EP1177171A1

EP1177171A1 - Substituted indole sulfonamides as antiviral agents

Info

Publication number: EP1177171A1
Application number: EP00929376A
Authority: EP
Inventors: Wolfgang Bender; Peter Eckenberg; Siegfried Goldmann; Michael Härter; Sabine Hallenberger; Jürgen Reefschläger; Jörg TRAPPE; Olaf Weber
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1999-04-30
Filing date: 2000-04-18
Publication date: 2002-02-06
Also published as: AU4748900A; DE19919793A1; US6498183B1; CA2371621A1; JP2002543180A; WO2000066553A1

Abstract

The invention relates to novel compounds that are suitable for use as medicaments, to methods for producing said compounds and to their use as medicaments, especially as antiviral agents.

Description

SUBSTITUTED INDOLSULPHONAMIDES AS AN ANTIVIRAL AGENT

The present invention relates to new compounds which are suitable as medicaments, processes for their preparation and their use as medicaments, in particular as antiviral agents.

α, β-Naphthyl linked phenylsulfonamides are mainly known from phototechnical publications [see see JP-06 122 669-A2, EP-684 515-A1; JP-59 174 836-A2, DE-2 902 074, US-3 925 347, US-4 035 401, US-3 622 603, US-3 482 971. EP-284 130].

WO 90/09 787 discloses sulfonamides as radio- or chemosensitizers and their use in the treatment of tumors.

The compound N- [4 - [[[5- (dimethylamino) -l-naphthalenyl] sulfonyl] amino] phenyl] acetamide is also known (J. Inst. Chem. (India) (1976), 48, Pt 6 , 280-5).

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

wherein

R ^{1 represents} a group selected from the following formulas

wherein - represents a single or a double bond,

R ^{3 represents} hydrogen, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, each of which can be substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, halogen, amino , Mono- or di (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkanoyloxy, (C _r C ₆ ) alkanoyl, carboxy, (C _r C ₆ ) alkoxy - carbonyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl and cyano, or

R ^{3 represents} (C ₆ -C ₁₀ ) arylsulfonyl, (C ₆ -C ₁₀ ) arylcarbonyl, the (C ₆ -

C ₁₀ ) aryl group can in each case be substituted by 1 to 3 substituents which are selected from the group consisting of halogen, (C ₁ -C ₃ ) alkyl, carboxy, (C ₁ -C ₃ ) alkoxycarbonyl, carbamoyl,

Mono- or di (C ₁ -C ₆ ) alkylamino-carbonyl, cyano, hydroxy and (C _r C ₃ ) alkoxy, or

R ^{3 represents} (C _r C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₃ -C ₆ ) cycloalkylcarbonyl, camphorsulfonyl or (C ₃ -C ₆ ) cycloalkylsulfonyl, or

R ^{3 represents} R ⁴ -X-CO- or R ⁴ -X-CS-, wherein

X is O, S, NR, where R is hydrogen or (C

C ₃ ) alkyl, and

R ^{4 represents} (C _r C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl, and R for

- stands in what

R ^{6 is} (C ₂ -C ₆ ) alkenyl or (C _r C ₈ ) alkyl, which is optionally one to three times the same or different by amino, protected amino, (C ₁ -C ₄ ) alkylamino, hydroxy, cyano, halogen, Azido, nitro, trifluoromethyl, carboxyl or phenyl is substituted, with phenyl in turn up to two, the same or different

10 which can be substituted by nitro, halogen, hydroxy, (C ₁ -C ₄ ) alkyl or (C _r C ₄ ) alkoxy, or

R ⁶ for residues of the formulas

or - LO-CO-Q stands,

15 where

represents a straight-chain or branched alkanediyl group with up to 6 carbon atoms,

20 Q stands for (C _r C ₆ ) alkyl, which is optionally substituted by carboxyl, or for residues of the formulas

^{, ι0υ} RR ¹ ' ¹ stands, wherein a represents the number 1 or 2,

R ^{8 is} hydrogen, 5

R ^{9 is} (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or hydrogen, or (C _r C ₈ ) alkyl,

where the (C _r C ₈ ) alkyl is optionally substituted by 10 cyano, methylthio, hydroxy, mercapto, guanidyl or by a group of the formula -NR ^I2 R ¹³ or R ¹⁴ -OC-,

wherein

15

R ¹² and R ¹³ independently of one another are hydrogen, (C _r C ₈ ) alkyl or phenyl,

20 and

R ^{M is} hydroxy, benzyloxy, (C ₁ -C ₆ ) alkoxy or the group -NR ¹² R ¹³ listed above

25 or the (C ₁ -C ₈ ) alkyl is optionally substituted by (C ₃ - C ₈ ) cycloalkyl or by (C ₆ -C ₁₀ ) aryl, which in turn is substituted by hydroxy, halogen, nitro, (C ₁ -C ₈ ) Alkoxy or substituted by the 30 group -NR ¹² R ¹³ . where R ¹² and R ^{13 have} the meaning given above,

or the (C _r C ₈ ) alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or by indolyl, in which the corresponding -NH functions are optionally substituted by (C ₁ -C ₆ ) alkyl or protected by an amino protecting group are,

R ¹⁰ and R ^{11 are} identical or different and denote hydrogen or an amino protecting group,

R ^{7 represents} hydrogen or a radical of the formula

^stands - in what

R ^{8 '} , R ^9' , R ^{10 '} and R ^{11' have} the meaning of R ⁸ given above,

R ⁹ , R ¹⁰ and R "and are the same or different with this, and their salts.

