WO2011058943A1 - Composition pharmaceutique formée par combinaison d'un composé ayant une activité antagoniste de mchr1 et un composé ayant une activité antagoniste de npy y5 - Google Patents

Composition pharmaceutique formée par combinaison d'un composé ayant une activité antagoniste de mchr1 et un composé ayant une activité antagoniste de npy y5 Download PDF

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WO2011058943A1
WO2011058943A1 PCT/JP2010/069812 JP2010069812W WO2011058943A1 WO 2011058943 A1 WO2011058943 A1 WO 2011058943A1 JP 2010069812 W JP2010069812 W JP 2010069812W WO 2011058943 A1 WO2011058943 A1 WO 2011058943A1
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compound
substituted
international publication
unsubstituted
antagonist activity
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日出男 雪岡
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塩野義製薬株式会社
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • the present invention relates to a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt or solvate thereof, and a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt or solvate thereof.
  • the present invention relates to a combined pharmaceutical composition.
  • the pharmaceutical composition is very useful for the prevention or treatment of obesity or obesity-related diseases.
  • the pharmaceutical composition is very useful for weight management in obesity.
  • Obesity is defined as the accumulation of excess fat or adipose tissue in the body relative to lean body mass, and is recognized as the main risk factor for health problems.
  • the body mass index (BMI) is a simple index of the height-weight ratio that is commonly used to classify an adult (over 15 years old) group or individual as overweight or obese. It is defined as the body weight (kg / m 2 ) expressed in kilograms divided by the height squared in meters. According to the World Health Organization, BMI of 25 kg / m 2 or more is “overweight” and 30 kg / m 2 or more is “obese”. On the other hand, the Japanese Obesity Society designates BMI of 25 kg / m 2 or more as “obesity”.
  • a drug containing a compound having an appetite suppressing action selective serotonin reuptake inhibitor such as fenfluramine and fluoxetine; mazindol, etc.
  • a compound having an action to suppress digestion and absorption of nutrients Drugs to be used are known.
  • compounds having an inhibitory action on nutrient digestion and absorption include compounds having an inhibitory action on sugar absorption ( ⁇ -glucosidase inhibitors such as acarbose and voglibose; SGLT-2 inhibitors such as dapagliflozin, remogliflozin and KGT-1075), fat absorption Examples thereof include compounds having an inhibitory action.
  • Compounds having fat absorption inhibitory action include lipase inhibitors (compounds having gastric lipase inhibitory action; compounds having pancreatic lipase inhibitory action such as orlistat, lipstatin, pancricin, cetiristat, etc.), bile acid adsorption such as cholestyramine, cholestyramide, etc. Resin etc. are mentioned.
  • Compounds considered as candidates for anti-obesity drugs include 5HT transporter inhibitor, NE transporter inhibitor, CB-1 antagonist / inverse agonist, ghrelin antagonist, H3 antagonist / inverse agonist, MCH R1 antagonist, MCH R2 agonist / Antagonist, NPY Y1 receptor antagonist, NPY Y2 receptor agonist, NPY Y4 receptor agonist, NPY Y5 receptor antagonist, mGluR5 antagonist, leptin, leptin agonist, leptin derivative, opioid antagonist, orexin antagonist, BRS3 agonist, CCK-A Agonist, CNTF, CNTF agonist, CNTF derivative, GHS agonist, 5HT2C agonist Mc4r agonist, monoamine reuptake inhibitor, GLP-1 agonist, UCP-1, 2 and 3 activators, ⁇ 3 agonist, thyroid hormone
  • MCH R1 antagonists or NPY Y5 receptor antagonists research and development of a number of compounds are being carried out as candidates for anti-obesity drugs.
  • Patent Document 1 discloses a formula that is an NPY Y5 receptor antagonist: Are described. 36 types of agonists and antagonists are enumerated as drugs that can be used with the above compounds. One of them is the MCH R1 antagonist. The specific combination of the MCH R1 antagonist and the NPY Y5 receptor antagonist is not described, and the combined effect is not disclosed or suggested.
  • Patent Document 2 describes that a combination of two appetite suppressants having different mechanisms can be an anti-obesity drug. As one of about 30 types of agonists and antagonists listed as appetite suppressants, NPY Y5 receptor antagonists and MCH R1 antagonists are described. The specific combination of the MCH R1 antagonist and the NPY Y5 receptor antagonist is not described, and the combined effect is not disclosed or suggested.
  • R 1 is alkyl
  • R 2 is hydrogen or alkyl
  • Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group
  • Is known to have an NPY Y5 receptor-specific antagonistic action Patent Documents 3 and 4).
  • Non-Patent Document 2 describes test results regarding the combined use of compound (a) and orlistat, which is a compound having pancreatic lipase inhibitory action.
  • Shionogi Pharmaceutical Co., Ltd. “Shionogi announces positive top-line efficacy results from year-long studies of velneperit, a novel NPY Y5 receptor antagonist being investigated for the treatment of obesity", 17 February 2009 Shionogi, Internet ⁇ URL: http://www.shionogi.co.jp/ir_en/news/detail/e_090217-2.pdf> Shionogi Pharmaceutical Co., Ltd., “1st Half and 2nd Quarter, of Fiscal 2009, Financial Results, [online], November 5, 2009, Shionogi, Internet ⁇ URL: http://www.shionogi.co.jp /ir_en/explanatory/pdf/e_p091105.pdf>
  • An object of the present invention is to provide a pharmaceutical composition that is very useful for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity.
  • the present inventor has found that the combined use (including co-administration) of a compound having MCH R1 antagonist activity and a compound having NPY Y5 receptor antagonist activity significantly reduces body weight in an obese model mouse in a dose-dependent manner. I found out that Furthermore, improvement of sugar metabolism was confirmed. Therefore, the pharmaceutical composition of the present invention is very useful for prevention or treatment of obesity or obesity-related diseases or weight management in obesity.
  • prevention or treatment of obesity is usually used in combination with drug therapy, diet therapy, exercise therapy, and the like.
