CA2543197A1 - Combination treatment of obesity involving selective cb1-antagonists and lipase inhibitors - Google Patents

Abstract

The present invention relates to a novel medical use of selective CB1 receptor antagonistic compounds in combination with lipase inhibitors. Said compounds are particularly suitable in combination with lipase inhibitors in the manufacture of medicaments for the treatment and/or prophylaxis of obesity in adolescent or in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as in adolescent patients. The CB1 receptor antagonistic compounds suitable according to the invention are elucidated in more detail in the description. Preferred lipase inhibitors are orlistat, panclicins, ATL-962 and/or lipstatin.

Description

COMBINATION TREATMENT OF OBESITY INVOLVING SELECTIVE CBS.-ANTAGONISTS AND
LIPASE
INHIBITORS
The present invention relates to a novel therapeutic and/or prophylactic treatment of obesity by administering a combination of CBS-antagonistic compounds together with a further active principle, and to pharmaceutical compositions containing at least one of these CBS-antagonistic compounds in combinatiowrvith said further active principle for the treatment and/or prophylaxis of obesity.
The combination provided by the present invention of a compound showing potent Cannabis-1 (CBS) receptor antagonistic activity with said further active principle are of particular utility for treating of obesity.
Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J.J. Prog.
Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CBS
and CB2) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, L.A.;
Bonner, T.I. Cannabinoid Receptors, Pertwee, R.G. Ed. 1995, 117, Academic Press, London). 1n addition, pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system. The wide distribution of CBS receptors in the brain, in combination with the strictly peripheral localization of the CBz receptor, makes the CBS receptor a very interesting molecular target for CNS-directed drug discovery in the areas of both psychiatric and neurological disorders (Consroe, P.
Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS
Investigational DiUgs 1999, 7, 587. Greenberg, D.A. Drug News Perspect.
1999, 72, 458). Hitherto, three types of distinct CBS receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CBS
receptor antagonists. A representative example is SR-141716A, which is currently undergoing Phase l! clinical development for psychotic disorders (Dutta, A.K.;
Sard, H.; Ryan, W.; Razdan, R.K.; Compton, D.R.; Martin, B.R. Med. Chem. Res.
1994, 5, 54. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S.R.; McCallion, D.;

Pertwee, R.; Makriyannis, A. J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E.M.; Moerschbaecher, J.M.; Barker, L.A. CNS Drug Rev. 1999, 5, 43).
Aminoalkylindoles have been disclosed as CBS receptor antagonists. A
representative example is lodopravadoline (AM-630), which was introduced in 1995. AM-630 is a CBS receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K.; Quock, R.M.; Hosohata, Y.; Burkey, T.H.;
Makriyannis, A.; Consroe, P.; Roeske, W.R.; Yamamura, H.i. Life Sc. 1997, 67, PL115). More recently, researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CBS receptor antagonists (e.g. LY -320135) (Felder, C,C.; Joyce, K.E.; Bri(ey, E.J.; Glass, M.; Mackie, K.P.; Fahey, K.J.;
Cullinan, G.J.; Hunden, D.C.; Johnson, D.W.; Chaney, M.O.; Koppel, G.A.; Brownstein, M.
J. Pharmacol. Exp. Ther. 1998, 284, 291 ). Recently, 3-alkyl-5,5'-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M.; Govaerts, S.J.; Hermans, E.; Poupaert, J.H., Lambent, D.M. 8iorg. Med,Chem. Lett. 1999, 9, 2233). Interestingly, many CBS receptor antagonists have been reported to behave as inverse agonists in vitro (i_andsman, R,S.; Burkey, T.H.; Consroe, P.;
Roeske, W.R.; Yamamura, H.I. Eur. J. PharmacoL 1997 , 334, R1 ). Recent reviews provide a nice overview of the current status in the cannabinoid research area (Mechoulam, R.; Hanus, L.; Fride, E. Prog, Med. Chem. 1998, 35, 199.
Lambent, D.M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, .R.; Fride, E.; Di Marzo, V. Eur. J. Pharmacol. 1998 , 359, 1 ). From the international patent application WO 01/70700 4,5-dihydro-1 H-pyrazole compounds are known which exhibit potent and selective cannabis CBS-receptor antagonistic activity.
It is an objective of the invention to provide improved methods of treatment and/or prophylaxis for the treatment of obesity, particularly methods of treatment and/or prophylaxis for the treatment of obesity suitable in patient groups with enhanced need of safety and tolerability, e.g . in particular such as juvenile obesity patients and/or patients subject to long term treatment, e.g. in drug induced obesity in juvenile or adolescent patients.
It has now surprisingly been found that selective CBS-antagonists in general, prodrugs thereof, tautomers thereof' and salts thereof, show a unigue pharmacological profile and therefore are particularly suited in combination with at least one lipase inhibiting compound (lipase inhibitor) for the use in the manufacture of a medicaments for the treatment and/or prophylaxis of obesity in patients of any age, and in particular also for the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile, as well as adolescent, patients. In this regard combinations of at least one CBS
antagonistic compound with at least one lipase inhibiting compound are highly valuable in providing medicaments for the treatment and/or prophylaxis of obesity in general, e.g. in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and also in drug induced obesity in adolescent and juvenile patients.
Therefore, the invention also pertains to the combination of a CBS
antagonistic compound, which is a potent and selective antagonist of the cannabis CB~-receptor, or a prodrug, tautomer or salt thereof, with at least one lipase inhibiting compound. In a variant, the invention pertains to the combination, wherein the combination is in a medicament for the treatment and/or prophylaxis of obesity, including in particular the treatment and/or prophylaxis of obesity in juvenile patients andlor drug induced obesity in juveniie as well as adolescent patients.
The term "selective" means that preferably there is no substantial other activity than the CBS-receptor antagonistic activity, or that at least the CB1-receptor antagonistic activity is substantially overcompensating any other activity.
The outstanding unique pharmacological profile of selective CBS-antagonistic compounds includes particularly high safety and tolerability which make the compounds particularly suitable in combination with lipase inhibiting compounds in patient groups with enhanced need of safety and tolerability, in particular such as juvenile patients and/or patients subject to long term treatment, e.g. in drug induced obesity.
Due to the potent and selective CBS antagonistic activity the compounds (CBS
antagonists) used according to the invention are suitable also in combination with other drugs, in particular in combination with lipase inhibiting compounds according to the present invention. Thus the CBS antagonistic compounds in combination with lipase inhibiting compounds are particuiariy suitable also in patient groups with enhanced need of safety and tolerability, in particular such as juvenile patients and/or patients subject to long term treatment, e.g. in drug induced obesity.
This safety and tolerability of CBS antagonistic compounds in combination with lipase inhibiting compounds is advantageous in the treatment and/or prophylaxis of obesity in those patient populations where a single treatment is not sufificientiy effective and a combination treatment and/or prophylaxis involving different medical or metabolic mechanisms is desired or required for achieving and stabilizing a defined degree of weight loss.
Hence, combination of CBS antagonistic compounds with lipase inhibiting compounds according to the present invention is expected to be very is advantageous in the treatment and/or prophylaxis of obesity in general, e.g.
of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug induced obesity.
The CB1 receptor modulating activity of the compounds of the invention makes them particularly useful in the treatment of obesity, juvenile obesity and drug induced obesity, when used in combination with lipase inhibitors. Specific examples of lipase inhibiting compounds which can be used in such combination preparations are (but not restricted to) the synthetic Lipase inhibitor orlistat, panclicins, lipase inhibitors isolated from micro organisms such as lipstatin (from Streptomyces toxytricini~, ebelactone B (from Strepfomyces aburaviensis), synthetic derivatives of these compounds, 2-oxy-4H-3,1-benzoxazin-4-one derivatives like ATL-962 and structurally related compounds, 2 -amino-4H-3,1-benzoxazin-4-one derivatives, as well as extracts of plants known to possess lipase inhibitory activity, for instance extracts of Alpinia officinarum Hance or compounds isolated from such extracts like 3-methylethergalangin (from A.
otficinarum). The lipase inhibiting compound may also be a lipase inhibiting polymer. These lipase inhibiting compounds and their manufacture are well known in the state of the art.
As indicated already above, the invention also pertains to a combination of a CBS
antagonistic compound, which is a potent and selective antagonist of the cannabis CBS-receptor, or a prodrug, tautomer or salt thereof, with at least one lipase inhibiting compound; and in a further variant, the invention pertains to a combination, wherein the combination is in a medicament for the treatment and/or prophylaxis of obesity, including in particular the treatment andlor prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients. In these combinations according to the invention the CBS receptor antagonistic compound is selected from the group of 1 ) Diarylpyrazole selective CBS receptor antagonists, preferably the compounds SR-141716A, rimonabant and related compounds, SR-147778, SR-140098 and/or WIN-54461;