The substances according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.

Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts are preferred with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, Toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. For example, particular preference is given to Sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are derived from ammonia, or organic amines, such as ethylamine, di- or.

Triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds of the general formula (I) according to the invention can occur in various stereochemical forms which are either like Figure and

Mirror image (enantiomers) or that do not behave like image and mirror image (diastereomers). The invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

Furthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art and such compounds are also within the scope of the invention.

In the context of the invention, (-C-Cg) alkyl generally represents straight-chain or branched-chain hydrocarbon radicals having 1 to 6 carbon atoms. Accordingly, (C _j -C ₄ ) alkyl or (C _j -C ₃ ) alkyl in the context of the invention generally represent straight-chain or branched-chain hydrocarbon radicals having 1 to 4 or 1 to 3 carbon atoms. Examples include: methyl, ethyl , Per- pyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

(C ₃ -C ₆ ) Cycloalkyl stands for cycloalkyl group with 3 to 6 carbon atoms. Includes, for example: cyclopropyl, cyclopentyl and cyclohexyl. Cyclopropyl is preferred.

The (C _j -C ₆ ) alkoxy group, as used in the present invention, and as also used in the definitions (-C-C6) alkoxycarbonyl, includes, for example, straight-chain or branched chain alkoxy groups with 1 to

6 carbon atoms, particularly preferably alkoxy groups with 1 to 4 carbon atoms ((C _j -C ₄ ) alkoxy), more preferably alkoxy groups with 1 to 3 carbon atoms ((C _j -C ₃ ) alkoxy). For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy and isohexoxy can be mentioned. Methoxy, ethoxy and propoxy are preferred.

In the context of the invention, mono- or di (-CC) alkylamino includes those whose alkyl groups have 1 to 6 carbon atoms. This can be symmetrical or asymmetrical alkylamino groups, such as dimethylamino, diethylamino, methylethylamino etc. This also applies to the mono- or di (-C-C ₆ ) alkylamino part in the mono- or di (C _j -C ₆ ) Alkylaminocarbonyl group.

(C ₆ -Cι ₀ ) aryl in the context of the invention is an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, 5- to 10-membered heteroaryl stands for rings containing 5- to 10-membered heteroatoms, which may contain 1 to 8 heteroatoms in the ring, which are selected from O, S and N and include, for example, a pyridyl. Furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, triazolyl.

Thiadiazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolicenyl, indolyL Benzo [b] thienyl, benzimdiazolyl, pyridoimidazolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, etc.

5- to 6-membered nitrogen-containing heterocycles include, for example: pyrolidine, piperidine, piperazine, morpholine, pyridyl, furyl, thienyl, pyrolyl, imidazolyl,

Pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.

Regarding (C ₆ -C _j o) arylsulfonyl and carbonyl, reference is made to the above-mentioned definitions for (C6-C _j o) aryl.

(Ci-Cg) alkanoyl and (C _] -C ₆ ) alkanoyl in the definition (Cι-Cg) alkanoyloxy and (C _j -Cg) alkanoylamino stands for straight-chain or branched chain alkanoyl with 1 to 6 carbon atoms in the context of the invention. Examples include: formyl, acetyl, propanoyl, butanoyl, pentanoyl, pivaloyl and hexanoyl.

The term “alkanediyl group with up to 6 carbon atoms” denotes straight-chain or branched-chain hydrocarbon groups which are linked to other radicals at two positions. Examples of alkanediyl groups are: -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -, -C (CH ₃ ) ₂ -CH ₂ -, -CH (CH ₃ ) -CH ₂ -, -C ( CH ₃ ) ₂ - CH ₂ -CH ₂ -, -CH (CH ₃ ) -CH ₂ -CH ₂ - etc.

Amino protecting groups in the context of the invention are the usual ones in the peptide—

Chemistry used amino protecting groups.

These preferably include: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,

3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-

4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxy- carbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, cyclohexoxycarbonyl, 1, 1-dimethylethoxycarbonyl, adamantylcarbonyl, trthalichloroethoxy, 2,2,2 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl.

In a preferred embodiment, the invention includes compounds of the formulas

wherein R ¹ and R ^{2 have} the meaning given above.

