CZ20013279A3 - Pharmaceutical composition - 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

Pharmaceutical composition

Technical field

The present invention relates to a pharmaceutical composition for the treatment of hiatal hernia and reflux esophagitis, as well as the use of an active ingredient for the preparation of a medicament for the treatment of said diseases.

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 UA 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 90/06110. 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. N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and its salts for improving glucose tolerance in people with impaired glucose tolerance or non-insulin-dependent diabetes mellitus is described in PCT Publication No. WO 95/20949.

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SUMMARY OF THE INVENTION

Use of a compound of formula I CH ₃ H ₃ cchch CHNR ₂ R ₂ including enantiomers and pharmaceutically acceptable salts thereof, wherein Ri and _R2 are independently H or methyl, for the manufacture of a medicament for the treatment of hernias or reflux hiátových esophagitidy.

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 understood by 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 encompasses 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; selectively reacting one enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction, followed by separation of the modified or unmodified enantiomers; or gas-liquid or liquid chromatography in chiral

media such as a chiral support such as a chiral ligand-bound silica 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, 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, α1- [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 také may also be prepared by preparing racemates of the corresponding primary amine, resolving the racemates into the individual enantiomers, and then converting the optically pure enantiomers of the primary amine to the desired secondary amine by the method described in British Patent 2098602.

Specific examples of compounds of formula I are:

(+) (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine;

(-) - N - {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine;

(+) - 1 - [1- (4-chlorophenyl) • (+) - 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.

The hydrochloride salts are preferred in each case, but the free base 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; a binder, such as microcrystalline cellulose or polyvinylpyrrolidone, and with 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 according to methods known in the art, such as those known in the art. In order to achieve a 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 hard 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 couple formed by an acid and a carbonate or bicarbonate salt, to facilitate dispersion formation 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 the known pharmaceutical forms for such a route of administration, such as

for example, suppositories with cocoa butter or a polyethylene glycol base.

Dosage forms for parenteral administration are known pharmaceutical forms for such a route of 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 of time for which the topical composition is to be applied to the skin.

The therapeutically active compound of Formula I may be prepared in a composition that is dispersed as an aerosol into the oral or nasal cavity of a patient. 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, e.g. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Internal sources include implantable containers containing the compound to be applied that continuously release the compound, for example, an osmosis axis, and implants that may be (a) liquid, such as an oil suspension of the compound to be applied, e.g. 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 a 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 particles of very small size which are obtained, for example, by fluid 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 the treatment of hiatal hernia.

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

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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 compound has many side effects. Such side effects include nausea, sexual dysfunction, photophobia, 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, R 1 = CH 3, R ₂ = CH ₃ ) has a pharmacological profile that is unique among monoamine reuptake inhibitors. Through pharmacologically active metabolites (metabolite 1, R _x = H, -R ₂ = CH ₃ in formula I, and metabolite 2, R 1 = H, R ₂ = H in formula I), sibutramine inhibits the re-uptake of all three monoamines, which distinguishes it from selective serotonin (5-HT) reuptake inhibitors such as fluoxetine, selective noradrenaline reuptake inhibitors such as desipramine, selective dcpamine reuptake inhibitors such as bupropion, and serotonin-noradrenaline reuptake inhibitors such as venlafaxine (Table 1). It is a unique combination of pharmacological effects that causes sibutramine and other compounds of formula I to be effective in the treatment of hiatal hormones and reflux esophagitis.

DETAILED DESCRIPTION OF THE INVENTION

The tests described below were performed in a similar manner to those described in WO98 / 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 [HJ-5-HT ^[LH] -dopamin 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

The results are averages of 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 the treatment of hiatal hernia is demonstrated in clinical studies in the relevant population. The improvement of the disease is related to weight loss.

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 the formula CH, I h ₃ cchch ₂ chnr, r ₂ including wherein R 1 drugs of its enantiomers and pharmaceutically mean independently H or methyl, for the manufacture of treatments for hiatal hernia or reflux esophagitis. acceptable salts, and R2 for 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 44 9999 • · 9999 99 4 4 9 9 9 9 • • 9 9 • · • 9 4 9 9 • 4 4 9 9 • 9 9 9 9 4 4 · 4 9 4 • 9 9 9 • • 9 4 • ·· 4 9 9 • 4 9 9 · »44 4 N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate. 3. A pharmaceutical composition for treating hiátových hernia or reflux esophagitidy, characterized in that it comprises a therapeutically effective amount of a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof, wherein Ri and _R2 are independently H or methyl, in conjunction with a pharmaceutically acceptable diluent or carrier . A pharmaceutical composition according to claim 3 wherein the compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. Pharmaceutical composition according to claim 3, characterized in that the compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate.