WO2005039579A1 - Traitement de l'obesite combinant des antagonistes de cb1 selectifs et des inhibiteurs de lipase - Google Patents

Traitement de l'obesite combinant des antagonistes de cb1 selectifs et des inhibiteurs de lipase Download PDF

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WO2005039579A1
WO2005039579A1 PCT/EP2004/052643 EP2004052643W WO2005039579A1 WO 2005039579 A1 WO2005039579 A1 WO 2005039579A1 EP 2004052643 W EP2004052643 W EP 2004052643W WO 2005039579 A1 WO2005039579 A1 WO 2005039579A1
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cbi
compound
obesity
antagonistic
treatment
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Jochen Antel
Peter-Colin Gregory
Günter Krause
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Solvay Pharmaceuticals Gmbh
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Priority to EP04791298A priority Critical patent/EP1680116A1/fr
Priority to CA002543197A priority patent/CA2543197A1/fr
Publication of WO2005039579A1 publication Critical patent/WO2005039579A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen

Definitions

  • the present invention relates to a novel therapeutic and/or prophylactic treatment of obesity by administering a combination of CBi-antagonistic compounds together with a further active principle, and to pharmaceutical compositions containing at least one of these CBi-antagonistic compounds in combination with 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 (CB ⁇ 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 (CBi and CB 2 ) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61.
  • AM-630 is a CBi 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 , 61, PL115). More recently, researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CB-] receptor antagonists (e.g. LY -320135) (Felder, C.C.; Joyce, K.E.; Briley, E.J.; Glass, M.; Mackie, K.P.; Fahey, K.J.; Cullinan,
  • selective CB antagonists in general, prodrugs thereof, tautomers thereof and salts thereof show a unique 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.
  • lipase inhibiting compound lipase inhibiting compound
  • combinations of at least one CB 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.
  • the invention also pertains to the combination of a CBi antagonistic compound, which is a potent and selective antagonist of the cannabis CBi- receptor, or a prodrug, tautomer or salt thereof, with at least one lipase inhibiting compound.
  • 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 and/or drug induced obesity in juvenile as well as adolescent patients.
  • selective means that preferably there is no substantial other activity than the CBrreceptor antagonistic activity, or that at least the CBi-receptor antagonistic activity is substantially overcompensating any other activity.
  • the outstanding unique pharmacological profile of selective CB 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.
  • the compounds (CBi 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.
  • the CBi antagonistic compounds in combination with lipase inhibiting compounds are particularly 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.
  • CB! 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 sufficiently 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.
  • combination of CBi 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 CBi 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.
  • lipase inhibiting compounds which can be used in such combination preparations are (but not restricted to) the synthetic lipase inhibitor oriistat, panclicins, lipase inhibitors isolated from micro organisms such as lipstatin (from
  • the lipase inhibiting compound may also be a lipase inhibiting polymer.
  • the invention also pertains to a combination of a CB-, 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; 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 and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.
  • the CBi receptor antagonistic compound is selected from the group of
  • Diarylpyrazole selective C receptor antagonists preferably the compounds SR-141716A, rimonabant and related compounds, SR- 147778, SR-140098 and/or WIN-54461 ; 2) Aminoalkylindoles selective CBi receptor antagonists, preferably the compound lodopravadoline (AM-630); 3) Aryl-aroyl substituted benzofuran compounds with selective CBi receptor antagonistic activity, preferably the compound LY-320135; 4) Selective CBi rec eptor antagonistic compounds AM251 and/or AM281 , and substituted imidazolyl compounds with selective CBi receptor antagonistic activity; 5) Azetidine derivatives with selective CBi receptor antagonistic activity; 6) The compound CP-55940; 7) Diaryl-pyrazine-amide with selective CBi receptor antagonistic activity; 8) The compounds ACPA and ACEA; 9) Pyrazole derivatives with selective CBi receptor antagonistic activity; 10) The compounds HU-210
  • the invention pertains to a combination, wherein the CBi 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 CBi 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.
  • selective CBi 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 CBi receptor antagonists, e.g. as representative example the compound SR-141716A, rimonabant and related compounds described e.g.
  • Aryl-aroyl substituted benzofurans described by Eli Lilly as selective CBi 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) ),
