SK18822001A3 - Therapeutic agents - Google Patents

Abstract

A method for the treatment of obesity and associated co-morbid conditions 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 lipase inhibitor with the exception of orlistat; wherein the compound of formula (I) and the lipase inhibitor are administered simultaneously, separately or sequentially.

Description

Technical field

The present invention relates to the use of a sibutramine hydrochloride compound of formula I including its enantiomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of obesity and associated co-morbid conditions in a patient also receiving lipase inhibitor therapy, with the exception of orlistat and formulations; compositions containing such compounds.

BACKGROUND OF THE INVENTION

Sibutramine is a 5-hydroxytryptamine and an inhibitor of noradrenaline uptake in vivo (Buckett, W.R., Thomas, P.C. & Luscombe, G. P. (1988). Neuro Psychopharmacol. Biol. Psychiat. 12, 575-584 and Luscombe, G. P., Hopcroft, R.

H., Thomas, P. C. & Buckett, W. R. (1989). Neuropharmacology, 28, 129-134). Studies have shown that it reduces body weight in two ways; decreases food intake by increasing satiety (Fantino, M. & Souquet, A.-M. (1995), Int. J. Obesity, 19, 145; Halford, JCG, Heal, DJ & Blundell, JE (1995). Brit. J. Pharmacol., 114, 387P, and Stricker-Krongrad, A., Souquet, A.-M. & Burlet, C. (1995) Int. J. Obesity, 19, 145), and this increases energy expenditure due to stimulation. Thermogenesis (Connoley, IP, Heal, DJ & Stock, MJ (1995). Brit. J. Pharmacol. 114, 388P; and Connoley, IP, Frost, I., Heal, DJ & Stock, MJ (1996). J. Pharmacol. 117,170P). Sibutramine has proven itself for use in the treatment of obesity in the US and at least twenty other countries around the world.

Lipase enzymes are responsible for the cleavage of the intake of fat (Borgstrom, B. (1988). Biochem. Biophys. Acta. 962 (3), 308-316); and as a result, unabsorbed fat is excreted in the faeces. One such lipase inhibitor, orlistat, which has now been proven for use in the treatment of obesity in the US and Europe, has the chemical name lactone (2S, 3S, 5S) -5 - [(S) -2-formamido-4-methylvaleryloxy] -2 -hexyl-3 hydroxyhexadecanoic acid. Also known as N-formyl-L-leucine ester with (3S, 4S) -3-hexyl-4 - [(2S) -2-hydroxy-tridecyl] -2-oxethanone, (-) - tetrahydrolipstatin, tetrahydrolipistatin and orlistat . Extraction and use of orlistat in the control or

The prevention of obesity and hyperlipemia are described in US Patent No. 4,598,089 (Hoffmann-La Roche Inc.). A process for the preparation of orlistat is described in US Patent 4,983,746 (Hoffmann-La Roche Inc.). A composition comprising orlistat and acarbose is described in EP 638317 (Hoffmann-La Roche AGF).

It has also been reported that orlistat should not be combined with appetite suppressants (The New York Times, May 15, 1997). Co-pending application PCT / EP98 / 08249 discloses the use of a combination of a compound of formula I, described below, orlistat for the treatment of obesity. It has now surprisingly been found that co-administration of sibutramine hydrochloride monohydrate and orlistat has beneficial effects in terms of weight loss.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to the use of a compound of formula I

CH,

I h ₃ cchch R ₂ CHNR

including enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are each independently H or methyl in the manufacture of a medicament for the treatment of obesity and associated co-morbid conditions in a patient who is also receiving treatment with a lipase inhibitor, a orlistat.

The present invention may provide the following advantages. First, the maximum weight loss achieved is higher than that achieved by either administration

A compound of formula I or a lipase inhibitor. Second, a synergistic weight loss is achieved wherein the weight loss achieved by administering the compound of Formula I and the lipase inhibitor in the first test group is greater than the total weight loss achieved by administering the compound of Formula I to the second test group and the weight loss achieved by administering the lipase inhibitor to the third test group. Third, if the weight loss reached after administration of either a compound of Formula I or a platelet lipase inhibitor, another weight loss is achieved by administering a second compound. Fourth, according to the present invention, lower doses of a compound of formula I and a lipase inhibitor may be used, thereby alleviating the side effects associated with administration of a higher dose of each of the compounds. Fifth, according to the present invention, a synergistic improvement can be achieved in the treatment of co-morbid conditions associated with obesity as compared to the separate administration of each compound.

A preferred compound of formula I is N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine or 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 monohydrate.

The preparation and use of compounds of formula I, such as N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine and its salts, in the treatment of depression is described in English patent document 2,098,602. compounds of formula I as well as N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine and its salts in the treatment of Parkinson's disease are described in published international patent application WO 88/06444. The use of N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} Ν, Ν-dimethylamine and its salts in the treatment of diseases of the brain is described in US Patent 4,939,175. The use of N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine hydrochloride in the treatment of obesity is described in European Patent Document EP 397831. A particularly preferred form of this compound is N- {1- [1- (4-Chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine hydrochloride (sibutramine hydrochloride monohydrate), which is described in European Patent No. 3,960,549; 230742. Use of N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine and its salts for improving glucose tolerance in humans,

Those who have impaired insulin-independent glucose tolerance or diabetes mellitus are described in published international application WO 95/20949.

Those skilled in the art will appreciate 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. The enantiomers may be resolved by methods well known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example by crystallization; forming diastereoisomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selectively reacting one enantiomer 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 support, for example silica bound with a chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted to another chemical entity using one of the above separation procedures, an additional step is required to release the desired enantiomeric form. Alternatively, specific 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. Enantiomers of secondary and tertiary amines of formula I can also be prepared by preparing the racemate of the primary amine, resolving the mixture into its individual enantiomers, and then converting the corresponding enantiomer of the optically pure primary amine to the desired secondary or tertiary amine product.

Preferred compounds of formula I are N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine, N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine and N-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, including racemates, individual enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof. Specific enantiomers of formula I are (+) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-5-methylbutyl} -N, N-dimethylamine, (-) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} Ν, Ν-dimethylamine, (R) - (+) - N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine, ( S) - (-) - N- {1- [1- (4-Chloro-phenyl) -cyclobutyl] -3-methyl-butyl} -N-methylamine, (R) (+) - 1- [1- (4-Chloro-phenyl)] cyclobutyl] -3-methylbutylamine and (S) - (-) - 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.

Suitable lipase inhibitors include pancreatic lipase inhibitors, gastric lipase inhibitors, and carboxylester lipase inhibitors and include, but are not limited to, the following:

caulerpenine, as described in Japanese Patent Specification No. 5,938,549; JP 10203974A2, Japanese patent application no. 97JP0014334;

panclicins A to E as described in J. Chem. Soc., Perkin Trans. 1, (1998), (8), 1373-1382;

(-) - panclicin D as described in Tetrahedron (1997), 53, (48), 16471-16488;

procyanidine and analogs as described in WO 97/23210;

lipase inhibitors isolated from cereals or legumes as described in Japanese patent specification no. JP 04321700A2, Japanese patent application no. 91JP0110814;

4- (acyloxyethyl) oxetan-2-ones of formula

as described in EP 444482, wherein Q represents a group of the formula

-6 ^{(R3, R4)} NCO (X) _n - CO - Q ¹ (R ^3, R ⁴⁾ NCO-X ¹ q ¹

and

R ¹ and R ² means an alkyl group of up to 18 carbon atoms which is substituted by one to three halogen atoms or alkyl, alkenyl, alkynyl or alkadienyl groups of up to 20 carbon atoms optionally interrupted by a 1,4arylene group, optionally substituted by an aryl group in the omega position and optionally substituted with aryl-C 1-4 -alkyl; wherein R ¹ may be interrupted by an oxygen or sulfur atom or a sulfinyl or sulfonyl group at a position other than the α-position to the unsaturated carbon atom, or R ¹ represents an aryl-NH group or an aryl-C 1-4 -alkyl-OCONH- group, R ³ and R ⁴ they represent hydrogen or a C 1-6 -alkyl group or, together with the nitrogen atom to which they are attached, form a saturated 3- to 6-membered ring which optionally contains an oxygen or sulfur atom in a position other than the position of the nitrogen atom, n represents the number 1 or 0; X represents an alkylene group containing up to 6 carbon atoms optionally interrupted by an oxygen or sulfur atom or a sulfinyl or sulfonyl group and optionally substituted by a hydroxyl, mercapto, aryl, aryloxy, arylhio, aryl-C 1-6 -alkyl group, aryl-C 1-4 -alkoxy, aryl-C 1-4 -alkylthio, aryl-C 1-4 -alkylidene, C ₃ . ₇ -cycloalkylidene or C 1-6

-7alkylidene or with one or two C 1-7 alkyl groups. ₆ alkyl groups, C. _6- alkoxy; _6- alkylthio groups, wherein two C 1-6 -alkyl groups, C 1-6 -alkoxy or C 1-6 -alkylthio groups on the same carbon atom or on two adjacent carbon atoms may form an optionally mono-unsaturated 3- to 7-membered ring and optionally present hydroxyl the group or mercapto group or any unsaturated carbon atom present must be in a position other than the position of the oxygen or sulfur atom, if any, or a sulfinyl or sulfonyl group, if any, or

X is a group of the formula = CHN (R, R °) or - CHN (R, R °) CH ₂ R and R 0 are hydrogen, C 1-6 -alkyl, C 1-6 -alkyl (CO or OCO) -, aryl , aryl (CO or OCO) -, aryl-C 1-4 -alkyl or aryl-C 1-4 -alkyl (CO or OCO) - and

X ¹ represents an alkylene group containing up to 6 carbon atoms which may be substituted by C 1-4 -alkoxy, aryl, aryloxy, arylthio, aryl-C 1-4 -alkyl, aryl-C 1-4 -alkoxy or aryl-C 1-4 -alkylthio or one or more; two C 1-6 -alkyl groups, wherein two C 1-6 -alkyl groups; _6- alkyl groups attached to adjacent carbon atoms can form a 3- to 7-membered ring; in particular a compound selected from the group consisting of:

(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester of (S) -2-isopropyl-malonamic acid, (S) -1 - [[(2S, 3S) (S or R) -2-Carbamoylvaleric acid -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester, (all-Z, S) -1 - [[(2S, 3S) -3-ethyl-4- (S) -2-isopropylmalonamic acid oxo-2-oxytanyl] methyl] -9,12-octadecadienyl ester, (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2] (S) -2-isopropylmalonamic acid-oxetanyl] methyl] dodecyl ester,

-8 [S: R (2: 1) -2-isopropylmalonamic acid -8 (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl ester, (S or R) 2-tert-butylmalonamic acid (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester, (S) -1 - [[ 1-Carbamoyl-cyclopentanecarboxylic acid (2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2- (RS) -2-benzylmalonamic acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester (3 - [(2-carbamoyl-ethyl) oxetanyl] methyl] dodecyl ester ) thio] propionic acid,

5-oxo-D-proline (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester,

5-oxo-L-proline (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester, (S) -1 - [[(2S, 3S)] (S or R) -2-Isopropylmalonamic acid -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2- oxetanyl] methyl] dodecyl (RS) -2-carbamoylvalerate (1: 1 epimers), (all-Z, S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxytanyl] methyl] (S or R) -2-isopropylmalonamic acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester (RS) -9,12-octadecadienyl ester 1-carbamoyl-cyclohexanecarboxylic acid -2-carbamoyl-4-methylvaleric (1: 1 epimers), (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester, (S) - (RS) -2-methylmalonamic acid 1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester (1: 1 epimers), (S) -1 - [[(2S, (RS) -2-ethylmalonamic acid 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester (epimers 1: 1),

