CZ20002676A3 - Naphthyl substituted and anilide substituted sulfonamides, process of their preparation, their use and medicament in which these substances are comprised - Google Patents

Abstract

The present invention relates to novel naphthyl substituted and anilido substituted sulfonamides of formula I, v wherein the substituents have the meanings given in the descriptive part, the way they are made, their use as antiviral especially the cytomegalieviruses and drugs containing.

Description

Naphthyl-substituted and anilide-substituted sulfonamides, process for their preparation, their use and medicament containing them

Technical field

The invention relates to novel naphthyl-substituted and anilide-substituted sulfonamides, to a process for their preparation, to their use as antiviral agents, in particular against cytomegalieviruses and to medicaments containing these.

BACKGROUND OF THE INVENTION α, β-Naphthyl-bonded phenylsulfonamides are known mainly from phototechnical publications (see for example 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 and EP-284,130).

WO 90/09 787 discloses sulfonamides as radiosensitizing and chemosensitizing agents and their use in the treatment of tumors.

In addition, the compound N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl Jamino] phenyl] acetamide is known (J. Inst. Chem. (India) (1976), 48, Pt 6, 280-285).

SUMMARY OF THE INVENTION

The present invention provides naphthylsubstituted sulfonamides of formula (I).

NR-CO-R ³ (1) wherein

R and R are the same or different and represent a hydrogen atom, a formyl group, optionally a phenyl or benzyl group substituted with one to three halogen atoms or a straight or branched alkyl or acyl group of up to 6 carbon atoms in each case; wherein the alkyl or acyl group may be optionally substituted with one to three substituents from the group consisting of a halogen atom and a hydroxy group,

A, D, E and G are the same or different and are hydrogen, halogen, nitro, cyano, hydroxy, carboxyl, trifluoromethyl, trifluoromethoxy or a straight or branched alkyl, alkoxy or alkoxycarbonyl group of up to 5 carbon atoms each,

R represents a straight or branched alkenyl group having up to carbon atoms, or a straight or branched alkyl group having up to 8 carbon atoms optionally bearing an amino group which may be substituted by an alkyl group having up to 4 carbon atoms or an amino protecting group, or an alkyl group optionally one to three times ί

·· ·· ·· ······

equally or differently substituted by hydroxy, cyano, halogen, azido, nitro, trifluoromethyl, carboxy or phenyl, which may itself be substituted up to twice, equally or differently by nitro, halogen, hydroxy or straight or branched alkyl or alkoxy of up to Or 4 carbon atoms;

R ³ represents radicals of the formulas

/ CH ₃

- 1 or -L-O-CO-Q, -O wherein

L represents a straight or branched alkanediyl group of up to 6 carbon atoms and

Q represents an alkyl group of up to 6 carbon atoms which is optionally substituted by a carboxyl group or radicals of the formulas

or

R \ R ⁶ ^^ NR ⁷ R ⁸ denotes the number 1 or 2, 9 9, 9 9

R ³ represents hydrogen,

AND

R °. denotes cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms, hydrogen or straight or branched alkyl of up to 8 carbon atoms, the alkyl group being optionally substituted by cyano, methylthio, hydroxy, mercapto, guanidyl or a group of the formula -NR ⁹ R ⁴¹ or R ⁴⁴ -OC-, wherein

R ⁹ and Κ ⁴ θ independently represent a hydrogen atom, a straight or branched alkyl group having up to 8 carbon atoms or a phenyl group, and

R ⁴⁴ represents hydroxy, benzyloxy, alkoxy of up to 6 carbon atoms or the above -NR ⁹ R ¹⁰ , or the alkyl group is optionally substituted with cycloalkyl of 3 to 8 carbon atoms or aryl of 6 to 10 carbon atoms itself substituted with hydroxy, halogen, nitro, alkoxy of up to 8 carbon atoms or -NR ⁹ R ⁴ , wherein R ⁹ and R ⁴ are as defined above,

or the alkyl group is optionally substituted by a 5- to 6-membered nitrogen heterocycle or indolyl, the corresponding NH functions being optionally substituted by an alkyl group of up to 6 carbon atoms or protected by an amino protecting group and

8 · o

R and R are the same or different and denote a hydrogen atom or an amino protecting group, denote a hydrogen atom or a radical of formula

IN

OWR ⁸ c 'A »7» oi wherein R ^J, R c, R' and R ° are as defined above, C 7 q.

for RR °, R ^z and R ° and are the same or different with them

X is as defined above for R ⁴ and is the same or different with R ⁴ and their stereoisomers, stereoisomeric mixtures and salts thereof, with the exception of N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl] amino phenyl] acetamide.

In a preferred embodiment, the present invention provides sulfonamides of formula (I) above wherein:

0 · 0

2

R and R are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl or acyl group of up to 6 carbon atoms,

A, D, E and G are the same or different and are hydrogen, halogen, nitro, cyano, hydroxy, carboxyl, trifluoromethyl, trifluoromethoxy or straight or branched alkyl, alkoxy or alkoxycarbonyl of up to 5 carbon atoms, and

R represents a straight or branched alkenyl group having up to carbon atoms, or a straight or branched alkyl group having up to 8 carbon atoms optionally bearing an amino group which may be substituted by an alkyl group having up to 4 carbon atoms or an amino protecting group, or an alkyl group optionally one to three times equally or differently substituted by hydroxy, cyano, halogen, azido, nitro, trifluoromethyl, carboxy or phenyl, which may itself be substituted up to twice, equally or differently by nitro, halogen, hydroxy or straight or branched alkyl or alkoxy a group of up to 4 carbon atoms, or

R @ - denotes residues of the formulas

CH

L — O or

-L-O-CO-Q, denotes a straight or branched alkanediyl group of up to 6 carbon atoms and denotes an alkyl group of up to 6 carbon atoms, which is optionally substituted with a carboxyl group, or radicals of the formulas

where a denotes 1 or 2,

S '’· -

R is a hydrogen atom, r6 is a C3-C8 cycloalkyl, a C6-C10 aryl, a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, the alkyl group being optionally substituted by cyano, methylthio, hydroxy , a mercapto group, a guanidyl group or a group of the formula -NR 4 R 6 O or R 6 -OC-, wherein:

R ^ and R -Ι independently represent a hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms or a phenyl group, and

R ¹¹ represents hydroxy, benzyloxy, alkoxy of up to 6 carbon atoms or the above-mentioned -NR 6 R 6 O, or the alkyl group is optionally substituted with cycloalkyl of 3 to 8 carbon atoms or aryl of 6 to 10 carbon atoms which it is itself substituted by hydroxy, halogen, nitro, alkoxy of up to 8 carbon atoms or -NR 4 R 7 ', and R ¹⁰ is as defined above, or the alkyl group is optionally substituted by a 5- to 6-membered nitrogen heterocycle, or indolyl, the corresponding NH-functions being optionally substituted by alkyl having up to 6 carbon atoms or protected by amino and β protecting groups,

R and R0 are the same or different and represent a hydrogen atom or an amino protecting group,

R ⁴ represents a hydrogen atom or a radical of formula

r \ r ⁵ '

In —CO NR R 'wherein R ^J , R °, R' and R ° have the meanings given above for, R 6, R ⁷ and R 6 and are the same or different to represent a hydrogen atom, and stereoisomers, stereoisomer mixtures and salts thereof except for N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl] amino] phenyl] acetamide.

Particularly preferred are the sulfonamides of the aforementioned general formula (I) in which:

R represents a straight or branched alkenyl group of up to 8 carbon atoms, or a straight or branched alkyl group of up to 8 carbon atoms. alkyl atoms bearing an amino group which may be substituted with an alkyl group having up to 4 carbon atoms or an amino protecting group, or the alkyl group optionally substituted one or three times equally or differently with hydroxy, cyano, halogen, azido, nitro, trifluoromethyl, carboxy or a phenyl group, which may itself be substituted up to twice, equally or differently with nitro, halogen, hydroxy or a straight or branched alkyl or alkoxy group of up to 4 carbon atoms, or

• φ φ φ φ φ φ φ

R is a radical of formula, CH,, CHL or

L-O wherein L and Q are as described above

-L-O-CO-Q, and is preferably hydrogen.

