CZ20014614A3 - Therapeutic formulation - 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

Therapeutic agents

Technical field

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

BACKGROUND OF THE INVENTION

Sibutramine is 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 Buckett WR, Neuropharmacology 28: 129-134 (1989). Studies have shown that weight loss by two activities decreases food intake by increasing satiety (Fantino N. and Souquet, AM, Int. J. Obesity 19, 145, 1995; Halford JCG, Heak DJ and Blunde 11 JE, Brit. J. Pharmacol. 114, 387P, 1995: and Stricker-Krongrad A., Souquet AM and Burlet C., Int. J. Obesity 19, 145, 1995) and increase energy expenditure by stimulating thermogenesis (Connoley IP, Heal DJ and Stock MJ, Brit. J. Pharmacol. 114, 388P (1995; and Connoley IP, Frost I. Heal DJ and Stock MJ, Brit. J. Pharmacol. 117, 170P, 1995). Sibutramine has proven itself in the treatment of obesity in Sp. st. and at least 20 other countries around the world.

Lipase enzymes are involved in the decomposition of ingested fat (Borgstrom, Biochem. Biophys. Acta 962 (3), pp. 308-316, 1988) and, as a result, unabsorbed fat is excreted in the faeces. One such lipase inhibitor orlistate, which has proven itself in the treatment of obesity in Sp. st. a. and in Europe, it is chemically ················· 4 · 4 · ····

4 4 4 4 9 4

944,444,449 • 4,444,444 9,4444 lactone (2S, 3S, 5S) -5 - [(S) -2-formamido-4-methyl valeryloxy] -2-hexyl-3-hydroxyhexadecanoic acid. It is also known as N-formyl-L-1-eucine, (3S, 4S) -3-hexyl-4 - [(2S) -2-hydroxytridecyl] -2-oxethanone ester, (-) - tetrahydrolipstatin, tetrahydrolipistatin and orlistat. 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 orlistate 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).

The newspaper reported that orlistat should not be combined with appetite suppressants (The New York Times May 15, 1997). Co-pending PCT / EP 98/08249 discloses the use of a combination of a compound of the formula I described below and orlistat in the treatment of obesity. Surprisingly, it has now been found that the simultaneous administration of sibutramine hydrochloride monohydrate and a lipase inhibitor has a beneficial effect on weight loss.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a method of treating obesity and obesity-related conditions in a mammal in need thereof, particularly in a human, comprising administering to a mammal in need of such treatment, particularly a human, a therapeutically effective amount of a compound of Formula I

· 4 · 44 · 4 · 44 · 4 · 4 · 44 · 4 · 4 · 44 · 4 · 4 · 44 · 4 · 4 · 44 · 4 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 lipase inhibitor, provided that the 1βase inhibitor is not orlistat, wherein the compound of formula I and the lipase the inhibitor is administered simultaneously, separately or sequentially.

The invention has the following advantages. First, the maximum weight loss achieved is greater than that achieved by the administration of only a compound of formula I or a lipase inhibitor. Second, synergistic weight loss is achieved since weight loss by administering the compound of formula I and the lipase inhibitor to the first test group is greater than the 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 group. Third, when weight loss is compensated by administration of either a compound of Formula I or a lipase inhibitor, a further increase in weight loss is achieved by administering a second compound. Fourth, lower doses of a compound of formula I and a lipase inhibitor can be administered, thereby reducing the side effects associated with the administration of higher doses of each. Fifth, a synergistic improvement in the treatment of obesity-related diseases can be achieved compared to the administration of each of these compounds alone.

A preferred compound of formula I is N- {1- [1- (4-chlorophenyl) cyclobutyl-3-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 monohydrate.

