HK1057552B - Thiazolyl amide derivatives - Google Patents
Thiazolyl amide derivatives Download PDFInfo
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Description
The present invention relates to novel compounds, namely thiazolyl amide derivatives, to processes for their preparation and to their use as pharmaceuticals, in particular as antiviral pharmaceuticals.
2-aminothiazole-5-sulfonamides are known from C.Ziegler et al in J.org.chem.25, 1960, 1454-1455, and N-thiazol-2-yl-amides and ureas having herbicidal action are described in German publication No. 2101640 (Offenlegungsschrift).
WO97/24343 relates to phenylthiazole derivatives having anti-herpes viral properties.
WO99/42455 likewise relates to phenylthiazole derivatives having anti-herpes viral properties.
WO99/47507 relates to 1.3.4-thiadiazole derivatives having anti-herpes viral properties.
The present invention relates to novel compounds which are thiazolyl amide derivatives of the general formula (I) and salts thereof:
wherein
R1Represents hydrogen, halogen, (C)1-C6) Alkyl radicals, (C)1-C6) -alkoxy, amino- (C)1-C6) -alkyl or halo- (C)1-C6) -alkanesThe base group is a group of a compound,
R2and R3Are the same or different and represent hydrogen, (C)1-C6) -alkoxy, (C)3-C8) -cycloalkyl or biphenylaminocarbonyl, or
Is (C)1-C6) -an alkyl group optionally substituted with 1 to 3 substituents selected from: (C)3-C6) -cycloalkyl, (C)1-C6) Alkoxy, halogen, hydroxy, amino, tri- (C)1-C6) -alkylsilyloxy, group
Or
Wherein R is2’Represents hydrogen or (C)1-C4) -an alkyl group,
a 5-to 6-membered aromatic heterocycle having up to 3 heteroatoms selected from S, N and/or O, wherein the nitrogen-containing heterocycle may also be attached via the nitrogen atom,
a 3-to 8-membered saturated or unsaturated non-aromatic heterocycle having up to 3 heteroatoms selected from S, N and/or O, optionally linked through a nitrogen atom, and (C)6-C10) Aryl, which may itself be substituted by hydroxy or (C)1-C6) -alkoxy substituted, or
Represents a group of the formula
Wherein R is8And R9Each of which is the same or different and represents hydrogen and (C)1-C4) -alkyl, or a group of formula
Wherein R is10Represents a naturally occurring alpha-amino acid side group, or represents a group of the formula
Wherein R is11Is represented by (C)1-C4) -alkyl, and R12Represents hydrogen, (C)1-C4) -alkyl or a group of formula
Wherein R is10’Represents a naturally occurring alpha-amino acid side group, or
R2And R3Together with the nitrogen atom, form a 5-to 6-membered saturated heterocyclic ring which may optionally also contain an oxygen atom,
R4represents hydrogen, (C)1-C6) -acyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, or R4Is represented by (C)1-C6) -an alkyl group, which may be optionally substituted with 1 to 3 substituents selected from: halogen, hydroxy, (C)3-C8) -cycloalkyl, (C)1-C6) -acyl, (C)1-C6) -alkoxy, carboxyl,
Wherein R is4’Represents hydrogen, - (OCH)2CH2)nOCH2CH3Wherein n is 0 or 1, phenoxy, (C)6-C10) -aryl and-NR13R14，
Wherein R is13And R14Are the same or different and represent hydrogen, (C)1-C6) -acyl, (C)1-C6) -alkyl, carbamoyl, mono-or di- (C)1-C6) -alkylamino- (C)1-C6) Alkyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, (C)6-C10) -aryl or (C)1-C6) -alkoxycarbonyl, or
R13And R14Together with the nitrogen atom, form a 5-to 6-membered saturated heterocyclic ring which may optionally contain a further heteroatom or group selected from S or O or-NR15And may be substituted by oxo,
wherein
R15Represents hydrogen or (C)1-C4) -alkyl, or
R4Is represented by (C)1-C6) Alkyl which is substituted by a 5-to 6-membered aromatic, optionally benzo-fused, heterocycle having up to 3 heteroatoms from the group S, N and/or O, where the nitrogen-containing heterocycle may also be bound via the nitrogen atom, or by a group of the formula
Or
Wherein
R16Represents hydrogen or (C)1-C6) -an alkyl group,
R17and R18Are identical or different and are hydrogen, (C)1-C6) -alkyl or (C)6-C10) -aryl, wherein (C) is as defined above1-C6) -alkyl and (C)6-C10) Aryl may optionally be substituted by 1 to 3 substituents selected from hydroxy, (C)1-C6) -alkoxy and halogen,
R5represents hydrogen, (C)1-C6) Alkyl, halogen, amino, mono-or di- (C)1-C6) -alkylamino or represents (C)1-C6) -an alkanoylamino group,
R6represents phenyl, which may be optionally substituted with 1 to 3 substituents selected from:
-halogen,
-(C6-C10) -aryl, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) Alkanoyl radical, (C)1-C6) -alkoxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxycarbonyl, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) -alkoxy, amino, (C)1-C6) Alkylthio, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, mono-or di- (C)1-C6) Alkanoylamino, (C)1-C6) -alkoxycarbonylamino group, (C)1-C6) -alkylsulfinyl (sulfoxy), (C)1-C6) -alkylsulfonyl, tri- (C)1-C6) -alkylsilyloxy, a 3-to 8-membered saturated or unsaturated non-aromatic mono-or bicyclic heterocycle having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, and/or cyano,
-(C1-C6) -alkoxy groups,
-(C1-C6) -an alkoxycarbonyl group,
-(C1-C6) -an alkylthio group,
-a hydroxyl group,
-a carboxyl group,
Partially fluorinated (C) having up to 6 fluorine atoms1-C6) -an alkoxy group,
-(C1-C6) -an alkyl group, optionally substituted with a group of formula:
-a 5-to 6-membered heteroaromatic ring having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) Alkanoyl radical, (C)1-C6) -alkoxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxycarbonyl, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) -alkoxy, amino, (C)1-C6) Alkylthio, hydroxy, carboxy, carbamoyl, aminocarbonyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, mono-or di- (C)1-C6) Alkanoylamino, (C)1-C6) -alkoxycarbonylamino group, (C)1-C6) -alkylsulfinyl, (C)1-C6) -alkylsulfonyl, a 3-to 8-membered saturated or unsaturated non-aromatic mono-or bicyclic heterocycle having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, and/or cyano,
-a 3-to 8-membered saturated or unsaturated non-aromatic mono-or bicyclic heterocyclic ring having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, which may be optionally substituted with 1 to 3 substituents selected from: oxo, halogen, hydroxy, (C)1-C6) Alkoxycarbonyl, (C)1-C6) -alkoxycarbonylamino group, (C)1-C6) -alkyl, halo- (C)1-C6) -alkyl and hydroxy- (C)1-C6) -an alkyl group,
-(C2-C6) -alkenyl radical
And a group of the formula
- -OR19、
- -NR20R21or-CO-NR22R23、
-carbazoles, dibenzofurans or dibenzothiophenes,
Xanthene or 9, 10-dihydroacridine,
wherein R is19Represents phenyl, which is itself optionally substituted by a group of formula-NR24R25The substitution is carried out by the following steps,
wherein
R24And R25Are identical or different and are hydrogen, (C)1-C6) -alkyl or (C)1-C6) -an acyl group,
or
R19Is represented by (C)1-C6) -alkyl, optionally substituted with hydroxyl and/or halogen 1 to 3,
R20and R21Identical or different and are hydrogen, carbamoyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, phenyl, (C)1-C6) -acyl or (C)1-C6) -an alkyl group,
wherein the foregoing (C)1-C6) -alkyl is optionally substituted by (C)1-C6) -alkoxy (C)1-C6) -acyl substituted by phenyl or by a 5-to 6-membered heteroaromatic ring having up to 3 heteroatoms selected from S, N and/or O,
wherein the aforementioned phenyl and aromatic heterocyclic rings are optionally mono-to trisubstituted by identical or different substituents from the group consisting of halogen and/or hydroxy, and
R22and R23Are identical or different and are hydrogen or (C)1-C6) -alkyl, and
R7may have a group with R5The same meaning and may be the same or different therefrom.
Physiologically acceptable salts of the compounds of the invention may be, for example, salts of the substances of the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Furthermore, salts which may be mentioned are salts with customary bases, such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts which are derived from ammonia or organic amines, such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, diarninamine, 1-Ephenamin or methylpiperidine.
Depending on the type of substituents, the compounds of the invention may exist in stereoisomeric forms, either as images and mirror images (enantiomers) or as images and mirror images (diastereomers). The present invention relates to both these enantiomers or diastereomers and to various mixtures thereof. Racemic forms, such as diastereomers, can likewise be separated into the individual stereoisomeric components in a known manner.
The scope of the present invention also includes compounds which are converted into the original active compound of formula (I) (so-called prodrugs) only in vivo.
(C 1 -C 6 ) -alkyl radicalSuitably it refers to a straight or branched alkyl group having 1 to 6 carbon atoms, preferably having 1 to 4 carbon atoms (C)1-C4) Linear or branched alkyl. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Particular preference is given to linear or branched alkyl ((C) having 1 to 3 carbon atoms1-C3) -an alkyl group).
