WO2000068186A1

WO2000068186A1 - Bis-sulfonamide with anti-hcmv effect

Info

Publication number: WO2000068186A1
Application number: PCT/EP2000/003687
Authority: WO
Inventors: Siegfried Goldmann; Wolfgang Bender; Jürgen Reefschläger; Peter Eckenberg; Michael Härter; Sabine Hallenberger; Jörg TRAPPE; Olaf Weber
Original assignee: Bayer Aktiengesellschaft
Priority date: 1999-05-06
Filing date: 2000-04-25
Publication date: 2000-11-16
Also published as: AU4555700A; DE19920790A1

Abstract

The invention relates to compounds of formula (I), wherein A, D, E and R1-R5 have the meaning cited in the description. The invention also relates to a method for the production and utilization thereof as medicament, especially as antiviral agents, particularly against human cytomegalovirus.

Description

Bis-sulfonamides with anti-HCMV activity

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 represents hydrogen or a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon group with 1 to 14 carbon atoms, in which case one or two carbon atoms in the chain can optionally be replaced by O or S, and which can be substituted by one to three substituents, which are selected from the group consisting of hydroxy, cyano, -N (R ⁶ ) R ⁷ , (C, -C ₆ ) alkoxycarbonyl, (C ₆ -C ₁₀ ) Nryl and 5- to 10-glie- drigem heteroaryl, where (C ₆ -Cιo) aryl and 5- to 10-membered heteroaryl may in turn be substituted by one to three substituents consisting of hydroxy, (GC ₆ ) alkyl, (Cι-C ₆ ) alkoxy, (GC ₆ ) -alkoxycarbonyl, halogen and halogen (-C-C ₆ ) alkyl are selected, and wherein

R ⁶ and R ^{7 are the} same or different and represent hydrogen, (C- _. -C ₆ ) alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon group with 1 to 10 carbon atoms, optionally with di (Cι- C ₆ ) alkylamino is substituted, or together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclic ring which can optionally be substituted by 1 to 3 (GC ₆ ) alkyl groups and or or or can contain two further heteroatoms selected from O, S or N,

or

R ^{1 represents} (C ₆ -Cιo) aryl or 5- to 10-membered heteroaryl, which can optionally be substituted by one to three substituents n, which are selected from the group consisting of (C - C ₆ ) alkyl , Hydroxy, (GC ₆ ) alkoxycarbonyl, halogen and amino, or

R stands for (-CC ₆ ) alkoxy, (Cr C ₆ ) alkoxycarbonyl, aminocarbonyl or may have one of the meanings of R mentioned above and may be the same or different from this meaning,

or

R and R together with the nitrogen atom to which they are attached form a saturated or unsaturated ring with up to 14 carbon atoms, the

Ring carbon atoms optionally by 1 to 4 radicals selected from the group Group consisting of O, S, S = 0, C = O and NR can be replaced, and where the ring can optionally be substituted by one to three substituents selected from the group consisting of hydroxy, (-C-C ₆ ) alkyl, benzyl, hydroxy (C] -C ₆ ) alkyl, phenylamino, benzoyl, (C ₁ -C ₆ ) acyl, (C _t -C ₆ ) alkoxy carbonyl, aminocarbonyl, mono- or di (-C-C ₆ ) alkylaminocarbonyl,

Morpholinocarbonyl, phenylaminocarbonyl, (C- _. -C ₆ ) alkoxycarbonyl- (-C-C ₆ ) - alkyl, (dC ^ alkoxyaminocarbonyl, (Cι-C ₆ ) -alkoxycarbonyl-amino, 1,3-dioxolane-2,2-diyl , Piperidyl, piperidino and imino,

wherein

R ^{8 represents} hydrogen, a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon group having up to 10 carbon atoms, which may be selected by 1 to 3 radicals from the group consisting of hydroxyl, pyrrolidinyl, pyridyl, phenyl, halophenyl, halogen (-C-C ₃ ) alkylphenyl and (-C-C ₆ ) alkoxycarbonyl exists, can be substituted,

or

R for (-CC ₆ ) alkoxycarbonyl, ( ₆ -C -oo) aryl or 5- to 10-membered

Heteroaryl is where (C6-Cιo) aryl and 5- to 10-membered heteroaryl can in turn be substituted by one to three substituents which are selected from the group consisting of halogen, hydroxy, (CC ₆ ) alkoxy, nitro and fluorine (CC ₃ ) alkyl, R ^{3 represents} hydrogen, halogen, hydroxy, (GC ₆ ) acyl, benzoyl or (GC ₆ ) acyloxy,