Further particularly preferred are the sulfonamides of the above general formula (I) in which

2

R and R are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl or acyl group of up to 5 carbon atoms,

A, D, E and G are the same or different and are hydrogen, fluorine, chlorine or bromine, nitro, cyano, hydroxy or a straight or branched alkyl, alkoxy or alkoxycarbonyl group of up to 3 carbon atoms,

R represents a straight or branched alkenyl group having up to carbon atoms, or a straight or branched alkyl group having up to 7 carbon atoms optionally bearing an amino group which may be substituted by an alkyl group having up to 3 carbon atoms, tert-butoxycarbonyl or benzyloxycarbonyl; is an alkyl group optionally one to three times the same or differently substituted by hydroxy, cyano, fluoro

O o

& o o <s <S o o $

ru, chlorine, azido, nitro, trifluoromethyl or phenyl groups that are employed, which itself may be substituted up to twice. <identically or differently by nitro, fluorine, chlorine or hydroxyl or by straight ^or:! or a branched alkyl or alkoxy group having up to 3 carbon atoms;

R denotes the remainder of the formulas

or -L-O-CO-Q, wherein

L represents a straight or branched alkanediyl group having up to 4 carbon atoms and

Q represents an alkyl group of up to 4 carbon atoms which is optionally substituted by a carboxyl group or radicals of the formulas

or

denoting 1 or 2,

denotes a hydrogen atom, ft ft ft ft ft ft <<<<<<<- <- - - - - - - - - - - - - - - - - - - - R6 denotes a cyclopentyl or cyclohexyl group, a phenyl group or a hydrogen atom, or a straight or branched alkyl group of up to 6 carbon atoms wherein the alkyl group is optionally substituted with cyano, methylthio, hydroxy, mercapto, guanidyl, amino, carboxy or h ₂ n-co-, or the alkyl is substituted with cyclohexyl, naphthyl or phenyl, which itself may be hydroxy substituted , fluorine, nitro or alkoxy of up to 4 carbon atoms, or the alkyl group is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl group, the corresponding NH-functions being for planks substituted by alkyl having up to 4 carbon atoms or are optionally protected by tert-butyloxycarbonyl or benzyloxycarbonyl group and and R ³ are identical or different and denote hydrogen or tert-butyloxycarbonyl or benzyloxycarbonyl, D ^R ·· ·· «·

R ⁴ denotes a hydrogen atom or a radical of formula __ c · 6 '

IN

-CO-nitro ⁸ wherein R ^3, R °, R ° and R ^Z have the meanings given above for _{(R and} R®. And are identical or different, preferably represents hydrogen, and their stereoisomers, stereoisomeric mixtures and salts Except N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl] amino] phenyl] acetamide.

Other preferred compounds of the present invention are the sulfonamides of formula I, wherein a

R represents a straight or branched alkenyl group of up to 3 carbon atoms, or a straight or branched alkyl group of up to 7 carbon atoms which bears an amino group which may be substituted by an alkyl group of up to 3 carbon atoms, i. -butyloxycarbonyl or benzyloxycarbonyl, or the alkyl group is one to three times equally or differently substituted by hydroxy, cyano, fluorine or chlorine, azido, nitro, trifluoromethyl or phenyl, which itself may be substituted up to two, equally or differently by nitro, fluorine or chlorine, hydroxy or a straight or branched alkyl or alkoxy group having up to 3 carbon atoms, or

0 ·· 0 0 0 0 · 0 ·· ··

0 0 0 0 0 0 0 0

0 * 0 0 ft 0 .0 .0 0

R is a radical of formula, CH, or -L-O-CO-Q, wherein L and Q are as defined above, and

X is preferably a hydrogen atom.

Other particularly preferred compounds of the present invention are the sulfonamides of formula (I) above wherein:

12 ·

R and R are the same or different and are hydrogen, phenyl or. a straight or branched alkyl or acyl group each having up to 4 carbon atoms,

A, D, E and G are the same or different and denote a hydrogen atom, a fluorine, chlorine or bromine atom, a hydroxy group, a methyl group or a methoxy group, α

R denotes a straight or branched alkenyl group having up to carbon atoms, or a straight or branched alkyl group having up to 5 carbon atoms, optionally bearing an amino group which may be substituted by a tert-butoxycarbonyl or benzyloxycarbonyl group, or is an alkyl group

Φ Φ Φ

Popřípadě Φ popřípadě popřípadě rát popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě or a phenyl group, which may itself be substituted up to twice, equally or differently with nitro, fluorine or chlorine, hydroxy, methyl, ethyl, methoxy or ethoxy, or

R ³ represents radicals of the formulas .CH,

ch ₃

j or -L-O-CO-Q, -O wherein

7 '

L denotes a straight or branched alkanediyl group having up to 4 carbon atoms and denotes an alkyl group having up to 3 carbon atoms, which is optionally substituted by a carboxyl group, or a radical of the formula t ·?;

R ⁶ 'NR ⁷ wherein ^R

R @ ³ denotes a hydrogen atom and r @ 6 denotes a cyclopentyl or cyclohexyl group or a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, the alkyl group being optionally substituted by cyano, methylthio, hydroxy, mercapto, guanidyl, amino, carboxy or h ₂ n-co-, or an alkyl substituted by cyclohexyl, naphthyl or phenyl, which itself may be substituted by a fluorine or chlorine atom, or an alkoxy group with up to 1-6 carbon atoms; Or an alkyl group substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl group, the corresponding NH-functions being optionally substituted by a methyl group or optionally protected by a tert-butyloxycarbonyl or benzyloxycarbonyl group and

R and R0 are the same or different and denote a hydrogen atom or a tert-butyloxycarbonyl group,

R ⁴ represents a hydrogen atom or a radical of formula

Wherein R, R, R 'and R have the meanings given above for R 1, R ⁶ , R ⁷ and R ⁸ and are the same or different with them preferably denotes a hydrogen atom, and stereoisomers, stereoisomer mixtures and salts thereof, except N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl] amino] phenyl] acetamide.

Other preferred compounds of the present invention are the sulfonamides of formula (I) above wherein:

R denotes a straight or branched alkenyl group having up to carbon atoms, or a straight or branched alkyl group having up to 5 carbon atoms carrying an amino group which may be substituted by a tert-butyloxycarbonyl or benzyloxycarbonyl group, or the alkyl group is one to three times the same or different substituted by hydroxy, cyano, fluoro or chloro, azido, trifluoromethyl or phenyl, which itself may be substituted up to twice, equally or differently with nitro, fluoro or chloro, hydroxy, methyl, ethyl, methoxy or ethoxy, or

- 18 · φ · · · 18 18

9 ·· Φ »· Φ Φ · 9 9 9

R @ - denotes residues of the formulas

CH ₃ .CH, or ^L 0 wherein L and Q have the above

-L-O-CO-Q, and is preferably hydrogen, and stereoisomers, stereoisomeric mixtures and salts thereof.

Other particularly preferred compounds of the present invention are the sulfonamides of formula (I) above wherein:

R and R denote a straight or branched alkyl group having up to 4 carbon atoms,

A, D, E and G denote a hydrogen atom,

R represents a straight or branched alkyl group having up to carbon atoms which is substituted by a hydroxy group, or

R is a radical of formula

-L-O-CO-Q, wherein

L represents straight-chain or branched alkanediyl ·· β • V • * · ti ti titi · · · • I '• I ¹ · ·· ·· · »· ·· titi • • · · · · · I« I • · titi A group having up to 4 carbon atoms and

Q represents a radical of formula ^R @ ⁵ = ^R @ ^{7 R} @ ⁸ in which r @ ⁵ and R @ ⁸ are hydrogen and

R

R and R denote a hydrogen atom,

R ⁴ represents hydrogen and

X is preferably a hydrogen atom, and stereoisomers, stereoisomer mixtures and salts thereof.

Very particularly preferred compounds of the present invention are sulfonamides selected from the group of compounds including

The present invention further provides a process for the preparation of the sulfonamides of the above-mentioned general formula (I), characterized in that [A] a compound of the general formula (II)

(Π) in which A, D, E, G, R ¹ and R ² as defined above, are first converted by catalytic hydrogenation on palladium / C or by reduction with stannous chloride in an inert solvent to compounds of formula III

in which A, D, E, G, R * and R are known as above, and then reacted with compounds of formula IV

T-CO-R ³ (IV) wherein R is as defined above and a

T represents a hydroxy group or a halogen atom, preferably chlorine, in inert solvents and optionally in the presence of a base and / or auxiliary agent, or

(V) in which they have

E, G, R ³ and R ⁴ , as previously described in paragraph [A], first convert by hydrogenation to Pd / C or by reduction with stannous chloride in inert solvents to compounds of formula VI, E

J-NR ⁴ -CO-R ³ h ₂ (VI)

Kterém kterém in which E, G, R ^-3 and R are as defined above and then reacted with compounds of formula VII

A D

Wherein A, D, R, and R are as defined above, and

V represents a halogen atom, preferably chlorine, in inert solvents, optionally in the presence of a base and / or auxiliary agent, or

4 [C] when R and / or R is a radical of the formula

-L-O-CO-Q, react the compounds of formula Ia

in which R ¹ , R ² , R ⁴ , A, D, E, G and L have the meanings given above, with amino acid esters of the general formula (VIII) · · · ·

- 23 - ··· · · · · · · · · · · · · · · · · · · · HO-CO-Q ' (VIII) in which Q 'has the meaning given above for Q of said terminal residues at , with any of here nitrogen denotes one of the

of the aforementioned protecting groups, preferably a tert-butylcarbonyl group, optionally with activation of the carboxylic acid by conventional methods, in inert solvents and in the presence of a base and excipient, and then deprotecting using conventional methods in peptide chemistry; wherein X is not a hydrogen atom, reacted with 2 or more equivalents of compounds of formula (VIII), optionally separating the stereoisomers by methods known per se, and optionally converting the free bases into salts or converting the salts into the free bases.

