ZA200307892B - Arylsulfonamides as antiviral agents. - Google Patents

Arylsulfonamides as antiviral agents. Download PDF

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Publication number
ZA200307892B
ZA200307892B ZA200307892A ZA200307892A ZA200307892B ZA 200307892 B ZA200307892 B ZA 200307892B ZA 200307892 A ZA200307892 A ZA 200307892A ZA 200307892 A ZA200307892 A ZA 200307892A ZA 200307892 B ZA200307892 B ZA 200307892B
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South Africa
Prior art keywords
group
hydroxyl
amino
alkyl
halogen
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ZA200307892A
Inventor
Tobias Wunberg
Wolfgang Bender
Peter Eckenberg
Sabine Hallenberger
Kerstin Henninger
Jorg Keldenich
Achim Kern
Siegfried Raddatz
Jurgen Reefschalager
Gunter Schmidt
Holger Zimmermann
Franz Zumpe
Martin Radtke
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Bayer Ag
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Publication of ZA200307892B publication Critical patent/ZA200307892B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Description

*] * ARYLSULPHONAMIDES AS ANTIVIRAL AGENTS
The present invention relates to novel compounds, to processes for their preparation and to their use as medicaments, in particular as antiviral agents, in particular against cytomegaloviruses.
From WO 99/37291, compound 2,2-dimethyl-N-[4-[[[4-(4-phenyl-2H-1,2,3-triazo}- 2-yDphenyl}-sulphonyl]aminolphenyl]-propanamide is known as having antiviral action.
The present invention relates to compounds of the general formula @
RA R® X q L i
A © M,
Li in which
R? and R? are identical or different and represent hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C,-Cs)-alkyl, (C,-Ce)-alkoxy or represent a group of the formula i 1] —C-0R® or —C-NR “rR? in which
R’, R® and R’ are identical or different and each represents hydrogen or (C;-
Ce)-alkyl which for its part may be substituted by one or two
‘ = 2 = substituents selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl! and trifluoromethoxy,
A represents five- or six-membered heteroaryl, which is attached to the adjacent phenyl ring via a C atom and has one to three heteroatoms selected from the group consisting of N, O and S,
R! represents (Cs-Cio)-aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl having in each case one to three heteroatoms selected from the group consisting of N, O and S, where
R! may be substituted by up to three substituents selected from the group consisting of hydroxyl, amino, mono-(C,-Cg)-alkylamino, di-(C,-Cg)- alkylamino, halogen, nitro, cyano, oxo, (C;-Ce)-alkyl, which for its part may be substituted by amino or hydroxyl, (C;-Cs)-alkoxy, phenyl, 5- or 6- membered heterocyclyl having up to two heteroatoms selected from the group consisting of N, O and S, 5- or 6-membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, -C(0)-O-R®, -
C(0)-NR°R'®, -NH-C(0)-R", -NH-C(0)-C(0O)-R'? and -NH-SO,-R"?, where
R®, R® and R' arc identical or different and each represents hydrogen or (C;-Ce)-alkyl, or
R® and R'° together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycle which may contain a further nitrogen or oxygen heteroatom and which may be mono- to disubstituted by identical or different substituents from the group consisting of (C;-
" . - 3 h
Ca)-alkyl, which for its part is optionally substituted by hydroxyl or amino, amino, hydroxyl, (C,-C,)-alkoxy, oxo, carboxyl and (C;-Ca)- alkoxycarbonyl,
R'! and R'? are identical or different and each represents trifluoromethyl, (C;-
Ce)-alkoxy, hydroxyl or represents (C;-Cg)-alkyl, which is optionally mono- or disubstituted by identical or different constituents from the group consisting of amino, (C;-Cg)-alkoxycarbonylamino, mono-(C;-
Ce)-acylamino, hydroxyl, amidino, guanidino, (C1-Ce)- alkoxycarbonyl, carboxyl and phenyl, and
RY represents (C1-Ce)-alkyl or (Cs-Cjo)-aryl which may in each case be substituted by halogen, amino, hydroxyl, (C;-Cq4)-alkoxy or (C-Cy4)- alkyl,
R* represents (C,-Ce)-alkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-Cs)-alkoxy, (C,-Cs)-alkanoyloxy and phenyl, which for its part is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, represents (C3-Cs)-cycloalkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C,-C¢)-alkoxy and (C;-Ce)-alkyl, which for its part is optionally substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen and (C,-Cs)-alkoxy,
or represents (Cs-Cjo)-aryl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, and in which
X represents oxygen or sulphur, and in which nitrogen-containing heterocycles may also be present as N-oxides, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacological acceptable salts.