  • HU-210 International Association for the Study of Pain - Ninth World Congress (Part II) Vienna, Austria, Dickenson AH, Carpenter K, Suzuki R, IDDB MEETING REPORT 1999, August 22-27
  • HU-243 Cannabinoid receptor agonists and antagonists, Barth F, Current Opinion in Therapeutic Patents 1998, 8:3 (301 -313)
  • 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-
  • pancreas lipase ((S)-2-4-methylvaleryloxy)-2-heyl-3-hydroxy-hexadecanoic acid lactone (tetrahydrolipstatin).
  • 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.
  • suitable lipase inhibitors which are structurally related to orlistat and/or lipstatin and which are known as panclicins.
  • 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
  • panclicins 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.
  • panclicins A and B alanine moiety in place of leucine in THL
  • panclicins C, D and E glycine moiety in place of leucine in THL
  • panclicins A, B, C, D and E also potently inhibited plasma lipases 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.
  • mice of these compounds at a dosage of 0.781 -50 mg/kg (i.p.) or 0.5 mg/kg (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.
  • the lipase inhibitors administered in combination with the selective CBi 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.
  • 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.
  • the lipase inhibiting group is an isosteric inhibitor of the enzyme.
  • 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.
  • serine protease inhibitors that can be covalently linked to a polymer are preferred lipase inhibiting groups.
  • a covalent bond can be formed between the lipase inhibiting group and a hydroxyl at or the catalytic site of the enzyme.
  • 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.
  • non-covalent interaction between the lipase inhibiting group and the enzyme can also result in inactivation of the enzyme.
  • the lipase inhibiting group can be an isostere of a fatty acid, which can interact non-covalently with the catalytic site of the lipase.
  • the lipase inhibiting group can compete for lipase hydrolysis with natural triglycerides.
  • 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 vinylalcohol) or condensation polymers.
  • the polymers can be a polyvinylalcohol, polyvinylamine, 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- alkylmethacrylamide, polystyrene, vinylnaphthalene, ethylvinylbenzene, aminostyrene, vinylbiphenyl, vinylanisole, vinylimidazolyl, vinylpyridinyl, dimethylaminomethylstyrene, trimethylammoniumethylmethacrylate, trimethylammoniumethylacrylate, carbohydrate, protein and substituted derivatives of the above (e.g., fluorinated monomers thereof) and copoly
  • R1 may be 7-22C alkyl; 2-4C alkyl substituted by 4-20C alkoxy, 6-10C aryl, 6-10C 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, NO2 or CF3); 7-20C alkenyl; or phenyl substituted by 6-12C alkyl or by phenoxy; and R2 to R5 each may be H, halogen, NO2, 1 -4C alkyl, 1-4C alkoxy, CF3 or OCF3; or (6-10C) aryl-(1-4C) alkoxy, 6-10C aryloxy, 6-10C aryl, 3-8C
  • 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.
  • 5- dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1 ,3,4)-oxadiazol-2-one had IC50 0.03 microM for inhibition of porcine pancreatic lipase.
  • these 5- hydrocarbyloxy-3-phenyl-1 ,3,4-oxadiazol-2-ones may be used as medicaments, especially for the treatment of obesity .
  • the 5- 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).
  • metabolic disorders e.g. diabetes
  • 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.
  • WO 03/072098 further 5 - hydrocarbyloxy-3-phenyl-1 ,3,4-oxadiazol-2-ones of formula (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 CBi antagonistic compounds used according to the present invention.
  • 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, NO2, 1-4C alkyl, 1-9C alkoxy which is substituted by F, 6-10C-aryl, amino or1-4C alkyl amino; 6-10C-aryl-1-4C-alkyloxy, 6-10C-aryloxy, 6-10C-aryl, 6-10C-aryloxy-1 -4C- alkyl, 3-8C cycloalkyl or 0(3-8 cycloalky), which may optionally be substituted by halogen, CF3,
  • 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), SO2-(1 -4C alkyl) or SO2-(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
  • 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).
  • 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.
  • R1a is 0) 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, -CO2R13, -SOR13, - SO2R13, --NR13R14, -OR13, -SR13, -C(O)NR13R14, -NR14C(O)R13, halogen, cyano, and nitro and/or optionally interrupted by one or more oxygen atoms with the proviso that any hetero atom in R1a must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms; ( ⁇ ) C2-25 alkenyl, C2-25 alkynyl, C3-6 cycloalkenyl, aryl-C2-25 alkenyl, heteroaryl-C2-25 alkenyl
  • R8a, R9a, R10a and R11a are each independently hydrogen, halo, hydroxy, amino, nitro, cyano, thiol, C1 -10 alkyl,
  • R15 and R16 each independently represent hydrogen or C1-10 alkyl with the proviso that when R8a, R9a, R10a, and R11 a are H, R1 a is not CH2CH2CI or
  • ATL-962 has the 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.
  • ATL-962 was safe and well tolerated and showed evidence of efficacy as indicated by an increase in excretion of fat from the diet.
  • 55% of subjects who received ATL-962 demonstrated a 3-fold or greater increase in fat excretion and 27% of subjects demonstrated a 7-fold or greater increase.