  • a drug containing a compound having a digestion and absorption inhibitory action known as a drug for preventing or treating obesity is known to show an effect of enhancing food intake while showing an effect of suppressing weight gain (International Journal of Obesity (1987) 11, Suppl.3, 35-42, Obesity 15 (Suppl. 9): A121, 2007, etc.).
  • Such drugs are difficult to use as a dietary supplement.
  • both the compound having MCH R1 antagonist activity and the compound having NPY Y5 receptor antagonist activity contained in the pharmaceutical composition of the present invention are compounds having an antifeeding effect and are very useful as an adjunct to diet therapy. is there.
  • Compound (a) which is a compound having NPY Y5 receptor antagonist activity, contained in the pharmaceutical composition of the present invention is a highly safe compound. This inventor examined the body weight suppression effect by the co-administration of the compound which acts on various mechanisms besides the compound (a) and the compound having MCH R1 antagonist activity.
  • sibutramine which is a monoamine reuptake inhibitor
  • compound (a) significantly reduces body weight in obese model mice, and the degree thereof is determined based on the compound having the MCH R1 antagonist activity of the present invention and Very inferior compared to co-administration of compounds with NPY Y5 receptor antagonist activity.
  • the body weight suppression effect obtained by co-administration of sibutramine and compound (a) is not so great as compared to administration of sibutramine and compound (a) alone.
  • sibutramine exhibits an appetite suppressing effect at the initial stage of administration, the inhibitory effect disappears with the lapse of the repeated administration period, but rather shows an appetite enhancing effect.
  • sibutramine is represented by the following structural formula.
  • the present invention relates to the following.
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof A pharmaceutical composition comprising a combination of a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the pharmaceutical composition according to (1) which is a compounding agent.
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvent thereof The pharmaceutical composition according to (1), which is a kit containing a drug containing a Japanese product.
  • a compound having NPY Y5 receptor antagonist activity is Formula (I-2): [Wherein, Ra is substituted or unsubstituted alkyl or cycloalkyl, Y is —S (O) n— (n is 1 or 2) or CO— Rb is hydrogen or substituted or unsubstituted alkyl; Ra and Rb together may form an alkylene, X is substituted or unsubstituted alkylene, Substituted or unsubstituted alkenylene, Substituted or unsubstituted CO-alkylene, Substituted or unsubstituted CO-alkenylene or Wherein R 3 , R 4 , R 5 and R 6 are each independently hydrogen or substituted or unsubstituted alkyl; Is substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkenylene, substituted or unsubstituted bicycloalkylene, substituted or
  • Obesity-related diseases include bulimia, hypertension, impaired glucose tolerance, diabetes, metabolic syndrome, lipid metabolism disorder, arteriosclerosis, hyperuricemia, gout, fatty liver, proteinuria, endometrial cancer, breast cancer, prostate (8)
  • the pharmaceutical composition according to (8) which is cancer, colon cancer, osteoarthritis, low back pain, obstructive sleep apnea syndrome, coronary artery disease, cerebral infarction, menstrual abnormality, Praderwillie syndrome, Freirich syndrome or Pickwick syndrome .
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof A method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity comprising the step of administering a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof in combination.
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof comprising administering a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof in combination.
  • a pharmaceutical composition used for inducing or promoting weight loss, or for maintaining or managing body weight comprising administering a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof in combination.
  • for producing a pharmaceutical composition used for inducing or promoting weight loss, or for maintaining or managing body weight comprising administering a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof in combination.
  • An agent for preventing or treating obesity or an obesity-related disease of a compound having an NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, or an enhancer of a weight management effect in obesity For manufacturing, A compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. (24) a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof; Mixing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof, The manufacturing method of the pharmaceutical composition of Claim 1.
  • a drug containing a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof Prevention of obesity or obesity-related diseases, characterized by administration to a patient undergoing treatment with a drug containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof Alternatively, a method for enhancing the therapeutic effect or the weight management effect in obesity.
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof and a compound having an NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof are combined.
  • the pharmaceutical composition may comprise other anti-obesity compounds, pharmaceutically acceptable salts or solvates thereof.
  • a compound containing a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • other compounds having anti-obesity action, pharmaceutically acceptable salts thereof, or solvates thereof may be contained.
  • a compound containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or the like.
  • a compound having other anti-obesity action, a pharmaceutically acceptable salt thereof, or a solvate thereof may be contained.
  • the pharmaceutical composition of the present invention is very useful for the prevention or treatment of obesity or obesity-related diseases.
  • the pharmaceutical composition is very useful for weight management in obesity.
  • the “compound having MCH R1 antagonist activity” may be any compound that exhibits MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the IC 50 value is measured in accordance with the method described in FIG. 2 of the European Journal of Pharmacology Vol. 438: 129-135 (2002) or FIG. 1 of Nature medicine Vol.8 825-830 (2002).
  • a compound having a ⁇ 1 ⁇ M, preferably less than 100 nM, can be used as a compound with MCH R1 antagonist activity.
  • the following documents collectively describe compounds that exhibit MCH R1 antagonist activity and can be used as the pharmaceutical composition of the present invention, and methods for preparing them.
  • MCH R1 antagonist examples include, but are not limited to, the compounds described below.
  • NPY neuropeptide Y, which is a peptide consisting of 36 amino acid residues, and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.
  • NPY receptor In the “NPY receptor”, subtypes Y1, Y2, Y3, Y4, Y5, and Y6 have been discovered so far (Trends Pharmacology Sciences, Vol.18, 372-386 (1997)).
  • the Y5 receptor is involved in at least the feeding function, and its antagonist has been suggested to be an anti-obesity drug (Peptides, Vol.18, 445-457 (1997); Obesity, Vol.14, No .9, A235 (2006); Obesity, Vol.15, No.9, A57 (2007)).
  • the “compound having NPY Y5 receptor antagonist activity” may be any compound showing NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • an IC 50 value is measured according to the method described in Test Example 1-1 or 1-2 of International Publication No. 2009/131096, and a compound whose value is less than 1 ⁇ M, preferably less than 100 nM, is obtained as NPY Y5 It can be used as a compound having receptor antagonist activity.
  • the following documents collectively describe compounds that exhibit NPY Y5 receptor antagonist activity and that can be used as the pharmaceutical composition of the present invention, and methods for preparing them.
