Chromene derivatives, their production and use

Details Chromene derivatives, their production and use Chromene derivatives, their production and use

1991-04-02

1994-01-11

Cintins, Marianne M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549399, A61F 31355, C07D31112

Patent

active

052781860

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to novel chromene derivatives, their production and use. The compounds of this invention possess excellent inhibitory action against acyl-CoA: cholesterol acyltransferase (ACAT). Especially, the compounds of this invention inhibit the absorption of cholesterol through the intestinal tract of a mammal and also restrain the accumulation of cholesterol ester at the arterial wall, and accordingly are useful as a drug for preventing and treating hypercholesterolemia, atherosclerosis and various diseases caused thereby (e.g., ischemic cardiac diseases such as myocardial infarction, cerebrovascular disturbance such as cerebral infarction, cerebral apoplexy, etc.).
2. Description of the Prior Art
Japanese Examined Patent Application No. 63(1988)-502348 mentions specifically 4-(3-methoxyphenyl)-3-methylaminochromene. However, compounds in which a urea or an acylamino group is substituted are not prepared in the above Japanese application.


SUMMARY OF THE INVENTION

The inventors of this invention have made various studies on chromene derivatives, and found that new compounds unexpectedly possess potent ACAT inhibitory activity and are useful as a drug for atherosclerosis.
Thus, this invention relates to
(1) a chromene derivative of the formula (I): ##STR2## wherein each ring of A and B can have one or more substituents; X is an oxygen atom or sulfur atom, Y is an oxygen or sulfur atom or H.sub.2, Z is a bond, --NH-- or a saturated or unsaturated lower alkylene group and R is a hydrocarbon radical which is unsubstituted or substituted, or its salt; and
(2) an ACAT inhibitory composition comprising a chromene derivative of the formula (I), or its salt.


THE PREFERRED EMBODIMENT OF THE INVENTION

Each of the ring A and B in the formula (I) can have one or more substituents. Examples of the substituents are a halogen atom, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, an optionally halogenated lower alkylthio group, nitro group, an optionally esterified carboxy group, a C.sub.1-3 acyloxy (e.g., formyloxy, acetoxy, propionyloxy, etc.), hydroxyl group and a C.sub.1-3 acyl group (e.g., formyl, acetyl, propionyl, etc.). The halogen atom as the substituent may be fluorine, chlorine, bromine or iodine atom.
The optionally halogenated lower alkyl groups can be straight or branched chain lower alkyl groups of 1-6 carbon atoms and these lower alkyl groups may be substituted with two to five halogen atoms, such as methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,6,6-trifluorohexyl or 5-trifluoromethylpentyl.
The optionally halogenated lower alkoxy groups and the optionally halogenated lower alkylthio groups can be those formed by the combination of the above mentioned lower alkyl groups or halogenated lower alkyl groups and an oxygen or sulfur atom.
The optionally esterified carboxyl groups may be a carboxyl group and carboxy groups esterified by an alkyl of 1-6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.
The substituent(s) on the rings A and B can be at any position of each ring, and these substituents may be the same or different, and the number of the substituent(s) may be 1 to 4. The suitable position(s) of the substituent(s) are 6-, 7- and/or 8- positions of the chromene nucleus for the ring A, and 2- position for the ring B.
Preferable examples for the ring A are a mono-substituted ring having a substituent of a halogen atom such as fluorine or chlorine atom, a C.sub.1-4 alkyl group such as methyl, ethyl, propyl or isopropyl at its 6-position, or 6,7-dimethyl, 6,7-difluoro, 6,8-difluoro, 6,7-dichloro, 6,8-dichloro, 6-methyl-7-chloro, 6-chlor

REFERENCES:
patent: 4387105 (1983-06-01), DeVries et al.
patent: 4585786 (1986-04-01), Berthelon
J. Med. Chem., 1986, vol. 29, pp. 1131-1133.

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