SK13392001A3 - The us of a compound and pharmaceutical composition comprising same - 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 treating hiatial hernias and reflux esophagitis.

Description

The use of a compound and a pharmaceutical composition comprising it

Technical field

The present invention relates to the use of a compound for the treatment of hiatal hernia and reflux esophagitis.

BACKGROUND OF THE INVENTION

Preparation and use of compounds of formula I, such as Ν, Ν-dimethyl-1- [1- (4-chlorophenyl) cyclic-1] -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 US patent 4,522,328. Use of compounds of formula I such as N, N-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 is described in U.S. Patent 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 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. 230 742. The use of N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and its salts for improving glucose tolerance in people with non-insulin-dependent glucose tolerance or diabetes mellitus is described in published PCT WO 95/20949.

SUMMARY OF THE INVENTION

The present invention provides a method of treating hiatal hernia comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of Formula I

including its enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are independently H or methyl, together 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 apparent 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 diastereoisomeric salts or complexes, which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction, followed by separation of the modified or unmodified enantiomers; or by gas-liquid or liquid chromatography in a chiral medium, for example on a chiral carrier 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 the other 1 '>

As a chemical entity by one of the separation processes mentioned above, the next necessary step is to release 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 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.

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 British Patent 2,098,602.

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;

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

(-) - N- {1- [1- (4-Chlorophenyl) cyclobutyl] -3-methylbutyl} -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 always at the discretion of the physician, it should be in the range of 0.1 to 50 mg, preferably 1 to 30 mg per day. 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, hydroxypropyl methylcellulose 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 other ingredients, 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 preferably each contain 1 to 50 mg of the active compound.

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 other ingredients. 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, for example, suppositories with cocoa butter 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 composition should be such that a therapeutically effective amount of the compound is delivered over the period during which the topical composition is to be applied to the skin.

The therapeutically active compound of Formula I may be formulated into a composition that is dispersed in the form of an aerosol into the patient's oral or nasal cavity. Such aerosols may be delivered from a pump or from a 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 weak derivative. a water-soluble, such as a dodecanoate salt or a 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 to be administered. 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 be, if desired; 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 the treatment of hiatal hernia.

In another aspect, the invention further provides pharmaceutical compositions for treating hiatal hernia comprising a compound of Formula I together with a pharmaceutically acceptable diluent or carrier.

r r

- r e r r r 'f

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, tremor, dry mouth, asthenia, insomnia, diarrhea, headache, vomiting, anxiety, drowsiness, dizziness, fever, rash or allergic reactions, arthralgia, myalgia, convulsions, hypomania and mania.

Sibutramine (Formula I, ^R1 = CH3, ^R2 = CH3) has a pharmacological profile which is unique amongst monoamine reuptake inhibitors. Through its pharmacologically active metabolites, (metabolite 1, R = H, ^R2 = CH3 in Formula I and metabolite 2, R = H, R ² = H in Formula I) sibutramine inhibits the reuptake of all three monoamines differentiating it from selective serotonin (5-HT) reuptake inhibitors, such as fluoxetine, selective noradrenaline reuptake inhibitors, such as desipramine, selective dopamine reuptake inhibitors, such as bupropion, and serotonin reuptake inhibitors such as serotonin, venlafaxine (Table 1). This is a unique combination of pharmacological effects that causes sibutramine and other compounds of Formula I to be effective in the treatment of hiatal hernia and reflux esophagitis.

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) [ ³ H] -noradrenaline ^[3 H] 5-HT [H] -dopamín Example 1 3 18 24 Example 2 5 26 3 1 bupropion 2590 18312 409 desipramine 2 200 4853 fluoxetine 320 11 2025 venlafaxine 196 26 2594

Results are means from> 3 separate assays.

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

Example 2: ^R1 = H, ^R2 = H in Formula I

T

Efficacy of the compounds of formula I in the treatment of hiatal hernia in clinical studies in the relevant population. Improvement with weight loss.

is a demonstrable disease related

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 spirit of the present invention.

Claims (5)

PATENT CLAIMS Use of a compound of formula I H ² CCH ² CH ² CH ² R ² R ^2, including its enantiomers and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are independently H or methyl, for the manufacture of a medicament for the treatment of hiatal hernia or reflux esophagitis. The use according to claim 1, wherein the compound of formula I is (+) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine (-) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine (+) - 1- (1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine (-) - 1- [1] - (4-chlorophenyl) cyclobutyl] -3-methylbutylamine (+) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine (-) - N- {1 - [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine (±) -N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine (+) - 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine (±) -N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine. N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate. 3. A pharmaceutical composition for the treatment of hiatal hernia or reflux ezophagitis, comprising a therapeutically effective amount of a compound of formula I CH, H ₃ CCHCH _t CHNR ¹ R ² Including its enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R are independently H or methyl, together with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition according to claim 16 wherein the compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methyl butylamine hydrochloride. Pharmaceutical composition according to claim 16, characterized in that the compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methyl butylamine hydrochloride monohydrate.