The present invention further provides sulfonamides of formula I for the prophylaxis or treatment of diseases.

The present invention further provides the use of the sulfonamides of formula I for the preparation of medicaments, in particular medicaments for treating viral diseases and preferably medicaments for combating cytomegalievir.

Finally, the present invention provides a medicament comprising the sulfonamides of formula (I) above.

The compounds of the present invention may also be present in the form of salts. Physiologically acceptable salts are preferred within the scope of the present invention.

Physiologically acceptable salts may be salts of the compounds of the present invention with inorganic or organic acids. Preferred are salts 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, acid tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts may also be metal or ammonium salts of the compounds of the present invention. Particularly suitable are, for example, sodium, potassium, magnesium or calcium salts as well as ammonium salts derived from ammonia or organic amines, such as ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine , ethylenediamine or 2-phenylethylamine.

with

The term "alkanediyl" refers to hydrocarbon groups which are linked in two positions to other radicals. Preferably, these attachment points are located on different carbon atoms. Examples of alkanediyl groups include -CH ₂ CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -, -C (CH ₃ ) ₂ -CH ₂ -, -CH (CH ₃ ) -CH ₂ -, -C (eH) ₃ ) -CH ₂ -CH ₂ and the like.

Amino acid protecting groups are common amino acid protecting groups used in peptide chemistry within the scope of the present invention.

These preferably include: a benzyloxycarbonyl group,

3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, methoxy-4,5-methoxybenzyloxycarbonyl, 2-nitro-4,5-methoxybenzyloxycarbonyl; ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethylbenzyl. adamantylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl,

2.2.2- trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl a 2,2,2-trifluoroacetyl group,

2.2.2- trichloroacetyl, benzoyl,

4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimide, isovaleroyl, benzyloxymethylene, 4-nitrobenzyl

a 2,4-dinitrobenzyl group or a 4-nitrophenyl group.

The compounds of formula (I) of the present invention can exist in various stereoisomeric forms, which exist either as an image and a mirror image (enantiomers) or not as an image and a mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms as well as to the diastereomeric mixtures. Like the diastereomers, the racemic forms can be resolved into stereoisomerically uniform components by known methods.

The compounds of the formula I according to the invention can, with respect to the amino acid residue, exist in both the D- or L-form and the R- or S-configuration. The invention includes optical antipodes as well as isomeric mixtures or racemates.

Within the scope of the invention, the compounds of the formula I according to the invention, with respect to the group -SO2NX, can be bonded in the α- or β-position to the naphthyl structure and the -NH-CO-R ^ group can be linked in o-, m- or p- position with a phenyl ring.

α

Preferably, the -SC 1 -NX group is bonded to the naphthyl structure at the α- or β- position and the -NR 2 -CO-R 6 group is attached at the m- or p- position to the phenyl radical.

·· ····

Particularly preferably, the -SO ₂ -NX group is bonded in the α-position to the naphthyl radical and the -NR ⁴ -CO-R ^{3 group} in the p-position to the phenyl radical.

Particularly preferred compounds of the present invention are listed in Table A below.

tr! * '...... -. _____ ______. and..

- 28 Table Α · φ φ φ φ · · · · · · · · · · · · ·

• ti ti ti ti ti · ti ti Iti ti ti tiititi ·· ·· ti ti ti ti ti. the ones you

• ti ti ti ti ti ti ti · ti · · · ·

The particularly preferred compounds mentioned in Table A may exist in the form of a base, as pharmaceutically acceptable salts, especially hydrochlorides, or optionally as zwitterions.

The compounds of the present invention of formula (I) may be prepared by [A] compounds of formula (II)

in which A, D, E, G, R and R are as defined above, first convert the catalytic hydrogenation to palladium / C or by reduction with stannous chloride in inert solvents to compounds of formula III

(III) in which A, D, E, G, R and R are as defined above and then reacted with compounds of formula IV

· · · · · · · · · · · · · · · · · · · · · · · · · · ·

T-CO-R ³ (IV), α

wherein R is as defined above and

T represents a hydroxy group or a halogen atom, preferably chlorine, in inert solvents and optionally in the presence of a base and / or an adjuvant, or [B] of a compound of formula V

in which E, G, R a and R význam have the meaning given above, first converted as described in paragraph [A] by hydrogenation to Pd / C or by reduction with stannous chloride in inert solvents to compounds of formula VI

E

NR ⁴ -CO-R ³ (VI) wherein they have:

E, G, R ³ and R ⁴ as defined above, and then reacted with compounds of formula

VII

(VII) ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti <

> Titi I • ti ti "in which A, D, R ^1, and

V is a halogen atom,

XV

R &lt; 4 &gt; is preferably chlorine, in inert solvents, optionally in the presence of a base and / or auxiliary agent, or [C] when R &lt; ³ & gt ^; and / or R &lt; ⁴ &gt;

-L-O-CO-Q, reacting compounds of Formula Ia

NR ¹ R

II

SO _r NH

NR-CO-L-OH

G (Ia), wherein R ¹ , R ² , R ⁴ , A, D, E, G and L are as defined above, with amino acid esters of formula VIII

HO-CO-Q '(VIII)

»· 99 99 ···

9 99 <· 9 · 9 9

9

9 9 9

9

99 99 in which

Q 'has the meaning given above for Q, wherein any of the terminal nitrogen residues mentioned herein denotes one of the abovementioned protecting groups, preferably a tert-butylcarbonyl group, optionally with activation of the carboxylic acid by conventional methods, in inert solvents and in the presence of a base; adjuvants, and then protecting groups are cleaved by methods conventional in peptide chemistry, and when X does not represent a hydrogen atom, it is reacted with 2 or more equivalents of compounds of formula VIII.

The process of the present invention may be illustrated by way of example by the following reaction scheme:

99 · »9 · 9 · 9

99 [A] h ₂

Pd / C. or

SnCI ₂

N _(CH3)

3'2

NH,

N _(CH3)

3'2

Cl-CO-C (CH ₃₎

3'3

N _(CH3)

3'2 [B]

CH.

^N ° 2 ^ \ /) - Lj ^-C0_ | - \ ^/ Cl CH ₃ H ₂

Pd / C or -> SnCi,

H ₂ N

CH, λ = -N-COλ

CH. Cl

N _(CH3)

SO ₂ -CI

CH, ch ₃ Cl • »· * '

4 Φ V 4 φ φ φ φ · ·

ΦΦ ·· <· ♦ • φ φ · φ φ 9 9 9

ΦΦΦ ΦΦ Φ

9φ • Φ · 9

9 9 9

Φ Φ · Φ Φ Φ Φ 9

9 99

IC]

Suitable solvents for all process steps are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers, for example diethyl ether, glycol monomethyl ether, glycol dimethyl ether, dioxane or tetrahydrofuran, hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions, halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or dimethylsulphide , dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned, optionally also with water. Particularly preferred are methylene chloride, tetrahydrofuran, pyridine and

in.

dioxane.

Suitable bases are organic amines, especially trialkylamines having 1 to 6 carbon atoms in each alkyl, such as triethylamine, or heterocycles, such as pyridine, methylpiperidine, piperidine or N-methylmorpholine. Particularly preferred are pyridine, triethylamine and N-methylmorpholine.

The bases are generally used in an amount of 0.1 mol to 5 mol, preferably 1 mol to 3 mol, in each case based on 1 mol of the compounds of the formulas III and IV.

Suitable adjuvants are carbodiimides such as dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, carbonyl compounds such as carbonyldiimidazole, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl -1,2-oxazolium-3-sulfonate, propanephosphoric anhydride, isobutyl chloroformate, benzotriazolyloxy-tris- (dimethylamino) phosphonium hexafluorophosphate, phosphonic acid diphenyl ester amide or methanesulfonic acid chloride, optionally in the presence of bases such as triethylamine, N-ethylmorpholine -methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

The reactions can be carried out at normal pressure, but also at elevated or reduced pressure, for example in the range of 0.05 to 0.3 MPa. In general, working at normal pressure.

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

The reductions can generally be carried out with hydrogen in water

or in inert organic solvents such as alcohols, ethers and halogenated hydrocarbons, or mixtures thereof, using catalysts such as Raney nickel, palladium, palladium on charcoal or platinum, or hydrides such as stannous chloride, or boranes in the _Ý inert - solvent, optionally in the presence of a catalyst.

