Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-06
2002-10-15
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S552000
Reexamination Certificate
active
06465451
ABSTRACT:
The present invention is concerned with new hypolipidemic compounds, with processes and novel intermediates for their preparation, with pharmaceutical compositions containing them and with their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions and associated conditions such as atherosclerosis.
Hyperlipidemic conditions are often associated with elevated plasma concentrations of low density lipoprotein (LDL) cholesterol. Such concentrations can be reduced by decreasing the absorption of bile acids from the intestine. One method by which this may be achieved is to inhibit the bile acid active uptake system in the terminal ileum. Such inhibition stimulates the conversion of cholesterol to bile acid by the liver and the resulting increase in demand for cholesterol produces a corresponding increase in the rate of clearance of LDL cholesterol from the blood plasma or serum.
The compounds of the present invention reduce the plasma or serum concentrations of LDL cholesterol and in consequence are particularly useful as hypolipidemic agents. By decreasing the concentrations of cholesterol and cholesterol ester in the plasma, the compounds of the present invention retard the build-up of atherosclerotic lesions and reduce the incidence of coronary heart disease-related events. The latter are defined as cardiac events associated with increased concentrations of cholesterol and cholesterol ester in the plasma or serum.
International Patent Application No. PCT/GB/9300328 describes 1,4-benzothiazepine compounds which have hypolipidemic activity. International Patent Application No. PCT/GB95/02700 (published as WO/9616051) describes 1,5-benzothiazepine compounds which also have hypolipidemic activity. A group of substituted 1,5-benzothiazepine compounds has been discovered which have surprising hypolipidemic activity over those specifically disclosed in the prior art.
Accordingly, the present invention provides a compound of formula (I)
wherein
R
1
is H or methyl; or a salt, solvate or physiologically functional derivative thereof.
Preferably R
1
is hydrogen.
Suitable compounds of formula (I) are selected from:
(±)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide;
(3S)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide; and
(±)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-1,5-benzothiazepine-1,1-dioxide; or a salt, solvate or physiologically functional derivative thereof.
Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, i.e., basic, compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulphuric acids, and organic acids, such as acetic, benzenesulphonic, benzoic, citric, ethanesulphonic, fumaric, gluconic, glycollic, isothionic, lactic, lactobionic, maleic, malic, methanesulphonic, succinic, p-toluenesulphonic, tartaric and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, and alkaline earth salts, such as magnesium and calcium salts.
Salts having a non-pharmaceutically acceptable anion are within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, applications.
Any references to “compound(s) of formula (I)”, “compounds of the present invention”, “compounds according to the invention” etc., refer to compound(s) of formula (I) as described above or their salts, solvates or physiologically functional derivatives as defined herein.
The term “physiologically functional derivative” as used herein refers to any physiologically acceptable derivative of a compound of the present invention, for example, an ester, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice.
Physiologically functional derivatives, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) a compound of the invention or an active metabolite thereof, are commonly referred to as prodrugs. These prodrugs may or may not be active in their own right. Suitably, prodrugs of the present invention are formed at position R
1
to give C
1-6
ester or C
1-6
alkoxy groups.
Active metabolites are those which may be generated in vivo by the metabolism of the compounds of the present invention and include, for example, glucuronides.
The compounds of the present invention can also exist in different polymorphic forms, for example, amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the invention and are a further aspect thereof.
The compounds of formula (I) are in forms wherein the carbon center —C(Et)(n-Bu)— is chiral. The present invention includes within its scope each possible optical isomer substantially free, i.e. as associated with less than 5%, of any other optical isomer(s), and mixtures of one or more optical isomers in any proportions, including racemic mixtures. The (S)-isomer is preferred.
According to further aspects of the invention, there are also provided:
(a) the compounds of formula (I) and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof for use as therapeutic agents, particularly in the prophylaxis and treatment of clinical conditions for which a bile acid uptake inhibitor is indicated, for example, a hyperlipidemic condition, and associated diseases such as atherosclerosis;
(b) pharmaceutical compositions comprising a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, or physiologically functional derivatives, at least one pharmaceutically acceptable carrier and, optionally, one or more other physiologically active agents;
(c) the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a bile acid uptake inhibitor is indicated, for example, a hyperlipidemic condition, and associated diseases such as atherosclerosis;
(d) a method of inhibiting the absorption of bile acids from the intestine of a mammal, such as a human, which comprises administering an effective bile acid absorption inhibiting amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the mammal;
(e) a method of reducing the blood plasma or serum concentrations of LDL cholesterol in a mammal, such as a human, which comprises administering an effective cholesterol reducing amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the mammal;
(f) a method of reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum of a mammal, such as a human, which comprises administering an effective cholesterol and cholesterol ester reducing amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the mammal;
(g) a method of increasing the fecal excretion of bile acids in a mammal, such a
Coleman Brenda
Morgan Lorie Ann
SmithKline Beecham Corporation
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