CN1867332A - Combination treatment of obesity involving selective cb1-antagonists and lipase inhibitors - Google Patents

Combination treatment of obesity involving selective cb1-antagonists and lipase inhibitors Download PDF

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CN1867332A
CN1867332A CNA2004800300886A CN200480030088A CN1867332A CN 1867332 A CN1867332 A CN 1867332A CN A2004800300886 A CNA2004800300886 A CN A2004800300886A CN 200480030088 A CN200480030088 A CN 200480030088A CN 1867332 A CN1867332 A CN 1867332A
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compound
receptor antagonist
obesity
selectivity
lipase
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J·安特尔
P-C·格雷戈里
G·克劳瑟
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Abbott Products GmbH
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Solvay Pharmaceuticals GmbH
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    • 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
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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

Comprise selectivity CB 1The therapeutic alliance of the obesity of-antagonist and lipase inhibitor
The present invention relates to by using CB 1The associating of-antagonist compound and another kind of active component and new the treating and/or preventing property treatment of the obesity of carrying out also relate to and comprise at least a these CB 1The pharmaceutical composition of associating of-antagonist compound and the described another kind of active component that treats and/or prevents that is used for obesity.Effective Fructus Cannabis-1 (the CB that shown provided by the invention 1) chemical compound of receptor antagonist activity and described another kind of active component unite the treatment that is used in particular for obesity.
Cannabinoid is present among the ganja Cannabis Sativa L., as severalth century of medicament (Mechoulam, R.; Feigenbaum, J.J.Prog.Med.Chem.1987,24,159).Yet, be that the research in cannabinoid field has just disclosed the key message of relevant Cannabined receptor and (endogenous) agonist and antagonist in the past 10 years.Two different subtype (CB of Cannabined receptor 1And CB 2) discovery and the research (Munro, the S. that have stimulated new cannabinoid receptor antagonists of clone subsequently; Thomas, K.L.; Abu-Shaar, M.Nature 1993,365,61.Matsuda, L.A.; Bonner, T.I.CannabinoidReceptors, Pertwee, R.G.Ed.1995,117, Academic Press, London).In addition, pharmaceuticals becomes interested for the exploitation that is used for the treatment of with the cannabinoid drugs of cannabinoid system disorders diseases related.CB 1The extensive distribution of receptor in brain adds CB 2The periphery location that receptor is very strict makes CB 1Receptor becomes the very interesting molecule target (Consroe of CNS-targeted drug invention in the P﹠N disease field, P.Neurobiology of Disease 1998,5,534.Pop, E.Curr.Opin.InCPNS Investigational Drugs 1999,1,587.Greenberg, D.A.DrugNews Perspec t.1999,12,458).Up to now, known three types different CB 1Receptor antagonist.Sanofi discloses them as selectivity CB 1The diaryl pyrazole congener of receptor antagonist.Representational example is SR-141716A, and it just carries out II phase clinical development (Dutta, the A.K. of mental disorder at present; 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).Amino alkyl indole is disclosed as CB 1Receptor antagonist.Representational example is lodopravadoline (AM-630), and it was suggested in nineteen ninety-five.AM-630 is CB 1Receptor antagonist, but show to such an extent that resemble weak partial agonist (Hosohata, K. sometimes; Quock, R.M.; Hosohata, Y.; Burkey, T.H.; Makriyannis, A.; Consroe, P.; Roeske, W.R.; Yamamura, H.I.LifeSc.1997,61, PL115).More recent, the researcher of Eli Lilly has described the benzofuran of aryl-aroyl replacement as selectivity CB 1Receptor antagonist (for example LY-320135) (Felder, C.C.; Joyce, K.E.; Briley, 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, describe 3-alkyl-5,5 '-zentropil points out that as cannabinoid receptor ligand it is cannabinoid antagonist (Kanyonyo, M.; Govaerts, S.J.; Hermans, E.; Poupaert, J.H., Lambert, D.M.Biorg.Med.Chem.Lett.1999,9,2233).What is interesting is, reported a lot of CB 1Receptor antagonist external as inverse agonist (Landsman, R.S.; Burkey, T.H.; Consroe, P.; Roeske, W.R.; Yamamura, H.I.Eur.J.Pharmacol.1997,334, R1).Nearest summary provides fine scanning (Mechoulam, the R. of the As-Is of cannabinoid research field; Hanus, L.; Fride, E.Prog.Med.Chem.1998,35,199.Lambert, D.M.Curr.Med.Chem.1999,6,635.Mechoulam, R.; Fride, E.; Di Marzo, V.Eur.J.Pharmacol.1998,359,1).Known 4 from International Patent Application WO 01/70700,5-dihydro-1 h-pyrazole chemical compound, it has effectively and Fructus Cannabis CB optionally 1-receptor antagonist activity.
The object of the invention provides improving one's methods for the treatment of and/or preventing property treatment of obesity, the method of the treatment for the treatment of and/or preventing property has higher demand to safety and toleration patient's obesity particularly is provided, for example, particularly for example juvenile obesity patient and/or the patient who carries out long-term treatment, for example drug induced obesity of teenager or adolescent patient.
It has surprisingly been found that generally speaking selectivity CB now 1-antagonist, its prodrug, its tautomer and salt thereof have demonstrated unique pharmacological characteristics, therefore be particularly suitable for uniting the medicine that is used to prepare the obesity that treats and/or prevents any age patient with at least a lipase inhibition chemical compound (lipase inhibitor), also be particularly suitable for preparation and treat and/or prevent juvenile patient's obesity, and/or the medicine of juvenile and the drug induced obesity of adolescent patient.In this respect, at least a CB 1Uniting providing of antagonist compound and at least a lipase inhibition chemical compound treats and/or prevents common bariatric, the adolescent patient obesity at any age for example, particularly the medicine aspect of children's or juvenile obesity and teenager and the drug induced obesity of juvenile patient is extremely valuable.
Therefore, the present invention also relates to CB 1Antagonist compound, it is Fructus Cannabis CB effectively and optionally 1-receptor antagonist, or its prodrug, tautomer or salt are with the associating of at least a lipase inhibition chemical compound.In the variant embodiment, the present invention relates to associating, wherein, this is united is to be used for the treatment of and/or prevent obesity, especially comprise treating and/or preventing juvenile patient's obesity, and/or in the medicine of teenager and the drug induced obesity of adolescent patient.
Term " selectivity " refers to preferably, except CB 1-receptor antagonist activity does not have other activity basically, or CB at least 1-receptor antagonist activity basically over compensation any other activity.
Selectivity CB 1Remarkable and unique pharmacological characteristics of-antagonist compound comprises extra high safety and toleration, this makes that this chemical compound is particularly suitable for uniting the patient who is used for safety and toleration are had higher demand with lipase inhibition chemical compound, particularly for example juvenile patient and/or carry out the patient's of long-term treatment for example drug induced obesity.
Because CB effectively and optionally 1Antagonistic activity, the chemical compound (CB that the present invention uses 1Antagonist) also be suitable for and other medicines associatings, particularly according to the present invention with the associating of lipase inhibition chemical compound.Therefore, CB 1The associating of antagonist compound and lipase inhibition chemical compound also is particularly suitable for safety and toleration are had the patient of higher demand, particularly for example juvenile patient and/or carry out the patient's of long-term treatment for example drug induced obesity.
CB 1This safety of antagonist compound and lipase inhibition chemical compound associating and toleration are favourable in the treating and/or preventing of these patient groups' obesity, wherein, single therapy is effective inadequately, and the therapeutic alliance and/or the prevention that comprise different medical science or metabolic mechanism are desired or needs for realization and losing weight of stable specified degree.
Therefore, wish CB of the present invention 1Antagonist compound and lipase inhibition chemical compound to unite for treating and/or preventing common bariatric (for example any age adolescent patient obesity, particularly children's or juvenile obesity) and drug induced obesity be very favorable.