-9 (S) -1 - [((2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-butylmalonamic acid dodecyl ester, (epimers 1: 1), (S) -1 - 1-carbamoyl-cyclohexanecarboxylic acid ([(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester,

I i

(S: R or R: S (2: 1) -2-) - [[(2S, 3S or 2R, 3R) -4-oxo-3-phenylthio-2-oxetanyl] methyl] dodecyl ester isopropylmalonamic acid (S) -1 - [[(2R, 3R) -3-benzyl-4-oxo-2-oxetanyl] methyl] dodecyl ester;

N-formylleucine 1- (oxetanonylmethyl) alkyl esters and analogs as described in US Patent Documents US 4,931,463, US 5,175,186 and US Pat.

5,246,960 formula

wherein R ¹ and R ² are, independently of one another, a C 1-6 alkyl group which is saturated or optionally interrupted by up to 8 double or triple bonds and / or optionally interrupted by an oxygen or sulfur atom present in a position other than α- position to an unsaturated carbon atom; or a phenyl group, a benzyl group or a -C6H4-X-C6H5 group substituted on the ring with up to three C1-6-alkyl- (O or S4) or o> X represents oxygen, sulfur or (CH2) 0-3, Ŕ ³ represents hydrogen, C 1-3 -alkyl or C _1-3 -alkanoyl, R ⁴ represents hydrogen or C 1-4 -alkyl, and R ⁵ represents hydrogen, Ar or Ar-C _1-3 -alkyl or C _1-7 -alkyl; alkyl group, optionally interrupted with R Y, and optionally substituted with a substituent Z, or R ⁴ forms with R ⁵ a 4- to 6-membered saturated ring, Y is O, s or N (R ⁶⁾ C (O) N ( R ⁶ ) or N (R ⁶ ) C (O), Z is - (O or S) -R ⁷ , N (R ⁷ , R ⁸ ), -C (O) N (R ⁷ , R ⁸ ) or -N (R ⁷ ) C (O) R ⁸ , n is an integer of 1 or 0, provided that R ⁵ is hydrogen when n is 1, Ar is phenyl, which is unsubstituted or substituted with up to three R ⁹ groups or OR ⁹ , and

- 10R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or C 1-6 alkyl, provided that R is not hydrogen when R is formyl and R is isobutyl or R ³ is acetyl and R ⁵ is carbamoylmethyl, R ² is undecyl or 2,5-undecadienyl and R ¹ is n-hexyl, their enantiomer or diastereoisomer, or a pharmaceutically acceptable acid addition salt thereof, in particular a compound which is selected from one of the following compounds:

N-formyl- (S) -leucine (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester, or a pharmaceutically acceptable acid addition salt thereof, in particular:

N-formyl-1-leucine 1 - [(trans-3-ethyl-4-oxo-2-oxetanyl) methyl] dodecyl ester,

N-formyl-L-leucine 1 - [(trans-3-allyl-4-oxo-2-oxetanyl) methyl] dodecyl ester,

N-formyl-S-leucine (5,9Z, 12Z) -1 - [(2 S _l 3 S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9,12oktadeka-dienyl ester

N-formyl-S-leucine (S, Z) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9-octadecenyl ester

N-formyl-S-leucine (R) -? - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -p-phenoxybenzyl ester;

or a pharmaceutically acceptable acid addition salt thereof;

and a tetrahydrolipstatin analog of the formula wherein R = ethyl, I, Helv. Chim. Acta (1987), 70, (5), 1412-1418

oxethanones of the formula

-11 wherein X ¹ is undecyl or 2Z, 5Z-undecadiencyl, C ₆ is n-hexyl, Y is isobutyl and Z is formyl or Y is carbamoylmethyl and Z is acetyl as described in the European patent document

EP 189577

1-substituted 2-alkanone derivatives as described in Chem. Pharm. Bull. (1986), 34, (3), 1118-1127;

soy proteins as described in J. Lipid Res. (1984), 25, (11), 1214-1221;

taurine and glycine derivatives of the formula

OR (CHMe) n (CH2) mCONHCH2R4

Wherein R = H, alkanoyloxy, BzO; R ¹ = CO 2 H, alkoxycarbonyl, CH 2 SO 3 H; m, n = 0.1) as described in US Patent No. 4,104,285;

