manufactured as described below. The methods for making the compounds of the invention are illustrated by the following synthetic schemes.

Synthesis scheme 1:

AC _j O, AcOH

Synthesis scheme 2:

Synthesis scheme 3:

R ³ NCO

The starting compounds used in these synthetic schemes are either known from the literature or are prepared as described in the examples.

The compounds of general formulas (I) according to the invention show an unpredictable surprising spectrum of action. They show an antiviral activity against representatives of the Heφes viridae group, especially against the Heφes simplex virus (HSV). They are therefore suitable for the treatment and prophylaxis of diseases which are caused by Heφes viruses, in particular diseases which are caused by Heφes simplex viruses. The invention further relates to the use of 6- (aminosulfonyl) -l-indolinecarboxamide derivatives or 6- (aminosulfonyl) -IH-indole-1-carboxamide derivatives for the production of medicaments, preferably for the production of medicaments for the treatment and or prevention of Heφes Infections in humans or animals. 6- (aminosulfonyl) -l-indolinecarboxamide derivatives or 6- (aminosulfonyl) -lH-indole-l-carboxamide derivatives in this context means those compounds which are substituted by at least one hydrogen atom from 6- (aminosulfonyl) - 1 - indoline carboxamide or ό- (aminosulfonyl) - 1H-indole-1 - carboxamide emerge.

In vitro activity

Viruses and cells:

HSV (HSV-1 walki, HSV-1F or HSV-2G) was tested on Vero cells (ATCC CCL-

81) propagated under the following conditions: The cells were 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% CO2. 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 incubated at a density of 4x10 ³ 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 "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 (300g, 10min, 4 ° C) and the supernatant was frozen away in aliquots at -80 ° C.

The virus titer was determined using a plaque assay. For this Vero cells with a density of 4xl0 ³ cells per well were sown in 24 well plates and after 24 Hours of incubation (37 ° C, 5% CO ₂ ) with dilutions of the virus stock from 10 ^"2 to 10 ^{" 12} (100 μl inoculum) infected 1 hour after infection, the medium was removed and the cells were coated with 1 ml overlay medium (0 5% Methylcellulose, 0 225 sodium bicarbonate, 2mM glutamine, 100 IU / ml penicillin, 100μg / ml streptomycin, 5% fetal calf serum in MEM-Eagle medium with Earl's salt) and coated for 3 days Fixed 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 lxl0 ⁶ / ml - lxl0 ⁸ / ml

The anti-HSV effect was determined in a screening test system in 96-well microplates with the help of various cells of neuronal, lymphoid and epithal origin, such as Vero (kidney tame of the green sea cat), MEF (male embryonic fibroblasts) , HELP (human embryonic fibroblasts), NT2 (human neuronal cell) or Jurkat (human lymphoid T-cell elms) were determined. The influence of the substances on the spread of the cytopathogenic effect was compared to the reference substance Acyclovir-Natπum (Zovιrax ^R ), a clinically approved anti-Heφes chemotherapy drug.

The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are measured on microplates (e.g. 96-well MTP) in final concentrations of 250 - 0.5 μM (micromolar) and 250 - 0.5 nM (nanomolar) in duplicate determinations (4th Substances / plate) examined Toxic and cytostatic substance effects are also recorded. After the corresponding substance dilutions (1 2) on the microtiter plate, a suspension of cells (1x10 cells per well) such as Vero cells in MI 99 (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 / 1 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 in each well and the cells in the relevant wells infected with a corresponding amount of virus (HSN-1 F or HSV-2 G with a moi (multiplicity of infection) of 0.0025 for HELF, Vero and MEF cells and a moi of 0.1 for ΝT2 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, for example, Vero cells is in the substance-free virus controls, starting from 25 infectious ones

Centers, completely lysed or destroyed by the cytopathogenic 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 aspirated again and all wells with 200 μl

Fluorescent dye solution (fluorescein diacetate, 10 μg / ml in PBS) filled. 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 for some compounds are summarized in the following table:

table

Example IC ₅₀ HSV-1 F / Vero IC ₅₀ HSV-2 G Vero

77 3 µM 3 µM

59 0.4 µM 0.75 µM

1 25 nM 40 nM

52 15 nM 100 nM

Zovirax 1 μM 3 μM

(Aciclovir-Natπum)

IC ₅₀ here means the half-maximum fluorescence intensity with reference to the non-infected cell control

The 6- (aminosulfonyl) -l-indon carboxamid derivatives or 6- (aminosulfonyl) -lH-mdol-1-carboxamid derivatives of the invention preferably have an IC ₅₀ (HSV-

1 F Vero) of 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 human Heφes virus, in particular Heφes simplex virus (HSV). Indications can be mentioned, for example

1) Treatment and prophylaxis of Heφes infections, especially HSV infections in patients with clinical pictures such as Heφes labiahs, Heφes genitahs, and HSV-related keratitis, encephalitis. Pneumomas, hepatitis etc

2) Treatment and prophylaxis of Heφes infections, in particular HSV infections in immunosuppressed patients (eg AIDS patients, Cancer patients, patients with genetic immunodeficiencies, transplant patients)

3) Treatment and prophylaxis of Heφes infections, especially HSV infections in newborns and young children

4) Treatment and prophylaxis of Heφes infections, especially HSV infections and HSV-positive patients to suppress recurrence (suppression therapy)

In vivo effect

Animals:

6-week-old female mice, strain BALB / cABom, were obtained from a commercial breeder (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 due to 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 treated with doses of 1-100 mg / kg body mass 3 times a day at 7:00 a.m., 2:00 p.m. and 7:00 p.m. over a period of 5 days. The substances were pre-dissolved in DMSO and resuspended in Tylose / PBS (Hoechst) (final concentration 1.5% DMSO, 0.5% Tylose in PBS). After the last application, the animals were observed further and the times of death determined.

For example, animals treated with Example 1 or Example 2 in the Lethal Challenge model (60 mg / kg, p.o., t.i.d., d0-d4 p.i.) showed an increased survival rate compared to animals treated with placebo.

The new active compounds can be converted into the customary formulations in a known manner, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients and solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.

The application is carried out in the usual way, preferably orally, parenterally or topically, in particular 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

To administer amounts of about 0.001 to 20 mg / kg, preferably about 0.01 to 10 mg / kg body weight for effective results, and oral Application is about 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of route of administration, on the individual behavior towards the drug, the type of its formulation and the time or interval at which the administration takes place . In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

It may make sense to combine the compounds according to the invention with other active ingredients.