In a further preferred embodiment, the invention includes compounds of the general formula (I) in which:

R ^{1 represents} a group selected from the formulas:

wherein

- represents a single or a double bond, and

R ^{3 has} the meaning given above, and their salts.

In a preferred embodiment, the invention includes compounds of general formula (I) in which:

R ^{3 represents} hydrogen, (C _r C ₆ ) alkyl or (C _r C ₆ ) alkanoyl, and

R for

R ⁷ R ^b

I.

-N- CO-R ⁶ or -CO- N- R ⁷ , wherein

R ^{6 is} (C ₁ -C ₈ ) alkyl, which is optionally substituted by halogen or hydroxy, and

R ^{7 is} hydrogen,

and their salts.

In a preferred embodiment, the invention includes compounds of the general formula (I) in which R ^{6 is} tert-butyl, which is optionally substituted by halogen or hydroxyl, and their 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 is} as defined above, with compounds of the general formula (III)

wherein R ^{2 is} as defined above to give compounds of general formula (I).

The reaction is preferably carried out in the presence of bases such as pyridine, triethylamine and Hunig base etc.

The reaction is preferably carried out in a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, etc.

The reaction is preferably carried out in a temperature range from -10 ° C to 70 ° C.

The reaction is preferably carried out at normal pressure.

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

wherein R ^{2 is} as defined above, and

R ^{a represents} a group selected from the following formulas:

with compounds of formula (IV): R ³ -A (IV)

wherein R ^{3 is} as defined above and A is a conventional leaving group, in a manner known per se in the presence of a base to give compounds of the general formula (Ib):

wherein R ^{2 is} as defined above and R ^{1b represents} a group selected from the following formulas:

wherein R ^{3 is} as defined above.

A represents a common leaving group used in nucleophilic substitution reactions, e.g. Halogen (e.g. chlorine, bromine, iodine), OTs (Ts = Tosyl) and OMes (Mes = Mesyl).

Bases preferred in the reaction are tertiary amines such as pyridine, Hunig base, etc., alkali metal hydroxide and alkali metal carbonate.

The reaction is preferably carried out in inert solvents such as tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethylformamide etc.

The reaction is preferably carried out in a temperature range from -10 ° C to 100 ° C.

The reaction is preferably carried out at normal pressure. In process (C), compounds of the general formula (Ic)

wherein R ^{2 is} as defined above and R ^{1c is} a group selected from the following formulas:

wherein R ^{3 is} as defined above, by oxidation with DDQ (2,3-dichloro-5,6-dicyano-para-benzoquinone) in a manner known per se to give compounds of the general formula (Id):

wherein R ^{2 is} as defined above, R ^{1d represents} a group selected from the following formulas:

wherein R ^{3 is} as defined above.

The reaction is preferably carried out in a solvent such as 1,4-dioxane or 1,2-

Dichloroethane performed.

The reaction is preferably carried out in a temperature range from room temperature to the boiling point of the particular solvent at atmospheric pressure.

The reaction is preferably carried out at normal pressure. In process (D), compounds of the general formula (Ie)

wherein R ^{2 is} as defined above and R ^{1e has} the following formulas:

CH- CH_

I be known per ^° Wxeise in G o ^° egenwartx of wat .the in at sr mi xt Alkalimxetallhyxdroxiden to compounds of formula (Ia) in order.

Alkali metal hydroxides include, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., with lithium hydroxide being preferred.

The reaction is preferably carried out in homogeneous aqueous solvent systems.

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

70 ° C carried out.

The reaction is preferably carried out at normal pressure.

In process (E), compounds of the general formula (If)

wherein R ^{2 is} as defined above and R ^{1f has} the following formulas: wherein R ^{3 is} (CC ₆ ) alkanoyl, in a manner known per se with complex metal hydrides to give compounds of the general formula (Ig):

wherein R ^{2 is} as defined above and R ^{1g has} the following formulas:

where R ^{C is} (C _r C ₆ ) alkyl.

Complex metal hydrides preferably used in the reaction are lithium aluminum hydride, diisobutyl aluminum hydride, etc.

The reaction is preferably carried out in a solvent such as tetrahydrofuran, 1,4-dioxane etc.

The reaction is preferably carried out in a temperature range from -50 ° C to 40 ° C.

The reaction is preferably carried out at normal pressure.

The processes according to the invention can be illustrated by the following reaction schemes.

The indole and indoline compounds can be represented as follows:

The compounds of the general formula (I) can then be obtained from the unsubstituted indole and indoline compounds (R ³ = hydrogen) by reaction with R ³ -A as described above.

The isoindoline compounds are available, for example, according to the following scheme:

The compounds of the general formula (I) can then be obtained from the unsubstituted isoindoline compounds (R ³ = hydrogen) by reaction with R ³ -A as described above.

