WO2012147765A1 - Dérivé de benzimidazole ayant une action antagoniste sur les récepteurs de npy y5 - Google Patents

Dérivé de benzimidazole ayant une action antagoniste sur les récepteurs de npy y5 Download PDF

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WO2012147765A1
WO2012147765A1 PCT/JP2012/061033 JP2012061033W WO2012147765A1 WO 2012147765 A1 WO2012147765 A1 WO 2012147765A1 JP 2012061033 W JP2012061033 W JP 2012061033W WO 2012147765 A1 WO2012147765 A1 WO 2012147765A1
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compound
substituted
unsubstituted
npy
acceptable salt
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直樹 大森
正彦 藤岡
友亮 田村
香奈 渡辺
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel benzimidazole derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.
  • 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”.
  • Neuropeptide Y (hereinafter referred to as NPY) 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. In previous reports, NPY has been found to have feeding promoting action, anticonvulsant action, learning promoting action, anti-anxiety action, anti-stress action, etc. in the central nervous system, and depression, It may be deeply involved in central nervous system diseases such as Alzheimer's dementia and Parkinson's disease. In peripheral tissues, NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders.
  • Non-Patent Document 1 a pharmaceutical composition having an NPY receptor antagonistic action is a preventive or therapeutic agent for various diseases involving the NPY receptor as described above.
  • subtypes Y1, Y2, Y3, Y4, Y5, and Y6 have been discovered for NPY receptors (see Non-Patent Document 2).
  • the Y5 receptor is involved in at least the feeding function, and it has been suggested that the antagonist becomes an anti-obesity drug (see Non-Patent Documents 3 to 5).
  • Patent Document 1 discloses a benzimidazole derivative having a substituent containing sulfamide, which has a growth hormone secretion promoting action and can be used as an anti-obesity drug.
  • Patent Document 2 discloses a benzimidazole derivative having a carboxyl group, which has an IL-8 and GRO ⁇ chemokine inhibitory action and can be used as a therapeutic agent for inflammatory diseases.
  • Patent Document 3 discloses a benzimidazole derivative having a carbonyl group, which has a ⁇ -secretase inhibitory action and can be used as an Alzheimer's therapeutic agent.
  • Non-Patent Document 6 describes one compound of a benzimidazole derivative having an ORL1 antagonist activity.
  • Patent Document 4 discloses a condensed heterocyclic derivative having a substituent containing benzoxazole, which has a glucokinase activating action and can be used as a diabetic drug.
  • Patent Documents 5, 6, and 7 describe benzimidazole derivatives having an NPY Y5 receptor antagonistic action.
  • Patent Document 7 describes two compounds of a benzimidazole derivative having an NPY Y5 receptor antagonistic action.
  • Patent Document 8 describes a benzoxazole derivative having an NPY Y5 receptor antagonistic action.
  • Patent Document 9 describes a thiazole derivative having an NPY Y5 receptor antagonistic action.
  • Patent Document 10 describes a tricyclic derivative having an NPY Y5 receptor antagonistic action.
  • An object of the present invention is to provide a novel benzimidazole derivative having an excellent NPY Y5 receptor antagonistic action.
  • the present inventors have succeeded in synthesizing a novel benzimidazole derivative having an excellent NPY Y5 receptor antagonistic action. Moreover, it discovered that this compound showed the strong eating suppression effect. Furthermore, the present inventors have also found that the compounds of the present invention have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. The compound of the present invention has low toxicity and is sufficiently safe for use as a medicine.
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted amino; p and q are each independently 0 or 1, provided that p and q are not 1 at the same time, L is an oxygen atom or a sulfur atom, R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted or un
  • R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano, or a pharmaceutically acceptable salt thereof. .
  • p and q are 0.
  • the compound of the present invention exhibits an NPY Y5 receptor antagonistic action, and is associated with drugs, particularly diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, It is very useful as a medicine for the treatment or prevention of hypertension, cerebral overflow, congestive heart failure or sleep disorder.
  • diseases involving NPY Y5 such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures
  • It is very useful as a medicine for the treatment or prevention of hypertension, cerebral overflow, congestive heart failure or sleep disorder.
  • the compound of the present invention since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity.
  • it is very useful as a medicament for the treatment or prevention of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis
  • Alkyl means a straight or branched hydrocarbon group 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.
