Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-21
2002-06-04
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S467000
Reexamination Certificate
active
06399657
ABSTRACT:
The invention relates to N-(3-benzofuranyl)urea-derivatives, processes for their preparation and their use in medicaments.
It is known that the NADPH oxidase of phagocytes is the physiological source to the superoxide radical anion and reactive oxygen species derived therefrom which are important in the defence against pathogens. Moreover, both inflammatory (e.g. TNF&agr;, IL-1 or IL-6) and anti-inflammatory cytokines (e.g. IL-10) play a pivotal role in host defence mechanism. Uncontrolled production of inflammatory mediators can lead to acute or chronic inflammation, auto immune diseases, tissue damage, multi-organ failure and to death. It is additionally known that elevation of phagocyte cyclic AMP leads to inhibition of oxygen radical production and that this cell function is more sensitive than others such as aggregation or enzyme release.
Benzofuran- and benzothiophene derivatives having lipoxygenase-inhibiting action are described in the publication EP 146 243.
The invention relates to N-(3-benzofuranyl)urea-derivatives of the general formula (I)
in which
A and D are identical or different and represent hydrogen, straight-chain or branched acyl or alkoxycarbonyl, each having up to 6 carbon atoms, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by carboxyl or alkoxycarbonyl having up to 6 carbon atoms, phenoxy or benzoyl, or represent halogen, carboxyl, cyano, nitro, trifluoromethyl, trifluoromethoxy or a group of a formula —OR
5
, —S(O)
a
R
6
, —(O—CH
2
—CO)
b
—NR
7
R
8
, —CO—NR
9
R
10
, —SO
2
—NR
11
R
12
or —NH—SO
2
R
13
,
in which
R
5
, R
6
, R
8
, R
9
, R
10
, R
11
and R
12
are identical or different and denote hydrogen, cycloalkyl having 3 to 6 carbon atoms, benzyl or a 5 to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and O and to which a phenyl ring can be fused and which is optionally substituted by identical or different substituents from the series comprising halogen, cyano, nitro or by a straight-chain or branched alkyl having up to 6 carbon atoms or denote straight-chain or branched alkyl, alkenyl or acyl each having up to 8 carbon atoms, or denote phenyl, which is optionally monosubstituted to disubstituted by identical or different substituents from the series comprising nitro, halogen, carboxy or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms,
or
R
5
denotes a hydroxyl protecting group or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or denotes straight-chain or branched alkyl having up to 8 carbon atoms, which is substituted by carboxyl, hydroxyl, straight-chain or branched acyl or alkoxycarbonyl each having up to 6 carbon atoms, phenoxyl, benzoyl or by a 5 to 7-membered unsaturated heterocycle having up to 3 hetero atoms from the series comprising N, S and/or O, which is optionally substituted by halogen, cyano, nitro or by straight-chain or branched alkyl having up to 6 carbon atoms
or
R
5
denotes a group of a formula SO
2
R
14
,
in which
R
14
denotes phenyl, trifluormethyl or straight-chain or branched alkyl having up to 4 carbon atoms,
a denotes a number 0, 1 or 2,
b denotes a number 0 or 1,
R
7
denotes hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms,
R
13
denotes aryl having up 6 to 10 carbon atoms, trifluoromethyl or straight-chain or branched alkyl having up to 6 carbon atoms,
R
1
represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, an aminoprotecting group or a group of the formula —CO—R
15
,
in which
R
15
denotes hydroxyl, straight chain or branched alkoxycarbonyl having up to 6 carbon atoms, cycloalkyl having up 3 to 6 carbon atoms, pyridyl, pyrrolidinyl or straight chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by halogen, carboxyl or straight chain or branched alkoxycarbonyl having up to 6 carbon atoms, or denotes phenyl, which is optionally substituted by hydroxyl, carboxyl or straight chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,
L represents an oxygen or sulfur atom,
R
2
and R
3
are identical or different and represent hydrogen, cycloalkyl having up to 6 carbon atoms, straight chain or branched alkyl, alkoxycarbonyl or alkenyl each having up to 8 carbon atoms, or represent benzoyl or aryl having 6 to 10 carbon atoms, which are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising halogen, cyano, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 6 carbon atoms,
or
R
2
and R
3
together with the nitrogen atom form a 5- to 7-membered saturated heterocycle optionally having a further O atom,
and
R
4
represents phenyl, which is optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising hydroxyl, thiophenyl, cycloalkyl having up to 3 to 6 carbon atoms, halogen, nitro, tetrazolyl, thiazolyl, furanyl, pyridyl, trifluoromethyl, difluoromethyl, cyano, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 8 carbon atoms, or phenyl is optionally substituted by phenyl, which is optionally monosubstituted to disubstituted by halogen, or by a group of a formula —NR
16
R
17
, —SR
18
, SO
2
R
19
or —O—SO
2
R
20
,
in which
R
16
and R
17
have the abovementioned meaning of R
7
and R
8
and are identical or different to the latter,
or
R
16
denotes hydrogen,
and
R
17
denotes straight-chain or branched acyl having up to 6 carbon atoms,
R
18
denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R
19
and R
20
are identical or different and represent straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, and salts thereof.
The N-(3-benzofuranyl)urea-derivatives according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the N-(3-benzofuranyl)urea-derivatives can be metal or ammonium salts of the substances according to the invention, which contain a free carboxylic group. Those which are particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclo-hexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids. Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the anti-podes and to the racemate forms, as well as the diastereomer mixtures. The racemate forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
Heterocycle in general represents a 5- to 7-membered saturated or unsaturated, preferably 5- to 6- membered, saturated or unsaturated ring which can contain up to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms and to which further aromatic ring can be fused.
The following are mentioned as preferred: thienyl, furyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxazolyl, cinnolyl, thiazolyl, dihydro
Abram Trevor S.
Bräunlich Gabriele
Es-Sayed Mazen
Fischer Rüdiger
Fitzgerald Mary F.
Bayer Aktiengesellschaft
Morris Patricia L.
Norris & McLaughlin & Marcus
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