1,2-dioleoyl-3- (alpha-1-adamantoyl) -sn-glycerol and 1-adamantanecarboxylic acid as described in J. Pharm. Sci. (1976), 65, (8), 1243-1245;

wheat derived peptides as described in Japanese patent document JP 07330794A;

peptides incorporating a C-terminal fragment of pancreatic lipase, including a co-lipase recognition site, as described in WO 98/30588;

flavanoid (s) and glycoside (s) thereof as described in Japanese Patent Document JP 09143070A;

tri-terpenes as described in Japanese patent document JP 09040689A;

hinocithiol as described in Japanese Patent Document JP 08268882A;

12-flavonoid compounds as described in the Japanese patent document

JP 07061927A;

(metal substituted) chlorophyll (s) as described in Japanese Patent Document JP 05252898 A;

2-oxethanone derivatives of formula I as described in European patent document E P 443449A:

where

R ¹ and R ² represent an alkyl group containing up to 17 carbon atoms optionally interrupted by an oxygen atom at a position other than α- or (β-position; or a benzyl group optionally substituted on the ring by one to three C 1-6 -alkyl groups or C 1-4 alkoxy,

X is hydrogen or a group of formula (R ^3, R ⁴⁾ NCH (R ⁵⁾ (CH 2) n COR ³ represents hydrogen, C | .3 alkyl or C. _{A 3-} alkanoyl group,

R ⁴ represents hydrogen or C 1-6 alkyl. _{A 3-} alkyl group;

R ⁵ is hydrogen, Ar or Ar-C 1-6. _{A 3-} alkyl group or a C 1-7 alkyl group which is optionally interrupted by Y and optionally substituted with Z, or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 4- to 6-membered ring,

Y is oxygen, sulfur or N (R ⁶ ), C (O) N (R ⁶ ) or N (R ⁶ ) C (O),

Z is - (O or S) -R ⁷ , NR ⁷ , R ⁸ ) or N (R ⁷ ) C (O) R ^B ,

- 13n represents the number 1 or 0, wherein R 5 represents hydrogen, as n represents the number 1,

Ar represents a phenyl group substituted with one to three groups

R ⁹ or OR ⁹ , a

R ⁶ to R ⁹ represent hydrogen or a C 1-3 -alkyl group, and salts of oxetanones of formula I in which X is not hydrogen with weak acids;

lipstatin and tetrahydrolipstatin derivatives as described in European patent document EP 129748A, with the exception of orlistat;

the non-absorbable cationic olefin-maleic acid copolymers described in U.S. Patent No. 4,211,765A;

bile acid-absorbing resins and triglyceride as described in GB 1 286 949; and compounds such as ATL-962 and analogs thereof as described in patent applications protecting this compound and patent applications protecting its analogs.

In the method of the present invention, the compound of formula I and the lipase inhibitor may be administered together or concurrently, for example in the form of separate dosage units, which may be used simultaneously, separately or sequentially.

In another aspect, the present invention provides a compound of formula I, including its enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are, independently of each other, H or methyl, and a lipase inhibitor other than orlistat, for simultaneous, separate or sequential use in the treatment of obesity and associated co-morbid conditions.

Still further, the present invention provides a compound of formula I, including its enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are, independently of one another, H or methyl, and a lipase inhibitor, with the exception of orlistat, as a combined preparation for simultaneous, separate or subsequent use in the treatment of obesity and associated co-morbid conditions.

In a further aspect, the present invention relates to a composition comprising a compound of formula I, including its enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are, independently of one another, H or methyl, and a lipase inhibitor other than orlistat, in the form of a combined for simultaneous, separate or sequential use in the treatment of obesity and associated comorbid conditions.

Still further, the present invention relates to the use of a compound of formula I, including its enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are, independently of one another, H or methyl, for the manufacture of a medicament for the treatment of obesity and associated co-morbidities in a patient also receiving treatment with a lipase inhibitor, with the exception of orlistat.

