Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-08-26
1996-05-28
Brust, Joseph Paul
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514183, 514210, 514331, 514575, 546234, 548568, 548950, 548967, 562621, 562623, A61K 3140, A61K 3133, A61K 31445, C07D295195
Patent
active
055212123
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT US92/08979 filed Oct. 27, 1992.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
This invention relates to novel cyclopropyl N-hydroxyurea end N-hydroxyacetamide derivatives. The compounds of the present invention inhibit the action of the enzyme lipoxygenase end are useful in the treatment or alleviation of inflammatory diseases, allergy end cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds end to the use of such compounds in treating inflammatory diseases, allergy end cardiovascular diseases in mammals. This invention further relates to methods of making such compounds.
Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglendins including prostacydins, thromboxenes end leukotrienes. The first step of arachidonic acid metabolism is the release of arachidonic acid end related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglendins end thromboxenes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the patiophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis end inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute end chronic inflammatory conditions.
Several review articles on lipoxygenase inhibitors have been reported (See H. Masamune et ed., Ann. Rep. Med. Chem., 24, 71-80 (1989) end B. J. Fitzsimmons et al., Leukotrienes and Lipoxygenases, 427-502 (1989).
Compounds of the same general class as the compounds of the present invention are disclosed in EP 279263 A2, EP 196184 A2, EP 436199 A, JP (Kohyo) 502179/88, JP (Appln.) 105648/90 and U.S. Pat. No. 4,822,809.
SUMMARY OF THE INVENTION
The present invention provides novel cyclopropyl N-hydroxyurea and N-hydroxyacetamide derivatives of the following formula and their pharmaceutically acceptable salts. ##STR3## wherein A is C1 to C3 alkylene, Ar is phenyl or styryl, R is halosubstituted C1 to C3 alkyl, NHR' or ##STR4## R' is hydrogen or C2 to C8 alkytthioalkyl, n is an integer of from 1 to 4 and p is an integer of from 2 to 5, with the proviso that when R' is hydrogen then Ar is styryl.
This invention also concerns pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound of the invention or a pharmaceutically acceptable salt thereof. This invention further concerns methods of treating inflammatory diseases, allergy and cardiovascular diseases in mammals comprising administration of such compounds or compositions.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following definitions are used.
"Halo" and "halogen" mean radicals derived from the elements fluorine, chlorine, bromine and iodine.
"Alkyl" means straight or branched saturated hydrocarbon radicals, for example, methyl, ethyl, n-propyl and isopropyl.
"Halosubstituted alkyl" refers to an alkyl radical as described above substituted with one or more halogen radicals, for example, chloromethyl, bromoethyl and trifluoromethyl.
"Alkylene" means straight or branched alkene radicals, for example, methylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene.
"Alkylthioalkyl" means a group of the structure -RSR wherein R is alkyl as defined above, for example, methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthioethyl and propylthiomethyl.
This invention includes pharmaceutical compositions for treatment of inflammatory diseases, allergy and cardiovascular diseases in a mammal which comprises a pharmaceutically acceptable carrier or diluent and a compound of the above formula or a pharmaceutically acceptable salt thereof.
This invention also includes pharmaceutical compositions for inhibiting the lipoxygenase in mammal which
REFERENCES:
patent: 4822809 (1989-04-01), Summers et al.
patent: 5037853 (1991-08-01), Brooks et al.
patent: 5120752 (1992-06-01), Brooks et al.
J. March, Advanced Organic Chemistry, J. Wiley, & Sons, 1992, p. 412.
Aldrich Catalogue, Aldrich Chemical Co. (Milwaukee, WI), 1994, pp. 120, 1148.
Ikeda Takafumi
Kawai Akiyoshi
Mano Takashi
Okumura Yoshiyuki
Stevens Rodney W.
Brust Joseph Paul
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Zielinski Bryan C.
LandOfFree
Cyclopropyl N-hydroxyurea and N-hydroxyacetamides which inhibit does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cyclopropyl N-hydroxyurea and N-hydroxyacetamides which inhibit , we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclopropyl N-hydroxyurea and N-hydroxyacetamides which inhibit will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-787272