Examples of starting compounds:

Output connection example 1:

l-acetyl-2-methyl-6-indoline sulfonyl chloride

The compound is prepared in analogy to literature P.R. Carlier, M.P. Lockshin, M.P. Filosa, J Org. Chem. 1994, 59, 3232-3236.

Output connection example 2:

N-FormyI-2-methyl-5-chlorosulfonyl-indoline

The connection is made in analogy to literature PR Carlier, MP Lockshin, MP Filosa, J. Org. Chem. 1994, 59, 3232-3236. Output connection example 3:

N, 2-DimethyI-6-indoline sulfonamide

1.19 ml of a 40% solution of methylamine in water are added dropwise to a solution of 0.500 g (1.46 mmol) of l-acetyl-2-methyl-6-mdohnsulfonylchloride in 9 ml of methylene chloride after room temperature. After stirring overnight at room temperature Diluted with 5 ml methylene chloride, the organic phase separated and washed successively with water, 1N hydrochloric acid and saturated sodium chloride solution. After drying the organic phase with sodium sulfate, the solvent is removed in vacuo.

The product is dissolved in 2.50 ml of methanolic HCl solution without further purification and heated under reflux overnight. The mixture is concentrated in vacuo, then saturated sodium bicarbonate solution is added and the mixture is stirred with ethyl acetate. After washing with water, the organic phase is dried with sodium sulfate. The solvent is removed in vacuo and the product is dried in a high vacuum. 0.282 g (85%) of a red oil is obtained.

LC (Liquid Chromatography) -MS (Mass Spectroscopy) (method. SMKL-Nl). Retention time: 2.48

MS (ESI) - 453 (2Mz + H), 268 (Mz + H + ACN), 227 (Mz + H). Output connection example 4:

N- (2-methoxyethyl) -2-methyl-6-indoinsuifonamide

0.19 ml (2.19 mmol) of 2-methoxyethylamine are added dropwise at room temperature to a solution of 0.500 g (1.46 mmol) of l-acetyl-2-methyl-6-indolinesulfonyl chloride in 9 ml of methylene chloride. After stirring overnight at room temperature, the organic phase is washed successively with water, 1N hydrochloric acid and saturated sodium chloride solution. After drying the organic phase with sodium sulfate, the solvent is removed in vacuo.

The product is dissolved in 2.50 ml of methanolic HCl solution without further purification and heated under reflux overnight. The mixture is concentrated in vacuo, then saturated sodium bicarbonate solution is added and the mixture is stirred with ethyl acetate. After washing with water, the organic phase is dried with sodium sulfate. The solvent is removed in vacuo and the product is dried in a high vacuum. 0.276 g (70%) of a red oil is obtained. LC-MS (method: SMKL-Nl): retention time: 2.73

MS (ESI): 541 (2Mz + H), 312 (Mz + H + ACN), 271 (Mz + H). Output connection example 5:

2-methyl-6 - [(methylamino) sulfonyl] -l-indoline carbonyl chloride

To a solution of 0.300 g (1.33 mmol) of N, 2-dimethyl-6-indolinesulfonamide in 5 ml of tetrahydrofuran are added 0.19 ml (0.795 mmol) of trichloimethyl chloroformate at room temperature. After stirring overnight at room temperature, the solvent is removed in vacuo and the product is dried in a high vacuum. 0.243 g (63%) of product is obtained.

Output connection example 6:

6 - {[(2-methoxyethyl) amino] sulfonyl} -2-methyl-l-indoline carbonyl chloride

8.03 ml (33.3 mmol) of trichloromethyl chloroformate are added to a solution of 15.0 g (55.5 mmol) of N- (2-methoxyethyl) -2-methyl-6-indoline-sulfonamide in 100 ml of tetrahydrofuran at room temperature. After stirring overnight at room temperature, the solvent is removed in vacuo and the product is dried in a high vacuum. 1.18 g (64%) of product are obtained. Output connection example 7:

l-acetyl-6-indoline sulfonyl chloride

The compound is prepared in analogy to literature P.R. Carlier, M.P. Lockshin, M.P. Filosa, J Org. Chem. 1994, 59, 3232-3236.

Output connection example 8:

N, N-dimethyl-6-indoline sulfonamide

To a solution of 14.2 g (54.7 mmol) of l-acetyl-6-indolinesulfonyl chloride in 50 ml

Methylene chloride 30 ml of a 40% solution of dimethylamine in water are added dropwise at room temperature. After stirring overnight at room temperature, the organic phase is separated off and washed successively with water, 1N hydrochloric acid and saturated sodium chloride solution. After drying the organic phase with sodium sulfate, the solvent is removed in vacuo. A solid is obtained.

The product is dissolved in 100 ml of methanolic HC1 solution without further purification and stirred overnight at room temperature. The solution is then heated under reflux for 8 h. The mixture is concentrated in vacuo, then saturated sodium bicarbonate solution is added and the mixture is stirred with ethyl acetate. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried with sodium sulfate. The solvent is removed in vacuo and the product is dried in a high vacuum. 7.73 g (62%) of a solid are obtained. MS (DCI): 453 (2Mz + H), 244 (Mz + NH4), 227 (Mz + H).

ΙH-NMR (DMSO): 7.20 (d, J = 7Hz, 1H), 6.85 (dd, 3 = 1.1 Hz, 1H), 6.72 (d, J = lHz, 1H), 5.97 (s, 1H), 3.50 (t, J = 7Hz, 2H), 3.00 (t, J = 7Hz, 2H), 2.57 (s, 6H).

Output connection example 9:

N, N-Dimethvl-6-indolesulfonamide

4.82 g (21.2 mmol) of 2,3-dichloro-5,6-dicyan-p-benzoquinone are added to a solution of 3.20 g (14.1 mmol) of N, N-dimethyl-6-indolinesulfonamide in 100 ml of dioxane. The solution is refluxed overnight. The solvent is then removed in vacuo. The crude product is purified on silica gel (mobile phase: cyclohexane / ethyl acetate 2: 1). 2.35 g (74%) of product are obtained as white crystals.

