SK13362001A3 - Use of a compound and pharmaceutical composition comprising such a compound - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof in which R1 and R2 are independently H or methyl (for example <u>N</u>,<u>N</u>-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl amine hydrochloride optionally in the form of its monohydrate) is used for aiding weight loss after pregnancy.

Description

Technical field

The present invention relates to the use of a compound for promoting weight loss after pregnancy and a pharmaceutical composition comprising it

BACKGROUND OF THE INVENTION

Preparation and use of compounds of formula I such as 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 and their salts in the treatment of depression is described in GB patent 2098602 and in US patent 4522328. The use of compounds of formula I such as N, N-dimethyl dimethyl -1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and its salts in the treatment of Parkinson's disease is described in published PCT application WO 88/06444. The use of N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and its salts in the treatment of disorders of the brain function is described in US patent 4939175. The use of N, N-dimethyl-1- [1- (4-Chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride in the treatment of obesity is described in published PCT application WO 90/061 10. A particularly preferred form of this compound is N, N-dimethyl-1- [1- (4-chlorophenyl) (cyclobutyl) -3-methylbutylamine hydrochloride monohydrate (sibutramine hydrochloride), which is described in European patent no. 230742. The use of N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and its salts for improving glucose tolerance in humans with non-insulin-dependent glucose tolerance or diabetes mellitus is described in published PCT application WO 95/20949.

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SUMMARY OF THE INVENTION

The present invention provides a method of promoting weight loss after pregnancy, wherein a human in need of such support is administered a therapeutically effective amount of a compound of Formula I

including enantiomers and pharmaceutically acceptable salts thereof, wherein R and R ₂ are independently H or methyl, in conjunction with a pharmaceutically acceptable diluent or carrier.

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 the hydrochloride is its monohydrate.

It will be clear to those skilled in the art that the 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 individual enantiomers and mixtures of enantiomers. Enantiomers may be resolved by methods known in the art, such as formation of diastereomeric salts or complexes, which may be separated, for example, by crystallization; formation of diastereomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed separáp f · t NR E R rr _R RF · C rcnrr. Xrrrrrrr hr, X c or modified or unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral medium, for example on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that when the desired enantiomer is converted to another chemical entity by one of the separation procedures described above, it is another necessary step in the release of the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active agents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

Preferred compounds of formula I are

Ν, Ν-dimethyl-l- [l- (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.

The individual enantiomers may be prepared by enantioselective synthesis from optically active precursors, or by resolution of a racemic compound, which may be prepared as described above. Enantiomers of secondary amines of formula I may also be prepared by preparing the racemate of the corresponding primary amine, resolving the racemate into the individual enantiomers, and then converting the optically pure enantiomer of the primary amine to the desired secondary amine by the method described in GB patent 2098602.

Specific examples of compounds of formula I are:

(+) - N- {1- [1- (4-Chloro-phenyl) -cyclobutyl] -3-methyl-butyl} -N-methylamine;

(-) - N- {1- [1- (4-Chloro-phenyl) -cyclobutyl] -3-methyl-butyl} -N-methylamine;

(+) - 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine;

(-) - l- [l- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine;

• · · ·-p r r r r r <c c r r

C Γ or r r ' . · R

r. c r i ,, r <

^R '• (+) - N- {1- [1- (4-Chloro-phenyl) -cyclobutyl] -3-methyl-butyl} -N, N-dimethylamine;

(-) - N- {1- [1- (4-Chloro-phenyl) -cyclobutyl] -3-methyl-butyl} -N, N-dimethylamine.

The hydrochloride salts are preferred in each case, but the free bases and other pharmaceutically acceptable salts are also suitable.

The compounds of formula I may be administered in any known pharmaceutical dosage form. The dose of the compound administered depends on many factors, including the age of the patient, the severity of the disease and the patient's personal history, and although it always depends on the judgment of the physician, it should range from 0.1 to 50 mg, preferably 1 to 30 mg per day. single dose or divided into multiple doses.