The CB of The compounds of this invention 1Receptor modulating activities makes them when uniting use with lipase inhibitor, and is particularly useful in the treatment of obesity, juvenile obesity and drug induced obesity.The instantiation that can be used for the lipase inhibition chemical compound of this combination formulations is (but being not limited to) synthetic lipase inhibitor orlistat, panclicins, isolating lipase inhibitor from microorganism, for example lipstatin (from the poison three plain streptomycetes (Streptomycestoxytricini)), ebelactone B (from Streptomyces aburaviensis), the synthesis of derivatives of these chemical compounds, 2-oxygen-4H-3, the chemical compound of 1-benzoxazine-4-ketone derivatives such as ATL-962 and structurally associated, 2-amino-4H-3,1-benzoxazine-4-ketone derivatives, and known plant extract with lipase inhibiting activity, Rhizoma Alpiniae Officinarum extract for example, or from this extract isolated compound, as 3-MEE galangin (from A.officinarum).Lipase inhibition chemical compound also can be the lipase inhibitory polymer.These lipase inhibition chemical compounds and preparation thereof are that prior art is known.
Pointed out as top, the invention still further relates to CB 1Antagonist compound, it is Fructus Cannabis CB 1Effectively and the optionally antagonist of-receptor, or its prodrug, tautomer or salt are with the associating of at least a lipase inhibition chemical compound; In another kind of variant mode, the present invention relates to associating, wherein, this is united is to be used for the treatment of and/or prevent obesity, especially comprise treating and/or preventing juvenile patient's obesity, and/or in the medicine of teenager and the drug induced obesity of adolescent patient.In these associatings of the present invention, CB 1Receptor antagonist compound is selected from down group:
1) diaryl pyrazole selectivity CB 1Receptor antagonist, preferred compound SR-141716A, Rimonabant and relevant chemical compound, SR-147778, SR-140098 and/or WIN-54461;
2) amino alkyl indole selectivity CB 1Receptor antagonist, preferred compound lodopravadoline (AM-630);
3) has selectivity CB 1The benzofuran compound that the aryl of receptor antagonist activity-aroyl replaces, preferred compound LY-320135;
4) selectivity CB 1Receptor antagonist compound AM251 and/or AM281 and have selectivity CB 1The imidazole-based compounds of the replacement of receptor antagonist activity;
5) has selectivity CB 1The azetidine derivatives of receptor antagonist activity;
6) Compound C P-55940;
7) has selectivity CB 1Diaryl-the pyrazine of receptor antagonist activity-amide;
8) compd A CPA and ACEA;
9) has selectivity CB 1The pyrazole derivatives of receptor antagonist activity;
10) compound H U-210 and/or HU-243;
11) chemical compound O-585, O-823, O-689, O-1072 and/or O-2093;
12) has selectivity CB 1The 3-alkyl-5 of receptor antagonist activity, 5 '-zentropil;
13) has selectivity CB 1The CB of receptor antagonist activity 1Antagonist compound.
In another kind of variant mode, the present invention relates to associating, wherein CB 1Receptor antagonist compound and at least a lipase inhibition chemical compound associating that is selected from lipase inhibitory polymer, orlistat, panclicins, ATL-962 and lipstatin.
Be used for selectivity CB of the present invention 1Antagonist compound can obtain according to known method.Being used for the synthetic suitable method of chemical compound of the present invention has description in the prior art, for example in the document that the application quotes, merges as a reference.
Relevant with the context of the invention and merge as a reference selectivity CB 1The example of antagonist compound is for example (but being not limited to):
1) Sanofi is disclosed as selectivity CB 1The diaryl pyrazole congener of receptor antagonist, for example as representational example, be described in compound S R-141716A, Rimonabant and relevant chemical compound among the EP0969835, SR-147778, SR-140098 (Central mediation of the cannabinoid cue:activity of aselective CBl antagonist, SR141716A PerioA, Rinaldi-CarmonaM, Maruani J Behavioural Pharmacology 1996,7:1 (65-71)); The disclosed WIN-54461 of Sanofi-Winthrop (Cannabinoid receptor ligands:Clinical and neuropharmacological considerations relevant tofuture drug discovery and development.Pertwee RG, ExpertOpinion on Investigational Drugs 1996,5:10 (1245-1253))
2) as CB 1The disclosed amino alkyl indole of receptor antagonist, for example as representational example, chemical compound lodopravadoline (AM-630),
3) Eli Lilly describe as selectivity CB 1The benzofuran that the aryl of receptor antagonist-aroyl replaces; LY-320135 (Cannabinoid receptor ligands:Clinical and neuropharmacological considerations relevant tofuture drug discovery and development.Pertwee RG for example; ExpertOpinion on Investigational Drugs 1996; 5:10 (1245-1253))
4) Merck ﹠amp; The chemical compound that Co describes, AM 251 and AM 281 (Conference:31st Annual Meeting of the Society forNeuroscience for example, San Diego, USA, 10-15.11.2001), the imidazolyl derivatives of US2003-114495 or the disclosed replacement of WO03/007887 for example
5) azetidine derivatives in for example WO02/28346 or EP1328269, described of Aventis Pharma,
6) from CP-55940 (Comparison of thepharmacology and signal transduction of the human cannabinoidCB1 and CB2 receptors, Felder CC, the Joyce KE of Pfizer Inc., Briley EM, MansouriJ, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL, MolecularPharmacology 1995,48:3 (443))
7) from diaryl-pyrazine Astra Zeneca, that in WO03/051851, describe-amide derivatives,
8) from ACPA and the ACEA of Med.Coll.Wisconsin (Aberdeen), (" Effects of AM 251 ﹠amp; AM 281, cannabinoid CB1 antagonists, onpalatable food intake in lewis rats " J.Pharmacol.Exp.Ther.289, No3,1427-33,1999),
9) pyrazole derivatives in WO01/29007 for example, described of Conneticut university,
10) from the Yissum R﹠amp of Jerusalem Hebrew university; The HU-210 of D Co, (International Association for the Study of Pain-Ninth WorldCongress, (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))
11) from the O-823 of Organix Inc. (Drug development pipeline:O-585, O-823, O-689, O-1072, nonamines, Orgaix, AltropaneOrganix Inc, Company Communication 1999, August 10; IDDbdatabase) with from O-2093 (" the Astructure/activity relationship study on arvanil of Consiglio Nazionale delle Ricerche; endocannabinoid and vanilloid hybrid. ", Marzo DV, Griffin G, Petrocellis L, Brandi I, Bisogno T, Journal of Pharmacology andExperimental Therapeutics 2002,300:3 (984-991))
12) 3-alkyl-5 as cannabinoid receptor ligand is described, 5 '-zentropil,
13) CB that develops by Bayer AG at present 1Antagonist compound (IDDb database:company communication 2002, February 28).
The lipase inhibition chemical compound that is used for the present invention associating can be any lipase inhibition chemical compound that is suitable for pharmaceutical applications, for example, and pancreatic lipase inhibitor particularly.Lipase is the key enzyme in the digestive system, and it is too big and can't be cracked into by the triglyceride of little intestinal absorption and diglyceride can absorbed fatty acid with molecule.Because lipase is responsible for fat splitting, the result who suppresses them has reduced fat splitting and absorption exactly.Therefore, suppressing lipase causes fat absorption to reduce.Preferred fat enzyme inhibition chemical compound is the chemical compound panclicins of synthetic lipase inhibitor orlistat and structurally associated, isolating lipase inhibitor lipstatin for example from microorganism, ebelactone B, or the synthesis of derivatives of these chemical compounds, 2-oxygen-4H-3, the chemical compound of 1-benzoxazine-4-ketone derivatives such as ATL-962 and structurally associated, 2-amino-4H-3,1-benzoxazine-4-ketone derivatives, yet, also can be the lipase inhibitory polymer.Most preferably orlistat, panclicins, ATL-962 and lipstatin.