  • Alkyl in R 1 includes methyl, ethyl, isopropyl, tert-butyl and the like.
  • ethyl, isopropyl and tert-butyl are preferable, and isopropyl and tert-butyl are more preferable.
  • alkyl in R 2 , R 3 , R 4 and R 5 include methyl, ethyl, isopropyl, tert-butyl and the like. In particular, isopropyl is preferred.
  • Alkenyl means a straight or branched hydrocarbon group 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.
  • Alkynyl means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. Examples include alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, and the like. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups.
  • Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl having 3 to 6 carbon atoms and cycloalkyl having 5 or 6 carbon atoms are preferable.
  • Examples of the ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.).
  • the bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
  • cycloalkyl groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position.
  • cycloalkyl in R 1 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are preferable.
  • “Cycloalkenyl” is a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups. Means.
  • Examples of the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
  • cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
  • the ring condensed with the C 3-8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (eg, benzene ring, naphthalene ring etc.), non-aromatic carbocycles (eg cycloalkane ring).
  • cyclohexane ring, cyclopentane ring, etc. examples include cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.)
  • the bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. .
  • the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position.
  • alkyl part of “alkyloxy” and “alkylsulfonyl” has the same meaning as the above “alkyl”.
  • Halogen includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
  • Haloalkyl and “haloalkyloxy” mean groups in which 1 to 5 (preferably 1 to 3) of the above “halogens” are substituted on the alkyl part of the above “alkyl” and “alkyloxy”. .
  • haloalkyl in R 2 , R 3 , R 4 and R 5 , difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like are preferable.
  • haloalkyloxy in R 2 , R 3 , R 4 and R 5 , difluoromethyloxy, trifluoromethyloxy, 2,2,2-trifluoroethyloxy and the like are preferable.
  • substituted alkyl substituted alkenyl, “substituted alkynyl”, “substituted cycloalkyl”, “substituted alkyloxy”, “substituted alkylsulfonyl” or “substituted cycloalkenyl”, halogen, hydroxy, mercapto, Nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted heterocyclyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted
  • Substituted or unsubstituted cycloalkyl “substituted or unsubstituted cycloalkenyl”, and “substituted or unsubstituted heterocyclyl” are oxo, thioxo or substituted or unsubstituted imino at any substitutable position. May be substituted.
  • substituents 1 to 2 arbitrary positions where substitution is possible may be substituted.
  • substituents of “substituted amino” in R 1 include monomethyl, monoethyl, dimethyl, diethyl and the like. In particular, dimethyl is preferable.
  • Substituents for “substituted aryl”, “substituted heteroaryl” or “substituted heterocyclyl” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, alkyl, Haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, carbamoyl, sulfamoyl, amidino, group represented by formula: —O—R 10 , formula: —O—C ( ⁇ O) — A group represented by R 10 , a group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula: —C ( ⁇ O) —O—R 10 , a group represented by the formula: —S—R 10 group or expression: group (wherein R
  • Aryl means a monocyclic or polycyclic aromatic carbocyclic group, and a group obtained by further condensing one or two 3- to 8-membered rings on these monocyclic or polycyclic aromatic carbocyclic groups Means.
  • Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
  • Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.).
  • the bond is assumed to be from a monocyclic or polycyclic aromatic carbocyclic group.
  • the following groups are also exemplified as aryl and are included in aryl. These groups may be substituted at any substitutable position.
  • Heteroaryl means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and monocyclic or polycyclic A group obtained by further condensing one or two 3- to 8-membered rings on an aromatic heterocyclic group.
  • a 5- or 6-membered heteroaryl is particularly preferable.
  • pyrrolyl imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl
  • examples include oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
  • the “polycyclic aromatic heterocyclic group” is particularly preferably a heteroaryl fused with a 5- or 6-membered ring, such as indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Bicyclic aromatic heterocyclic groups such as zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyra
  • any ring may have a bond.
  • Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene). Ring, cyclopentene ring, etc.)) and non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.).
  • the bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.
  • the following groups are also exemplified as heteroaryl, and are included in heteroaryl. These groups may be substituted at any substitutable position.
  • Heterocyclyl refers to non-aromatic heterocyclic groups having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and to these non-aromatic heterocyclic groups This means a group in which one or two 3- to 8-membered rings are condensed. It contains a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.