Oral dosage forms are preferred compositions for use in the present invention, and known pharmaceutical forms for this mode of administration include, for example, tablets, capsules, granules, syrups and aqueous or oily suspensions. The ingredients used in the preparation of these compositions are those known in the pharmaceutical art. Tablets may be prepared from a mixture of the active compound with fillers such as calcium phosphate; disintegrants, such as corn starch; glidants such as magnesium stearate; binders, such as microcrystalline cellulose or polyvinylpyrrolidone, and other optional agents known in the art to allow tabletting of the mixture using known methods. The tablets may, if desired, be coated by known methods and using known ingredients including an enteric coating using, for example, hydroxypropylmethylcellulose phthalate. Tablets may be prepared by methods known in the art to provide sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with an enteric coating using known methods, for example using cellulose acetate phthalate. Similarly, capsules, for example solid or soft gelatin capsules, containing the active ingredient with or without further additives, can be prepared by known methods and, if desired, the capsules can be provided with enteric coatings using known methods. The contents of the capsules can be prepared by known methods so as to achieve a delayed release of the active compound. Tablets and capsules each preferably contain 1 to 50 mg of the active compound.

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Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium together with a non-toxic suspending agent, such as sodium carboxymethylcellulose, and oily suspensions containing the compound of the present invention in a suitable vegetable oil, such as peanut oil. The active compound may be prepared in the form of granules with or without further additives. The granules may be ingested directly by the patient, or may be added to a suitable liquid carrier (for example, water) prior to ingestion. The granules may contain disintegrants, such as an effervescent vapor formed by an acid and a carbonate or bicarbonate salt, to facilitate dispersion in the liquid medium.

The therapeutically active compounds of formula I may be formulated in a composition which the patient retains in the mouth such that the active compound is administered through the mucosa of the oral cavity.

Dosage forms for rectal administration are known pharmaceutical forms for such a route of administration, such as cocoa butter laces or polyethylene glycol bases.

Dosage forms for parenteral administration are known pharmaceutical forms for such administration, such as sterile suspensions or sterile solutions in a suitable solvent.

Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed such that the compounds are kept in contact with the skin and are administered transdermally. Suitable transdermal compositions can be prepared by mixing the pharmaceutically active compound with a topical vehicle such as inorganic oil, white petrolatum and / or wax, for example paraffin wax or beeswax, together with a transdermal penetration enhancing agent such as dimethylsulfoxide or propylene glycol. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in the topical formulation β e r r r * p p ere ere ere ere c c r r r r r,,,

6n y - - y. The therapeutic agent should be such that a therapeutically effective amount of the compound is delivered over the period of time for which the topical composition is to be applied to the skin.

The therapeutically active compound of Formula 1 may be prepared in a composition that is dispersed in the form of an aerosol into the oral or nasal cavity of a patient. Such aerosols may be delivered from a pump or pressurized container containing a volatile propellant.

The therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion, or from a source of the compound placed in the body. Internal sources include implantable containers containing the compound to be applied that continuously release the compound, for example by osmosis, and implants that may be (a) liquid, such as an oil suspension of the compound to be applied, for example, as a very poorly derivative derivative. water soluble, such as a dodecanoate salt or lipophilic ester, or (b) in the form of an implanted carrier, such as a synthetic resin or a waxy material, for the compound to be applied. The carrier may be a single body containing all of the compound, or it may be a series of several bodies each containing a portion of the compound. The amount of active compound present in the internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.

In some compositions, it may be advantageous to use the compounds of the present invention in the form of very small particles, for example obtained by fluidized-bed milling.

In the compositions of the present invention, the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.

The invention further provides the use of compounds of formula I in the manufacture of a medicament for promoting weight loss after pregnancy.

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In another aspect, the invention further provides pharmaceutical compositions for promoting weight loss after pregnancy comprising a compound of Formula I together with a pharmaceutically acceptable diluent or carrier.

Pregnancy can lead to excessive weight gain and consequently maintain this weight gain., Some weight gain during pregnancy is desirable. However, the weight gain above the desired value is mainly due to the increase in adipose tissue. This adipose tissue contributes to a large extent to the postnatal retention of weight gained during pregnancy. This retention reflects the postpartum energy balance, which does not lead to catabolism of the obtained adipose tissue. Administration of a compound of formula I aids in altering this energy balance.