  • NPY Y5 receptor antagonist examples include, but are not limited to, the following compounds.
  • Formula (I-2) [Wherein, Ra is substituted or unsubstituted alkyl or cycloalkyl, Y is —S (O) 2 —; Rb is hydrogen or substituted or unsubstituted alkyl; X is Wherein R 3 , R 4 , R 5 and R 6 are each independently hydrogen or substituted or unsubstituted alkyl; Is a substituted or unsubstituted cycloalkylene, and p and q are each independently an integer of 0 to 2), W is a single bond, NR 7 or CONR 7 ; R 7 is hydrogen or alkyl; Za is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocycl
  • R 1 is alkyl
  • R 2 is hydrogen or alkyl
  • Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Alkyl means linear or branched alkyl having 1 to 10 carbon atoms. Examples include alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 3 carbon atoms, and the like.
  • R 1 is particularly preferably isopropyl or t-butyl.
  • alkyl for example, (1) halogen; (2) cyano; (3) (i) hydroxy, (ii) alkoxy, (iii) mercapto, (iv) alkylthio, each optionally substituted with one or more substitutable groups selected from the substituent group ⁇ defined below.
  • Substituent group ⁇ is halogen, optionally protected hydroxy, mercapto, alkoxy, alkenyl, amino, alkylamino, alkoxycarbonylamino, alkylthio, acyl, carboxy, alkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, phenoxy , Alkylphenyl, alkoxyphenyl, halogenophenyl, naphthyl and heterocyclic groups.
  • Alkenyl means a straight or branched alkenyl having 2 to 10 carbon atoms having one or more double bonds at an arbitrary position. Examples include alkenyl having 2 to 8 carbon atoms and alkenyl having 3 to 6 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
  • alkenyl include halogen, alkoxy, alkenyl, amino, alkylamino, alkoxycarbonylamino, alkylthio, acyl, carboxy, alkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, alkylphenyl, alkoxyphenyl, naphthyl and Examples thereof include one or more substituents selected from heterocyclic groups.
  • Alkoxy means a group in which the above “alkyl” is bonded to an oxygen atom. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, pentoxy, neopentoxy, hexoxy, isohexoxy, n-heptoxy, isoheptoxy, n -Octoxy, isooctoxy and the like.
  • alkoxy includes one or more groups selected from the above substituent group ⁇ , and is preferably phenyl, alkylphenyl, alkoxyphenyl, naphthyl, or a heterocyclic group.
  • Alkylthio "alkylcarbamoyl”, “alkylthiocarbamoyl”, “alkylamino”, “alkylsulfinyl”, “alkylsulfonyl”, “alkylsulfamoyl”, “hydroxyalkyl”, “alkylphenyl”, “alkoxyalkyl” , “Halogenoalkyl” or “phenylalkylthio” is the same as the above “alkyl”.
  • alkoxy moiety of “alkoxycarbonyl”, “alkoxyalkyl”, “alkoxycarbonylamino”, “alkoxyphenyl” or “phenylalkoxy” is the same as the above “alkoxy”.
  • substituent of “amino” the above substituent group ⁇ , substituted or unsubstituted benzoyl and substituted or unsubstituted heterocyclic carbonyl (wherein the substituent is one or more selected from hydroxy, alkyl, alkoxy and alkylthio) 1 or more substituents selected from (substituents).
  • “Hydrocarbon cyclic group” includes “cycloalkyl”, “cycloalkenyl”, “bicycloalkyl” and “aryl”. “Cycloalkyl” means cyclic alkyl having 3 to 8 carbon atoms. Includes 5 or 6 cyclic alkyls. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned. “Cycloalkenyl” means one having one or more double bonds at any position in the cycloalkyl ring.
  • Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and the like.
  • “Bicycloalkyl” means a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two rings share two or more atoms. Specific examples include bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl.
  • Aryl means a monocyclic or polycyclic aromatic carbocyclic group.
  • phenyl Including phenyl, naphthyl, anthryl, phenanthryl and the like. Also included are aryls fused with other non-aromatic hydrocarbon cyclic groups. For example, indanyl, indenyl, biphenylyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned. Particularly preferred is phenyl.
  • the substituent of the “hydrocarbon cyclic group” (“cycloalkyl”, “cycloalkenyl”, “bicycloalkyl” and “aryl”) is one or more selected from the substituent group ⁇ and the substituent group ⁇ described above. Group etc. are mentioned, Arbitrary positions may be substituted.
  • Substituent group ⁇ is (1) halogen; (2) oxo; (3) Cyano; (4) Nitro; (5) an imino optionally substituted with alkyl or hydroxy; (6) (i) hydroxy, (ii) alkyl, (iii) alkenyl, (iv) alkoxy, (v) carboxy, each optionally substituted with one or more substitutable groups selected from substituent group ⁇ , (Vi) alkoxycarbonyl, (vii) acyl, (viii) acyloxy, (ix) imino, (x) mercapto, (xi) alkylthio, (xii) carbamoyl, (xiii) alkylcarbamoyl, (xiv) cycloalkylcarbamoyl, (Xv) thiocarbamoyl, (xvi) alkylthiocarbamoyl, (xvii) alkylsulfinyl, (xviii)
  • phenyl optionally substituted (i) phenyl, (ii) naphthyl, (iii) phenoxy, (iv) phenylalkoxy, (v) phenylthio, (vi) phenylalkylthio, (vii) phenylazo, (viii) hetero Cyclic group, (ix) heterocyclic oxy, (x) heterocyclic thio O, (xi) heterocyclic carbonyl and (xii) heterocyclic sulfonyl.
  • cycloalkyl part of “cycloalkylcarbamoyl”, “cycloalkylsulfamoyl” and “cycloalkyloxy” is the same as the above “cycloalkyl”.
  • aryl part of “arylsulfonyl” is the same as the above “aryl”.
  • Heterocyclic group means a group derived from a heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • heterocyclic group is the same as those in the case where the “hydrocarbon cyclic group” is substituted.
  • heterocyclic moiety of “heterocyclic oxy”, “heterocyclic thio”, “heterocyclic carbonyl” or “heterocyclic sulfonyl” is the same as the above “heterocyclic group”.
