Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-09-30
1993-09-28
Springer, David B.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546175, 546174, 514314, C07D40112, C07D21504, A61K 3147, A61K 3144
Patent
active
052486850
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to substituted 1-[3-heteroarylmethoxy)phenyl]alkanols 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, stroke and related disease states in mammals. The present invention is also directed to pharmaceutical compositions, and to a method of treatment.
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 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 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.
Eggler et al., in copending International application PCT/US87/02745 filed Oct. 19, 1987, have described similarly active compounds, including chromans of the formula ##STR2## wherein R.sup.x is substantially defined as above, R.sup.z is aryl or heteroaryl, X.sup.a is, for example, oxygen or CH.sub.2, and X.sup.b is C=O or CHOH.
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 compounds having the structural formula ##STR3## wherein
X is CH.sub.2 or O;
Y is hydroxy or an acyloxy group which is hydrolyzed to form a hydroxy group under physiological conditions;
R is attached by means of aromatic or heteroaromatic carbon and is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, naphthyridinyl, pyrrolyl, N-[(C.sub.1 -C.sub.4)alkyl]pyrrolyl, indolyl, N-[(C.sub.1 -C.sub.4)alkyl]-indolyl, isoindolyl, N-[(C.sub.1 -C.sub.4)alkyl]isoindolyl, indolizinyl, pyrazolyl, 1-[(C.sub.1 -C.sub.4)alkyl]pyrazolyl, indazolyl, 1-[(C.sub.1 -C.sub.4)alkyl]-1H-indazolyl, 2-[(C.sub.1 -C.sub.4)-alkyl]-2H-indazolyl, imidazolyl, 1-[(C.sub.1 -C.sub.4)alkyl]imidazolyl, benzimidazolyl, 1-[(C.sub.1 -C.sub.4)alkyl]benzimidazolyl, furyl, benzofuranyl, isobenzofuranyl, oxazolyl, benzoxazolyl, isoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl, thienyl, benzothiophenyl, isobenzothienyl, thiazolyl, benzothiazolyl, isothiazolyl, benzo[c]isothiazolyl, or benzo[d]isothiazolyl; or one of said groups which is mono- or disubstituted on carbon with the same or different groups which are bromo, chloro, fluoro, hydroxy, hydroxymethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, carboxy, [(C.sub.1 -C.sub.4)alkoxy]carbonyl, or substituted on adjacent carbons with trimethylene, tetramethylene, --CH.sub.2 --O--CH.sub.2 -- or -- O--CH.sub.2 --O--; or substituted on tertiary nitrogen to form an N-oxide; and
R.sup.1 is 2-, 3- or 4-pyridyl, 2-, 3-, 4 or 8-quinolyl, 1-, 3- or 4-isoquinolyl, 3- 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 14 C.
REFERENCES:
patent: 4567184 (1986-01-01), Musser et al.
patent: 4625034 (1986-11-01), Neiss et al.
patent: 4661499 (1987-04-01), Young et al.
patent: 4661596 (1987-04-01), Kreft, III et al.
patent: 4826987 (1989-05-01), Nielsen et al.
Eggler James F.
Marfat Anthony
Masamune Hiroko
Melvin, Jr. Lawrence S.
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
Springer David B.
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