Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-25
2003-08-26
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S299000, C514S333000, C514S336000, C514S369000, C514S380000, C514S397000, C514S407000, C514S414000, C514S470000, C544S153000, C546S172000, C546S256000, C546S275100, C546S280400, C546S284100, C548S185000, C548S243000, C548S311400, C548S364400, C548S454000
Reexamination Certificate
active
06610687
ABSTRACT:
The invention relates to Benzofuranylsulfonates, 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 derivatives having phosphodiesterase IV (PDE IV)-inhibiting action are described in the publication EP 731 099. The reference describes only one methanesulfonic acid ester, however.
In order to provide alternative compounds of similar or improved PDE IV-inhibitory activity, the present invention relates to Benzofuranylsulfonates of the general formula
in which
A represents hydrogen, straight-chain or branched acyl or alkoxycarbonyl, each having up to 6 carbon atoms, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl or trifluoromethoxy, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by carboxyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, phenoxy or benzoyl,
R
1
represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, an amino protecting group or a group of the formula —CO—R
5
in which
R
5
denotes straight chain or branched alkoxy having up to 4 carbon atoms,
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
R
2
and R
3
together with the nitrogen atom form a 5- to 7-membered saturated heterocycle optionally having a further O atom,
R
4
represents aryl having 6 to 10 carbon atoms or represents a 5 to 7 membered, aromatic, saturated or unsaturated heterocycle, which can contain up to 3 oxygen, sulphur and/or nitrogen atoms as hetero-atoms or a residue of a formula —NR
6
,
wherein
R
6
denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having up to 6 carbon atoms,
and to which further a benzene ring can be fused and wherein aryl and/or the heterocycle 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 6 carbon atoms or by straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of formula —NR
7
R
8
, —SR
9
, —(NH)
a
—SO
2
R
10
or —O—SO
2
R
11
,
in which
R
7
and R
8
are identical or different and denote hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms,
or
R
7
denotes hydrogen
and
R
8
denotes straight-chain or branched acyl having up to 6 carbon atoms
R
9
denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
a denotes a number 0 or 1,
R
10
and R
11
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 4 carbon atoms,
L represents an oxygen or sulfur atom,
D represents a residue of a formula
or aryl having 6 to 10 carbon atoms or a 5 to 7-membered aromatic, 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, wherein all abovementioned residues and ring systems are optionally monosubstituted to trisubstituted by halogen, carboxyl, straight-chain or branched alkyl or alkoxycarbonyl each having up to 6 carbon atoms, pyridyl and/or by a residue of a formula —NR
12
—E—R
13
, —NR
14
—CO—NR
15
R
16
, —NR
17
—SO
2
—NR
18
R
19
, —SO
2
—R
20
or —(SO
2
)
b—NR
21
R
22
,
wherein
b denotes a number 0 or 1,
E denotes a residue of formula SO
2
or CO
R
12
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
21
and R
22
are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
R
13
denotes straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
R
20
denotes benzyl, phenyl, pyridyl or straight-chain or branched alkyl having up to 6 carbon atoms,
or
D represents straight-chain or branched alkyl or alkenylen having up to 8 carbon atoms, which are monosubstituted to trisubstituted by halogen, aryl having 6 to 10 carbon atoms 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 or by a residue of a formula —NR
23
R
24
or
wherein
R
23
and R
24
have the abovementioned meaning of R
15
and R
16
and are identical or different to the latter,
wherein the abovementioned ring systems are optionally substituted by halogen,
and in the case that
R
4
does not represent phenyl or substituted phenyl,
D in addition can represent benzyl or straight-chain or branched alkyl having up to 5 carbon atoms,
or
D optionally represents a residue of a formula —NR
25
R
26
wherein
R
25
and R
26
have the abovementioned meaning of R
21
and R
22
and are identical or different to the latter,
and salts thereof.
The benzofuranylsulfonates 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 Benzofuranylsulfonates 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, 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 antipodes and to the racemate forms, as well as to individual diastereomers and to 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, aromatic, saturated or unsaturated, preferably 5- to 6-membered, aromatic, saturated or unsaturated ring which can contain up to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms and to which further aromatic rings can be fused.
The following are mentioned as preferred: thienyl, furyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, q
Bräunlich Gabriele
Briggs Barbara
Bullock William
Concepcion Arnel
Es-Sayed Mazen
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