S-oxide lipid lowering compounds

Details S-oxide lipid lowering compounds S-oxide lipid lowering compounds

2001-06-08

2002-09-17

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S254070, C544S366000, C544S367000, C544S370000

Reexamination Certificate

active

06451802

ABSTRACT:

The present invention is concerned with novel S-oxide derivatives having apolipoprotein B inhibiting activity and concomitant lipid lowering activity. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds.
WO-96/13499, published on May 9, 1996, discloses structurally related heteroaryl substituted 1,3-dioxolan-4-yl-methoxyphenyl-1-piperazinyl-phenyl-2,4-dihydro-2-alkyl-3H-1,2,4-triazol-3-one derivatives having apolipoprotein B inhibiting activity and concomitant lipid lowering activity and their use in the treatment of patients suffering from hyperlipidemia. In particular, WO-96/13499 discloses (−)-[2S-[2&agr;,4&agr;(S*)]]-4-[4-[4-[4-[[-2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazol-3-yl)thio]methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one as compound 40. Said compound 40 of WO-96/13499 is referenced to in this application as “compound A”.
The compounds of the present invention differ from the cited art-known compounds structurally, by the presence of an oxidized sulfur moiety.
Unexpectedly, compared to the structurally closest art compound, i.e. compound A, the compounds of the present invention have more favourable pharmacokinetic properties: the mean plasma concentrations of the present compounds when administered chronically are more constant and also the present compounds at least partially avoid a “first-pass” effect.
Said compound A undergoes extensive metabolisation when it passes the liver resulting in plasma levels that are dependent upon the metabolism of each treated individual. The plasma levels of compund A differ inter-individually and therefore for each subject to be treated the exact dosage and frequency of administration has to be determined individually to compensate for said individual-dependent metabolism.
The compounds of the present invention at least partially avoid the first-pass effect thereby lowering the need to adjust the exact dosage and frequency of administration for each treated subject individually thus giving improved patient compliance.
The present invention concerns compounds of formula (I)
the N-oxides, the stereochemically isomeric forms thereof, and the pharmaceutically acceptable acid addition salts, wherein
n is 1 or 2;
R
1
is hydrogen, C
1-6
alkyl or halo;
R
2
is hydrogen or halo;
R
3
is C
1-8
alkyl or C
3-6
cycloalkyl;
Het is a radical of formula
 wherein
R
4
is hydrogen, C
1-4
alkyl, trifluoromethyl, amino or hydroxy;
R
5
is hydrogen or C
1-4
alkyl;
R
6
is hydrogen or C
1-4
alkyl; and
—A—B— is a bivalent radical of formula
—CH═CH—  (b-1)
—N═CH—  (b-2)
—CH═N—  (b-3)
wherein optionally one of the hydrogen atoms is replaced by C
1-4
alkyl.
As used in the foregoing definitions halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 2-methylpropyl and the like; C
1-6
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2-methyl-butyl, pentyl, hexyl and the like; C
1-8
alkyl defines C
1-6
alkyl and the higher homologues thereof containing 7 or 8 carbon atoms such as, for example, heptyl or octyl and the branched isomers thereof; C
3-6
cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
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 pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such 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 (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
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.
The N-oxide forms of the compounds of formula (I), which may be prepared in art-known manners, are meant to comprise those compounds of form nitrogen atom is oxidized to the N-oxide.
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 (partially) saturated radicals may have either the cis- or trans-configuration. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereoisomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. The same applies to the intermediates as described herein, used to prepare end products of formula (I).
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term ‘stereoisomerically pure’ being equivalent to ‘chirally pure’ concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms ‘enantiomerically pure’ and ‘diastereomerically pure’ should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.
The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and refer to the position of the substituents on a ring moiety, more in particular on the dioxolane ring in the compounds of formula (I). For instance, when establishing the cis or trans configuration of the dioxolane ring in a radical of formula (I), the substituent with the highest priority on the carbon atom in the 2 position of the dioxolane ring, and the substituent with the highest priority on the carbon atom in the 4 position of the dioxolane ring are considered (the priority of a substituent being determined according to the Cahn-Ingold-Prelog sequence rules). When said two substituents with highest priority are at the same side of the ring then the configuration is designated cis, if not, the configuration is designated trans.
All compounds of formula (I) have at least 2 stereogenic centers as indicated with an asterisk as indicated below. In the sulfoxides of formula (I-a) an additional stereogenic center is present, while the sulfones of formula (I-b) do not have said additional stereogenic

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