Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-31
2002-12-31
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217100, C514S227800, C514S229200, C514S236800, C514S254040, C514S326000, C514S342000, C514S364000, C514S369000, C540S603000, C544S060000, C544S065000, C544S124000, C544S133000, C544S367000, C546S209000, C546S270700, C548S131000, C548S181000, C548S185000
Reexamination Certificate
active
06500817
ABSTRACT:
The present invention relates to thiazolylurea derivatives, a process for their preparation, and their use as pharmaceuticals, in particular as antiviral pharmaceuticals.
The publication by C. Ziegler et al., J. Org. Chem. 25, 1960, 1454-1455 discloses 2-aminothiazole-5-sulphonamides. In addition, Gennan Offenlegungsschrift 2101640 describes N-thiazol-2-ylamides and -ureas with a herbicidal action.
WO 97/24343 relates to phenylthiazole derivatives with anti-herpes virus properties.
WO 99/42455 likewise relates to phenylthiazole derivatives with anti-herpes virus properties.
WO 99/47507 relates to 1,3,4-thiadiazole derivatives with anti-herpes virus properties.
The present invention relates to thiazolylurea derivatives of the general formula (I)
in which
R
1
represents hydrogen, halogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, amino(C
1
-C
6
)alkyl or halogeno(C
1
-C
6
)alkyl,
R
2
and R
3
are identical or different and represent hydroten, (C
3
-C
8
)-cycloalkyl or biphenylylaminocarbonyl, or
represent (C
1
-C
6
)-alkyl which is optionally substituted by 1 to 3 substituents selected from the group consisting of (C
3
-C
6
)-cycloalkyl, (C
1
-C
6
)-alkoxy, halogen, hydroxyl, radicals of the formula
a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and/or O, it also being possible for a nitrogen-containing heterocycle to be bonded via the nitrogen atom,
a 3- to 8-membered saturated or unsaturated, nonaromatic heterocycle which has up to 3 heteroatoms from the series S, N and/or O and is optionally bonded via a nitrogen atom, and (C
6
-C
10
)-aryl which in turn may be substituted by hydroxyl or (C
1
-C
6
)-alkoxy, or
R
2
and R
3
form, together with the nitrogen atom, a 5- to 6-membered saturated heterocycle which may optionally also have an oxygen atom,
R
4
represents hydrogen, (C
1
-C
6
)-acyl, (C
2
-C
6
)-alkenyl, or
R
4
represents (C
1
-C
6
)-alkyl which can optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, (C
1
-C
6
)-acyl, (C
1
-C
6
)-alkoxy, phenoxy (C
6
-C
10
)-aryl and —NR
7
R
8
,
in which R
7
and R
8
are identical or different and denote hydrogen, (C
1
-C
6
)-acyl, (C
1
-C
6
)-alkyl, carbamoyl, mono- or di(C
1
-C
6
)-alkylamino(C
1
-C
6
)alkyl, mono- or di(C
1
-C
6
)-alkyl-aminocarbonyl, (C
6
-C
10
)-aryl or (C
1
-C
6
)-alkoxycarbonyl, or R
7
and R
8
form, together with the nitrogen atom, a 5- to 6-membered saturated heterocycle which may optionally contain another heteroatom from the series S or O or a radical of the formula —NR
9
and may be substituted by oxo,
in which R
9
denotes hydrogen or (C
1
-C
4
)-alkyl, or
R
4
represents (C
1
-C
6
)-alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms in the series S, N and/or O, it also being possible for a nitrogen-containing heterocycle to be bonded via the nitrogen atom, or is substituted by radicals of the formulae
in which
R
10
denotes hydrogen or (C
1
-C
6
)-alkyl,
R
11
and R
12
are identical or different and denote hydrogen, (C
1
-C
6
)-alkyl or (C
6
-C
10
)-aryl, it being possible for the aforementioned (C
1
-C
6
)-alkyl and (C
6
-C
10
)-aryl optionally to be substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, (C
1
-C
6
)-alkoxy and halogen,
R
5
represents hydrogen or (C
1
-C
6
)-alkyl,
R
6
represents a radical of the formula
or
R
6
represents phenyl which can optionally be substituted by one to three substituents selected from the group consisting of
halogen, (C
6
-C
10
)-aryl which can optionally be substituted by 1 to 3 substituents selected from (C