The preparation of the sulfonyl chloride starting compounds of the formula (II) is illustrated by the following reaction scheme:

U AcCI

HQ _ C ^ ^ o ^ oc _c . O

The sulfonyl chloride 1 is prepared, for example, according to ALBorrer, E. Chinoporos, M. Filosa, SR Herrchen, CR Petersen, CA Stern, J Org. Chem. 53, 2047 (1988). The sulfonyl chloride 3 can be prepared analogously to the above reaction.

The production of the sulfonyl chloride 2 takes place e.g. according to P.R. Carlier, M.P. Lockshin, M.P. Filosa, J. Org. Chem. 59, 3232 (1994).

The compounds of the general formula (I) can then be obtained from these compounds after reaction with the amines of the formula (III), saponification of the acetyl group, for example with LiΟH / H ₂ Ο and subsequent reaction with R ³ -A.

The preparation of the compounds of the general formula (III) is illustrated, for example, using the following reaction schemes:

4 (m-, X = H)

5 (m-, X = F)

6 (p-, X = H)

7 (m-, X = H)

8 (p-, X = H)

9 (P-, X = F)

Therein means pyr. Pyridine.

The aniline 4 is produced e.g. in accordance with U.S. Patent No. 3,979,202.

The aniline 6 is produced e.g. according to S. Rajappa, R. Sreenivasan, A.

Khalwadekar, J. Chem. Res. Miniprint 5, 1657 (1986).

Aniline 7 is produced, for example, according to WO 9631462. Aniline 8 is produced, for example, according to RW Hartmann, M. Reichert, S. Goehring, Ewr. J Med. Chem Chim. Ther. 29: 807 (1994).

Anilines 5 and 9 are prepared in an analogous manner.

With regard to the exact reaction conditions, reference is made to the examples and starting examples.

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

The invention further relates to a pharmaceutical composition which comprises a compound of the general formula (I) in admixture with at least one pharmaceutically acceptable carrier or excipient.

The invention further relates to the use of the compound of general formula (I) for the manufacture of a medicament.

The invention further relates to the use of a compound of general formula (I) for the manufacture of a medicament for the treatment of viral infections, in particular infections by cytomegaloviruses.

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 group of herpes viridae, especially against the human cytomegalovirus (HCMV). They are therefore suitable for the treatment and prophylaxis of diseases caused by herpes viruses, in particular diseases caused by human cytomegalovirus (HCMV).

The anti-HCMV activity was determined in a screening test system in 96-well microtiter plates with the aid of human embryonic lung fibroblasts (HELF) cell cultures determined. The influence of the substances on the spread of the cytopathogenic effect was determined in comparison to the reference substance ganciclovir (Cymevene ^R sodium), a clinically approved anti-HCMV chemotherapeutic agent (EC ₅₀ , corresponding to the effective concentration at which 50% inhibition of virus activity is achieved).

The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on microtiter plates (96-well) in duplicate (4 substances / plate). Toxic and cytostatic substance effects are also recorded (CC ₅₀ , corresponding to the concentration at which half of the cells are destroyed due to the substance administration). After the corresponding substance dilutions (1: 2) on the microtiter plate, a suspension of 50-100 HCMV-infected HELF cells and 30 × 10 ⁵ non-infected HELF cells in Eagle's MEM with 10% fetal calf serum is added to each well, and the plates Incubated at 37 ° C in a CO ₂ incubator for several days. After this time, the cell lawn in the substance-free virus controls, starting from 50 - 100 infectious centers, is completely destroyed by the cytopathogenic effect of HCMV (100% CPE). After staining with neutral red and fixation with formalin / methanol, the plates are evaluated using a projection microscope (plaque viewer).

The results for two exemplary compounds are given below:

The compounds according to the invention are therefore valuable active substances for the treatment and prophylaxis of diseases which are triggered by human cytomegalovirus. The following can 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 suffer from life-threatening HCMV pneumonitis, encephalitis, and gastrointestinal and systemic HCMV infections.

3) Treatment and prophylaxis of HCMV infections in newborns and

Toddlers.

4) Treatment of acute HCMV infection in pregnant women.

In vivo effect

Animals

5 week old male mice, strain NOD / LtSz-Prkdc (scid) / J, were obtained from a commercial breeder (The Jackson Lab., Bar Harbor). The animals were kept in isolators under sterile conditions (including bedding and feed).

Virus / infection

Murine cytomegalovirus (MCMV), Smith strain, was passaged in vivo (BALB / c) and purified by fractional centrifugation. The titer was examined using a plaque assay for primary embryonic mouse fibroblasts.

The mice were infected with a dose of ⁵ × 10 ⁵ pfu in a total volume of 0.2 ml intraperitoneally. This dose leads to death in 100% of the infected animals after about 1 1 days. Treatment / evaluation

24 hours after infection, the mice were treated with substance orally twice daily (morning and evening) over a period of 8 days. The dose was 25 mg / kg body mass, the application volume 10 ml / kg body mass. The substances were formulated in the form of a 0.5% tylose suspension. 16

Hours after the last substance application, the animals were killed painlessly and the salivary gland, liver and kidney were removed.