In the context of the invention, (C;-Ce)-alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. The following radicals may be mentioned by way of example: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and n-hexyl.
In the context of the invention, (C3-C;)-cycloalkyl represents a cycloalkyl group having 3 to 7 carbon atoms. The following radicals may be mentioned by way of example: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In the context of the invention, (C,-C¢)-alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. The following radicals may be mentioned by way of example: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n- hexoxy. Preference is given to methoxy and ethoxy.
In the context of the invention, (C¢-C,o)-aryl represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
u . h 5 ©
In the context of the invention, aralkyl represents (Cg-Cjo)-aryl, which for its part is attached to (C,;-Cg)alkyl. Preference is given to benzyl.
In the context of the invention, mono-(C;-C¢)-alkylamino represents an amino group having a straight-chain, branched or cyclic alkyl substituent having 1 to 6 carbon atoms. The following radicals may be mentioned by way of example: methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, t-butylamino, n-pentylamino, cyclopentylamino and n-hexylamino.
In the context of the invention, di-(C;-C¢)-alkylamino represents an amino group having two identical or different straight-chain, branched or cyclic alkyl substituents, having in each case 1 to 6 carbon atoms. The following radicals may be mentioned by way of example: N,N-dimethylamino, N N-diethylamino, N-ethyl-N-methylamino,
N-methyl-N-n-propylamino, N-methyl-N-cyclopropylamino, N-isopropyl-N-n-propyl- amino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N- methylamino.
In the context of the invention, (C;-Cg)-alkoxycarbonyl represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, which is attached via a carbonyl group. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.
In the context of the invention, (C;-C¢)-alkoxycarbonylamino represents an amino group having a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 carbon atoms in the alkoxy radical and is attached via the carbonyl group.
Preference is given to an alkoxycarbonylamino radical having 1 to 4 carbon atoms in the alkoxy radical. The following radicals may be mentioned by way of example and by way of preference: methoxycarbonylamino, ethoxycarbonylamino, n-propoxy- carbonylamino and t-butoxycarbonylamino.
In the context of the invention, mono-(C;-Cs)-acylamino represents an amino group having a straight-chain or branched alkanoyl substituent which has 1 to 6 carbon atoms and is attached via the carbonyl group. Preference is given to a monoacylamino radical having 1 to 2 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
In the context of the invention, (C,-Cs)-alkanoyloxy preferably represents a straight- chain or branched alkyl radical having 1 to 5 carbon atoms which carries a doubly attached oxygen atom in the 1-position and which is attached in the 1-position via a further oxygen atom. Preference is given to a straight-chain or branched alkanoyloxy radical having 1 to 3 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: acetoxy, propionoxy, n-butyroxy, i-butyroxy and pivaloyloxy.
In the context of the invention, halogen generally represents fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine and bromine. Particular preference is given to fluorine and chlorine.
In the context of the invention, 5- to 10-membered heteroaryl represents 5- to 10- membered hetero-containing aromatic rings which may contain 1 to 4 heteroatoms selected from the group consisting of O, S and N, including, for example: pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolicenyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, etc.
In the context of the invention, 5- to 10-membered or 5- to 6-membered saturated or partially unsaturated heterocyclyl having up to 3 heteroatoms from the group consisting of S, N and O generally represents a mono- or bicyclic heterocycle which may contain one or more double bonds and which is attached via a ring carbon atom or a ring nitrogen atom. The following radicals may be mentioned by way of example: tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, piperidin-1-yl, piperidin-3-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl, piperazin-1-yl, morpholin-1-yl, azepin-1-yl, 1,4-diazepin-1-yl.
Preference is given to piperidinyl, morpholinyl and pyrrolidinyl. 1.2.4-Oxadiazole which is attached via the 3- or 5-position represents an oxadiazole which is attached to the phenylsulphonamide via the ring carbon atom in the 3- or 5-position.
In the context of the invention, the preferred salts are pharmacologically acceptable salts of the compounds according to the invention.