  • Adverse events and their frequency were similar between ATL-962 and placebo and were mainly gastrointestinal, with the predominant event being oily stool.
  • the lipase inhibiting compounds of formula (B) like ATL-962 and structurally 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 2- amino-4H-3,1-benzoxazin-4-one compound structure.
  • the CBi antagonistic compound indicated above which is a potent and selective antagonist of the cannabis CB 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.
  • the selective CBi 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.
  • 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 and/or using (conventional) pharmaceutical excipients, adjuvants and/or auxiliaries, such as tablet disintegrating agents, solubilisers or preservatives.
  • the invention also pertains to a pharmaceutical composition containing at least one selective CBi 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 CBi antagonistic compound, preferably the CBi 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.
  • compositions according to the invention are characterized in that the at least one CBi 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.
  • 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.
  • the above defined selective CBi 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 CBi antagonistic compound as defined above, or a prodrug, tautomer or salt thereof, and a leaflet indicating that said CBi 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.
  • 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 CBi antagonistic compound as defined above, which is a potent and selective antagonist of the cannabis CB 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.
  • a CBi antagonistic compound as defined above which is a potent and selective antagonist of the cannabis CB 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 prophylaxis of obesity may be directed to obesity in adolescent or in juvenile patients and/or to drug induced obesity in juvenile as well as adolescent patients.
  • the method of treatment and/or prophylaxis is characterized in that the treating is directed to obesity in juvenile patients.
  • the method of treatment and/or prophylaxis is characterized in that the treating is directed to drug induced obesity in juvenile or adolescent patients.
  • the selective CBi 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.
  • the above defined selective CBi 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.
  • 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.
  • 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.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • 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.
  • the method of treatment and/or prophylaxis is directed to the treating of obesity in juvenile patients.
  • the method of treatment and/or 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.
  • the method of treatment and/or prophylaxis is directed to the treating of obesity in juvenile patients.
  • Cannabinoid antagonists are suitable for the treatment of Childhood Obesity and related Comorbidities as for example Type 2 Diabetes.
  • Childhood Obesity and related Comorbidities as for example Type 2 Diabetes.
  • the prevalence of overweight in children grew from 5% to 11 % (Sorof and Daniels 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,
  • 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 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.
  • CBi antagonists used according to the present invention in combination 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, especially the treatment of childhood obesity, dictated by safety.
  • CBi antagonists used according to the present invention in combination with lipase inhibitors are suggested to be superior to current standard medications, and these CBi 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.
  • 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.
  • the CBi antagonists according to the present invention are suggested to be superior to current standard medications, and these CBi antagonists will be especially suited for the treatment and prevention of drug induced obesity in juvenile as well as in adolescent patients.
  • 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.
  • the beneficial pharmacological effects of the combination of a CBi 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 CBi antagonist with a lipase inhibitor on the driving and characteristic parameters associated with obesity.
  • 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 CBi antagonist will be dosed 1h before the lipase inhibitor is administered.
  • the following daily dosing schedule is applicable for a given period of e.g. days, weeks or months:
  • the CBi antagonist in particular the CBi 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.
  • 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.
  • 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.
  • biochemical parameters may be measured at slaughter of the rats.
  • Control group The rats receive only vehicle according to the protocol to simulate administration (placebo group).
  • CBi group The rats receive a CBi antagonist in a vehicle.
  • LI group The rats receive as lipase inhibitor ("LI”) e.g. the compound orlistat in a vehicle.
  • CB 1 +LI group (combination group): The rats receive a CBi antagonist in a vehicle and as lipase inhibitor ("LI”) e.g. the compound orlistat in a vehicle.

