Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Utility Patent
1999-01-05
2001-01-02
Kight, John (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S302000, C514S291000, C514S301000, C546S116000, C546S089000, C546S114000, C544S253000
Utility Patent
active
06169092
ABSTRACT:
This application is a 371 of PCT/EP97/03432. Filed Jul. 1, 1997.
The invention relates to 3-urea-pyridofurans and -pyridothiophenes, 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. L-10) play a pivotal role in host defence mechanisms. Uncontrolled production of inflammatory medicators can lead to acute and chronic inflammation, tissue damage, multi-organ failures 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 3-urea-pyridofurans and -pyridothiophenes of the general formula (I)
in which
E, G, L and M are identical or different and represent a nitrogen atom or a residue of a formula —C—A, wherein at least one of the substituents E, G, L or M must represent a nitrogen atom and wherein
A represents hydrogen, straight-chain or branched acyl or alkoxy-carbonyl 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, halogen, hydroxyl, straight-chain or branched alkoxycarbonyl, or alkoxy each having up to 6 carbon atoms, phenoxy, benzoyl or by a group of a formula —O—CO—CH
3
, or represents 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
6
, R
8
, R
10
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 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,
R
7
, R
9
and R
11
are identical or different and denote hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms,
or
R
7
and R
8
together with the nitrogen atom form a 5- to 6-membered heterocycle,
R
5
has the abovementioned meaning of R
6
, R
8
, R
10
or R
12
and is identical or different from the latter,
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 optionally substituted by carboxyl, hydroxyl, straight-chain or branched acyl, oxyacyl or alkoxy-carbonyl each having up to 6 carbon atoms, phenoxy, benzoyl or by a 5- to 7-membered unsaturated heterocycle having up to 3 heteroatoms 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,
and/or alkyl is substituted by a (group of a formula —(CO)
c
—NR
14
R
15
in which
R
14
and R
15
are identical or different and have the above-mentioned meaning of R
7
and R
8
and
c denotes a number 0 or 1,
or
R
5
denotes a group of the formula —SO
2
—R
16
R
16
denotes phenyl, trifluoromethyl 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
13
has the abovementioned meaning of R
16
and is identical or different from the latter.
or
E and G represent the CH-group
and
L and M represent a residue of a formula —CD and —CD′
in which
D and D′ together form a pyridine ring,
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
17
in which
R
17
denotes hydroxyl, straight chain or branched alkoxycarbonyl having up to 6 carbon atoms, cycloalkyl having 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,
T 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 subsubstituents 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 represent a group of a formula —P(O)(OR
18
(OR
19
),
in which
R
18
and R
19
are identical or different and denote hydrogen or straight chain or branched alkyl 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 aryl having 6 to 10 carbon atoms or represents a 5 to 7 membered, saturated or unsaturated heterocycle, which can contain up to 4 oxygen, sulphur and/or nitrogen atoms as heteroatoms and to which further a benzene ring can be fused and wherein both rings are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising hydroxyl, halogen, nitro, 1H-tetrazolyl, pyridyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, cyano, carboxy, straight-chain or branched alkoxy, alkoxycarbonyl or acyl each having up to 8 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or by a group of a formula —NR
20
R
21
—, —SR
22
, SO
2
R
23
or —O—SO
2
R
24
,
in which
R
20
and R
21
have the meaning shown above for R
7
and R
8
,
or
R
20
denotes hydrogen,
and
R
21
denotes straight-chain or branched acyl having up to 6 carbon atoms,
R
22
denotes straight-chain or branched alkyl having up to 6 carbon atoms,
R
23
and R
24
are identical or different and represent straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which are optionally substituted by trifluoromethyl, halogen or straight-chain or branched alkyl having up to 6 carbon atoms,
Q represents an oxygen or sulfur atom,
and salts thereof.
The 3-urea-pyridofurans and -pyridothiophenes according to the invention can also be present in the form of their salts and pyridinium 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 3-urea-pyridofurans and -pyridothiophenes 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, dicyclohexylamine, d
Briggs Barbara
Br{umlaut over (a)}unlich Gabriele
Concepcion Arnel
Es-Sayed Mazen
Fischer R{umlaut over (u)}diger
Bayer Aktiengesellschaft
Kight John
Norris McLaughlin & Marcus P.A.
Robinson Binta
LandOfFree
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