Orlistat (tetrahydrochysene lipstatin) and lipstatin are described in U.S. Pat 4,598, in 089, describe more in detail in its European patent families EP0129748B1.This chemical compound is 2-hexyl-3-hydroxy-hexadecanoic acid lactone derivatives, chemistry (2S by name, 3S, 5S, 7Z, 10Z)-5-((S)-2-formamido-4-methylpent acyloxy)-2-hexyl-3-hydroxy-7,10-hexadecane dienoic acid lactone (lipstatin) and (2S, 3S, 5S)-5-((S)-2-4-methylpent acyloxy)-2-hexyl-3-hydroxy-hexadecanoic acid lactone (tetrahydrochysene lipstatin).Known this chemical compound is a pancreatic lipase inhibitor, and it can be used for prevention or treatment of obesity and hyperlipemia, and for this purpose, they can be made medicine or mix in the food of industrial preparation.Suppress pancreatic lipase and prevented that food fat is hydrolyzed into absorbable free fatty and monoglyceride, makes fat drain steadily.The IC50 that lipstatin and tetrahydrochysene lipstatin suppress the hydrolysis of glycerol trioleate porcine pancreatic lipase is respectively 0.07 and 0.18mcg/ml.
In addition, the suitable lipase inhibitor of existence and orlistat and/or lipstatin structurally associated, it is known as panclicins.These panclicines are derived from orlistat, and comprise 4-cyclic lactone (Mutoh M; Nakada N; Matsukima S; Ohshima S; YoshinariK; Watanabe J Location:Kanagawa, Japan Issue Date:19-JAN-1995Journal:J.Antibiot., 47, No.12,1369-75,1994).The biological data of these panclicins may be summarized as follows: Panclicins A, B, C, D and E are the analogs of tetrahydrochysene lipstatin (THL), dose dependent ground suppresses the glycerol trioleate of fatty acid by the porcine pancreatic lipase hydrolysis, and the IC50 value is respectively 2.9,2.6,0.62,0.66 and 0.89 μ M.The weak 2-3 of the inhibition specific activity THL of panclicins A and B (alanine has partly replaced the leucine among the THL) doubly; On the contrary, the inhibition specific activity THL of panclicins C, D and E (glycine has partly replaced the leucine among the THL) is strong 2 times.Panclicins A, B, C, D and E are respectively that 1.0,1.2,0.29,0.25 and 0.15 μ M also suppresses the blood plasma lipase effectively with the IC50 value.Panclicins A suppresses the blood plasma lipase with B and has identical effectiveness with THL, and panclicins C, D and E are than the active big 3-6 of the inhibition of THL doubly.The performance of Panclicins A, B, C, D and E inhibition antibacterial and fungal lipase is similar to the performance that suppresses porcine pancreatic lipase.Panclicins irreversibly suppresses pancreatic lipase, but littler than the irreversibility of THL.Panclicins A, B, C, D and E irreversibly suppress pancreatic lipase.
Ebelactone B is described in U.S. Pat 4,358,602 and its German patent families DE 3 109 335 C1 in.Ebelactone A and ebelactone B belong to the active one group of chemical compound with cell-mediated immune responses in the enhancing living animal, and they also suppress the inflammation of living animal.Therefore, they can be used for the immunization therapy of tumor and are used to strengthen for example bleomycin of antitumor agent.This chemical compound has the active and anti-formylmethionine amino peptidase activity of antiesterase.These chemical compounds carry out administration with the dosage of the dosage of 0.781-50mg/kg (lumbar injection) or 0.5mg/kg (oral) to mice and have strengthened the development that DTH replys, and the immunity of this chemical compound pair cell mediation has demonstrated potentiation.Ebelactone B has weakened the inductive swelling of mice carrageenin.
In the context of the invention, with selectivity CB 1Antagonist compound unites that the patient is carried out administration also can be polymer with the lipase inhibitor of treatment of obesity, and it is replaced or comprise one or more such groups by one or more groups that can suppress lipase.Such lipase inhibitory polymer is described among U.S. Pat 6572850, US6558657, US6352692, the US6267952 and in the International Patent Application WO 99/34786.In one embodiment, it can be " mechanism-based irreversible inhibitor " that lipase suppresses group, and it suppresses lipase active by active site or other position formation covalent bond with enzyme.In another embodiment, lipase inhibition group is (isosteric) inhibitor of same joining of enzyme.
Of the present invention aspect first in, when using except selectivity CB 1During lipase inhibitory polymer outside the antagonist compound, lipase suppresses group makes lipase for example stomach, pancreas and lingual lipase deactivation.By forming covalent bond, deactivation can cause kinase inactive.Can on the active site of enzyme or near, or as long as the formation of covalent bond has caused the inhibition to enzymatic activity, also can be at residue place and amino acid residue formation covalent bond away from active site.Lipase comprises catalysis three to be levied, and it is responsible for lipid hydrolysis is become fatty acid.Catalysis three is levied by serine, aspartic acid and histidine amino acid residue and is formed.This three hydrolysis of levying amido link in the also responsible serine protease, what be worth expectation is that the serpin chemical compound also can suppress lipase.Therefore, can with the covalently bound serpin of polymer preferably lipase suppress group.For example, covalent bond can form between lipase suppresses the hydroxyl at group and enzyme catalysis position.For example, can form covalent bond with serine.Lipase suppress group and the aminoacid that has with a certain distance from active site for example cysteine form covalent bond and also can cause deactivation.In a second aspect of the present invention, when using except selectivity CB 1During lipase inhibitory polymer outside the antagonist compound, the noncovalent interaction that lipase suppresses between group and the enzyme also can cause enzyme-deactivating.For example, it can be the homotype space ligand of fatty acid that lipase suppresses group, and it can interact with the catalytic site of lipase non-covalently.In addition, lipase inhibition group can be competed the lipase hydrolysis effect with natural glycerin three esters.
Multiple polymers can be used in the invention described herein.Polymer can be aliphatic, alicyclic or aromatic or synthetic or natural generation.Yet, preferred aliphat and alicyclic synthetic polymer.In addition, polymer can be the copolymer of hydrophobic, hydrophilic or hydrophobic and/or hydrophilic monomer.Polymer is all or part of can be non-ionic (for example neutral), anionic or cationic.In addition, can belong to monomer (for example vinyl alcohol) from olefinic or ethylene, or condensation polymer prepares polymer.For example, polymer can be a polyvinyl alcohol, polyvinylamine, poly--N-alkyl vinylamine, polypropylene amine, poly--N-alkyl allylamine, polyalkyleneimine, polyethylene, polypropylene, polyethers, poly(ethylene oxide), polyamide, polyacrylic acid, polyalkyl acrylate, polyacrylamide, polymethylacrylic acid, polyalkyl methacrylate, PMAm, poly--the N-alkyl acrylamide, poly--N-alkyl methyl acrylamide, polystyrene, vinyl naphthalene, vinyl xylene, ethyl vinyl benzene, aminobenzene ethylene, the vinyl diphenyl, the vinyl benzene methyl ether, the vinyl imidazole base, the vinylpyridine base, dimethylaminomethyl styrene, the trimethylammonium ethyl methacrylate, the trimethylammonium ethyl acrylate, carbohydrate, substitutive derivative of protein and above material (for example their fluorinated monomer) and copolymer thereof.Preferred polymer comprises polyethers, for example poly alkylene glycol.
Polymer that adopts in the method described herein and intermediate and the method for preparing polymer are described in detail in U.S. Pat 6572850, US6558657, US6352692, US6267952 and the International Patent Application WO 99/34786, and it is all introduced the present invention as a reference.
Recently, described new formula (A) 5-alkyl oxygen base-3-phenyl-1,3 in International Patent Application WO 03/072555,4- diazole-2-ketone is used for the treatment of metabolic disease, cardiovascular disease or especially obesity as pancreatic lipase inhibitor.