2) Aminoalkylindoles selective CBS receptor antagonists, preferably the compound lodopravadoline (AM-630);
3) Aryl-aroyl substituted benzofuran compounds with selective CBS receptor antagonistic activity, preferably the compound LY-320135;

5 4) Selective CBS rec eptor antagonistic compounds AM251 and/or AM281, and substituted imidazolyl compounds with selective CBS receptor antagonistic activity;
5) Azetidine derivatives with selective CBS receptor antagonistic activity;

6) The compound CP-55940;

7) Diaryl-pyrazine-amide with selective CBS receptor antagonistic activity;

8) The compounds ACPA and ACEA;

9) Pyrazole derivatives with selective CBS receptor antagonistic activity;

10) The compounds HU-210 and/or HU-243;

11 ) The compounds O-585, O-823, O-689, O-1 D72, andior O-2093;

12) 3-Alkyl-5,5'-diphenylimidazolidinediones with selective CBS receptor antagonistic activity 13) CB1 antagonistic compounds with selective CB1 receptor antagonistic activity.
In yet a further variant, the invention pertains to a combination, wherein the CBS
receptor antagonistic compound is in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.
The selective CBS antagonistic compounds used in the present the invention can be obtained according to known methods. Suitable ways of synthesis for the compounds used according to the present invention are described in the state of the art, e.g. in the documents cited in the present application and incorporated by reference.
Examples of selective C8~ antagonistic compounds being relevant in the context of the present invention and incorporated by reference are for example (but not being limited thereto):
1 ) Diarylpyrazole congeners disclosed by Sanofi as selective CBS receptor antagonists, e.g. as representative example the compound SR-141716A, rimonabant and related compounds described e.g. in EP 0969835, SR-147778, SR-140098 (Central mediation of the cannabinoid cue: activity of a selective CB1 antagonist, SR 141716A Perio A, Rinaldi-Carmona M, Maruani J Behavioural Pharmacology 1996, 7:1 (65-71) ); WIN-54461 disclosed by Sanofi-Winthrop (Cannabinoid receptor ligands : Clinical and neuropharmacological considerations relevant to future drug discovery and development. Pertwee RG, Expert Opinion on Investigational Drugs 1996, 5:10 (1245-1253) ) 2) Aminoalkylindoles having been disclosed as CBS receptor antagonists, e.g. as a representative example the compound iodopravadofine (AM-630), 3) Aryl-aroyl substituted benzofurans described by Eli Lilly as selective CBS

receptor antagonists, e.g.LY-320135 (Cannabinoid receptor ligands Clinical and neuropharmacological considerations relevant to future drug discovery and development. Pertwee RG, Expert Opinion on Investigational Drugs 1996, 5:10 (1245-1253) ), 4) Compounds described by Merck & Co, e.g. AM 251 and (Conference: 31 st Annual Meeting of the Society for Neuroscience, San Diego, USA, 10-15.11.2001 ), and substituted imidazolyl derivatives disclosed e.g. in US 2003-114495 or WO 03/007887, 5) Azetidine derivatives described by Aventis Pharma e.g. in WO 02/28346 or EP 1328269, 6) CP-55940 from Pfizer Inc. (Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors, Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL, Molecular Pharmacology 1995, 48:3 (443) ), 7) Diaryl-pyrazine-amide derivatives from Astra Zeneca described e.g. in the WO 03/051851, 8) ACPA and ACEA from Med. Coll. Wisconsin (Univ. Aberdeen), ("Effects of AM 251 & AM 281, cannabinoid CB1 antagonists, on palatable food intake in lewis rats" J.PharmacoLExp.Ther. 289, No3, 1427-33, 1999), 9) Pyrazole derivatives described by the University of Conneticut e.g. in the WO 01 /29007, 10) HU-210 (internationai Association for the Study of Pain -Ninth Worid Congress (Part II) Vienna, Austria, Dickenson AH, Carpenter K, Suzuki R, IDDB MEETING REPORT 1999, August 22-27) and HU-243 (Cannabinoid receptor agonists and antagonists, Barth F, Current Opinion in Therapeutic Patents 1998, 8:3 (301-313)) from Yissum R&D Co Hebrew Univ. of Jerusalem, 11 ) O-823 from Organix Inc. (Drug development pipeline:
O-585, O-823, 689, O-1072, nonamines, Orgaix, Altropane Organix inc, Company Communication 1999, August 10; IDDb database) and O-2093 from r Consiglio Nazionale delle Ricerche ("A structure/activity relationship study on arvanil, endocannabinoid and vanilloid hybrid.", Marzo DV, Griffin G, Petrocellis L, Brandi I, Bisogno T, Journal of Pharmacology and Experimental Therapeutics 2002, 300:3 (984-991 ) ), 12) 3-Alkyl-5,5'-diphenylimidazolidinediones which were described as cannabinoid receptor ligands, 13) CB~ antagonistic compounds currently under development by Bayer AG
(IDDb database: company communication 2002, February 28 ).
Lipase inhibiting compounds used in the combinations according to the present invention may be any lipase inhibiting compound suitable for pharmaceutical use, e.g. in particular inhibitors of pancreatic lipases. Lipases are key enzymes in the digestive system which break down tri- and diglycerides, which are too large to be absorbed by the small intestine into fatty acids which can be absorbed. Since lipases are responsible for the hydrolysis of fat, a consequence of their inhibition is a reduction in fat hydrolysis and absorption. Therefore, inhibition of lipases results in a reduction in the absorption of fat. The lipase inhibiting compound is preferably the synthetic lipase inhibitor orlistat and structurally related compounds, panclicins, lipase inhibitors isolated from micro organisms such as lipstatin, ebelactone B, or synthetic derivatives of these compounds, 2-oxy-4H-3,1-benzoxazin-4-one derivatives like ATL-962 and structurally related compounds, 2-amino-4H-3,1-benzoxazin-4-one derivatives, however may also be a lipase inhibiting polymer. Most preferred are orlistat, panclicins, ATL-962 and lipstatin.
Orlistat (tetrahydrolipstatin) and lipstatin are described in the US-patent US
4,598,089 and its European equivalent EP 0 129 748 B1 in more detail. The compounds are 2-hexyl-3-hydroxy-hexadecanoic acid lactone derivatives with the chemical names (2S,3S,5S,7Z,10Z)-5-((S)-2-formamido-4-methylvaleryloxy)-2-hexyl-3-hydroxy-7,10-hexadecadienoic acid lactone (lipstatin) and (2S,3S,5S)-5-((S)-2-4-methylvaleryioxy)-2-heyi-3-hydroxy-hexadecanoic acid 4actone (tetra-hydrolipstatin). The compounds are known to be inhibitors of pancreas lipase which can be used for the prevention of treatment of obesity and hyperlipaemia, for which purpose they can be formulated as medicaments or incorporated into industrially prepared foodstuffs. Inhibition of pancreas lipase prevents the hydrolysis of dietary fats to give absorbable free fatty acids and monoglycerides, so that the fats are excreted unchanged. IC50's for lipstatin and tetrahydrolipstatin for inhibition of hydrolysis of triolein by porcine pancrease lipase are 0.07 and 0.18 mcg/ml, respectively.

