Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-14
1998-02-10
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549401, A61K 3137, C07D31176
Patent
active
057169837
DESCRIPTION:
BRIEF SUMMARY
This application is 371 of PCT/EP94/02251 which is now published as No. 95/02588.
The present invention concerns the use of coumarins and carbostyrils as PLA.sub.2 inhibitors, new coumarin and carbostyril derivatives, processes for the production thereof and pharmaceutical agents which contain these compounds.
The invention concerns coumarin and carbostyril derivatives of the general formula I ##STR2## in which R.sub.1 denotes hydrogen or C.sub.1 to C.sub.6 alkyl form a 3-membered to 7-membered carbocyclic ring C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkanoyl or T.sub.1 and T.sub.2, together with the atoms to which they are bound, form a 5-membered to 7-membered heterocyclic ring which can be substituted if desired with oxo or thioxo, or form a pyridine ring, be substituted if desired with a hydroxyl group or an amino group, a phenylene residue which can be substituted if desired once or several times with hydroxyl, halogen, C.sub.1 to C.sub.6 alkyl or carboxyl alkoxycarbonyl, cyano or a group NR.sub.5 R.sub.6 in which hydrogen or C.sub.1 to C.sub.6 alkyl or bound, form a 3-membered to 7-membered heterocyclic ring which can be substituted if desired with oxo, hydroxy or C.sub.1 to C.sub.6 alkoxy or contains a further heteroatom such as oxygen or sulphur
Some of the compounds of formula I are known. Thus compounds of formula I are described in Chem. Abstr. 60, 4114b in which R.sub.1 =R.sub.4 =H, R.sub.2 =R.sub.3 =OH, Q=O, X=Y=valency and Z=NR.sub.5 R.sub.6 as agents for the treatment of vascular diseases. In Chem. Abstr. 84, 159773k it is stated that such substances do not inhibit a carrageenin oedema.
Compounds in which R.sub.1 =R.sub.4 =H, R.sub.2 and R.sub.3 =OH or alkyl =OH, Q=O, X=valency, A=alkylene and Z=hydrogen are described for example in Chem. Abstr. 68, 76748z as inhibitors of phenylalanine hydrolase; compounds in which R.sub.1 =R.sub.4 =H, R.sub.2 and R.sub.3 together are methylene-dioxy or R.sub.2 =R.sub.3 =OCH.sub.3, Q=O, X=Y= valency and Z= carboxyl or alkoxycarbonyl are described in Chem. Abstr. 100, 31674k and 112, 151027 as fluorescent markers.
The synthesis of 4-methyl-6,7-dihydroxycoumarin is described in Chem. Ber. 34, 423 (1901). 4-Chloromethyl- 6,7-dihydroxycoumarin is known from Chem. Abstr. 60, 4113 (1964) and Beilstein 18/3 V 233.
An anti-inflammatory action or specifically a PLA.sub.2 inhibitor is not stated.
The compounds of formula I have valuable pharmacological properties and in particular they can inhibit the activity of phospholipases. Thus they are suitable for the treatment of acute and chronic, allergic, non-allergic and traumatic and inflammatory diseases such as for example rheumatoid arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis, inflammatory and allergic respiratory tract diseases, septic shock, allergic shock, serum sickness, autoimmune diseases, graft-versus-host reactions, host-versus graft diseases, ischaemic or thrombotic diseases, such as coronary infarction or cerebral infarction.
Aklyl residues in the said groups alkyl, alkoxy and alkanol can be straight-chained or branched. Preferred residues are the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl and 3-pentyl residue.
Alkylene residues can be straight-chained or branched. Preferred residues are methylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene and 2,2-propylene.
Halogen atoms are in particular fluorine, chlorine and bromine.
Residues which enable R.sub.1 and R.sub.2 to together form a carbocyclic ring are preferred: --CH.sub.2 -- or CH.dbd.CH--CH.dbd.CH--.
Residues which enable R.sub.2 and R.sub.3 to together form a heterocyclic ring are preferred: ##STR3##
Residues which enable R.sub.5 and R.sub.6 to form a heterocyclic ring together with a nitrogen atom are preferred: --CH.sub.2 --CH.sub.2 --CH.sub.2 --, --S--CH.sub.2 --CH.sub.2 --
All substances which have every possible combination of the substituents stated in the examples are in particular a subject matter of the invention in addition to the compounds stated in the examples.
T
REFERENCES:
patent: 4863942 (1989-09-01), Wenk et al.
patent: 5124334 (1992-06-01), Wilkerson
patent: 5534533 (1996-07-01), Ohtani et al.
Friebe Walter-Gunar
Schaefer Wolfgang
Scheuer Werner
Tibes Ulrich
Aulakh Charanjit S.
Boehringer Mannheim GmbH
Ivy C. Warren
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