CZ20014613A3 - Therapeutic agents - Google Patents

Abstract

A method for the treatment of co-morbid conditions associated with 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 R1 and R2 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.

Description

Therapeutic agents

Technical field

The invention relates to therapeutic agents for the treatment and prevention of obesity-related conditions. In particular, the invention relates to pharmaceutical compositions for the treatment of obesity-related conditions in which sibutramine or a salt thereof or a metabolite and orlistate thereof are administered.

BACKGROUND OF THE INVENTION

Sibutramine hydrochloride monohydrate and orlistate are currently developed active substances for the treatment of obesity. These two compounds achieve a weight loss through a completely different mechanism of action.

Sibutramine is a 5-hydroxytryptamine and an inhibitor of noradrenaline reuptake in vivo (Buckett, WR, Thomas PC and Luscombe GP, Prog. Neuro-Psychopharmacol. Biol. Psychiat. 12, pp. 575-584, 1988) and Luscombe GP, Hopcroft RH, Thomas PC and food intake quet, AM, Int. G., Heak D.

129-134, 1989).

activities: decreases (Fantino N. and Sou145, 1995: Hal ford J. C.

Pharmacol. 114, p.

and Burlet C., energy expenditure

Heal D.J. and Stock M.

Buckett W.R., Neuropharmacology 28, p.

Studies have shown that it reduces weight by increasing the satiety feeling of J. Obesity 19, p

J. and und1unde11 J.E. , Br et al.

387P, 1995: and Stricker-Krongrad A., Souguet A.M

Int. J. Obesity 19, 145, 1995) and increases by stimulating thermogenesis (Connoley I.P

J., Brit. J. Pharmacol. 114, 388P, 1995: and Connoley I.P.,

Prost I. Heal D.J. and Stock M.J., Brit. J. Pharmacol. 117, p. 170P, 1995).

Orlistát inhibits the lipase enzymes involved in the decomposition of the ingested fat (Borgstrom B., Biochem. Biophys. Acta.).

962 (3), pp. 308-316 (1988) and consequently unabsorbed fat is excreted in the faeces.

The newspaper 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 has a positive effect on weight loss.

SUMMARY OF THE INVENTION

The invention thus relates to a method of treating obesity-related conditions in a human in need of such treatment comprising administering to a human a therapeutically effective amount of a compound of Formula I

CH,

AND

HXCHCH -CHNR ^ j ^A <T Ϊ

wherein R ¹ and R ² are each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and a therapeutically effective amount of a compound of Formula II

(II) β β β β β β β β β β β β β β II II II II II II II II II II II II II II Wherein the compounds of formula I and formula II are administered simultaneously, separately or sequentially.

The invention has the following advantages. First, the beneficial effect obtained is greater than when the compound of formula I or formula II is administered alone. Second, a synergistic effect is achieved since the efficacy by administering the compound of formula I and the compound of formula II to the first test group is greater than that achieved by administering the compound of formula I to the second test group and the efficacy achieved by administering the compound of formula II to the third group. Third, when the efficacy of administration of either a compound of formula I or a compound of formula II is equal, a further increase in efficacy is achieved by administering a second compound. Fourth, lower doses of a compound of formula I and a compound of formula II can be administered, thereby reducing the side effects associated with the administration of higher doses of each.

As used herein, obesity-related conditions refer to obesity-related diseases known to those skilled in the art. Without limitation, such conditions include: diabetes, including non-insulin dependent diabetes mellitus, impaired sugar tolerance, hypertension, coronary thrombosis, stroke, depression, anxiety, psychosis (e.g. schizophrenia), slowly developing dyskinesia, drug addiction, drug abuse, consciousness disorders, Alzheimer's disease, cerebral ischemia, compulsive behavior, anxiety attacks, social phobia, digestive disorders such as bulimia, anorexia, confusion and drunkenness,

Lipid syndromes, hyperglycemia, hyperlipidemia and stress in mammals, particularly humans.

In addition, the invention may be useful in the treatment or prevention of conditions such as metabolic diseases and conditions resulting therefrom, for example non-activity thermogenesis, and · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · , sexual dysfunction, respiratory arrest, premenstrual syndrome, urinary incontinence including stress incontinence, hyperactive disorders, hernia and oesophageal inflammation, soreness, especially neuropathic pain, weight gain associated with drug treatment, chronic fatigue syndrome, osteoarthritis and posterity, cancer associated weight gain, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension.