A preferred catalyst is palladium on charcoal or stannous chloride.

The reaction can be carried out at normal pressure, but also at elevated or reduced pressure, for example in the range of 0.05 to 0.3 MPa. In general, working at normal pressure.

The reduction is generally carried out at a temperature between 0 ° C and 60 ° C, preferably between 10 ° C and 40 ° C.

Suitable solvents for the acylation are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran and glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane and petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene and trichlorethylene. chlorobenzene, and ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acectonitrile, acetone and nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane and pyridine are preferred.

The acylation in the above solvents is carried out at a temperature in the range of 0 ° C to 150 ° C, preferably at room temperature to 100 ° C and at normal pressure.

and

Suitable solvents for process [C] are the customary organic solvents which do not change under the reaction conditions. These preferably include organic solvents such as alcohols such as methanol, ethanol or n-propyl alcohol, ethers such as diethyl ether, glycol monoethyl ether, glycol dimethyl ether, dioxane and tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane and petroleum. fractions, or halogenated hydrocarbons such as methylene chloride, dichloroethane (DCE), trichloromethane, carbon tetrachloride, and ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide and picoline. It is also possible. use mixtures of the solvents mentioned. Preference is given to dichloromethane, dichloroethane, dimethylformamide and n-propyl alcohol.

Condensing agents, which may also be bases, are preferably used as adjuvants for the corresponding peptide couplings, especially when the carboxyl group is activated as an anhydride. Preferably, conventional condensing agents such as carbodiimides are used, for example Ν, N'-diethylcarbodiimide, Ν, N'-dipropylcarbodiimide, N, N'-diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide and N- (3-dimethylaminoisopropyl) -N 1'-ethylcarbodiimide hydrochloride, or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate and 2-tert-butyl-5 methyl isoxazolium perchlorate or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline and propanephosphonic anhydride, isobutyl chloroformate, benzotriazolyloxy-tri- (dimethylamino) phosphonium hexafluorophosphate or 1-hydroxybenzonitrile; alkali metals such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, or organic bases such as trialkylamines such as triethylamine, N-ethylmorpholine, N-methylpiperidine or diisopropy lethylamine. Dicyclohexylcarbodiimide, N-methylmorpholine and 1-hydroxybenztriazole are particularly preferred.

The cleavage of the amino protecting groups is carried out by known methods under acidic or basic conditions or by reductive catalytic hydrogenation, for example by Pd / C in organic solvents such as ethers, for example tetrahydrofuran or dioxane, or alcohols, for example methanol, ethanol or isopropyl alcohol.

The cleavage of the amino protecting groups can also be carried out by conventional methods with acids such as hydrochloric acid or trifluoroacetic acid.

The reactions are generally carried out at a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 60 ° C.

The reaction may be carried out at normal pressure, but also at elevated or reduced pressure, for example in the range of 0.5 to 5 bar.

The compounds of formula VIII are known.

The compounds of formula (Ia) are novel and can be prepared by processes [A] and [B] above.

The compounds of the formulas II, III, IV, V, VI and VII are known per se or are obtainable by methods known from the literature.

It is also an object of the present invention to use N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl] amino] phenyl] acetamide as an antiviral agent, especially against cytomegalieviruses.

The compounds of the present invention of formulas (I) and (Ia) exhibit an unforeseeable surprising spectrum of activity. They have an antiviral effect against representatives of the Herpes viridae group, in particular against human cytomegalievir (HCMV). They are therefore suitable for the treatment and prophylaxis of diseases caused by herpesviruses, in particular those caused by human cytomegalievir (HCMV).

The anti-HCMV effect is determined in a 96 well screening dough system using human embryonic lung fibroblasts ((HELF) cell culture). The effect of test substances on the spread of the cytopathogenic effect is determined in comparison with the reference substance ganciclovir (Cymevene®-Sodium), a clinically acceptable anti-HCMV-chemotherapeutic.

Test substances (50 mM) dissolved in dimethylsulfoxide were assayed in a 96-well microtiter plate by duplicate assay (4 substances / plate). The toxic and cytotoxic properties of the substances are understood together. After appropriate dilution of the compound (1: 2) on a microtiter plate, a suspension of 50-100 HCMV-infected HELF cells and 3 x 10 6 uninfected HELF cells in Eagles MEM with 10% fetal calf serum is added to each well and plates are incubated at 37 ° C in a CCl 3 incubation box for several days.

After this time, cell seeding in the viral control without test substance, starting from 50 to 100 infectious centers, is completely destroyed by the cytopathogenic effect of HCMV (100% CPE). After neutral red staining and formaldehyde / methanol alcohol fixation, plates are evaluated using a projection microscope -Viewer). The results are for some of the compounds listed in the following table

Table

Example HCMV EC ₅₀ 1 0.16 2 ·. . 0.27 13 0,064 16 0,0,28 24 0.88 .. ' 25; . '·. , -. 0.64 - -. And.

It has now been found that the compounds of the present invention inhibit the multiplication of HCMV in HELF cells at ten to fifty times lower concentrations than Cymeven®-sodium and exhibit a much higher selectivity index.

The compounds of the present invention are therefore valuable active substances for the treatment and prophylaxis of human cytomegalievir diseases. Indicator areas include:

1) treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections);

- 43 2) treatment and prophylaxis of HCMV infections in patients with bone marrow and organ transplantation, who are often life-threatening with HCMV-pneumotitis, HCMVencephalitis, as well as gastrointestinal and systemic HCMV infections;

3) treatment and prophylaxis of HCMV infections in newborns and young children;

4) treatment of acute HCMV infections in pregnant women.

In vivo effect

Animals from week-old male NOD / LtSz-Prkdc (scid) / J mice are taken from a commercial breed (The Jackson Lab., Bar Harbor). Animals are maintained under sterile conditions (including litter and feed) in insulators.

Virus / infection

Murines Cytomegalievirus (MCMV), a Smith strain, is passaged in vivo (BALB / c) and purified by fractional centrifugation. titer is assayed by plaque experiment on primary embryonic mouse fibroplasts. Mice are infected at a dose of 5 x 10 6 pfu in a total volume of 0.2 ml intraperitoneally. This dose results in death in about 100% of infected animals after about 11 days.

Treatment / evaluation of hours after infection with mice for 8 days twice • ·

The dose of 10 ml / kg daily (morning and evening) is administered orally by the test substance at 25 mg / kg body weight and the application volume of body weight. The formulation of the test substance is carried out in the form of 0.5% succes in tylose. 16 hours after the last administration of the test substance, animals are sacrificed in pain and salivary glands, liver and kidney are collected.

Genomic DNA was purified from 25 mg tissue by phenol / chloroform extraction. DNA quantification is performed photometrically using the formula ^^ 260 ^x ~ ^m g / ^m l ·

The purity of the DNA is checked over quotients of 0.260 / 0.280 and the pH of the DNA is then adjusted to 8.0 with EDTA.

Quantification of MCMV-DNA is performed by DNA-Dot-Blot hybridization. The probe used was digoxygenin-gelabeltes (Boehringer Mannheim, also buffer, unless otherwise indicated), a 1.2 kb fragment from the MCMV region, Smith,

Hindi J. J. Signal detection is accomplished by chemoluminescence. For this, the membranes are washed once for 3 minutes with dioxygenin wash buffer. The filter is then incubated once with dioxygenin blocking buffer for 30 minutes at room temperature with shaking. The filter is then incubated for 30 minutes in a 20 ml / 100 cm membrane area using an anti-DIG-alkaline phosphatase-conjugate solution (1: 20,000 in 1 x digoxygenin blocking solution).

Two 15 minute wash steps are followed with 1 x digoxygenin wash buffer. This is followed by a five minute equilibration of the filter in 1 x digoxygenin detection buffer and detection with a 1 ml / 100 cm membrane area of the CDP-Star solution diluted 1: 100. After the CDP-Star solution has been drained and incubated for five minutes in a dark box, chemoluminescence or evaluation is performed.

using X-ray film (Kodak) or Lumilmager (Boehringer Mannheim).

All results are provided statistically (variance analysis using statistics; StatSoft Inc).

The novel active compounds ae can be converted into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using known methods, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. The active ingredient is present in a concentration of about 0.5 to 90% by weight of the total composition, i.e. in an amount sufficient to achieve the said dosage range.

For example, the preparations may be prepared by mixing the active ingredient with a solvent and / or carriers, optionally with emulsifying agents and / or dispersing agents, for example when using water as the diluent, organic solvents may be used as co-solvents.

Administration is effected by conventional means, preferably orally, parenterally or topically, in particular perlingually, intravenously or intravitally, optionally as a depot in the implant.

