Triazolones as apolipoprotein-B synthesis inhibitors

Details Triazolones as apolipoprotein-B synthesis inhibitors Triazolones as apolipoprotein-B synthesis inhibitors

1997-10-07

1999-07-13

Morris, Patricia L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544366, A61K 31495, C07D40314

Patent

active

059227184

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns novel compounds of formula (I), pharmaceutical compositions comprising said compounds, the preparation thereof as well as the use as a medicine in the treatment of hyperlipidemia.
The causal relationship between hypercholesterolemia, particularly that associated with increased plasma concentrations of low density lipoproteins (LDL) and very low density lipoprotein (VLDL) remnants, and premature atherosclerosis has gained widespread acceptance over the last few years. The consensus that treatment of hypercholesterolemia has therapeutic benefit has become widely accepted by both physicians and the public. A limited number of drugs are available for the treatment of hyperlipidemia. The primary agents used for the management of hyperlipidemia included bile acid sequestrants, fibrates, nicotinic acid and HMG Co A-reductase inhibitors. The inconvenience of administration and gastrointestinal side-effects of available bile acid sequestrants make compliance a major problem. The fibrates have only limited usefulness in the treatment of certain types of hypercholesterolemia. Treatment with nicotinic acid encompasses side-effects and toxicity problems. The HMG Co A-reductase inhibitors, presently forming a first line treatment of familiar hypercholesterolemia, are sometimes contraindicated because of the occurrence of myopathy and liver toxicity. Consequently, there still remains a need for new lipid lowering agents that act preferably via other mechanisms than the above mentioned drugs.
EP-0,006,711-A, published on Sep. 9, 1980, discloses heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazo les and -1H-1,2,4-triazoles having antifungal properties. EP-0,228,125-A, published on Jul. 8, 1987, discloses -imidazoles and 1H-1,2,4-triazoles having favourable anti-microbial properties. EP-0,283,992-A, published on Sep. 28, 1988, discloses -methoxy!phenyl!-1-piperazinyl!phenyl!triazolones as anti-microbial agents.
The presently claimed compounds differ therefrom by their structure (novel triazolone moiety) and by their pharmacological profile, in particular their apolipoprotein B synthesis inhibiting activity.
The present invention provides novel compounds of formula ##STR2## wherein R.sup.1 is C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl or C.sub.1-6 alkyl substituted with C.sub.3-7 cycloalkyl; alkyl; and Ar is unsubstituted phenyl; phenyl substituted with up to two substituents selected from halo, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy; unsubstituted naphthyl; or naphthyl substituted with up to two substituents selected from halo, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy; the stereochemically isomeric forms thereof, and the pharmaceutically acceptable acid addition salts thereof.
As used in the foregoing definitions the term halogen atom is generic to fluoro, chloro, bromo and iodo; C.sub.1-6 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 2-methylpropyl and the like; C.sub.1-10 alkyl defines C.sub.1-6 alkyl and the higher homologues thereof containing 7 up to 10 carbon atoms such as, for example, heptyl, octyl, nonyl or decyl, and the branched isomers thereof; C.sub.3-7 cycloalkyl defines saturated cyclic hydrocarbon radicals having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; C.sub.1-3 alkanediyl represents straight or branched chain bivalent alkane radicals such as, for example, methylene, ethylene or propylene.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the

REFERENCES:
patent: 4791111 (1988-12-01), Heeres et al.
patent: 4916134 (1990-04-01), Heeres et al.
patent: 5707977 (1998-01-01), Heeres et al.
Craw and Hammond, "Organic Chemistry", McGrawHill Book Co., NY (1964) 2nd ed., pp. 565-567.

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