Furthermore, there are suitable lipase inhibitors which are structurally related to orlistat and/or lipstatin and which are known as panclicins. These panclicines are derived from orlistat and contain a 4-ring lactone (Mutoh M; Nakada N;
Matsukima S; Ohshima S; Yoshinari K; Watanabe J Location: Kanagawa, Japan Issue Date: 19-JAN-1995 Journal: J.Antibiot., 47, No. 12, 1369-75, 1994). The biological data of these panclicins may be summarized as fofiows: Panciicins A, B, C, D and E, structural analogs of tetrahydrolipstatin (THL), dose-dependently inhibited hydrolysis of triolein of fatty acids by porcine pancreatic lipase, with IC50 values of 2.9, 2.6, 0.62, 0.66 and 0.89 microM, respectively. The inhibitory activity of panclicins A and B (alanine moiety in place of leucine in THL) was 2-3-fold weaker than that of THL; in contrast, the inhibitory activity of panclicins C, D and E (glycine moiety in place of leucine in THL) was 2-fold stronger than that of THL.
Panclicins A, B, C, D and E also potently inhibited plasma iipases with iC50 values of 1.0, 1.2, 0.29, 0.25 and 0,15 microM, respectively. Panclicins A and B
inhibited plasma lipases with the same potency as THL, while panclicins C, D
and E had a 3-6-fold greater inhibitory activity than THL. Panclicins A, B, C, D
and E
inhibited bacterial and fungal lipases with profiles similar to those for porcine pancreatic lipase. Panclicins inhibited pancreatic lipase irreversibly, but less irreversibly than THL. Panclicins A, B, C, D and E irreversibly inhibit pancreatic lipase.
Ebelactone B is described in the US-patent US 4,358,602 and its German equivalent DE 3 109 335 C1. Ebelactone A and ebelactone B belong to a group of compounds that exhibit activity to enhance the cell mediated immune response in living animals and they also inhibit inflammations in living animals. Thus they may be used in the immunological treatment of tumours and for enhancing anti-tumour agents such as bleomycins. The compounds have anti-esterase activity and anti-formylmethionine aminopeptidase activity. Admininistration to mice of these compounds at a dosage of 0.781-50 mg/kg (i.p.) or 0.5 mglkg (per os) enhances the development of DTH response and the compounds show a potentiating effect on cell-mediated immunity. Ebelactone B reduces carragheenin-induced swelling in mice.
In the context of the present invention the lipase inhibitors administered in combination with the selective CBS antagonistic compounds to a patient for treating obesity may be also a polymer that has been substituted with or comprises one or more groups which can inhibit a lipase. Such lipase inhibiting polymers are described in the US patents US 6572850, US 6558657, US

6352692, US 6267952 and in the international patent application WO 99/34786.
In one embodiment, the lipase inhibiting group can be a "suicide substrate"
which inhibits the activity of the lipase by forming a covalent bond with the enzyme either at the active site or elsewhere. In another embodiment, the lipase inhibiting group is an isosteric inhibitor of the enzyme.
1n a first aspect of the present invention when using lipase inhibiting polymers in addition to the selective CBS antagonistic compounds, the lipase inhibiting group inactivates a lipase such as gastric, pancreatic and lingual lipases.
Inactivation can result by forming a covalent bond such that the enzyme is inactive. The covalent bond can be formed with an amino acid residue at or near the active site of the enzyme, or at a residue which is distant from the active site provided that the formation of the covalent bond results in inhibition of the enzyme activity.
Lipases contain a catalytic triad which is responsible for the hydrolysis of lipids into fatty acids. The catalytic triad consists of a serine, aspartate and histidine amino acid residues. This triad is also responsible for the hydrolysis of amide bonds in serine proteases, and it is expected that compounds that are serine protease inhibitors will also inhibit lipases. Therefore, serine protease inhibitors that can be covalently linked to a polymer are preferred lipase inhibiting groups.
For example, a covalent bond can be formed between the lipase inhibiting group and a hydroxyl at or the catalytic site of the enzyme. For instance, a covalent bond can be formed with serine. Inactivation can also result from a lipase inhibiting group forming a covalent bond with an amino acid, for example cysteine, which is at some distance from the active site. In a second aspect of the present invention when using lipase inhibiting polymers in addition to the CBS
antagonistic compounds, non-covalent interaction between the lipase inhibiting group and the enzyme can also result in inactivation of the enzyme. For example, the lipase inhibiting group can be an isostere of a fatty acid, which can interact non-covalently with the catalytic site of the lipase. In addition, the lipase inhibiting group can compete for lipase hydrolysis with natural triglycerides.
A variety of polymers can be employed in the invention described herein. The polymers can be aliphatic, alicyclic or aromatic or synthetic or naturally occurring.
However, aliphatic and alicyclic synthetic polymers are preferred.
Furthermore, the polymer can be hydrophobic, hydrophilic or copolymers of hydrophobic and/or hydrophilic monomers. The polymer can be non-ionic (e.g., neutral), anionic or cationic, in whole or in part. Furthermore, the polymers can be manufactured from olefinic or ethylenic monomers (such as vinylalcohoi) or condensation polymers. For example, the polymers can be a polyvinylalcohol, polyvinylami ne, poly-N-alkylvinylamine, polyallylamine, poly-N-alkylallylamine, polyalkylenimine, polyethylene, polypropylene, polyether, polyethylene oxide, polyamide, polyacrylic acid, polyalkylacrylate, polyacrylamide, polymethacrylic acid, polyalkylmethacrylate, polymethacrylamide, poly-N-alkylacrylamide, poly-N-5 alkylmethacrylamide, polystyrene, vinylnaphthalene, ethylvinylbenzene, aminostyrene, vinylbiphenyl, vinylanisole, vinylimidazolyl, vinylpyridinyl, dimethylaminomethylstyrene, trimethylammoniumethyfmethacryfate, trimethylammoniumethylacrylate, carbohydrate, protein and substituted derivatives of the above (e.g., fluorinated monomers thereof) and copolymers 10 thereof. Preferred polymers include polyethers, such as polyalkylene glycols.
The polymers employed in the methods described herein as well as intermediates and methods for preparing the polymers are described in detail in the US
patents US 6572850, US 6558657, US 6352692, US 6267952 and in the international patent application WO 99/34786, which are all incorporated by reference into the present invention.
Recently, in the international patent application WO 03/072555 new 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones of formula (A) are described to be pancreatic lipase inhibitors useful for treating metabolic diseases, cardiovascular diseases or especially obesity.