The preparation and use of compounds of formula I, such as N-N- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl-N, N-dimethyl amine and its salt, for the treatment of depression is described in British Pat. No. 2098602. Use of compounds of general formula I, such as N- (1 -Ci- (4-chlorophenyl) cyclobutyl] -3-methylbutyl) N, N-dimethylamine and its salts, for the treatment of Parkinson's disease are described in PCT Publication No. WO 88/06444, the use of Ν- (1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl) -Ν , N-dimethylamine and its salts for the treatment of cerebral functional disorders is described in U.S. Pat. No. 4,939,175. The use of (- (1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl 1-N, N-dimethylamine hydrochloride for the treatment of obesity is described in European Patent Specification No. 397831. A particularly preferred form of this compound is Ν- <1- [1- (4-chlorophenyl) cyclobutyl 1-3-methyl] butyl 1-N, N-dimethylamine hydrochloride monohydrate (sibutramine hydrochloride monohydrate), which is described in European patent specification 230742. The use of N- (1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl) -N, N-dimethylamine and its salts for improving glucose tolerance in humans with impaired glucose tolerance or non-insulin-dependent diabetes mellitus are described in PCT publication WO 95/20949.

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; 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 environment, for example on a chiral carrier, for example on a silica with a chiral ligand attached, 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-Cl (4-chlorophenyl) cyclobutyl-3-methylbutyl-3-N, N-dimethylamino, N- <1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl-3-N -methylamine and N-1- [1- (4-chlorophenyl3cyclobutyl3-3-methylbutylamine) including racemates, individual enanantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof. Specific enantiomers of formula I are the (+3 -N- {1- [1- (4-chlorophenyl3cyclobutyl3-3-methylbutyl3 - N, N-dimethylamine, (-) - N- (1- [1- (4-chlorophenyl3cyclobutyl 3-3-methylbutyl) -N, N-dimethylamine), (R) - ( + - - N - [1- (4-Chlorophenyl) cyclobutyl-3-methylbutyl] -N-methylamine, (S3 (-) - N - [1- (4-chlorophenyl) -3-cyclobutyl] -3-methylbutyl) -N-methylamine, (R) - (+) -1-11- (4-chlorophenyl3-cyclobutyl3-3-methylbutylamine) and (S) (-) - 1-11- (4-chlorophenyl3-cyclobutyl3-3-methylbutylamine).

Suitable lipase inhibitors include pancreatic lipase inhibitors, gastric lipase inhibitors, carboxyester lipase inhibitors and further include, but are not limited to, kaulerpenine disclosed in Japanese Patent Publication No. JP 10203974A2, Application No. 97JP-0014334;

The panelicin A-E described in J. Chem. Soc. Perkin Trans. 1 (8), pp. 1373-1382, 1998;

(-) - panelicin D described in Tetraahedron 53 (48, 16471-16488, 1997;

procyanidine and its analogs described in WO 97/23210;

lipase inhibitors isolated from cereals or from legumes described in Japanese Patent Application JP04321700A2, Application No. 91JP-0110814;

EP-444482 describes 4- (acyloxyethyl) oxetan-2-ones of the general formula

where it means

Q group of formula (R ₃ , R 4) NCO (X) _n -CO-Q 1 (R ₃ , R 4) NCO-X, q ₂

q ₃ carbon to substrate

R ¹ and R ^{2 are} C ¹ -C ³ alkyl or C 1 -C 3 alkyl, alkenyl, alkynyl or alkadienyl, optionally interrupted by 1,4-arylene, optionally substituted by aryl in the omega position and optionally substituted (C 1 -C 4) arylalkyl;

wherein R ¹ is optionally interrupted by an oxygen or sulfur atom or a sulfinyl or sulfonyl group in a position other than the α position to the unsaturated carbon atom or R ¹ represents an aryl-NH- or arylalkyl-OCONH group having 1 to 4 carbon atoms in the alkyl moiety,

R ³ and R ^{4 are} hydrogen or alkyl of 1 to 4 carbon atoms or together with the nitrogen atom to which they are attached a saturated three to six-membered ring optionally containing an oxygen or sulfur atom in a position other than the a-nitrogen position, η 1 or O,

X is an alkylene group having up to 6 carbon atoms optionally interrupted by an oxygen or sulfur atom or a sulfinyl or sulfonyl group and optionally substituted by hydroxy, mercapto, aryl, aryloxy, arylthio, arylalkyl of 1 to 4 carbon atoms in the alkyl moiety, arylalkoxy of 1 and carbon atoms in the alkyl moiety, arylalkylthio of 1 to 4 carbon atoms in the alkyl moiety, arylalkylidene of 1 to 4 carbon atoms in the alkylidene moiety, a cycloalkylidene of 3 to 7 carbon atoms or an alkylidene of 1 to 6 carbon atoms or one or two (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio and two (C1-C6) alkyl, (C1-C6) alkoxy or (C1-C6) alkylthio on the same carbon atom or on two adjacent carbon atoms they may form an optionally monounsaturated three to seven membered ring and optionally a hydroxyl group or mer8

