Compositions of lipid lowering agents

Details Compositions of lipid lowering agents Compositions of lipid lowering agents

2000-04-24

2002-01-29

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S464000, C424S463000, C424S489000, C424S494000, C424S493000, C424S496000, C424S497000, C424S465000, C424S474000, C424S470000, C514S252010, C548S127000, C548S129000, C548S182000, C548S213000, C548S225000, C548S228000, C548S229000, C548S263200, C548S144000, C548S251000, C548S255000, C548S311100

Reexamination Certificate

active

06342245

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
This application is the national stage of PCT/EP98/06998, filed Oct. 27, 1998, which application claims priority from EP 97203407.8, filed Nov. 3, 1997.
The present invention is concerned with novel pharmaceutical compositions of lipid lowering agents which can be administered to a mammal suffering from hyperlipidemia, obesitas or atherosclerosis whereby a single such dosage form can be administered once daily. These novel compositions comprise innovative particles obtainable by melt-extruding a mixture comprising a lipid lowering agent and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture.
The present invention provides particles of lipid lowering agents previously disclosed in WO-96/13499 that have the formula
the N-oxides, one or more stereochemically isomeric forms, and the pharmaceutically acceptable acid addition salts thereof, wherein A and B taken together form a bivalent radical of formula:
—N═CH—  (a),
—CH═N—  (b),
—CH
2
—CH
2
—  (c),
—CH═CH—  (d),
—C(═O)—CH
2
—  (e),
—CH
2
—C(═O)—  (f),
wherein in the bivalent radicals of formula (a) and (b) the hydrogen atom may be replaced by C
1-6
alkyl; and wherein in the bivalent radicals of formula (c), (d), (e), (f), one or two hydrogen atoms may be replaced by C
1-6
alkyl;
R
1
is hydrogen, C
1-6
alkyl or halo;
R
2
is hydrogen or halo;
R
3
is hydrogen; C
1-8
alkyl; C
3-6
cycloalkyl; or C
1-8
alkyl substituted with hydroxy, oxo, C
3-6
cycloalkyl or aryl;
Het is a heterocycle selected from the group consisting of pyridine; pyridine substituted with one or two substituents selected from C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, trihalomethyl, amino, mono- or di(C
1-6
alkyl)amino or aryl; pyrimidine; pyrimidine substituted with one or two substituents selected from C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, trihalomethyl, amino, mono- or di(C
1-6
alkyl)-amino or aryl; tetrazole; tetrazole substituted with C
1-6
alkyl or aryl; triazole; triazole substituted with one or two substituents selected from C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, trihalomethyl, amino, mono- or di(C
1-6
alkyl)-amino; thiadiazole; thiadiazole substituted with one or two substituents selected from C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, trihalomethyl, amino, mono- or di(C
1-6
alkyl)amino; oxadiazole substituted with one or two substituents selected from C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, trihalomethyl, amino, mono- or di(C
1-6
alkyl)amino; imidazole; imidazole substituted with one or two substituents selected from C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, trihalomethyl, amino, mono- or di(C
1-6
alkyl)amino; thiazole; thiazole substituted with one or two substituents selected from C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, trihalomethyl, amino, mono- or di(C
1-6
alkyl)amino; oxazole; oxazole substituted with one or two substituents selected from C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, trihalomethyl, amino, mono- or di(C
1-6
alkyl)amino; and aryl is phenyl or phenyl substituted with C
1-6
alkyl or halo.
The compounds of formula (I) and their salts have a very limited aqueous solubility and hardly dissolve when in crystalline form. In order to ensure that the compounds of formula (I) have sufficient bioavailability, they may be dissolved in water in the presence of solubilizing agent such as a cyclodextrin derivative e.g. 2-hydroxypropyl-beta-cyclodextrin. The present invention provides an alternative dosage form that does not require the use of a solubilizing agent and still has sufficient bioavailability.
In the compounds of formula (I) defined hereinbefore, the heterocyclic radical “Het” is bound to the sulfur atom via a carbon atom.
As used in the foregoing definitions halo 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, pentyl, hexyl, 1-methylethyl, 2-methylpropyl 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 defines saturated cyclic hydrocarbon radicals having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
Het may in particular be a radical of formula
wherein:
R
4
is hydrogen or C
1-6
alkyl;
R
5
and R
6
are hydrogen, C
1-6
alkyl or amino;
R
7
is hydrogen or C
1-6
alkyl;
each R
8
independently is hydrogen or C
1-6
alkyl;
each R
9
independently is hydrogen, C
1-6
alkyl, trifluoromethyl, amino or hydroxy;
R
12
is hydrogen or C
1-6
alkyl
R
10
and R
11
each independently are hydrogen or C
1-6
alkyl;
R
13
is hydrogen or C
1-6
alkyl;
R
14
is hydrogen, C
1-6
alkyl or hydroxy;
R
15
is hydrogen or C
1-6
alkyl.
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 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, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, 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 stereoisomeric forms in which the compounds of formula (I) may exist, thus, also including all enantiomers, enantiomeric mixtures and diastereomeric mixtures. 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. The same applies to the intermediates as described herein, used to prepare endproducts of formula (I).
Pure enantiomeric forms of the compounds of formula (I) are defined as enantiomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds.
Asymmetric centers have ether the R- or the S-configuration. 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). In the latter instance, when establishing the cis or trans configuration, 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.
The compounds of formula (I) wherein the stereogenic carbon atom in the 2-position of the dioxolane moiety has the S-configuration are particularly preferred.
The compounds of formula (I) may also exist in their tautomeric forms. For instance, heterocycles such as, for example, pyridine, pyrimidine, triazole, thiadiazole, oxadiazole, imidazole, thiazole and oxazole, which are substituted with hydroxy, amino or C
1-6
alkylamino may exist in their tautomeric form. Suc

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