The subject invention may be useful for preventing cardiovascular disease and reducing platelet adhesion, promoting weight loss after pregnancy, reducing the craving for smoking, promoting weight loss after smoking cessation. The present invention may further be useful in reducing uric acid and lipid levels in mammals, and particularly in humans.

A preferred compound is N- {1- 1- (4-chlorophenyl) cyclobutyl-33-methylbutyl-N, N-dimethylamine and 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 or monohydrate.

The preparation and use of compounds of formula I, such as N-N- [1- (4-chlorophenyl) cyclobutyl-3-methylbutyl} -N, N-dimethylamine and a salt thereof, for the treatment of depression is described in British Patent Specification No. 2098602. The use of compounds of formula I, such as N-1- [1- (4-chlorophenyl) cyclobutyl-3-methylbutyl] N, N-dimethylamine and its salts, for the treatment of Parkinson's disease is described in PCT Publication No. WO 88/06444 . The use of N- {1- [1- (4-chlorophenyl) cyclobutyl-3-methylbutyl] -N, N-dimethylamine and its salts for the treatment of cerebral functional disorders is described in U.S. Patent 4,939,175. (4-Chlorophenyl) cyclobutyl-3-methylbutyl 1-N, N-dimethylamine hydrochloride for the treatment of obesity is described in European Patent Specification No. 397831. In particular, F f f f c c c c c c hodn hodn hodn hodn formou formou (formou formou formou (((((( - (4-chlorophenyl) cyclobutyl 1-3-methylbutyl-N, N-dimethylamine hydrochloride monohydrate (sibutramine hydrochloride monohydrate), which is described in European patent specification 230742. Use of N- (1- [1- (4-chlorophenyl) cyclobutyl] -3 -methylbutyl-N, N-dimethylamine and its salts to improve glucose tolerance in humans with impaired glucose tolerance or insulin independent diabetes mellitus nu is described in PCT Publication No. WO 95/20949.

The compound of formula (II) is chemically lactone of (2S, 3S5S) -5 - [(S) -2-formamido-4-methylvaleryloxy] -2-hexyl-3-hydroxy hexadecanoic acid. He is also known. under the designation N-formyl-L-leucine, (3S, 4S) -3-hexyl-4 - [(2S) -2-hydroxytridecyl-2-oxethanone ester, (-) - tetrahydrolipstatin, tetrahydrolipistatin, and potassium.

The extraction and use of orlistat for the treatment or prevention of obesity and hyperlipaemia is described in U.S. Pat. No. 4,598,889 (Hoffmann-La Roche Inc). A process for the preparation of orlistat is described in U.S. Pat. No. 4,983,746 (Hoffmann-La Roche Inc). A composition comprising orlistat and acarbose is described in European Patent Publication No. EP 638317 (Hoffmann-La Roche AGF).

It is known to those skilled in the art that the compounds of formula I have a chiral center. When a compound of formula I contains one chiral center, it may exist in two enantiomeric forms. The invention relates to the use of individual enantiomers and mixtures of enantiomers. Enantiomers can be resolved by methods known in the art, for example, by formation of diastereoisomeric salts or complexes, which can be separated, for example, by crystallization; forming diastereoisomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; by the selective reaction of one enantiomer to this to this to this to this to this to With an enantiomer-specific reagent, for example by enzymatic oxidation or reduction followed by separation of the modified and unmodified enantiomers; or by gas-liquid or liquid chromatography in a chiral medium, for example on a chiral carrier, for example on a silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that when converting the desired enantiomer to another chemical compound by one of the separation methods described above, an additional step is required to release the desired enantiomeric form. Alternatively, enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. The enantiomers of the secondary and tertiary amines of formula I may also be prepared by preparing the primary amine racemate, dissolving the mixture into its individual enantiomers, and then converting the corresponding optically pure primary amine enantiomers to the desired secondary or tertiary amine product.