Figure A20048003008800161
Formula (A)  diazolones and salt thereof and acid-addition salts also are suitable for the CB with the present invention's use 1The antagonist compound associating.In formula (A), substituent group can be as follows:
R1 can be the 7-22C alkyl; By 4-20C alkoxyl, 6-10C aryl, 6-10C aryloxy group or (4-12C) the 2-4C alkyl that replaces of the alkoxyl (aryl wherein can be replaced by one or more halogens, 1-4C alkyl, 1-4C alkoxyl, NO2 or CF3) of alkoxyl-(2-4C); The 7-20C alkenyl; Or by the phenyl of 6-12C alkyl or phenoxy group replacement; With
R2 can be H, halogen, NO2,1-4C alkyl, 1-4C alkoxyl, CF3 or OCF3 separately to R5; Or (6-10C) alkoxyl, 6-10C aryloxy group, 6-10C aryl, 3-8C cycloalkyl or the 3-8C cycloalkyloxy of aryl-(1-4C) (optional replaced) by halogen, CF3,1-4C alkoxyl or 1-4C alkyl.
These 5-alkyl oxygen base-3-phenyl-1,3,4- diazole-2-ketone are described to have for example anorexia, anti-diabetic, brings high blood pressure down or the pharmacological property of heart excitement, and mechanism of action is as pancreatic lipase inhibitor.For example the IC50 of 5-dodecyl oxygen base-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)- diazole-2-ketone inhibition porcine pancreatic lipase is 0.03 μ M.Therefore, these 5-alkyl oxygen base-3-phenyl-1,3,4- diazole-2-ketone useful as drug is in particular for treatment of obesity.As pancreatic lipase inhibitor, 5-alkyl oxygen base-3-phenyl-1,3,4- diazole-2-ketone has suppressed the absorption again of food fat, thereby has reduced fat absorption and reduced body weight (perhaps stoping weight increase).And, it is reported 5-alkyl oxygen base-3-phenyl-1,3,4- diazole-2-ketone also has beneficial effect in treatment metabolic disease (for example diabetes) or cardiovascular disease (for example hypertension and myocardial infarction).Formula (A) lipase inhibition chemical compound is described in greater detail among the WO03/072555, can obtain according to known method.The suitably synthetic of formula (A) lipase inhibition chemical compound also is described in the International Patent Application WO 03/072555.The full content of International Patent Application WO 03/072555 be introduced into the application about the open part of formula (A) lipase inhibitor with for referencial use.
In addition, further described formula (A) 5-alkyl oxygen base-3-phenyl-1,3 in International Patent Application WO 03/072098,4- diazole-2-ketone is used for the treatment of obesity or I type and type ii diabetes as pancreatic lipase inhibitor.The formula of describing in WO03/072098 (A)  diazolones and their salt and acid-addition salts also are suitable for the CB with the present invention's use 1The antagonist compound associating.In formula (A), substituent group can be as follows:
R1 can be the 1-6C alkyl; 3-9C-cycloalkyl, these two groups can be chosen wantonly by phenyl, 1-4C alkoxyl, S-1-4C alkyl, N (1-4C-alkyl) 2 and replace; With the optional phenyl that can be replaced by halogen, 1-4C alkyl, 1-4C-alkoxyl, nitro or CF3; With
R2 can be H to R5 independently of one another, halogen, and NO2, the 1-4C alkyl is by the 1-9C alkoxyl of F, 6-10C-aryl, amino or the replacement of 1-4C alkylamino; 6-10C-aryl-1-4C-alkoxyl, 6-10C-aryloxy group, 6-10C-aryl, 6-10C-aryloxy group-1-4C-alkyl, 3-8C cycloalkyl or O (3-8 cycloalkyl), it randomly can be replaced by halogen, CF3,1-4 alkoxyl or 1-4C alkyl; The optional SO2-NH-(1-6C alkyl) that is replaced by N (1-6C alkyl) 2, SO2-NH-(2,2,6,6-tetramethyl piperidine-4-yl), the optional SO2-NH-(3-8C cycloalkyl) that is replaced by the 1-4C alkyl, SO2-N (1-6C alkyl) 2 or COX; 2-oxygen-pyrrolidine-1-base, 2,5-dimethyl pyrrole-1-base or NR6-A-R7;
Condition is that R2, R3, R4 and R5 are not H simultaneously when following situation occurring:
X is O (1-6C alkyl), NH (1-6C alkyl), NH (3-8C cycloalkyl) or N (1-6C alkyl) 2, N (1-6C alkyl) 2 is pyrrolidine, piperidines, morpholine, thiomorpholine or piperazine also, and it is replaced 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) are optional;
R6 is H, 1-4C alkyl or 6-10C-aryl-1-4C-alkyl, and aryl wherein can be replaced by halogen, CF3,1-8C alkoxyl or 1-4C alkyl;
A is a singly-bound, COn, SOn or CONH;
N is 1 or 2;
R7 is H; 1-18C alkyl or 2-18C alkenyl, its can by 1-4C alkyl, halogen, CF3,1-4C alkoxyl, N (1-4C alkyl) 2 ,-COOH, 1-4C alkoxy carbonyl group, 6-12C aryl, 6-12C aryloxy group, 6-12C aryl carbonyl, 6-10-aryl-1-4C-alkoxyl or oxygen is to polysubstituted three times, aryl wherein itself can be replaced by halogen, 1-4C alkyl, amino-sulfonyl or methyl mercapto are optional;
6-10C-aryl-1-4C-alkyl, 5-8C-cycloalkyl-1-4C-alkyl, the 5-8C cycloalkyl, 6-10-aryl-2-6C-alkenyl, the 6-10C aryl, diphenyl, diphenyl-(1-4 alkyl), indanyl, it can be by the 1-18C alkyl, the 1-18C alkoxyl, the 3-8C cycloalkyl, COOH, hydroxyl, the 1-4C alkyl-carbonyl, 6-10C-aryl-1-4C alkyl, 6-10C-aryl-1-4C-alkoxyl, the 6-10C aryloxy group, nitro, cyano group, the 6-10C aryl, fluorosulfonyl, the 1-6C alkoxy carbonyl group, the 6-10 aryl-sulfonyl oxygen, pyridine radicals, NHSO2-(6-10 aryl), halogen, CF3 or OCF3 are optional to be replaced, and alkyl wherein also can be by the 1-4C alkoxy carbonyl group, CF3 or carboxyl substituted and aryl also can be by halogens, CF3 or 1-4C alkoxyl replace;
Or group Het-(CH2) r-, r=0,1,2 or 3 and the saturated or undersaturated 5-7-of Het=unit heterocycle wherein, it can be benzo, optional being increased by 1-4C alkyl, 6-10C aryl, halogen, 1-4C alkoxyl, 1-4C alkoxy carbonyl group, 6-10C-aryl-1-4C alkyl, 6-10C-aryl-1-4C-alkyl sulfenyl or nitro encircles or replacement, wherein the benzo that is increased ring by aryl can be replaced by halogen, 1-4C alkoxyl or CF3, and the alkyl in the aralkyl can be replaced by methoxyl group and CF3.
Formula (A) lipase inhibition chemical compound is described in greater detail among the WO03/072098, can obtain according to known method.The suitably synthetic of formula (A) lipase inhibition chemical compound also is described in the International Patent Application WO 03/072098.The full content of International Patent Application WO 03/072098 introduce the present invention about the open part of formula (A) lipase inhibitor with for referencial use.