~ ~ ~N R1 (A) R3 ~ ~N ~~O
R2 /~-~ O
O
Such oxadiazolones of formula (A) and their salts and acid addition salts are also suitable for combinations with the CBS antagonistic compounds used according to the present invention. In formula (A) the substituents may be as follows:
R1 may be 7-22C alkyl; 2-4C alkyl substituted by 4-20C alkoxy, 6-10C aryl, 6-aryloxy or (4-12C) alkoxy-(2-4C) alkoxy (where aryl can be substituted by one or more of halogen, 1-4C alkyl, 1-4C alkoxy, N02 or CF3); 7-20C alkenyl; or phenyl substituted by 6-12C alkyl or by phenoxy; and R2 to R5 each may be H, halogen, N02, 1-4C alkyl, 1-4C alkoxy, CF3 or OCF3;
or (6-10C) aryl-(1-4C) alkoxy, 6-10C aryloxy, 6-10C aryl, 3-8C cycloalkyl or 3-8C cycloalkoxy (optionally substituted by halogen, CF3, 1-4C alkoxy or 1-4C

alkyl).
These 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones are described to have pharmacological properties as anorectic, antidiabetic, hypotensive or cardiant, with mechanism of action as pancreatic lipase inhibitors. For example 5-dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one had IC50 0.03 microM for inhibition of porcine pancreatic lipase. Hence, these 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones may be used as medicaments, especially for the treatment of obesity . As pancreatic lipase inhibtors, the hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones inhibit the resorption of the fat content of foods and thus reduce fat uptake and body weight (or prevent increase in body weight). Furthermore, the 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones are reported to also have a beneficial effect in the treatment of metabolic disorders (e.g. diabetes) or cardiovascular disorders (e.g.
hypertension and cardiac infarction). The lipase inhibiting compounds of formula (A) are described in more detail in the WO 03/072555 and can be obtained according to known methods. A suitable synthesis for the lipase inhibiting compounds of formula (A) is described also in the international patent application WO
03/072555. The whole content of the international patent application WO
03/072555 is incorporated by reference into the present application regarding the disclosure of lipase inhibitors of formula (A).
In addition, in the international patent application WO 03/072098 further 5 -hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones of formuia (A) are described to be pancreatic lipase inhibitors useful for treating of obesity or diabetes mellitus type 1 and 2. Such oxadiazolones of formula (A) as described in WO 03/072098 and their salts and acid addition salts are also suitable for combinations with the CBS antagonistic compounds used according to the present invention. In formula (A) the substituents may be as follows:
R1 may be 1-6C alkyl; 3-9C-cycloalkyl, both groups optionally may be substituted by phenyl, 1-4C alkoxy, S-1-4C alkyl, N(1-4C-alkyl)2; and phenyl optionally may be also substituted by halogen, 1-4C alky, 1-4C-alkyloxy, nitro or CF3;
and R2 to R5 each may be independently H, halogen, N02, 1-4C alkyl, 1-9C alkoxy which is substituted by F, 6-10C-aryl, amino or1-4C alkyl amino;
6-1 OC-aryl-1-4C-alkyloxy, 6-1 OC-aryloxy, 6-1 OC-aryl, 6-1 OC-aryloxy-1-4C-alkyl, 3-8C cycloalkyl or O(3-8 cycloalky), which may optionally be substituted by halogen, CF3, 1-4 alkyloxy or 1-4C alkyl;
S02-NH-(1-6C alkyl), optionally substituted by N(1-6C alkyl)2, S02-NH-(2,2,6,6-tetramethylpiperidin-4-yl), S02-NH-(3-8C cycloalkyl), optionally substituted by 1-4C alkyl, S02-N(1-6Calkyl)2 or COX;
2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7 with the proviso that R2, R3, R4 and R5 are not H at the same time when X is O(1-6C alkyl), NH(1-6C alkyl), NH(3-8C cycloalkyl or N(1-6C alkyl)2 and N(1-6C alkyl)2 may be also pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which optionally substituted by 1-4C alkyl, benzyl, 6-10C aryl, CO-(1-4 alkyl), CO-(6-10 aryl), CO-O-(1-4C
alkyl), S02-(1-4C alkyl) or S02-(6-10C aryl);

R6 is H, 1-4C alkyl or 6~10C-aryl-1-4C-alkyl, wherein aryl may be substitutet by halogen, CF3, 1-8C alkyloxy or 1-4C alkyl;

A is a single bond, COn, SOn or CONH;

n is 1 oder2:

R7 is H; 1-18C alkyl or 2-18G aikenyl, which may up to three times substituted by 1-4C alkyl, halogen, CF3, 1-4C alkyloxy, N(1-4C alkyl)2, -COOH, 1-4C

alkyloxycarbonyl, 6-12C aryl, 6-12C aryloxy, 6-12C arylcarbonyl, 6-10-aryl-1-4C-alkyloxy or oxo, wherein aryl itself may be optionally substituted by halogen, 1-4C alkyl, aminosulfonyl or methylmercapto;

6-10C-aryl-1-4C-alkyl, 5-8C-cycloalkyl-1-4C-alkyl, 5-8C
cycloalkyl, 6-10-aryl-2-6C-alkenyl, 6-10C aryl, biphenylyl, diphenyl-(1-4 alkyl), indanyl, which may be optionally substituted by 1-18C alkyl, 1-18C
alkyloxy, 3-8C

cycloalkyl, COOH, hydroxy, 1-4C alkylcarbonyl, 6-10C-aryl-1-4C
alkyl, 6-10C-aryl-1-4C-alkyloxy, 6-10C aryloxy, nitro, cyano, 6-10C
aryl, fluorsulfonyl, 1-6C alkyloxycarbonyl, 6-10 arylsulfonyloxy, pyridyl, NHS02-(6-10 aryl), halogen, CF3 or OCF3, wherein alkyl may be additionally substituted by 1-4C alkyloxycarbonyl, CF3 or carboxy and aryl by halogen, CF3 or 1-4C alkyloxy;

or the group Het-(CH2)r- with r = 0, 1, 2 or 3 and Het =
saturated or unsaturated 5-7-membered heterocyclus, which may be optionally benzo anellated and substituted by 1-4C alkyl, 6-10C aryl, halogen, alkyloxy, 1-4C alkyloxycarbonyl, 6-10C-aryl-1-4Calkyl, 6-10C-aryl-1-4C-alkylmercapto or nitro, wherein benzo anellated aryl may be substituted by halogen, 1-4C alkyloxy or GF3 and alkyl in arylalkyl may be substituted by methoxy and CF3.