LC-MS (method: SMKL-Nl-lLow Vol HC1): retention time: 3.52 MS (ESI): 449 (2Mz + H), 266 (Mz + H + ACN), 225 (Mz + H). Examples

example 1

2-Methyl-6 - [(methylamino) sulfonyl] -N- [4- (l-pyrrolidinyl) phenyl] -l-indoline-carboxamide

3.00 g (10.4 mmol) of 2-methyl-6 - [(methylamino) sulfonyl] -l-indoline carbonyl chloride are dissolved in 30 ml of dioxane and at room temperature with 1.85 g (11.4 mmol) of 4-

(l-Pyrrolidinyl) phenylamine and 4.34 ml (31.2 mmol) of triethylamine were added. The solution is refluxed overnight. After concentrating the solution, it is taken up in ethyl acetate, mixed with 10% citric acid solution and stirred. The crystals are suctioned off and it is washed with ethyl acetate. The mother liquor is washed with water, dried and concentrated.

The combined fractions are pre-cleaned on silica gel 60 (mobile phase: toluene-acetone 10: 1, 8: 1, 6: 1, 4: 1, 2: 1). After chromatography on silica gel, the fractions are combined and finely cleaned on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient). 0.831 g (19%) of product is obtained. LC (Liquid Chromatography) -MS (Mass Spectroscopy) (method: SMKL-Nl-lLow

Vol HC1): Retention time: 2.84

MS (EI): 829 (2Mz + H), 415 (Mz + H). ΙH-NMR (DMSO): 8.54 (s, IH), 8.30 (d, J = lHz, IH), 7.46-7.22 (m, 5H), 6.75-6.52 (m, 2H), 4.99-4.78 (m, IH ), 3.45 (dd, J = 10.18Hz, IH), 3.34-3.15 (m, 4H), 2.78 (d, J = 18Hz, IH), 2.40 (d, J = 5Hz, 3H), 2.08-1.85 ( m, 4H). 1.25 (d, J = 7Hz, 3H). Example 2

6 - {[(2-methoxyethyl) amino] sulfonyl} -2-methyl-N- [4- (l-pyrrolidinyl) phenyl] -l-indoline carboxamide

3.86 g (11.6 mmol) 6 - {[(2-methoxyethyl) amino] sulfonyl} -2-methyl-l-indoline-carbonyl chloride are dissolved in 30 ml dioxane and at room temperature with 2.07 g (12.8 mmol) 4- (l- Pyrrolidinyl) phenylamine and 4.85 ml (34.8 mmol) triefhylamine. The solution is refluxed overnight. A solid precipitates, which is filtered off. After concentrating the solution, it is taken up in ethyl acetate and the organic phase is washed with 10% citric acid solution and water. The organic phase is dried and concentrated. The crude product is pre-cleaned on silica gel 60 (mobile phase: toluene-acetone 10: 1, 8: 1, 6: 1, 4: 1). After chromatography on silica gel, the fractions are combined and finely cleaned on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient). 1.88 g (35%) of product are obtained. LC-MS (method: SMKL-NI-III Low Vol HC1): retention time: 2.93 MS (EI): 917 (2Mz + H), 459 (Mz + H).

ΙH-NMR (DMSO): 8.51 (s, IH), 8.30 (d, J = lHz, IH), 7.65 (t. J = 7Hz, IH), 7.42-7.28 (m, 4H), 6.69-6.57 (m , 2H), 4.97-4.78 (m, IH), 3.45 (dd, J = 10.18Hz, IH), 3.35-3.20 (m, 6H), 3.18 (s, 3H), 2.88 (q, J = 7Hz, 2H), 2.77 (d, J = 18Hz, IH), 2.05-1.90 (m, 4H), 1.25 (d, J = 7Hz, 3H). Example 3

N- (4-Ethoxyphenyl) -6 - {[(2-methoxyethyl) amino) sulfonyl} -2-methyl-l-indoline carboxate nid

5.00 g (18.5 mmol) of N- (2-methoxyethyl) -2-methyl-6-indoline sulfonamide are placed in 25 ml of ethyl acetate. 4.53 g (27.7 mmol) of 4-ethoxyphenyl isocyanate in 20 ml of ethyl acetate are added dropwise at room temperature. The solution is stirred overnight at room temperature. The organic phase is washed with water, 10% citric acid solution and saturated sodium chloride solution, dried and concentrated. The crude product is pre-cleaned on silica gel 60 (mobile phase: toluene-acetone 10: 1, 3: 1). After chromatography on silica gel, the fractions are combined and finely cleaned on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient). 1.57 g (20%>) of product are obtained.

LC-MS (method: SMKL-Nl-lLow Vol HC1): retention time: 3.98

MS (EI): 867 (2Mz + H), 434 (Mz + H). ΙH-NMR (DMSO): 8.60 (s, IH), 8.30 (d, J = lHz, IH), 7.65 (t, J = 7Hz, IH), 7.46-7.32 (m, 4H), 6.92-6.82 (m , 2H), 4.98-4.79 (m, IH), 4.00 (q, J-7Hz, 2H), 3.45 (dd, J = 10.18Hz, IH), 3.30 (t, J = 7Hz, 2H), 3.18 ( s, 3H), 2.88 (q, J = 7Hz, 2H), 2.78 (d,

J = 18Hz, IH), 1.32 (t, J = 7Hz, 3H), 1.25 (d, J = 7Hz, 3H).

Example 18

N- [1, 1 '-Biphenyl] -4-yl-2-methyl-6 - [(methylamino) sulfonyl] -1-indoline carboxamide

0.050 g (0.221 mmol) of N, 2-dimethyl-6-indolinesulfonamide are placed in 2 ml of ethyl acetate. 0.065 g (0.331 mmol) of [l, l'-biphenyl] -4-yl isocyanate are added at room temperature. The solution is stirred overnight at room temperature. Crystals fall out. The crystals are filtered off and washed with ether. 0.067 g (72%) of product is obtained. LC-MS (method: SMKL-Nl): retention time: 4.65

MS (ESI): 843 (2Mz + H), 422 (Mz + H). ΙH-NMR (DMSO): 8.85 (s, IH), 8.35 (s, IH), 7.75-7.32 (m, 12H), 5.08-4.89 (m, IH), 3.50 (dd, J = 10.18Hz, IH ), 2.81 (d, J = 18Hz, IH), 2.41 (d, J = 7Hz, 3H), 1.28 (d, J = 7Hz, 3H).