Pharmacologically acceptable salts of the compounds according to the vention may be acid addition salts of the compounds according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
However, salts that may be mentioned include salts with customary bases, such as, for example, alkali metal salts (for example sodium salts or potassium salts), alkaline earth metal salts (for example calcium salts or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine, or derived from natural amino acids, such as, for example, glycine, lysine, arginine or histidine.
The compounds according to the invention may exist in stereoisomeric forms which are either like image and mirror image (enantiomers) or which are not like image and
“ - 8 © mirror image (diastereomers). The invention relates both to the enantiomers Or diastereomers and to their respective mixtures. The racemic forms can, like the diastereomers, be separated into the stereoisomerically uniform components in a manner known per se.
In addition, the invention also embraces prodrugs of the compounds according to the invention. According to the invention, prodrugs are derivatives of the compounds of the general formula (I) which for their part may be biologically less active or even inactive, but, following administration, are converted under physiological conditions into the corresponding biologically active form (for example metabolically, solvolytically or in another manner).
The invention also relates to compounds of the general formula (I), in which
R? and R? are identical or different and represent hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C;-Ce)-alkyl, (C;-C¢)-alkoxy or represent a group of the formula 0) il 5 9 _R® —C—OR" or —C—N
NT
R B in which
R’, R® and R’ are identical or different and each represents hydrogen or (C;-
Ce)-alkyl, which for its part may be substituted by one or two substituents selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethy! and trifluoromethoxy,
. © 9 -
A represents five- or six-membered heteroaryl, which is attached to the adjacent phenyl ring via a C atom and has one to three heteroatoms selected from the group consisting of N, O and S,
R! represents (Cg-Cio)-aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl having in each case one to three heteroatoms selected from the group consisting of N, O and S, where
R! may be substituted by up to three substituents selected from the group consisting of hydroxyl, amino, mono-(C,-Cs)-alkylamino, di-(C;-Ce)- alkylamino, halogen, nitro, cyano, oxo, (C;-Ce)-alkyl, which for its part may be substituted by amino or hydroxyl, (C;-C¢)-alkoxy, phenyl, 5- or 6- membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, -C(0)-O-R®, -C(0)-NR°R'? and -NH-C(0)-
RY, where
R%, R’ and R'® are identical or different and each represents hydrogen or (C;-Ce)-alkyl, and
R!' represents (C;-Cg)-alkyl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of amino, hydroxyl, guanidino, carboxyl and phenyl,
R* represents (C;-Ce)-alkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-Ce)-alkoxy and phenyl, which for its part is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, represents (C3-C;)-cycloalkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-Ce)-alkoxy and (C;-Ce)-alkyl, which for its part is optionally substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen and (C,-Cs)-alkoxy, or represents (Cs-Cig)-aryl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, and in which
X represents oxygen or sulphur, and in which nitrogen-containing heterocycles may also be present as N-oxides, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacologically acceptable salts.
The invention preferably relates to compounds of the general formula (I), in which
R? and R? are identical or different and represent hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C;-Ce)-alkyl, (C;-Ce)-alkoxy or represent a group of the formula
0 0) 6 1] J —C-OR® or —Ln-R ‘rR’ in which
R®, R® and R’ are identical or different and each represents hydrogen or (Ci-
Ce)-alkyl, which for its part may be substituted by one or two substituents selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy,
A represents five- or six-membered heteroaryl, which is attached to the adjacent phenyl ring via a C atom and has one to three heteroatoms selected from the group consisting of N, O and S,
R! represents (Ce-Cp)-aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl having in each case one to three heteroatoms selected from the group consisting of N, O and S, where
R! may be substituted by up to three substituents selected from the group consisting of hydroxyl, amino, mono-(C;-Cs)-alkylamino, di-(Ci-Cs)- alkylamino, halogen, nitro, cyano, oxo, (C;-Ce)-alkyl, which for its part may be substituted by amino or hydroxyl, (C;-C¢)-alkoxy, phenyl, 5- or 6- membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, -C(0)-O-R%, -C(0)-NR’R"® and -NH-C(0)-
RI! where
R®, R® and R' are identical or different and each represents hydrogen or (C1-Co)-alkyl,
and
RY represents (C;-Cg)-alkyl, which is optionally mono- or disubstituted by identical or different substituents from the group consisting of amino, hydroxyl, guanidino, carboxyl and phenyl,
R* represents (C;-Cg)-alkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-Ce)-alkoxy and phenyl, which for its part is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, represents (Cs-Cs)-cycloalkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-Cs)-alkoxy and (C;-Ce)-alkyl, which for its part is optionally substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen and (C,-C¢)-alkoxy, or represents (Cq-Cio)-aryl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, and in which
X represents oxygen, and in which nitrogen-containing heterocycles may also be present as N-oxides, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacologically acceptable salts.
