Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-03-25
2001-02-13
Jordan, Kimberly (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S824000
Reexamination Certificate
active
06187820
ABSTRACT:
This invention relates to a method of improving lipid levels in the human body.
Complications of atherosclerosis, such as myocardial infarction, stroke and peripheral vascular disease are a major cause of mortality and morbidity. In addition, the quality of life of millions of people is adversely affected by angina and heart failure caused by coronary heart disease. Hyperlipidaemia has been associated with an increased risk of developing these conditions. For this reason it is desirable to understand the etiology of hyperlipidaemia and to develop effective treatments for this condition. Hyperlipidaemia has been defined as plasma cholesterol and triglyceride levels that exceed “normal” (95th percentile of levels of the general population) levels. However, the ideal cholesterol level is much less than the normal level of the general population. Many people have cholesterol levels above the ideal (hypercholesterolaemia) and are therefore at an elevated risk of coronary artery disease (CAD). It is known that reducing the cholesterol level in such people is very effective in reducing the risk of CAD. Hypertriglyceridaemia may also be involved in atherosclerosis and can, in extreme cases, cause potentially life-threatening pancreatitis.
There are several ways in which treatment of people with high lipid levels can be beneficial. These include lowering the total cholesterol level, lowering the total triglyceride level and increasing the ratio of high density lipoprotein (HDL) cholesterol to low density lipoprotein (LDL) cholesterol. This latter improvement is important because there is evidence that LDL is proatherogenic and HDL is antiatherogenic so that increasing HDL: LDL ratio provides a degree of protection from atherosclerosis and CAD.
Hyperlipidaemia can arise through a genetic disorder, as a result of other medical conditions or environmental influences, or a combination of these factors. Surprisingly, it has now been found that the administration of certain arylcyclobutylalkylamine compounds is effective in reducing lipid levels, particularly cholesterol and triglyceride levels.
Accordingly, the present invention provides a method for the prophylaxis and/or treatment of hyperlipidaemia, hypercholesterolaemia or hypertriglyceridaemia, comprising the administration, to a human in need thereof, 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, in conjunction with a pharmaceutically acceptable diluent or carrier.
The method may also be used for the prophylaxis of atherosclerosis, coronary heart disease and/or coronary artery disease in humans at increased risk of developing these conditions.
The preparation and use of compounds of formula
1
, such as N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (or 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,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof in the treatment of Parkinson's disease is described in European Patent Number 282206. The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof in the treatment of cerebral function disorders is described in U.S. Pat. No. 4,939,175. The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride in the treatment of obesity is described in European Patent Number 397831. A particularly preferred form of this compound is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate (sibutramine hydrochloride monohydrate) which is described in European Patent Number 230742. The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine 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 WO95120949.
It may be appreciated by those skilled in the art that compounds of formula I may exist as salts with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [eg (+)-tartrates, (−)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. Compounds of formula I and their salts may exist in the form of solvates (for example hydrates).
It will be appreciated by those skilled in the art that compounds of formula I contain a chiral centre. When a compound of formula I contains a single chiral centre 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.
Specific compounds of formula I are N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine, N-(1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl)-N-methylamine, and 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine including racemates, individual enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof. A preferred compound of formula I is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine or a salt thereof, for example the hydrochloride salt. A preferred form of this hydrochloride is its monohydrate.
The compound of formula I may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 50 mg preferably 1 to 30 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmacists art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may, if desired, be coated u
Jones Stephen Paul
Kelly Peter Finian
Jordan Kimberly
Keil & Weinkauf
Knoll Aktiengesellschaft
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