  • ⁇ monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
  • polycyclic non-aromatic heterocyclic group examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
  • any ring may have a bond.
  • the following groups are also included in heterocyclyl.
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted amino.
  • substituted or unsubstituted alkyl is preferable.
  • p and q are 0 or 1, provided that p and q are not 1 at the same time.
  • R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, hydroxy, carboxy, halogen or cyano, including a hydrogen atom, alkyl, alkylsulfonyl, halogen, Haloalkyl, haloalkyloxy or cyano are preferred.
  • R 2 and R 5 are particularly preferably hydrogen
  • R 3 is particularly preferably halogen, haloalkyl or haloalkyloxy
  • R 4 is particularly preferably hydrogen or halogen.
  • the substituent of “substituted alkyl” in R 3 is preferably halogen. In particular, fluorine is preferable.
  • halogen is preferable. In particular, fluorine is preferred.
  • R 1 is substituted or unsubstituted alkyl or substituted amino; p and q are each independently 0 or 1, provided that p and q are not 1 at the same time and L is an oxygen atom;
  • R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano.
  • R 1 is substituted or unsubstituted alkyl; p is 1, q is 0, L is an oxygen atom, A compound or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 and R 5 are each independently a hydrogen atom or halogen, and R 3 is alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano. .
  • R 1 is substituted or unsubstituted alkyl; p and q are 0, L is an oxygen atom, A compound or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 and R 5 are each independently a hydrogen atom or halogen, and R 3 is alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano. .
  • the compound of the present invention is not limited to a specific isomer, but all possible isomers (eg, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) ), Racemates or mixtures thereof.
  • One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compounds of the present invention also include compounds substituted with such isotopes.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound of the present invention.
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • the radioactive label of the compound of the present invention can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound of the present invention include a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium, barium, etc.). , Magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids Salts, or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, Citric acid, lactic acid, tartaric acid, oxalic acid, maleic
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention includes such various solvates and crystals. Also includes polymorphs.
  • the “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound of the present invention.
  • solvent molecules for example, water molecules
  • the compound of the present invention or a pharmaceutically acceptable salt thereof When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the crystalline polymorph may be formed by recrystallizing the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the invention that has a group that can be chemically or metabolically degraded and is a compound that becomes a pharmaceutically active compound of the invention in vivo by solvolysis or under physiological conditions.
  • Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed and converted to the compounds of the present invention under physiological conditions in vivo, compounds that are hydrolyzed by gastric acid, etc., and converted to the compounds of the present invention, etc. Include. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anion.
  • a compound having a hydroxyl group and an appropriate acyl halide an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anion.
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with hydride or reacting with a condensing agent.
  • CH 3 COO—, C 2 H 5 COO—, t-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p— CH 3 —O—PhSO 3 —, PhSO 3 —, and p—CH 3 PhSO 3 — can be mentioned.
  • R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, hydroxy, carboxy, halogen, or cyano.
  • Compound a3 can be obtained by reacting a solution of compound a1 with compound a2 and reacting with methyl iodide.
  • the solvent include tetrahydrofuran, DMF, DMA and the like.
  • the compound a2 can be used in an amount of 1 to 3 equivalents with respect to the compound a1.
  • Methyl iodide can be used in an amount of 1 to 5 equivalents relative to compound a1.
  • the reaction temperature is 0 ° C. to room temperature.
  • the reaction time is 0.1 hour to 12 hours, preferably 1 hour to 5 hours.
  • Compound a5 can be obtained by reacting a solution of compound a3 with compound a4 in the presence of a base.
  • the solvent include DMF, NMP, THF, DMA and the like.
  • compound a4 include 2- (chloromethoxy) ethyltrimethylsilane, BOC 2 O, MOMCl, and the like, and 1 to 3 equivalents can be used with respect to compound a3.
  • the base include sodium hydride, triacylamine, DIEA and the like, and 1 to 5 equivalents can be used with respect to compound a3.
  • the reaction temperature is 50 ° C. to heating under reflux, preferably under heating under reflux.
  • the reaction time is 0.1 to 5 hours, preferably 0.5 to 2 hours.
  • Compound a6 can be obtained by reacting a solution of compound a5 with peracid.