R ⁴ and R ^{5 are} independently a (GC ₃ ) alkyl group or together with the carbon atom to which they are attached form a 3- to 6-membered carbocyclic ring,

A is a divalent (C ₆ -C ₁ o) aryl radical or a divalent 5- to 10-membered heteroaryl radical which may be optionally substituted by one to three substituents selected from the group consisting of (C * -C ₃ ) Alkyl, hydroxy or halogen atoms, and

D and E are the same or different and represent hydrogen, fluorine, chlorine, nitro, cyano, hydroxy or (GC ₃ ) alkyl (GC ₃ ) alkoxy or (C, -C ₃ ) alkoxycarbonyl,

and their pharmaceutically acceptable 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 with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, 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. Particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, 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 either behave like images and mirror images (enantiomers) or do not behave like images and mirror images (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, a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon group having 1 to 14 carbon atoms includes, for example, a straight-chain or branched alkyl radical having 1 to 14 carbon atoms, a straight-chain or branched alkenyl radical having 2 to 14 carbon atoms, a straight-chain or branched Alkynyl radical with 2 to 14 carbon atoms and a saturated or unsaturated cyclic hydrocarbon radical with 3 to 6 carbon atoms in the definition of R ¹ . Furthermore, radicals in which 1 to 2 carbon atoms of the abovementioned hydrocarbon groups in the chain can be replaced by O or S, for example (C 1 -C 6) alkoxyalkyl, (C 1 -C 6) alkylthioalkyl radicals. Regarding the straight-chain or branched alkyl group with 1 to 14 carbon atoms, examples may be mentioned: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, nonyl, decyl, Undecyl and dodecyl.

Examples of straight-chain or branched alkenyl groups with 2 to 14 carbon atoms are: allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.

As the alkynyl group having 2 to 14 carbon atoms, straight-chain or branched radicals can be mentioned which have one or more C könnenC groups. Alkynyl radicals having 2 to 8 carbon atoms are preferred and, for example, acetylenyl, 2-butynyl, 2-pentynyl and 2-hexynyl may be mentioned.

The above-mentioned cycloalkyl group having 3 to 6 carbon atoms includes, for example, cyclopropyl, cyclopentyl and cyclohexyl. Cyclopropyl is preferred.

The straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon group having 1 to 14 carbon atoms in the definition of R 1 is preferably a straight-chain alkyl group having 1 to 12 carbon atoms or a (C i -C ₆ ) alkoxy (C i -C6) alkyl group.

Regarding the (-C -Cg) alkoxy group, reference is made to the definition mentioned below.

(-C -Cg) alkyl in the context of the invention generally represents straight-chain or branched-chain hydrocarbon radicals having 1 to 6 carbon atoms, and in this regard reference is made to the groups mentioned by way of example in the explanations for the alkyl group having 1 to 14 carbon atoms above. The (Cι-C6) alkoxy group, as used in the present invention, and as they also in the definitions (Cι-C6) alkoxycarbonyl, (Cι-Cö) alkoxycarbonyl (Cι-Cö) alkyl and (Cι -C6 ) Alkoxycarbonylamino used includes, for example, straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms, particularly preferably alkoxy groups having 1 to 4 carbon atoms, more preferably alkoxy groups having 1 to 3 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy and isohexoxy can be mentioned. Methoxy, ethoxy and propoxy are preferred.

The straight chain, branched or cyclic, saturated or unsaturated hydrocarbon group with 1 to 10 carbon atoms in the definition of R ^ and R ^ includes, for example, the above for the definition of the straight chain, branched chain or cyclic, saturated or unsaturated hydrocarbon groups with 1 to 14 carbon atoms in the definition of Rl groups with 1 to 10 carbon atoms. A straight-chain or branched-chain (Ci-Cg) alkyl group is preferred here.

In the context of the invention, (C 1 -C 6) alkylamino includes the alkylamino groups whose alkyl groups have 1 to 6 carbon atoms. These can be symmetrical or asymmetrical alkylamino groups, such as dimethylamino, diethylamino, methyl, ethylamino, etc.