In addition, in U.S. Pat 6,624,161 and its corresponding International Patent Application WO 00/040569 and WO00/40247 in further described lipase inhibition chemical compound, it also is suitable in the context of the invention and CB1 antagonist compound associating described herein.These patent documents US6,624,161 and WO00/040569 a series of chemical compounds have been described, they are 2-oxygen base-4H-3,1-benzoxazine-4-ketone derivatives comprises ATL-962, and they comprise application in the type ii diabetes at obesity and obesity relevant disease.2-oxygen base-4H-3,1-benzoxazine-4-ketone derivatives have formula (B) structure, or the acceptable salt of its pharmacy, ester, amide or prodrug:
Figure A20048003008800191
Wherein:
R1a is
(i) C10-30 side chain or unbranched alkyl, optional by one or more C3-6 cycloalkyl, the C3-6 cycloalkenyl group, aryl, heteroaryl, reductive heteroaryl (reduced heteroaryl),-C (O) R13,-CO2R13,-SOR13,-SO2R13,-NR13R14,-OR13 replaces independently,-SR13,-C (O) NR13R14,-NR14C (O) R13, halogen, cyano group and nitro, and/or optional inserted by one or more oxygen atoms, condition is that any hetero atom among the R1a must be by at least two carbon atoms and the outer oxygen atom of ring (or with any other hetero atom) isolation;
(ii) C2-25 alkenyl, the C2-25 alkynyl, the C3-6 cycloalkenyl group, aryl-C2-25 alkenyl, heteroaryl-C2-25 alkenyl, reductive heteroaryl, the substitutive derivative of reductive heteroaryl-C1-25 alkyl or any aforementioned group, substituent group wherein is one or more C1-6 alkyl independently, the C1-6 alkyl that halogen replaces, aryl, aryl-C1-6 alkyl, heteroaryl, reductive heteroaryl, reductive heteroaryl-C1-6 alkyl, the C1-6 alkoxyl, aryl-C1-6 alkoxyl,-C (O) R13,-CO2R13,-SOR13,-SO2R13,-NR13R14,-OR13,-SR13,-C (O) NR13R14,-NR14C (O) R13, halogen, cyano group and nitro, condition are that any hetero atom among the R1a must be by at least two carbon atoms and the outer oxygen atom of ring (or with any other hetero atom) isolation;
The (iii) C2-9 alkyl that is inserted by one or more oxygen atoms, optional independently by one or more C3-6 cycloalkyl, C3-6 cycloalkenyl group, aryl, heteroaryl, reductive heteroaryl ,-C (O) R13 ,-CO2R13 ,-SOR13 ,-SO2R13, NR13R14, OR13, SR13 ,-C (O) NR13R14 ,-NR14C (O) R13, halogen, cyano group and nitro replace, condition is that any hetero atom among the R1a must be by at least two carbon atoms and the outer oxygen atom of ring (or with any other hetero atom) isolation; Perhaps
(iv) be selected from the C1-9 alkyl that following radicals replaces :-C (O) R13 ,-CO2R13, SOR13, SO2R13, NR13R14, OR13, SR13, C (O) NR13R14, NR14C (O) R13; Bicyclic heteroaryl except the reductive heteroaryl of tetralyl, pyridine radicals, pyrrole radicals, piperidyl, halogen, cyano group, nitro, aryl bicyclic, bicyclic heteroaryl, monocycle or bicyclo-, the imidazole radicals;
(v) be selected from the phenyl that following radicals replaces: OR17 ,-COR13 ,-CO2R13, SOR13, SO2R13, CONR13R14, NR14C (O) R13; C1-6 alkyl, aryl, aryl C1-6 alkyl, heteroaryl and heteroaryl C1-6 alkyl that halogen replaces; Perhaps
(the vi) bicyclic heteroaryl except reductive heteroaryl of aryl bicyclic, bicyclic heteroaryl, monocycle or bicyclo-or the imidazole radicals, they by OR17 ,-COR13 ,-CO2R13, SOR13, SO2R13, CONR13R14, NR14C (O) R13 is optional replaces; C1-6 alkyl, aryl, aryl C1-6 alkyl, heteroaryl and heteroaryl C1-6 alkyl that halogen replaces;
Wherein R13 and R14 represent hydrogen independently of one another, the C1-10 alkyl, the C2-10 alkenyl, the C2-10 alkynyl, the C3-6 cycloalkyl, the C3-6 cycloalkenyl group, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, reductive heteroaryl or reductive heteroaryl, C1-10 alkyl and R17 represent hydrogen or C2-10 alkenyl, the C2-10 alkynyl, the C3-6 cycloalkyl, the C3-6 cycloalkenyl group, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, reductive heteroaryl or reductive heteroaryl C1-10 alkyl
With R8a, R9a, R10a and R11a,
Be hydrogen, halogen, hydroxyl, amino, nitro, cyano group, sulfydryl, C1-10 alkyl, C1-10 alkoxyl, C1-10 cycloalkyl, C1-10 cycloalkyloxy, C (O) R15, C (O) NR15R16, S (O) R15 or halo C1-10 alkyl independently of one another;
Wherein R15 and R16 represent hydrogen or C1-10 alkyl independently of one another, and condition is when R8a, R9a, R10a and R11a are H, and R1a is not CH2CH2Cl or C3 alkenyl.
In addition, relate to 2-amino-4H-3 in International Patent Application WO 00/40247,1-benzoxazine-4-ketone derivatives is used for the treatment of obesity as lipase inhibition chemical compound.In formula (B) ,-OR1a substituent group quilt-NR1R2 group is replaced, and being defined among the WO00/40247 of R1 and R2 provides.
The chemical compound of above structurally associated comprises ATL-962, and a kind of oral non-absorbent synthctic fat enzyme inhibitor is obtained from Alizyme ' s pancreatic lipase inhibitor project, is carrying out effective treatment of obesity and the effectively exploitation of treatment type ii diabetes.ATL-962 chemistry 2-hexadecane oxygen base by name-6-methyl-4H-3,1-benzoxazine-4-ketone.Preclinical study shows that ATL-962 has the similar effectiveness with orlistat, and does not observe toxicity.The clinical data of these chemical compounds also can obtain in the public sphere, for example obtains the clinical research of obesity from ATL-962.
Therefore, the result that plans to be obtained delivers in the obesity international conference of Sao Paulo of Brazil the Ib phase of carrying out with ATL-962.Three Ib phases test and have comprised 99 healthy male volunteers altogether, are divided into 7 groups or 9 groups, give a kind of (66 experimenters) or placebo (24 experimenters) in several dosage of ATL-962, three times on the one, take totally 5 days with food.In one group, 9 patients are given orlistat (qv) 120mg, three times on the one.Generally speaking, ATL-962 is safe with well-tolerated, and the drainage increase of fat shows effectively in the food.Is 4.9 (+/-4.3) to 11.2 (+/-6.9) g/ days with giving food every day 50mg for twice to the excretory fatty average of the patient of 300mg dosage ATL-962, is 1.4 (+/-1.0) g/ days with respect to placebo, and orlistat is 5.6 (+/-3.8) g/ days.Compare with placebo, 55% patient who accepts ATL-962 (50mg is to 300mg) has shown 3 times or the more increase on fat is drained, and 27% patient has shown 7 times or more increasing.The evidence that has dose dependent.Side effect and frequency thereof are similar, between ATL-962 and placebo, mainly are gastrointestinal side effects, and main side effect is an oiliness feces.
Multicenter that comprises 370 clinical obese patients, at random, the result of double blinding, parallel group of test (the IIb phase is studied) carries out in 5 specialist clinics of European countries, reported PRELIMINARY RESULTS in JIUYUE, 2003.For all treatment groups, all dosage levels of ATL-962 (60,120 and 240mg) have shown all that with respect to placebo body weight significantly alleviates.The degree that loses weight between the treatment group is as broad as long.The LDL-cholesterol has reduced in the treatment group, and does not reduce in placebo group.The HDL-cholesterol levels is as broad as long between the treatment group, yet it increases in the placebo treatment group to some extent.The T-CHOL of treatment group has reduced, and placebo group demonstrates increase.ATL-962 is safe and generally well-tolerated.
The chemical compound of formula (B) lipase inhibition chemical compound such as ATL-962 and structurally associated is described in U.S. Pat 6,624 in further detail, 161 and corresponding International Patent Application WO 00/040569 in, can obtain according to known method.The suitably synthetic US6 that also is described in of formula (B) lipase inhibition chemical compound, 624,161 and International Patent Application WO 00/040569 in.US6,624,161 are introduced into the open part of the relevant formula of the application (B) lipase inhibitor with for referencial use with the full content of International Patent Application WO 00/040569.The full content of International Patent Application WO 00/040247 also is introduced into the relevant 2-amino-4H-3 that has of the relevant wherein description of the application, and the open part of the lipase inhibitor of 1-benzoxazine-4-ketonic compound structure is with for referencial use.