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Abstract

La présente invention concerne une nouvelle utilisation médicale des composés antagonistes sélectifs des récepteurs du CB1 combinés à des inhibiteurs de lipase. Lesdits composés sont particulièrement adaptés lorsque combinés aux inhibiteurs de lipase dans la fabrication de médicaments utilisés dans le traitement et/ou la prophylaxie de l'obésité chez les patients adolescents ou juvéniles et/ou dans le traitement et/ou la prophylaxie de l'obésité induite par les médicaments chez des patients juvéniles et adolescents. Les composés antagonistes des récepteurs du CB1 adaptés selon la présente invention sont étudiés de manière plus détaillée dans la description. Les inhibiteurs de lipase préférés sont l'orlistat, les panclicines, ATL-962 et/ou la lipstatine.
PCT/EP2004/052643 2003-10-24 2004-10-22 Traitement de l'obesite combinant des antagonistes de cb1 selectifs et des inhibiteurs de lipase WO2005039579A1 (fr)

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EP04791298A EP1680116A1 (fr) 2003-10-24 2004-10-22 Traitement combine de l'obesite contenant des antagonistes selectives de cb1 et des inhibiteurs de lipase
CA002543197A CA2543197A1 (fr) 2003-10-24 2004-10-22 Traitement de l'obesite combinant des antagonistes de cb<sb>1</sb> selectifs et des inhibiteurs de lipase

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EP03103962.1 2003-10-24
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EP2305220A3 (fr) * 2004-03-09 2011-05-18 Institut National de la Santé et de la Recherche Médicale - Inserm Utilisation d'antagonistes des récepteurs CB1 pour la fabrication d'un médicament destiné au traitement des maladies hépatiques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005046689A2 (fr) * 2003-10-24 2005-05-26 Sanofi-Aventis Utilisation d’un derive du pyrazole pour la prevention et le traitement des dyslipidemies et des maladies associees aux dyslipidemies et/ou a l’obesite
WO2005046689A3 (fr) * 2003-10-24 2005-10-13 Sanofi Aventis Utilisation d’un derive du pyrazole pour la prevention et le traitement des dyslipidemies et des maladies associees aux dyslipidemies et/ou a l’obesite
EP2305220A3 (fr) * 2004-03-09 2011-05-18 Institut National de la Santé et de la Recherche Médicale - Inserm Utilisation d'antagonistes des récepteurs CB1 pour la fabrication d'un médicament destiné au traitement des maladies hépatiques

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