1
-C
6
)alkanoyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkyl, halogen, (C
1
-C
6
)alkoxycarbonyl, nitro, halogeno(C
1
-C
6
)alkyl, halogeno(C
1
-C
6
)alkoxy, amino, (C
1
-C
6
)alkylthio, hydroxyl, carboxyl, carbamoyl, mono- or di(C
1
-C
6
)alkylaminocarbonyl, mono- or di(C
1
-C
6
)acylamino, (C
1
-C
6
)alkylsulphinyl, (C
1
-C
6
)alkylsulphonyl, and/or cyano, or (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl, (C
1
-C
6
)-alkylthio, hydroxyl, carboxyl, partially fluorinated (C
1
-C
6
)-alkoxy with up to 6 fluorine atoms,
radicals of the formulae
in which R
13
denotes hydrogen or (C
1
-C
6
)-alkyl,
(C
1
-C
6
)-alkyl which is optionally substituted by a radical of the formula
a 5- to 6-membered aromatic heterocycle which has up to 3 heteroatoms from the series S, N and/or O, is optionally bonded via a nitrogen atom and can optionally be substituted by 1 to 3 substituents selected from (C
1
-C
6
)alkanoyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkyl, halogen, (C
1
-C
6
)alkoxycarbonyl, nitro, halogeno(C
1
-C
6
)alkyl, halogeno(C
1
-C
6
)alkoxy, amino, (C
1
-C
6
)alkylthio, hydroxyl, carboxyl, carbamoyl, mono- or di(C
1
-C
6
)alkylaminocarbonyl, mono- or di(C
1
-C
6
)acylamino, (C
1
-C
6
)alkylsulphinyl, (C
1
-C
6
)alkylsulphonyl, and/or cyano,
a 3- to 8-membered saturated or unsaturated, nonaromatic mono- or bicyclic heterocycle which has up to 3 heteroatoms from the series S, N and/or O, is optionally bonded via a nitrogen atom and may optionally be substituted by 1 to 3 substituents selected from oxo, halogen, hydroxyl, (C
1
-C
6
)-alkoxycarbonyl, (C
1
-C
6
)alkoxy-carbonylamino, (C
1
-C
6
)-alkyl, halogeno(C
1
-C
6
)-alkyl and hydroxy(C
1
-C
6
)-alkyl,
and groups of the formulae —OR
14
, —NR
15
R
16
or —CO—NR
17
R
18
,
in which
R
14
denotes a radical of the formula
or denotes phenyl which in turn is optionally substituted by a group of the formula —NR
19
R
20
,
in which
R
19
and R
20
are identical or different and denote hydrogen, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl,
or
R
14
denotes (C
1
-C
6
)-alkyl which is optionally substituted once to three times by hydroxyl,
R
15
and R
16
are identical or different and denote hydrogen, carbamoyl, mono- or di(C
1
-C
6
)alkylaminocarbonyl, phenyl, (C
1
-C
6
)-acyl or (C
1
-C
6
)-alkyl,
where (C
1
-C
6
)-alkyl is optionally substituted by (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and/or O,
where aforementioned phenyl and aforementioned aromatic heterocycle are optionally substituted once to three times, identically or differently, by halogen and/or hydroxyl, and
R
17
and R
18
are identical or different and denote hydrogen or (C
1
-C
6
)-alkyl,
and the salts thereof.
Physiologically acceptable salts of the compounds according to the invention may be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred examples are 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.
Salts which may be mentioned are salts with conventional bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium 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.
The invention also includes within its scope those compounds which are converted only in the body into the actual active substances of the formula (I) (called prodrugs).
The compounds according to the invention may, depending on the substitution pattern, exist in stereoisomeric forms which are either related as image and mirror image (enantiomers) or which are not related as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers or mixtures thereof in each case. The racemic forms can, just like the diastereomers, be separated into the stereoisomerically homogeneous components in a known manner.
(C
1
-C
6
)-Alkyl represents a strai
Baumeister Judith
Bender Wolfgang
Betz Ulrich
Eckenberg Peter
Fischer Rüdiger
Bayer Aktiengesellschaft
Chiu Jerrie L.
Stockton Laura L.
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