9 * 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 9 9

the capo group or optionally unsaturated carbon atom must be in a position other than the position and to the optionally present oxygen or sulfur atom or the optionally contained sulfvinyl or sulfonyl group or

X is = CHN (R, R °) or -CHN (R, R °) CH 3 -, where

R, R ° are hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl - C 1 -C 4 alkyl, aryl, aryl (CO or OC 0) -, C 1 -C 4 arylalkyl in the alkyl moiety, arylalkyl (CO or OC) - (C 1 -C 4) alkyl moiety, and

^X 'is alkylene having up to 6 carbon atoms which is optionally substituted by alkoxy having 1 to 4 carbon atoms, an aryl group, ary1oxyskupinou, arylthio, arylalkyl having from 1 to 4 carbon atoms in the alkyl moiety, aryl having 1 to 4 carbon atoms in the alkyl or a (C 1 -C 4) arylalkylthio group or one or two (C 1 -C 6) alkyl groups, wherein the two (C 1 -C 6) alkyl groups attached to adjacent carbon atoms may form a three to seven membered ring:

such particularly preferred compounds are selected from the group consisting of:

(S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanylmethyl] dodecyl (S) -2-isopropylmalonamate, (S) -1- [[(2S, 3S) -3- hexyl 4-oxo-2-oxetanyl] methyl dodecyl (S or R) -2-carbamoyl valerate, (all Z, S) -1-CC (2S, 3S) -3-ethyl-4-oxo-2-oxetanylmethyl1-9 -12-octadecadienyl (S) -2-isopropylmalonamate, (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] 9

methylIdodecyl (S) -2-isopropylmalonamate, (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methylIdodecyl (S: R (2: 1)) - 2 -isopropylmalonamate, (S) -1- [t (2S, 3S) -3-ethyl-4-oxo-2-oxetanylmethyl-octadecyl (S or R) -2-tert-butylmalonamate, (S) -1 - [[(2S) (3S) -3-ethyl-4-oxo-2-oxetanylmethyl-octadecyl-1-carbamoyl-cyclopentanecarboxylate, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanylmethyl] -dodecyl (RS) -2 -benzyl malonamate, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanylmethyl] dodecyl (3 - [(2-carbamoylethyl) thiolpropionate,

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

5-oxo-L-proline- (S) -1 -C [(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl-3-methyl-octadecyl ester, (S) -1 - [[(2S, 3S) -3- hexyl 4-oxo-2-oxetanylmethylidodecyl (S or R) -2-isopropylmalonamate, (S) -1 - (((2S, 3S) -3-hexyl-4-oxo-2-oxetanyl3-methyl 3dodecyl (RS) -2 -carbamoylvalerate (1: 1 epimers), (all Z, S) -1-11 (2S, 3S) -3-ethyl-4-oxo-2-oxetanylmethyl] -9,12-octadecadienyl (S or R) -2 (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-carbamoyl-4-methyl valerate (epimers 1: 1) (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl 3dodecyl-1-carbamoylcyclohexanecarboxylate, (S) -1 - [[(2S, 3S) -3- hexyl 4-oxo-2-oxetanylmethyl3 dodecyl (RS) -2-methylmalonamate (epimers 1 = 1), (S) -1 - (((2S, 3S) -3-hexyl-4-oxo-2-oxetanylmethyl) dodecyl ( RS) -2-ethylmalonamate (1: 1 epimers), (S) -1-t C (2S, 3S) -3-hexyl-4-oxo-2-oxetanylmethyl-dodecyl (RS) -2-butylmalonamate (1: 1 epimers) (S) -1-CC (2S, 3S) -3-ethyl-4-oxo-2-oxetanylmethyl-octadecyl-1-carbamoylcyclohexanecarboxylate, (S) -1 - [[(2S, 3S or 2R, 3R) -4- oxo-3-pentylthio-2-oxethanes13 10