  • “Acyl” includes the following. (1) straight or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, alkylcarbonyl or alkenylcarbonyl having 1 to 6 carbon atoms, or alkylcarbonyl or alkenylcarbonyl having 1 to 4 carbon atoms. (2) C4-9 cycloalkylcarbonyl or C4-7 cycloalkylcarbonyl. (3) Arylcarbonyl having 7 to 11 carbon atoms.
  • Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
  • the acyl part of “acyloxy” is the same as above.
  • Protecting groups for “optionally protected hydroxy” or “optionally protected hydroxyalkyl” include all commonly used hydroxy protecting groups. For example, acyl (acetyl, trichloroacetyl, benzoyl etc.), alkoxycarbonyl (t-butoxycarbonyl etc.), alkylsulfonyl (methanesulfonyl etc.), alkoxyalkyl (methoxymethyl etc.), trialkylsilyl (t-butyldimethylsilyl etc.), etc. Is mentioned.
  • Halogen includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
  • the halogen part of “halogenophenyl” or “halogenoalkyl” is the same as the above “halogen”.
  • Alkylene means a divalent group of 1 to 6 consecutive methylenes. A divalent group in which 2 to 6 methylenes are continuous and a divalent group in which 3 to 6 methylenes are continuous are included. Examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Particularly preferred is tetramethylene.
  • R 1 and R 2 together form an alkylene
  • the case of forming is included. Preferably It is.
  • alkylene part of “alkylenedioxy” is the same as the above “alkylene”, preferably methylenedioxy or ethylenedioxy.
  • Alkenylene is a divalent group of 2 to 6, preferably 3 to 6, more preferably 4 to 5 consecutive methylene groups in which at least one carbon-carbon bond is a double bond. Includes something.
  • Cycloalkylene is a divalent group formed by removing one hydrogen atom from the above “cycloalkyl”.
  • cycloalkylene 1,4-cyclohexanediyl is preferable.
  • Cycloalkenylene includes a group having at least one double bond in the ring of the “cycloalkylene”.
  • Bicycloalkylene includes a group formed by removing one hydrogen from the above “bicycloalkyl”. Specific examples include bicyclo [2.1.0] pentylene, bicyclo [2.2.1] heptylene, bicyclo [2.2.2] octylene, bicyclo [3.2.1] octylene.
  • “Arylene” includes a divalent group formed by removing one hydrogen atom from the above “aryl”. Preferable is phenylene.
  • Heterocyclic diyl includes a divalent group formed by removing one hydrogen atom from the above “heterocyclic group”. Preferred are piperidine diyl, piperazine diyl, pyridine diyl, pyrimidine diyl, pyrazine diyl, pyrrolidine diyl or pyrrole diyl, and more preferred is piperidine diyl.
  • the substituent of “unsubstituted arylene” and “substituted or unsubstituted heterocyclic diyl” includes one or more substitutable groups selected from the substituent group ⁇ , preferably halogen, hydroxy, alkyl, Halogenoalkyl, alkoxy, amino, alkylamino, acyl, carboxy, alkoxycarbonyl and the like. Any position may be substituted with these groups.
  • -NRb-X- is And preferably U is methylene or ethylene, more preferably It is.
  • the compound used in the pharmaceutical composition of the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.). Moreover, when this invention compound has a double bond, when both E body and Z body may exist, both are included.
  • “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Examples thereof include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid
  • salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid
  • ammonium examples thereof include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium
  • solvate examples include a hydrate of a compound or a salt thereof, an alcohol solvate, and the like.
  • a hydrate of a compound or a salt thereof examples include an alcohol solvate, and the like.
  • monohydrate, dihydrate, monoalcohol hydrate, dialcohol solvate and the like can be mentioned.
  • the prodrug of the compound contained in the pharmaceutical composition of the present invention is included in the range of the compound contained in the pharmaceutical composition of the present invention.
  • the prodrug of the compound contained in the pharmaceutical composition of the present invention is a functional derivative of the compound contained in the pharmaceutical composition of the present invention, and the compound contained in the pharmaceutical composition of the present invention is easily converted in vivo. Converted. Therefore, the “compound” contained in the pharmaceutical composition of the present invention is a compound specifically disclosed as an element of the pharmaceutical composition of the present invention or, in some cases, a compound not specifically disclosed, but obesity and And a compound that is converted into the specific compound in vivo after administration to a patient with an obesity-related disease.
  • the usual procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs ed (ed. H. Bundgaard, Elsevier, 1985).
  • the compound represented by the formula (I-2) used in the pharmaceutical composition of the present invention the following compounds, pharmaceutically acceptable salts thereof, or solvates thereof are particularly preferable.
  • the compound represented by the formula (I-2) used in the above pharmaceutical composition of the present invention is prepared by the method described in International Publication No. 2007/1255952, International Publication No. 2009/054434, International Publication No. 2008/134228. Can be prepared.
  • the compound represented by the formula (I) used in the pharmaceutical composition of the present invention the following compounds, pharmaceutically acceptable salts thereof, or solvates thereof are particularly preferable.
  • the compound represented by the formula (I) used in the above pharmaceutical composition of the present invention is WO 01/37826, WO 2003/076374, WO 2006/001318, JP 2005-255630. It can prepare by the method as described in gazette and international publication 2009/136617.
  • Process A Compound (IV) is obtained by reacting compound (IV) with compound (V) having substituent R 1 corresponding to the target compound in an appropriate solvent in the presence of a base, if necessary.
  • Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, water, and mixed solvents thereof. Can be mentioned. Preferred are dioxane, dichloromethane and the like. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is about 0 ° C. to 50 ° C., preferably about 20 to 30 ° C.
  • the reaction time is about 5 minutes to 30 hours, preferably about 5 to 20 hours.
  • known compounds may be used, or compounds synthesized from known compounds by a conventional method may be used.
  • Process B Compound (II) is reacted with compound (III) having substituents Z and R 2 corresponding to the target compound in a suitable solvent.
  • Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, water, and mixed solvents thereof.
  • Preferred are dimethylformamide, tetrahydrofuran, ethyl acetate and the like.