For parenteral administration, solutions of the active compounds using suitable liquid carrier materials can be used.

In general, it has been found advantageous to administer an amount of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg of body weight and for oral administration in order to obtain effective results when administered intravenously. the dose is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be desirable to deviate from the indicated amounts, depending on the body weight or the mode of administration, the individual tolerability of the medicament, the type of formulation and the time or interval at which the administration takes place. Thus, in some cases it may be sufficient to start from less than the abovementioned minimum quantities, while in other cases the upper limit must be exceeded. In the case of administration of larger amounts, it is advisable to divide these doses into several individual doses during the day.

Optionally, it may be useful to combine the compounds of the present invention with other active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

Mixtures moving phases AND methylene chloride methyl alcohol 100 ALIGN! 0 (B) methylene chloride methyl alcohol 100 ALIGN! 1 C methylene chloride methyl alcohol 100 ALIGN! 2 D methylene chloride methyl alcohol 100 ALIGN! 3 E methylene chloride methyl alcohol 100 ALIGN! 5 F methylene chloride methyl alcohol 10: 1 G methylene chloride 0.1 methyl alcohol ammonia H AND methylene chloride: · cyclohexane 1 cyclohexane: ethyl acetate 95: 5 1

- 47 - TO cyclohexane ethyl acetate 90 10 L cyclohexane ethyl acetate 85 15 Dec M cyclohexane ethyl acetate 80 20 May N cyclohexane ethyl acetate 75 25 0 cyclohexane ethyl acetate 70 30 P cyclohexane ethyl acetate 60 40 Q cyclohexane ethyl acetate 50 50 R . . cyclohexane ethyl acetate 40 60 WITH cyclohexane ethyl acetate 30 70 T Butyl alcohol: glacial acetic acid AT 4: 1: 1 methylene chloride: methanol 9: IN IN acetonitrile cyclohexane : water 9: 1 ethyl acetate 1: 10 X acetonitrile : water 95: 5 Y methylene chloride: methanol 95: of petroleum ether : ethyl acetate 1 1 FOR petroleum ether : ethyl acetate 1 2 ZB petroleum ether : ethyl acetate 1 3.

Starting compounds

Example I

4- [5-N, N-dimethylamino-naphthyl-1-sulfonylamino] nitrobenzene

N _{(CH3) 2}

0 «

0 0000

0. 0 ι *

51.2 g (0.37 mol) of p-nitroaniline are introduced into 700 ml of pyridine under argon and cooled with an ice bath and 100 g (0.37 mol) of dansyl chloride are added in portions and the reaction is stirred overnight at room temperature. DC-control using petroleum ether: ethyl acetate 7: 3 showed a uniform reaction. For working up, the reaction mixture was freed from pyridine in vacuo and the residue was taken up in 1 N sodium hydroxide. The aqueous phase was again freed of residual pyridine in vacuo and then adjusted to pH 4 with hydrochloric acid. The precipitated product is filtered off with suction and dried in a hot-air oven at 60 DEG C. to give 82 g (60%) of the sulfonamide as a lemon-yellow solid.

MS (CI, NH ₃ , m / z): 372 ([M + H] &lt; + &^gt;, 100%).

1 H-NMR (200 MHz, DMSO-d 6, δ / ppm): 8.46 (d, J = 9.0 Hz; 1H). 8.40 to 8.31 (m, 2H), 8.05 (d, J = 10 Hz, 2H), 7.65 (dt, J = 7.5 Hz, J ₂ = 5 Hz, 2H), 7.28 to 7.18 (m, 3H), 2.80 (s, 6H).

They did

4- [5-N, N-dimethylamino-naphthyl-1-sulfonylamino] aniline?

6.3 g (0.17 mol) of the compound of Example I are dissolved in 400 ml of ethanol, mixed with 1.5 g of 10% titanium.

of palladium on charcoal and hydrogen at 50 psi hydrogen was hydrogenated for 25 hours. DC-control using petroleum ether: ethyl acetate (PE: EE) 1: 1 (Rf = 0.28) shows complete reaction. For working-up, the catalyst is filtered off and the filtrate is freed from the solvent under vacuum. The hard foam thus obtained was dissolved in 1 N sulfuric acid and then esterified. The mixture is neutralized with 2.5 N sodium hydroxide and the precipitate is filtered off with suction. The product was dried at 60 ° C in a hot-air oven to give 50 g (86%) of the amine as a white solid. _Rf = 0.29 (E)

MS (CI, NH ₃ , m / z): 342 ([M + H] &lt; + &^gt;, 100%). . ,.

Δ-NMR (200 MHz, DMSO-d 6, δ / ppm): 9.80 (s, 1H), 8.42 (d, J = 8.0Hz; 1H), 8.38 (d, J = 8.0Hz; 1H), 8.00 (d) J = 7.5 Hz; 1H); 7.60 (t, J = 7: 5 Hz; 1H); 7.54 (t, J = 7.3 Hz; 1H); 7.25 (d, J = 7.5 Hz; 1H); J = 9.0 Hz; 2H); 6.40 (d, J = 9.0 Hz; 2H); 4.90 (s; 2H); 2.80 (s; 6H).

Example III

N- (nitrophenyl) -pivaloylamide

C (CH ₃ )

3'3

O ₂ N

Dissolve 20.0 g (0.14 mol) of 4-nitroaniline in a 1 L three-necked flask in 400 mL of methylene chloride and 100 mL of dioxane and then mix with 23.4 mL of pyridine. While cooling with ice, 19.2 g (0.16 mol) of pivalic acid chloride are added dropwise and stirred for 24 hours at room temperature. The reaction mixture is then shaken three times with 200 ml of water, the organic phase is separated and dried over anhydrous sodium sulphate. The organic phase is then evaporated, the residue is stirred well with 100 ml of diisopropyl ether for 2 hours, filtered off with suction, washed with diisopropyl ether and pentane and the residue is dried.

Yield: 30 g (93% of theory).

Example 1 a d IV

N- (4-aminophenyl) -pivaloylamide

C (CH,)

3'3

H ₂ N g (0.11 mol) of the compound of Example III was dissolved in 500 ml dioxane in a one liter round-bottom flask with stirring and then overlayed with argon and 5 g of 10% palladium on charcoal was added. Hydrogenate at room temperature and under normal pressure. The catalyst was filtered off with suction over kieselguhr and the filtrate was evaporated in vacuo. The residue is stirred well in 200 ml of heptane for 2 hours, filtered off with suction, washed with heptane and the crystals are dried.

Yield 19.6 g (90.6%).

Manufacturing examples

ΦΦ φφφφ • φ φ · φφφφ Φ ·

Example 1

Ν- [4- (5-N, N-dimethylamino-naphthyl-1-sulphonylamino) phenyl] -2,2-dimethylpropionamide

N _(CH3)

17.8 g (0.09 mol) of the compound of Example IV are introduced into pyridine under argon and 25 g (0.09 mol) of dansyl chloride are added in portions and the reaction mixture is stirred for 18 hours at room temperature (DC- control PE: EE 7: 3). For work-up, pyridine is removed in vacuo, the residue is taken up in dioxane and precipitated again with water. The product first precipitates as an oily substance, is separated from the aqueous solvent, the oily substance is stirred with diethyl ether and the crystalline precipitate is filtered off with suction. A slightly yellowish solid is obtained.

M.p. = 174 ° C.

Example 2

N- [4- (5- (N, N-dimethylamino) naphthyl-1-sulfonylamino) phenyl] -3-hydroxy-2,2-dimethylpropionamide

H, C

«*« · · · · 944 9 · t

4

O 9

O

g (0.15 mol) of the compound of Example II was mixed with 203 ml (1.46 mol) of triethylamine and 51.9 g (0.44 mol) of 3-hydroxy-2,2-dimethylpropionic acid in 800 ml of methylene chloride. While cooling, 200 ml of a 1.7 M solution of n-propanephosphonic anhydride in ethyl acetate are added dropwise over 30 minutes so that the internal temperature does not exceed 15 ° C and the reaction mixture is stirred overnight at room temperature. The DC-control in methylene chloride / methanol 100: 5 (Rf = 0.29) showed complete reaction.

For working-up, it is diluted with 800 ml of methylene chloride, washed four times with water and once with dilute acetic acid, dried over sodium sulphate and freed from the solvent in vacuo. The resulting foam was purified on a silica gel column (mobile phase: D, E, F, G) and the foam was recrystallized from toluene. 33 g (51%) of the amide are obtained in the form of a white solid.

MS (Cl. NH _J? M / z): 442 ([M + H] \ 100%).