Example 82

N- [1, 1 '-Biphenyl] -4-yl-6 - [(dimethylamino) sulfonyl] -1-indole carboxamide

350 mg (1.56 mmol) of N, N-dimethyl-6-indolesulfonamide are dissolved in 15 ml of dichloroethane, and 356 mg (2.34 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene are added at room temperature and then 1 h heated to 75 ° C. The solution is cooled and 457 mg (2.34 mmol) of biphenyl isocyanate in 10 ml of dichloroethane are added dropwise. The solution is heated to 70 ° C overnight. The mixture is cooled and diluted with water and ethyl acetate. The crystals are filtered off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried with sodium sulfate and then the solvent is removed in vacuo. After concentration, the crystals are combined and purified on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient). 318 mg (48%) of product are obtained.

LC-MS (method: SMKL-NI-III Low Vol HC1): retention time: 4.97 MS (ESI): 839 (2Mz + H), 461 (Mz + H + ACN), 420 (Mz + H). General work regulations:

In the following, general working prescriptions for the production of the end products (general working prescriptions B, D) and for the production of the intermediate products (general working prescriptions A, C to F) are given

General working procedure A

Reaction of l-AcetyI-2- (R) -6-indolinesulfonyl chloride with secondary and primary amines (HNR ⁴ R ⁵ ) and subsequent cleavage of the acyl protecting group

To a solution of 1 46 mmol l-acetyl-2- (R ¹ ) -6-ιndohnsulfonylchloπd in 10 ml methylene chloride 2 19 mmol of a secondary or pπmaren Amms (HNR ⁴ R ⁵ ) are added dropwise after stirring overnight at room temperature the organic phase is separated off and washed successively with water, 1N hydrochloric acid and saturated sodium chloride solution. After drying the organic phase with sodium sulfate, the solvent is removed in vacuo

The crude product is dissolved in 2 50 ml of methanolic HCl solution and 5-16 hrs

The mixture is concentrated in vacuo, then saturated sodium bicarbonate solution is added and the mixture is stirred with ethyl acetate. After washing with water, the organic phase is dried with sodium sulfate. The solvent is removed in vacuo and the product is dried under high vacuum. Red oils are obtained (hereinafter referred to as without A) General working instruction B:

Reaction with isocyanates (R | 3 -NCO, the general formula III)

0.300 mmol of isocyanate (R ³ -NCO) in 2 ml of ethyl acetate are pipetted into a solution of 0.200 mmol of the indolines A or F prepared in accordance with working instructions A or F in 2 ml of ethyl acetate using an automatic pipetting device (synthesizer) and then pipetted overnight at room temperature at room temperature touched. After adding a spatula tip of aminomethyl polystyrene resin, the mixture is stirred at room temperature for a further 18 h. The mixture is shaken well and filtered through 1.8 g Extreluf ^® / 1.8 g silica gel. It is washed with ethyl acetate. After removing the solvent, the pure product is obtained.

General working instruction C:

Implementation with diphosgene

72 μl (0.299 mmol) of trichloromethyl chloroformate are added to a solution of 0.500 mmol of the indolines A or F prepared in accordance with working instructions A or F in 3 ml of tetrahydrofuran at room temperature. After stirring overnight at room temperature the solvent is removed in vacuo and the product is dried in a high vacuum (hereinafter referred to as indoline C).

General working instructions D:

Reaction with primary and secondary amines (HNR 2 _n R3) x

To a solution of 0.260 mmol primary or secondary amine (HNR ² R ³ ) in 2.0 ml THF, 0.173 mmol triethylamine in

Pipette 0.5 ml THF and 0.173 mmol of the indoline C produced according to general working instructions C into 2.0 ml THF. After stirring overnight at room temperature, a spatula tip of aminomethylpolystyrene resin is added and the mixture is stirred for a further 4 hours at room temperature. Then a spatula tip of methyl isocyanate polystyrene resin is added and the mixture is stirred again overnight at room temperature. The mixture is filtered through 3 g of silica gel. After removing the solvent, the pure product is obtained.

General working instruction E:

Reaction of N-formyl-5-chlorosulfonyl-indoline with secondary and primary amines (HNR Γ R »5)

A solution of 15.4 mmol of N-formyl-5-chlorosulfonyl-indolm in 30 ml of THF is mixed at 0 ° C with 18.5 mmol of triethylamine and 18.5 mmol of pπmarem or secondary amine (HNR ⁴ R ^D ) and stirred overnight at room temperature. The solution is poured onto 150 ml of water / ethyl acetate, the organic phase is separated off and the water phase is extracted twice with ethyl acetate. The combined organic phases are washed with 10% citric acid and saturated sodium chloride solution and dried over sodium sulfate. After removing the solvent, the product is obtained (hereinafter referred to as Indolm E)

General Working Instructions F

Cleavage of the formyl group

16.8 mmol of the indohn E prepared according to the general working procedure E are stirred in 50 ml HC1 saturated methanol overnight at room temperature. The solvent is then removed, the residue is taken up in 150 ml of water / ethyl acetate and the pH is adjusted to 8 using saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the solvent is removed. The product is called indoline F.

The compounds listed in the following table are prepared analogously to the above-mentioned specifications and the examples already mentioned above:

Example 78

Melting point: 124-126 ° C

Example 79

Molecular weight: 407.50

Retention time: 4.43

LC / MS method: SMKL-Nl-lLow Vol HCL

MS (M + H): 408

In the tables, -N- means an -NH group

Example 93

1 - (1, 1 '-Biphenyl-4-ylacetyl) -N, 2-dimethyl-6-indoline sulfonamide

0.300 g (1.33 mmol) of N, 2-dimethyl-6-indolinesulfonamide and 0.367 g (1.59 mmol) of l, l'-biphenyl-4-ylacetyl chloride are dissolved in 10 ml of tetrahydrofuran and are dissolved at room temperature with 0.411 g ( 3.18 mmol) of N, N-diisopropylethylamine were added. The solution is stirred overnight at room temperature. After concentration of the solution is taken up in ethyl acetate and the organic phase with

Washed water and saturated sodium chloride solution. The organic phase is dried and concentrated. The crude product is finely cleaned on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient). 0.389 g (95%) of product is obtained. LC-MS (method: SMKL-Nl-lLow Vol HCI): retention time: 4.78

MS (ESI): 841 (2Mz + H), 421 (Mz + H).