Halo- (C) 1 -C 6 ) -alkyl radicalSuitably means (C) as defined above1-C6) Alkyl and having 1 to 3 halogen atoms, i.e. F, Cl, Br and/or I, preferably chlorine or fluorine as substituents, examples which may be mentioned being: trifluoromethyl, fluoromethyl and the like.
Hydroxy- (C) 1 -C 6 ) -alkyl radicalSuitably means (C) as defined above1-C6) Alkyl groups and having 1 to 3 hydroxyl groups as substituents, and there may be mentioned hydroxymethyl groups and the like.
In the context of the present invention(C 2 -C 6 ) -alkenyl radicalSuitable are straight-chain or branched alkenyl groups having 2 to 6 carbon atoms. Examples which may be mentioned are: vinyl, n-prop-2-en-1-yl and n-but-2-en-1-yl. Straight-chain or branched alkenyl groups having 2 to 4 carbon atoms are preferred.
(C 1 -C 6 ) -alkoxy radicalSuitably means a straight or branched alkoxy group having 1 to 6 carbon atoms, preferably having 1 to 4 carbon atoms (C)1-C4) Linear or branched alkoxy groups of (1). Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Particularly preferably having 1 to 3 carbon atoms (C)1-C3) Linear or branched alkoxy groups of (1).
Halo- (C) 1 -C 6 ) -alkoxy radicalSuitably it is mono-or polyhalogenated (C)1-C6) -alkoxy groups. About(C1-C6) The definitions of the alkoxy moiety and halogen are given above. Halo- (C)1-C6) Examples of alkoxy radicals comprise one or more parts of chloro-and/or fluoro-or perfluoro (C)1-C6) Alkoxy radicals such as trifluoromethoxy, fluoromethoxy, chloromethoxy, pentafluoroethoxy, trifluoromethylmethoxy and the like.
Partially fluorinated- (C) having up to 6 fluorine atoms 1 -C 6 ) -alkoxy radicalSuitable is a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, which may be substituted by 1 to 6, preferably 1 to 4, more preferably 1 to 3 fluorine atoms. Preference is given to linear or branched alkoxy having 1 to 4 carbon atoms and 1 to 4 fluorine atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy, each of which has 1 to 4 fluorine atoms. Particularly preferred are (1, 3-difluoropropan-2-yl) -oxy and 1, 1, 2, 2-tetrafluoroethoxy.
(C 1 -C 6 ) -alkylthio groupSuitably means a straight or branched alkylthio group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (C)1-C4) A straight or branched alkylthio group of (1). Examples which may be mentioned are: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio. Particular preference is given to linear or branched alkylthio (C) having 1 to 3 carbon atoms1-C3) -alkylthio.
(C 1 -C 6 ) -alkoxycarbonyl groupSuitably means a straight or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, preferably having 1 to 4 carbon atoms (C)1-C4) Linear or branched alkoxycarbonyl groups. Examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. Particularly preferably having 1 to 4 carbon atoms (C)1-C4) Linear or branched alkoxycarbonyl groups.
Mono-or di- (C) 1 -C 6 ) -alkylaminocarbonyl radicalSuitable in the context of the present invention is carbamoyl (H)2N-CO-), wherein one or two hydrogen atoms are replaced by (C)1-C6) -alkyl substitution. About (C)1-C6) Alkyl is as defined above for (C)1-C6) Description of the alkyl groups. Examples which may be mentioned are: methylaminocarbonyl, dimethylaminocarbonyl, and the like.
Mono-or di- (C) 1 -C 6 ) -acylaminoIn the context of the present invention, suitably refers to amino (H)2N-), wherein one or two hydrogen atoms are replaced by (C)1-C6) -acyl substitution. About (C)1-C6) -acyl groups are as defined above for (C)1-C6) Description of the acyl groups. An example which may be mentioned is (C)1-C6) Alkanoyl, e.g. in (C)1-C6) -as mentioned in the definition of acyl.
(C 1 -C 6 ) -alkylsulfinyl radicalSuitably is a group (C)1-C6) -alkyl-S (═ O) -, where (C) is concerned1-C6) Alkyl groups can be found in the definitions given above for this group.
(C 1 -C 6 ) -alkylsulfonyl radicalSuitably is a group (C)1-C6) -alkyl-SO2-, in which for (C)1-C6) Alkyl groups can be found in the definitions given above for this group.
(C 6 -C 10 ) -aryl radicalTypically represents an aryl group having 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl.
(C 1 -C 6 ) -acyl radicalSuitable in the context of the present invention are straight-chain or branched acyl groups having from 1 to 6 carbon atoms. Examples which may be mentioned are: formyl, acetyl, propionyl, isopropionyl, n-butyryl, isobutyrylA group and a pentanoyl group. Preference is given to straight-chain or branched acyl groups having from 1 to 4 carbon atoms. Acetyl is particularly preferred.
(C 3 -C 8 ) -cycloalkyl radicalIn the context of the present invention means cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Mention may preferably be made of cyclopropyl, cyclopentyl, cyclohexyl.(C 3 -C 6 )- Cycloalkyl radicalsCorrespondingly, cyclopropyl, cyclopentyl, cyclobutyl and cyclohexyl.
Halogen in the context of the present invention generally denotes fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.
(C 1 -C 6 ) -alkanoyl radicalIn the context of the present invention, formyl radicals and (C)1-C5) -alkylcarbonyl, wherein (C)1-C5) Alkyl can be a linear or branched alkyl having from 1 to 5 carbon atoms, such as acetyl, propionyl, butyryl, pentanoyl.
Having up to 3 members selected fromS、OAnd/orN5-to 6-membered heteroaromatic ring of a heteroatomRepresents pyridyl, pyrimidinyl, thienyl, furyl, pyrrolyl, thiazolyl, N-triazolyl, oxazolyl or imidazolyl. Pyridyl, furyl, thiazolyl and N-triazolyl are preferred.
Having up to 3 members selected fromS、OAnd/orN5-to 6-membered aromatic benzo-condensed with hetero atoms of Hetero ringsFor example, represents a benzimidazolyl group.
A 5-to 6-membered saturated heterocycle linked via a nitrogen atom,which may be formed by two substituents together with the nitrogen atom to which they are attached and may optionally contain another heteroatom or group-NR-selected from S or O15Wherein R is15As defined above, in the context of the present invention denotes generally morpholinyl, piperidinyl, piperonylOxazinyl, methylpiperazinyl, thiomorpholinyl or pyrrolidinyl, particular preference being given to morpholinyl, piperidinyl, pyrrolidinyl and thiomorpholinyl.
Optionally linked via a nitrogen atom, having up to 3 groups selected fromS、NAnd/orOHetero atom of (A) 3-to 8-membered saturated or unsaturated non-aromatic heterocyclic ring ofIncluding, for example, the 5-to 6-membered saturated heterocycles described above attached via a nitrogen atom, as well as 3-, 7-, and 8-membered heterocycles, such as aziridine (e.g., 1-aziridin-1-yl), azetidine (e.g., 1-azetidin-1-yl), and aza (e.g., 1-Azepan-1-yl). Unsaturated heterocycles may contain 1-2 double bonds in the ring.
At R10In the meaning ofSide chain groups of naturally occurring alpha-amino acidsExamples include: hydrogen (glycine), methyl (alanine), alanine-2-yl (valine), 2-methyl-alanine-1-yl (leucine), 1-methyl-alanine-1-yl (isoleucine), alanine-1, 3-diyl (proline) attached to the nitrogen atom of an amino group, 2-hydroxypropan-1, 3-diyl (hydroxyproline) attached to the nitrogen atom of an amino group, a group of the formula
(tryptophan), benzyl (phenylalanine), methylthioethyl (methionine), hydroxymethyl (serine), p-hydroxybenzyl (tyrosine), 1-hydroxy-eth-1-yl (threonine), mercaptomethyl (cysteine), carbamoylmethyl (asparagine), carbamoylethyl (glutamine), carboxymethyl (aspartic acid), carboxyethyl (glutaminic acid), 4-aminobut-1-yl (lysine), 3-guanidinopro-1-yl (arginine), imidazol-4-ylmethyl (histidine), 3-ureidoprop-1-yl (citrulline), mercaptoethyl (homocystine), hydroxyethyl (homoserine), 4-amino-3-hydroxybut-1-yl (hydroxylysine), 3-amino-prop-1-yl (ornithine), and the like.
