Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-04-11
2000-12-26
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514312, 546152, 546153, 546180, A61K 3147, A61P 114, A61P 1106, A61P 1706
Patent
active
061660310
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to substituted tetralins, chromans and related compounds of the formula (I), depicted below, which by inhibiting 5-lipoxygenase enzyme and/or blocking leukotriene receptors, are useful in the prevention or treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related disease states in mammals. The present invention is also directed to pharmaceutical compositions, a method of treatment and to intermediates useful in the synthesis of said compounds of the formula (I).
Kreft et al., in U.S. Pat. No. 4,661,596, describe compounds which are disubstituted naphthalenes, dihydronaphthalenes or tetralins having the formula ##STR1## wherein the dotted lines represent optional double bonds, R.sup.a is 2-pyridyl, 2-quinolyl, 2-pyrazinyl, 2-quinoxalinyl, 2-thiazolyl, 2-benzothiazolyl, 2-oxazolyl, 2-benzoxazolyl, 1-alkyl-2-imidazolyl or 1-alkyl-2-benzimidazolyl and R.sup.b is hydroxy, lower alkoxy, lower alkyl or perfluoro alkyl. Like the compounds of the present invention, these compounds inhibit lipoxygenase enzyme and antagonize the effects of leukotriene D4, and so are useful in the prevention and treatment of asthma.
The chemical nomenclature employed herein generally follows that of "I.U.P.A.C. Nomenclature of Organic Chemistry, 1979 Edition," Pergammon Press, New York, 1979.
SUMMARY OF THE INVENTION
The present invention is directed to racemic or optically active compounds having the structural formula ##STR2## wherein n is 0 or 1; Y.sup.1 are taken separately, Y is hydrogen and Y.sup.1 is hydroxy or an acyloxy group which is hydrolyzed to form a hydroxy group under physiological conditions; ; or 4-pyridazinyl, 3- or 4-cinnolinyl, 1-phthalazinyl, 2- or 4-pyrimidinyl, 2- or 4-quinazolinyl, 2-pyrazinyl, 2-quinoxalinyl, 1-, 2- or 3-indolizinyl, 2-, 4- or 5-oxazolyl, 2-benzoxazolyl, 3-, 4- or 5-isoxazolyl, 5-benzo[c]isoxazolyl, 3-benzo[d]isoxazolyl, 2-, 4- or 5-thiazolyl, 2-benzothiazolyl, 3-, 4- or 5-isothiazolyl, 5-benzo[c]isothiazolyl, 3-benzo[d]isothiazolyl, 1-[(C.sub.1 -C.sub.4)alkyl]-2-, 4- or 5-imidazolyl, 1-[(C.sub.1 -C.sub.4)alkyl]-2-benzimidazolyl, 1-[(C.sub.1 -C.sub.4)alkyl]-3-, 4- or 5-pyrazolyl, 2-[(C.sub.1 -C.sub.4)alkyl]-3(2H)-indazolyl, or 1-[(C.sub.1 -C.sub.4)alkyl]-3(1H)-indazolyl; or one of said groups mono- or disubstituted on carbon with the same or different substituents which are bromo, chloro, fluoro, (C.sub.1 -C.sub.4)alkyl, trifluoromethyl, hydroxy, hydroxymethyl or (C.sub.1 -C.sub.4)alkoxy, or substituted on adjacent carbons with trimethylene, tetramethylene, --CH.sub.2 --O--CH.sub.2 -- or --O--CH.sub.2 --O--; and
R.sup.1 is (C.sub.1 -C.sub.8)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.7 -C.sub.10)bicycloalkyl, (C.sub.4 -C.sub.10)cycloalkylalkyl, (C.sub.8 -C.sub.11)bicycloalkylalkyl, or one of said groups mono- or disubstituted with the same or different groups which are fluoro, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, carboxy, [(C.sub.1 -C.sub.4)alkoxy]carbonyl, or (C.sub.2 -C.sub.5)alkanoyl; carboxy group.
Because of their ease of preparation and valuable biological activity, the preferred compounds of the formula (I), regardless of the value of Y and Y.sup.1, have n as 1, Z as CH.sub.2, Z.sup.1 as CH, X and X.sup.1 each independently as CH.sub.2 or O. More preferred compounds further have R as 2-pyridyl or 2-quinolyl and R.sup.1 as (C.sub.2 -C.sub.8)alkyl or (C.sub.3 -C.sub.8)cycloalkyl. Most preferred are racemic or optically active compounds having the relative stereochemical formula ##STR3## most particularly those racemic or optically active compounds of the formula (II) or (III) wherein X and X.sup.1 are each O, R is 2-quinolyl, and R.sup.1 is isopropyl or cyclohexyl; or X and X.sup.1 are each CH.sub.2, R is 2-pyridyl or 2-quinolyl and R.sup.1 is n-propyl, as well as the pair of optically active enantiomeric compounds of the formula (III) wherein X and X.sup.1 are each CH.sub.2, R is 2-quinolyl and R.sup.1 is n-propyl.
Said pharmaceutically-acceptable acid addition salts include, but a
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Eggler James F.
Marfat Anthony
Melvin, Jr. Lawrence S.
Ginsburg Paul H.
Jacobs Seth H.
McKane Joseph K.
Oswecki Jane C.
Pfizer Inc
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