Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-10
2002-09-03
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S597000, C546S306000, C564S049000, C564S050000
Reexamination Certificate
active
06444691
ABSTRACT:
TECHNICAL FIELD
The invention relates to compounds the principal characteristics of which include inhibition of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) enzyme activity, and to a method for the preparation of such compounds.
BACKGROUND ART
The acyl-coenzyme A: cholesterol O-acyltransferase (EC 2.3.1.26) (ACAT) enzyme is responsible for the catalysis of the intracellular esterification of cholesterol. ACAT is present in most tissues such as the intestine, liver, and arterial wall. The enzyme is assumed to be involved in numerous processes which underlie the development of atherosclerosis, absorption of dietary cholesterol, accumulation of cholesterol esters, hepatic secretion of cholesterol esters into the blood plasma in the form of VLDL cholesterol.
A number of substances of the urea type have been described to inhibit ACAT. We shall show several more, recent examples describing 1,3-disubstituted ureas as ACAT enzyme inhibitors. Patents EP 506532, FR 2674522, JP 93097802, U.S. Pat. No. 5,219,859 describe ureas containing indole derivatives in their molecules. A combination of aromatic and aliphatic moieties has been described in Patents EP 665216, JP 95258199. Introduction into the molecule of a 1,3-dioxolane ring has been reported in Bioorg. Med. Chem. Lett. 1995, 5(15): 1581.
Despite the fact, the some 1,3-disubstituted ureas of the similar structure have been described in U.S. Pat. No. 3,284,433 as anticoccidial agents and one compound of similar structure is mentioned in patent application EP 0709225 as color developing agent, 1,3-disubstituted ureas of the present invention have not been described in literature yet.
DISCLOSURE OF INVENTION
1,3-Disubstituted ureas of general formula I,
wherein R
1
is 2-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,6-di(methylethyl)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 1-adamantyl, and R
2
is nitro, and X═O,
wherein R
1
is 4-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,6-di(methylethyl)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 1-adamantyl, and R
2
is nitro, and X═S;
and for R
1
being 2,4-difluorophenyl, 2,3-dichlorophenyl, 2,6-dimethylphenyl, 2,6-di(methylethyl)-phenyl R
2
is amino, and X═O, S.
The method for the preparation of the above compounds according to this invention consists in reacting an isocyanate (as prepared in situ or as commercially available) with amine to give an urea the nitro group of which may subsequently be reduced to the amino group. Ureas prepared in this way show inhibitory effect on acyl-coenzyme A: cholesterol acyltransferase (ACAT).
REFERENCES:
patent: 3284433 (1966-11-01), Becker et al.
patent: 3933814 (1976-01-01), Haberkorn et al.
patent: 5008456 (1991-04-01), Murata et al.
patent: 5219859 (1993-06-01), Festal et al.
patent: 1802739 (1969-06-01), None
patent: 0709225 (1969-06-01), None
patent: 0 506 532 (1992-09-01), None
patent: 0 665 216 (1995-08-01), None
patent: 0 709 225 (1996-06-01), None
patent: 2 674 522 (1992-10-01), None
patent: 5-097802 (1993-04-01), None
patent: 7-258199 (1995-10-01), None
Fáberová Viera
Kakalík Ivan
Oremus Vladi{acute over (m)}ir
Schmidtová {haeck over (L)}udmila
Zemánek Marián
O'Sullivan Peter
Solvakofarma, a.s.
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