In another embodiment, the present invention relates to compounds of general formula (I) according to claim 1 and salts thereof:
wherein the content of the first and second substances,
R1represents hydrogen, halogen, (C)1-C6) Alkyl radicals, (C)1-C6) -alkoxy, amino- (C)1-C6) -alkyl or halo- (C)1-C6) -an alkyl group,
R2and R3Are the same or different and represent hydrogen, (C)1-C6) -alkoxy, (C)3-C8) -cycloalkyl or biphenylaminocarbonyl, or is (C)1-C6) -an alkyl group optionally substituted with 1 to 3 substituents selected from: (C)3-C6) -cycloalkyl, (C)1-C6) Alkoxy, halogen, hydroxy, amino, radical
Or
A 5-to 6-membered aromatic heterocycle having up to 3 heteroatoms selected from S, N and/or O, wherein the nitrogen-containing heterocycle may also be attached via the nitrogen atom,
a 3-to 8-membered saturated or unsaturated non-aromatic heterocycle having up to 3 heteroatoms selected from S, N and/or O optionally linked through a nitrogen atom and
(C6-C10) Aryl, which may itself be substituted by hydroxy or (C)1-C6) -alkoxy-substituted, or represents a group of formula
Wherein R is8And R9Each being the same or different and representingHydrogen and (C)1-C4) -alkyl, or a group of formula
Wherein R is10Represents a naturally occurring alpha-amino acid side group, or represents a group of the formula
Wherein R is11Is represented by (C)1-C4) -alkyl, and R12Represents hydrogen, (C)1-C4) -alkyl or a group of formula
Wherein R is10’Represents a naturally occurring alpha-amino acid side group, or
R2And R3Together with the nitrogen atom, form a 5-to 6-membered saturated heterocyclic ring which may optionally also contain an oxygen atom,
R4represents hydrogen, (C)1-C6) -acyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, or
R4Is represented by (C)1-C6) -an alkyl group, which may be optionally substituted with 1 to 3 substituents selected from: halogen, hydroxy, (C)1-C6) -acyl, (C)1-C6) -alkoxy, - (OCH)2CH2)nOCH2CH3Wherein n is 0 or 1, phenoxy, (C)6-C10) -aryl and-NR13R14，
Wherein R is13And R14Are the same or different and representHydrogen, (C)1-C6) -acyl, (C)1-C6) -alkyl, carbamoyl, mono-or di- (C)1-C6) -alkylamino- (C)1-C6) Alkyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, (C)6-C10) -aryl or (C)1-C6) -alkoxycarbonyl, or R13And R14Together with the nitrogen atom, form a 5-to 6-membered saturated heterocyclic ring which may optionally contain a further heteroatom selected from S or O or a group-NR15And may be substituted by oxo, wherein R15Represents hydrogen or (C)1-C4) -alkyl, or
R4Is represented by (C)1-C6) Alkyl which is substituted by a 5-to 6-membered aromatic, optionally benzo-fused, heterocycle having up to 3 heteroatoms from the group S, N and/or O, where the nitrogen-containing heterocycle may also be bound via the nitrogen atom, or by a group of the formula
Or
Wherein
R16Represents hydrogen or (C)1-C6) -an alkyl group,
R17and R18Are identical or different and are hydrogen, (C)1-C6) -alkyl or (C)6-C10) -aryl, wherein (C) is as defined above1-C6) -alkyl and (C)6-C10) Aryl is optionally substituted by 1 to 3 substituents selected from hydroxy, (C)1-C6) -alkoxy and halogen,
R5represents hydrogen, (C)1-C6) Alkyl, halogen, amino, mono-or di- (C)1-C6) -alkylamino or represents (C)1-C6) -an alkanoylamino group,
R6represents phenyl, which may be optionally substituted with 1 to 3 substituents selected from:
-halogen,
-(C6-C10) -aryl, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) Alkanoyl radical, (C)1-C6) -alkoxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxycarbonyl, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) -alkoxy, amino, (C)1-C6) Alkylthio, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, mono-or di- (C)1-C6) Alkanoylamino, (C)1-C6) -alkoxycarbonylamino group, (C)1-C6) -alkylsulfonyloxy, (C)1-C6) -alkylsulfonyl, tri- (C)1-C6) -alkylsilyloxy, a 3-to 8-membered saturated or unsaturated non-aromatic mono-or bicyclic heterocycle having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, and/or cyano,
-(C1-C6) -alkoxy groups,
-(C1-C6) -an alkoxycarbonyl group,
-(C1-C6) -an alkylthio group,
-a hydroxyl group,
-a carboxyl group,
Partially fluorinated (C) having up to 6 fluorine atoms1-C6) -an alkoxy group,
-(C1-C6) -an alkyl group, optionally substituted with a group of formula:
-a 5-to 6-membered heteroaromatic ring having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) Alkanoyl radical, (C)1-C6) -alkoxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxycarbonyl, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) -alkoxy, amino, (C)1-C6) Alkylthio, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, mono-or di- (C)1-C6) Alkanoylamino, (C)1-C6) -alkoxycarbonylamino group, (C)1-C6) -alkylsulfonyloxy, (C)1-C6) -alkylsulfonyl, a 3-to 8-membered saturated or unsaturated non-aromatic mono-or bicyclic heterocycle having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, and/or cyano,
-a 3-to 8-membered saturated or unsaturated non-aromatic mono-or bicyclic ring, optionally linked via a nitrogen atom, having up to 3 heteroatoms selected from S, N and/or O, which may be optionally substituted with 1 to 3 substituents selected from: oxo, halogen, hydroxy, (C)1-C6) Alkoxycarbonyl, (C)1-C6) -alkoxycarbonylamino group, (C)1-C6) -alkyl, halo- (C)1-C6) -alkyl and hydroxy- (C)1-C6) -an alkyl group,
and a group of the formula
- -OR19、
- -NR20R21or-CO-NR22R23，
Wherein R is19Represents phenyl, which is itself optionally substituted by a group of formula-NR24R25The substitution is carried out by the following steps,
wherein
R24And R25Are identical or different and are hydrogen, (C)1-C6) -alkyl or (C)1-C6) -an acyl group,
or
R19Is represented by (C)1-C6) -alkyl, optionally substituted with hydroxyl and/or halogen 1 to 3,
R20and R21Identical or different and are hydrogen, carbamoyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, phenyl, (C)1-C6) -acyl or (C)1-C6) -alkyl, wherein (C) is as defined above1-C6) -alkyl is optionally substituted by (C)1-C6) -alkoxy (C)1-C6) -acyl substituted by phenyl or by a 5-to 6-membered heteroaromatic ring having up to 3 heteroatoms selected from S, N and/or O,
wherein the aforementioned phenyl and aromatic heterocyclic rings are optionally mono-to trisubstituted by identical or different substituents from the group consisting of halogen and/or hydroxy, and
R22and R23Are identical or different and are hydrogen or (C)1-C6) -alkyl, and
R7may have a group with R5The same meaning and may be the same or different therefrom.
In a preferred embodiment, the invention relates to compounds of the general formula (I), wherein R1Represents hydrogen or (C)1-C6) -an alkyl group.
In another preferred embodiment, the invention relates to compounds of the general formula (I), wherein R2And R3Each independently represents hydrogen or (C)1-C6) -an alkyl group.
In another preferred embodiment, the invention relates to compounds of the general formula (I), wherein R4Represents hydrogen or (C)1-C6) -an alkyl group.
In another preferred embodiment, the invention relates to compounds of the general formula (I), wherein R5Represents hydrogen.
In another preferred embodiment, the invention relates to compounds of the general formula (I), wherein R6Represents phenyl, which may be optionally substituted with 1 to 3 substituents selected from:
-halogen,
-(C6-C10) -aryl, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) Alkanoyl radical, (C)1-C6) -alkoxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxycarbonyl, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) Alkoxy, amino, hydroxy, mono-or di- (C)1-C6) -alkylamino, mono-or di- (C)1-C6) Alkanoylamino, (C)1-C6) -alkoxycarbonylamino, and/or cyano, and
-a 5-to 6-membered heteroaromatic ring having up to 3 heteroatoms selected from S, N and/or O, optionally substituted by one to 2 halogen atoms, optionally linked via a nitrogen atom.
In another preferred embodiment, the present invention relates to compounds having the formula and salts thereof,
wherein
R1、R2、R3、R4、R5And R7As defined in claim 1, the first and second,
R26and R27Are the same or different and represent hydrogen, halogen, (C)1-C6) -alkoxy, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylthio, hydroxy, carboxy, partially fluorinated (C) having up to 6 fluorine atoms1-C6) -alkoxy, (C)1-C6) Alkyl, radical-OR19、-NR20R21or-CO-NR22R23，
Wherein R is19Is phenyl, which is itself optionally substituted by a group of the formula-NR24R25Is substituted with a group (b) of (a),
wherein R is24And R25Are identical or different and are hydrogen, (C)1-C6) -alkyl or (C)1-C6) An acyl group, or
R19Is (C)1-C6) -alkyl, optionally mono-to trisubstituted by hydroxy and/or halogen,
R20and R21Identical or different and are hydrogen, carbamoyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, phenyl, (C)1-C6) -acyl or (C)1-C6) -an alkyl group,
wherein the foregoing (C)1-C6) -alkyl is optionally substituted by (C)1-C6) -alkoxy, (C)1-C6) -acyl, phenyl or substituted with a 5-to 6-membered heteroaromatic ring having up to 3 heteroatoms selected from S, N and/or O,
wherein the aforementioned phenyl and the aforementioned aromatic heterocyclic ring are optionally mono-to trisubstituted by identical or different radicals of halogen and/or hydroxy, and
R22and R23Are identical or different and are hydrogen or (C)1-C6) -an alkyl group,
R28is represented by (C)6-C10) -aryl, optionally substituted with 1 to 3 substituents selected from: (C)1-C6) Alkanoyl radical, (C)1-C6) -alkoxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxycarbonyl, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) -alkoxy, amino, (C)1-C6) Alkylthio, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, mono-or di- (C)1-C6) Alkanoylamino, (C)1-C6) -alkoxycarbonylamino group, (C)1-C6) -alkylsulfonyloxy, (C)1-C6) -alkylsulfonyl, tri- (C)1-C6) -alkylsilyloxy, a 3-to 8-membered saturated or unsaturated non-aromatic mono-or bicyclic heterocycle having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, and/or cyano, or
R28Represents a 5-to 6-membered heteroaromatic ring having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, which may be optionally substituted by 1 to 3 substituents selected from: (C)1-C6) Alkanoyl radical, (C)1-C6) -alkoxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxycarbonyl, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) -alkoxy, amino, (C)1-C6) Alkylthio, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -alkylaminocarbonyl, mono-or di- (C)1-C6) Alkanoylamino, (C)1-C6) -alkoxycarbonylamino group, (C)1-C6) -alkylsulfonyloxy, (C)1-C6) -alkylsulfonyl, a 3-to 8-membered saturated or unsaturated non-aromatic mono-or bicyclic heterocycle having up to 3 heteroatoms selected from S, N and/or O, optionally linked via a nitrogen atom, and/or cyano.
