Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-12-17
1995-12-26
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540593, C07D22316, A61K 3155
Patent
active
054788226
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US 92/04197 filed May 27, 1992.
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to novel tetrahydrobenzazepine N-hydroxyurea derivatives. The compounds of the present invention inhibit the action of the enzyme lipoxygenase and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treating inflammatory diseases, allergy and 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, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.
Several review articles on lipoxygenase inhibitors have been reported (See H. Masamune et al., Ann. Rep, Med. Chem., 24, 71-80 (1989) and 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, JP (Kohyo) 502179/88 and U.S. Pat. No. 4,822,809.
SUMMARY OF THE INVENTION
The present invention provides novel tetrahydrobenzazepine N-hydroxyurea derivatives of the following formula and their pharmaceutically acceptable salts: ##STR2## wherein n is 1 to 5; R is hydrogen, C.sub.1 to C.sub.4 alkyl, arylalkyl having from one to four carbon atoms in the alkyl moiety or arylalkyl substituted with one or more substituents selected independently from the group consisting of halogen, nitro, cyano, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 halosubstituted alkyl, C.sub.1 to C.sub.6 hydroxysubstituted alkyl, C.sub.2 to C.sub.7 alkoxycarbonyl and aminocarbonyl.
This invention also concerns pharmaceutical compositions comprising a pharmaceutically acceptable carder 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
Definitions
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.
"Alkoxy" means --OR.sup.1 wherein R.sup.1 is an alkyl radical, for example, methoxy, ethoxy, propoxy, isopropoxy and butoxy.
"Alkoxycarbonyl" means --C(.dbd.0)R.sup.2 wherein R.sup.2 is an alkoxy radical, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
"Arylalkyl" means an aromatic radical appended to an alkyl radical, for example, phenylethyl(benzyl), phenylethyl, phenylpropyl, phenylbutyl and naphthylmethyl.
"Hydroxysubstituted alkyl" refers to an alkyl radical as described above substituted with one or more hydroxy radicals, for example, hydroxymethyl, dihydroxyethyl and trihydroxypropyl.
Some of the compounds of the above formula may form acid salts. The pharmaceutically acceptable acid salts are those formed from acids which form n
REFERENCES:
patent: 4981865 (1991-01-01), Belliotti et al.
J. March, Advanced Organic Chemistry, 1992, pp. 448, 771, 958-959.
Hoshino Yoko
Ikeda Takafumi
Bernhardt Emily
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Zielinski Bryan C.
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