ΦΦΦΦ ·· 9 φφ φ ·

Φ Φ 9 ΦΦΦΦ ΦΦΦΦ

9 9 9 9 9

4-H-methyl-dodecyl (S: R or R = S (2: 1)) -2-isopropylmalonamate, (S) -1 - [[(2R, 3R) -3-benzyl-4-oxo-2] -oxetanyl] -methylidodecyl (S or R) -2-isopropylmalonamate;

N-formylleucine-1- (oxetanoylmethyl) alkyl esters and analogs disclosed in U.S. Pat. Nos. 4,931,463, 5,175,186, 5,246,660 of the general formula

where it means

R @ ¹ and R @ ^{2 are} each independently C1 -C17 alkyl which is saturated or optionally interrupted by up to eight double or triple bonds and / or optionally interrupted by an oxygen or sulfur atom which is present in a position other than the cf-position to an unsaturated carbon atom, or to a phenyl, benzyl or -C6H4-X-C6H5 ring substituted with up to three alkyl (O or S) groups of 1 to 6 carbon atoms,

X is oxygen, sulfur or (CH 2) 0-3,

R ³ is hydrogen, alkyl of 1-3 carbon atoms, use or alkanoyl group having 1-3 carbon atoms;

R ( ⁴⁾ is hydrogen, (C1-C3) -alkyl,

R @ ⁵ is hydrogen, Ar or C1 -C3 -alkyl, or C1 -C7 -alkyl optionally interrupted by Y and optionally substituted by Z, or

R ⁴ and R ⁵ together form a four to six-membered saturated ring, w * ·· ♦ 4 • 4 4 ·· 4 44 44 • 4 4 4 4 4 4

4 4 4 4 4

444 44 444

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

N (R ^fe ) C (O)

Z is - (0 or S) R ^7, -N (R ^7, R ^S), - C (O) N (R ^7, R ^s) or

-N (R ⁷ ) C (O) R ^S , η 1 or O, provided that R ⁵ represents a hydrogen atom when n represents 1,

Ar phenyl unsubstituted or substituted by up to three R ⁹ or OR ⁹ groups,

R ^6, R ^7, R ^s and R ⁹ are independently hydrogen or alkyl having 1-3 carbon atoms with the proviso that R ⁴ is not hydrogen when R ³ is formyl and R ⁵ butyl or R ³ acetyl and R ⁵ carbamoylmethyl and simultaneously R ² group, undecyl or 2,5-undekadienylovou and R ¹ is n-hexyl, enantiomers or diastereomers thereof, or a pharmaceutically acceptable addition salt thereof, especially a compound selected from the following group:

N-formyl- (S) -leucine- (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanylmethyl-octadecyl ester, or a pharmaceutically acceptable acid addition salt thereof, particularly

N-formyl-L-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-L-leucine (9Z, 12Z) -1-C [(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl) methyl 3-9,12-octadecadienyl ester, • fc. · Fcfc · fcfc · * * β β β β β c c c c c * c * *

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

N-formyl-L-1-fluoro- (R) - <* - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl) methyl] -p-phenoxybenzyl ester, or a pharmaceutically acceptable salt thereof an acid addition salt;

the tetrahydrolipstatin analog described in Helv. Chim. Acta 70 (5), pp. 1412-1418 (1987), in which R represents an ethyl group o

OCH-Leu — 0

Me (CH 2) 1 oxetanones disclosed in EP 189577 of the general formula

Y O X, o

I II I / V from the -NH-CH-C-O-CH-CH ₂ - (S) + A ⁰ (S) (S) ^x (S)

C ₆ where X is undecyl or 2Z, 5Z-undekadienylovou, R ⁶ is n-hexyl, Y is isobutyl and Z is formyl or Y is carbamoylmethyl and Z acetyl!

at the 1-position substituted 2-alkanone derivatives described in Chem. Pharm. Bull. 34 (3): 1118-1127 (1986);

