Triazolones as apolipoprotein-B synthesis inhibitors

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

1999-02-17

2001-03-06

Morris, Patricia L. (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06197972

ABSTRACT:

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 gastro-intestinal 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-phenylpiperazin1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and -1H-1,2,4-triazoles having antifungal properties. EP-0,228,125-A, published on Jul. 8, 1987, discloses [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]-methyl]-1H-imidazoles and 1H-1,2,4-triazoles having favourable anti-microbial properties. EP-0,283,992-A, published on Sep. 28, 1988, discloses 4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]-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
wherein
R
1
is C
1-10
alkyl, C
3-7
cycloalkyl or C
1-6
alkyl substituted with C
3-7
cycloalkyl;
R
2
is hydrogen or C
1-6
alkyl;
Alk represents C
1-3
alkanediyl;
—A— represents a bivalent radical of formula
—CH═CH—N═CH— (a),
—N═CH—N═CH— (b),
—CH═N—N═CH— (c),
—CH═CH—CH═N— (d);
in said bivalent radicals a hydrogen atom may be replaced by C
1-6
alkyl; and Ar is unsubstituted phenyl; phenyl substituted with up to two substituents selected from halo, C
1-6
alkyl or C
1-6
alkyloxy; unsubstituted naphthyl; or naphthyl substituted with up to two substituents selected from halo, C
1-6
alkyl or C
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
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
1-10
alkyl defines C
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
3-7
cycloalkyl defines saturated cyclic hydrocarbon radicals having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; C
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 like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methane-sulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like. Conversely the salt form can be converted by treatment with alkali into the free base form.
The term “stereochemically isomeric forms” as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic saturated radicals may have either the cis- or trans-configuration. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
A group of interesting compounds are those compounds of formula (I) wherein R
1
is C
1-10
alkyl.
A further group of interesting compounds are those compounds of formula (I) wherein R
2
is hydrogen or methyl.
Another group of interesting compounds are those compounds of formula (I) wherein Ar is unsubstituted naphthyl or phenyl substituted with one or two halogen atoms, preferably with chloro or fluoro.
More interesting compounds are those interesting compounds wherein R
1
is methyl, ethyl, propyl or butyl, preferably 2-propyl or 2-butyl.
Another group of more interesting compounds are those interesting compounds wherein Ar is naphthyl, 4-chlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl or 2,4-dichlorophenyl.
Preferred compound is cis-2-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-4-(1-methylpropyl)-3H-1,2,4-triazol-3-one or a stereochemically isomeric form thereof or a pharmaceutically acceptable acid addition salt thereof.
The compounds of formula (I) may be prepared by O-alkylating a phenol of formula (II), wherein R
1
and R
2
are as defined under formula (I), with a 1,3-dioxolane derivative of formula (III), wherein A, Alk and Ar are defined as under formula (I) and W represents an appropriate leaving group such as halo, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. 4-methylbenzenesulfonyloxy (tosylate) or methanesulfonyloxy (mesylate).
Said O-alkylation reaction can conveniently be conducted following art-known procedures, e.g. by stirring and heating the reactants in an appropriate solvent such as a dipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, in the presence of a base such as, an alkali metal hydroxide or carbonate, e.g. sodium or potassium hydroxide, or sodium or potassium carbonate.
Another manner of preparing the compounds of formula (I) is by N-alkylating an intermediate of formula (IV), wherein A, Alk, Ar and R
2
are as defined u

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