3 to 8 rings which R6 and R ^* * ^{7 can form} together with the nitrogen atom to which they are attached include, for example, pyrrolidine, piperidine, morpholine etc.

In the context of the invention, (Cg-Cι o) aryl stands for an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl. 5- to

In the context of the invention, 10-membered heteroaryl is 5- to 10-membered Rings containing heteroatoms, which can contain 1 to 4 heteroatoms, which are selected from O, S and N and include, for example, pyridyl, furyl, thienyl, pyrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinizyl, indolyl, benzo [b] thienyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, etc.

Preferred are 6- or 10-membered aromatic heterocycles which can optionally be substituted as defined in the claims.

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

Halogen (C 1 -C 6) alkyl in the context of the invention includes (C 1 -C 6) alkyl groups, as defined above, which can be substituted by 1 to 3 halogen atoms, preferably fluorine or chlorine, such as monofluoroalkyl groups having 1 to 3

Carbon atoms, monochloroalkyl groups with 1 to 3 carbon atoms, and difluoroalkyl groups with 1 to 6 carbon atoms, dichloroalkyl groups with 1 to 6 carbon atoms and trifluoro or trichloroalkyl groups with 1 to 6 carbon atoms. With regard to the alkyl groups, reference is made to the above explanations.

Fluoromethyl, chloromethyl and trifluoromethyl are particularly preferred.

Saturated or unsaturated rings with up to 14 carbon atoms, the R * and R-2 together with the nitrogen atom to which they are attached and in which 1 to 4

In the context of the invention, ring carbon atoms can be replaced by 1 to 4 radicals selected from the group consisting of O, S, S = O, C = O and N-R8, for example: morpholino, piperazinyl, piperidyl, which, if appropriate may be mono- or di-unsaturated, 1-azacycloheptane, 1,4-diazacycloheptane, pyrrolidinyl, thiomorpholino (l, 4-thiazinan-4-yl), 1-azacyclooctan-l-yl, 1-aza- cycloheptan- 1 -yl, 1, 3-thiazolidin-3-yl, 1-aza-4,7, 10, 13 -tetraoxocyclopentadecan- 1-yl and dihydropyrrol-1-yl.

With regard to straight-chain, branched-chain or cyclic, saturated or unsaturated hydrocarbons with up to 10 carbon atoms in the definition for

R8 is referred to the above-mentioned definition of straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon groups with 1 to 10 carbon atoms in the definition of R "and R.

In the context of the invention, fluoro (C 3 -C 3) alkyl includes alkyl groups with 1 to 3

Carbon atoms with up to 3 fluorine atoms such as Trifluoromethyl.

In the context of the invention, hydroxy (C 1 -C 6) alkyl includes the above-mentioned straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms, which can be substituted by 1 to 3 hydroxyl groups. Hydroxy-methyl is preferred.

In the context of the invention, (C 1 -C 6) acyl and (C 1 -C) acyl in the definition (C 1 -C 6) acyloxy stand for straight-chain or branched-chain alkanoyl with 1 to 6 carbon atoms. Examples include: formyl, acetyl, propanoyl,

Isopropanoyl, butanoyl, isobutanoyl, pentanoyl and hexanoyl.

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

Rl stands for hydrogen, a (Cß-Cß ^ cycloalkyl group, a (C2-Cö) alkenyl group or a straight-chain or branched-chain (Cj-C 12) - alkyl group, in which a chain carbon atom is optionally replaced by oxygen, and the may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, cyano,

-N (R ⁶ ) R ⁷ , (Cι-C6) alkoxycarbonyl, (C ₆ -Cιo) aryl and 5- to 10-glie- third heteroaryl, where (C -C \ Q) aryl \ and 5- to 10-membered heteroaryl may in turn be substituted by 1 to 3 substituents which are selected from (Ci -C3) alkoxy and (Ci -C3) -Alkyl, and

woπn

R6 and R ^{7 are the} same or different and represent hydrogen, (Ci -Cß) -

Alkoxycarbonyl and / or (Cι -Cö) alkyl, which if necessary by

Di (C ₁ -C ₆ ) alkylamino is substituted, or together with the nitrogen atom to which they are attached, a 3 to