In yet another aspect, the present invention relates to a method of treating obesity and associated co-morbid conditions, the method comprising administering to a patient in need thereof a supportive therapy comprising a therapeutically effective amount of a compound of formula I and a lipase inhibitor other than orlistat.

The present invention also relates to the use of the aforementioned combination of medicaments for the manufacture of a medicament for the treatment of obesity and associated co-morbid conditions. In addition, the invention relates to a combination for use in the treatment of obesity.

As used herein, the term co-morbid conditions refers to medical conditions known to those skilled in the art to be associated with obesity. The term includes, but is not limited to, the following conditions: diabetes, including insulin-independent diabetes mellitus, impaired glucose tolerance, depression, anxiety, psychosis (e.g. schizophrenia), late dyskinesia, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, cerebral ischemia, obsessive-compulsive behavior, panic attacks, social phobia, eating disorders such as bulimia, anorexia, excessive knockdown and uncontrolled overeating, hyperglycemia, hyperlipidemia and stress in mammals, especially in humans.

The present invention can further be used in the treatment or prevention of metabolic diseases and conditions arising therefrom, such as thermogenesis without physical activity and increased metabolic intensity, sexual

-15 dysfunction, short-term respiratory distress during sleep, premenstrual syndrome, urinary incontinence, including stress incontinence, hyperactivity, hiatal rupture and esophageal reflux, pain, especially neuropathic pain, drug use weight gain, chronic fatigue syndrome and osteoarthritis, osteoarthritis weight gain, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension.

The present invention can further be used in the prevention of cardiovascular diseases and in reducing platelet adhesion, to aid in weight loss after pregnancy, to reduce the appetite for smoking, and to assist in weight loss after smoking cessation. The present invention may also be useful in reducing uric acid levels and lipid levels in mammals, particularly humans.

The amount of each compound to be administered depends on a variety of factors, including the age of the patient, the severity of the condition, and the patient's prior medical history, and is always based on careful judgment by the attending physician. administered, will be in the range of 0.1 to 50 mg, preferably 1 to 30 mg per day, administered in one or more doses, and particularly preferably 10 mg, 15 mg, 20 mg, 25 mg or 30 mg per day, and most preferably 20 mg. The dose of the lipase inhibitor to be administered will be in the range of 5 to 2000 mg, administered in one or more doses, preferably three times a day, particularly preferably in the range of 50 to 1500 mg, and most preferably in the range of 100 to 1000 mg. The compound of formula I, preferably sibutramine hydrochloride monohydrate, can be administered in any of the known pharmaceutical dosage forms. The lipase inhibitor is preferably administered orally.

According to a preferred embodiment of the present invention, sibutramine hydrochloride monohydrate is administered once daily, preferably in the fasted morning, and the lipase inhibitor is administered three times daily either with or before a meal. A preferred dose of sibutramine hydrochloride monohydrate is 20 mg or 30 mg, administered once daily, and the lipase inhibitor dose is 50 mg, 100 mg, 120 mg or 150 mg, administered three times daily either with or before a meal. Most preferably, the dose of sibutramine hydrochloride monohydrate is administered prior to the first dose of the lipase inhibitor, preferably in the range of 30 minutes to 3 hours, e.g.

-16 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours, before the first dose of the lipase inhibitor.

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

including enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are, independently of each other, H or methyl, and a lipase inhibitor, with the exception of orlistat, together with a pharmaceutically acceptable diluent or carrier.

Oral dosage forms are preferred compositions for use according to the present invention and these are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are those known in the pharmaceutical art. Tablets may be prepared from a mixture of the active compounds with fillers, such as calcium phosphate; disintegrating agents such as corn starch; lubricating agents such as magnesium stearate; binders, such as microcrystalline cellulose or polyvinylpyrrolidone, and optionally other ingredients known in the art that allow tabletting of the mixture by known techniques. The tablets may be coated if necessary using known techniques and excipients, which may include an enteric coating, using for example hydroxypropyl methylcellulose phthalate. Tablets may be formulated in a manner known to those skilled in the art to achieve sustained release of the compounds of the present invention. Such tablets may, if necessary, be provided with enteric coatings, using known techniques, for example using cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without the addition of excipients, can be prepared using known procedures and, if necessary, equipped.

