Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1992-04-02
1996-10-08
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 1, 560100, 560 53, 560105, 560106, 560163, 560312, 562463, 562621, 568425, 568659, 568662, 568807, C07C 6702
Patent
active
055632920
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to certain phenyl-alkylphenyl compounds which are useful as inhibitors of the lipoxygenase pathways in the metabolism of arachidonic acid.
BACKGROUND OF THE INVENTION
A number of lipoxygenase inhibitors are known. For example, International Application Number PCT/US86/02548, International Publication Number WO 88/03800 published Jun. 2, 1988 discloses compounds having the formula: ##STR2## wherein D, E, F, X, Y, Z, may be H; OH; O-alkyl; or O-acyl optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl, or carbalkoxyl; R.sub.1 to R.sub.6 may be H; lower alkyl or lower alkoxyl optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl, or carbalkoxyl; carbonyl; alkoxy; aryl; or aralkyl; and n may be 0 to 5.
Arachidonic acid is metabolized by means of the enzymes 5-lipoxygenase and cyclooxygenase into various leukotrienes, including slow reacting substances, and prostaglandins which cause allergic reactions, inflammation and hyperproliferative skin diseases. Inhibition of the activity of 5-lipoxygenase (5-LO) reduces the manifestation of the symptoms of allergic reactions, e.g. chronic obstructive lung disease such as asthma, allergic or seasonal rhinitis, bronchitis, and the like; inflammatory diseases such as arthritis, bursitis, tendonitis, gout and inflammatory bowel disease; hypoproliferative skin disease, a symptom of which is accelerated skin cell production manifested by flaking, scales or papular lesions, e.g., psoriasis, lichenified eczema, dandruff, and the like.
A welcome contribution to the art would be novel organic compounds which are useful as lipoxygenase inhibitors. Such a contribution is provided by this invention.
SUMMARY OF THE INVENTION
This invention provides compounds having particularly advantageous properties useful in the treatment of inflammatory and allergic reactions by inhibiting the formation of 5-lipoxygenase derived products of arachidonic acid metabolism. One embodiment of this invention provides compounds represented by Formula 1: ##STR3## or a pharmaceutically acceptable salt or solvate thereof wherein:
(A) R.sup.1 and R.sup.2 are the same or different and are selected from: substituted aryl, heteroaryl, --OR.sup.5, and --NR.sup.6 R.sup.7 ; independently substituted by substituents selected from alkyl and --O-alkyl; and
(B) R.sup.3 and R.sup.4 are the same or different and are independently selected from H, R.sup.1 and R.sup.2 ;
(C) U, V, and Z are the same or different and are independently selected from H, R.sup.1, R.sup.2, --OR.sup.10, --O(CH.sub.2).sub.m R.sup.8, --OC(O)R.sup.9, and --OC(O)NR.sup.6 R.sup.7 ; and
(D) W is --(CH.sub.2).sub.n X wherein X is selected from:
n is an integer from 1 to 8;
wherein
R.sup.5 is selected from H, alkyl, aryl, alkaryl, aralkyl, cycloalkyl, and heteroaryl with the proviso that said heteroaryl group is bound through a ring carbon;
R.sup.6 and R.sup.7 are the same or different and are independently selected from H, alkyl, aryl, aralkyl, acyl substituted aryl, cycloalkyl and heteroaryl, with the proviso that when R.sup.6 and/or R.sup.7 is a heteroaryl group said heteroaryl group is bound by a ring carbon;
R.sup.8 is selected from aryl, substituted aryl, and heteroaryl, with the proviso that said heteroaryl group is bound through a ring carbon;
R.sup.9 is selected from H, alkyl, aryl, substituted aryl, aralkyl, cycloalkyl, and heteroaryl, with the proviso that said heteroaryl group is bound through a ring carbon;
m is an integer from 1 to 4;
R.sup.10 is selected from H and alkyl; and.
R.sup.11 is selected from H, --OR.sup.5, --NR.sup.6 R.sup.7, and --NR.sup.5 OH.
Preferred compounds of this invention are represented by Formula 2: ##STR4## wherein R.sup.12 and R.sup.13 are the same or different and are independently selected from U, V, and Z as defined for Formula 1 and R.sup.1, R.sup.2, R.sup.3, R.sup.4 and W are as defined for Formula 1.
More preferred compounds of this invention are represented by Formula 3: ##STR5## wherein R.sup.14 and R.sup.15 are th
REFERENCES:
patent: 4584320 (1985-04-01), Rubin
patent: 4708964 (1987-11-01), Allen
Asahara et al Bull. Jap. Petrol Insl. 12 49-53 1970.
Mangiaracina Pietro
Shih Neng-Yang
Jeanette Henry C.
Killos Paul J.
Schering Corporation
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