Form a 6-membered heterocyclic ring which may optionally contain an additional oxygen atom,

or

Rl represents phenyl or 5- to 10-membered heteroaryl, which may contain 1 to 2 heteroatoms selected from nitrogen and sulfur, each optionally with 1 to 2 substituents selected from amino, (C1 -C3) -

Alkyl, hydroxy, (-C-C4) alkoxycarbonyl and halogen, may be substituted, or

R2 stands for (C 1 -C 6) alkyl, (C 5 -C 6) alkoxy, and aminocarbonyl, or can have the abovementioned meaning of R ¹ and can be identical or different from this meaning, or

Rl and R2 together with the nitrogen atom to which they are attached form a saturated or unsaturated ring having 4 to 14 carbon atoms, the ring carbon atoms of which are optionally selected from 1 to 4 radicals from the group consisting of O, S, S = O, C = O and NR °, may be replaced, and the ring may optionally be substituted by 1 to 3 substituents selected from the group consisting of Imino, hydroxy, (Cι-C3) alkyl, l, 3-dioxolane-2,2-diyl, (Cι -C3) alkoxycarbonyl, (Cι -Cg) alkoxycarbonylamino, benzyl, phenylamino, piperidyl, hydroxy- (Cι- C3) alkyl, benzoyl, aminocarbonyl, (Cι -C3) acyl, (C \ -C) - alkylaminocarbonyl, morphohnocarbonyl and phenylaminocarbonyl,

and in what

R * for hydrogen, a straight-chain or branched-chain (Ci -Cg) -

Alkyl group which can optionally be selected by 1 to 2 substituents, which can be substituted from the group consisting of

Phenyl, hydroxy, halophenyl, pyrrolidinyl and (-C -C3) alkoxycarbonyl, or

R8 stands for (C3-C6) cycloalkyl or phenyl, which can optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C 1 -C 3) alkoxy, nitro and trifluoromethyl, or

R8 represents pyridyl or (Ci-Cg) alkoxycarbonyl,

R3 represents hydrogen, halogen, hydroxy or (Ci -C3) acyloxy,

and

R ^ and R-5 each independently represent a (C1-C3) alkyl group,

A represents a naphthalenediyl radical or a phenylene radical, which may optionally be substituted by a (C 3 -C 3) alkyl group, halogen or hydroxy, and

D and E represent hydrogen, and their pharmaceutically acceptable salts.

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

Rl represents hydrogen, cyclopropyl, or a straight-chain or branched-chain (Ci-C3) alkyl group,

or

Rl represents phenyl, which may optionally be substituted by hydroxy,

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

Rl and R2 together with the nitrogen atom to which they are attached form a ring which is selected from the group consisting of morpholino, which may optionally be substituted by 1 to 3 (C1-C3) alkyl groups,

Thiomorpholino,

a 5- to 8-membered saturated ring, in which a ring carbon atom can optionally be replaced by a group of the formula -NR ⁸ , wherein

R is selected from hydrogen, (C1-C3) alkyl, which can optionally be substituted by phenyl, phenyl and cyclopropyl, and which is optionally selected from 1 to 2 substituents from oxo, (-C -Czi) alkanoyl, phenyl, which is optionally replaced by ( Cj-C- ^ alkoxy may be substituted, benzoyl may be substituted, R ^ represents hydrogen, chlorine, fluorine or acetyloxy,

R ⁴ and R ^{5 represent} methyl,

A represents naphthalene-1, 5-diyl or 1,3-phenylene, which is optionally by

Chlorine or fluorine may be substituted, and wherein

D and E represent hydrogen.

In a further preferred embodiment, the invention includes compounds of the following formula (V):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A are as defined above.

In a further preferred embodiment, the invention includes compounds of formula (I) or (F), wherein A is naphthalenediyl.

In a further preferred embodiment, the invention includes compounds of formula (I) or (I '), wherein

R3 represents hydrogen or halogen,

R ⁴ and R ^ each represent a methyl group,

A represents a phenylene or naphthalenediyl radical, and

D and E represent hydrogen. The invention further relates to a process for the preparation of compounds of the general formula (I) or (V) (the compounds of the general formula (I) include the compounds of the general formula (F)), characterized in that compounds of the general formula (II)

wherein the substituents have the meaning given above, with amines of the general formula (III)

H

N (HI)

in which the substituents have the meaning given above, or

Compounds of the general formula (IV)

wherein the substituents have the meaning given above, with carboxylic acid chlorides of the general formula (V)

in which the substituents have the meaning given above, or a process in which compounds of the formula (VI)

wherein the substituents have the meaning given above, with anilines of the formula (VII)

wherein the substituents have the meanings given above.