  • condensing agents such as 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylamino) carbodiimide (WSCD; water-soluble carbodiimide), 1-hydroxybenzotriazole, 3,4-dihydro-
  • the reaction may be performed in the presence of an acidic additive such as 3-hydroxy-4-oxo-1,2,3-benzotriazine.
  • the reaction temperature is about 0 ° C. to 50 ° C., preferably about 20 to 30 ° C.
  • the reaction time is about 5 minutes to 30 hours, preferably about 5 to 20 hours.
  • the amino group of the compound may be protected by a conventional method at an appropriate stage.
  • the protecting group phthalimide, alkoxycarbonyl, alkenyloxycarbonyl, halogenoalkoxycarbonyl, arylalkoxycarbonyl, trialkylsilyl, alkylsulfonyl, halogenoalkylsulfonyl, arylsulfonyl, alkylcarbonyl, arylcarbonyl and the like can be used.
  • the protection it is subjected to the reaction in each of the above steps, and may be deprotected by treating with an acid or base in an appropriate solvent at an appropriate stage.
  • solvent tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof are used.
  • the base include hydrazine, pyridine, sodium hydroxide, and potassium hydroxide
  • examples of the acid include hydrochloric acid, trifluoroacetic acid, hydrofluoric acid, and the like.
  • the pharmaceutical composition of the present invention is useful for the prevention or treatment of diseases associated with excessive fat accumulation in the body due to excessive food intake and lack of exercise, such as obesity and obesity-related diseases.
  • the pharmaceutical composition is useful for weight management in obesity.
  • “Obesity” is defined as an excessive accumulation of adipose tissue, but at present there is no accurate, simple and practical method for measuring body fat mass.
  • BMI is used.
  • BMI is defined as the weight per height (kg / m 2 ) expressed in square meters.
  • the incidence of obesity-related diseases increases in Orientals with a lower body mass index (BMI).
  • An obese patient in need of medical intervention is a person who has a BMI of 30 kg / m 2 or more and develops an obesity-related disease, a person who has a BMI of 30 kg / m 2 or more and has not developed an obesity-related disease, or A person having a BMI of 25 kg / m 2 or more, at least one obesity-related disease and / or a visceral fat area (VFA) of 100 cm 2 or more.
  • obesity-related diseases include hypertension, impaired glucose tolerance, diabetes, dyslipidemia, dyslipidemia, hyperuricemia, gout, fatty liver, coronary artery disease, cerebral infarction and the like.
  • the Japan Obesity Society is medically losing weight. Is defined as “obesity”.
  • obesity includes obesity caused by any cause including genetic or environmental.
  • An obesity-related disease is a disease associated with, caused by, or caused by obesity.
  • obesity-related diseases include bulimia, hypertension, impaired glucose tolerance, diabetes, metabolic syndrome, lipid metabolism disorder, arteriosclerosis, hyperuricemia, gout, fatty liver, proteinuria, obese nephropathy, endometrium Cancer, breast cancer, prostate cancer, colon cancer, osteoarthritis, low back pain, lumbar spondylosis, obstructive sleep apnea syndrome, coronary artery disease (myocardial infarction, coronary heart disease such as angina pectoris), cerebral infarction, cerebral thrombus Disease, transient cerebral ischemic attack, menstrual abnormalities, Prader-Willi syndrome, Frehrich syndrome, Pickwick syndrome and the like.
  • the pharmaceutical composition of the present invention is also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
  • the pharmaceutical composition of the present invention is also useful for the treatment of Alzheimer's
  • “Metabolic syndrome” is defined in the 3rd report (ATP-III) of the “National Cholesterol Education Plan Expert Panel on Detection, Evaluation, and Treatment of Adult High Blood Cholesterol” (ES Ford) JAMA, vol. 287 (3), January 16, 2002, p356-359). Briefly, a person with three or more symptoms of abdominal obesity, excess triglycerides, low HDL cholesterol, hypertension, fasting hyperglycemia is defined as a metabolic syndrome.
  • Diabetes includes both insulin-dependent diabetes (IDDM®, type I diabetes) and non-insulin-dependent diabetes (NIDDM, type II diabetes).
  • Type I diabetes is caused by an absolute deficiency of insulin, a hormone that regulates glucose utilization.
  • Type II diabetes occurs even when insulin levels are normal or elevated and occurs because the tissue is unable to respond properly to insulin. Many patients with type II diabetes are also obese.
  • the pharmaceutical compositions of the present invention are useful for the treatment of both type I and type II diabetes.
  • the pharmaceutical composition of the present invention is particularly effective for the treatment of type II diabetes.
  • the pharmaceutical composition of the present invention is also useful for the treatment and / or prevention of gestational diabetes.
  • Treatment of obesity and obesity-related diseases refers to administration of the pharmaceutical composition of the present invention to reduce or maintain the weight of obese patients. As a result of the treatment, it is possible to reduce the weight of the obese patient compared to the weight of the obese patient just before the start of administration of the pharmaceutical composition of the invention. Another outcome of treatment is to prevent weight loss resulting from past diet, exercise, or medication from being reweighted. Another outcome of treatment is the development and / or reduction in severity of obesity-related diseases. As a result of treatment, maintenance of weight loss or weight management is possible.
  • Treatment appropriately reduces the patient's food and caloric intake, including reduced total food intake or reduced intake of certain food ingredients such as carbohydrates and fats, impaired nutrient absorption, reduced metabolic rate It is possible to suppress the weight of a patient who needs to be suppressed or lose weight, or to manage the weight. Treatment can result in changes in metabolic rate, such as increased metabolic rate, and / or minimize metabolic resistance normally caused by weight loss, rather than suppression or additional suppression of metabolic rate reduction It is.
  • “Prevention” of obesity and obesity-related diseases refers to administration of the pharmaceutical composition of the present invention to reduce or maintain the weight of a person at risk for obesity.
  • the weight of the subject can be reduced compared to the weight of a person at risk for obesity immediately before the start of administration of the pharmaceutical composition of the invention.
  • Another outcome of prevention is to prevent weight loss as a result of past diet, exercise or drug therapy from being reweighted (weight management).
