Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-04-23
2000-09-12
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514277, 514290, 514291, 546 80, 546 84, 546 87, A61K 3144, A61K 31435, A61K 31437, C07D47104
Patent
active
061178810
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a series of carboline derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents. In particular, the invention relates to carboline derivatives which are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP specific PDE) having utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.
Thus, according to a first aspect, the present invention provides compounds of formula (I) ##STR2## wherein R.sup.0 represents -hydrogen or -halogen; selected from oxygen, nitrogen and sulphur (optionally substituted by --(.dbd.O)OR.sup.a or C.sub.1-4 alkyl), heterocyclic group as defined above, 6-membered heterocyclic group as defined above, heterocyclic group as defined above, alkenylene chain, optionally containing at least one heteroatom; alkenylene chain, optionally containing at least one heteroatom; selected from hydrogen and C.sub.1-6 alkyl; C.sub.4-6 cycloalkyl can be optionally substituted by one or more halogen atoms, one or more --C(.dbd.O)OR.sup.a or one or more --OR.sup.a ;
The terms alkyl or alkylene as used herein repetitively contain the appropriate indicated number of carbon atoms and appropriately include straight chained and branched alkyl or alkylene groups, typically methyl, methylene, ethyl and ethylene groups, and straight chained and branched propyl, propylene, butyl and butylene groups. The term C.sub.2-6 alkenylene as used herein contains 2 to 6 carbon atoms and appropriately includes straight chained and branched alkenylene groups, in particular ethenylene or the like.
The terms C.sub.4-6 cycloalkyl denotes cyclic groups containing 4 to 6 carbon atoms, namely cyclobutane, cyclopentane and cyclohexane.
The term halogen as used herein includes fluorine, chlorine, bromine and iodine.
The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6-membered heterocycloalkyl and heteroaryl groups, e.g. tetrahydrofuranyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, imidazolyl, furyl and tetrazolyl.
Appropriately, R.sup.0 represents hydrogen. Alternatively R.sup.0 may represented halogen, in particular fluorine.
R.sup.1 may represent any of the substituents as hereinbefore described, or more particularly may represent any of --OR.sup.a, --O--C.sub.2-4 alkylene NR.sup.a R.sup.b, --O--C.sub.1-4 alkylene Het and --O--C.sub.2-4 alkylene-OR.sup.a. In particular, R.sup.1 represents --O--C.sub.2-4 alkylene NR.sup.a R.sup.b, wherein suitably C.sub.2-4 alkylene may represent ethylene and aptly, R.sup.a and R.sup.b may independently represent methyl.
Particularly suitable R.sup.2 represents hydrogen. Alternatively, in the case where R.sup.1 and R.sup.2 together form a 3- or 4-membered alkylene or alkenylene chain optionally containing at least one heteroatom as hereinbefore described, suitably R.sup.1 and R.sup.2 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or --NR.sup.a ethylene-O--. Aptly, R.sup.1 and R.sup.2 together form methylenedioxy, propylene or --N(CH.sub.3)--(CH.sub.2).sub.2 --O--.
Suitably R.sup.3 and R.sup.4, together form a 3- or 4-membered alkylene or alkenylene chain, optionally containing at least one heteroatom as hereinbefore described. Particularly suitably R.sup.3 and R.sup.4 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or --NR.sup.a ethylene-O--. Aptly R.sup.3 and R.sup.4 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain or a propylene chain. In particular, R.sup.3 and R.sup.4 together form methylenedioxy or ethyleneoxy, most particularly ethyleneoxy.
A particular subgroup of compounds according to the present invention can be represented by formula (Ia) ##STR3## wherein R.sup.5 is sel
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ICOS Corporation
Rotman Alan L.
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