1 H-NMR (200 MHz, DMSO-d 6, δ / ppm): 10.46 (s; 1H), 9.10 (s; 1H), S.40 (t breit; J = 7.5 Hz; 2H), 8.14 (d, J = 7.5Hz, 1H), 7.62 (t, J = 7.5Hz, 1H), 7.55 (t, J = 7.5Hz, IH), 7.36 (d, J = 10.0Hz, 2H), 7.24 (d, J = 7.5 Hz (1H), 6.92 (d, J = 10.0Hz; 2H), 5.04 (t, J = 5.0Hz; IH), 3.42 (d, J = 5.0Hz; 2H), 2.80 (s; 6H), 1.07 (s, 6H).

Examples 3 and 4

N- [4- (5-Ν, N-dimethylaminonaphthyl-1-sulfonylamino) phenyl] -3 - ((2S) -2- (N-tert-butyloxycarbonylamino) -2-isopropylacetoxy) -2,2-dimethylpropionamide ( Example 3) a

N- [4- (5-N, N-dimethylaminonaphthyl-1-sulfonylamino) phenyl] -N53 ·· ··

- [(2S) -2- (N-tert-butyloxycarbonylamino) -2-isopropylacetyl] -3- (2S) -2- (N-tert-butyloxycarbonylamino) -2-isopropylacetoxy) -2,2-dimethylpropionamide ( example 4)

H ₃ C

(ex. 3) (ex. 4)

10.0 g (0.02 mol) of the compound of Example 2, 6.4 g (0.03 mol) of N-Boc-L-valine and 1.1 g (0.0 mol) of dimethyl-aminopyridine The reaction mixture was added to 170 ml of methylene chloride and 6.1 g (0.03 mol) (0.03 mol) EDC was added and the reaction mixture was stirred overnight at room temperature. It is then diluted with ethyl acetate, extracted twice with saturated sodium bicarbonate solution and dried. Purification was performed on a silica gel column using petroleum ether / ethyl acetate 2: 1.

Yield:

Example 3: 10.8 g (74.4%) R _f = 0.55 (Z)

Example 4: 1.7 g (8.9%) = 0.65 (Z).

Example

N- [4- (5-N, N-dimethylaminonaphthyl-1-sulfonylamino) phenyl] -3

• 9

9999 ··

- ((2S) -2-amino-2-isopropylacetoxy) -2,2-dimethylpropionamide dihydrochloride

10.5 g (0.02 mol) of the compound of Example 3 are mixed with 200 ml of 4 N hydrochloric acid in dioxane and stirred for 4 hours. The reaction mixture was then evaporated in vacuo, the residue was dissolved twice in 100 ml of water and evaporated again. It is then treated twice with 100 ml of acetonitrile, evaporated under vacuum and twice with diethyl ether and evaporated again in vacuo. Dry overnight in an oil pump vacuum.

9.7 g (96%) of a pale yellow powder are obtained (m.p. 130 DEG C., decomposition).

Example 6

N- [4- (5-N, N-dimethylaminonaphthyl-1-sulfonylamino) phenyl] -3- (2- (N-tert-butyloxycarbonylamino) -2-acetoxy) -2,2-dimethylpropionamide

14.3 g (0.08 mol) of BOC-glycine in 300 ml of methylene chloride are introduced at room temperature into 300 ml of methylene chloride, mixed with 13.2 g (0.08 mol) of carboxydiimidazole and stirred for 2 hours at this temperature. temperature.

After DC-control, 30.0 g (0.07 mol) of the compound of Example 2 was added and stirred overnight at room temperature.

For working-up, the mixture was diluted with 500 ml of methylene chloride, washed twice with 300 ml of 0.01 N sulfuric acid and once with water, dried over anhydrous sodium sulphate and evaporated in vacuo. A greenish, hard foamy solid is obtained which is recrystallized from toluene.

43.0 g (88% of theory) of the compound of Example 43 were obtained as greenish crystals.

MS (CI, NH 3, m / z): 616 ([M + H] ⁺ , 100%).

1 H-NMR (200 MHz, DMSO-d 6, δ / ppm): 10.50 (s; 1H), 9. )2 (s; 1H), 8.40 (t, J = 8.0 Hz; 2H), 8.14 (d, J = 8.0 Hz; 1H); 7.68-7.52 (m; 2H); 7.35 (d, J = 10.0 Hz; 2H); 7.26 (d, J = 8.0 Hz; 1H); 6.94 (d, J = 10.0 Hz; 2H); 4.12 (s; 2H); 3.62 (d, J = 6.0 Hz; 2H); 2.80 (s; 6H); 1.32 (s; 9H); 1.15 (s; 6H).

Example 7

N- [4- (5-N, N-dimethylaminonaphthyl-1-sulfonylamino) phenyl] -3- (2-aminoacetoxy) -2,2-dimethylpropionamide hydrochloride

Cl

39.5 g (0.07 mol) of the compound of Example 6 are introduced into 200 ml of dichloromethane and slowly mixed with 80 ml of a 4 N solution of hydrochloric acid in dioxane with stirring. The reaction mixture was stirred until gas evolution was complete (about 3 hours). The suspension product is finely ground, filtered off with suction, washed with 100 ml of dichloromethane and dried under high vacuum overnight.

35.4 g (98%) of the title compound are obtained as a white solid.

MS (CI, NH ₃ , m / z): 442 ([M-Glycine + H] +, 100%), 499 ([M + H] ⁺ , 20%) 1 H-NMR (400 MHz, D, O) -d 2, δ / ppm): 8.80 (d, J = 8.0 Hz; 1H); 8.42 (d, J = 8.0 Hz; 1H); 8.35 (d, J = 8.0 Hz; 1H); 8.0 Hz (1H), 7.92 (t, J = 8.0 Hz; 1H), 7.82 (dd, J = 7.0 Hz, J = 8.0 Hz; 1H), 7.15 (d, J = 10.0 Hz; 2H), 6.98 (d, J = 10.0 Hz; 2H); 4.34 (s; 2H); 3.94 (s; 2H); 3.50 (s; 6H); 1.32 (s; 6H).

Example 8

4-acetamidonaphthalene-1-sulfonic acid N- [4- (N-2,2-dimethylpropanoyl) aminophenyl] -amide

A solution of 3.46 g (18.00 mmol) of 4- (N-2,2-dimethylpropanoyl) -aminoaniline (Example IV) in 72 mL of anhydrous pyridine was treated with a solution of 5.87 g (20.70 mmol) of 4-acetamidonaphthalene. Of 1-sulfonyl chloride in 72 mL of anhydrous tetrahydrofuran and the reaction mixture was stirred at room temperature overnight. Then the solvent mixture on a rotary evaporator is evaporated and the residue is mixed with a mixture of 20 ml of ethyl acetate and 150 ml of 2 M hydrochloric acid. The precipitated solid is filtered off with suction and washed with water, a small amount of ethyl acetate and diethyl ether.

After drying under high vacuum, 1.0 g (76% of theory) of the title compound is obtained in the form of a light pink color, which is recrystallized from ethyl alcohol.

M.p. Mp > 240 ° C

R _f: 0.13 (CH ₂ Cl ₂ / MeOH 100: 5).

MS (CI, NH + m / z): 457 (M + NH +), 440 (M + H ⁺ ).

1 H-NMR (300 MHz, DMSO-d ₆ , δ / ppm): 10.39 (IH, s), 10.11 (IH, s), 8.98 (IH, s), 8.74 (IH, dd), 8.28 (IH, dd) ), 8.12 (IH, d), 7.91 (IH, d), 7.73 (IH, dt), 7.68 (IH, dt), 7.33 (2H, d), 6.90 (2H, d), 2.21 (3H, s) 1.13 (9H, s).

·· j · · · ·

Example 9

4-Aminonaphthalene-1-sulphoric acid N- [4- (N-2,2-dimethylpropanoyl) aminophenyl] -amide

5.83 g (13.26 mmol). 4-Acetamidonaphthalene-1-sulfonic acid N- [4- (N-2,2-dimethylpropanoyl) aminophenyl] amide (Example 8) is dissolved in 165 ml of 5% aqueous lithium hydroxide solution and heated at 60 DEG C. for 14 hours. Deň: 32 ° C. After cooling, the reaction mixture was acidified with 2 M '. hydrochloric acid to pH 4, whereupon a pale pink colored precipitate precipitates, which is filtered off with suction and washed with water.

After drying under high vacuum, 5.0 g (12.58 mmol, 91% yield) of the title compound are obtained:

R _f: 0.28 (CH ₂ Cl ₂ / MeOH 100: 5).

MS (CI, NH ₃ , m / z): 415.1 (M + NH 4), 398 (M + H +).

H-NMR (300 MHz, DMSO-d _s, δ / ppm): 9.98 (1H, s), 8.93 (1H, s), 8.57 (1H, d), 8.17 (1H, d), 7.87 (1H, d), 7.60 (1 H, t), 7.45 (1 H, t), 7.31 (2 H, d), 6.87 (2 H, d), 6.69 (2 H, s), 6.57 (1 H, d), 1.13 (9 H, s) ).