^! H-NMR (DMSO): 8.45 (s, IH), 7.70-7.31 (m, 12H), 4.97-4.84 (m, IH), 4.08 (d, J = 18Hz. IH) , 390 (d, J = 18Hz), 3.47 (dd, J = 10.18Hz), IH). 2.80 (d, J = 18Hz, IH), 2.49 (d, J = YHz.3H), 1.30 (d, J = 7Hz, 3H). Method: SMKL-N1

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

Device type HPUTSP: P4000, AS3000, UV3000HR pump head: normal

Column: Symmetry C 18

150 mm x 2.1 mm 5 μm

Delivery company: Waters

UV detector DAD: 210 nm oven temp .: 40 ° C

Gradient: Time A:% B:% C:% D:% Flow

0 10, 0 45 45 0.6

4 90 5 5 0.6

9 90 5 5 0.6

9.5 10, 0 45 45 - 0.8

1 1, 5 10, 0 45 45 - 0.8

12 10, 0 45 45 0.6

A ChbCN

HCI Q, 01 n HzO Method: SMKL-N1-1 Low Vol HCI

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

Device type HPLC: TSP: P4000, AS3000, UV3000HR pump head: low volume

Column: Symmetry C 18

150 mm x 2.1 mm 5 μm

Delivery company: Waters

UV detector DAD: 210 nm oven temp .: 40 ° C

Gradient: Time A:% B:% C:% D:% Flow

0 10, 0 45 45 - 0.6

4 90 5 5 0.6

9 90 5 5 0.6

9.5 10, 0 45 45 0.8

11.5 10.0 45 45 0.8

12 10, 0 45 45 - 0.6

A CHsCN

HCI Q, 01 n

Claims

claims

1. Compounds of the general formula (I):

where is a single or a double bond,

D is N or CH,

R ^{1 is} hydrogen or (-CC ₆ ) alkyl,

R ^{2 is} hydrogen or (-CC ₆ ) alkyl,

R ^{3 represents} phenyl, which can optionally be substituted by one to two substituents selected from the group consisting of halogen, (C ₆ -Cιo) aryl, which can optionally be substituted by one to three substituents, which are from the group can be selected from (CιYY) alkoxycarbonyl, halogen. (-CC ₆ ) alkyl, (-C-C _ö ) alkoxy, nitro, halogen (-C-Cö) -ilkyl and cyano. (Ci-C ₆ ) alkanoyl, (C] -C ₆ ) alkoxy, (-C-C ₆ ) alkoxycarbonyl,

kylthio, hydroxy, carboxy, partially fluorinated (-C-C) alkoxy with up to 6 fluorine atoms, (C] -C ₆ ) alkyl. which can optionally be substituted by 1 to 3 halogen atoms, a 5- to 6-membered aromatic heterocycle with 1 to 4 heteroatoms from the series S, N and O. can also be substituted by 1 to 3 halogen atoms, a 3- to 8-membered saturated or unsaturated non-aromatic heterocycle, optionally bonded via a nitrogen atom, with up to three heteroatoms from the series S, N and O, optionally with 1 to 3 substituents made of oxo, halogen, hydroxy,

(-C-C ₆ ) -alkoxycarbonyl, (C, -C ₆ ) alkyl, halogen (C, -C ₆ ) alkyl and hydroxy (-C-C ₆ ) -alkyl may be substituted, and groups of the formulas -OR ⁶ , - NR ⁷ R ⁸ and -CO-NR ⁹ R ¹⁰ , wherein R ^{6 is} phenyl, optionally by 1 to 3 substituents selected from the group consisting of

Halogen, (-CC ₆ ) alkoxy and (-C-C ₆ ) alkyl may be substituted,

R ⁷ and R ^{8 are the} same or different and are hydrogen, (d-C ₆ ) alkyl, (C, -C ₆ ) alkanoyl, and

R ⁹ and R ^{10 are the} same or different and are hydrogen or (Ci-C ₆ ) alkyl,

or

R ³ is _(Cι-C6) alkyl, which is substituted by (C ₆ -Cιo) -aryl which may optionally be substituted with 1 to 3 substituents selected from the group _(ό Cι-C) selected from halogen, Alkoxy, trifluoromethyl and phenyl,

or

R ^" (-C-C _ö ) alkyl, which is substituted by a 5- to 6-membered aromatic optionally bonded via a nitrogen atom

Heterocycle with 1 to 4 heteroatoms from the series S, N and O, or

R ^{J is} a group of the following formula

R ^{4 is} hydrogen, (-CC ₆ ) alkyl or Cg-Cio-A y! i ^st _> which can be optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, amino, mono- or di (-CC ₆ ) alkylamino, (-C-C ₆ ) alkoxy, triazolyl, furyl , Tetrahydrofuryl, (C -C ₆ ) cycloalkyl, pyrrolidino, optionally with (Q-

C ₆ ) alkyl substituted pyrrolidinyl, Moφholino, pyridyl, trifluoromethyl, (-C-C ₆ ) alkoxycarbonylamino and phenyl, or (C ₃ -C ₆ ) cycloalkyl,

R ^{5 is} hydrogen, (-CC ₆ ) alkyl, or

R ⁴ and R ^D together form a (C -C ₇ ) alkanediyl group which with the

Nitrogen atom to which it is bound forms a 3- to 8-membered ring, in which a methylene group can optionally be replaced by O or NR ^{1 1} , in which R ^{u is} hydrogen, (-C ₆ ) alkyl, which, if appropriate can be substituted with amino, mono (-C ₆ -C) alkylamino or di (- C ₆ ) alkylamino, (-C -C ₆ ) alkanoyl, (Ci -C ₆ ) alkoxycarbonyl, pyridyl or pyrimidinyl.

and their pharmaceutically acceptable salts. Compounds according to claim 1 of the general formula (I), wherein

- is a single or a double bond,

D N is

R ^{1 is} hydrogen or (-CC ₆ ) alkyl,

R ^{2 is} hydrogen or (C j-) alkyl,

R ^{3 represents} phenyl, which can optionally be substituted by one to two substituents selected from the group consisting of halogen, (C ₆ -Cιo) aryl, which can optionally be substituted by one to three substituents, which are from the group can be selected from (Cι-C6) alkoxycarbonyl, halogen, (Cι-C ₆ ) - alkyl,

(-C-C ₆ ) alkoxy, nitro, halogen (-C-C ₆ ) alkyl and cyano, (C _\ - C ₆ ) alkanoyl, (C, -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, ( C, -C ₆ ) A1- kylthio, hydroxy, carboxy, partially fluorinated (-C-C ₆ ) alkoxy with up to 6 fluorine atoms, (-C-C ₆ ) - alkyl, which can optionally be substituted by 1 to 3 halogen atoms, one if necessary via a

Nitrogen-bonded 5- to 6-membered aromatic heterocycle with 1 to 4 heteroatoms from the series S, N and O, which can optionally be substituted by 1 to 3 halogen atoms, a 3- to 8-membered saturated or unsaturated, optionally bonded via a nitrogen atom non-aromatic heterocycle with up to three heteroatoms from the series S, N and O. optionally with 1 to 3 substituents selected from oxo, halogen, hydroxy. (-C-C ₆ ) alkoxycarbonyl, (-C-C ") alkyl, halogen (C, -C ₆ ) alkyl and hydroxy (CιYY) alkyl may be substituted, and groups of the form -OR ⁶ , -NR ^7th R ⁸ and -CO-NR R ¹⁰ exists. wherein R ^{6 is} phenyl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, (-C-C ₆ ) alkoxy and (C | -C ₆ ) alkyl.