The full content of mentioned document is introduced into the relevant CB of the application in the description of the present invention 1The antagonist compound and the open part of lipase inhibitor of uniting use according to the present invention are with for referencial use.
The acceptable salt of pharmacy, hydrate, solvate and the prodrug of above-mentioned all lipase inhibition chemical compounds also can be used in the context of the present invention.
By using pharmaceutical adjuvant, auxiliary substance and/or liquid or solid carrier mass, use conventional method, above-indicated CB 1(it is Fructus Cannabis CB effectively and optionally to antagonist compound 1-receptor antagonist) or the lipase inhibition chemical compound that uses of its prodrug, tautomer or salt and the present invention can make the dosage form that is suitable for treating and/or preventing obesity, for example be used for teenager or children's's administration, and the administration that is used for the treatment of drug induced obesity.As therapeutic agent, selectivity CB 1Antagonist compound and/or lipase inhibition chemical compound can be contained in pharmaceutical preparation for example in tablet, capsule, suppository or the solution together with (conventional) pharmacy adjuvant, adjuvant and/or adjuvant.These pharmaceutical preparatioies can be used conventional solid or liquid excipient for example lactose, starch or Pulvis Talci according to known method, or liquid paraffin prepares, and/or for example tablet disintegrant, solubilizing agent and antiseptic prepare to use (conventional) pharmacy adjuvant, adjuvant and/or adjuvant.
Therefore, the present invention also relates on the other hand and comprises above-indicated at least a selectivity CB 1Antagonist compound or its prodrug, tautomer or salt are with the pharmaceutical composition of at least a lipase inhibition chemical compound associating.Preferred pharmaceutical composition of the present invention comprises at least a CB as active component 1Antagonist compound, the CB of preferred above definition 1Antagonist compound, or its prodrug, tautomer or salt, with at least a lipase inhibition chemical compound, be used for the treatment of and/or prevent teenager or juvenile patient's obesity, and/or be used for the treatment of and/or prevent juvenile and the drug induced obesity of adolescent patient.Certain drug compositions of the present invention is characterised in that, at least a as defined above CB 1Antagonist compound or its prodrug, tautomer or salt and at least a lipase inhibition chemical compound, the effective dose with juvenile patient's obesity of being suitable for treating and/or preventing this treatment of needs exists respectively.In another embodiment of the invention, described antagonist compound and lipase inhibition chemical compound are respectively to be suitable for the treating and/or preventing teenager of this treatment of needs and the effective dose of the drug induced obesity of adolescent patient is present in the pharmaceutical composition.In pharmaceutical composition of the present invention, above Ding Yi selectivity CB 1Antagonist compound or its prodrug, tautomer or salt are preferably united use with at least a lipase inhibition chemical compound that is selected from lipase inhibitory polymer, orlistat, panclicins, ATL-962 and lipstatin.
The present invention also relates to pharmaceutical product, this product comprises the CB as defined above as medicine 1Antagonist compound or its prodrug, tautomer or salt, and description, this description is indicated described CB 1Antagonist compound can be united with lipase inhibition chemical compound, is administered for simultaneously, respectively or step by step and treats and/or prevents obesity.
At last, the present invention also comprises the method that treats and/or prevents teenager for example or juvenile patient's obesity, and/or is used for the treatment of and/or prevents juvenile and the drug induced obesity of adolescent patient, it is characterized in that CB as defined above 1(it is Fructus Cannabis CB effectively and optionally to antagonist compound 1-receptor antagonist) or its prodrug, tautomer or salt, the patient who unites this kind treatment demand is arranged with at least a lipase inhibition chemical compound carries out administration.The method that the present invention treats and/or prevents obesity can be used for teenager or juvenile patient's obesity, and/or is used for juvenile and the drug induced obesity of adolescent patient.In a variant embodiment of the present invention, the method for the treatment of and/or preventing is characterised in that this treatment is at juvenile patient's obesity.In another variant embodiment of the present invention, the method for the treatment of and/or preventing is characterised in that this treatment is at teenager or the drug induced obesity of adolescent patient.Treat and/or prevent in the method for the present invention, as defined above selectivity CB 1Antagonist compound or its prodrug, tautomer or salt are preferably united with at least a lipase inhibition chemical compound that is selected from lipase inhibitory polymer, orlistat, panclicins, ATL-962 and lipstatin and are carried out administration.
According to the present invention, selectivity CB as defined above 1Antagonist compound or its prodrug, tautomer or salt, with lipase inhibition chemical compound associating, with simultaneously, respectively or the substep route of administration carry out administration.
The chemical compound that is used for administering drug combinations of the present invention or compositions separately preferably be enough to prevent and/or treat disease, disorder or disease symptoms for example the amount of obesity the patient of treatment demand is arranged.For all aspects of the present invention especially medical application, the administration of chemical compound or compositions has a dosage, this dosage will finally be determined by the attending doctor, to consider these factors, the seriousness of for example employed chemical compound, type of animal, age, body weight, symptom, the method for administration, side effect and/or other contraindication.The dosage range of Que Dinging can pass through the standard design clinical trial especially, and omnidistance monitored patient disease process and recovery situation are determined.This test can be used the dosage design that strengthens gradually, uses the initial dose of the low percent of animal maximum tolerated dose as the people.
The acceptable chemical compound of physiology that is used for administering drug combinations of the present invention or compositions will be used (for adult patient) with the daily dose scheme usually separately, for example oral dose 1mg is to 2000mg, preferred 30mg is to 1000mg, for example 10 arrive 250mg, perhaps intravenous injection, subcutaneous or intramuscular dosage 0.1mg be to 100mg, and preferred 0.1mg is to 50mg, for example 1 formula (I) chemical compound or the acceptable salt of its physiology that arrives 25mg, press free alkali and calculate this chemical compound administration every day 1 to 4 time.Suitable compound is carried out the continuous treatment in one period with administration, for example a week or the longer time.For juvenile patient, give the part of adult patient oral dose usually, for example aforementioned adult patient oral dose 1/5th or half.
Preferably, in one embodiment of the invention, this treats and/or prevents method and is used for the treatment of juvenile patient's obesity.In another preferred embodiment of the present invention, this treats and/or prevents method and is used for the treatment of teenager or the drug induced obesity of adolescent patient.This drug induced obesity especially can be caused by medicine such as atypical antipsychotic agents.
In one embodiment of the invention, this treats and/or prevents method and is used for the treatment of juvenile patient's obesity.Therefore, useful is that the cannabinoid antagonist is suitable for treating childhood obesity and relevant comorbidities, for example I type i diabetes.There is tangible medical need to improving treatment, because not only in the colony that grows up, and in child and (younger and older) teenager, obesity has become the medical problem that becomes more and more important.From 19th-century sixties to the nineties, in the national survey of the U.S., the prevalence that the child is overweight is increased to 11% (Sorof and Daniels 2002) from 5%.Another example is that in the past 20 years, Canadian childhood obesity has been increased to original 3 times (Spurgeon 2002).Childhood obesity has caused large-scale severe complication, has increased precocious disease and dead in the future risk, has increased public health concern (Ebbeling, people such as Pawlak 2002).In last decade, observed rolling up of type ii diabetes case, especially in the child.This fashion trend obviously reflects advancing the speed of obesity.Type ii diabetes is considered to be grown up and gerontal patient's disease in the past, rather than child disease (Arslanian 2002).A main hazard factor of children's's type ii diabetes is an obesity.
Child's type ii diabetes (the same with the adult) is the part (Rosenbloom 2002) of insuline resistance syndrome, it comprises hypertension, dyslipidemia and other risk factors for atherosclerosis and hyperandrogenism such as precocious adrenarche and polycystic ovary syndrome.Other result relevant with childhood obesity comprises left ventricular hypertrophy, non-alcoholic fatty liver disease, obstructive sleep apnea, orthopaedic problem and serious psychology problem.
In addition, it is more prevalent that essential hypertension becomes in the child, and relevant obesity becomes mainly independently risk factor once more.Obese children ratio not Obese children is suffered from high about 3 times (the Sorof and Daniels 2002) of hypertensive risk.The child loses weight benefit that blood pressure is reduced in observation property with get involved and obtain proof in the Journal of Sex Research.