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

taurine and glycine derivatives disclosed in U.S. Pat

99 449 9 ·· 9 99 44 4 »» 4 • • 49 4 • 4 4 • • • 4 • 9 * 4 • • 9 4 4 • 9 • 4 • 99 • 4 « • 49 99 • • 44

wherein R represents hydrogen, alkanoyloxy or BzO R ¹ group, CO2H, alkoxycarbonyl, CH2SO3H, m and n is 0 or 1;

1,2-dioleoyl-3- (α-1-adamantoyl) -sn-glycerol and 1-adamantanecarboxylic acid, described in J. Pharm. Sci. 65 (8), pp. 1,243-1245, 1976;

wheat-derived peptides described in JP07330794 A;

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

flavanoid and flavanoids and their glycoside or glycosides thereof described in Japanese Patent Specification JP09143070 A. ' triterpenes disclosed in Japanese Patent No. JP 09040689 A;

hinokitiol disclosed in Japanese Patent JP 08268882 A;

flávanoid compounds disclosed in JP 07061927 A;

the (metal-substituted) chlorophilin described in JP 05252898 A;

2-oxethanone derivatives disclosed in European Patent No. EP 443449a of the general formula

···················································· ···

R ¹ and R ^{3 are} C ¹ -C 17 alkyl optionally interrupted by an oxygen atom other than α or β or a benzyl group optionally substituted with one to three C 1 -C 16 alkyl or C 1 -C 16 alkoxy groups ku,

X is hydrogen or (R ³ , R ⁴ ) NCH (R ⁵ ) (CH 2) n - CO -,

R ³ is hydrogen or alkyl having 1-3 carbon atoms or an alkanoyl group having 1-3 carbon atoms;

R ( ⁴⁾ is hydrogen or (C1-C3) -alkyl;

R ⁵ is hydrogen, Ar or Ar-C 1 -C 3 -alkyl or C 1 -C 7 -alkyl optionally interrupted by Y and optionally substituted by Z; or

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

Y is an oxygen or sulfur atom or a N (R ⁶ ), C (O) N (R ⁶ ) or N (R ⁶ ) C (O) group,

Z - (O or S) R ⁷ , N (R ⁷ R ^S ) or N (R ⁷ ) C (O) R ^S , n 1 or O, wherein when R ⁵ is hydrogen, n is 1, ···· · · · · · · · · · · · · ·

Ar phenyl substituted with one to three groups R ⁹ or OR ⁹ a

R ( ⁶⁾ to R ( ⁹⁾ is hydrogen or alkyl of 1 to 3 carbon atoms and oxethanone salts of the formula (I) in which X is not hydrogen with weak acids;

lipstatin and tetrahydrolipstatin derivatives disclosed in EP 129748A with the exception of orlistat;

the non-absorbable cationic derivative of the olefin-maleic acid copolymers disclosed in U.S. Pat. No. 4,211,765A:

bile acid and triglyceride-absorbent resin disclosed in British Patent Specification GB 1 286949: and compounds such as ATL-962 and analogs thereof described in the patent applications for this compound and in the patent publications concerning its analogs.

In the method of the invention, the compound of formula I and the lipase inhibitor 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 thereof and a lipase inhibitor with the exception of orlistat for simultaneous, separate or sequential administration for the treatment of obesity and disease conditions associated with obesity.

The invention also relates to compounds of formula I,

444444 ·· · 4 4 ·· • 4 4 4 4 4 4 · · 4 4 4 4 4 · · · · · · 4 4 «4 4 ··· ·

4 4444444 • 4 4 44 444 44 4444 wherein R ¹ and R ³ are independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof and a lipase inhibitor with the exception of orlistat as a combined preparation for simultaneous, separate or sequential administration in the treatment of obesity and obesity-related conditions.

The invention also relates to a product comprising a compound of formula I, wherein R ¹ and R ^{3 are} each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and a lipase inhibitor, with the exception of orlistat as a combined preparation for simultaneous, separate or sequential administration in the treatment of obesity and 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 the manufacture of medicaments for the treatment of obesity and disorders associated with obesity in a patient who is being treated with also with a lipase inhibitor except orlistat.

The invention further 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 a lipase inhibitor, with the exception of orlistat.