The invention preferably also relates to compounds of the general formula (I), in which
R? and R? are identical or different and represent hydrogen or halogen,
A represents the radical (A-I) 4
N
4
Xs
Y—N 1 2 (AD) which is attached to the adjacent phenyl ring via one of the carbon atoms in position 3 or 5, and in which
Y represents oxygen or sulphur, or
A represents the radical (A-II)
Y
N, AL 4 °N 3 (A-11) which is attached to the adjacent phenyl ring via one of the carbon atoms in position 2 or §,

Claims (1)

  1. N - 109 - Patent claims
    1. Compounds of the general formula (I) 2 3 x Be A ada is A © ®; y R in which R? and R’ are identical or different and represent hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C;-Cs)-alkyl, (C,-Ce)-alkoxy or represent a group of the formula 1] —C-OR® or —-N “RY in which R® R® and R’ are identical or different and each represents hydrogen or (C;-Cg)-alkyl which for its part may be substituted by one or two substituents selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy, A represents five- or six-membered heteroaryl, which is attached to the adjacent phenyl ring via a C atom and has one to three heteroatoms selected from the group consisting of N, O and S,
    R! represents (Cg-Cjo)-aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl having in each case one to three heteroatoms selected from the group consisting of N, O and S, where
    R' may be substituted by up to three substituents selected from the group consisting of hydroxyl, amino, mono-(C;-Ce)-alkylamino, di-(C;-Ce)- alkylamino, halogen, nitro, cyano, oxo, (C;-Ce)-alkyl, which for its part may be substituted by amino or hydroxyl, (C,;-C¢)-alkoxy, phenyl, 5- or 6-membered heterocyclyl having up to two heteroatoms selected from the group consisting of N, O and S, 5- or 6-membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, -C(0)-O-R), -C(O)-NR°R!° -NH-C(O)-R", -NH-C(O)-C(0)-R"? and -NH-SO,-R", where R8, R’ and R'? are identical or different and each represents hydrogen or (C,-Ce)-alkyl, or R® and R'° together with the nitrogen atom to which they are attached - form a 5- to 6-membered heterocycle which may contain a further nitrogen or oxygen heteroatom and which may be mono- to disubstituted by identical or different substituents from the group consisting of (C;-Cy)-alkyl, which for its part is optionally substituted by hydroxyl or amino, amino, hydroxyl, (C;-Cy)-alkoxy, oxo, carboxyl and (C;-Cs4)-alkoxycarbonyl,
    B 111 - R'" and RY are identical or different and each represents trifluoromethyl, (C;-C¢)-alkoxy, hydroxyl or represents (C,-C¢)-alkyl, which is optionally mono- or disubstituted by identical or different constituents from the group consisting of amino, (C;-Ce)-alkoxycarbonylamino, mono-(C;-Cg)-acyl- amino, hydroxyl, amidino, guanidino, (C;-Ce)-alkoxycarbonyl, carboxyl and phenyl, and
    RP represents (C;-Cg)-alkyl or (Cs-Cip)-aryl which may in each case be substituted by halogen, amino, hydroxyl, (C;-Cs)- alkoxy or (C,-Cy4)-alkyl,
    R* represents (C,;-Cg¢)-alkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-C¢)-alkoxy, (C;-Cs)-alkanoyloxy and phenyl, which for its part is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro,
    cyano, amino and hydroxyl, represents (C;-C;)-cycloalkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C,-Cs)-alkoxy and (C;-Ce)-alkyl, which for its part is optionally substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen and (C,-C¢)-alkoxy,
    B - 112 - or represents (C¢-Cio)-aryl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, and in which X represents oxygen or sulphur, and in which nitrogen-containing heterocycles may also be present as N- oxides, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacological acceptable salts.