Preferred compounds of formula I are N-tert -butyl-4-chlorophenyl) cyclobutyl] -3-methylbutyl) -N, N-dimethylamine, N-tert- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl-N- methylamine; and Ν-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine including racemates, individual enanantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof. Specific enantiomers of formula I are (+) - --1- [1- (4-chlorophenyl) cyclobutyl-3-methylbutyl} -N, N-dimethylamine, (-) - N-η-E1-β-chlorophenyl) cyclobutyl 1- (3-methylbutyl) -N, N-dimethylamine, (R) - (+) - N- (1- [1- (4-chlorophenyl) cyclobutyl-3-methylbutyl] -N-methylamine, (S) (-) - (-) - (+) - 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine; S) (-) - 1- [1- (4-chlorophenyl) cyclobutyl-3-methylbutylamine.

In the process according to the invention, the compound of the formula:

4 9 4 · 4 · 4 · · ·

4 4 4 999 99 ·

9 4949 4 · 9 · · 4 · ·

9 94 444 44 4444

I and the compound of formula II may be administered simultaneously or concurrently, for example in the form of separate dosage units for simultaneous, separate or sequential administration.

The invention also relates to compounds of formula I wherein R ¹ and R ² are independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts and compounds of formula II for simultaneous, separate or sequential administration for the treatment of comorbid conditions associated with obesity .

The invention yet also relates to compounds of formula I wherein R ¹ and R ² are independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof and compounds of formula II as a combined preparation for simultaneous, separate or sequential administration in the treatment of obesity-related disease states.

The invention further also relates to a product comprising a compound of formula I wherein R ¹ and R ² are independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof and compounds of formula II as a combined preparation for simultaneous, separate or sequential administration in the treatment of obesity-related conditions.

The invention further relates to the use of a compound of formula I wherein R ¹ and R ² are independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof for producing medicaments for the treatment of comorbid conditions associated with obesity in a patient who is being treated also with orlistat .

Further, the invention relates to a method of treating obesity-related conditions by administering a supportive medicament comprising a therapeutically effective amount of a compound of Formula I and orlistat to a patient in need thereof.

• • • • a

The invention relates to the use of said combination of drugs for the manufacture of a medicament for the treatment of obesity-related conditions. In addition, the invention provides a combination for use in the treatment of obesity-related conditions.

The amount of each compound administered depends on a number of factors, including the age of the patient, the severity of the condition and the history of its treatment, and is always at the discretion of the attending physician: however, a compound of Formula I is generally administered in an amount of 0.1 to 50 mg. 30 mg per day in single or multiple doses, and more preferably 10 mg, 15 mg, 20 mg, 25 mg or 30 mg per day, and most preferably 20 mg. Orlistate may be administered in an amount of 50 to 1440 mg in single or multiple doses, preferably three times a day, more preferably 120 to 720 mg, and most preferably 120 to 360 mg. The compound of formula (I), preferably sibutramine hydrochloride monohydrate, can be administered in any known dosage form. Orlistat is preferably administered orally.

In a preferred embodiment of the invention, sibutramine hydrochloride monohydrate is administered once daily, preferably on the first morning, and orlistat is administered three times daily with or before a meal. Preferably, a dose of 20 or 30 mg of sibutramine hydrochloride monohydrate is administered once daily and a dose of 120 mg of orlistat is administered three times daily with or before a meal. Preferably the dose of sibutramine hydrochloride monohydrate is administered before the first dose of oristat, preferably 30 minutes to 3 hours, for example 30 minutes, hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours before the first dose of orlistat.

The invention also relates to a pharmaceutical composition comprising a compound of formula I

Cl ·· ·· • »• · · ·» · • • «* • · · · · · · which R ¹ and R ² are independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and compounds of formula II

with a pharmaceutically acceptable diluent or carrier.

Preferred are oral forms of the compositions of the invention, such as tablets, capsules, granules, syrups, and aqueous or oily suspensions. The excipients used to prepare such compositions are excipients known in the pharmaceutical art. Tablets may be prepared from a mixture containing the active compounds and fillers, for example calcium phosphate, disintegrating agents, for example corn starch, lubricants, for example magnesium stearate, binders, for example microcrystalline cellulose or polyvinylpyrrolidone, and other conventional ingredients known in the art to enable the tablet to be tabletted by known methods. The tablets may optionally be coated by known methods with excipients which may contain enteric coatings, for example hydroxypropyl methylcellulose phthalate. Tablets may be shaped in a manner known to those skilled in the art to provide sustained release of the compounds of the invention. Such tablets may optionally be provided with enteric coatings by known methods, for example using cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound optionally with added excipients, can be prepared by known methods and optionally can be provided with enteric coatings in a known manner. The contents of the capsules can be formulated using known methods to ensure sustained release of the active compound. Tablets and capsules may conveniently contain 1 to 50 mg of a compound of formula I and 1 to 380 mg of orlistat.

