Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-02-05
1999-09-28
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514326, 514340, 514341, 514365, 546199, 5462697, 5462734, 548181, 548201, A61K 31425, A61K 31445, A61K 3144
Patent
active
059589507
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel compounds and medical methods of treatment of inflammation, atherosclerosis and restenosis. More particularly, the present invention concerns the use of novel benzimidazole derivatives.
BACKGROUND OF THE INVENTION
Lipoxygenases are nonheme iron-containing enzymes that catalyze the oxygenation of certain polyunsaturated fatty acids such as lipoproteins. Several different lipoxygenase enzymes are known, each having a characteristic oxidation action. One specific lipoxygenase, namely 15-LO, has been detected in atherosclerotic lesions in mammals, specifically rabbit and man. The enzyme, in addition to its role in oxidative modification of lipoproteins, is important in the inflammatory reaction in the atherosclerotic lesion. Indeed, 15-LO has been shown to be induced in human monocytes by the cytokine IL-4, which is known to be implicated in the inflammatory process.
We have now found that inhibitors of 15-LO are especially useful to prevent and treat inflammation and atherosclerosis. While there are several lipoxygenase enzymes, specific inhibition of 15-LO is important in the inflammatory and atherosclerosis process. All that is required according to this invention is to administer a 15-LO inhibitor, and especially one that is a specific 15-LO inhibitor.
SUMMARY OF THE INVENTION
Accordingly, a first embodiment of the present invention provides a method of treatment of chronic or acute inflammatory disease, atherosclerosis and restenosis in mammals in need thereof comprising administering to such mammal an effective amount of a benzimidazole of Formula I or a pharmaceutically acceptable salt thereof:
FORMULA I
##STR2## where W, X, Y and Z can be independently C-R.sub.2, C--R.sub.3, C--R.sub.4, C--R.sub.5, or N; S which is substituted by 6 to 12 atoms, either with up to 3 substitutents as R.sub.2, mono or polyaryl of from 6 to 10 carbon atoms with up to 3 substitutents as R.sub.2, mono or polyheterocyclic of from 5 to 10 atoms having at least one N, O or S atom and up to 3 substitutents as R.sub.2, substituted by R.sub.4 or R.sub.5 or an amino group; (1-12 carbon atoms) or unsaturated (2-12 carbon atoms) hydrocarbon with terminal functionality of --NR.sub.9 R.sub.10 or nitrogen heterocycle of from 5 to 7 atoms or piperidine with nitrogen or oxygen in position 4 on the ring; or benzyl; or
A still further and second embodiment of the present invention is a method of treatment of atherosclerosis in mammals in need thereof comprising administering to such mammal an effective amount of a compound selected from the group consisting of: a compound of formula I in combination with one or more agents selected from the group consisting of:
(a) ACAT inhibitor;
(b) HMG-COA reductase inhibitor;
(c) Lipid regulator; and
(d) Bile acid sequestrant;
Also, the invention is directed to the novel compositions of Formula I.
Finally, the present invention is directed to a pharmaceutical composition for administering an effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above.
DETAILED DESCRIPTION OF THE INVENTION
In the compounds of Formula I, the term "lower alkyl" means a straight or branched hydrocarbon radical having from 1 to 4 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
The term "lower alkoxy" is O-alkyl as defined above for alkyl. "Halogen" is fluorine, chlorine, bromine, or iodine.
Heterocycle is defined as five or six-membered mono, bicyclic or fused ring structures which may contain one or more heteroatom such as N, O or S; examples of heterocycle are pyridine, thiophene, pyrimidine, pyridazine, pyrazole, thiazole, oxazole, indole, N-alkylindole, quinoline, quinazoline, quinazolinone, piperidine, morpholine, piperazine, pyrrolidine and the like. Substitutents can be hydrogen, alkyl of from 1-4 carbon atoms; cycloalkyl of from 5-7 carbon atoms, SR.sub.6, (CH.sub.2).sub.n --NR.sub.6 R.sub.7, CN, --COOR.sub.6, --(CH).sub.n OR.sub
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Padia Janak Khimchand
Roth Bruce David
Trivedi Bharat Kalidas
Anderson Elizabeth M.
Higel Floyd D.
Warner-Lambert & Company
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