    2. Compounds of the general formula (I) according to Claim 1, in which R? and R’ are identical or different and represent hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C;-Ce)-alkyl, (C,-Ce)-alkoxy or represent a group of the formula 0 0) 6 i 1! —C—OR® or —&-nR No? R in which R®, R® and R’ are identical or different and each represents hydrogen or (C;-Cg)-alkyl, which for its part may be substituted by one or two substituents selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy, A represents five- or six-membered heteroaryl, which is attached to the adjacent phenyl ring via a C atom and has one to three heteroatoms selected from the group consisting of N, O and S, R! represents (C¢-Cig)-aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl having in each case one to three heteroatoms selected from the group consisting of N, O and S, where R! may be substituted by up to three substituents selected from the group consisting of hydroxyl, amino, mono-(C;-Ce)-alkylamino, di-(C,-C)- alkylamino, halogen, nitro, cyano, oxo, (C;-C¢)-alkyl, which for its part may be substituted by amino or hydroxyl, (C;-Cg¢)-alkoxy, phenyl, 5- or 6-membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, -C(0)-O-R?, -C(O)-NR’R!° and -NH-C(O)-R"!, where R®, R® and R'? are identical or different and each represents hydrogen - or (C,1-Cg)-alkyl, and R'"' represents (C;-Ce)-alkyl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of amino, hydroxyl, guanidino, carboxyl and phenyl,
    R* represents (C;-Cg)-alkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-Cg)-alkoxy and phenyl, which for its part is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, represents (C;-C7)-cycloalkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-Ce)-alkoxy and (C;-Cs)-alkyl, which for its part is optionally substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen and (C,-Cg)-alkoxy, or represents (C¢-Cjp)-aryl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, and in which X represents oxygen or sulphur, - and in which nitrogen-containing heterocycles may also be present as N-oxides, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacologically acceptable salts.
    3. Compounds of the general formula (I) according to Claim 1,
    in which R?> and R® are identical or different and represent hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C;-Cg)-alkyl, (C,-Ce)-alkoxy or represent a group of the formula 0 I 5 ? _R® —C—OR" or —C—N_ Rr’ in which R®, R® and R’ are identical or different and each represents hydrogen or (C;-Cg)-alkyl, which for its part may be substituted by one or two substituents selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy,
    A represents five- or six-membered heteroaryl, which is attached to the adjacent phenyl ring via a C atom and has one to three heteroatoms selected from the group consisting of N, O and S,
    R! represents (Cg-Cig)-aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl having in each case one to three heteroatoms selected from the group consisting of N, O and S, where
    R! may be substituted by up to three substituents selected from the group consisting of hydroxyl, amino, mono-(C,-Ce)-alkylamino, di-(C;-Cg)- alkylamino, halogen, nitro, cyano, oxo, (C,-Ce)-alkyl, which for its part may be substituted by amino or hydroxyl, (C,-C¢)-alkoxy, phenyl,
    © - 116 - 5- or 6-membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, -C(0)-O-R?, -C(0)-NR’R"® and -NH-C(O)-R"!, where R®, R® and R' are identical or different and each represents hydrogen or (C,-Ce)-alkyl, and R!" represents (C;-Ce)-alkyl, which is optionally mono- or disubstituted by identical or different substituents from the group consisting of amino, hydroxyl, guanidino, carboxyl and phenyl,
    R* represents (C1-Ce)-alkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-C¢)-alkoxy and phenyl, which for its part is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, : represents (C3-C;)-cycloalkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen, (C;-Cs)-alkoxy and (C;-Ce)-alkyl, which for its part is optionally substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, halogen and (C,-Cg)-alkoxy,
    N -117 - or represents (Cs-Co)-aryl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, and in which X represents oxygen, and in which nitrogen-containing heterocycles may also be present as N-oxides, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacologically acceptable salts. 4, Compounds of the general formula (I) according to Claim 1, in which R? and R? are identical or different and represent hydrogen or halogen,
    A represents the radical (A-I) 4 N 2 ~~ Y—N 1 2 (A-1) which is attached to the adjacent phenyl ring via one of the carbon atoms in position 3 or 5,
    and in which Y represents oxygen or sulphur, or A represents the radical (A-I) 3% 2 No # 4 °N 3 (A-11)
    which is attached to the adjacent phenyl ring via one of the carbon atoms in position 2 or 5, and in which
    Y represents oxygen or sulphur, R! represents 5- to 10-membered heteroaryl or 5- or 10-membered heterocyclyl having in each case up to three heteroatoms selected from the group consisting of N, O and S, or represents phenyl, where R! may be substituted by one to three substituents selected from the group consisting of (C;-Cs4)-alkyl, which for its part is optionally substituted by hydroxyl or amino, hydroxyl, oxo, halogen, amino, mono-(C;-C,)- alkylamino, di-(C,-Ca)-alkylamino and -NH-C(O)-R"!, where
    R!" represents (C;-Cg)-alkyl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of amino, hydroxyl, guanidino and carboxyl, R* represents (C;-C4)-alkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine and (C;-Ca)- alkoxy, represents (C3-Cs)-cycloalkyl, which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine, (C;-Cy)- alkoxy and (C;-Cs)-alkyl, which for its part is optionally substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine and (C;-Cj)-alkoxy, and in which X represents oxygen or sulphur, and in which nitrogen-containing heterocycles may also be present as N-oxides, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacologically acceptable salts.