The lipase inhibiting compounds of formula (A) are described in more detail in the WO 03/072098 and can be obtained according to known methods. A suitable synthesis for the lipase inhibiting compounds of formula (A) is described also in the international patent application WO 03/072098. The whole content of the international patent application WO 03/072098 is incorporated by reference into the present application regarding the disclosure of lipase inhibitors of formula (A).

In addition, in the US patent US 6,624,161 and its corresponding international patent application WO 00/040569 and WO 00/40247 further lipase inhibiting compounds are described which are also suitable in the context of the present invention for combination with CB1 antagonistic compounds described herein.
These patent documents US 6,624,161 and WO 00/040569 describe a series of compounds which are 2-oxy-4H-3,1-benzoxazin-4-one derivatives, including ATL-962, and their use in obesity and obesity-related disorders, including type 2 diabetes. The 2-oxy-4H-3,1-benzoxazin-4-one derivatives have the formula (B) or are or a pharmaceutically acceptable salt, ester, amide or prodrug thereof:
R9a ~ O
/R,a (B) R~oa ~ ~ N O
R~~a wherein:
R1 a is (i) a C10-30 branched or unbranched alkyl , optionally substituted by one or more independently of C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, --C(O)R13, --C02R13, --SOR13, --S02R13, --NR13R14, --OR13, --SR13, --C(O)NR13R14, --NR14C(O)R13, halogen, cyano, and vitro and/or optionally interrupted by one or more oxygen atoms with the proviso that any hetero atom in R1 a must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms;
(ii) C2-25 alkenyl, C2-25 alkynyl, C3-6 cycloalkenyl, aryl-C2-25 alkenyl, heteroaryl-C2-25 alkenyl, reduced heteroaryl, reduced heteroaryl-C1-25 alkyl or a substituted derivative of any of the foregoing groups wherein the substituents are one or more independently of C1-6 alkyl, halosubstituted C1-6 alkyl, aryl, aryl-C1-6 alkyl, heteroaryl, reduced heteroaryl, reduced heteroaryl-C1-6 alkyl, C1-6 alkoxy, aryl-C1-6 alkoxy, --C(O)R13, --C02R13, --SOR13, --S02R13, --NR13R14, --OR13, --SR13, --C(O)NR13R14, --NR14C(O)R13, halogen, cyano, and vitro, with the proviso that any hetero atom in R1 a must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms;
(iii) a C2-9 alkyl group interrupted by one or more oxygen atoms and optionally substituted by one or more independently of C3-6 cycioalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, --C(O)R13, --C02R13, -SOR13, -S02R13, NR13R14, OR13, SR13, -C(O)NR13R14, -NR14C(O)R13, halogen, cyano and nitro with the proviso that any hetero atom in R1 a must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms; or (iv) a C1-9 alkyl group substituted by a group selected from --C(O)R13, -C02R13, SOR13, S02R13, NR13R14, OR13, SR13, C(O)NR13R14, NR14C(O)R13; tetrahydronaphthyl, pyridyl, pyrrolyl, piperidinyl, halogen, cyano, nitro, bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic reduced heteroaryl, monocyclic heteroaryl other than imidazolyl;
(v) a phenyl group substituted by a group selected from OR17, --COR13, --C02R13, SORB, S02R13, CONR13R14, NR14C(O)R13 ;
halosubstituted C1-6 alkyl, aryl, arylC1-6 alkyl, heteroaryl and heteroarylC1-6 alkyl; or (vi) a bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic reduced heteroaryl, or monocyciic heteroaryi group other than imidazoiyl, optionally substituted by a group selected from OR17, --COR13, --C02R13, SOR13, S02R13, CONR13R14, NR14 C(O)R13; halosubstituted C1-6 alkyl, aryl, arylC1-6 alkyl, heteroaryl and heteroarylC1-6 alkyl;
where R13 and R14 each independently represents hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, reduced heteroaryl or reduced heteroaryl, C1-10 alkyl, and R17 represents hydrogen or C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, reduced heteroaryl or reduced heteroarylC1-10 alkyl and RBa, R9a, R10a and R11a are each independently hydrogen, halo, hydroxy, amino, nitro, cyano, thiol, C1-alkyl, C1-10 alkoxy, C1-10 cycloalkyl, C1-10 cycloalkoxy, C(O)R15, C(O)NR15R16, S(O)R15 or haloC1-10 alkyl;
where R15 and R16 each independently represent hydrogen or C1-10 alkyl with the proviso that when R8a, R9a, R1 Oa, and R11 a are H, R1 a is not CH2CH2CI
or C3 alkenyl.
Furthermore in the international patent application WO 00/40247 reiated 2-amino-4H-3,1-benzoxazin-4-one derivatives are described as lipase inhibiting compounds for the treatment of obesity. In formula (B) then the -OR1a substituent is replaced by a -NR1R2 group with the definitions for R1 and R2 as given in the WO 00140247.

The above group of structurally related compounds include ATL-962, an oral non-absorbed synthetic lipase inhibitor derived from Alizyme's pancreatic lipase inhibitor research program, is under development for the potential treatment of obesity and the potential management of type 2 diabetes. ATL-962 has the 5 chemical name 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one. Preclinical studies showed that ATL-962 had similar efficacy to orlistat and no toxicity was observed. Clinical data for these compounds is also available in the public domain, e.g. resulting from clinical studies with ATL-962 in obesity.
10 Thus, the results from a phase Ib program with ATL-962 were presented at the International Congress of Obesity in Sao Paulo, Brazil. The three phase Ib trials involved a total of 99 healthy male volunteers in groups of seven or nine, given one of several doses of ATL-962 (66 subjects) or placebo (24 subjects), tid with food for 5 days. In one group the nine subjects were given orlistat (qv) 120 mg 15 tid. Overall, ATL-962 was safe and well toierated and showed evidence of efficacy as indicated by an increase in excretion of fat from the diet.
Subjects given doses between 50 mg and 300 mg ATL-962 bid with meals excreted fat at an average of between 4.9 (+/-4.3) and 11.2 (+/-6.9) g/day compared to 1.4 (+/-1.0) glday on placebo and 5.6 (+/-3.8) g/day on orlistat. Compared to placebo, 55% of subjects who received ATL-962 (50 mg to 300 mg) demonstrated a 3-fold.
or greater increase in fat excretion and 27% of subjects demonstrated a 7-fold or greater increase. There was evidence of dose-dependency. Adverse events and their frequency were similar between ATL-962 and placebo and were mainly gastrointestinal, with the predominant event being oily stool.
The results of a multicenter, randomized, double-blind, parallel-group trial (phase Ilb study), involving 370 clinically obese patients, was being performed in specialist clinics in 5 European countries, and in September 2003 preliminary results were reported. All dose levels of ATL-962 (60, 120 and 240 mg) demonstrated a significant reduction in weight, compared to placebo, for all treatment groups. There was no difference in the extent of weight loss between treatment groups. LDL-cholesterol decreased in the treatment groups, but not for placebo. There was no difference in HDL-cholesterol levels in the treatment groups, whilst it increased in placebo-treated patients. Total cholesterol decreased in the treatment groups, whilst placebo showed an increase. ATL-962 was safe and generally well tolerated.
The lipase inhibiting compounds of formula (B) like ATL-962 and structuraliy related compounds are described in more detail in the US patent US 6,624,161 and its corresponding international'patent application WO 00/040569, and can be obtained according to known methods. A suitable synthesis for the lipase inhibiting compounds of formula (B) is described also in the US 6,624,161 and international patent application WO 00/040569. The whole content of the US