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

The usual inert solvents which do not change under the reaction conditions are suitable as solvents for all process steps. These preferably include organic solvents such as ethers e.g. Diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid triamidine, triamidine, triamidine, or trisaminophenamide,. It is also possible to use mixtures of the solvents mentioned, if appropriate also with water. Methylene chloride, tetrahydrofuran, pyridine and dioxane are particularly preferred.

Suitable bases are organic amines, in particular trialkyl (C ₁ -C ₆ ) amines such as triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or N-methylmorpholine. Pyridine, triethylamine and N-methylmorpholine are preferred. The reactions can be carried out under normal pressure, but also under elevated or reduced pressure (for example 0.5 to 3 bar). Generally one works at normal pressure.

The reactions are carried out in a temperature range from 0 ° C. to 100 ° C., preferably at 0 ° C. to 30 ° C. and under normal pressure.

The invention further relates to compounds of formula (I) or (1 ') for use as a medicament.

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

The invention further relates to the use of the compound of the general

Formula (I) or (F) for the manufacture of a medicament.

The invention further relates to the use of a compound of the general formula (I) or (F) 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 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 substances on the spread of the The cytopathogenic effect was determined in comparison to the reference substance ganciclovir (Cymevene ^R sodium), a clinically approved anti-HCMV chemotherapeutic.

The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on microtiter plates (96-well) in duplicate (4 substances / plate). Toxic and cytostatic effects are also included. After the appropriate substance dilutions (1: 2) on the microtiter plate, a suspension of 50-100 HCMV-infected HELF cells and 30 x 10 ⁵ non-infected HELF cells in Eagle's MEM with 10% fetal calf serum in each

Wells were given, and the plates were incubated at 37 ° C. in a CO 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 with the aid of a projection microscope (plaque viewer). The results for some compounds are summarized in the following table:

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 areas of indication can be mentioned, for example:

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 checked using a plaque assay on primary embryonic mouse fibroblasts. is looking for. 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 approx. 11 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 ₂₆ ox50 = mg / ml.

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

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 wash buffer 1 for 3 minutes. The filters were then used for 30

Incubated for 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: 20,000 in 1 x digoxygenin blocking solution). 2 washing steps of 15 minutes each with 1 x digoxygenin washing puff followed. It followed 5 minutes

Equilibration of the filters in 1 x digoxygenin detection buffer and detection using 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 compounds 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 a 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 intravitreally, 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 for intravenous administration

Amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg of body weight to achieve effective results, and with 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 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

Output connections:

Example I

5- {4 - [(3-chloro-2,2-dimethylpropanoyl) amino] anilino} sulfonyl-l-naphthalenesulfonyl chloride

8.0 g (24.6 mmol) of 1,5-naphthalenedisulfonyl chloride are dissolved in 200 mL of dry THF and, while stirring, first with 5.58 g (24.6 mmol) of N- (4-aminophenyl) -3-chloro-2 , 2-dimethylpropanamide (synthesis analogous to: Rajappa, Srinivasacha; Sreenivasan, Ramaswami; Khalwadekar, Asha, JRMPDM, J. Chem. Res. Miniprint, EN, 5, 1986, 1657-1675) and then with 2 g NaHCO ₃ (in 30 ml of water) are added. After 30 min, ethyl acetate is added and the mixture is extracted twice with water. The organic phase is dried and concentrated. Chromatography on silica gel (cyclohexane: ethyl acetate = 1: 1) gives 9.0 g (71%) of product. FP: 184 ° C (Rf value: 0.36, cyclohexane: ethyl acetate = 1: 1). Example II

5- {4 - [(3-Acetoxy-2,2-dimethylpropanoyI) amino] anilino} sulfonyl-l-naphthalenesulfonyl chloride

The preparation is analogous to Example I. Yield: 52%, Rf: 0.28 (cyclohexane: ethyl acetate = 1: 1).