Genomic DNA was purified from 25 mg of the tissue by phenol / chloroform extraction. The DNA was quantified photometrically and using the

Formula OD ₂₆₀ x50 = mg / ml.

The purity of the DNA was checked using the quotient OD ₂₆₀ / OD ₂₈₀ and the DNA was then adjusted to pH = 8.0 with Tris-EDTA.

The MCMV-DNA was quantified by means of DNA dot blot hybridization. A digoxygenin-labeled (Boehringer-Mannheim, also listed buffer, unless otherwise described) 1.2 kb fragment from the MCMV range, Smith, Hindlll J, was used as the probe. The signals were detected by means of chemiluminescence. For this, the membrane was washed in 1 x digoxygenin washing buffer 1 for 3 minutes. The filters were then incubated for 30 minutes at room temperature with shaking in 1 x digoxygenin blocking solution. The filters were then incubated for 30 minutes in 20 ml / 100 cm ² membrane with the anti-DIG alkaline phosphatase conjugate solution (1: 20000 in 1 x digoxygenin blocking solution). 2 washing steps each lasting 15 minutes with 1 x digoxygenin washing buffer followed. This was followed by 5 minutes of equilibration of the filters in 1 x digoxygenin detection buffer and detection by means of 1 ml / 100 cm ² membrane area 1: 100 diluted CDP-Star solution. After spreading out the CDP-Star solution and incubating for 5 minutes in a dark box, the chemiluminescence was detected or evaluated using X-ray film (Kodak) or

Lumilmager (Boehringer Mannheim). All results were backed up statistically (analysis of variance using statistics; StatSoft Inc.).

The new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, 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, intravenously or intravitally, optionally as a depot in an implant.

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

In general, it has proven to be advantageous to administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg of body weight in the case of intravenous administration, in order to achieve effective results, and in the case of oral administration the dosage is about 0. 01 to 25 mg / kg, preferably 0.1 to 10 mg / kg body weight. Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, 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 minimum quantity mentioned above, while in other cases the above-mentioned upper limit has to 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

Output connections

A) Sulfonyl chlorides

N-Acetyl-indoline-5-sulfonyl chloride was obtained using literature methods (AL Borrer, E. Chinoporos, M. Filosa, SR Herrchen, CR Petersen, CA. Stern, J. Org. Chem. 53, 2047 (1988)) as well as N -Acetyl-indoline-6-sulfonyl chloride (PR Carlier, MP Lockshin, MP Filosa, J. Org. Chem. 59,

3232 (1994)). N-acetyl-isoindoline-5-sulfonyl chloride was prepared from N-acetylisoindoline and chlorosulfonic acid in analogy to N-acetyl-indoline-5-sulfonyl chloride.

B) Anüine

The required anilines were produced by literature processes (Monsanto, US Pat. No. 3,979,202, S. Rajappa, R. Sreenivasan, A. Khalwadekar, J. Chem. Res. Miniprint 5, 1657 (1986), WO 96/31462, RW Hartmann , M. Reichert, S. Göring, Eur. J. Med. Chem. Chim. Ther. 29, 807 (1994)) as shown in the above schemes.

Examples

A) N-Acetyl- (iso) indoline-suIfonamide

Example 26

N- (N-Acetylindolin-5-sulfonyl) -N '- (3-fluoro-2,2-dimethylpropanoyl) -l, 3-diaminobenzene A solution of 3.50 g (16.65 mmol) of N-3-fluoro-2,2-dimethylpropanoyl) -l, 3-diaminobenzene in 10 ml of dry THF was added dropwise to a solution of 3.93 g (15 , 13 mmol) of N-acetyl-indoline-5-sulfonyl chloride and 5.99 g (75.67 mmol) of pyridine in 50 ml of dry THF at 0 ° C. The ice bath was removed and stirring was continued at room temperature for 24 hours. Then that became

Solvent and excess pyridine removed in vacuo. The resulting slurry was treated with a mixture of 25 ml ether, 5 ml ethyl acetate and 2 molar aqueous hydrochloric acid. The crystalline product was isolated and washed successively with water and ether. 4.90 g (11.30 mmol, 75% yield) of a pale pink solid was obtained.

R _f : 0.40 (ethyl acetate).

'H-ΝMR (300 MHz, DMSO-d ₆ , δ / ppm): 10.09 (1H, s), 9.31 (1H, s), 8.07 (1H, d), 7.62 (1H, s), 7.61 (1H, d), 7.53 (1 H, t), 7.24 (1H, dd), 7.1 1 (1H, t), 6.78 (1H, dd), 4.49 (2H, d), 4.1 1 (2H, t), 3.13 ( 2H, t), 2.13 (3H, s), 1.22 (6H, s). MS (ESI +,

CH ₃ CΝ / Η ₂ O / CH ₃ CO ₂ H, m / z): 434.2 (M + H ⁺ ).

