Heterocyclic benzenesulfonylimine derivatives as inhibitors of I

Details Heterocyclic benzenesulfonylimine derivatives as inhibitors of I Heterocyclic benzenesulfonylimine derivatives as inhibitors of I

1996-07-03

1997-09-16

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514312, 514313, 514432, 514457, 514539, 514608, 514620, A61K 3144, A61K 3138, A61K 3135, A61K 3116

Patent

active

056681437

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to heterocyclic benzenesulfonylimine derivatives and their use as inhibitors of Interleukin-1 (IL-1) action. Such inhibitors are useful in the treatment of various disease states as disclosed herein including rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis, septic shock and pulmonary fibrosis.


SUMMARY OF THE INVENTION

The present invention provides a method of inhibiting IL-1 action comprising administration of to a patient in need thereof an effective amount of a compound of the formula: ##STR1## wherein
A is NH, O, or S;
Q.sub.1 is --OR or --NR.sub.1 R.sub.2 ; wherein R is hydrogen or C.sub.2 -C.sub.6 alkyl radical of branched, straight chained, or cyclic configuration and R.sub.1 and R.sub.2 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl radical of branched, straight chained, or cyclic configuration;
Z is from 1 to 3 substituents chosen independently from the group: hydrogen, halogen, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and halogen.
Some of the compounds of the present invention are novel heterocyclic benzenesulfonylimine derivatives. These novel compounds are useful inhibitors IL-1 action. These novel compounds of Formula II are encompassed by the Formula I. The present invention provides novel heterocyclic benzenesulfonylimine derivatives of the formula: ##STR2## wherein
A is NH, O, or S;
Q.sub.2 is --OR.sub.3 or --NR.sub.1 R.sub.2 ; wherein R.sub.3 is C.sub.1 -C.sub.6 alkyl radical of branched, straight chained, or cyclic configuration and R.sub.1 and R.sub.2 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl radical of branched, straight chained, or cyclic configuration with the provisos; 1) that when A is NH, R.sub.3 is not C.sub.1, 2) that when A is NH and Z is para-methyl, Y is not 7-methoxy, 6-methoxy, 5,8-dimethoxy, and 3) that when A is NH, Z is hydrogen, and R.sub.3 is ethyl Y is not 5-ethyl-7-bromo;
Z is from 1 to 3 substituents chosen independently from the group: hydrogen, halogen, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and halogen.
The compounds encompassed by the provisos were disclosed as synthetic intermediates by Wright in Syn, 1058 (1984) and as NMDA antagonists in PCT Patent Application WO 92/15565 published Sep. 17, 1992. These compounds as disclosed herein, are active as inhibitors of IL-1 action. The compounds encompassed by the provisos are compounds of Formula I and should be considered within the scope of any method, use, or formulation claims.


DETAILED DESCRIPTION OF THE INVENTION

As used in this application: atom, or iodine atom; chained alkyl radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc; straight chained alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, etc; alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc; acid addition salt or a basic addition salt;
The expression "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-be

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