Particularly preferred are N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -2- [1, 1' -biphenyl ] -4-yl-N-methylacetamide compounds, for example of the formula:
an N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -2- (2 '-fluoro [1, 1' -biphenyl ] -4-yl) -N-methylacetamide compound of the formula:
and N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide compounds of the formula:
and pharmaceutically acceptable salts thereof.
Furthermore, the invention relates to compounds of the general formula (IV)
Wherein R is1、R4、R5、R6And R7Each having the meaning specified for formula (I), and D is a halogen atom.
The invention further relates to a method for producing compounds of the general formula (I),
[A] a compound of the general formula (II)
Wherein R is1、R2、R3And R4Each having the above-mentioned meanings, are disclosed,
with a compound of the general formula (III) in an inert solvent, optionally in the presence of a base and/or an auxiliary agent to form a compound of the formula (I)
Wherein
A represents a leaving group, such as halogen, preferably chlorine, or hydroxy, and R5、R6And R7Each having the above-mentioned meanings, are disclosed,
[B] a compound of the general formula (IV)
Wherein
R1、R4、R5、R6And R7Each having the above-mentioned meaning, and D is a halogen atom, preferably chlorine, with an amine of the general formula (V) in an inert solvent to give a compound of the formula (I):
HNR2R3 (V)
wherein
R2And R3Each having the above-mentioned meanings.
[C] A compound of the formula (X)
Wherein R is1、R2、R3、R4、R5、R7、R26And R27Each having the above-mentioned meaning, and E is triflate (triflate) or halogen, preferably bromine or iodine,
with boric acid or stannane of the formula (XI)
R28M (XI)
Wherein R is28Have the above-mentioned meaning and M may be, for example, tri- (C)1-C6) Alkyl stannyl, such as trimethylstannyl or boranyl,
in an inert solvent in the presence of a palladium catalyst, e.g. tetrakis (triphenylphosphine) palladium (0), optionally in the presence of a base, e.g. potassium phosphate, at a temperature of 50-140 ℃ to yield a compound of formula (XIV)
And
[D] a compound of the formula (XII)
Wherein
R1、R2、R3、R4、R5、R7、R26And R27Each having the above meaning, and M having the above meaning, with a triflate or halide of the formula (XIII):
R28E (XIII)
wherein
R28Having the above-mentioned meanings and E has the above-mentioned meanings,
in an inert solvent in the presence of a palladium catalyst, e.g. tetrakis (triphenylphosphine) palladium (0), optionally in the presence of a base, e.g. potassium phosphate, at a temperature of 50-140 ℃ to yield a compound of formula (XIV).
The process [ A ] according to the invention can be illustrated by the following reaction scheme:
abbreviations indicate:
HOBt: 1-hydroxy-1H-benzotriazole
EDC: n' - (3-dimethylaminopropyl) -N-ethylcarbodiimide x HCl
DMF: n, N-dimethylformamide
The process [ C ] according to the invention can be illustrated by the following reaction scheme:
abbreviations indicate:
DMF: n, N-dimethylformamide
The process [ D ] according to the invention can be illustrated by the following reaction scheme:
abbreviations indicate:
DMF: n, N-dimethylformamide
Suitable solvents for processes [ A ], [ B ], [ C ] and [ D ] are the customary solvents which do not change under the reaction conditions, for which preference is given to ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, dimethyl sulfoxide, Dimethylformamide (DMF) or acetonitrile. Mixtures of these solvents may also be used. DMF is preferred.
For the method of the invention [ A]Of (2)Suitable bases are the customary inorganic or organic bases, for which organic amines (trialkyl (C)1-C6) Amines) such as triethylamine, or heterocycles such as 1, 4-diazabicyclo [2.2.2]Octane (DABCO), 1.8-diazabicyclo [5.4.0]Undec-7-ene (DBU), pyridine, diaminopyridine, N-methylmorpholine or N-methylpiperidine or morpholine. Triethylamine is preferred.
Dehydration or coupling agents known per se are suitable as auxiliaries, such as carbodiimides, for example diisopropylcarbodiimide, Dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N '-Ethylcarbodiimide (EDC), or carbonyl compounds, such as Carbonyldiimidazole (CDI) or isobutyl-chloroformate, or 1, 2-oxazolium compounds, such as 2-ethyl-5-phenyl-1, 2-oxazolium-3' -sulfonate, or phosphorus compounds, such as propanephosphonic anhydride, diphenyl phosphate azide, benzotriazolyl-N-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) or Uronium (Uronium) -compounds, such as O-benzotriazol-1-yl-N, n, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), or methanesulfonyl chloride, optionally in the presence of an adjuvant such as N-hydroxysuccinimide or N-hydroxybenzotriazole.
In general, the base is used in an amount of 0.05 to 10 mol, preferably 1 to 2mol, based on 1mol of the compound of the formula (III). The process of the invention is generally carried out at from-50 ℃ to +100 ℃ and preferably from-30 ℃ to +60 ℃.
The process of the invention is generally carried out under normal pressure, but may also be carried out under increased or reduced pressure (for example at from 0.5 to 5 bar).
The compounds of the general formula (II) can be prepared, for example, as follows: by reacting a compound of the formula (VI)
Wherein R is1Has the meaning of the above-mentioned formula,
with chlorosulfonic acid/SOCl2Reaction of the system to convert into a compound of the formula (VII)
Wherein R is1Has the meaning of the above-mentioned formula,
then with amines of the formula (V)
HNR2R3 (V)
Wherein R is2And R3Each having the above-mentioned meanings, are disclosed,
preparing the compound of the general formula (VIII) in an inert solvent
Wherein R is1、R2And R3Each having the above-mentioned meanings, are disclosed,
and finally with amines of the formula (IX) in an inert solvent in the presence of a base
H2N-R4′ (IX)
Wherein R is4’Having the above-mentioned R4And the same or different therefrom, but not hydrogen.
With chlorosulfonic acid/SO2The reaction of Cl is carried out first at room temperature and then at the reflux temperature of the ether mentioned.
The reaction is generally carried out under normal pressure, but may also be carried out under elevated or reduced pressure (for example at from 0.5 to 5 bar).
Suitable solvents for the reaction with the amines of the formula (V) are alcohols, such as methanol, ethanol, propanol and isopropanol. Methanol is preferred.
The reaction with the amines of the formula (V) is carried out first at room temperature and then at the reflux temperature of the ethers mentioned.
The reaction is generally carried out under normal pressure, but may also be carried out under elevated or reduced pressure (for example at from 0.5 to 5 bar).
The reaction with the compound of the formula (IX) is carried out in ethers, such as diethyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether, preferably methanol.
Suitable bases which can be used are the customary inorganic or organic bases, for which organic amines (tri (C) are preferred1-C6) Alkylamines, e.g. triethylamine) or heterocycles, e.g. 1.4-diazabicyclo [2.2.2]Octane (DABCO), 1.8-diazabicyclo [5.4.0]Undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Triethylamine is preferred.
In general, the base is used in an amount of 0.05 to 10 moles, preferably 1 to 2 moles, based on 1 mole of the compound of formula (VIII).
The compounds of formula (VI) are in part known or may be prepared according to conventional methods [ see Hantzsch, chem. be. 1927, 60, 2544 ].
The compounds of the general formulae (VII) and (VIII) are novel and can be prepared as described above.
Amines of the general formulae (V) and (IX) are known.
The compounds of the general formula (III) are known or can be prepared according to methods known from the literature.
The biphenylmethylcarboxylic acid or biphenylacetic acid derivatives of the general formula (III) can be prepared in a manner known per se by transition metal-catalyzed, for example palladium-catalyzed, coupling reactions, for example Suzuki or Stille couplings. The pyridylphenylmethylcarboxylic acid derivatives of the general formula (III) are known from the literature (cf., for example, M.Artico et al in Eur.J.Med.chem. (1992)27, 219-228) or can be prepared in a manner known per se. The following schemes A, B, C and D illustrate the synthesis of biphenylacetic acid derivatives from the corresponding boronic acids and the synthesis of pyridylphenylacetic acid derivatives from the corresponding stannyl compounds:
wherein R is5And R7The compounds of general formula (III) which are fluorine can be prepared, for example, by the process represented by the following reaction scheme:
fluorination with DAST (N, N-diethylaminosulfur trifluoride) was carried out according to j.fluor.chem.61, 1993, 117.
