Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1995-10-03
1997-10-28
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
564 47, 564 52, 564 56, 564 57, 564 61, 564 62, A61K 3117, C07C27524, C07C27302
Patent
active
056818580
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP94/00567 filed Apr. 5, 1994.
TECHNICAL FIELD
This invention relates to novel cycloalkylhydroxyureas. The compounds of the present invention inhibit the action of the lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals, especially human subjects. This invention also relates to pharmaceutical compositions comprising such compounds.
BACKGROUND ART
Arachidonic acid is known to be the biological precursor of several groups of biologically active endogenous metabolites. The first step in the metabolism of arachidonic acid is its release from membrane phospholipids, via the action of phospholipase A2. Arachidonic acid is then metabolized either by cyclooxygenase to produce prostaglandins including prostacyclin, and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes.
The leukotrienes are extremely potent substances which elicit a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The peptidoleukotrienes (LTC.sub.4, LTD.sub.4, LTE.sub.4) are important bronchoconstrictors and vasoconstrictors, and also cause plasma extravasation by increasing capillary permeability. LTB.sub.4 is a potent chemotactic agent, enhancing the influx of leukocytes and inducing their subsequent degranulation at the site of inflammation. A pathophysiological role for leukotriene has been implicated in a number of human disease states including asthma, rheumatoid arthritis and gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel diseases (e.g. Crohn's disease), endotoxin shock, and ischemia-induced myocardial injury. Any agent that inhibits the action of lipoxygenases is expected to be of considerable therapeutic value for the treatment of acute and chronic inflammatory conditions.
Compounds of similar structure to the compounds of the present invention are disclosed in the following publications: WO92/01682, WO92/09566 and WO92/09567.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides novel cycloalkyl-N-hydroxyurea compounds of the following chemical formula (I): ##STR2## wherein R.sup.1 and R.sup.2 are each independently hydrogen or C.sub.1 -C.sub.4 alkyl; one double bond or one triple bond in the chain, and optionally having one or more C.sub.1 -C.sub.4 alkyl groups attached to the chain; clearable group; and
Preferably, when Ar is mono-, di- or trisubstituted phenyl, the substituents are independently selected from the group consisting of halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halosubstituted (C.sub.1 -C.sub.6) alkyl and halosubstituted (C.sub.1 -C.sub.6) alkoxy. Particularly preferred groups for Ar are phenyl and monohalo phenyl, especially phenyl and 4-fluorophenyl.
Preferably M is hydrogen or a pharmaceutically acceptable cation.
A preferred group of the compounds of this invention consists of the compounds of formula (I), wherein R.sup.1 and R.sup.2 are each hydrogen; Ar is mono-, di- or trisubstituted phenyl, wherein the substituents are independently selected from the group consisting of halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halosubstituted (C.sub.1 -C.sub.6) alkyl and halosubstituted (C.sub.1 -C.sub.6) alkoxy; X is oxygen; n is 4 or 5; and M is hydrogen or a pharmaceutically acceptable cation. Within this preferred group, particularly preferred compounds are those in which A is a valence bond, --CH(CH.sub.3)-- or --C.tbd.C--CH(CH.sub.3)--.
Preferred compounds of the present invention are: N-hydroxy-N-(1S,3S)-3-phenoxycyclopentylurea; xyurea; xyurea; xyurea; and xyurea.
The compounds of the formula I can inhibit the action of lipoxygenase. Therefore the compounds are useful for treating a medical condition for which a 5-lipoxygenase inhibitor is needed, in a mammalian subject, e.g., a human subject. The compounds are especially useful for treating inflammatory diseases, allergy and cardiovascular diseases. This invention al
REFERENCES:
patent: 5476873 (1995-12-01), Brooks et al.
Mano Takashi
Nakane Masami
Okumura Yoshiyuki
Stevens Rodney William
Benson Gregg C.
Kumar Shailendra
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
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