  • the solvent include dichloromethane and dichloroethane.
  • the peracid include m-chloroperbenzoic acid, hydrogen peroxide solution, t-butyl hydroperoxide NaBO 3 and the like, and 1 to 10 molar equivalents can be used with respect to the compound a5.
  • the reaction temperature is ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 50 ° C.
  • the reaction time is 1 to 5 hours.
  • L is an oxygen atom or sulfur atom
  • Z is a leaving group such as alkylsulfonyl
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted amino, and other symbols are as defined above.
  • Compound a9 can be obtained by reacting a solution of compound a7 with compound a8 (for example, compound a6 obtained in Step C) in the presence of a base.
  • the solvent include DMF, NMP, THF, DMA and the like.
  • 1 to 3 equivalents of compound a8 can be used with respect to compound a7.
  • Examples of the base include sodium hydride and the like, and 1 to 5 equivalents can be used with respect to compound a7.
  • the reaction temperature is room temperature to heating under reflux, preferably 50 ° C. to 100 ° C.
  • the reaction time is 1 to 24 hours, preferably 3 to 12 hours.
  • Process E (The symbols in the formula are as defined above.)
  • Compound (I ′) can be obtained by deprotecting compound a9 with an acid.
  • the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the reaction temperature is 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.1 to 12 hours, preferably 1 to 12 hours.
  • Process F (In the formula, Ra is substituted or unsubstituted alkyl, and other symbols are as defined above.)
  • Compound a11 can be obtained by reacting compound a10 with alcohol in the presence of sulfuric acid.
  • the alcohol include methanol and ethanol.
  • the reaction temperature is 50 ° C. to heating under reflux.
  • the reaction time is 1 to 24 hours, preferably 5 to 12 hours.
  • Compound a14 can be obtained by reacting a solution of compound a11 with compound a13 in the presence of a base.
  • the solvent include DMF, NMP, THF, DMA and the like.
  • compound a11 include tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, and the like, and 1 to 3 equivalents can be used with respect to compound a11.
  • the base include imidazole, triethylamine, DIEA and the like, and 1 to 5 equivalents can be used with respect to compound a11.
  • the reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
  • the reaction time is 1 to 24 hours.
  • Compound a15 can be obtained by reacting compound a14 with a reducing agent.
  • the solvent include tetrahydrofuran, methanol and the like.
  • the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride and the like, and 1 to 5 molar equivalents can be used with respect to compound a14.
  • the reaction temperature is 0 ° C. to room temperature.
  • the reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
  • Process I (In the formula, Ts is a tosyl group, and other symbols are as defined above.)
  • Process 1 Compound a16 can be obtained by reacting a solution of compound a15 with tosyl chloride in the presence of a base.
  • the solvent include methylene chloride, dichloroethane, THF, and the like.
  • Tosyl chloride can be used at 1 to 3 equivalents relative to compound a15.
  • Examples of the base include DIEA, triethylamine, pyridine and the like, and 1 to 3 equivalents can be used with respect to compound a7.
  • the reaction temperature is 0 ° C. to room temperature.
  • the reaction time is 0.2 to 12 hours, preferably 0.5 to 5 hours.
  • Process J Compound a18 can be obtained by reacting a solution of compound a16 with compound a17 in the presence of a base.
  • a base examples include DMF, NMP, acetonitrile, DMA and the like.
  • the base examples include cesium carbonate and potassium carbonate, and 1 to 5 equivalents can be used with respect to compound a16.
  • the reaction temperature is room temperature to heating under reflux, preferably 50 ° C. to 100 ° C.
  • the reaction time is 1 to 24 hours, preferably 3 to 12 hours.
  • the compound of the present invention can be obtained according to steps D and E while appropriately performing protection and deprotection as necessary.
  • Process K Compound a21 can be obtained by reacting a solution of compound a19 with compound a20 in the presence of an acid and reacting with a reducing agent.
  • the solvent include methylene chloride and chloroform. 1 to 3 equivalents of compound a20 can be used with respect to compound a19.
  • the acid include acetic acid and the like, and 1 to 3 equivalents can be used with respect to the compound a7.
  • the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like, and 1.5 to 3 equivalents can be used.
  • the reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
  • the reaction time is 1 to 24 hours, preferably 3 to 12 hours.