Example III

4-nitro-phenyl- (2,2-dimethyl-3-fluoro) propanamide

30 g (217 mmol) of 4-nitroaniline are dissolved in 600 ml of dioxane and 43 g of pyridine and cooled with 35 g (250 mmol) of 2,2-dimethyl-3-fluoropropanoyl chloride (EP-A-

240818). After 30 h at RT, the mixture is diluted with 3 l of water, suction filtered and washed. 47 g (90%) of product are obtained. Example IV

4-aminophenyl- (2,2-dimethyl-3-fluoro) propanamide

47.0 g (196 mmol) of 4-nitro-phenyl- (2,2-dimethyl-3-fluoro) propanamide are dissolved in 800 ml of dioxane and with 10 g of Pd / C (10%) for 40 h at room temperature and normal pressure hydrated. After the catalyst has been separated off, the mixture is concentrated and the residue is crystallized. Yield 37 g (90%).

End products:

example 1

3-Chloro-2,2-dimethyl-N- [4 - ({[5- (morpholinosulfonyl) -l-naphthyljsulfonyl} - amino) phenyl] propanamide

100 mg (0.19 mmol) of 5- {4 - [(3-chloro-2,2-dimethylpropanoyl) amino] anilino} sulfonyl-1-naphthalenesulfonyl chloride are dissolved in 2 ml of dry THF and with 84 mg (1 mmol) of morpholine transferred. After 3 h at RT, ethyl acetate is added and the mixture is extracted twice with water. The organic phase is dried over Na ₂ SO ₄ and concentrated. Residue 106 mg (99%). Rf value: 0.56 (CH ₂ Cl ₂ / MeOH = 9: l) Example 21

2,2-DimethyI-3-fluoro-N- [4- (3-dimethylaminosulfonylphenyl) sulfonylaminopheny 1] propanamide

0.32 g (1.5 mmol) of 4-aminophenyl- (2,2-dimethyl-3-fluoro) propanamide are dissolved in 6 ml of dioxane, with 0.39 g of pyridine and 0.57 g of 3-dimethylaminosulfonylbenzene - Sulfonyl chloride (WO 9736903) was added and the mixture was stirred at room temperature for 1 hour. 40 ml of water are added, the mixture is stirred for 15 h, pentane is added, the mixture is washed until neutral and concentrated. Yield: 0.45 g (66%) product.

The following were prepared analogously to Examples 1 and 21:

Eluent (LM)

(a) Methylene chloride / MeOH = 95: 1

(b) Petroleum ether / ethyl acetate = 1: 1

(c) Petroleum ether / ethyl acetate = 1: 2

(d) Methylene chloride / MeOH = 9: 1

(e) Methylene chloride / MeOH = 20: 1

(f) Methylene chloride / MeOH = 25: 1

-N- in the tables means -NH-

Claims

1. Compounds of the general formula (I):

wherein

R ^{1 represents} hydrogen or a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon group with 1 to 14

Carbon atoms, wherein one or two carbon atoms in the chain can optionally be replaced by O or S, and which can be substituted by one to three substituents selected from the group consisting of hydroxy, cyano, -N (R ⁶ ) R ⁷ , (- C ₆ ) alkoxycarbonyl, (C ₆ -Cιo) aryl and 5- to 10-membered heteroaryl, wherein (C ₆ -Cιo) aryl and 5- to 10-membered heteroaryl in turn are substituted by one to three substituents can be selected from hydroxy, (-C-C ₆ ) alkyl, (C-C ₆ ) alkoxy, (Cι-C ₆ ) alkoxycarbonyl, halogen and halogen (Cι-C ₆ ) alkyl, and wherein

R ⁶ and R ^{7 are the} same or different and are hydrogen, (C-- C ₆ ) alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon group with 1 to 10 carbon atoms, optionally with di (-C ₆ ) alkylamino is substituted, or together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclic ring which can optionally be substituted by 1 to 3 (C * -C ₆ ) alkyl groups and / or can contain one or two further heteroatoms selected from O, S or N,

or

R ^{1 represents} (C ₆ -Cιo) aryl or 5- to 10-membered heteroaryl, which may optionally be substituted by one to three substituents which are selected from the group consisting of (Ci