17enteric coatings, using known techniques. The contents of the capsule can be formulated using known procedures to achieve sustained release of the active compound. Tablets and capsules may conveniently each contain 1 to 50 mg of a compound of formula I and 1 to 1000 mg of a lipase inhibitor.

Other dosage forms for oral administration include, for example, ^1, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing the active compound in a suitable vegetable oil, for example arachis oil. The active compounds may be formulated into granules with or without additional excipients. The granules may be swallowed directly by the patient or added to a suitable liquid carrier (such as water) prior to swallowing. The granules may contain disintegrating agents, for example, an effervescent component formed from an acid and a carbonate or bicarbonate salt, to facilitate dispersion in the liquid medium.

The compounds of formula I may be formulated into a composition which the patient holds in the mouth such that the active compounds are administered through the mucosa of the oral cavity.

Dosage forms of the compounds of formula I suitable for rectal administration are known pharmaceutical forms for such administration, for example, cocoa butter laces or polyethylene glycol bases.

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

Dosage forms of the compounds of formula I 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 to administer the compounds transdermally. A suitable transdermal composition can be prepared by mixing the pharmaceutically active compound with a topical vehicle such as mineral oil, petrolatum 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 base. number

Each of the active compounds contained in the topical preparation should be such that a therapeutically effective amount of each compound is delivered during the period of time for which the topical preparation is expected to act on the skin.

The compounds of formula I may be formulated into 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 pack or a pressurized pack containing a volatile propellant.

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

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

In the compositions of the present invention, the active compounds may be associated, as necessary, with other compatible pharmacologically active ingredients. Optionally, vitamin supplements may be administered with the compounds of the present invention.

Pharmaceutical compositions comprising both compounds, a compound of formula I and a lipase inhibitor are important embodiments of the present invention.

Such pharmaceutical compositions contain a therapeutically effective amount of each of the compounds. Each dosage unit may contain daily doses of both compounds or may comprise a portion of the daily dose, such as one-third of the doses. Alternatively, each dosage unit may contain the entire dose of one of the compounds and a portion of the dose of the other compound. In such a case, the patient could take one of the combination of dosage units and one or more units containing only the next compound daily.

The use of the compounds of the present invention for the manufacture of pharmaceutical compositions is illustrated by the following description. In this specification, the term active compound refers to either one of the two or both of the compounds of the invention, unless otherwise indicated.

DETAILED DESCRIPTION OF THE INVENTION

(a) Capsules

In the preparation of capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are deagregated and mixed. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of the active compound.

(b) Tablets

Tablets are prepared from the following ingredients.

Weight parts Active compound 10 lactose 190 Maize starch 22 polyvinylpyrrolidone 10 Magnesium stearate 3

The active compound, lactose and a portion of the starch are deagregated and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granulate is mixed with magnesium stearate and starch residue. The mixture is then compressed in a tabletting machine

Machines to obtain tablets each containing a unit dose or part of a unit dose of the active compound.

c) Enteric-coated tablets

Tablets were prepared as described under (b) above. The tablets were enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

(d) Lace (compound of formula I only)

To prepare suppositories, 100 parts by weight of the active compound was incorporated into 1300 parts by weight of the triglyceride lace base, and the mixture was formed into laces, each containing a therapeutically effective amount of the active ingredient.

Preparation 1

Hard gelatin capsules were prepared using the following ingredients:

Quantity (mg / capsule) Sibutramine hydrochloride monohydrate 20 Lipase inhibitor 50, 100, 120 or 150 starch 200 Magnesium stearate 10 Pretty 280 to 380

Preparation 2

Tablets were prepared using the following ingredients:

Quantity (mg / capsule) Sibutramine hydrochloride monohydrate 10 Lipase inhibitor 50, 100, 120 or 150 Microcrystalline cellulose 400 Silicon dioxide 10 Stearic acid 5 Pretty 475 to 575

The ingredients were mixed and compressed into tablets.