The invention also relates to the use of the compounds of general formula (I) as medicaments.
The invention also relates to a pharmaceutical composition comprising a compound of general formula (I) in admixture with at least one pharmaceutically acceptable carrier or excipient.
The invention also relates to the use of the compounds of general formula (I) for the production of medicaments, in particular for the treatment and/or prophylaxis of viral infections, such as herpes viruses, in particular herpes simplex viruses.
The invention also relates to the use of N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] acetamide derivatives, preferably N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] -2-phenylacetamide derivatives, more preferably N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] -2- [1, 1' -biphenyl ] -4-ylacetamide derivatives for the preparation of a medicament, in particular for the preparation of a medicament for the treatment and/or prophylaxis of viral infections, such as infections with herpes viruses, in particular with herpes simplex viruses, in humans or animals. N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] acetamide derivatives, N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] -2-phenylacetamide derivatives and N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] -2- [1, 1' -biphenyl ] -4-ylacetamide derivatives are referred to herein as being prepared from N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] acetamide, N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] -2-phenylacetamide and N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl ] -2- [1, 1' -biphenyl ] -4-yl acetamide, wherein one or more hydrogen atoms are substituted.
The compounds of the general formula (I) according to the invention exhibit an unforeseeable surprising spectrum of action. They exhibit antiviral action on representatives of herpes viridae, in particular on Herpes Simplex Virus (HSV). They are therefore suitable for the treatment and prophylaxis of diseases which are caused by herpes viruses, in particular by herpes simplex viruses.
In vitro Activity
Viruses and cells：
HSV (HSV-1 Walki, HSV-1F or HSV-2G) was propagated on Vero-cells (ATCC CCL-81) under the following conditions: in M199 Medium (5% fetal bovine serum, 2mM glutamine, 100IU/ml penicillin, 100. mu.g/ml streptomycin) in cell culture flasks at 37 ℃ and 5% CO2The cells were cultured. Cells were separated 2 times a week at 1: 4 each time. For infection, the medium was removed, the cells were washed with Hank's solution, detached with 0.05% trypsin, 0.02% EDTA (Seromed L2143) and plated at 4X 105The density of individual cells/ml was cultured under the above conditions for 24 hours. The medium was then separated and expressed at 2ml/175cm2Surface area virus solution with m.o.i < 0.05 was added. After 1 hour of incubation under the conditions described, the medium was supplemented to 50ml/175cm2-a bottle. Cultures showed clear signs of cytopathy 3 days after infection. The virus was released by two freezes (-80 ℃) and thawing (37 ℃). Cell debris was separated by centrifugation (300g, 10min, 4 ℃), and the supernatant was aliquoted and frozen at-80 ℃.
Viral titers were determined by plaque assay. Vero cells were used for this purpose in the order of 4X 105Density of individual cells/well in 24-well plates and incubation (37 ℃, 5% CO)2) After 24 hours, use 10-2-10-12(100μlInoculum) was infected with a dilution of the virus stock. 1h after infection, the medium was removed and the cells were covered with 1ml of overlay medium (0.5% methylcellulose, 0.22% sodium bicarbonate, 2mM glutamine, 100IU/ml penicillin, 100. mu.g/ml streptomycin, 5% fetal bovine serum in MEM-eagle medium with Earl salt) and incubated for 3 days. The cells were then fixed with 4% formalin for 1 hour, washed with water, stained with giemsa (merck) for 30min and subsequently washed and dried. Virus titers were determined using a plaque counter. Viral stock titres for the assay were 1X 106/ml-1×108/ml。
anti-HSV effects were determined in a screening system in 96-well microtiter plates using various cell lines of neuronal, lymphoid and epithelial origin, such as Vero (green monkey kidney cell line), MEF (murine embryonic fibroblasts), HELF (human embryonic fibroblasts), NT2 (human neuronal cell line) or Jurkat (human lymphoid T cell line). The effect of the substance on the spread of the cytopathic effect was determined by comparison with the substance Acyclovir sodium (Zovirax)RAn approved clinical anti-herpes chemotherapeutic).
The assay of DMSO (DMSO) dissolved substances (50mM) (4 substances/plate) was repeated twice at a final concentration of 250-0.5. mu.M (micromolar) on a microtiter plate (e.g., 96-well MTP). In the case of the active substance, dilution to 0.5pM (picomolar) was continued through the multiple plates. Toxicity and cytostatic effects of these substances were also determined. After appropriate dilution (1: 2) of the material with medium on a microtiter plate, the cell suspension (1X 10)4Individual cells/well), e.g.Vero cells in M199 (medium 199) containing 5% foetal calf serum, 2mM glutamine and optionally 100IU/ml penicillin and 100. mu.g/ml streptomycin or MEF-cells in EMEM (Eagle's minimum essential medium) containing 10% foetal calf serum, 2mM glutamine and optionally 100IU/ml penicillin and 100. mu.g/ml streptomycin, or HELF-cells in EMEM containing 10% foetal calf serum, 2mM glutamine and optionally 100IU/ml penicillin and 100. mu.g/ml streptomycin or HELF-cells containing 10% foetal calf serum, 2mM glutamine, 1mM sodium pyruvate, non-essential amino acids and optionally 100IU/ml penicillin and 100. mu.g/ml streptomycinNT 2-and Jurkat-cells in DMEM (4.5mg/l glucose plus pyridol) were added to each well and the cells in the relevant well were infected with the appropriate amounts of the corresponding virus (HSV-1F or HSV-2G with m.o.i (multiplicity of infection) of 0.0025 for HELF, Vero and MEF cells and m.o.i of 0.1 for NT 2-and Jurkat-cells). The plates were then CO at 37 ℃2In the culture Chamber (5% CO)2) Incubate for several days. Thereafter, for example, Zellrasenin of Vero-cells in the virus control without the substance starts from 25 infection centers and is completely dissolved or destroyed by the cytopathogenic action of HSV-virus (100% CPE). The plates were evaluated visually using a microscope and then analyzed using fluorescent staining. For this, the cell supernatants of all wells of the MTP were aspirated, 200. mu.l PBS-wash was added, PBS was aspirated and 200. mu.l fluorochrome solution (fluorescein diacetate, 10. mu.g/ml in PBS) was added, and after an incubation time of 30-90min the test plates were tested for fluorescence on a fluorescence analyzer at an excitation wavelength of 485nm and an emission wavelength of 538 nm.
The results of the tests for some of the compounds are summarized in the table below.
Watch (A)
| Examples | IC50 HSV-1F/Vero | IC50 HSV-2G/Vero |
| 14 | 0.1μM | 0.75μM |
| 57 | ＜0.01μM | ＜0.01μM |
| 8 | 0.1μM | 0.1μM |
| 23 | 0.03μM | 0.1μM |
| 38 | 0.05μM | 0.016μM |
| 87 | ＜ 0.01μM | ＜0.01μM |
| 126 | 0.01μM | 0.1μM |
| Zovirax (Acyclovir sodium salt) | 1μM | 3μM |
In this context, IC50Refers to the half maximal fluorescence intensity compared to uninfected cell controls (100% values). IC (integrated circuit)50The values can also be compared with suitable active compound controls (see description of the test: infected cells in the presence of suitable concentrations of substances having an anti-herpes effect, such as 20. mu.M Zovirax). This active compound control reached about 85-95% of the fluorescence intensity of the cell control.
Preferred are N- [5- (aminosulfonyl) -1, 3-thiazol-2-yl radicals of the invention]Acetamide derivatives, their IC in the in vitro screening test systems described above50(HSV-1F/Vero) is preferably less than 50. mu.M, more preferably less than 25. mu.M and particularly preferably less than 10. mu.M.
The compounds according to the invention are therefore active compounds which are useful for the therapy and prophylaxis of diseases which are caused by herpes viruses, in particular herpes simplex viruses. The indications which may be mentioned by way of example are:
1) treatment and prevention of herpes infections, especially herpes simplex infections, in patients exhibiting symptoms such as herpes labialis, genital herpes and HSV-related keratitis, encephalitis, pneumonia, hepatitis and the like.
2) Treatment and prevention of herpes infections, especially herpes simplex infections, in immunosuppressed patients (e.g. AIDS patients, cancer patients, patients with inherited immunodeficiency, transplant patients)
3) Treatment and prevention of neonatal and pediatric herpes infections, especially herpes simplex infections
4) Treatment and prevention of herpes infections, especially herpes simplex infections, and herpes positive patients, especially herpes simplex positive patients, to inhibit their recurrence (inhibition therapy)
In vivo Effect
Animal(s) production：
Female mice of 6 weeks of age, of the BALB/cABom variety, were obtained from commercial breeders (Bomholtgard Breeding and Research Centre Ltd.).
Infection:
animals were anesthetized with ether (Merck) in sealed glass containers.
Dilutions of 50. mu.l virus stock (infectious dose 5X 10) were pipetted using an Eppendorf pipette4Pfu) was added to the nose of the anesthetized animals. This infectious dose died on average 5-8 days in 90-100% of animals by systemic infection with significant respiratory and central nervous symptoms.