Example 10

N - [4- (N- (N-2,2-dimethylpropanoyl) -aminophenyl] -amide)

Claims (15)

PATENT CLAIMS 1. Naphthyl-substituted and anilide-substituted sulfonamides of the general formula I NR = CO-R ³ (I) wherein R and R ^a are identical or different and denote hydrogen, formyl, optionally one to three halogen atoms, phenyl or benzyl group or a linear or branched alkyl or acyl each having up to 6 carbon atoms, the alkyl or acyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen and hydroxy, A, D, E and G are the same or different and are hydrogen, halogen, nitro, cyano, hydroxy, carboxyl, trifluoromethyl, trifluoromethoxy or a straight or branched alkyl, alkoxy or alkoxycarbonyl group of up to 5 carbon atoms each, R ³ represents a straight or branched alkenyl group of up to 6 carbon atoms, or a straight or branched alkyl group having up to 8 carbon atoms optionally bearing an amino group which may be substituted with an alkyl group having up to 4 carbon atoms or an amino protecting group, or the alkyl group optionally one to three times the same or differently substituted by hydroxy, cyano, halogen , azido, nitro, trifluoromethyl, carboxy or phenyl, which itself may be substituted up to twice, equally or differently with nitro, halogen, hydroxy or a straight or branched alkyl or alkoxy of up to 4 carbon atoms, or R is a radical of formula or -L-O-CO-Q wherein L represents a straight or branched alkanediyl group having up to 6 carbon atoms and Q represents an alkyl group of up to 6 carbon atoms which is optionally substituted by a carboxyl group or radicals of the formulas Or wherein a represents 1 or 2, represents a hydrogen atom, denotes a cycloalkyl group having from 3 to 8 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a hydrogen atom or a straight or branched alkyl group having up to 8 carbon atoms, the alkyl group is optionally substituted by cyano, methylthio, hydroxy, mercapto, guanidyl or -NR ⁴ R ⁴ ® or R ⁴⁴ -OC-, wherein R ^{4 is} independently hydrogen, straight or branched alkyl of up to Or a phenyl group; and R ⁴⁴ represents hydroxy, benzyloxy, alkoxy of up to 6 carbon atoms or the above-mentioned -NR 4 R 6, or the alkyl group is optionally substituted with cycloalkyl of 3 to 8 carbon atoms or aryl of 6 to 10 carbon atoms which is itself substituted by hydroxy, or a halogen atom, a nitro group, an alkoxy group having up to 8 carbon atoms or an -NR 6 R-LQ group, wherein R 6a are as defined above, or the alkyl group is optionally substituted with a 5- to 6-membered nitrogen heterocycle or indolyl wherein the corresponding NH- the functions are optionally substituted with an alkyl group of up to 6 carbon atoms or protected with an amino protecting group and a R ⁷ and R ³ are the same or different and denote a hydrogen atom or an amino protecting group, R ⁴ represents a hydrogen atom or a radical of formula R ^5, R ⁶ ' X 7 '3' —CO NR R wherein R ³ , R, R and R have the meanings given above for R ⁵ , R ⁶ , R ⁷ and R 6 and are the same or different thereto and X is as defined above for R ⁴ and is the same or different with R ⁴ and their stereoisomers, stereoisomeric mixtures and salts thereof, with the exception of N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl] amino phenyl] acetamide. • ·· · ·· · Sulfonamides according to claim 1, in which R ⁴ and R ² are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, A, D, E and G are the same or different and are hydrogen, halogen, nitro, cyano, hydroxy, carboxyl, trifluoromethyl, trifluoromethoxy or a straight or branched alkyl, alkoxy or alkoxycarbonyl group of up to 5 carbon atoms each, R ³ represents a straight or branched alkenyl group of up to 6 carbon atoms, or a straight or branched alkyl group of up to 8 carbon atoms, optionally bearing an amino group which may be substituted with an alkyl group of up to 4 carbon atoms or an amino protecting group, or optionally one to three times the same or differently substituted by hydroxy, cyano, halogen, azido, nitro, trifluoromethyl, carboxy or phenyl, which may itself be substituted up to twice, equally or differently by nitro, halogen, hydroxy or straight or branched alkyl or an alkoxy group of up to 4 carbon atoms, or is a radical of formula 9 · * • 99 9 · '· XH, or -L-O-CO-Q, wherein L denotes a straight or branched alkanediyl group having up to 6 carbon atoms and denotes an alkyl group having up to 6 carbon atoms which is optionally substituted by a carboxyl group or radicals of the formulas or R \ R ^p NR ⁷ R ^and wherein a denotes 1 or 2 denotes a hydrogen atom, denotes a cycloalkyl group having 3 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, a hydrogen atom or a straight or branched alkyl group having up to 8 carbon atoms, the alkyl group is optionally substituted with cyano, methylthio, hydroxy, mercapto, guanidyl or -NR ⁹ R ⁴⁰ or R ⁴⁴ -OC-, wherein: R ⁹ and RLO independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl and R represents hydroxyl, alkoxy having up to 6 carbon atoms or the abovementioned group -NR ⁹ R ¹⁰ or is C optionally substituted by cycloalkyl of 3 to 8 carbon atoms or aryl of 6 to 10 carbon atoms, which itself is substituted by hydroxy, halogen, nitro, alkoxy of up to 8 carbon atoms or -NR ⁹ r ¹⁰ , wherein R ⁹ and are as defined above, or the alkyl group is optionally substituted by a 5- to 6-membered nitrogen heterocycle or indolyl, the corresponding NH functions being optionally substituted by an alkyl group of up to 6 carbon atoms or protected by an amino protecting group, and 7 8 o R and R ° are the same or different and denote a hydrogen atom or an amino protecting group. 83 groups, represents a hydrogen atom or a radical of formula R ^s \ R ⁶ ' IN NR ⁷ CO wherein ^R, R @ ⁷ to R @ ^5, R @ ^6, R @ ⁷ and R @ ⁸ O '. _z ', _z and R ° have the meanings given above and are the same or different with them X represents a hydrogen atom, and stereoisomers, stereoisomeric mixtures and salts thereof, with the exception of N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl] amino] phenyl] acetamide. . , Sulfonamides according to claim 1 or 2, in which: R denotes a straight or branched alkenyl group with up to 6 carbon atoms or a straight or branched alkyl group having up to 8 carbon atoms which bears an amino group which may be substituted by an alkyl group having up to 4 carbon atoms or an amino protecting group, or the alkyl group being optionally substituted one or three times the same or differently by hydroxy; cyano, halogen, azido, nitro, trifluoromethyl, carboxy or phenyl, which may itself be substituted up to twice, equally or differently with nitro, halo, hydroxy or straight or branched alkyl or alkoxy of up to 4 carbon atoms or R ~ indicates remnants of formulas ch ₃ ch ₃ - ^ 0 —I or 1 L-0 wherein L and Q are as defined above. Sulfonamides according to claim 1 or 2 of the general formula I, in which ^One of R _t and R are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, A, D, E and G are identical or different and denote hydrogen, fluorine, chlorine, bromine, nitro, cyano, hydroxyl or straight-chain or branched alkyl, Alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, ^{3 * 5} · £ R denotes a straight or branched alkenyl group with up to Or a straight or branched alkyl group having up to 7 carbon atoms optionally bearing an amino group which may be substituted with an alkyl group having up to 3 carbon atoms, a tert-butoxycarbonyl or a benzyloxycarbonyl group, or the alkyl group optionally one to three times the same or differently substituted by hydroxy, cyano, fluorine or chlorine, azido, nitro, trifluoromethyl or phenyl, which itself may be substituted up to twice, in the same or differently by nitro, fluorine or chlorine, hydroxy or straight or branched alkyl or alkoxy up to 3.carbon atoms, or R 'represents radicals of the formula ^C ₃ H - or j -L-O-CO-Q, -O, wherein a denotes a straight or branched alkanediyl group of up to 4 carbon atoms, and Q represents an alkyl group of up to 4 carbon atoms which is optionally substituted by a carboxyl group or radicals of the formulas 4fi (H ₂ C) _and —A In or FRI ¹ -XXip ⁷ NR R denoting the number 1 or 2, 0 'jd> 0 j -> 9? 