Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-01
2002-03-12
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S282700
Reexamination Certificate
active
06355658
ABSTRACT:
The invention relates to novel coumarin derivatives, to processes for preparing them, and to their use as medicinal products which can inhibit serine proteases and cysteine proteases.
The invention applies more particularly to serine or cysteine proteases, such as leukocyte elastase, thrombin, clotting factors (for example IXa, Xa, XIa, XIIa and VIIa), complement factors, plasmin, plasminogen activators (u-PA and t-PA), cathepsin G, acrosin, chymases, tryptases, chymotrypsin, trypsin and cathepsin B.
More specifically, the invention relates to novel coumarin derivatives which can act selectively on a given protease.
Serine protease and cysteine protease are involved in a great many physiological processes. Pathological states can become established when a disequilibrium is observed between the protease and its natural macromolecular inhibitor(s). Low-molecular-weight synthetic inhibitors can be used in this case to counteract excess proteolysis and can thus be of great therapeutic value in the following pathologies: pulmonary emphysema, rheumatoid arthritis, ageing of the skin and inflammation (involvement of leukocyte elastase and cathepsin G); pancreatitis (involvement of pancreatic elastase, chymotrypsin and trypsin): tumor invasion and metastasis (plasmin, plasminogen activators and cathepsin B); thrombosis, cerebral and coronary infarction (involvement of thrombin and clotting factors); thrombolysis and fertility disorders (plasmin and plasminogen activators); attacks by parasites and viruses (some of these organisms produce serine and cysteine proteases).
Among the serine protease inhibitors described in the literature and obtained by total synthesis, modified peptides or compounds of totally non-peptide nature are distinguished (Demuth 1990,
J. Enzym. Inhib.
3:249-278; Bernstein et al. 1994,
in Progress in Medicinal Chemistry
31: 59-120). These inhibitors have the advantage of being potentially more stable with respect to in vivo metabolization processes and of optionally being able to be administered orally.
Many classes of synthetic non-peptide compounds which have serine protease inhibitory properties are known from the prior art. Among these, suicide substrates have been prepared, such as haloenol and ynenol lactones (Daniels et al. 1983,
J. Biol Chem.
258: 15046-15053;Katzenellenbogen et al. 1992,
Bioorg. Med. Chem. Lett.
2: 1399-1404; Tam et al. 1984,
J. Am. Chem. Soc.
106: 6849-6851), isocoumarins (Harper et al. 1985,
Biochemistry
24: 1831-1841; Harper 1985,
Biochemistry
24: 7200-7213), 3,4-dihydro-6-halomethylcoumarins (Béchet et al. 1973,
Eur. J. Biochem.
35: 527-539; Mor et al. 1990
Biochim. Biophys. Acta
1038: 119-124), functionalized arylcyclopeptides (Reboud-Ravaux et al. 1991,
Boichem. Biophys. Res. Commun.
178: 352-359; Wakselman et al. 1993,
J. Med. Chem.
36: 1539-1547) and &bgr;-lactams (Doherty et al. 1986,
Nature
322:192-194; Knight et al. 1992,
Biochemistry
31: 8160-8170; Maillard et al. 1990,
Eur. J. Biol.
52: 213-221; Wakselman et al. 1991,
FEBS Lett.
282: 377-381).
Among these inhibitors of suicide substrate type, halomethyldihydrocoumarins have attracted particular attention. They have shown good inhibitory activity with respect to a large number of serine proteases, in particular including &agr;-chymotrypsin, pig pancreatic elastase, human leukocyte elastase, urokinase and thrombin (Béchet et al. 1973,
Eur. J. Biochem.
35: 527-539; Béchet et al. 1977,
Biochimie
59: 231-239; Béchet et al. 1973,
Biochimie
59: 241-246; Vilain et al. 1991,
Biochim. Biophys. Acta
1076: 401-405; Reboud-Ravaux et al. 1990,
Biochim. Biophys. Acta
1038: 119-124). However, these products, which are difficult to synthesize, lack selectivity.
It is of the greatest interest to synthesize protease inhibitors which are specific for a given protease, in order to inhibit this enzyme without acting on nearby proteases.
The present invention relates to the preparation of novel coumarin derivatives which allow this aim to be achieved since they combine activity and specificity.
The invention also relates to the preparation of novel coumarin derivatives whose synthesis is more readily accessible.
The invention relates to compounds corresponding to the general formula (I) below:
in which:
X, X′ and X″, independently of each other, represent O or S,
Y represents O, S, NH or NHS,
R
3
represents
a cycloalkyl group, in particular of 3 to 12 carbon atoms and optionally containing at least one hetero atom chosen from O, S and N, optionally substituted by one or more linear or branched alkyl group(s) of 1 to 6 carbon atoms,
an aryl group, in particular a phenyl or naphthyl group optionally substituted by 1 to 7 and in particular 1 to 5 substituents chosen from: a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a perhaloalkyl group of 1 or 2 carbon atoms, in particular —CF
3
; a hydroxyl group; a mercapto; a nitro group; a cyano group; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a carbaldehyde group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group;
a 5- to 14-membered, in particular 5- or 6-membered, mono- or polycyclic heteroaryl group containing one or more nitrogen and/or sulfur and/or oxygen atoms, in particular a pyridyl group, optionally substituted by 1 to 6 substituents chosen from: a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; an aryl group; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a perhaloalkyl group of 1 or 2 carbon atoms, in particular —CF
3
; a hydroxyl group; a mercapto group; a nitro group; a cyano group; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a carbaldehyde group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group,
with the proviso that R
3
is other than a cycloalkyl group or an aryl group when Y represents NH;
R
3
advantageously representing —C
6
H
5
, —C
6
H
4
CH
3
, —C
6
H
4
I, —C
6
H
4
NO
2
, —C
6
H
4
F, —C
6
H
4
Br, —C
6
H
4
Cl, —C
6
H
4
CF
3
, —C
6
H
4
OCH
3
, —C
6
H
3
Cl
2
, —C
6
H
3
ClCH
3
, —C
6
H
3
ClOCH
3
,
R
5
, R
6
, R
7
and R
8
, which may be identical or different, represent hydrogen; a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched haloalkyl group of 1 to 6 carbon atoms, in particular halomethyl and in particular —CH
2
Cl; a perhaloalkyl group of 1 or 2 carbon atoms, in particular —CF
3
; a linear or branched alkyl group of 1 to 6 carbon atoms bearing an amine, amidine or guanidine function or a sulfonium function bearing two linear or branched alkyl substituents of 1 to 6 carbon atoms, an aryl or aralkyl group in which the alkyl group contains from 1 to 6 carbon atoms; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an aralkyl group in which the linear or branched alkyl radical contains from 1 to 6 carbon atoms; an aryl group optionally substituted by one or more groups chosen from halogen, linear or branched alkyl of 1 to 6 carbon atoms or linear or branched alkoxy of 1 to 6 carbon atoms; an amino group optional
Boggetto Nicole
Delarge Jacques
Doucet Caroline
Pirotte Bernard
Pochet Lionel
Centre National de la Recherche Scientifique
Rotman Alan L.
LandOfFree
Coumarin derivatives, methods of preparation and application... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Coumarin derivatives, methods of preparation and application..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Coumarin derivatives, methods of preparation and application... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2830175