Treatment and evaluation:
animals were treated 6 hours after infection with doses of 0.1-100mg/kg body weight three times a day at 7, 14 and 19 for 5 consecutive days. The material was previously dissolved in DMSO and resuspended in sodium celluloseacetate/PBS (hoechst) (final concentration 1.5% DMSO, 0.5% sodium celluloseacetate in PBS).
After the last dose, animals were observed and the time to death was determined.
Comparison of survival curves shows that the compound of example 57, e.g. ED for HSV-250About 0.7mg/kg, wherein ED50Meaning that 50% of the animals survive the dose.
The novel active substances can be converted in a known manner into the customary formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically acceptable carriers and solvents. Wherein the therapeutic amounts of the active compounds should each be present in a concentration of about 0.5-90% by weight of the total mixture, i.e. in an amount sufficient to achieve the given dosage range.
The formulations are prepared, for example, by adding the active substances to solvent and/or carrier substances, optionally using emulsifiers and/or dispersants, if possible, for example in the case of using water as diluent, optionally using organic solvents as dissolving assistants.
Administration is carried out in a conventional manner, preferably orally, parenterally or topically, especially lingually or intravenously.
For parenteral administration, solutions of the active substance in suitable fluid carrier materials can be administered.
It has been advantageously demonstrated that in general, an intravenous dose of about 0.001-20mg/kg, preferably about 0.01-10mg/kg body weight is used to obtain effective results, whereas in the case of oral administration, a dose of about 0.01-30mg/kg, preferably 0.1-20mg/kg body weight is used.
Nevertheless, it may be necessary to administer deviations from the above-described dosages in the case of particular needs, i.e. depending on the body weight or mode of administration, the individual's response to the drug, the type of formulation thereof and the time or interval of administration. Thus, in some cases less than the minimum dose mentioned above may be sufficient, while in other cases it may be necessary to exceed the maximum dose mentioned above. In the case of higher doses administered, it may be advisable to divide them into several administrations over the course of the day.
It is optionally useful to combine the compounds of the invention with other active substances, especially with antiviral active substances.
Raw materials
Example I
2-chloro-4-methyl-1, 3-thiazole-5-sulfonylchloride
150g (1.12mol) of 2-chloro-4-methyl-1, 3-thiazole were added dropwise to a solution of 331g (2.81mmol) of thionyl chloride in 653g (5.61mmol) of chlorosulfonic acid at room temperature. The solution was heated to reflux for 48h, then the mixture was poured into 3 l ice water and extracted with 4X 400ml dichloromethane. The combined organic phases were washed with 2.5 l of water, dried over sodium sulfate and concentrated. The crude product was distilled to give 233.7g of oily product (bp 87-96 ℃, 0.7mbar, GC 98.1%, yield 89.6%).
Example II
2-chloro-4-methyl-1, 3-thiazole-5-sulfonamide
To a solution of 208g (95% strength, 0.9mol) of 2-chloro-4-methyl-1, 3-thiazole-5-sulfonyl chloride in 1000ml of tetrahydrofuran at-10 ℃ were added dropwise 117.7g (1.8mol) of a 26% strength aqueous ammonia solution. The cooling bath was removed, stirring was continued for 2 hours and the reaction mixture was subsequently concentrated on a rotary evaporator. The crude product was used in the next step without further purification.
Example III
4-methyl-2- (methylamino) -1, 3-thiazole-5-sulfonamide
144g (0.576mol) of 2-chloro-4-methyl-1, 3-thiazole-5-sulfonamide are added to 600ml of acetonitrile at room temperature, and 147g (1.9mol) of a 40% strength aqueous methylamine solution are added dropwise at room temperature. The reaction mixture was stirred at 50 ℃ for a further 6h and then concentrated on a rotary evaporator. The residue is treated with water, filtered off with suction and dried.
Yield: 78g (66%)
Melting point: 194 deg.C
Example IV
2-fluorophenyl boronic acid
155g (0.86mol) of 2-fluorobromobenzene are introduced under argon into 732ml of anhydrous tetrahydrofuran and 600ml of a 1.6M n-butyllithium hexane solution are slowly added at-78 ℃. Stirring was then continued for 2 hours at-78 ℃. 298ml (1.28mol) of trimethyl borate are subsequently added dropwise at-78 ℃. After 1 hour the cooling was removed and the reaction mixture was stirred overnight to warm to room temperature. For working up, the reaction mixture is treated at 0 ℃ with 346ml of saturated ammonium chloride solution, the pH of which is adjusted to 6 with 1N HCl and the aqueous phase is extracted three times with 250ml of dichloromethane each. The combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. Example IV was obtained as a beige solid.
Yield: 60.0g (48%)
MS(EI，m/z)：140(80％，[M]+)，96(100％，[C6H5F]+)
Example V
(2 '-fluoro- [ 1.1' -biphenyl ] -4-yl) acetic acid methyl ester
47.6g (0.21mol) of methyl 4-bromophenylacetate are added to 400ml of anhydrous tetrahydrofuran under argon and mixed at room temperature with 320ml of a 1M soda solution and 40g (0.28mol) of 2-fluorophenylboronic acid. 7.0g (0, 01mol) of bis (triphenylphosphine) palladium (II) chloride was added and the mixture was refluxed for 18 hours. After cooling, dilution with 500ml of water and extraction three times with 300ml of ethyl acetate in each case, the combined organic phases are washed with 400ml of saturated ammonium chloride solution, water and saturated sodium chloride solution, respectively, dried over magnesium sulfate and the solvent is removed under reduced pressure. Example V was obtained as a colorless oil after filtration through silica gel (petroleum ether/ethyl acetate 10: 1).
Yield: 46.0g (94%)
1H-NMR(500MHz，CDCl3，δ/ppm)：3.71(s，2H)，3.76(s，3H)，7.18-7.46(m，4H)，7.40(d，J＝8.3Hz；2H)，7.56(dd，J1＝8.3Hz，J2＝1.7Hz；2H).
Example VI
(2 '-fluoro [1, 1' -biphenyl ] -4-yl) acetic acid
26.5g (0.11mol) of methyl (2 '-fluoro [1, 1' -biphenyl ] -4-yl) acetate were added to 50ml of ethanol and treated at room temperature with 12.8g (0.19mol) of a 25ml aqueous solution of platelet-shaped potassium hydroxide, followed by heating under reflux for 4 h. After cooling, the crude mixture is concentrated under reduced pressure, the residue is dissolved in 100ml of water and acidified with concentrated hydrochloric acid. The precipitate was filtered and washed with water several times and the solid was dried to give example VI as white crystals.
Yield: 22.7g (91%)
Melting point: 102 deg.C
1H-NMR(500MHz，CDCl3，δ/ppm)：3.74(s，2H)，7.18-7.47(m，4H)，7.41(d，J＝8.2Hz；2H)，7.57(dd，J1＝8.2Hz，J2＝1.6Hz；2H).
Example VII
[4- (2-pyridyl) phenyl ] acetic acid methyl ester
Under argon 7.85g (34.3mmol) of methyl 4-bromophenylacetate are added to 95ml of toluene and treated at room temperature with 7.97g (61.7mmol) of diisopropylethylamine, 9.50g (37.7mmol) of 2-trimethylstannylpyridine and 0.4g (0.3 mmol) of tetrakis (triphenylphosphine) palladium (0), and then heated at reflux for 18 h. After cooling, the reaction mixture is washed with 100ml of 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic phase is discarded, the acidic and basic aqueous phases are neutralized, extracted with 100ml of each dichloromethane, the combined organic phases are dried over sodium sulfate, the solvent is distilled off under reduced pressure and purified by chromatography on silica (toluene/ethyl acetate gradient elution 5: 1 to 1: 1) to give example VII as a colorless oil.
Yield: 1.6g (19%)
1H-NMR(400MHz，d6-DMSO, δ/ppm): 3.64(s, 3H), 3.76(s, 2H), 7.33-7.40(m, 1H), 7.39(d, J ═ 8.2 Hz; 2H), 7.86-7.90(m, 1H), 7.96(d, J ═ 8.0 Hz; 1H), 8.05(d, J ═ 8.2 Hz; 2H), 8,67(d, J ═ 4.2Hz, broad peak; 1H).
Example VIII
[4- (2-pyridyl) phenyl ] acetic acid
700mg (3.11mol) of methyl [4- (2-pyridyl) phenyl ] acetate are added to 5ml of tetrahydrofuran and treated at room temperature with 6.2ml of 1M aqueous potassium hydroxide solution, which is then stirred at room temperature for 18h, most of the solvent is removed under reduced pressure, the residue is treated with 10ml of water and brought to a pH of about 5 with 2N hydrochloric acid. The aqueous phases are extracted twice with 10ml of dichloromethane each, the combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure to give the compound of example VIII in the form of a solid.
Yield: 300mg (46%)
1H-NMR(400MHz，d6-DMSO，δ/ppm)：3.76(s，2H)，7.45-7.51(m，1H)，7.50(d，J＝8.3Hz；2H)，8.00(td，J1＝7.7Hz，J2＝1.9Hz；1H)，8.07(d，J＝7.9Hz；1H)，8.15(d，J＝8.3Hz，2H)，8,78(dt，J1＝4.0Hz，J2＝0.9Hz；1H).