Other dosage forms for oral administration are, for example, aqueous suspensions containing the active compounds in an aqueous medium in the presence of a non-toxic carrier, such as carboxymethylcellulose, and oily suspensions containing the active compounds in a suitable vegetable oil, for example, peanut oil. The active ingredients may be formulated as granules, optionally together with excipients. The granules may be swallowed directly by the patient, or may be added to a suitable liquid carrier (e.g., water) prior to ingestion. The granules may contain disintegrants, for example, an effervescent mixture formed of an acid and a carbonate or bicarbonate salt to facilitate dispersion in a liquid medium.

The compounds of formula (I) and orlistat may be formulated into a composition to be retained by the patient in the mouth by administering the active compounds through the oral mucosa.

Dosage forms of the compounds of formula (I) suitable for rectal administration are known pharmaceutical forms for administration, such as cocoa butter suppositories or polyethylene glycol.

Dosage forms of the compounds of formula I suitable for parenteral administration are known pharmaceutical forms for such administration such as sterile suspensions or sterile solutions in a suitable solvent.

Dosage forms of the compounds of formula (I) suitable for topical administration may comprise a matrix in which the pharmacologically active compounds of the invention are dispersed such that the compounds are kept in contact with the skin for administration of the compound.

9 9 9 9 9 9 * »8 ·

9 9 9 9 9 9 9 9 ♦ • 9 9999 999 · 9 * 9 9 • 99 999 «99 · 99 999 9» 9999 Legs transdermally. A suitable transdermal composition is prepared by mixing the pharmaceutically active compound with a topical carrier such as mineral oil, paraffin and / or wax, for example paraffin wax or beeswax, together with a potential transdermal accelerator such as dimethylsulfoxide or propylene glycol. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment. The amount of each active compound contained in the topical formulation should be such that a therapeutically effective amount of each compound is delivered during the time that the topical formulation is to be in contact with the skin.

The compounds of formula (I) may be formulated into a composition which is dispersed as an aerosol in the oral or nasal cavity of the patient. Such aerosols may be administered with a pump or volatile propellant package.

The compounds of formula (I) may be administered by continuous infusion of either an external 2 source, for example by intravenous infusion or from a source of the compound located within the body. The internal devices may be implanted containers containing infusible compounds which are continuously released, for example by osmosis, and implants which may be (a) liquid, as an oil suspension of infusible compounds, for example in the form of a very sparingly water-soluble derivative such as dodecanoate. a salt or lipophilic ester; or (b) solid in the form of an implanted carrier, for example, a synthetic resin or a waxy material for infused compounds. The carrier may be a single body containing all of the compounds or a series of several bodies, each containing part of the released compounds. The amount of active compounds contained in the internal source should be such that an effective amount of each compound is released over a long period of time.

In some formulations it may be advantageous to use the compounds of the invention in the form of particles of very small size, for example obtained by liquid energy grinding.

In the compositions of the invention, the active compounds may optionally be together with other compatible pharmaceutically active ingredients. The addition of vitamins to the compounds of the invention is optimal.

The invention is illustrated by the following examples

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutical compositions containing both a compound of Formula I and orlistat are important embodiments of the invention. Such pharmaceutical compositions contain therapeutically effective amounts of each compound. Each dosage unit may contain a daily dose of both compounds, or may comprise a fraction of the daily dose, for example a third of the daily dose. Alternatively, each dosage unit may contain the entire dose of one compound and a fraction of the dose of the other compound. In any case, the patient would take one of the combined units and one or more units containing only the other compound.

The use of the compounds of the invention in the manufacture of pharmaceutical compositions is described below. The term active compound refers to one or both of the compounds of the invention, unless otherwise indicated.

(a) Kaps1e

To prepare the capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are comminuted and mixed. The mixture is filled into hard gelatin capsules containing a unit dose or part of a unit dose of the active compound.