In the same manner, the other N-acetyl-indoline and isoindoline sulfonamides of Examples 25, 28, 32, 33, 18, 36, 56, 50, 49, 63, 61 and 59, as shown in the table below, manufactured.

B) N-ethyl (iso) indoline sulfonamides

Example 19

N- (N-Ethylindolin-5-sulfonyl) -N '- (3-fluoro-2,2-dimethylpropanoyl) -l, 3-diaminobenzene

At 0 ° C a solution of 1.0 g (2.31 mmol) of N- (yV-acetylindolin-5-sulfonyl) - N '- (3-fluoro-2,2-dimethylpropanoyl) -l, 3-diaminobenzene in 30 ml of dry THF

2.80 ml (2.77 mmol) of a 1 molar solution of lithium aluminum hydride in THF implemented. The ice water bath was removed and stirring continued at room temperature for 2 hours. The reaction was stopped by adding methanol. The mixture was diluted with ethyl acetate and washed successively with aqueous Seignette saline, aqueous (5%) sodium hydrogen phosphate solution, water and brine and dried over anhydrous sodium sulfate.

The product was purified by preparative HPLC. 105 mg (0.25 mmol, 11% yield) of a white solid were obtained.

Rj: 0.17 (cyclohexane / ethyl acetate, 1: 1). 'H NMR (300 MHz, DMSO-d ₆ , δ / ppm): 9.87 (1H, s), 9.31 (1H, s), 7.51 (1H, t), 7.42

(1H, dd), 7.34 (1H, d), 7.23 (1H, dd), 7.10 (1H, t), 6.78 (1H, d), 4.49 (2H, d), 3.44 (2H, t), 3.17 ( 2H, quart.), 2.91 (2H, t), 1.05 (3H, t). MS (ESI +, CH ₃ CN / H ₂ O / CH ₃ CO ₂ H, m / z): 442 (M + Na ⁺ ), 420 (M + H ⁺ ).

The other N-ethylindoline and isoindoline sulfonamides of Examples 15, 20, 35, 30, 34, 8, 11, 27, 46, 41, 40, 62, 60 and 57 of the following table were obtained in the same way.

C) (Iso) indoline sulfonamides

Example 16

4- [N- (5-indolinesulfonyl)] amino-N- (tert-butyl) benzoic acid amide

300 mg (0.72 mmol) of [N- (N-acetylindoline-5-sulfonyl)] amino-N-tert-butyl) benzoic acid amide were dissolved in 21 ml of aqueous (5%) lithium hydroxide solution. The mixture was kept at 60 ° C for 24 hours. After cooling, aqueous (5%) sodium hydrogen phosphate solution was added. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine successively and over anhydrous Dried sodium sulfate. The product was recrystallized from ether. 230 mg (0.62 mmol, yield 85%) of a white solid were obtained.

R _f : 0.56 (ethyl acetate). 'H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.18 (1H, s), 7.63 (2H, d), 7.53 (1H, s),

7.36 (1H, d), 7.35 (1H, s), 7.08 (2H, d), 6.42 (1H, s), 6.41 (1H, d), 3.49 (2H, t), 2.93 (2H, t), 1.32 (9H, s). MS (CI, NH ₃ , mz): 391 (M + NH ₄ ⁺ ), 374 (M + H ⁺ ).

In the same way, the other indoline and isoindoline sulfonamides of Examples 24, 38, 23, 37, 31, 55, 54, 53, 58, 65 and 64 of the following table were obtained.

D) N-Acetylindol sulfonamides

Example 2

4- [N-Acetylindol-5 -sulfonyl] amino-N- (tert-butyl) benzoic acid amide

A mixture of 200 mg (0.481 mmol) of 4- [N-acetylindoline-5-sulfonyl] amino-N-tert-butyl) benzoic acid amide and 164 mg (0.722 mmol) of DDQ in 10 ml of dry 1,4-dioxane was used for 48 Heated under reflux for hours. After 6 and 24 hours, 80 mg (0.352 mmol) of DDQ were added in each case. The product was isolated by flash chromatography (silica gel, ethyl acetate / cyclohexane, 4: 1). 85 mg (0.206 mmol, 42% yield) of a white solid were obtained.

1 ^: 0.62 (ethyl acetate).

Η NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.54 (1H, s), 8.43 (1H, d), 8.1 1 (1H, d), 8.01 (1H, d), 7.74 (1H, dd), 7.61 (2H, d), 7.53 (1H, s), 7.1 1 (2H, d), 6.88 (1H, d), 2.66 (3H, s), 1.30 (9H, s). MS (CI, NH ₃ , m / z): 431 (M + NH ₄ ⁺ ), 414 (M + H ⁺ ).

In the same way, the other N-acetylindole sulfonamides of the examples

4, 7, 21, 29, 13, 43, 47 and 48 of the following table. E) N-Ethylindolsulfonamides

example 1

N - [(N-Ethylindol) -5-sulfonyl] -N '- (3-fluoro-2,2-dimethylpropanoyl) -l, 3-diaminobenzene and 27 mg (0.25 mmol) DDQ in 7 ml dry 1,4-Dioxane was refluxed for 3 hours. After evaporation of the solvent, the product was isolated by flash chromatography (silica gel, cyclohexane / ethyl acetate, 1: 1). 55 mg (0.132 mmol, 79% yield) of a white solid were obtained.

R _f : 0.30 (cyclohexane / ethyl acetate, 1: 1).

Η NMR (300 MHz, DMSO-d ₆ , δ / ppm): 10.08 (1H, s), 9.80 (1H, s), 8.07 (1H, d), 7.63-7.52 (4H, m), 7.21 (1H , d), 7.08 (1H, t), 6.81 (1H, d), 6.59 (1H, d), 4.48 (2H, d), 4.22 (2H, quart,), 1.32 (3H, t), 1.20 (6H , s). MS (CI, NH ₃ , m / z): 435 (M + NH ₄ ⁺ ), 418

(M + H ⁺ ).

In the same way, the other N-ethylindolsulfonamides of Examples 9, 22, 3, 5, 10, 44, 51 and 45 of the following table were obtained.

F) Indole sulfonamides

Example 6

4- [N- (Indole-5-sulfonyl)] amino-N- (tert-butyl) benzoic acid amide

A mixture of 230 mg of 4- (indoline-5-sulfonyl) amino-N- (tert-butyl) benzoic acid amide and 210 mg (0.924 mmol) of DDQ in 10 ml of dry 1,4-dioxane was used for 4

Heated under reflux for hours. After evaporation of the solvent, the product was purified by flash chromatography (silica gel, cyclohexane / ethyl acetate, 1: 1) isolated. 78 mg (0.21 mmol, 34% yield) of a white solid were obtained.

R _f : 0.30 (dichloromethane / methanol, 100: 5). Η NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.58 (IH, s), 10.40 (IH, s), 8.08 (IH, s),

7.60 (2H, d), 7.52-7.50 (4H, m), 7.12 (2H, d), 6.60 (IH, d), 1.30 (9H, s). MS (CI, NH ₃ , m / z): 743 (2M + H ⁺ ), 389 (M + NH ₄ ⁺ ), 372 (M + H ⁺ ).

The other indole sulfonamides of Examples 12, 17, 42, 52 and 39 in the following table were obtained in the same way.

The following table shows Examples 1 to 65, their structural formulas and the Rp values obtained.

[a] solvent:

A: Ethyl acetate

B: Cyclohexane / ethyl acetate (V / V = 1: 1)

C: Cyclohexane / ethyl acetate (V / V = 2: 1)

D: dichloromethane / methanol (V / V = 100: 1)

E: ethyl acetate / methanol (V / V = 4: 1)

The group -N- in the notation of the formulas in the table above means that the group may be saturated by a hydrogen atom (-NH-) •

Claims

claims

1. Compounds of the general formula (I)

woπn

R ^{1 represents} a group selected from the following formulas

wherein

- represents a single or a double bond,

R ^{3 represents} hydrogen, (C ^ C ^ alkyl or (C ₃ -C ₆ ) cycloalkyl, each of which may be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, amino, mono - or di (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkanoyloxy, Carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl and

Cyano, or

C ₁₀ ) aryl group can in each case be substituted by 1 to 3 substituents which are selected from the group consisting of halogen,

(C _r C ₃ ) alkyl, carboxy, (C ₁ -C ₃ ) alkoxycarbonyl, carbamoyl, mono- or di (C _r C ₆ ) alkylamino-carbonyl, cyano, hydroxy and (C _r C ₃ ) alkoxy, or

R ^{3 represents} (C ₁ -C ₆ ) alkanoyl, (C _r C ₆ ) alkylsulfonyl, (C ₃ -C ₆ ) cycloalkylcarbonyl, camphorsulfonyl or (C ₃ -C ₆ ) cycloalkylsulfonyl, or

R ^{3 represents} R ⁴ -X-CO- or R ⁴ -X-CS-, wherein

X represents O, S, NR ⁵ , wherein R ^{5 represents} hydrogen or (C _r C ₃ ) alkyl, and

R ^{4 represents} (C _r C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl, and

R ² for

R ⁷ R ^b N —CO-R ^ö or -CO— N— R ⁷ , wherein

R ^{6 is} (C ₂ -C ₆ ) alkenyl or (C _r C ₈ ) alkyl, which is optionally protected one to three times the same or different by amino

