Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
1998-12-16
2002-06-11
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
Reexamination Certificate
active
06403641
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a method for treating obesity and to products and pharmaceutical compositions suitable for use in such a method. More particularly, the invention relates to a method for the treatment of obesity by the administration of sibutramine or a salt or a metabolite thereof and; orlistat and to products and compositions containing such compounds.
Sibutramine hydrochloride monohydrate and orlistat are both currently being developed for use in the treatment of obesity. The two compounds, however, achieve weight loss through entirely different mechanisms.
Sibutramine is a 5-hydroxytryptamine and noradrenaline reuptake inhibitor in vivo (Buckett, W. R., Thomas, P. C. & Luscombe, G. P. (1988). Prog. Neuro-Psychopharmacol. Biol. Psychiat. 12, 575-584 and Luscombe, G. P., Hopcroft, R. H., Thomas, P. C. & Buckett, W. R. (1989). Neuropharmacology, 28, 129-134.) Studies have shown that it reduces body weight by a dual mode of action; it decreases food intake by enhancing satiety (Fantino, M. & Souquet, A. -M. (1995). Int. J. Obesity, 19, 145; Halford, J. C. G., Heal, D. J. & Blundell, J. E. (1995). Brit. J. Pharmacol. 114, 387P; and Stricker-Krongrad, A., Souquet, A. -M. & Burlet, C. (1995). Int. J. Obesity, 19, 145.), and it increases energy expenditure by stimulating thermogenesis (Connoley, I. P., Heal, D. J. & Stock, M. J. (1995). Brit. J. Pharmacol. 114, 388P; and Connoley, I. P., Frost, I., Heal, D. J. & Stock, M. J. (1996). Brit. J. Pharmacol. 117, 170P).
Orlistat inhibits lipase enzymes which are responsible for breaking down ingested fat (Borgstrom, B. (1988). Biochem. Biophys. Acta. 962 (3), 308-316); as a consequence of this, unabsorbed fat is egested in the faeces,
It has been reported that orlistat should not be combined with appetite suppressants ( The New York Times May 15, 1997). Surprisingly, it has now been found that co-administration of sibutramine hydrochloride monohydrate and orlistat results in beneficial effects with respect to weight-loss.
Accordingly, the present invention provides a method for the treatment of obesity in a human in need of such treatment which comprises administration to the human of a therapeutically effective amount of a compound of formula I
including enantiomers and pharmaceutically acceptable salts thereof, in which R
1
and R
2
are independently H or methyl, and a therapeutically effective amount of a compound of formula II
wherein the compound of formula I and the compound of formula II are administered simultaneously, separately or sequentially.
The present invention may provide the following advantages. Firstly, the maximum weight loss achieved is greater than that achieved by the sole administration of either a compound of formula I or compound II. Secondly, a synergistic weight loss is achieved in which the weight loss obtained by the administration of a compound of formula I and the compound of formula II to a first test group is greater than the total weight loss achieved by administration of the compound of formula I to a second test group and the weight loss achieved by administration of compound II to a third test group. Thirdly, when weight loss has reached a plateau after administration of either a compound of formula I or the compound II, a further weight loss is achieved by administering the other compound. Fourthly, lower doses of the compound of formula I and the compound of formula II may be used in the present invention thus reducing the side-effects associated with administration of a higher dose of each compound.
A preferred compound of formula I is
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
,
N
-dimethylamine or a salt thereof, for example the hydrochloride salt, known as sibutramine hydrochloride. A preferred form of this hydrochloride is its monohydrate, known as sibutramine hydrochloride monohydrate.
The preparation and use of compounds of formula I, such as
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
,
N
-dimethylamine and salts thereof, in the treatment of depression is described in British Patent Specification 2098602. The use of compounds of formula I such as
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
,
N
-dimethylamine and salts thereof in the treatment of Parkinson's disease is described in published PCT application WO 88/06444. The use of
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
,
N
-dimethylamine and salts thereof in the treatment of cerebral function disorders is described in U.S. Pat. No. 4,939,175. The use of
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
,
N
-dimethylamine hydrochloride in the treatment of obesity is described in European Patent Number 397831. A particularly preferred form of this compound is
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
,
N
-dimethylamine hydrochloride monohydrate (sibutramine hydrochloride monohydrate) which is described in European Patent Number 230742. The use of
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
,
N
-dimethylamine and salts thereof for improving the glucose tolerance of humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus is described in published PCT application WO95/20949.
The compound of formula II has the chemical name (2S, 3S, 5S)-5-[(S)-2-formamido-4-methylvaleryloxy]-2-hexyl-3-hydroxyhexadecanoic acid lactone. It is also known as “N-formyl-L-leucine, ester with (3S, 4S)-3-hexyl4-[(2S)-2-hydroxy-tridecyl]-2-oxetanone”, (−)-tetrahydrolipstatin, tetrahydrolipistatin, and orlistat.
The extraction and use of orlistat in the control or prevention of obesity and hyperlipaemia is described in U.S. Pat. No. 4598089 (Hoffmann-La Roche Inc.). A process for the preparation of orlistat is described in U.S. Pat. No. 4983746 (Hoffmann-La Roche Inc.). A composition comprising orlistat and acarbose is described in EP638317 (Hoffmann-La Roche AGF).
It will be appreciated by those skilled in the art that compounds of formula I contain a chiral center. When a compound of formula I contains a single chiral center it may exist in two enantiomeric forms. The present invention includes the use of the individual enantiomers and mixtures of the enantiomers. The enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. Enantiomers of secondary and tertiary amines of formula I can also be prepared by preparing the primary amine racemate, resolving this mixture into its individual enantiomers and then converting the relevant optically pure primary amine enantiomer into the desired secondary or tertiary amine product.
Preferred compounds of formula I are
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
,
N
-dimethylamine,
N
-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-
N
-methylamine, and N-1-[1-(4-chlorophenyl)cyclobut
Heal David John
Jackson Helen Christine
Abbott Labortories
Jones Dwayne C.
Keil & Weinkauf
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