5 6 .i y o *> o • j in ftOOO O O *> ó -9 o O> ô o> Í5č ^- - '• O3 (JO jb 0> □ 7> '' 3 -> ® About Tr J.J> 0 R @ 1 denotes a hydrogen atom, R @ ¹ denotes a cyclopentyl or cyclohexyl group, a phenyl group or a hydrogen atom, or a straight or branched alkyl group of up to 6 carbon atoms; v - t. Wherein the alkyl group is optionally substituted by cyano, methylthio, hydroxy, mercapto, guanidyl, amino, carboxy or h ₂ n-co-, or the alkyl group is substituted by cyclohexyl, naphthyl or phenyl, which may itself be substituted hydroxy, fluoro, nitro or alkoxy of up to 4 carbon atoms, or / or the alkyl group is substituted with ί 3) · indolyl, imidazolyl, pyridyl, A is a triazolyl or pyrazolyl group, wherein the corresponding NH functions are optionally; , is substituted with an alkyl group of up to Or optionally protected by a tert-butyloxycarbonyl or benzyloxycarbonyl group; and R ^Z and R are identical or different and denote vodíko4 · 'i • · ♦ • · · φ β'> ··· ·· ·· above hydrogen or tert-butyloxycarbonyl or benzyloxycarbonyl group, is hydrogen or a radical of formula . -CO-NR ⁷ R ⁸ t 2 t 7 a 'wherein R, R, R and R have the meanings given above for R ^5, R ^6, R and R @ ³ and are identical or different, and their stereoisomers, stereoisomeric mixtures and salts, with the exception of N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] sulfonyl] amino] phenyl] acetamide. The sulfonamides according to claim 4 of the general formula I, in which R ³ represents straight-chain or branched alkenyl having up to 5 carbon atoms or straight-chain or branched alkyl having up to 7 carbon atoms which carries an amino group which may be substituted by alkyl having up to 3 carbon atoms, tert-butyloxycarbonyl or benzyloxycarbonyl, or the alkyl group is one to three times equally or differently substituted by hydroxy, cyano, fluorine or chlorine, azido, nitro, trifluoromethyl or phenyl, which may itself be substituted up to two, equally or differently by nitro, fluorine or chlorine, hydroxy or straight or branched alkyl or alkoxy group ftft ftft ftft ftft ftft R ^@ 1 has up to 3 carbon atoms, or is a radical of the formula &quot; -L-O-CO-Q, -O wherein L and Q are as defined above. Sulfonamides according to claim 1, 2 or 4 of the general formula I, in which 1 2 R and R are the same or different and denote a hydrogen, atom, phenyl or straight or branched alkyl or acyl group of up to 4 carbon atoms, A, D, E and G are the same or different and denote a hydrogen atom, a fluorine, chlorine or bromine atom, a hydroxy group, a methyl group or a methoxy group, R denotes a straight or branched alkenyl group with up to Or a straight or branched alkyl group having up to 5 carbon atoms optionally bearing an amino group which may be substituted by a tert-butoxycarbonyl or benzyloxycarbonyl group, or the alkyl group optionally being one to three times the same or differently substituted by a hydroxy, cyano, atom fluorine or chlorine, azido, nitro, trifluoromethyl or phenyl, which itself may be substituted up to twice, equally or differently by nitro, fluorine or chlorine, hydroxy, methyl, ethyl, methoxy or ethoxy, or R ~ denotes residues of formulas ft. · · .CH. A · » CH. A ·> or -L-O-CO-Q, -O wherein L represents a straight or branched alkanediyl group having up to 4 carbon atoms and Q represents an alkyl group of up to 3 carbon atoms optionally substituted by a carboxyl group, or a radical of formula wherein: R 6 denotes a hydrogen atom and r 6 denotes a cyclopentyl or cyclohexyl group or a hydrogen atom, or a straight or branched alkyl group having up to 4 carbon atoms, the alkyl group being optionally I •• 'i. substituted with cyano, methylthio, hydroxy, mercapto, guanidyl, amino, carboxy or h ₂ n-co-, or an alkyl substituted with cyclohexyl, naphthyl or phenyl *, which may itself be substituted by a fluorine or chlorine atom or an alkoxy group C 1-4 alkyl, or the alkyl group is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl group, the corresponding NH-functions being optionally substituted by methyl or optionally protected by tert-butyloxycarbonyl or benzyloxycarbonyl and 7 8. O R and R are the same or different and represent a hydrogen atom or a tert-butyloxycarbonyl group, R ⁴ represents a hydrogen atom or a radical of formula 91 «? and are the same or different with R, R °, R ^z and R °, and stereoisomers, stereoisomeric mixtures and salts thereof, with the exception of N- [4 - [[[5- (dimethylamino) -1-naphthalenyl] [sulfonyl] amino] phenyl] acetamide. Sulfonamides according to any one of claims 1 to 6 of the general formula I, in which o R denotes a straight or branched alkenyl group with up to Or a straight or branched (C 5 -C 5) alkyl group bearing an amino group which may be substituted by a tert-butyloxycarbonyl or benzyloxycarbonyl group, or the alkyl group is one or three times the same or differently substituted by hydroxy, cyano, fluorine or chloro, azido, trifluoromethyl or phenyl, which may itself be substituted up to twice, equally or differently with nitro, fluorine or chlorine, hydroxy, methyl, ethyl, methoxy or ethoxy, or R @ - denotes residues of the formulas CH ₃ -lO or inhibit the de-CO-Q, -O wherein L and Q are as defined above · », ^κ ·· '· · · ·" and their stereoisomers, stereoisomeric mixtures and salts. Sulfonamides according to any one of claims 1 to 7 of the general formula I, in which 1 2 R ^x and R denote a straight or branched alkyl group having up to 4 carbon atoms, A, D, E and G denote a hydrogen atom, R. denotes a straight or branched alkyl group having up to 5 carbon atoms which is substituted by a hydroxy group, or R is a radical of formula -L-O-CO-Q, wherein L denotes straight or branched alkanediyl a group having up to 4 carbon atoms -ý Q represents the remainder of the formula and ^r5 \ R ⁶ ^^ nr ⁷ r ⁸ * in which R ³ and r ⁶ denote a hydrogen atom and y o R and R denote a hydrogen atom and R ⁴ denotes a hydrogen atom, and its stereoisomers, stereoisomeric mixtures and salts thereof. Sulfonamides according to any one of claims 1 to 8 of the general formula I, selected from the group consisting of 10. A process for the preparation of the sulfonamides of the above-mentioned general formula (I), characterized in that [A] compounds of the general formula (II) in which A, D, E, G, R and R are as defined above, are first converted by catalytic hydrogenation to palladium / C or by reduction with stannous chloride in inert solvents to compounds of formula III wherein A, D, E, G, R and R are as defined above, and then reacted with compounds of formula IV T-CO-R ³ (IV), and wherein R is as defined above and T represents a hydroxy group or a halogen atom, preferably chlorine, in inert solvents and optionally in the presence of a base and / or auxiliary agent, or 44 ·· «« • i '· Ί •' · * The compounds of the general formula V i and nr ⁴ -co-r ³ (V) o ₂ n in which E, G, R ³ and R ^{4 are} as defined above will first convert as described in [4] A] by hydrogenation to Pd / C or by reduction with stannous chloride in inert solvents to compounds of formula VI H ₂ N / O G nr ⁴ -co-r ³ (VI) in which E, G, R ³ and R ^{4 are} as defined above, and then reacted with compounds of formula VII NR ^ ² with ₂ -v (VII) In which A, D, R and R are as defined above and represent a halogen atom, preferably chlorine, in inert solvents, optionally in the presence of a base. .. ’· · ·· '· J. '· ·: · »· · *. . . · · · · · ·, · _% . - · - · '· · · An ed and / or auxiliary agent, or [C] when and / or R ⁴ is a radical of the formula -L-O-CO-Q, let the compounds of formula (Ia) react NR ¹ R ² ° zAnico-1-oh SOjNhAJv ^{Ι &} ' G 194 wherein R, R, R, A, D, E, G, and L are as defined above, with amino acid esters of formula VIII HO-CO-Q '(VIII) in which Q 'has the meaning given above for Q, wherein any of the terminal nitrogen residues mentioned herein denotes one of the abovementioned protecting groups, preferably a tert-butylcarbonyl group, optionally with activation of the carboxylic acid by conventional methods, in inert solvents and in the presence of a base; adjuvants, and then protecting groups are cleaved by conventional methods · Ϊ «« «$ $« «$« «« «$ $ $ $ $ $ in peptide chemistry, and when X, R X is not a hydrogen atom, it is reacted with 2 or more equivalents of compounds of formula VIII, optionally stereoisomers are separated by methods known in the art, and optionally the free bases are converted into salts or converted into salts on free bases. Sulfonamides of the formula I according to any one of claims 1 to 9 for the prophylaxis or treatment of diseases. Use of the sulfonamides of the general formula I according to any one of claims 1 to 9 for the manufacture of medicaments. Use according to claim 12, wherein the medicaments are for the treatment of viral diseases. Use according to claim 12 or 13, wherein the medicaments are for combating cytomegalievir. A medicament comprising the sulfonamides of the formula I according to any one of claims 1 to 9.