R ⁷ and R ^{8 are the} same or different and are hydrogen, (C _\ - C ₆ ) alkyl, (Cι-C _ό ) alkanoyl, and

R ⁹ and R ¹⁰ are identical or different and are hydrogen or - mean (C _\ -C ₆₎ alkyl,

or

R ^{J is} (-C-C _ö ) alkyl, which is substituted by (C ₆ -C ₁ o) -aryl, which may optionally be substituted by 1 to 3 substituents, selected from the group consisting of halogen, (Cι -C ₆ ) alkoxy, trifluoromethyl and phenyl,

or

R ^{J is} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 hetero atoms from the series S, N and O,

or

R ^{J is} a group of the following formula

R ^{4 is} hydrogen, (-CC ₆ ) alkyl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, amino, mono- or di (-CC ₆ ) alkylamino, (Ci - C ₆ ) alkoxy, triazolyl, furyl, (C -C ₆ ) cycloalkyl, pyrrolidino, optionally substituted with (C] -C ₆ ) alkyl pyrrolidinyl, Moφholino, pyridyl, trifluoromethyl, (Cι-C ₆ ) alkoxycarbonylamino and phenyl, or (C ₃ -C ₆ ) cycloalkyl,

R ^{5 is} hydrogen, (-CC ₆ ) alkyl, or

R ⁴ and R ³ together form a (C ₂ -C ₇ ) alkanediyl group which, together with the nitrogen atom to which it is bonded, forms a 3- to 8-membered ring in which a methylene group can optionally be replaced by O or NR ^u , wherein R ^{1 1 is} hydrogen, (-CC ₆ ) alkyl, which may optionally be substituted with amino, mono (-C-C ₆ ) alkylamino or di (-C-C ₆ ) alkylamino, (-C-Cö) alkanoyl , (Ci- C ₆₎ alkoxycarbonyl, pyridyl or pyrimidinyl,

and their pharmaceutically acceptable salts.

Compounds according to claim 1 or 2 of the general formula (! '):

woπn

DN is R ^{1 is} hydrogen or (-CC ₆ ) alkyl,

R ^{2 is} hydrogen or (-CC ₆ ) alkyl,

R ^{3 represents} phenyl, which can optionally be substituted by one to two substituents selected from the group consisting of halogen, (C ₆ -Cιo) aryl, which can optionally be substituted by one to three substituents, which are from the group can be selected from (CιY-Y) alkoxycarbonyl, halogen, (Cι-C _ö ) alkyl,

(-C-C ₆ ) alkoxy, nitro, halogen (CιYY) alkyl and cyano, (Q-C ₆ ) alkanoyl, (C, -C ₆ ) alkoxy, (C, -C ₆ ) alkoxycarbonyl, (Cι-C ₆ ) A1- Kylthio, hydroxy, carboxy, partially fluorinated (-C-C ₆ ) alkoxy with up to 6 fluorine atoms, (-C-C ₆ ) alkyl, which can optionally be substituted by 1 to 3 halogen atoms, one optionally via a

Nitrogen-bonded 5- to 6-membered aromatic heterocycle with 1 to 4 heteroatoms from the series S, N and O, which can optionally be substituted by 1 to 3 halogen atoms, a 3- to 8-membered saturated or unsaturated, optionally bonded via a nitrogen atom non-aromatic heterocycle with up to three heteroatoms from the series S, N and O, optionally with 1 to 3 substituents selected from oxo, halogen, hydroxy, (CιYY) alkoxycarbonyl, (Cι-C ₆ ) alkyl, halogen (Cι- C ₆ ) alkyl and hydroxy (-CC ₆ ) -alkyl can be substituted, and groups of the form -OR ⁶ , -NR ⁷ R ⁸ and -CO-NR ⁹ R ¹⁰ , where R ° is phenyl, that optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, (Cι-C _ό ) alkoxy and (Cι-C ₆ ) alkyl, R ⁷ and R ^{8 are the} same or different and are hydrogen, (C _\ - C ₆ ) alkyl, (Cι-C _ö ) alkanoyl, and

R ⁹ and R ¹⁰ are identical or different and are hydrogen or - mean (C _\ -C ₆₎ alkyl,

or

R ^{J is} (-C ₆ ) alkyl. which is substituted by (C ₆ -Cιo) aryl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, (C] -C ₆ ) alkoxy, trifluoromethyl and phenyl.

or

R ^{3 is} (-C-C _ö ) alkyl. which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 heteroatoms from the series S, N and O,

or

R is a group of the following formula,

R is hydrogen, (-CC ₆ ) alkyl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of Ammo. Mono- or di (-CC ₆ ) alkylamιno, (-C-C _ö ) alkoxy, Tnazolvl, furyl, (C ₃ -C ₆ ) cycloalkyl, pyπolidino, optionally substituted with (C | -C ₆ ) alkyl pyrrolidinyl, Moφholino, Pyridyl, tri- fluoromethyl, (C] -C ₆ ) alkoxy-carbonylamine and phenyl, or (C ₃ -C ₆ ) cycloalkyl,

R ^{5 is} hydrogen, (-CC ₆ ) alkyl, or

R ⁴ and R ⁵ together form a (C ₂ -C ₇ ) alkanedyl group, which with the

Nitrogen atom to which it is bound forms a 3- to 8-ghedπgen ring, in which a methylene group can optionally be replaced by O or NR ^{1 1} , where R ^{1 1 is} hydrogen, (-C-C ₆ ) Alkvl, that optionally with ammo, mono (Cι-C ₆ ) alkylamιno or Dι (Cι-