Amino, (C ₁ -C ₄ ) alkylamino, hydroxy, cyano, halogen, azido, nitro, trifluoromethyl, carboxyl or phenyl is substituted, whereby phenyl in turn is up to two, identical or different, by nitro, halogen, hydroxy, (C ₁ - C ₄ ) alkyl or (CC ₄ ) alkoxy may be substituted, or

R ⁶ for residues of the formulas or -LO-CO-Q stands,

wherein

represents (C ₁ -C ₆ ) alkyl, which is optionally substituted by carboxyl, or

10 for remnants of the formulas

ιo _R n stands wherein

the number 1 or 2 means

15

R ^{8 represents} hydrogen,

R ^{9 is} (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or hydrogen, or (C ₁ -C ₈ ) alkyl,

20 where the (C ₁ -C ₈ ) alkyl is optionally substituted by cyano, methylthio, hydroxy, mercapto, guanidyl or by a group of the formula -NR ¹² R ¹³ or R ¹⁴ -OC-,

25 where R ¹² and R ¹³ independently of one another are hydrogen, (C, -C ₈ ) alkyl or phenyl, 5 and

R ¹⁴ denotes hydroxy, benzyloxy, (C ₁ -C ₆ ) alkoxy or the group 10 -NR ^{, 2} R ¹³ listed above,

or the (C _r C ₈ ) alkyl is optionally substituted by (C ₃ -C ₈ ) cycloalkyl or by (C ₆ -C ₁₀ ) aryl, which in turn is substituted by hydroxy, halo, nitro, (C ₁ -C ₈ ) -alkoxy or through the

Group -NR ¹² R ^{13 is} substituted,

where R ¹² and R ^{13 have} the meaning given above,

20 or the (C ₁ -C ₈ ) alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or by indolyl, in which the corresponding -NH functions

25 optionally substituted by (C ₁ -C ₆ ) alkyl or protected by an amino protecting group,

R '° and R "are the same or different and represent hydrogen or an amino protecting group, R ^{7 represents} hydrogen or a radical of the formula

^stands - in what

R ⁸ , R ⁹ , R '° ^' and R ^{11 have} the meaning given above for R ⁸ , R ⁹ , R ¹⁰ and R "and are the same or different with this,

and their salts.

2. Compounds according to claim 1 of the formulas

wherein R ¹ and R ^{2 have} the meaning given above.

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

R ^{1 represents} a group selected from the formulas:

wherein

- represents a single or a double bond, and

R ^{3 has} the meaning given above, and their salts.

4. Compounds of general formula (I) according to any one of claims 1 to 3, wherein

R ^{3 represents} hydrogen, (C _r C ₆ ) alkyl or (C _r C ₆ ) alkanoyl, and

R ² for

R 'R ^b ^"N - ^C ° - ^R6 or -CO-NR ⁷ _stand wherein

R ^{7 is} hydrogen,

and their salts.

5. Compounds of general formula (I) according to any one of the claims

1 to 4, wherein R ^{6 is} tert-butyl, which is optionally substituted by halogen or hydroxy, and their salts.

6. A process for the preparation of the compounds of formula (I) according to claim 1, characterized in that

(A) compounds of the general formula (II) wherein R ^{1 is} as defined above, with compounds of the general

Formula (III)

wherein R ^{2 is} as defined above, to give compounds of the general formula (I),

(B) compounds of the general formula (Ia)

wherein R ^{2 is} as defined above, and

R ^{1a represents} a group selected from the following formulas:

with compounds of formula (IV)

R ³ -A (IV) wherein R ^{3 is} as defined above and A is a customary leaving group, in a manner known per se in the presence of a base to give compounds of the general formula (Ib):

_R. ! _ _NH γγ ^F

(Ib) wherein R ^{2 is} as defined above and R ^{1b represents} a group selected from the following formulas:

wherein R is as defined above, or

(C) compounds of the general formula (Ic)

wherein R ^{2 is} as defined above, R ^{d represents} a group selected from the following formulas:

wherein R ^{3 is} as defined above, or

(D) compounds of the general formula (Ie)

wherein R ^{2 is} as defined above and R ^{1e has} the following formulas:

converts tallhydroxiden to compounds of formula (Ia), which is as defined above, or

(E) compounds of the general formula (If)

wherein R ^{2 is} as defined above and R ^{1f has} the following formulas: where R ^{3 is} (C ₁ -C ₆ ) alkanoyl, in a manner known per se with complex metal hydrides to give compounds of the general formula (gh):

wherein R ^{2 is} as defined above and R ^{1α has} the following formulas:

wherein R ^{3c is} (C ₁ -C ₆ ) alkyl.

7. Compounds according to claim 1, for use as a medicament.

8. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1 in admixture with at least one pharmaceutically acceptable carrier or excipient.

9. Use of the compound of general formula (I) according to claim 1 for the manufacture of a medicament.

10. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections, in particular infections by cytomegaloviruses.