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

As used herein, obesity-related conditions refer to obesity-related diseases known to those skilled in the art. Without limitation, the disease states include: diabetes, including non-dependent diabetes mellitus

insulin, impaired glucose tolerance, depression, anxiety, psychoses (eg schizophrenia), slowly developing dyskinesia, drug addiction, drug abuse, consciousness disorders, Alzheimer's disease, cerebral ischemia, compulsive behavior, anxiety attacks, social phobias, 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, e.g. incontinence, hyperactive disorders, hernia and inflammation of the esophagus, soreness, especially neuropathic soreness, weight gain associated with drug treatment, chronic fatigue syndrome, osteoarthritis and posterior gland, weight-related cancer, 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.

The amount of each compound administered depends on a variety 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: generally 0.1 to 50 mg, preferably 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. The lipase inhibitor may be administered in an amount of 50 to 1440 mg in single or multiple doses, e.g., 9 to 9 mg / day. tttt tttttt tttttttt tt ttttt ttttttttt preferably three times a day, more preferably 50 to 1500 mg and most preferably 100 to 1000 mg. The compound of formula (I), preferably sibutramine hydrochloride monohydrate, can be administered in any known dosage form. The lipase inhibitor is preferably administered orally.

In a preferred embodiment of the invention, sibutramine hydrochloride monohydrate is administered once daily, preferably on the first morning, and the lipase inhibitor is administered three times daily with or before a meal. Preferably, a dose of 20 or 30 mg sibutramine hydrochloride monohydrate is administered once daily and a dose of 50, 100, 120 or

150 mg lipase inhibitor is administered three times a day with or before a meal. Preferably, the dose of sibutramine hydrochloride monohydrate is administered before the first dose of the lipase inhibitor, preferably 30 minutes to 3 hours, for example 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours before the first dose of the lipase inhibitor.

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

CH,

H, CCHCH ₂ CHNR ₁ R ₂ (I)

Cl

wherein R ¹ and R ^{2 are} each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and a lipase inhibitor except orlistat 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 in the preparation of such compositions are excipients known in the art of medicaments19. 4 4 4 4 4 4

4 44 ··· ·· ····. Tablets may be formulated with mixtures 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. The tablets may optionally be coated with known 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 1000 mg of a lipase inhibitor.

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 compounds 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, effervescent mixtures formed of an acid and a carbonate or bicarbonate salt to facilitate dispersion in a liquid medium.

The compounds of formula (I) and the lipase inhibitor may be formulated into formulations which the patient retains in an oral manner by administering the active compounds to 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 to administer the compounds 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 from a pump or volatile propellant package.

The compounds of formula (I) may 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. The internal sources may be implanted containers containing infused compounds that are continuously released, for example by osmosis, and implants which may be (a) liquid, as an oil suspension of infused 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 a portion 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.

Pharmaceutical compositions containing both a compound of Formula I and a lipase inhibitor 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 means one or both of the compounds of the invention, unless otherwise indicated.

The invention is illustrated by the following examples

DETAILED DESCRIPTION OF THE INVENTION

(a) Capsules

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 and new capsules containing a unit dose or part of a unit dose of the active compound.

(b) Tablets

Tablets are prepared from these ingredients in parts by weight ¹ active compound 10 lactose 190 corn 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.

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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 is incorporated into 1300 parts of the triglyceride carrier and the mixture is formed into suppositories containing a therapeutically effective amount of the active ingredient.

Formulation 1

Hard gelatin capsules are prepared from the following ingredients:

Amount (mg / capsule with butyramine hydrochloride monohydrate 20 May 1-phase inhibitor 50, 100, 120 or 150 starch 200 • magnesium stearate 10 in Total 350

Formulation 2

The tablet is prepared from the following ingredients:

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4 · 4 4 · ··· ··

Quantity (mg / tablet) with butyramine hydrochloride monohydrate 20 May 1 i stroke i nh i b i tor 50, 100, 120 or 150 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 the following tests

Test 1

Groups of normal adult male Sprague-Dawley CD rats (n = 8-12) are treated as follows:

(a) Group 1 daily administration of sibutramine hydrochloride monohydrate (1, 3 or 10 mg / kg orally) plus orally administered lipase inhibitor carriers.