C ₆ ) alkylamιno can be substituted,

l, (Ci-C ₆ ) alkoxycarbonyl, pyπdyl or pyrimidinyl,

and their pharmaceutically contractual salts

Compounds according to claim 1 of the general formula (I), woπn

- is a single or a double bond,

R ^{1 is} hydrogen or (C, -C ₆ ) alkyl,

R ^{2 is} hydrogen or (C | -C ₆ ) alkyl,

R ^{3 represents} phenyl, which can optionally be substituted by one or two substituents which are selected from the group consisting of halogen, (C ₆ -Cιo) aryl, which can optionally be substituted by one to three substituents, which can be selected from the group consisting of (C | YY) alkoxycarbonyl, halogen. (Cι-C _< ) alkyl,

Nitro. Halogen (Cι-C ₆ ) alkyl and Cya o consists (C | - C ₆ ) alkanoyl, (dC ₆ ) alkoxy, (C, -C ₆ ) alkoxycarbonyl, (Cι-C ₆ ) A1-kylthio, hydroxy, carboxy, partially fluorinated (Cι-C ₆ ) alkoxy with up to 6 fluorine atoms, ( C ₁ -C ₆ -alkyl, which may optionally be substituted by 1 to 3 halogen atoms, a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, having 1 to 4 heteroatoms from the series S, N and O, which may be substituted by 1 to 3 halogen atoms can be substituted, a 3- to 8-membered saturated or unsaturated non-aromatic heterocycle, optionally bonded via a nitrogen atom, with up to three heteroatoms from the series S, N and O, optionally with 1 to 3 substituents selected from oxo , Halogen, hydroxy, (C, -C ₆ ) alkoxycarbonyl, (C, -C ₆ ) alkyl, halogen (Cι-C ₆ ) alkyl and hydroxy (Cι-C ₆ ) alkyl may be substituted, and groups of the formulas -OR ⁶ , -NR ⁷ R ⁸ and -CO-NR ⁹ R ¹⁰ , wherein R ^{6 is} phenyl, which is optionally by 1 to 3 Substituents selected from the group consisting of halogen, (Cι ~ C ₆ ) alkoxy and (CιY ₆ ) alkyl can be substituted,

R ⁷ and R ^{8 are the} same or different and are hydrogen, (Ci

C ₆ ) alkyl, (-C-C ₆ ) alkanoyl, and

R and R are the same or different and are W ^τ aerstoff or (d- C ₆ ) alkyl,

or

R ^J is (C ₆ -C ₆ ) alkyl which is substituted by (C ₆ -C ₆ ) aryl which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, (C ₆ -C ₆ ) Alkoxy, Trifluoπnefhyl and

Phenyl exists. or

R ^{3 is} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 hetero atoms from the series S, N and O,

or

R ^{3 is} a group of the following formula,

R ^{4 is} hydrogen, (-CC ₆ ) alkyl or Cg-Ci _Q- aryl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, ammo, mono- or di (Cι -C ₆ ) alkylammo, (-C-C ₆ ) alkoxy, Tπazolyl, furyl, tetrahydrofuryl, (C ₃ -C ₆ ) cycloalkyl, pyrrolidino, optionally substituted with (Ci- C ₆ ) alkyl pyrrolidinyl, Moφholino, Pyπdyl, Tπ - fluoromethyl, (-C-C ₆ ) alkoxycarbonylamιno and phenyl, or (C ₃ -C ₆ ) cycloalkyl,

R ^{2 is} hydrogen, (C] -C ₆ ) alkyl, or

R and R ² together form a (C ₂ -C ₇ ) alkanedioyl group, which with the

Nitrogen atom to which it is bound forms a 3- to 8-ghedπgen ring, in which a methylene group can optionally be replaced by O or NR ^{1 1} , where R ^{1 1 is} hydrogen, (-C-C ₆ ) Alkvl, that optionally substituted with amino, mono (-C ₆ -alkyl) or Dι (Cι-C ₍ ,) alkylamino, (C 1 -C ₆ ) alkanoyl, (Ci-C) alkoxycarbonyl, pyridyl or Pvπmidinvl , and their pharmaceutically contractual salts

5 compounds according to claim 1 or 4 of the general formula (I), woπn

-5

- is a single bond,

D is CH

0 R ^{1 is} (C, -C ₆ ) alkyl,

R ^{2 is} hydrogen

R ^{3 represents} phenyl, which may optionally be substituted with a substituent selected from the group consisting of

(C ₆ -Cιo) aryl and (Cι-C _ö ) alkoxycarbonyl,

R ^{4 is} hydrogen, (-C-C ₆ ) alkyl or Cg-C _j o-aryl, which may optionally be substituted by a substituent selected from the group consisting of (-C-C ₆ ) alkoxy and tetrahydro furyl , or is (C ₃ -C ₆ ) cycloalkyl,

R ^{D is} hydrogen, or

R and R ^{^} together form a (C2YY) alkanedyl group which with the

The nitrogen atom to which it is attached forms a 3- to 8-membered ring in which a methylene group has been replaced by NR ^{1 1} in which R ^{1 1 is} hydrogen or (C ¹ -C ₆ ) alkyl,

and their pharmaceutically acceptable salts

6. Compounds according to claim 1, 2 or 3, wherein the compounds of the general formula (I) or (! ') Have the following structure:

wherein the substituents have the meaning given in claim 1, and their pharmaceutically acceptable salts.

7. Compounds of general formula (I) according to claim 1, 2, 3, 4, 5 or 6, wherein R ^{1 is} hydrogen or methyl, and their pharmaceutically acceptable salts.

8. Compounds of general formula (I) according to claim 1, 2, 3, 4, 5, 6 or 7, wherein

R ^{5 is} hydrogen or methyl. and their pharmaceutically acceptable salts.

9. Compounds of general formula (I) according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein

R ^{4 is} methyl, methoxyethyl, triazolylethyl, benzyl, cyclopropyl, furylmethyl, cyclopropylmethyl or sec-butyl, and their pharmaceutically acceptable salts.

10. Compounds of general formula (I) according to claim 1, 2, 3, 4 or 5 wherein R ⁴ and R ³ together with the nitrogen atom to which they are bound form Moφholino, and their pharmaceutically acceptable salts.