6,624,161 and international patent application WO 00/040569 is incorporated by reference into the present application regarding the disclosure of lipase inhibitors of formula (B). The whole content of the international patent application WO
00/040247 is also incorporated by reference into the present application regarding the disclosure of lipase inhibitors described therein, with related amino-4H-3,1-benzoxazin-4-one compound structure.
The whole content of the literature mentioned in the description of the present invention is incorporated by reference into the present application regarding the disclosure of the CBS antagonistic compounds as well as the lipase inhibitors used according to the present invention in combination.
Pharmaceutically acceptable salts, hydrates and solvates, and prodrugs of all the above described lipase inhibiting compounds may also be used in the context of the present invention.
The CBS antagonistic compound indicated above, which is a potent and selective antagonist of the cannabis CBS-receptor, or a prodrug, tautomer or salt thereof, and the lipase inhibiting compound used according to the invention can be brought into forms suitable for treatment and/or prophylaxis of obesity, e.g.
for adolescent or pediatric administration, as well as for the administration in treating drug induced obesity by means of usual processes using pharmaceutical excipients, auxiliary substances and/or liquid or solid carrier materials. As therapeutic agents, the selective CBS antagonistic compound and/or the lipase inhibiting compounds may be contained together with (conventional) pharmaceutical excipients, adjuvants and/or auxiliaries in pharmaceutical preparations such as tablets, capsules, suppositories or solutions. These pharmaceutical preparations may be prepared according to known methods, using conventional solid or liquid vehicles such as lactose, starch or talc, or liquid paraffins andlor using (conventional) pharmaceutical excipients, adjuvants and/or auxiliaries, such as tablet disintegrating agents, solubilisers or preservatives.
Hence, in a further aspect the invention also pertains to a pharmaceutical composition containing at least one selective CBS antagonistic compound as indicated above, or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound. A preferred pharmaceutical composition according to the invention contains as active components at least one CBS
antagonistic compound, preferably the CBS antagonistic as defined above, or a prodrug, tautomer or salt thereof, and at least one lipase inhibiting compound for the treatment and/or prophylaxis of obesity in adolescent or in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients. Particular pharmaceutical compositions according to the invention, are characterized in that the at least one CBS antagonistic compound as defined above, or the prodrug, tautomer or salt thereof, and the at least one lipase inhibiting compound each are present in an amount effectively suited for the treatment and/or prophylaxis of obesity in a juvenile patient in need of such treating. in a further embodiment of the invention said antagonistic compound and the lipase inhibiting compound are each present in the pharmaceutical composition in an amount effectively suited for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients in need of such treating. In the pharmaceutical compositions according to the invention the above defined selective CBS antagonistic compound, or the prodrug, tautomer or salt thereof, is used preferably in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.
The invention also pertains to a pharmaceutical product containing as a medicament a CBS antagonistic compound as defined above, or a prodrug, tautomer or salt thereof, and a leafilet indicating that said CBS antagonistic compound may be administered in combination with a lipase inhibiting compound for simultaneous, separate or step-wise administration in the treatment and/or prophylaxis of obesity.
Finally the invention also includes a method of treatment and/or prophylaxis of obesity, e.g. in adolescent or in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients, characterized in that a CBS antagonistic compound as defined above, which is a potent and selective antagonist of the cannabis CBS-receptor, or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibiting compound to a patient in need of such treating. The method of treatment and/or prophyiaxis of obesity according to the present invention may be directed to obesity in adolescent or in juvenile patients and/or to drug induced obesity in juvenile as well as adolescent patients. In a variant of the invention the method of treatment and/or prophylaxis is characterized in that the treating is directed to obesity in juvenile patients. In a further variant of the invention the method of treatment and/or prophylaxis is characterized in that the treating is directed to drug induced obesity in juvenile or adolescent patients. In the method of treatment and/or prophylaxis according to the invention the selective CBS
antagonistic compound as defined above, or a prodrug, tautomer or salt thereof, is administered preferably in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.
According to the invention the above defined selective CBS antagonistic compound, or a prodrug, tautomer or salt thereof, is administered in combination with the lipase inhibiting compound by simultaneous, separate or step-wise administration route.
The compounds used in the combinations or compositions according to the present invention each are preferably administered to a patient in need thereof and in a quantity sufficient to prevent and/or treat the symptoms of the condition, disorder or disease, e.g. obesity. For all aspects of the invention, particularly medical ones, the administration of a compound or composition has a dosage regime which will ultimately be determined by the attending physician and will take into consideration such factors such as the compound being used, animal type, age, weight, severity of symptoms, method of administration, adverse reactions and/or other contraindications. Specific defined dosage ranges can be determined by standard design clinical trials with patient progress and recovery being fully monitored. Such trials may use an escalating dose design using a low percentage of the maximum tolerated dose in animals as the starting dose in man.
The physiologically acceptable compounds used in the combinations or compositions according to the present invention each are will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
For a juvenile patient usually a part of the oral dose for an adult patient is administered, e.g. 1 fifth to 1 half of the oral dose described before for an adult patient.
Preferably, in one embodiment of the invention the method of treatment and/or prophylaxis is directed to the treating of obesity in juvenile patients. In another preferred embodiment of the invention the method of treatment andlor prophylaxis is directed to the treating of drug induced obesity in juvenile or adolescent patients. This drug induced obesity may be in particular caused by drugs like atypical antipsychotics.
In one embodiment of the invention the method of treatment and/or prophylaxis is directed to the treating of obesity in juvenile patients. Thus, it is advantageous that Cannabinoid antagonists are suitable for the treatment of Childhood Obesity and related Comorbidities as for example Type 2 Diabetes. There is a clear medical need for improved therapy as obesity has become an increasingly important medical problem not only in the adult population but increasingly in children and (young and older) adolescents. In national surveys from the 1960s to the 1990s in the United States, the prevalence of overweight in children grew from 5% to 11 % (Sorof and Daniels 2002). In Canada as another example childhood obesity has tripled in the past 20 years (Spurgeon 2002). Obesity in childhood causes a wide range of serious complications, and increases the risk of premature illness and death later in life, raising public-health concerns (Ebbeling, Pawlak et al. 2002). Over the last decades a tremendous increase of cases of type 2 diabetes was observed, especially also in children. This epidemic trend is clearly reflecting the increasing rates of obesity. Type-2-diabetes was in the past considered a disease of adults and older individuals, not a pediatric condition (Arslanian 2002). One of the main risk factor of pediatric type 2 diabetes is obesity.
Type 2 diabetes in children (as is in adults) is part of the insulin resistance syndrome (Rosenbloom 2002) that includes hypertension, dyslipidemia and other atherosclerosis risk factors, and hyperandrogenism seen as premature adrenarche and polycystic ovary syndrome. Other outcomes related to childhood obesity include left ventricular hypertrophy, nonalcoholic steatohepatitis, obstructive sleep apnea, orthopedic problems, and severe psychosocial problems. .
In addition primary hypertension has become increasingly common in children again associated obesity as a major independent risk factor. Obese children are at approximately a 3-fold higher risk for hypertension than non-obese children (Sorof and Daniels 2002). The benefits of weight loss for blood pressure reduction in children have been demonstrated in both observational and interventional studies.
Public concerns are rising because of a rapid development of the childhood obesity epidemic in genetically stable populations. Driving factors are assumed to be mainly adverse environmental factors for which straightforward recommendations of life style modifications exists. Obesity and it's related co-morbidities are very serious medical conditions and state of the art measures and treatment of obesity and especially childhood obesity remain largely ineffective at 5 the time being (Ebbeling, Pawlak et al. 2002). The management of type 2 diabetes in is also especially difficult in children and the adolescent age group (Silink 2002). Craving for and over consumption of palatable food is one of the important factors of life-style related obesity in humans and especially also in children and adolescents, Treatment of type 2 diabetes and other co-morbid 10 conditions by the degree of metabolic derangement and symptoms: The only data on the use of oral hypoglycemic agents in children with type 2 diabetes has been with metformin (Rosenbloom 2002).
Thus, CBS antagonists used according to the present invention in combination 15 with lipase inhibitors offer a unique opportunity for the treatment of obesity by interacting with these "driving forces". They are superior to current medical treatments and especially suited for adolescent as well as for pediatric treatment because of their outstanding safety profile and/or tolerability and surprisingly beneficial combination effects. Besides efficacy, the treatment of obesity, 20 especially the treatment of childhood obesity, dictated by safety.
Obesity in childhood is a medical condition that is likely to require long-term management. The safety profile of CBS antagonists used according to the present invention in combination with lipase inhibitors are suggested to be superior to current standard medications, and these CBS antagonists in combination with lipase inhibitors will be especially suited for the treatment and prevention of obesity in adolescents and childhood obesity and related co-morbidities.
Literature:
Arslanian, S. (2002). "Type 2 diabetes in children: clinical aspects and risk factors." Horm Res 57 Suppl 1: 19-28.
Ebbeling, C. B., D. B. Pawlak, et al. (2002). "Childhood obesity: public-health crisis, common sense cure." Lancet 360(9331): 473-82.
Rosenbloom, A. L. (2002). "Increasing incidence of type 2 diabetes in children and adolescents: treatment considerations." Paediatr Druas 4(4): 209-21.
Silink, M. (2002). "Childhood diabetes: a global perspective." Horm Res 57 Suppl 1: 1-5.