  • Another consequence of prevention is that it is possible to prevent the occurrence of obesity when a person at risk for obesity is treated before it begins.
  • Another consequence of prevention is the occurrence of obesity-related diseases and / or a reduction in severity when treatment is performed before obesity begins in a person at risk for obesity.
  • Another consequence of prevention is an extension of resistance to weight gain.
  • Another consequence of prevention is the prevention of weight reweighting.
  • the above “treatment” can prevent the occurrence, progression or severe symptoms of obesity-related diseases.
  • the pharmaceutical composition of the present invention comprises: A compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof; A pharmaceutical composition comprising a combination of a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the “pharmaceutical composition to be combined” includes a mode in which each compound is used as a combination agent, a mode in which the compounds are used as a kit, a mode in which the compounds are administered simultaneously, and a mode in which a certain drug is used in combination with another drug.
  • the present invention also relates to a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, Also included is a method for producing the above pharmaceutical composition, which comprises mixing a pharmaceutical composition comprising a compound having an NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. .
  • the pharmaceutical composition of the present invention includes: A compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof; A pharmaceutical composition comprising a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, or A drug comprising a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof; A kit comprising a compound comprising a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the pharmaceutical composition of the present invention comprises a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, a compound having NPY Y5 receptor antagonist activity, and a pharmaceutically acceptable salt thereof. Or it is not limited to the quantity ratio of those solvates.
  • the pharmaceutical composition of the present invention is a compounding agent, the compound having MCH R1 antagonist activity and the compound having NPY Y5 receptor antagonist activity for the pharmaceutically acceptable salt or solvate thereof, the pharmaceutical
  • the weight ratio of the above acceptable salts or solvates thereof is, for example, 100: 1 to 1: 100, preferably 10: 1 to 1:10, more preferably 5: 1 to 1: 5 ⁇ . is there.
  • the pharmaceutical composition of the present invention is a kit, a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a compound having NPY Y5 receptor antagonist activity for a solvate thereof
  • the pharmaceutical weight ratio of the above acceptable salts or solvates thereof is, for example, 100: 1 to 1: 100, preferably 10: 1 to 1:10, more preferably 5: 1 to 1: 5. is there.
  • An orally administered drug comprising a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient, and A kit comprising a vial for intravenous infusion comprising a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient .
  • a first enclosure comprising a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient; and A kit comprising a second enclosure containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient (infusion solution) pack).
  • a drug comprising a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient
  • a kit comprising a package insert describing a method of use in combination with a pharmaceutical composition containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a drug comprising a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient
  • a kit comprising a package insert describing a method of use in combination with a pharmaceutical composition containing a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • each vial, each drug, etc. contained in one package of the kit is not limited. For example, there are 1 to 5 each vial or each drug. Preferably, there are 1 to 3 each vial or each drug.
  • drug means a composition containing a compound as an active ingredient.
  • Orally administered drug means a drug administered using an oral route of administration.
  • a drug containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof is pre-administered, and then the MCH R1 antagonist You may administer the chemical
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate containing the same is pre-administered, and then a compound having NPY Y5 receptor antagonist activity, A drug containing a pharmaceutically acceptable salt or a solvate thereof may be administered.
  • a compound containing a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, a compound having NPY Y5 receptor antagonist activity, or a pharmaceutically acceptable product thereof may be administered simultaneously.
  • the pharmaceutical composition of the present invention the drug used in the pharmaceutical composition of the present invention (for example, a drug containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, MCH R1
  • a compound having an antagonist activity, a pharmaceutically acceptable salt thereof or a drug containing a solvate thereof can be administered either orally or parenterally.
  • Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered.
  • Various pharmaceutical additives such as agents, lubricants, and diluents can be mixed as necessary to form a pharmaceutical preparation. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • excipient examples include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like.
  • binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone.
  • disintegrant examples include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate.
  • lubricant examples include talc, magnesium stearate or macrogol.
  • suppository bases include cocoa butter, macrogol, and methyl cellulose.
  • solubilizers When preparing as a liquid or emulsion or suspension injection, add commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. Also good. In the case of oral administration, flavoring agents, fragrances and the like may be added.
  • the dose of the drug used in the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, administration route, etc., but it is effective when administered orally to adults.
  • a compound having MCH R1 antagonist activity or a compound having NPY Y5 receptor antagonist activity used in the pharmaceutical composition of the present invention as a component is usually 0.05 to 100 mg / kg / day, preferably 0.1 to Within the range of 50 mg / kg / day.
  • the compound having MCH R1 antagonist activity or the compound having NPY Y5 receptor antagonist activity used in the pharmaceutical composition of the present invention, which is an active ingredient is usually 0.005, although it varies greatly depending on the administration route.
  • -50 mg / kg / day preferably in the range of 0.01-10 mg / kg / day. This may be administered once to several times a day.
  • Examples of the method of using the pharmaceutical composition of the present invention include the following, but these do not limit the present invention.
  • a method for preventing or treating obesity or obesity-related diseases administered together as part of the same drug (a method for preventing or treating the above-mentioned combination agent).
  • Appropriate dosing regimens, doses for each administration, and specific dosing intervals for each drug will depend on the specific combination of drugs used, the condition of the patient and the severity of the condition, etc.
  • Examples of administration regimes include the following. These do not limit the dosage regimen of the pharmaceutical composition of the present invention.
  • Compound having MCH R1 antagonist activity, pharmaceutically acceptable salt or solvate thereof, and compound having NPY Y5 receptor antagonist activity, pharmaceutically acceptable salt or solvate thereof The agent is administered 1 to 3 times a day.
  • a compound having an NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, and a compound having an MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvent thereof Drugs containing Japanese products are co-administered 1 to 3 times a day.
  • Compound having NPY Y5 receptor antagonist activity, a compound containing NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a drug containing a solvate thereof administered, and several days to several weeks later A drug containing a pharmaceutically acceptable salt thereof or a solvate thereof and a compound having an MCH R1 antagonist activity, a drug containing a pharmaceutically acceptable salt thereof or a solvate thereof are used in combination.