1. Compounds of general formula (I) or (V) according to claim 1 or 2, wherein

R ^{1 is} hydrogen or (dC ₃ ) alkyl,

R ^{2 is} hydrogen or (C, -C ₃ ) alkyl,

R ^{3 represents} phenyl which may optionally be substituted with one to two substituents selected from the group consisting of

Halogen, phenyl, which may optionally be substituted by one to three substituents selected from the group consisting of (C, -C ₄ ) alkoxycarbonyl, halogen, (-C-C ₄ ) alkyl, (Cι-C ₄ ) Alkoxy, nitro, halogen (Cι ~ C ₄ ) alkyl and cyano, (Cι-C) alkanoyl, (C, -C ₄ ) alkoxy, (Cι-C ₄ ) alkoxycarbonyl, (Cι-C ₃ ) alkylthio, hydroxy,

Carboxy, partially fluorinated (-C-C) alkoxy with up to 6 fluorine atoms, (-C-C ₃ ) alkyl, which can optionally be substituted by 1 to 3 halogen atoms, with a 5- to 6-membered aromatic heterocycle optionally bonded via a nitrogen atom 1 to 4 heteroatoms from the S, N and O series, which can optionally be substituted by 1 to 3 halogen atoms, a 3- to 8-membered saturated or unsaturated non-aromatic heterocycle, optionally bonded via a nitrogen atom, with up to three heteroatoms from the S series N and O, optionally with 1 to 3 substituents selected from oxo,

Halogen, hydroxy, (-C-C ₄ ) alkoxycarbonyl, (-C-C ₃ ) alkyl, halogen (C] -C;,) alkyl and hydroxy (Cι-C) alkyl can be substituted, and groups of the formulas -OR ⁶ , -NR ⁷ R ⁸ and -CO-NR ⁹ R ¹⁰ , wherein R ^{6 is} phenyl, optionally by 1 to 3 substituents selected from the group consisting of Halogen, (-CC ₃ ) alkoxy and (-C-C) alkyl can be substituted,

R ⁷ and R ^{8 are} identical or different and are hydrogen, (Ci-C ₃ ) alkyl, (C, -C ₃ ) alkanoyl, and

R ⁹ and R ^{10 are the} same or different and are hydrogen or (Cj-C) alkyl,

or

R ^{3 is} (C ₁ -C ₃ ) alkyl which is substituted by phenyl, which may optionally be substituted by 1 to 3 substituents, selected from the group consisting of halogen, (C 1 -C) alkoxy, trifluoromethyl and phenyl,

or

R ^{3 is} (C ₁ -C ₃ ) alkyl which is substituted by a 5- to 6-membered aromatic optionally bonded via a nitrogen atom

Heterocycle with 1 to 4 heteroatoms from the series S, N and O,

or

R is a group of the following formula,

R ^→ hydrogen, (-CC ₃ ) alkyl, which may optionally be substituted by 1 to 3 substituents selected from the group, from halogen, amino, mono- or di (-C-C ₃ ) alkylamino, (Q- C ₃ ) alkoxy, triazolyl, furyl, (C ₃ -C ₆ ) cycloalkyl, pyrrolidino, optionally with (Cι-C ₃ ) alkyl substituted pyrrolidinyl, Moφholino, pyridyl, trifluoromethyl, (Cι-C ₄ ) alkoxy-carbonylamino and phenyl, or (C ₃ -C ₆ ) cycloalkyl,

R ^{5 is} hydrogen, (-CC ₃ ) alkyl, or

R and R ³ together form a (C ₂ -C ₇ ) alkanediyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-membered ring in which a methylene group can optionally be replaced by O or NR ^{1 1} , wherein R ^{1 1 is} hydrogen, (-C-C ₃ ) alkyl, which may optionally be substituted with amino, mono (Cι-C ₃ ) alkylamino or di (Cι-C ₃ ) alkylamino, (C] - C) alkanoyl, (-C-C ₃ ) alkoxycarbonyl, pyridyl or pyrimidinyl,

and their pharmaceutically acceptable salts.

12. A process for the preparation of the compound according to claim 1 or 2 and its pharmaceutically acceptable salts, characterized in that

(A) compounds of the general formula (II)

wherein R ¹ , R ⁴ and R ^{3 have} the meaning given above,

with compounds of the general formula (III) R ^j -NCO (III)

in which R has the meaning given above, to give compounds of the general formula (Ia):

wherein R, R, R and R ^{3 have} the meaning given above,

or

(B) compounds of the general formula (IV)

wherein R, R and R have the meaning given above, and

X halogen, such as chlorine, with compounds of the general formula (V)

HNR ² R ³ (V)

converts to compounds of general formula (I),

or (C) compounds of the general formula (II)

wherein -, R, R ⁴ and R have the meaning given above,

with compounds of the general formula (VI)

R ² R ³ CHCOY (VI)

in which Y represents an electronegative group such as halogen and in which R ² and RR ddiiee oobbeenn have general meaning, to compounds of the general formula (Ia)

wherein - ~ -, R, R ² , R ^J , R and R ^{D have} the meaning given above,

implements

and optionally converting the compounds thus obtained into the pharmaceutically acceptable salts in a customary manner.

13. Connections of Foπnel:

wherein -, R ¹ , R ⁴ , R ^{3 have} the meaning given in claim 1 and X is a halogen atom.

14. Compounds according to claim 1, 2 or 3 for use as a medicament.

15. A pharmaceutical composition comprising a compound of general formula (I) or (P) according to claim 1, 2 or 3 in admixture with a pharmaceutically acceptable carrier or excipient.

16. Use of 6- (aminosulfonyl) -l-indoline carboxamide derivatives or 6- (aminosulfonyl) -IH-indole-l-carboxamide derivatives for the production of medicaments.

17. Use of 6- (aminosulfonyl) -l-indolinecarboxamide or 6- (aminosulfonyl) -IH-indole-l-carboxamide derivatives for the manufacture of medicaments for the treatment and / or prevention of Heφes infections in humans or animals .

18. Use of 6- (aminosulfonyl) -l-indoline carboxamide derivatives after

Claim 14 or 15.

19. Use of a compound of general formula (I) or (V) according to claim 1, 2 or 3 for the manufacture of a medicament.

20. Use of a compound of general formula (I) or (V) according to claim 1, 2 or 3 for the manufacture of a medicament for the treatment of viral infections.

21. Use of a compound of the general formula (I) or (V) according to

Claim 1, 2 or 3 for the manufacture of a medicament for the treatment of viral infections by Heφes viruses.

22. Use of a compound of general formula (I) or (V) according to claim 1, 2 or 3 for the manufacture of a medicament for the treatment of viral infections by Heφes simplex viruses.