(b) Group 2; twice daily administration per os of a lipase inhibitor (e.g., 10, 20, 30, 40, 50, 100 or 150 mg / kg orally, preferably 10 or 20 mg / kg) plus orally administered sibutramine carriers.

(c) Group 3; combined oral treatment with sibutramine hydrochloride monohydrate and lipase inhibitor.

d) Group 4: control, orally administered sibutramine and a lipase inhibitor carrier.

Rats allowed free access to a fat-rich diet.

Food intake, water intake and body weight are measured daily and the treatment lasts 15, 21 or 28 days.

Test 2

Groups of obese female Zucker rats (n = 8-12) maintained on a high fat rich diet are treated as follows:

(a) Group 1, daily administration of sibutramine hydrochloride monohydrate for 14 days at a dose that significantly reduces body weight compared to vehicle-treated controls (1, 3 or 10 mg / kg orally). Daily treatment for an additional 14 days is administering the same dose of sibutramine hydrochloride monohydrate orally plus a dose of a 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 administration of sibutramine hydrochloride monohydrate for 14 days. Daily treatment for an additional 14 days is oral administration of sibutramine and a lipase inhibitor carrier.

c) Group 3: daily administration per os of the carrier of sibutramine hydrochloride monohydrate for 14 days followed by combined treatment for an additional 14 days per os by administration of the carrier sibutramine hydrochloride monohydrate and per os carrier of the lipase inhibitor.

Test 3

Groups of normal adult male Sprague-Dawley CD rats (n = 8-12) are treated as follows:

a) Group 1: oral administration of sibutramine hydrochloride monohydrate (1, 3 or 10 mg / kg) plus lipase inhibitor carriers per os.

b) Group 2: oral administration of lipase inhibitor plus sibutramine carriers per os.

(c) Group 3; administration of the lipase inhibitor orally plus carriers of sibutramine orally.

(d) Group 4; administration of the lipase inhibitor carrier per os plus the sibutramine carrier per os.

Sibutramine is dosed once daily, lipase inhibitor »4,444« · 4

It is administered (in suitable doses) up to three times a day. Groups 1, 3 and 4 still have free access to a fat-rich diet. Group 2 is paired with the sibutramine treated group (group 1), i.e. the animals are given the same amount of feed (fat-rich diet) as the sibutramine treated group during 24 hours. hours. Food intake and body weight are measured daily at the 4-5 day test duration.

Statistical comparison of animal body weight in each group in one or more of the above assays provides results demonstrating the advantages of the invention.

and

Industrial applicability

Use of sibutramine or a salt or metabolite thereof and a lipase inhibitor for the manufacture of a pharmaceutical composition for the treatment of obesity and obesity-related conditions.

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Claims (8)

PATENT CLAIMS A method for treating obesity and 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, H ₃ CCHCH ₂ CHNR, R _{2 '} ; 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 lipase inhibitor with the exception of orlistat, wherein the compounds of formula I and the lipase inhibitor are administered simultaneously, separately or then. 2. 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. The method of claim 2, wherein the compound of formula I is administered 30 minutes to 3 hours prior to administration of the lipase inhibitor. 4. A compound of formula I wherein R ¹ and R ² are independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof and a lipase inhibitor with the exception of orlistat for simultaneous, separate or sequential administration for the treatment of obesity and related disease states with obesity. • 9 · 999 · 9 9 9 9 · 9 9 9 99 9 9 9 • 99 9 9 9 9 9 9 99 99 99 99 99 99 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 lipase inhibitor, with the exception of orlistat, as a combined preparation for simultaneous, separate or sequential administration for the treatment of obesity; obesity-related disease states. 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 lipase inhibitor with the exception of orlistat as a combined preparation for simultaneous, separate or sequential administration for treatment obesity and obesity-related disease states. 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 the manufacture of a medicament for the treatment of obesity and obesity-related conditions for patients treated with a 1-phase inhibitor except orlistátu. 8. A pharmaceutical composition comprising a compound of formula (I) H ₃ CCHCH ₂ CHNR ₁ R ₂ wherein R ¹ and R ^{2 are} each independently hydrogen or methyl, including enantiomers and pharmaceutically acceptable salts thereof, and a lipase inhibitor with the exception of orlistate.