  • Process L Compound a23 can be obtained by reacting a solution of compound a21 with compound a22 in the presence of a base.
  • a solvent include methylene chloride, DMF, THF, and the like.
  • the base include triethylamine, DIEA, pyridine and the like, and 1 to 3 equivalents can be used with respect to compound a21.
  • the reaction temperature is 0 ° C. to room temperature.
  • the reaction time is 0.1 to 5 hours.
  • Process M Compound a24 can be obtained by reacting the solution of compound a23 with a peracid.
  • the solvent include dichloromethane, chloroform, ethyl acetate and the like.
  • the peracid include m-chloroperbenzoic acid, hydrogen peroxide solution, t-butyl hydroperoxide and the like, and 1 to 3 equivalents can be used with respect to compound a23.
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 1 to 5 hours.
  • Compound a25 can be obtained by reacting a solution of compound a24 with tetrabutylammonium fluoride.
  • the solvent include tetrahydrofuran.
  • Tetrabutylammonium fluoride can be used in an amount of 1 to 5 equivalents based on compound a24.
  • the reaction temperature is from room temperature to 100 ° C, preferably from 50 ° C to 80 ° C.
  • the reaction time is 1 to 5 hours.
  • Process O By reacting Compound a25 obtained in Step N with Compound a6 obtained in Step C (or Compound a8 described in Step D) according to Step D, and then deprotecting according to Step E, Inventive compounds can be obtained.
  • Process P (The symbols in the formula are as defined above.)
  • Compound a27 can be obtained by reacting a solution of compound a26 with compound a8 (for example, compound a6 obtained in Step C) in the presence of a base.
  • the solvent include DMF, NMP, THF, DMA and the like. 1 to 3 equivalents of compound a8 can be used with respect to compound a26.
  • the base include sodium hydride and the like, and 1 to 5 equivalents can be used with respect to compound a7.
  • the reaction temperature is room temperature to heating under reflux, preferably 50 ° C. to 100 ° C.
  • the reaction time is 1 to 24 hours, preferably 3 to 12 hours.
  • the compound of the present invention thus obtained can be purified by crystallization with various solvents.
  • Solvents used include alcohol (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ether (diethyl ether, diisopropyl ether, etc.), acetic acid methyl ester, acetic acid ethyl ester, chloroform, methylene chloride, tetrahydrofuran, N, N—
  • Examples include dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water, or a mixed solvent thereof. After dissolving in these solvents under heating to remove impurities, the temperature may be gradually lowered and the precipitated solid or crystals may be collected by filtration.
  • the compounds of the present invention prevent NPY Y5 related diseases in general, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders And / or effective treatment. It is particularly useful for the prevention and / or treatment of obesity and weight management in obesity. It is also effective for the prevention and / or treatment of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndrome. Furthermore, the compound of the present invention has not only an NPY Y5 receptor antagonistic action but also a usefulness as a medicine, and has any or all of the following excellent features.
  • CYP1A2, CYP2C9, CYP3A4, etc. The inhibitory action against CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak. b) Good pharmacokinetics such as high bioavailability and moderate clearance. c) Low toxicity such as anemia-inducing action. d) High metabolic stability. e) High water solubility. f) High brain transferability. g) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
  • the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and has high Y5 receptor selectivity.
  • NPY induces a sustained vasoconstrictive action in the periphery, but this action is mainly mediated by the Y1 receptor. Since the Y5 receptor is not involved in such an action at all, it is unlikely to induce side effects based on peripheral vasoconstriction, and the compound of the present invention considered to have high Y5 receptor selectivity is used as an active ingredient.
  • the pharmaceutical composition to be used can be suitably used as a safe medicine.
  • the pharmaceutical composition containing the compound of the present invention as an active ingredient suppresses food intake and exhibits an anti-obesity effect. Therefore, side effects such as indigestion as seen in drugs that exhibit anti-obesity effects by inhibiting digestion and absorption, and central side effects such as antidepressant effects such as serotonin transporter inhibitors that exhibit anti-obesity effects Not doing so is one of the features of the pharmaceutical composition.
  • 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.
  • a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • parenteral administration 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. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • excipients such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • Excipients 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 include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate.
  • the lubricant include talc, magnesium stearate, and macrogol.
  • cacao butter, macrogol, methyl cellulose or the like can be used as a suppository base.
