Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-02-21
1997-05-06
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546118, A61K 31435, C07D47104
Patent
active
056271913
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/01774 filed Jul. 3, 1993.
The present invention relates to novel therapeutic agents and, in particular, to novel substituted cyclobut-3-ene-1,2-diones, to processes for their preparation, to pharmaceutical compositions containing them and to their therapeutic activity in the treatment of cardiovascular diseases.
Angiotensin II is a key mediator of the reninangiotensin system. It is known that angiotensin II is an arterial vasconstrictor that exerts its action by interacting with specific receptors on cell membranes. Recently, several non-peptide compounds have been reported as angiotensin II antagonists and as useful antihypertensive agents.
The present invention provides compounds of formula I ##STR2## and pharmaceutically acceptable sales thereof; wherein R.sub.50 is hydrogen or C.sub.1-4 alkyl, A.sub.51 is oxygen, sulphur or a group of the formula --NR.sub.52 -- wherein R.sub.52 is hydrogen or C.sub.1-4 alkyl; A.sub.50 comprises i) a mono or bicyclic aromatic ring optionally containing one or more nitrogen, oxygen or sulphur atoms, ii) a cycloalkendiyl group, iii) an acyclic bridging group having a chain of one, two or three atoms between the cyclobutenedione group and X.sub.50, said chain being a chain of one or two carbon atoms or a chain of one carbon atom and one or more nitrogen, oxygen or sulphur atoms or iv) a bond; X.sub.50 is either a bond or a spacer group providing a chain between A.sub.50 and B.sub.50 of one or two atoms length; B.sub.50 is a mono or bicyclic aromatic ring optionally containing one or more nitrogen, oxygen or sulphur atoms; r is an integer from 1 to 6; and Het is a ring system optionally containing one or more nitrogen, oxygen or sulphur atoms or is a phosphonate, phosphinate or amine derivative (wherein each of A.sub.50, X.sub.50, B.sub.50 and Het are optionally substituted).
Preferably, A.sub.50 is a group selected from the groups represented by (i) to (xii) below (wherein in each case Z.sub.50 is a bond to X.sub.50 and the other free valency is connected to the cyclobutenedione group). ##STR3## wherein R.sub.70 and R.sub.71 are each independently hydrogen, hydroxy, alkyl (optionally substituted by halo, C.sub.3-8 cycloalkyl or phenyl), C.sub.3-12 cycloalkyl or phenyl (both optionally substituted by halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy) or R.sub.70 and R.sub.71 together complete a 3 to 7 membered carbocycle (optionally substituted by one or two C.sub.1-6 alkyl, C.sub.1-6 alkoxy, phenyl, hydroxy or halo groups); ##STR4## wherein A.sub.60 is nitrogen or methine; A.sub.61 is imino, oxygen or sulphur and either R.sub.80 and R.sub.81 are each independently hydrogen, halo, fluoro, nitro, cyano, alkyl C.sub.2-10 (preferably C.sub.2-4)alkenyl, alkylthio, mono-, di- or trihalo-(C.sub.1-6 alkyl), hydroxyalkyl, oxoalkyl, carboxy or esterified carboxy, or, when R.sub.80 and R.sub.81 are on adjacent carbon atoms, R.sub.80 and R.sub.81 together may be 1,3-butadienylene thereby completing a fused aromatic ring; ##STR5## wherein R.sub.90 to R.sub.97 are each independently hydrogen, halo, fluoro, nitro, amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, trifluoromethyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or a group of the formula --SO.sub.2 NHR.sub.98 (wherein R.sub.98 is hydrogen, C.sub.1-5 alkyl, aryl or arylmethyl); ##STR6## wherein --A.sub.70 --A.sub.71 --A.sub.72 --A.sub.73 -- is a group of formula --NC(R.sub.100)C(R.sub.101)C(R.sub.102)--, --C(R.sub.100)NC(R.sub.101)C(R.sub.102)--, --C(R.sub.100)C(R.sub.101)NC(R.sub.102)--, --C(R.sub.100)C(R.sub.101)C(R.sub.102)N--, --NC(R.sub.100)NC(R.sub.101)--, --C(R.sub.100)NC(R.sub.101)N--, --NNC(R.sub.100)C(R.sub.101)--, --C(R.sub.100)NNC(R.sub.101)--, --C(R.sub.100)C(R.sub.101)NN--, --NC(R.sub.100)C(R.sub.101)N--, --C(R.sub.100)C(R.sub.101)C(O)N(R.sub.103)----C(R.sub.100)C(R.sub.101)N(R. sub.103)C(O)--, --C(O)N(R.sub.103)C(R.sub.100)C(R.sub.101)--, --N(R.sub.103)C(O)C(R.sub.100)C(R.sub.101)--, --C(O)N(R.sub.103)C(R.sub.100)N--, --C(R.sub.100)NC(O)N(R.sub.103)--, --N(R.sub.103)C(O)NC(R.sub.100)--, -
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Birch Alan M.
Hitchin Barbara W.
Steele Robert W.
Watts John P.
Dentz Bernard
The Boots Company PLC
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