Develop rapidly because childhood obesity is popular among the hereditary fixedly crowd, public attention rate has improved.Suppose that driving factors mainly are the hostile environment factors,, have the direct suggestion that life style is changed this.Obesity and relevant comorbidities thereof are very serious medical conditions, in the prior art for the measure and the treatment of obesity especially childhood obesity, still invalid to a great extent at present (Ebbeling, people such as Pawlak 2002).The treatment of type ii diabetes also is especially difficult (Silink 2002) in child and teenager age group.Serious hope to dainty is a key factor of the relevant obesity of human life style with excessively eating, especially in the middle of child and teenager.Degree treatment type ii diabetes and other comorbidities according to metabolism disorder and symptom: the type ii diabetes child uses the only data of oral hypoglycemic to be to use metformin (Rosenbloom 2002).
Therefore, the CB of the present invention's use 1Uniting of antagonist and lipase inhibitor for coming treatment of obesity that a kind of probability of uniqueness is provided by influencing these " driving forces ".They are better than present therapeutic treatment method, are particularly suitable for teenager and children's treatment, because their significant security performances and/or toleration and wonderful useful combined effect.Except effectiveness, treatment of obesity, especially treatment treatment childhood obesity requires to have safety.
Childhood obesity is a kind of medical conditions, and it may need long-term treatment.The CB that the present invention uses 1The security performance of antagonist and lipase inhibitor associating is better than the Current Standard Drug therapy, these CB 1The uniting of antagonist and lipase inhibitor to be particularly suitable for treating and to prevent teenager obesity and childhood obesity and relevant comorbidities.
Document:
Arslanian，S.(2002).″Type?2?diabetes?in?children：clinicalaspects?and?risk?factors.″ Horm?Res?57?Suppl?1：19-28.
Ebbeling, C.B., D.B.Pawlak waits people (2002). " Childhoodobesity:public-health crisis, common sense cure. " Lancet360 (9331): 473-82.
Rosenbloom，A.L.(2002).″Increasing?incidence?of?type?2diabetes?in?children?and?adolescents：treatmentconsiderations.″ Paediatr?Drugs?4(4)：209-21.
Silink，M.(2002).″Childhood?diabetes：a?globalperspective.″ Horm?Res?57?Suppl?1：1-5.
Sorof，J.and?S.Daniels(2002).″Obesity?hypertension?inchildren：a?problem?of?epidemic?proportions.″ Hypertension40(4)：441-7.
Spurgeon，D.(2002).″Childhood?obesity?in?Canada?hastripled?in?past?20?years.″ Bmj?324(7351)：1416.
In another embodiment of the present invention, the method for the treatment of and/or preventing is used for the treatment of teenager or the drug induced obesity of adolescent patient.Drug induced weight increase also is main focus, to improving treatment higher medical demand is arranged.In addition, advise CB of the present invention in this article 1Antagonist is better than the Current Standard Drug therapy, these CB 1Antagonist is particularly suitable for treatment and prevention is juvenile and the drug induced obesity of adolescent patient.
About drug induced weight increase, according to Zimmermann, U., people such as T.Kraus (2003, " Epidemiology; implications and mechanisms underlyingdrug-induced weight gain in psychiatric patients. " J PsychiatrRes 37 (3): 193-220) report, the health weight increase often occurs in during the psychosis medicine treatment, and often is accompanied by that appetite increases or the serious hope of food is increased.Yet the generation of this side effect and time course are difficult to prediction, and its finally cause fat in most of patient disease and relative sickness rate often cause them to end treatment, even this treatment is effective.In the patient who uses some second filial generation antipsychotic drug and the treatment of some mood stabilizers, it is the most outstanding that weight increase shows.Significant weight increase also often occurs in the therapeutic process of most of tricyclic antidepressants.
Huge weight increase is relevant with medicine, resembles for example atypical antipsychotics clozapine and olanzapine.Yet, some atypical antipsychotics are easy to cause significant weight increase, compliance a little less than it can cause and other disadvantageous health effect (Nasrallah, H. (2003). " A review of the effect of atypical antipsychotics on weight. " Psychoneuroendocrinology 28 Suppl 1:83-96.).Though serotoninergic, histamine has involved other metabolic mechanism with Adrenergic affinity, the mechanism of the weight increase that antipsychotic drug is relevant is also uncertain.The atypical antipsychotics class causes the tendency difference of body weight change in long-term treatment.Follow-up investigation shows that maximum weight increase is relevant with clozapine and olanzapine, Quetiapine and Ziprasidone minimum.The body weight that risperidone is accompanied by appropriateness changes, and this is not that dosage is relevant.When making up a kind of being used for the treatment of owing to during the method for serious drug induced obesity, suppose that the effectiveness of atypical antipsychotics equates that the weight increase performance is the factor that should consider.Under this consideration, the present invention is CB as defined above 1Uniting of antagonist and lipase inhibitor is effective.
Research CB 1Antagonist compound lipase inhibitor is to the experimental program of the effect of obesity
By measuring CB 1Antagonist and the administering drug combinations pair driving relevant with obesity of lipase inhibitor and the influence of characterisitic parameter can demonstrate CB of the present invention with the standard test animal model 1The useful pharmacological effect of the associating of antagonist and lipase inhibitor.
In order to study CB 1Antagonist and lipase inhibitor unite influence to obesity, the weight increase that can measure rat is as pharmacology's index.Thus, can adopt following experimental program at rat:
The dark period that for example 21:15h turns on light, 09:15h turns off the light in the 12h/12h photoperiod of putting upside down, rat can be without restriction near food, 2.5 hours 2 of every days.To provide higher fatty acid, high-carbonhydrate diet (western diet) to rat.When just beginning the feeding rat, give lipase inhibitor.Gave CB before 1 hour giving lipase inhibitor 1Antagonist.
For instance, for example can use following day dosage regimen in day, week or the moon in given period:
CB 1Antagonist, formula (I) CB especially as defined above 1Antagonist compound, or excipient, about in the morning 07:45 is to the 08:00h orally give.Lipase inhibitor, for example orlistat especially, or excipient, at about 08:45 to the 09:00h orally give.After the administration, rat can ad libitum access from 09:15 to 11:45h, and approximately 11:45 takes food away to 14:45h afterwards.Another lipase inhibitor dosage, for example orlistat especially, or excipient (Labrasol) in the afternoon approximately 14:15 to the 14:30h orally give, afterwards from 14:45 to the 17:15h ad libitum access.Subsequently, take food away from 17:15-09:15h.
The result of this experimental program will compare with food intake every day and weight increase, as during the experimental stage to the index of obesity therapeutic alliance effect.Except the parameter that provides previously, also can collect feces, be used to estimate fat digestibility.Also can carry out the spoil analysis at last.
In addition, finish the experiment feeding and after the administration stage, can when slaughtering rat, measure biochemical parameter.
For research effect, the sum of the rat of the scheme that experimentizes is divided into following each group, and the number of rat is roughly the same in every group:
1) matched group: according to design, rat is only accepted excipient and simulates administration (placebo group).
2) CB 1Group: rat is accepted the CB in the excipient 1Antagonist.
3) LI group: rat is accepted the lipase inhibitor (" LI ") in the excipient, for example chemical compound orlistat.
4) CB 1+ LI organizes (uniting group): rat is accepted the CB in the excipient 1Lipase inhibitor in antagonist and the excipient (" LI "), for example chemical compound orlistat.
The result of this design and separately studies show that CB as defined above 1Antagonist and lipase inhibitor unite useful fitness in treating and/or preventing obesity.

Claims (22)

1.CB 1Antagonist compound, it is Fructus Cannabis CB effectively and optionally 1-receptor antagonist, or its prodrug, tautomer or salt, be used for the treatment of and/or prevent obesity with uniting of at least a lipase inhibition chemical compound, especially comprise the application in the medicine that treats and/or prevents juvenile patient's obesity and/or juvenile and the drug induced obesity of adolescent patient in preparation.