    5. Compounds of the general formula (I) according to Claim 1,
    in which R? and R? are identical or different and represent hydrogen or halogen, A represents the radical (A-I) 4 N 4 Xn Y=—N 1 2 (A-1) which is attached to the adjacent phenyl ring via one of the carbon atoms in position 3 or 5, and in which Y represents oxygen or sulphur,
    or A represents the radical (A-II) Y N, AE 4 °N 3 (A-11) which is attached to the adjacent phenyl ring via one of the carbon atoms in position 2 or 5,
    and in which Y represents oxygen or sulphur,
    R! represents 5- to 10-membered heteroaryl or 5- or 10-membered heterocyclyl having in each case up to three heteroatoms selected from the group consisting of N, O and S, or represents phenyl, where
    R! may be substituted by one to three substituents selected from the group consisting of (C;-Cy4)-alkyl, which for its part is optionally substituted by hydroxyl or amino, hydroxyl, oxo, halogen, amino, mono-(C;-Ca)- alkylamino, di-(C;-C4)-alkylamino and -NH-C(O)-R', where
    R'"" represents (C;-Ce)-alkyl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of amino, hydroxyl, guanidino and carboxyl, R* represents (C;-Cy)-alkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine and (C;-C4)-alkoxy, or - represents (C;-Cs)-cycloalkyl which may be substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine, (C,-Cs)-alkoxy and (C,-Cy)- alkyl, which for its part is optionally substituted up to three times by identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine and (C;-C;)-alkoxy,
    and in which X represents oxygen, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacologically acceptable salts.
    6. Compounds of the general formula (I) according to Claim 1, in which R?and R® represent hydrogen, A represents one of the radicals 1 5 NY N 1 R~y > R 0) S Yr Yr Xr. Xr Oo-N ON , N-N N-N 12 1 2 R! represents a radical selected from the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl, where ’ R! may be substituted by one or two substituents selected from the group consisting of methyl, aminomethyl, hydroxyl, bromine, chlorine, fluorine, amino, dimethylamino and -NH-C(0)-R"}, where
    R! represents (C;-Cg)-alkyl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of amino, hydroxyl, guanidino and carboxyl, R* represents tert-butyl which is optionally substituted up to three times by identical or different substituents from the group consisting of hydroxyl, fluorine and chlorine, or represents cyclopropyl or cyclobutyl which are substituted by methyl, which for its part is optionally substituted by hydroxyl, fluorine or chlorine, and in which X represents oxygen, and in which nitrogen-containing heterocycles may also be present as N-oxides, and their tautomers, stereoisomers, stereoisomer mixtures and their pharmacologically acceptable salts.
    7. Compounds of the general formula (I) according to Claim 1, in which R? and R® represent hydrogen, A represents one of the radicals
    4 4 RLEN 5 N_-R' 1 0 1 _S R R Xr ~~ Ts ~( al i ~( al O—N O—N ' , N—N N—N 1 2 1 2 R! represents a radical selected from the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl, where R! may be substituted by one to two substituents selected from the group consisting of methyl, aminomethyl, hydroxyl, bromine, chlorine, fluorine, amino, dimethylamino and -NH-C(0O)-R"},
    where R!"" represents (C;-Ce)-alkyl which is optionally mono- or disubstituted by identical or different substituents from the group consisting of amino, hydroxyl, guanidino and carboxyl, R* represents tert-butyl which is optionally substituted up to three times by identical or different substituents from the group consisting of hydroxyl, fluorine and chlorine, or represents cyclopropyl or cyclobutyl which are substituted by methyl, which for its part is optionally substituted by hydroxyl, fluorine or chlorine, and in which X represents oxygen.