• Φ 4 • 9

9 9999

(b) Tablets

Tablets are prepared from the following ingredients in parts by weight:

Active Compound 10 lactose2a 190 maize starch 22 polyvinylpyrrolidone 10 magnesium stearate 3

The active compound, lactose and some starch are ground, mixed and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granulate is mixed with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine into tablets each containing a unit dose or part of a unit dose of the active compound.

c) Enteric-coated tablets

Tablets are prepared by method (b). The tablets were enteric coated in a conventional manner using a solution containing 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

(d) Suppositories (only compounds of formula I)

In the manufacture of suppositories, 100 parts by weight of the active compound are incorporated into 1300 parts of the triglyceride carrier and the mixture is formed into suppositories containing a therapeutically effective amount of the active ingredient.

• fcfcfcfcfcfc

Formulation 1

Hard gelatin capsules are prepared with the following 2 ingredients ^:

Quantity (mg / capsule) with butyramine hydrochloride monohydrate 20 May or1istat 120 starch 200 magnesium stearate 10 Total 350

Formulation 2

The tablet is prepared with 2 ingredients:

Amount (mg / tablet) sibutramine hydrochloride monohydrate 20 or 120 microcrystalline cellulose 400 silica 10 stearic acid 5 total 545

The ingredients are mixed and compressed into 545 mg tablets.

The advantages of the invention can be illustrated by 2-door models or by clinical tests, as is known to those skilled in the art. Suitable 2-door models and clinical tests are described in the literature:

(1) New Antidiabetic Drugs by C.J. Bailey & P.R.

Flatt 1990 Smith-Gordan & Company Ltd., UK (2) Obesity editors P. Bjorntorp & Brodoff, 1992 J.B.

Lippincott Company, Philadelphia, Sp. st. a. a

4 · · 4. 4 4 4 4 4 4 4 4 4

4 4 4 4 4 4 9 · 4 • 9 444 · · 4 9 9 4 9 9 9

4 4 4 · 4 ··· ·· · 444 94 4444 (3) Obesity, Trends and Treatments S. Parker 1996 Written Report PJB Publications Ltd. and the references therein.

Studies have been conducted in which a compound of formula I is administered to a first test group, a compound of formula II is administered to a second test group, and a combination of compounds of formula I and formula II is administered to a third test group with appropriate controls.

Statistical analysis of the effects achieved in each group provides results demonstrating the advantages of the invention.

Industrial applicability

The use of sibutramine or its salts or metabolite and orlistate for the manufacture of a medicament for the treatment of obesity-related conditions.

Claims (8)

PATENT • 4 4 4 • 4 4 ·· «• 4 4 Claims * 444 4 A method for treating obesity-related conditions in a human in need of such treatment comprising administering to a human a therapeutically effective amount of a compound of Formula I CH, wherein R ¹ and R ² are each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and a therapeutically effective amount of a compound of Formula II wherein the compounds of Formula I and Formula II are administered simultaneously, separately or sequentially with a pharmaceutically acceptable diluent or carrier. A process according to claim 1, wherein the compound of formula I is N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl) -N, N-dimethylamine or a salt thereof. A method according to claim 2, characterized in that: 4 4 4 4 4 5 4 4 4 4 4 4 4444 44 4 <4 4 4 4 The compound of formula I is administered 30 minutes to 3 hours prior to administration of the compound of formula II. A compound of formula I wherein R ¹ and R ^{2 are} each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and a compound of formula II for simultaneous, separate or sequential administration for the treatment of obesity-related conditions. A compound of formula I wherein R ¹ and R ^{2 are} each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and a compound of formula II as a combined preparation for simultaneous, separate or sequential administration for the treatment of a disease-related condition with obesity. A product comprising a compound of formula I, wherein R ¹ and R ^{2 are} each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and a compound of formula II as a combined preparation for simultaneous, separate or sequential administration for the treatment of conditions associated with obesity. Use of a compound of formula I, wherein R ¹ and R ^{2 are} each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of a disease-related condition. 8. A pharmaceutical composition comprising a compound of formula (I ₎ H ₃ CCHCH ₂ CHNR ₁ R ₂ (I) Cl • Φ # ·· · φ ΦΦΦ · · φ φ Wherein R ¹ and R ² independently of each other represent an atomic group, including enantiomers and its acceptable salts, and a compound of the formula: hydrogen or methylpharmaceutically together with a pharmaceutically acceptable diluent or carrier.