Monoamine reuptake inhibitors have been used to treat some of the diseases described in the present invention. However, it is known that these compounds have many disadvantages. First, these compounds are not effective in all patients. Second, if these compounds are effective they cannot lead to a complete cure of the disease. Thirdly, this type of compounds has many side effects. Such side effects include nausea, sexual dysfunction, lightheadedness, somnolence, sweating, shaking, dry mouth, asthenia, insomnia, exaggeration, headache, vomiting, anxiety, ignorance, dizziness, fever, rash or allergic reactions, arthralgia, myalgia, convulsions, hypomania and mania.

Sibutramine (Formula I, R = CH3, _R2 = CH3) has a pharmacological profile which is unique amongst monoamine reuptake inhibitors. Through its pharmacologically active metabolites, (metabolite 1, Ri = H, _R2 = CH3 in Formula I and metabolite 2, Ri = H, _R2 = H in Formula I) sibutramine inhibits the reuptake of all three monoamines differentiating it from serotonin inhibitors serotonin (5-HT) reuptake inhibitors such as fluoxetine, selective noradrenaline reuptake inhibitors such as desipramine, selective dopamine reuptake inhibitors such as bupropion, and serotonin-noradrenaline reuptake inhibitors (e.g. 1). This is a unique combination of pharmacological effects that causes sibutramine

And other compounds of formula I are effective in promoting weight loss after pregnancy.

DETAILED DESCRIPTION OF THE INVENTION

The tests described below were performed in a similar manner to those described in WO 98/41528.

Table: In vitro comparison of inhibitory profiles of monoamine uptake inhibitors according to Examples 1 and 2 and various reference monoamine uptake inhibitors in rat brain tissue

Ki (nM) Q [H] -noradrenaline [ ³ H] - 5-HT [ ³ H] -dopamine Example 1 3 18 24 Example 2 5 26 31 bupropion 2590 18312 409 desipramine 2 200 4853 fluoxetine 320 11 2025 venlafaxine 196 26 2594

Results are means from> 3 separate measurements.

Example 1: R 1 = H, R ₂ = CH 3 in Formula I;

Example 2: R 1 = H, R ₂ = H in Formula I.

The efficacy of the compounds of formula I in promoting weight loss after pregnancy has been demonstrated in clinical studies in the relevant population.

The invention has now been described in terms of various specific embodiments.

However, there are many variations and modifications that fall within the scope and scope of the present invention.

Claims (14)

PATENT CLAIMS (in response to the assessment on 10/01/2002) Use of a compound of formula I CH including its enantiomers and pharmaceutically acceptable salts thereof, wherein R 1 and R are independently H or methyl, for the manufacture of a medicament for promoting weight loss after pregnancy. Use according to claim 1, characterized in that the compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. Use according to claim 1, characterized in that the compound of formula I is j, Ν-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate. Use according to claim 1, characterized in that the compound of formula I is j (+) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine. Use according to claim 1, characterized in that the compound of formula I is (-) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine. Use according to claim 1, characterized in that the compound of formula I is (+) - 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine. Use according to claim 1, characterized in that the compound of formula I is (-) - 1- [1- (4-chlorophenyl) cyclic-1] -3-methylbutylamine. Use according to claim 1, characterized in that the compound of formula I is (+) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine. Use according to claim 1, characterized in that the compound of formula I is (-) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine. Use according to claim 1, characterized in that the compound of formula I is (±) -N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine. Use according to claim 1, characterized in that the compound of formula (I) is (±) -1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine. Use according to claim 1, characterized in that the compound of formula I is (±) -N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine. A pharmaceutical composition for use in promoting weight loss after pregnancy, comprising a therapeutically active amount of a compound of Formula I H ₃ CCHCH ₂ CHNR, Rj CI including enantiomers and pharmaceutically acceptable salts thereof, wherein R and R ₂ are independently H or methyl, in combination with a pharmaceutically acceptable diluent or carrier. Pharmaceutical composition according to claim 13, characterized in that the compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. The pharmaceutical composition of claim 13, wherein the compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate. , i