Sorof, J. and S. Daniels (2002). "Obesity hypertension in children: a problem of epidemic proportions." Hypertension 40(4): 441-7.
Spurgeon, D. (2002). "Childhood obesity in Canada has tripled in past 20 years."
Bm~ 324(7351 ): 1416.
In another embodiment of the invention the method of treatment and/or prophylaxis is directed to the treating of drug induced obesity in juvenile or adolescent patients. Drug induced weight gain is also of major concern and subject to high medical need of improved treatments. Again, in this context the CBS antagonists according to the present invention are suggested to be superior to current standard medications, and these CBS antagonists will be especially suited for the treatment and prevention of drug induced obesity in juvenile as well as in adolescent patients.
Regarding drug induced weight gain, it is reported by ~immermann, U., T.
Kraus, et al. (2003, "Epidemiology, impiications and mechanisms underlying drug-induced weight gain in psychiatric patients." J Psychiatr Res 37(3): 193-220) that body weight gain frequently occurs during drug treatment of psychiatric disorders and is often accompanied by increased appetite or food craving. While occurrence and time course of this side effect are difficult to predict, it ultimately results in obesity and the morbidity associated therewith in a substantial part of patients, often causing them to discontinue treatment even if it is effective.
Weight gain appears to be most prominent in patients treated with some of the second generation antipsychotic drugs and with some mood stabilizers. Marked weight gain also frequently occurs during treatment with most tricyclic antidepressants.
Very large weight gains are associated with drugs like for example the atypical antipsychotics clozapine and olanzapine. Some atypical antipsychotics, however, tend to cause significant weight gain, which may lead to poor compliance and other adverse health effects (Nasrallah, H. (2003). "A review of the effect of atypical antipsychotics on weight." Psychoneuroendocrinology 28 Suppl 1: 83-96.). The mechanisms invaived in antipsychotic drug-re4ated weight gain are as yet uncertain, although serotoninergic, histaminic, and adrenergic affinities have been implicated along with other metabolic mechanisms. The atypical antipsychotics vary in their propensity to cause weight change with long-term treatment. Follow-up studies show that the largest weight gains are associated with clozapine and olanzapine, and the smallest with quetiapine and ziprasidone.
Risperidone is associated with modest weight changes that are not dose related.
Given the equivalent efficacy of atypical antipsychotics, weight-gain profile is a legitimate factor to consider when constructing an algorithm for treatment due to the serious medical consequences of obesity. In this regard co-administration of a CBS antagonist as defined above in combination with lipase inhibitors according to the invention is suggested to work beneficiafiy.
Experimental protocol for study of CBS antagonistic compound plus lipase inhibitor effects on obesity The beneficial pharmacological effects of the combination of a CBS antagonist with a lipase inhibitor according to the invention can be shown by standard experimental animal models by measuring the influence of the administered combination of a CBS antagonist with a lipase inhibitor on the driving and characteristic parameters associated with obesity.
For investigation of the influence of the combination of a CBS antagonist with a lipase inhibitor on obesity the body weight gain in rats may be measured as a pharmacological indicator. Here fore, the following experimental protocol for rats may be applied:
The rats will have unlimited access to feed for two 2.5h periods per day, during the dark phase of a reversed 12h/12h light cycle, e.g. lights are put on at 21.15h and put off at 09.15h. The rats will be offered a high fat, high sucrose diet (Western diet). The lipase inhibitor will be dosed immediately before the rats are fed. The CBS antagonist will be dosed 1 h before the lipase inhibitor is administered.
As an example, the following daily dosing schedule is applicable for a given period of e.g. days, weeks or months:
The CBS antagonist, in particular the CBS antagonisic compound of formula (I) as defined above, or a vehicle dose is administered (po) in the morning at ca.
07.45 to 08.00 h. The lipase inhibitor, e.g. in particular orlistat, or a vehicle dose is administered (po) ca. 08.45 to 09.00 h. After medication the rats are set to ad-libitum feed from 09.15 to 11.45h, followed by feed removal from about 11.45 to 14.45 h. Another dose of lipase inhibitor, e.g. in particular orlistat, or vehicle (Labrasol) dose is administered (po) in the afternoon at about 14.15 to 14.30h, followed by ad-libitum feed from 14.45 to 17.15 h. Thereafter, the rats are set to feed deprivation from 17.15 - 09.15 h.
The experimental protocol results will compare daily food intake and body weight gain as indicators for the effects of the combination treatment on obesity during the experimental phase. In addition to the before given parameters it may be desired to also collect faeces and to estimate fat digestibility. Eventually it may be also desired to perform a carcass analysis.
Furthermore, after finishing the experimental feeding and administering phase, biochemical parameters may be measured at slaughter of the rats.
For investigating the effects the total number of rats subject to the experimental protocol is divided into the following groups with approximately the same number of rats in each group:
1 ) Control group: The rats receive only vehicle according to the protocol to simulate administration (placebo group).
,20 2) CBS group: The rats receive a CBS antagonist in a vehicle.
3) LI group: The rats receive as lipase inhibitor ("LI") e.g. the compound orlistat in a vehicle.
4) CBS+LI group (combination group): The rats receive a CBS antagonist in a vehicle and as lipase inhibitor ("LI") e.g. the compound orlistat in a vehicle.
The results of this protocol and the respective investigations show the beneficial suitability of the combination of a CBS antagonist as defined above and a lipase inhibitor in the treatment and / or prophylaxis of obesity.