C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, halogen and amino, or

R ^{2 represents} (CrC ₆ ) alkoxy, (C] -C ₆ ) alkoxycarbonyl, aminocarbonyl or can have one of the meanings of R ¹ mentioned above and can be the same or different from this meaning,

or

R and R together with the nitrogen atom to which they are attached form a saturated or unsaturated ring with up to 14 C atoms, the ring carbon atoms of which may be 1 to 4

Residues selected from the group consisting of O, S, S = O, C = O and NR ⁸ can be replaced, and wherein the ring can optionally be substituted by one to three substituents selected from the group consisting of Hydroxy, (-C-C ₆ ) alkyl, benzyl, hydroxy (Cι- C ₆ ) alkyl, phenylamino, benzoyl, (Cι-C ₆ ) acyl, (Cι-C ₆ ) alkoxycarbonyl, aminocarbonyl, mono- or di ( C ₁ -C ₆ ) alkylaminocarbonyl, morphohnocarbonyl, phenylaminocarbonyl, (C * -C ₆ ) alkoxycarbonyl- (C i -C ₆ ) alkyl, (C ι -C ₆ ) alkoxyaminocarbonyl, (C i -C ₆ ) - alkoxycarbonylamino, 1,3-dioxolane-2,2-diyl, piperidyl, piperidino and imino, wherein R represents hydrogen, a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon group with up to 10 carbon atoms, which may be represented by 1 to 3

Residues selected from the group consisting of hydroxy, pyrrolidinyl, pyridyl, phenyl, halophenyl, halogen (-C-C ₃ ) alkylphenyl and (C ₁ -C ₆ ) alkoxycarbonyl, can be substituted, or

R ^{8 stands} for (-CC ₆ ) alkoxycarbonyl, (C ₆ -C _{] 0} ) aryl or 5- to 10-membered heteroaryl, with (C ₆ -C] o) aryl and 5- to 10-membered heteroaryl in turn one to three substituents can be substituted, which are selected from the group consisting of halogen, hydroxy, (-C-C ₆ ) alkoxy, nitro and fluorine (-C-C ₃ ) alkyl,

R> 3 represents hydrogen, halogen, hydroxy, (-C-C ₆ ) acyl, benzoyl or (CrC ^ acyloxy,

R ⁴ and R ⁵ independently of one another are a (C ₁ -C ₃ ) alkyl group or, together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring,

A represents a divalent (C ₆ -C) o) aryl radical or a divalent 5- to 10-membered heteroaryl radical which may optionally be substituted by one to three substituents which are selected from the group consisting of (C ₁ -C ₃ ) Alkyl, hydroxy or halogen atoms, and

D and E are identical or different and represent hydrogen, fluorine, chlorine, nitro, cyano, hydroxy or (C ₁ -C ₃ ) alkyl (dC ₃ ) alkoxy or (C ₁ -C ₃ ) alkoxycarbonyl,

and their pharmaceutically acceptable salts.

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

R ^{1 represents} hydrogen, a (C -Cg ^ cycloalkyl group, a (C ₂ -Cg) alkenyl group or a straight-chain or branched (C _j -C ^) - alkyl group in which a chain carbon atom is optionally replaced by oxygen, and the may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, cyano, -N (R ⁶ ) R ⁷ , (CC ^ -alkoxycarbonyl,

(C ₆ -C ₁ o) aryl and 5- to 10-membered heteroaryl, where (C6-Cιo) aryl and 5- to 10-membered heteroaryl may in turn be substituted by 1 to 3 substituents which are selected from (C ₁ -C 3) alkoxy and (C _j -C3) alkyl, and wherein

R ⁶ and R ^{7 are the} same or different and represent hydrogen, (C _j -Cg) -

Alkoxycarbonyl and / or (C Cg) alkyl, which is optionally substituted by di (C] -C ₆ ) alkylamino, or together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic ring, which can optionally contain an additional oxygen atom, or

R ^{1 represents} phenyl or 5- to 10-membered heteroaryl, which may contain 1 to 2 heteroatoms selected from nitrogen and sulfur, each optionally with 1 to 2 substituents selected from amino, (C Cß) - alkyl, Hydroxy, (C _j -C ^ alkoxycarbonyl and halogen, may be substituted, or

R ^{2 stands} for (CJ-C _Ö ) alkyl, (C C6) alkoxy, and aminocarbonyl, or may have the abovementioned meaning of R and may be identical or different from this meaning, or

