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Wo 2009/080693 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 2 July 2009 (02.07.2009) WO 2009/080693 A2 (51) International Patent Classification: AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, A61K 31/46 (2006.01) A61P 3/04 (2006.01) CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (21) International Application Number: IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, PCT/EP2008/067856 LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, MX, MY,MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, (22) International Filing Date: RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, 18 December 2008 (18.12.2008) TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, PA 2007 01834 20 December 2007 (20.12.2007) DK ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 61/016,067 2 1 December 2007 (21.12.2007) US European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, (71) Applicant (for all designated States except US): NEU- NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, ROSEARCH A/S [DK/DK]; Pederstrupvej 93, DK-2750 CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Ballerup (DK). (72) Inventor; and Declaration under Rule 4.17: (75) Inventor/Applicant (for US only): MEIER, Dieter, H. — as to applicant's entitlement to applyfor and be granted a [DE/DK]; NeuroSearch A/S, Pederstrupvej 93, DK-2750 patent (Rule 4.17(U)) Ballerup (DK). Published: (81) Designated States (unless otherwise indicated, for every — without international search report and to be republished kind of national protection available): AE, AG, AL, AM, upon receipt of that report (54) Title: PHARMACEUTICAL COMPOSITIONS (57) Abstract: This invention relates to novel pharmaceutical compositions comprising a therapeutically effective combination of a compound of Formula I and a beta blocker. The pharmaceutical compositions for use according to the invention are contemplated particularly useful for combating obesity or an obesity associated disease. PHARMACEUTICAL COMPOSITIONS TECHNICAL FIELD This invention relates to novel pharmaceutical compositions comprising a therapeutically effective combination of a compound of Formula I and a beta blocker. The pharmaceutical compositions for use according to the invention are contemplated particularly useful for combating obesity or an obesity associated disease. BACKGROUND ART Within the past decades the prevalence of obesity has risen in virtually all ethnic, racial and socioeconomic populations, in both genders and in all age groups. Obesity is associated with a significantly elevated risk for type 2 diabetes, coronary heart diseases, hypertension and numerous other major illnesses and overall mortality from all causes. Therefore, weight reduction is critical for the obese patient. Thus there is impetus for creating new and alternative treatments for management of obesity. Results from clinical studies with NeuroSearch proprietary compound tesofensine showed that the compound has a good safety profile and was well tolerated. However, though no clinically relevant cardiovascular adverse events or changes in either blood pressure or pulse were seen, some cardiovascular effects were measured with slight increases in heart rate and trends in blood pressure. Although such small effects have no immediate risk to the patient some medical and regulatory concerns have been raised based on observational studies that even small changes in cardiovascular parameters may have long term implications on patients' benefit/risk evaluation. SUMMARY OF THE INVENTION Investigations carried out by the inventors have lead to the conclusion that a combination of a compound of Formula I and a beta blocker constitute a particularly useful combination for use in therapy associated with obesity or an obesity associated disease. In its first aspect the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof and a beta blocker or a pharmaceutically acceptable salt thereof, together with one or more adjuvants, excipients, carriers and/or diluents. In another aspect the invention relates to the use of a combination of a compound of Formula I, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof and a beta blocker or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention or alleviation of obesity or an obesity associated disease of a mammal, including a human. In a third aspect the invention provides a kit of parts comprising at least two separate unit dosage forms (A) and (B), wherein (A) comprises a compound of Formula I, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof; and (B) comprises a beta blocker or a pharmaceutically acceptable salt thereof; and optionally (C) instructions for the simultaneous, sequential or separate administration of the compound of (A) and the beta blocker of (B) to a patient in need thereof. In a fourth aspect the invention provides a method of treatment, prevention or alleviation of obesity or an obesity associated disease of a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of a compound of Formula I, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof; and a beta blocker or a pharmaceutically acceptable salt thereof. Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples. DETAILED DISCLOSURE OF THE INVENTION In its first aspect the invention provides a pharmaceutical composition comprising a therapeutically effective amount of (i) a compound of Formula I wherein Ra represents hydrogen or alkyl; Rb represents a dihalophenyl group; any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof; and (ii) a beta blocker; or a pharmaceutically acceptable salt thereof; together with one or more adjuvants, excipients, carriers and/or diluents. Compounds of Formula I The compounds of Formula I for use according to the invention are monoamine neurotransmitter re-uptake inhibitors, and are described in WO 97/30997 (NeuroSearch A/S). The compounds may be prepared by conventional methods for chemical synthesis, e.g. those described in WO 97/30997 and WO 2005/073228. a In one embodiment of the compound of Formula I, R represents hydrogen or methyl. In a special embodiment, Ra represents hydrogen. In a further embodiment, Ra represents methyl. In a further embodiment of the compounds of Formula I, Rb represents dichlorophenyl. In a special embodiment, Rb represents 3,4-dichlorophenyl. In a still further embodiment, the compound of Formula I is tesofensine [(-/R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl- 8-azabicyclo[3.2.1]octane]; or (7R2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8- azabicyclo[3.2.1]octane; or a pharmaceutically acceptable salt thereof. In a special embodiment, the compound of Formula I is tesofensine or a pharmaceutically acceptable salt thereof. In a further special embodiment, the compound of Formula I is the citrate salt of tesofensine. Definition of Substituents In the context of this invention halo represents fluoro, chloro, bromo or iodo. In the context of this invention an alkyl group means a straight chain or branched chain of one to six carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl; methyl, ethyl, propyl and isopropyl are preferred groups. Steric isomers It will be appreciated by those skilled in the art that the compounds of Formula I may exist in different stereoisomer^ forms - including enantiomers, diastereomers and cis-trans-isomers. The invention includes all such isomers and any mixtures thereof including racemic mixtures. Beta blockers The present invention involves the use of a class of drugs known as beta blocking compounds or simply beta blockers. The beta blocker for use according to the invention is any conventional beta blocker known in the art. Preferably, the beta blocking drug is selected from the following groups of compounds, which groups of compounds are known in the art and may be commercially available under different brand names, or may be obtained as described in the literature: Non-selective beta blockers In one embodiment, the beta blocker for use according to the invention is a non-selective beta blocker. Examples of non-selective beta blockers include alprenolol, amosulalol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol. In one embodiment, the beta blocker is selected from the group consisting of alprenolol, amosulalol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol and pharmaceutically acceptable salts thereof. Beta 1-selective beta blockers In a further embodiment, the beta blocker for use according to the invention is a beta 1-selective beta blocker. Examples of beta 1-selective beta blockers include acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, metoprolol and nebivolol. In one embodiment, the beta blocker is selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, metoprolol, nebivolol and pharmaceutically acceptable salts thereof.
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