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a drug containing a solvate thereof is administered, and a compound having NPY Y5 receptor antagonist activity after several days to several weeks,
  • a drug containing a pharmaceutically acceptable salt or a solvate thereof and a compound having MCH R1 antagonist activity, a drug containing a pharmaceutically acceptable salt or a solvate thereof are used in combination.
  • the pharmaceutical composition of the present invention can also be used in combination with other antiobesity agents.
  • the pharmacotherapy by administration of the pharmaceutical composition of the present invention can be used in combination with diet therapy, exercise therapy, other drug therapy, and the like.
  • “Diet therapy” includes reduced diet therapy, low calorie diet (LCD) therapy, very low calorie diet (VLCD) therapy, reduced calorie diet (RCD) therapy and the like.
  • “Low diet therapy” is a light diet that reduces daily calorie intake to about 1200 kcal.
  • a “low calorie diet” is a diet that limits the daily calorie intake to about 600-1000 kcal.
  • the low calorie is ingested by a well-balanced diet, the low calorie is ingested by a diet rich in special nutrients such as a high fat diet, a low calorie diet, and a high protein low calorie diet.
  • “Very low calorie diet” is a diet that limits the daily calorie intake to about 200-600 kcal. Semi-starvation therapy for severely obese people.
  • the “reduced calorie diet” is a diet therapy in which a meal obtained by subtracting about 800 kcal from the necessary daily calorie amount calculated from the basal metabolism is taken.
  • various dosage regimens can be utilized. Examples include the following. (1) Diet therapy and / or exercise therapy and drug therapy using the pharmaceutical composition of the present invention are started simultaneously. (2) In order to start drug therapy using the pharmaceutical composition of the present invention, diet therapy and / or exercise therapy is performed for several days to several weeks, and the body weight is reduced to some extent.
  • the present invention also includes the following modes.
  • the compound having MCH R1 antagonist activity and the compound having NPY Y5 receptor antagonist activity contained in the pharmaceutical composition of the present invention each have an action of inducing weight loss, an action of promoting weight loss and / or an action of different weights. Or the effect
  • the present invention includes the following modes. Containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, An agent for enhancing the prevention or treatment effect of obesity or obesity-related diseases of a drug containing a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. Containing a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof, A potentiator for preventing or treating obesity or obesity-related diseases of a drug containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof is an obesity or obesity of a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the prevention or treatment effect of related diseases can be enhanced.
  • Compounds having NPY Y5 receptor antagonist activity, pharmaceutically acceptable salts thereof, or solvates thereof are obese or obese of compounds having MCH R1 antagonist activity, pharmaceutically acceptable salts thereof, or solvates thereof.
  • the prevention or treatment effect of related diseases can be enhanced. Therefore, the pharmaceutical composition of the present invention can prevent or treat obesity or obesity-related diseases very efficiently compared to the case where each compound is used alone.
  • a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof and a compound having an NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof are combined.
  • the pharmaceutical composition may comprise other anti-obesity compounds, pharmaceutically acceptable salts or solvates thereof.
  • a compound containing a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound having MCH R1 antagonist activity, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • other compounds having anti-obesity action, pharmaceutically acceptable salts thereof, or solvates thereof may be contained.
  • a compound containing a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound having NPY Y5 receptor antagonist activity, a pharmaceutically acceptable salt thereof or the like.
  • a compound having other anti-obesity action, a pharmaceutically acceptable salt thereof, or a solvate thereof may be contained.
  • Other compounds having anti-obesity action, pharmaceutically acceptable salts thereof or solvates thereof include compounds having anorectic action (selective serotonin reuptake inhibitors such as fenfluramine and fluoxetine; mazindol, etc.) , Compounds that inhibit nutrient absorption of nutrients (compounds that inhibit saccharide absorption ( ⁇ -glucosidase inhibitors such as acarbose and voglibose; SGLT-2 inhibitors such as dapagliflozin, remogliflozin, and KGT-1075), fat absorption inhibition) Compounds having activity (lipase inhibitors (compounds having gastric lipase inhibitory activity; compounds having pancreatic lipase inhibitory activity such as orlistat, lipstatin, pancricin, cetiristat, etc.), bile acid adsorption resins such as cholestyramine, cholestyramide, etc.), 5HT Transpo Inhibit
  • a compound having an action of suppressing fat absorption is preferable, and a lipase inhibitor is more preferable.
  • a lipase inhibitor is more preferable.
  • compounds having pancreatic lipase inhibitory action such as orlistat, lipstatin, pancricin, cetiristat and the like are preferable, and orlistat is preferable.
  • mice Seven-week-old male C57BL / 6J mice (19.8-24.3 g, supplied by Claire Japan) were given a high fat diet (Test Diet) for 4 weeks to induce weight gain. Thereafter, an aqueous solution of 0.5% hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) was orally administered twice a day (8: 30-10: 30, 15: 30-18: 00 pm) for 40 days. Accustomed to it. Based on the weight of the mouse and the amount of change in weight during the acclimation period, the mice were divided into the following 6 groups.
  • Compound (1) was orally administered once a day at 15:30 to 18:00 pm, and 0.5% hydroxypropylmethylcellulose was orally administered in the morning for groups 2) and 3). These were carried out for 40 days.
  • the mouse body weight at the start of drug administration was 29.4-34.3 g.
  • the body weight after 40 days was as follows: 1) Group: Compound (1) 5.9 g suppression in 1 mg / kg group compared to control group, 3) Group: Compound (1) 10 mg / kg group 7.7 g of suppression, 4) group: 3.3 g of suppression was achieved in the compound (a) 50 mg / kg group.
  • mice Seven-week-old male C57BL / 6J mice (19.7-23.3 g, supplied by Claire Japan) were given a high fat diet (Test Diet) for 6 weeks to induce weight gain. Then, 0.5% hydroxypropylmethylcellulose (Shin-Etsu Chemical Co., Ltd.) aqueous solution was orally administered twice a day (8: 30-10: 30, 15: 30-18: 00 pm) for 3 weeks. Accustomed to it. Based on the weight of the mouse and the amount of weight change during the acclimatization period, the mice were divided into the following 4 groups.