Claims (22)

1. Use of a CBS antagonistic compound, which is a potent and selective antagonist of the cannabis CBS-receptor, or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound in the manufacture of a medicaments for the treatment and/or prophylaxis of obesity, including in particular the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.

2. Use of a CBS receptor antagonistic compound according to claim 1, wherein the compound is selected from the group of 1 ) Diarylpyrazole selective CBS receptor antagonists, preferably the compounds SR-141716A, rimonabant and related compounds, SR-147778, SR-140098 and/or WIN-54461;

2) Aminoalkylindoles selective CB1 receptor antagonists, preferably the compound lodopravadoline (AM-630);

3) Aryl-aroyl substituted benzofuran compounds with selective CB1 receptor antagonistic activity, preferably the compound LY-320135;

4) Selective CB1 rec eptor antagonistic compounds AM251 and/or AM281, and substituted imidazolyl compounds with selective CB1 receptor antagonistic activity;

5) Azetidine derivatives with selective CB1 receptor antagonistic activity;

6) The compound CP-55940;

7) Diaryl-pyrazine-amide with selective CB1 receptor antagonistic activity;

8) The compounds ACPA and ACEA;

9) Pyrazole derivatives with selective CB1 receptor antagonistic activity;

10) The compounds HU-210 and/or HU-243;

11 ) The compounds O-585, O-823, O-689, O-1072, and/or O-2093;

12) 3-Alkyl-5,5'-diphenylimidazolidinediones with selective CB1 receptor antagonistic activity

13) CBS antagonistic compounds with selective CB1 receptor antagonistic activity.

3. Use of a CBS receptor antagonistic compound according to claim 1, wherein the use is in the manufacture of a medicament for the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile, as well as adolescent, patients.

4. Use according to anyone of the claims 1 to 3 of a CB1 receptor antagonistic compound, wherein the CB1 antagonistic compound is used in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.

5. A pharmaceutical composition containing at least one CBS receptor antagonistic compound according to claim 1 or 2, or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound.

6. A pharmaceutical composition according to claim 5 containing as active components at least one CB1 antagonistic compound according to claim 1 or 2, or a prodrug, tautomer or salt thereof, and at least one lipase inhibiting compound for the treatment and/or prophyiaxis of obesity in adolescent or in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients.

7. A pharmaceutical composition according to any of the claims 5 to 6, wherein the at least one CB1 receptor antagonistic compound and the at least one lipase inhibiting compound each are present in an amount effectively suited for the treatment and/or prophylaxis of obesity in a juvenile patient in need of such treating.

8. A pharmaceutical composition according to any of the claims 5 to 6, wherein the at least one CB1 receptor antagonistic compound, or the prodrug, tautomer or salt thereof, and the at least one lipase inhibiting compound each are present in an amount effectively suited for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients in need of such treating.

9. A pharmaceutical composition according to any of the claims 5 to 8, wherein the CB1 antagonistic compound, or the prodrug, tautomer or salt thereof, is used in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.

10. A method of treatment and/or prophylaxis of obesity, characterized in that a CB1 antagonistic compound according to claim 1 or 2, which is a potent and selective antagonist of the cannabis CB1-receptor, or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibiting compound to a patient in need of such treating.

11. A method of treatment and/or prophylaxis of obesity according to claim 10, characterized in that a CB1 antagonistic compound according to claim 2, which is a potent and selective antagonist of the cannabis CB1-receptor, or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibiting compound to a patient in need of such treating.

12. A method of treatment and/or prophylaxis of obesity according to any of the claims 10 to 11, characterized in that the treatment and/or prophylaxis is directed to obesity in adolescent or in juvenile patients and/or to drug induced obesity in juvenile as well as adolescent patients.

13. A method of treatment and/or prophylaxis according to any of the claims 10 to 12, characterized in that the treating is directed to obesity in juvenile patients.

14, A method of treatment and/or prophylaxis according to any of the claims 10 to 12, characterized in that the treating is directed to drug induced obesity in juvenile or adolescent patients.

15. A method of treatment and/or prophylaxis according to any of the claims 10 to 14, characterized in that the CB1 antagonistic compound, preferably the CB1 antagonistic compound as defined in claim 2, or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.

16. A method of treatment and/or prophylaxis according to any of the claims 10 to 15, characterized in that the CB1 antagonistic compound, preferably the CB1 antagonistic compound as defined in claim 2, or a prodrug, tautamer or salt thereof, is administered in a combination with the lipase inhibiting compound by simultaneous, separate or step-wise administration route.

17. Pharmaceutical product containing as a medicament a CB1 antagonistic compound, preferably the CB1 antagonistic compound as defined in claim 2, or a prodrug, tautomer or salt thereof, as a combination preparation with a lipase inhibiting compound for simultaneous, separate or step wise administration in the treatment and/or prophylaxis of obesity.

18. Pharmaceutical product containing as a medicament a CB1 antagonistic compound, preferably the CB1 antagonistic compound as defined in claim 2, or a prodrug, tautomer or salt thereof, and a leaflet indicating that said CB1 antagonistic compound may be administered in combination with a lipase inhibiting compound for simultaneous, separate or step-wise administration in the treatment and/or prophyiaxis of obesity.

19. Combination of a CB1 antagonistic compound, which is a potent and selective antagonist of the cannabis CB1-receptor, or a prodrug, tautomer or salt thereof, with at least one lipase inhibiting compound.

20. Combination according to claim 19, wherein the combination is in a medicament for the treatment and/or prophyiaxis of obesity, including in particular the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.

21. Combination according to claim 19 or claim 20, wherein the CB1 receptor antagonistic compound is selected from the group of 1) Diarylpyrazole selective CB1 receptor antagonists, preferably the compounds SR-141716A, rimonabant and related compounds, SR-147778, SR-140098 and/or WIN-54461;

2) Aminoalkylindoles selective CB1 receptor antagonists, preferably the compound lodopravadoline (AM-630);

3) Aryl-aroyl substituted benzofuran compounds with selective CB1 receptor antagonistic activity, preferably the compound LY-320135;

4) Selective CB1 receptor antagonistic compounds AM251 and/or AM281, and substituted imidazolyl compounds with selective CB1 receptor antagonistic activity;

5) Azetidine derivatives with selective CB1 receptor antagonistic activity;

6) The compound CP-55940;

7) Diaryl-pyrazine-amide with selective CB1 receptor antagonistic activity;

8) The compounds ACPA and ACEA;

9) Pyrazole derivatives with selective CB1 receptor antagonistic activity;

10) The compounds HU-210 and/or HU-243;

11 ) The compounds O-585, O-823, O-689, O-1072, and/or O-2093;

12) 3-Alkyl-5,5'-diphenyfimidazolidinediones with selective CB1 receptor antagonistic activity 13) CB1 antagonistic compounds with selective CB1 receptor antagonistic activity.

22. Combination according to any of the claims 19 to 21, wherein the CB1 receptor antagonistic compound is in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.