The advantages of the present invention can be demonstrated by one or more of the following studies.

Study 1

Groups of normal adult male Sprague-Dawley CD rats (n = up to 12) received the following treatment

(a) Group 1; daily dose with sibutramine hydrochloride monohydrate (1, 3 or 10 mg / kg orally) plus lipase inhibitor adjuvant, oral.

(b) Group 2; twice daily a dose of a lipase inhibitor orally (e.g., 10, 20, 30, 40, 50, 100, or 150 mg / kg orally, preferably 10 or 20 mg / kg) plus the sibutramine excipient orally.

(c) Group 3; combination oral therapy with sibutramine hydrochloride monohydrate doses and a lipase inhibitor.

(d) Group 4; control, doses containing excipients of sibutramine and a lipase inhibitor.

Rats were allowed free access to a high fat diet. Food intake, water intake and body weight were measured daily and the duration of treatment was 15.21 or 28 days.

Study 2

Groups of obese female Zucker rats (n = 8-12) who received a high fat diet were given the following treatment

(a) Group 1; daily oral doses with sibutramine hydrochloride monohydrate for 14 days at a dose that significantly reduced body weight compared to the vehicle control (1, 3 or 10 mg / kg orally). Daily treatment for the next 14 days was performed with the same dose of sibutramine hydrochloride monohydrate orally plus

-22 lipase inhibitor (e.g. 10, 20, 30, 40, 50, 100 or 150 mg / kg orally, preferably 10 or 20 mg / kg).

(b) Group 2; daily doses with sibutramine hydrochloride monohydrate orally for 14 days. Daily treatment for the next 14 days with sibutramine orally and lipase inhibitor orally.

(c) Group 3; daily dosing with sibutramine hydrochloride monohydrate orally for 14 days followed by the combination therapy with sibutramine hydrochloride monohydrate orally and lipase inhibitor excipient orally for the following 14 days.

Study 3

Groups of normal adult male Sprague-Dawley CD rats (n = 8-12) received the following treatment:

(a) Group 1; administration with sibutramine hydrochloride monohydrate (1, 3 or 10 mg / kg orally) plus oral lipase inhibitor adjuvant

(b) Group 2; administration of a lipase inhibitor plus the adjuvant sibutramine orally

(c) Group 3; administration of the lipase inhibitor orally, plus the sibutramine excipient orally

(d) Group 4; administration of an oral lipase inhibitor plus a sibutramine excipient

Sibutramine was administered once daily, lipase inhibitors were administered (at the appropriate dose) up to three times daily. Groups 1, 3 and 4 had free access to a high fat diet all the time. Group 2 is a pair-fed group to the group treated with sibutramine (group 1), i. the animals were given the amount of food (high fat diets) received by the sibutramine-treated group during the previous 24-hour period. Food intake and body weight were measured daily and the duration of treatment was 4-5 days.

Statistical comparison between animal body weights in each group in one or more of the above studies provides results that demonstrate the advantage of the present invention.

Claims (5)

Use of a compound of formula I t CH, I h ₃ cchch ₂ CHNR r including enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are each independently H or methyl in the manufacture of a medicament for the treatment of obesity and associated co-morbid conditions in a patient who is also administered treatment with a lipase inhibitor, with the exception of orlistat. The use 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. The use of claim 2, wherein the compound of formula I is administered 30 minutes to 3 hours prior to administration of the lipase inhibitor. A composition comprising a compound of formula I, including its enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are, independently of one another, H or methyl, and a lipase inhibitor, with the exception of orlistat, as a combined preparation for simultaneous, separate or sequential use in the treatment of obesity and associated co-morbid conditions. A pharmaceutical composition comprising a compound of formula I CH, I h ₃ cchch CHNR ₂ R (H Including its enantiomers and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are, independently of one another, H or methyl, and a lipase inhibitor, with the exception of orlistat, together with a pharmaceutically acceptable diluent or carrier.