Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-21
1999-10-12
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514277, 514357, 514365, 514381, 514522, 514557, 514561, 514568, 5462704, 546336, 546337, 548201, 548204, 562429, 562455, 562459, 562473, 562474, 562475, 562480, C07D21340, C07D25704, C07C 6521, C07C31718, A61K 3119, A61K 31275
Patent
active
059657413
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel, aromatic compounds and pharmaceutically-acceptable salts thereof which possess useful pharmacological properties. More particularly the compounds of the invention are antagonists of the pain enhancing effects of E-type prostaglandins. The invention also relates to processes for the manufacture of the aromatic compounds and pharmaceutically-acceptable salts thereof; to novel pharmaceutical compositions containing them; and to use of the compounds in pain relief.
The compounds of the invention are useful in the treatment of pain such as the pain associated with joint conditions (such as rheumatoid arthritis and osteoarthritis), postoperative pain, post-partum pain, the pain associated with dental conditions (such as dental caries and gingivitis), the pain associated with burns (including sunburn), the treatment of bone disorders (such as osteoporosis, hypercalcaemia of malignancy and Paget's disease), the pain associated with sports injuries and sprains and all other painful conditions in which E-type prostaglandins wholly or in part play a pathophysiological role.
Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates are the main classes of drugs in pain relief. However both possess undesireable side effects. NSAIDS are known to cause gastrointestinal irritation and opiates are known to be addictive.
We have now found a class of compounds structurally different to NSAIDS and opiates, and useful in relief of pain.
The compounds of the invention may also possess anti-inflammatory, anti-pyretic and anti-diarrhoeal properties and be effective in other conditions in which prostaglandin E.sub.2 (PGE.sub.2) wholly or in part plays a pathophysiological role.
According to the invention there is provided a compound of the formula I; ##STR2## wherein:
A is an optionally substituted: 8- to 10-membered bicyclic heteroaryl, 5- or 6-membered heteroaryl, naphthyl or phenyl; provided that the --OCH(R.sup.3)- and -X- linking groups are positioned in a 1,2 relationship to one another on ring carbon atoms;
B is an optionally substituted 5- or 6-membered heteroaryl ring system or optionally substituted phenyl;
D is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or phenyl;
X is of the formula --(CHR.sup.4).sub.n --or--(CHR.sup.4).sub.p CR.sup.4 .dbd.CR.sup.4 (CHR.sup.4).sub.q --wherein n is 1 to 3 and p and q are either both 0 or one of p and q is 1 and the other is 0;
R.sup.1 is positioned on ring B in a 1,3 or 1,4 relationship with the --OCH(R.sup.3)-- linking group in 6-membered rings and in a 1,3 relationship with the --OCH(R3)-- linking group in 5-membered rings and is carboxy, carboxyC.sub.1-3 alkyl, tetrazolyl, tetrazolylC.sub.1-3 alkyl, tetronic acid, hydroxamic acid, sulphonic acid, or R.sup.1 is of the formula --CONR.sup.a R.sup.a1 wherein R.sup.a is hydrogen or C.sub.1-6 alkyl and R.sup.a1 is hydrogen or optionally substituted; C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-6 alkyl, C.sub.3-7 cycloalkylC.sub.2-6 alkenyl, C.sub.3-7 cycloalkylC.sub.2-6 alkynyl, C.sub.5-7 cycloalkenyl, C.sub.3-7 cycloalkenylC.sub.1-6 alkyl, C.sub.5-7 cycloalkenylC.sub.2-6 alkenyl, C.sub.5-7 cycloalkenylC.sub.2-6 alkynyl, C.sub.1-3 alkyl substituted by a 5- or 6-membered saturated or partially saturated heterocyclic ring, 5- or 6-membered heteroaryl C.sub.1-3 alkyl, 5- or 6-membered saturated or partially saturated heterocyclic ring, or 5- or 6-membered heteroaryl; or wherein R.sup.a and R.sup.a1 together with the amide nitrogen to which they are attached (NR.sup.a R.sup.a1) form an amino acid residue or ester thereof; or R.sup.1 is of the formula --CONHSO.sub.2 R.sup.b wherein R.sup.b is optionally substituted: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-6 alkyl, C.sub.3-7 cycloalkylC.sub.2-6 alkenyl, C.sub.3-7 cycloalkylC.sub.2-6 alkynyl, C.sub.5-7 cycloalkenyl, C.sub.5-7 cycloa
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Breault Gloria Anne
Oldfield John
Tucker Howard
Warner Peter
Higel Floyd D.
Mitchell Kenneth F.
Zeneca Limited
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