Preparation examples
Example 15
N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -2- [1, 1' -biphenyl ] -4-yl-N-methylacetamide
138.2mg (0.65mmol) of 4-biphenylacetic acid and 99.7mg (0.65mmol) of 1-hydroxy-1H-benzotriazole hydrate are added to 5ml of dimethylformamide at room temperature, 150mg (0.72mmol) of 2-methylamino-4-methyl-1, 3-thiazole-5-sulfonamide and 138.7mg (0.72mmol) of N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride are added and the mixture is stirred at room temperature for 72H, after which the mixture is filtered with suction and the residue is recrystallized from 2-propanol to give a white solid.
Yield: 240mg (83.0%)
Melting point: 191 deg.C
1H-NMR(300MHz，d6-DMSO, δ/ppm): 2.47(s, 3H; partial overlap with DMSO signal), 3.71(s, 3H), 4.20(s, 2H), 7.32-7.70(m, 11H).
Example 38
N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide
300mg (1.41mmol) of [4- (2-pyridyl) phenyl ] acetic acid and 190mg (1.41mmol) of 1-hydroxy-1H-benzotriazole hydrate are added to 4ml of dimethylformamide at room temperature, 307mg (1.48mmol) of 2-methylamino-4-methyl-1, 3-thiazole-5-sulfonamide and 284mg (1.48mmol) of N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride are added and the mixture is stirred at room temperature for 18H. The solvent is then distilled off under reduced pressure, the residue is treated with toluene and the solvent is removed again under reduced pressure, the residue is stirred in 15ml of water and 3ml of methanol, then filtered and the filtrate is extracted with 20ml of dichloromethane. The solid and dichloromethane phases were combined and the solvent was removed under reduced pressure to give the compound of example 38 as a white solid.
Yield: 440mg (74.0%)
Melting point: 188 ℃ C., 192 ℃ C
MS(ESI，m/z)：403(100％，[M+H]+)
1H-NMR(400MHz，d6-DMSO, δ/ppm): 2.38(s, 3H; partially overlapping with DMSO signal), 3.64(s, 3H), 4.15(s, 2H), 7.28-7.26(m, 1H), 7.32(d, J ═ 8 Hz; 2H), 7.58(s, 2H), 7.82-7.96(m, 2H), 7.98(d, J ═ 8.0 Hz; 2H), 8.61 (m; 1H).
Example 57
N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -2- (2 '-fluoro [1, 1' -biphenyl ] -4-yl) -N-methylacetamide
17.33g (73.3mmol) of (2 ' -fluoro [1.1 ' -biphenyl ] -4-yl) acetic acid and 9.9g (73.3mmol) of 1-hydroxy-1H-benzotriazole hydrate are added to 600ml of dimethylformamide at room temperature, 16.84g (81.4mmol) of 2-methylamino-4-methyl-1, 3-thiazole-5-sulfonamide and 15.58g (81.4mmol) of N ' - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride are added and the mixture is stirred at room temperature for 18H. Most of the dimethylformamide was removed under high vacuum at 50 ℃ and the residue was treated with 400ml of dichloromethane, then washed with 350ml of water and 10% citric acid solution each, dried over magnesium sulfate and the solvent was removed under reduced pressure to give the compound of example 57 as a white solid.
Yield: 23.2g (76.0%)
Melting point: 211 ℃ C
1H-NMR(400MHz，CDCl3δ/ppm): 2.58(s, 3H), 3.73(s, 3H), 4.07(s, 2H), 5,91(s, 2H), 7.13-7.46(m, 4H), 7.34(d, J ═ 8.1 Hz; 2H), 7.56(d, broad peak, J ═ 8.1 Hz; 2H).
Example 87
N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -2- (2 ', 5 ' -difluoro-1, 1 ' -biphenyl-4-yl) -N-methylacetamide
1.00g (4.0mmol) of (2 ', 5 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) acetic acid and 0.54g (4.0mmol) of 1-hydroxy-1H-benzotriazole hydrate were added to 15ml of dimethylformamide at room temperature, 0.84g (4.0mmol) 2-methylamino-4-methyl-1, 3-thiazole-5-sulfonamide and 0.77g (4.0mmol) N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride are added and the mixture is stirred at room temperature for 18h, most of the dimethylformamide was removed at 50 ℃ under high vacuum, the residue was filtered 3 times with 50ml of water each, with 50ml of isopropanol and then filtered again, and the solvent was removed under reduced pressure to give the compound of example 87 as a pale yellow solid.
Yield: 0.83g (47.3%)
Melting point: 184 ℃ C
1H-NMR(400MHz，DMSO，δ/ppm)：2.49(s，3H)，3.71(s，3H)，4.24(s，2H)，7.22-7.46(m，3H)，7.38(d，J＝8.2Hz；2H)，7.56(d，J＝8.2Hz；2H)，7.65(s，2H).
Example 126
N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (1H-pyrazol-1-yl) phenyl ] acetamide
0.100g (0.48mmol) 2-methylamino-4-methyl-1, 3-thiazole-5-sulfonamide was dissolved in 10ml N, N-dimethylformamide and 0.110g (0.53mmol) 4- (1H-pyrazol-1-yl) phenyl ] acetic acid, 0.070g (0.53mmol) 1-hydroxy-1H-benzotriazole and 0.070g (0.53mmol) N, N' -diisopropylcarbodiimide were added at room temperature. The solution is stirred at room temperature overnight, the mixture is then poured into water, the aqueous phase is extracted 3 times with ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated, and the crude product is purified by preparative HPLC (RP 18-column; mobile phase: acetonitrile-water gradient elution).
Yield: 0.11g (59%)
LC-MS (method: SMKL-N1-1Low Vol HCl): retention time: 3.65
MS(ESI)：783(2Mz+H)，392(Mz+H).
1H-NMR(300MHz，DMSO，δ/ppm)：2.48(s，3H)，3.72(s，3H)，4.20(s，2H)，6.55(t，J＝2Hz；1H)，7.38(d，J＝7Hz；2H)，7.65(s，2H)，7.75(d，J＝2Hz；1H)，7.82(d，J＝7Hz；2H)，8.49(d，J＝2Hz；1H).
The compounds listed in the table below were prepared analogously to the above procedure:
in the above table the Rf-values represent the retention indices of the silica thinner layer chromatography. SMKL-N1-1 refers to the LC-MS-method described below
The method comprises the following steps: SMKL-N1
| MS instrument model: finnigan MAT 900S ionization: ESI correction |
| HPLC instrument model: TSP: p4000, AS3000, UV3000HR pump head: standard of merit |
| Column: symmetry C18150 mm × 2.1mm 5 μm supplier: waters |
| UV-detector DAD: 210nm furnace temperature:40℃ | ||||||
| gradient: | time of day | A：％ | B：％ | C：％ | D：％ | Flow rate of flow |
| 0 | 10.0 | 45 | 45 | -- | 0.6 | |
| 4 | 90 | 5 | 5 | -- | 0.6 | |
| 9 | 90 | 5 | 5 | -- | 0.6 | |
| 9.5 | 10.0 | 45 | 45 | -- | 0.8 | |
| 11.5 | 10.0 | 45 | 45 | -- | 0.8 | |
| 12 | 10.0 | 45 | 45 | -- | 0.6 | |
| A： CH3CN |
| B： HCl 0.01n |
| C： H2O |
| D： -- |
Claims (18)
1. A compound of the general formula (I):
wherein
R1Represents hydrogen or (C)1-C6) -an alkyl group,
R2and R3Are the same or different and represent hydrogen, (C)1-C6) -alkoxy, (C)3-C8) -cycloalkyl or (C)1-C6) -alkyl, wherein (C)1-C6) -alkyl is optionally substituted with 1 to 3 substituents selected from: (C)3-C6) -cycloalkyl, (C)1-C6) Alkoxy, halogen, hydroxy, amino, tri- (C)1-C6) -alkanes
Silyloxy, wherein R2’Represents hydrogen or (C)1-C4) The radicals morpholinyl, thiomorpholinyl and piperidinyl of alkyl,
R4represents hydrogen, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, or
R4Is represented by (C)1-C6) -an alkyl group, which may be optionally substituted with 1 to 3 substituents selected from: hydroxy, (C)3-C8) -cycloalkyl, (C)1-C6) -alkoxy, carboxy, wherein R4’Radicals representing hydrogenA group- (OCH) wherein n is 0 or 12CH2)nOCH2CH3Phenyl and-NR13R14Wherein R is13And R14Are the same or different and represent hydrogen or (C)1-C6) -alkyl, or R13And R14Together with the nitrogen atom, form a 5-to 6-membered saturated heterocyclic ring which may optionally contain a further heteroatom selected from S or O or a group-NR15And may be substituted by oxo,
wherein
R15Represents hydrogen or (C)1-C4) -alkyl, or
R4Is represented by (C)1-C6) -alkyl substituted by pyridyl or by a group of formula
R5Represents hydrogen or(C1-C6) -an alkyl group,
R6represents phenyl, which may be optionally substituted with 1 to 3 substituents selected from:
-halogen,
-phenyl, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) -alkoxy, (C)1-C6) Alkyl, cyano, halogen, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) Alkoxy, amino, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -alkanoylamino, tri- (C)1-C6) -an alkylsilyloxy group and a 5-membered saturated non-aromatic heterocyclic ring having up to 3 heteroatoms selected from S, N and O connected via one nitrogen atom,
-(C1-C6) -alkoxy groups,
Partially fluorinated (C) having up to 6 fluorine atoms1-C6) -an alkoxy group,
-a 5-to 6-membered aromatic heterocycle having up to 3 heteroatoms selected from N and O, optionally linked via a nitrogen atom, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) -alkoxy, (C)1-C6) Alkyl, cyano, halogen, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) Alkoxy, amino, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -an alkanoylamino group, and a 5-membered saturated non-aromatic heterocyclic ring having up to 3 heteroatoms selected from S, N and O, connected via a nitrogen atom,
-(C2-C6) -alkenyl radical
And a group of the formula
-dibenzofurans
And
R7having a radical of formula (I) with R5Have the same meaning and can be as R5The same or different;
or a compound selected from:
and
2. a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
R1represents hydrogen or (C)1-C6) -an alkyl group,
R2and R3Are the same or different and represent hydrogen, (C)1-C6) -alkoxy, (C)3-C8) -cycloalkyl or (C)1-C6) -alkyl, wherein (C)1-C6) -alkyl is optionally substituted with 1 to 3 substituents selected from: (C)3-C6) -cycloalkyl, (C)1-C6) -alkoxy, halogen, hydroxy, amino, morpholinyl, thiomorpholinyl and piperidinyl,
R4represents hydrogen, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, or
R4Is represented by (C)1-C6) -an alkyl group, which may be optionally substituted with 1 to 3 substituents selected from: hydroxy, (C)1-C6) -alkoxy, - (OCH)2CH2)nOCH2CH3Wherein n is 0 or 1, phenyl and-NR13R14Wherein R is13And R14Are the same or different and represent hydrogen or (C)1-C6) -alkyl, or
R13And R14Together with the nitrogen atom, form a 5-to 6-membered saturated heterocyclic ring which may optionally contain a further heteroatom selected from S or O or a group-NR15And may be substituted by oxo, wherein R15Represents hydrogen or (C)1-C4) -alkyl, or
R4Is represented by (C)1-C6) -alkyl substituted by pyridyl or by a group of formula
R5Represents hydrogen or (C)1-C6) -an alkyl group,
R6represents phenyl, which may be optionally substituted with 1 to 3 substituents selected from:
-halogen,
-phenyl, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) -alkoxy, (C)1-C6) Alkyl, cyano, halogen, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) Alkoxy, amino, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -alkanoylamino, tri- (C)1-C6) -an alkylsilyloxy group and a 5-membered saturated non-aromatic heterocyclic ring having up to 3 heteroatoms selected from S, N and O connected via one nitrogen atom,
-(C1-C6) -alkoxy groups,
Partially fluorinated (C) having up to 6 fluorine atoms1-C6) -an alkoxy group,
-a 5-to 6-membered aromatic heterocycle having up to 3 heteroatoms selected from N and O, optionally linked via a nitrogen atom, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) -alkoxy, (C)1-C6) Alkyl, cyano, halogen, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) Alkoxy, amino, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -an alkanoylamino group, and a 5-membered saturated non-aromatic heterocyclic ring having up to 3 heteroatoms selected from S, N and O, connected via a nitrogen atom,
-C2-C6an alkenyl group which is a radical of an alkylene group,
R7having a radical of formula (I) with R5Have the same meaning and can be as R5The same or different.
3. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R2And R3Each independently represents hydrogen or (C)1-C6) -an alkyl group.
4. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R4Represents hydrogen or (C)1-C6) -an alkyl group.
5. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R5Represents hydrogen.
6. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R6Represents phenyl, which may be optionally substituted with one to three substituents selected from:
-halogen,
-phenyl, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) -alkoxy, (C)1-C6) Alkyl, cyano, halogen, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) -alkoxy, amino, hydroxy, and mono-or di- (C)1-C6) -an alkanoylamino group,
-a 5-to 6-membered heteroaromatic ring having up to 3 heteroatoms selected from N and O, optionally linked via a nitrogen atom.
7. A compound of general formula (I) according to claim 1 having the formula or a pharmaceutically acceptable salt thereof
Wherein R is1、R2、R3、R4、R5And R7Each is asAs defined in claim 1, wherein the first and second substrates are,
R26and R27Are the same or different and represent hydrogen, halogen, (C)1-C6) Alkoxy, or partially fluorinated (C) having up to 6 fluorine atoms1-C6) -an alkoxy group,
R28represents phenyl, optionally substituted with 1 to 3 substituents selected from: (C)1-C6) -alkoxy, (C)1-C6) Alkyl, cyano, halogen, nitro, halo- (C)1-C6) -alkyl, halo- (C)1-C6) Alkoxy, amino, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -alkanoylamino, tri- (C)1-C6) -alkylsilyloxy and a 5-membered saturated non-aromatic heterocycle having up to 3 heteroatoms selected from S, N and O, linked via a nitrogen atom, or
R28Represents a 5-to 6-membered aromatic heterocyclic ring having up to 3 heteroatoms selected from N and O, optionally linked via a nitrogen atom, which may be optionally substituted with 1 to 3 substituents selected from: (C)1-C6) -alkoxy, (C)1-C6) Alkyl, cyano, halogen, nitro, halo- (C)1-C6) -alkyl, halo-C1-C6) Alkoxy, amino, hydroxy, carboxy, carbamoyl, mono-or di- (C)1-C6) -an alkanoylamino group, and a 5-membered saturated non-aromatic heterocyclic ring having up to 3 heteroatoms selected from S, N and O, attached via a nitrogen atom.
8. A compound according to claim 1 of the formula or a pharmaceutically acceptable salt thereof
9. A compound according to claim 1 of the formula or a pharmaceutically acceptable salt thereof
10. A compound according to claim 1 of the formula or a pharmaceutically acceptable salt thereof
11. A compound according to claim 1 of the formula or a pharmaceutically acceptable salt thereof
12. A compound according to claim 1 of the formula or a pharmaceutically acceptable salt thereof
13. A compound of the general formula (IV)
Wherein R is1、R4、R5、R6And R7Has the meaning given in claim 1, and D is a halogen atom.
14. A process for preparing a compound of the formula (I) according to claim 1,
[A] a compound of the general formula (II)
Wherein R is1、R2、R3And R4Having the meaning given in claim 1,
with a compound of the general formula (III) in an inert solvent, optionally in the presence of a base and/or an auxiliary
Wherein
A represents a leaving group, and R5、R6And R7Having the meaning given in claim 1,
or
[B] A compound of the general formula (IV)
Wherein
R1、R4、R5、R6And R7Having the meaning given in claim 1, and D is a halogen atom, with an amine of the formula (V) in an inert solvent
HNR2R3 (V)
Wherein
R2And R3Has the meaning given in claim 1, or
[C] A compound of the formula (X)
Wherein R is1、R2、R3、R4、R5、R7、R26And R27Has the meaning given in claim 7, and E is trifluoromethanesulfonate or halogen,
with boric acid or stannane of the formula (XI)
R28M (XI)
Wherein R is28Has the meaning given in claim 7 and M is tri- (C)1-C6) -an alkylstannyl or boronic acid group,
in an inert solvent in the presence of a palladium catalyst, optionally in the presence of a base, at a temperature of from 50 to 140 ℃ to form a compound of formula (XIV)
Wherein R is1、R2、R3、R4、R5、R7、R26、R27And R28Having the meaning given in claim 7,
or
[D] A compound of the formula (XII)
Wherein
R1、R2、R3、R4、R5、R7、R26And R27Having the meaning given in claim 7 and M has the meaning given in the preamble of this claim,
with a triflate or halide of the general formula (XIII):
R28E (XIII)
wherein
R28Having the meaning given in claim 7 and E having the meaning given in the preamble of the present claim,
in an inert solvent in the presence of a palladium catalyst, optionally in the presence of a base, at a temperature of from 50 to 140 ℃ to form a compound of formula (XIV).
15. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1 and a pharmaceutically acceptable carrier or excipient.
16. Use of a compound of general formula (I) according to claim 1 for the preparation of a medicament for the treatment of viral infections.
17. Use according to claim 16 for the preparation of a medicament for the treatment of viral infections caused by herpes viruses.
18. Use according to claim 16 for the preparation of a medicament for the treatment of viral infections caused by herpes simplex virus.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19962532A DE19962532A1 (en) | 1999-12-23 | 1999-12-23 | New 2-acylamino-5-aminosulfonyl-1,3-thiazole derivatives, useful as antiviral agents, especially for treatment or prophylaxis of herpes simplex virus infections |
| DE19962532.8 | 1999-12-23 | ||
| DE10039265.2 | 2000-08-11 | ||
| DE10039265A DE10039265A1 (en) | 2000-08-11 | 2000-08-11 | New 2-acylamino-5-aminosulfonyl-1,3-thiazole derivatives, useful as antiviral agents, especially for treatment or prophylaxis of herpes simplex virus infections |
| PCT/EP2000/012564 WO2001047904A1 (en) | 1999-12-23 | 2000-12-12 | Thiazolyl amide derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1057552A1 HK1057552A1 (en) | 2004-04-08 |
| HK1057552B true HK1057552B (en) | 2006-08-25 |
Family
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