  • the body weight after 42 days was as follows: 1) Group: 2.67 g suppression in the compound (a) 50 mg / kg group compared to the control group, 3) Group: Compound (2) 10 mg / kg group 3) Group: Compound (a) 50 mg / kg group + Compound (2) 6.8 g suppression in the 10 mg / kg group, Compound (a) and Compound (2) co-administered, It was clarified that a weight suppression effect stronger than the sum of the effects of the drugs alone was obtained (see FIG. 2).
  • the amount of food intake during 42 days was as follows: 1) group: 2) compared to control group 2) group: compound (a) suppression of 8.63 g in 50 mg / kg group, 3) group: compound (2) 5 in 10 mg / kg group. 98 g inhibition, 4) group: Compound (a) 50 mg / kg group + Compound (2) 14.04 g inhibition in 10 mg / kg group, when compound (a) and compound (2) are co-administered, each drug alone It was clarified that a strong antifeeding effect was obtained compared to the action of.
  • mice Seven-week-old male C57BL / 6J mice (18.8-25.0 g, supplied by CLEA Japan) were given a high fat diet (Test Diet) for 4 weeks to induce weight gain. Thereafter, 0.5% hydroxypropylmethylcellulose (Shin-Etsu Chemical Co., Ltd.) aqueous solution was orally administered twice a day (8: 30-10: 30, 16: 00-18: 00 pm) for 4 weeks. Accustomed to it. Based on the weight of the mouse and the amount of weight change during the acclimatization period, the mice were divided into the following 4 groups.
  • the body weight after 42 days was as follows: 1) Group: compared with the control group 2) Group: Compound (a) 1.9 g suppression in the 50 mg / kg group, 3) Group: Sibutramine in the 6.25 mg / kg group 1.3 g inhibition, 4) group: Compound (a) 50 mg / kg group + sibutramine 2.5 g inhibition in 6.25 mg / kg group, when compound (a) and sibutramine are co-administered, the action of each drug alone Although it became clear that a stronger body weight suppression effect was obtained (see FIG. 3), the degree thereof was inferior to the combination with the compounds (1) and (2) which are MCH antagonists.
  • the amount of food intake for 42 days was as follows: 1) Group: 2 g compared to control group: Compound (a) 4.0 g suppression in 50 mg / kg group, 3) Group: 1.2 g in sibutramine 6.25 mg / kg group 4) Group: Compound (a) 50 mg / kg group + sibutramine 6.25 mg / kg group, 0.2 g of inhibition, co-administration of compound (a) and sibutramine, antifeeding effect of compound (a) Almost disappeared.
  • the pharmaceutical composition of the present invention is very useful for the prevention or treatment of obesity or obesity-related diseases.
  • the pharmaceutical composition is very useful for weight management in obesity.

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Abstract

La présente invention concerne une composition pharmaceutique formée par la combinaison d'un composé ayant une activité antagoniste de récepteur MCH ou le sel pharmaceutiquement acceptable de celui-ci ou un solvate desdits composé et sel avec un composé ayant une activité antagoniste de récepteur NPY Y5 ou un sel pharmaceutiquement acceptable de celui-ci ou un solvate desdits composé et sel, qui présente un effet de réduction significative du poids corporel. Ladite composition pharmaceutique est utile pour le traitement ou la prévention de l'obésité ou de troubles associés à l'obésité, et pour le contrôle du poids pour des patients obèses.
PCT/JP2010/069812 2009-11-11 2010-11-08 Composition pharmaceutique formée par combinaison d'un composé ayant une activité antagoniste de mchr1 et un composé ayant une activité antagoniste de npy y5 WO2011058943A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013002313A1 (fr) * 2011-06-29 2013-01-03 塩野義製薬株式会社 Médicament destiné à la régulation du poids
WO2023242810A1 (fr) * 2022-06-17 2023-12-21 Richter Gedeon Nyrt. Antagonistes de mchr1 pour le traitement du syndrome de prader-willi

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037826A1 (fr) * 1999-11-26 2001-05-31 Shionogi & Co., Ltd. Antagonistes npyy5
US20040122033A1 (en) * 2002-12-10 2004-06-24 Nargund Ravi P. Combination therapy for the treatment of obesity
JP2005533849A (ja) * 2002-07-18 2005-11-10 メルク　エンド　カムパニー　インコーポレーテッド 肥満治療のための組み合わせ療法
WO2006001318A1 (fr) * 2004-06-24 2006-01-05 Shionogi & Co., Ltd. Compose de sulfonamide
WO2008026563A1 (fr) * 2006-08-30 2008-03-06 Shionogi & Co., Ltd. Dérivé d'hydrazine amide
WO2010098298A1 (fr) * 2009-02-27 2010-09-02 塩野義製薬株式会社 Composition pharmaceutique contenant une combinaison d'un composé possédant une activité inhibitrice de la digestion/absorption des nutriments et d'un dérivé de cyclohexanecarboxamide

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037826A1 (fr) * 1999-11-26 2001-05-31 Shionogi & Co., Ltd. Antagonistes npyy5
JP2005533849A (ja) * 2002-07-18 2005-11-10 メルク　エンド　カムパニー　インコーポレーテッド 肥満治療のための組み合わせ療法
US20040122033A1 (en) * 2002-12-10 2004-06-24 Nargund Ravi P. Combination therapy for the treatment of obesity
WO2006001318A1 (fr) * 2004-06-24 2006-01-05 Shionogi & Co., Ltd. Compose de sulfonamide
WO2008026563A1 (fr) * 2006-08-30 2008-03-06 Shionogi & Co., Ltd. Dérivé d'hydrazine amide
WO2010098298A1 (fr) * 2009-02-27 2010-09-02 塩野義製薬株式会社 Composition pharmaceutique contenant une combinaison d'un composé possédant une activité inhibitrice de la digestion/absorption des nutriments et d'un dérivé de cyclohexanecarboxamide

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013002313A1 (fr) * 2011-06-29 2013-01-03 塩野義製薬株式会社 Médicament destiné à la régulation du poids
WO2023242810A1 (fr) * 2022-06-17 2023-12-21 Richter Gedeon Nyrt. Antagonistes de mchr1 pour le traitement du syndrome de prader-willi

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