2. according to the CB of claim 1 1The application of receptor antagonist compound, wherein, chemical compound is selected from down group:
1) diaryl pyrazole selectivity CB 1Receptor antagonist, preferred compound SR-141716A, Rimonabant and related compound, SR-147778, SR-140098 and/or WIN-54461;
2) amino alkyl indole selectivity CB 1Receptor antagonist, preferred compound lodopravadoline (AM-630);
3) has selectivity CB 1The benzofuran compound that the aryl of receptor antagonist activity-aroyl replaces, preferred compound LY-320135;
4) selectivity CB 1Receptor antagonist compound AM251 and/or AM281 and have selectivity CB 1The imidazole-based compounds of the replacement of receptor antagonist activity;
5) has selectivity CB 1The azetidine derivatives of receptor antagonist activity;
6) Compound C P-55940;
7) has selectivity CB 1Diaryl-the pyrazine of receptor antagonist activity-amide;
8) compd A CPA and ACEA;
9) has selectivity CB 1The pyrazole derivatives of receptor antagonist activity;
10) compound H U-210 and/or HU-243;
11) chemical compound O-585, O-823, O-689, O-1072 and/or O-2093;
12) has selectivity CB 1The 3-alkyl-5 of receptor antagonist activity, 5 '-zentropil;
13) has selectivity CB 1The CB of receptor antagonist activity 1Antagonist compound.
3. according to the CB of claim 1 1The application of receptor antagonist compound wherein, is to be used for the treatment of and/or to prevent application in the medicine of juvenile patient's obesity and/or juvenile and the drug induced obesity of adolescent patient in preparation.
4. according to each CB of claim 1-3 1The application of receptor antagonist compound, wherein, CB 1Antagonist compound is used for and at least a lipase inhibition chemical compound associating that is selected from lipase inhibitory polymer, orlistat, panclicins, ATL-962 and lipstatin.
5. pharmaceutical composition, it comprises the CB of at least a claim 1 or 2 1Receptor antagonist compound or its prodrug, tautomer or salt and the associating of at least a lipase inhibition chemical compound.
6. according to the pharmaceutical composition of claim 5, it comprises as at least a claim 1 of active component or 2 CB 1Antagonist compound or its prodrug, tautomer or salt, with at least a lipase inhibition chemical compound, be used for the treatment of and/or prevent teenager or juvenile patient's obesity, and/or be used for the treatment of and/or prevent juvenile and the drug induced obesity of adolescent patient.
7. according to the pharmaceutical composition of claim 5 or 6, wherein, at least a CB 1Receptor antagonist compound and at least a lipase inhibition chemical compound exist with the effective dose that is suitable for treating and/or preventing the juvenile patient's obesity that needs this kind treatment separately.
8. according to the pharmaceutical composition of claim 5 or 6, wherein, at least a CB 1Receptor antagonist compound or its prodrug, tautomer or salt and at least a lipase inhibition chemical compound exist to be suitable for treating and/or preventing the teenager that needs this kind treatment and the effective dose of the drug induced obesity of adolescent patient separately.
9. according to each pharmaceutical composition of claim 5-8, wherein, CB 1Antagonist compound or its prodrug, tautomer or salt are used for and at least a lipase inhibition chemical compound associating that is selected from lipase inhibitory polymer, orlistat, panclicins, ATL-962 and lipstatin.
10. treat and/or prevent the method for obesity, it is characterized in that, claim 1 or 2 CB 1Antagonist compound, it is Fructus Cannabis CB effectively and optionally 1-receptor antagonist, or its prodrug, tautomer or salt, the patient who unites the treatment of this kind of needs with at least a lipase inhibition chemical compound carries out administration.
11. the method that treats and/or prevents obesity according to claim 10 is characterized in that, the CB of claim 2 1Antagonist compound, it is Fructus Cannabis CB effectively and optionally 1-receptor antagonist, or its prodrug, tautomer or salt, the patient who unites the treatment of this kind of needs with at least a lipase inhibition chemical compound carries out administration.
12. the method that treats and/or prevents obesity according to claim 10 or 11 is characterized in that, treats and/or prevents to be used for teenager or juvenile patient's obesity, and/or is used for juvenile and the drug induced obesity of adolescent patient.
13., it is characterized in that treatment is at juvenile patient's obesity according to each the method that treats and/or prevents of claim 10-12.
14., it is characterized in that treatment is at teenager or the drug induced obesity of adolescent patient according to each the method that treats and/or prevents of claim 10-12.
15., it is characterized in that CB according to each the method that treats and/or prevents of claim 10-14 1Antagonist compound, preferably CB as defining in the claim 2 1Antagonist compound, or its prodrug, tautomer or salt are united with at least a lipase inhibition chemical compound that is selected from lipase inhibitory polymer, orlistat, panclicins, ATL-962 and lipstatin and to be carried out administration.
16., it is characterized in that CB according to each the method that treats and/or prevents of claim 10-15 1Antagonist compound, preferably CB as defining in the claim 2 1Antagonist compound, or its prodrug, tautomer or salt, unite by simultaneously with lipase inhibition chemical compound, respectively or the substep route of administration carry out administration.
17. drug products, it comprises the CB as medicine 1Antagonist compound, preferably CB as defining in the claim 2 1Antagonist compound, or its prodrug, tautomer or salt, with lipase inhibition chemical compound as combination formulations, be used for simultaneously, respectively or substep be administered for and treat and/or prevent obesity.
18. drug products, it comprises the CB as medicine 1Antagonist compound, preferably CB as defining in the claim 2 1Antagonist compound, or its prodrug, tautomer or salt, and description, description is indicated described CB 1Antagonist compound can be united with lipase inhibition chemical compound, is administered for simultaneously, respectively or step by step and treats and/or prevents obesity.
19.CB 1Antagonist compound, it is Fructus Cannabis CB effectively and optionally 1-receptor antagonist, or its prodrug, tautomer or salt are with the associating of at least a lipase inhibition chemical compound.
20. according to the associating of claim 19, wherein, this is united is to be used for the treatment of and/or prevent obesity, especially comprise treating and/or preventing juvenile patient's obesity, and/or in the medicine of juvenile and the drug induced obesity of adolescent patient.
21. according to the associating of claim 19 or claim 20, wherein, CB 1Receptor antagonist compound is selected from down group:
1) diaryl pyrazole selectivity CB 1Receptor antagonist, preferred compound SR-141716A, Rimonabant and related compound, SR-147778, SR-140098 and/or WIN-54461;
2) amino alkyl indole selectivity CB 1Receptor antagonist, preferred compound lodopravadoline (AM-630);
3) has selectivity CB 1The benzofuran compound that the aryl of receptor antagonist activity-aroyl replaces, preferred compound LY-320135;
4) selectivity CB 1Receptor antagonist compound AM251 and/or AM281 and have selectivity CB 1The imidazole-based compounds of the replacement of receptor antagonist activity;
5) has selectivity CB 1The azetidine derivatives of receptor antagonist activity;
6) Compound C P-55940;
7) has selectivity CB 1Diaryl-the pyrazine of receptor antagonist activity-amide;
8) compd A CPA and ACEA;
9) has selectivity CB 1The pyrazole derivatives of receptor antagonist activity;
10) compound H U-210 and/or HU-243;
11) chemical compound O-585, O-823, O-689, O-1072 and/or O-2093;
12) has selectivity CB 1The 3-alkyl-5 of receptor antagonist activity, 5 '-zentropil;
13) has selectivity CB 1The CB of receptor antagonist activity 1Antagonist compound.
22. according to each associating of claim 19-21, wherein, CB 1Receptor antagonist compound and at least a lipase inhibition chemical compound associating that is selected from lipase inhibitory polymer, orlistat, panclicins, ATL-962 and lipstatin.
CNA2004800300886A 2003-10-24 2004-10-22 Combination treatment of obesity involving selective cb1-antagonists and lipase inhibitors Pending CN1867332A (en)

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