R ¹ and R ² together with the nitrogen atom to which they are attached form a saturated or unsaturated ring with 4 to 14 carbon atoms, the ring carbon atoms of which are optionally selected from 1 to 4 radicals from the group consisting of O, S, S = O, C = O and NR ⁸ , may be replaced, and the ring may optionally be substituted by 1 to 3 substituents selected from the group consisting of imino, hydroxy, (C C3) alkyl, 1,3- Dioxolane-2,2-diyl, (C _j -C3) alkoxycarbonyl, (C _j -Cg) alkoxycarbonylamino, benzyl, phenylamino, piperidyl, hydroxy- (C C3) - alkyl, benzoyl, aminocarbonyl, (C * _[ - C3) acyl, (Ci-C ^ alkylamino-carbonyl, morphohnocarbonyl and phenylaminocarbonyl, and in which

R ^{8 represents} hydrogen, a straight-chain or branched-chain (C Cg) alkyl group, which can optionally be selected by 1 to 2 substituents, which can be substituted from the group consisting of phenyl, hydroxy, halophenyl,

Pyrrolidinyl and (C _j -C3) alkoxycarbonyl, or R ^{8 represents} (C3-C6) cycloalkyl or phenyl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C _j -C3) alkoxy, nitro and trifluoromethyl, or

R ^{8 represents} pyridyl or (C C 1-4 alkoxycarbonyl,

R ^{3 represents} hydrogen, halogen, hydroxy or (C _j -C3) acyloxy,

and

R ⁴ and R ⁵ each independently represent a (C1-C3) alkyl group,

A represents a naphthalenediyl radical or a phenylene radical, which may optionally be substituted by a (C1-C3) alkyl group, halogen or hydroxy, and

D and E represent hydrogen,

and their pharmaceutically acceptable salts.

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

R ^{1 represents} hydrogen, cyclopropyl, or a straight-chain or branched-chain (Cι-C3) alkyl group,

or

R ^{1 represents} phenyl, which may optionally be substituted by hydroxy, R ^{2 represents} hydrogen or (C _λ -C ₃ ) alkyl,

R ¹ and R ² together with the nitrogen atom to which they are attached form a ring which is selected from the group consisting of

Morpholino, which may optionally be substituted by 1 to 3 (C ₁ -C 3) alkyl groups,

Thiomo holino,

a 5- to 8-membered saturated ring in which an o

R Riinnggkkoohhlleennsatomatom can be replaced by a group of the formula -NR, wherein

O

R is selected from hydrogen, (C1-C3) alkyl, which may optionally be substituted by phenyl, phenyl and cyclopropyl, and which is optionally selected from 1 to 2 substituents from oxo,

Phenyl, optionally by

(C _j -C ^ alkoxy may be substituted, benzoyl may be substituted,

R ^{3 represents} hydrogen, chlorine, fluorine or acetyloxy,

R ⁴ and R ^{5 represent} methyl,

A represents naphthalene-1,5-diyl or 1,3-phenylene, which may optionally be substituted by chlorine or fluorine, and in which

D and E represent hydrogen.

. Compounds according to any one of claims 1 to 3 of the formula:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A are as defined above,

5. Compounds according to any one of claims 1 to 4, wherein A is naphthalenediyl.

6. A compound according to any one of claims 1 to 5, wherein

R ^{3 represents} hydrogen or halogen,

R ⁴ and R ⁵ each represent a methyl group,

A represents a phenylene or naphthalenediyl radical, and

D and E represent hydrogen.

Process for the preparation of compounds of the general formula (I) according to Claim 1, characterized in that compounds of the general formula (II)

wherein the substituents have the meanings given in claim 1, with amines of the general formula (III)

H I N (III)

R / ',

implements, or

Compounds of the general formula (IV)

wherein the substituents have the meanings given in claim 1, reacted with carboxylic acid chlorides of the general formula (V)

wherein the substituents have the meanings given in claim 1,

or a process in which compounds of the formula (VI)

wherein the substituents have the meanings given in claim 1, reacted with anilines of the formula (VII)

wherein the substituents have the meanings mentioned in claim 1.

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

9. Pharmaceutical composition, which is a compound of general

Formula (I) according to claim 1 in admixture with at least one pharmaceutically acceptable carrier or excipient.

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

11. 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.