    8. Compounds according to Claim 1 of the general formula (Ia) R’ R’ A " Clg jul 1 I (Ia), NE O in which R!, R*, A and X are as defined above, and R? and R’ are identical or different and represent hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C;-Cg)-alkyl or (Cy-Ce)-alkoxy.
    9. Compounds of the general formula (I) according to Claim 1, in which R* represents one of the radicals H,C —] or —< OF HC CH;
    10. Compounds of the general formula (I) according to Claim 1, in which
    A represents a 1,2,4-oxadiazole attached via the 3-position.
    11. Compounds according to Claim 1, selected from the group of the following compounds: O=-N = N N 0 0 >S CH, o N N CH, 5 F =N Oo 0 HN S TL CH, oN N CH, o F =N = N N 0 JO 0 / CH PN NG i O H H O-N (0) Oo & £ 1 Len “4° N N O H H O=-N ha S 3 =o o ~N NG H,C H H
    12. Process for preparing compounds of the general formula (I) according to Claim 1, in which A represents the radical (A-I) 4 N 4 Xs Y—N 1 2 (Al) which is attached to the adjacent phenyl ring via one of the carbon atoms in position 3 or 5, and in which Y represents oxygen, by reacting amidoximes of the general formula [D-1]
    - R® 0 A H,N I] Ch rR’ S< H It °N O H [D-1] in which X, R?, R> and R* are as defined above,
    with a carboxylic acid [E-1] R'-COOH [E-1]
    in which R' is as defined above, or condensing sulphonamides of the general formula [F-3] R? HOOC § AH nm oN [F-3] : : in which
    X, R?, R® and R? are as defined above, with an amidoxime of the general formula [G-1] NH, R= N—OH [G-1] in which R! is as defined above,
    giving compounds of the general formula [G-2],
    H NR 0 0 x Ww LI Y R'” “N—N “N 3 1 | R H H FH R> H-2] in which X, R! , R? , R? and R* are as defined above, and FH represents hydrogen, an amino protective group or a polymeric support, with elimination of water, to give compounds of the general formula (I).
    14. Process for preparing compounds of the general formula (I) according to Claim 1, in which X represents oxygen, A represents the radical (A-II) pH
    N. ~ 4 °N 3 Ad) which is attached to the adjacent phenyl ring via one of the carbon atoms of position 2 or 5, and in which
    Y represents sulphur,
    by cyclizing hydrazides of the general formula [H-3]
    H NR Oo oO x Ww LTT R'” “N—N “N , R H H FH R2 [H-3]
    in which R!, R%, R® are as defined above,
    FH represents hydrogen, an amino protective group or a polymeric support,
    and
    RY represents (C;-Cg)-alkoxy, (C;-Cs)-alkenoxy or aralkoxy,
    in the presence of a thio donor, preferably Lawesson’s reagent, to give compounds of the general formula (I) in which Y represents sulphur, then :
    removing group -C(O)-R* and finally reacting with compounds of the general formula
    X 4 in which R* and Q are as defined above.
    ’ 15. Use of compounds of the general formula (I) according to any one of Claims 1 ‘ to 11 in the manufacture of medicament for the prophylaxis or treatment of diseases.
    16. Use of compounds of the general formula (I) according to any of Claims 1 to 11 for preparing medicaments.
    17. Use of compounds of the general formula (I) according to Claim 16, where the medicaments are for controlling viral disorders.
    18. Use of compounds of the gencral formula (I) according to Claim 16 or 17, where the medicaments are for controlling cytomegalovirus infections.
    19. Medicaments, comprising compounds of the general formula (I) according to Claim 1.
    20. Compounds of the general formula (la) according to Claim 1 A R’ Rr’ Ay I (1a), yy Oo in which RY, R?, rR’, R*, A and X are as defined above.
    21. Compounds of the general formula (I) substantially as herein described with reference to and as exemplified in any one of examples 1 to 154.
    22. Process for preparing compounds according to claims 21 substantially as herein described with reference to and as exemplified in any one of examples 1 to 154. AMENDED SHEET
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US8703774B2 (en) 2007-12-07 2014-04-22 AbbVie Deutschland GmbH & Co. KG Carbamate-substituted oxindole derivatives and use thereof for the treatment of vasopressin-dependent diseases
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