  • solubilizers when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (pharmaceutical compositions containing compounds having an anti-obesity action, drugs that can be used for weight management in obesity or obesity, etc.).
  • pharmaceutical compositions containing compounds having an anti-obesity action drugs that can be used for weight management in obesity or obesity, etc.
  • a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, it can be used for prevention and / or treatment of obesity, weight management in obesity, and the like.
  • the pharmaceutical composition containing the compound of the present invention can be used in combination with a pharmaceutical composition containing a compound having an anti-obesity action for the prevention and / or treatment of obesity or weight management in obesity. it can.
  • the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.
  • Prevention of obesity or obesity-related diseases comprising administering a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a method of weight management in treatment or obesity comprising administering a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a pharmaceutical composition containing a compound having an anti-obesity action is administered to a patient undergoing prevention or treatment by administration of the compound of the present invention, 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 administering a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • R a, combination of R b and p are the following (R a, R b, p), compound.
  • (R a , R b , p) (R a1 , R b1 , p 1 ), (R a1 , R b1 , p 2 ), (R a1 , R b2 , p 1 ), (R a1 , R b2 , p 2 ), (R a1 , R b3 , p 1 ), (R a1 , R b3 , p 2 ), (R a1 , R b4 , p 1 ), (R a1 , R b4 , p 2 ), (R a1 , R b5 , p 1 ), (R a1 , R b5 , p 2 ), (R a1 , R b6 , p 1 ), (R a1 , R b6
  • RT represents a retention time in LC / MS: liquid chromatography / mass spectrometry.
  • the measurement conditions for LC / MS analysis are as follows.
  • Second step Sodium hydride (160 mg, 4.01 mmol) was added to a DMF (10 mL) solution of compound 3 (380 mg, 2.47 mmol) obtained in the first step under ice cooling, and the mixture was stirred for 5 minutes.
  • 2- (chloromethoxy) ethyltrimethylsilane 0.652 ml, 3.67 mmol was added dropwise and stirred for 30 minutes.
  • Example 2 Compound I-014 Synthesis First Step Sodium hydride (60%, 1.08 g, 27.2 mmol) was added to a solution of compound 8 (5 g, 22.7 mmol) in DMF (50 ml), and 2- (chloromethoxy) ethyltrimethylsilane (5.63 ml, 31.31) was added. 7 mmol) was added and stirred at room temperature for 3 hours. Water was added to the reaction solution and extracted with AcOEt. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 9 (6.52 g, yield 82%).
  • Second step Sodium hydride (60%, 42 mg, 1.05 mmol) was added to a DMF (5 ml) solution of compound 10 (130 mg, 0.37 mmol), and the mixture was stirred at room temperature for 10 minutes.
  • Compound 9 (185 mg, 0.53 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours.
  • Example 3 First Step of Synthesis of Compound 19 To a solution of compound 12 (20 g, 139 mmol) in ethanol (200 ml) was added sulfuric acid (8 ml), and the mixture was stirred at 85 ° C. for 10 hours. After cooling to room temperature, about half of the solvent was distilled off under reduced pressure and added dropwise to a saturated aqueous sodium bicarbonate solution. Extraction was performed with AcOEt, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to obtain Compound 13 (25.1 g).
  • Test Example 1 Affinity for Mouse NPY Y5 Receptor
  • a cDNA sequence encoding the mouse NPY Y5 receptor was expressed in the expression vector pME18S (Takebe et al. Mol. Cell. Biol., 8, 466-472).
  • the obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
  • Membrane preparations prepared from CHO cells expressing the mouse NPY Y5 receptor were assayed together with the compounds of the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM, manufactured by GE Healthcare).
  • the solution was incubated in a solution (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter.
  • Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC 50 value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].
  • the compound according to the present invention inhibited the binding of peptide YY (NPY and homologous substances) to the mouse NPY Y5 receptor. That is, this compound showed affinity for the mouse NPY Y5 receptor. The results are shown below.
  • Test Example 2 Affinity for human NPY Y5 receptor
  • pME18S cDNA sequence encoding human NPY Y5 receptor (see WO96 / 16542) was expressed in expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466-472). Cloned into. The obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
  • Membrane preparation prepared from CHO cells expressing human NPY Y5 receptor was assay buffer together with the compound of the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). Incubation was performed in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. . After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter.
  • Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC 50 value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].
  • Test Example 3 Rat Brain Migration Evaluation Intravenous to rats (Crl; CD (SD), ⁇ , 8weeks) using the cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) From the plasma and brain concentration 30 minutes after administration (0.5 mg / mL / kg), brain transferability (brain / plasma partition coefficient; Kp) was evaluated.
  • Test Example 4 Evaluation of transferability to mouse brain Oral administration to mice (Jcl; C57BL / 6J, ⁇ , 8weeks) using a cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) Brain transferability (brain / plasma partition coefficient; Kp) can be evaluated from plasma and brain concentrations after 3 or 5 hours at 2 mg / 10 mL / kg).
  • Test Example 5 Pharmacokinetic Evaluation in Rats Using the cassette dosing method, the half-life was determined from the change in plasma concentration after intravenous administration (0.5 mg / mL / kg) in rats (Crl; CD (SD), ⁇ , 8 weeks). (T1 / 2) and systemic clearance (CLtot) were evaluated. As a result, the compound of the present invention showed good pharmacokinetics such as high bioavailability and appropriate clearance.
  • Test Example 6 Inhibition of cAMP production in CHO cells CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), and then the compound according to the present invention was added and incubated for 5 minutes, and then 50 nMNPY and 10 ⁇ M forskolin (Sigma) were added and incubated for 30 minutes. After stopping the reaction by adding 1N HCl, the amount of cAMP in the supernatant was measured using EIA kit (manufactured by Amersham LIFE SIENCE).
  • SIGMA isobutylmethylxanthine
  • Test Example 7 NPY Y5 Receptor Selectivity Similar to Test Example 2 using a Y1-expressing cell (human neuroblastoma, SK-N-MC) membrane sample and a Y2-expressing cell (human neuroblastoma, SMS-KAN) membrane sample The method is tested to determine the affinity of the compounds of the invention for the NPY Y1 and NPY Y2 receptors. As a result, it can be confirmed that the compound according to the present invention has NPY Y5 receptor selectivity.
  • Test Example 8 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the external occipital crest to the back of the nose of male C57BL / 6J mice (12-14 weeks old, 28-35 g) to expose the upper skull .
  • a hole having a diameter of about 1 mm was formed using an electric drill at a position about 1 mm rearward from the exposed part bregma toward lamda, about 1 mm from the midline to the left side.
  • a 0.5% hydroxypropylmethylcellulose aqueous solution (manufactured by Shin-Etsu Chemical Co., Ltd.) or a test substance suspended in this aqueous solution is forcibly orally administered to mice after waking up from anesthesia, and received physiological saline or NPY Y5 one hour after administration.
  • Body-specific agonist [cPP 1-7 , NPY 19-23 , Ala 31 , Aib 32 , Gln 34 ] -h Pancreatic Polypeptide: manufactured by Tocris) 0.1 nmol using a cannula from the head opening previously provided Injected.
  • the food intake of mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the group administered with 0.5% hydroxypropylmethylcellulose solution and the group administered with the test substance was investigated.
  • Test Example 9 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan ( CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 ⁇ mol / L (4 points).
  • reaction solution in a 96-well plate 5 kinds of each substrate, human liver microsome, and test drug are added in the above composition in 50 mM Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index.
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model.
  • NADPH final concentration 1 mM, in the case of oxidative metabolism
  • liver microsomes final concentration 0.5 mg
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet 15 mg of the present compound Starch 15mg Lactose 15mg Crystalline cellulose 19mg Polyvinyl alcohol 3mg 30ml distilled water Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule Compound of the present invention 10 mg Magnesium stearate 10mg Lactose 80mg Are mixed uniformly to make a powder as a fine powder or powder. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules Compound of the present invention 30 g Lactose 265g Magnesium stearate 5g After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.

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Abstract

Nouveau composé ayant une action antagoniste sur les récepteurs de NPY Y5, ledit composé, représenté par la formule (I) : (Formule chimique 1) s'étant avéré avoir une action antagoniste sur les récepteurs de NPY Y5. (Dans la formule, R1 est un alkyle substitué ou non ou autre; p et q sont chacun indépendamment 0 ou 1, p et q n'étant pas simultanément 1; L est un atome d'oxygène ou un atome de soufre; et R2, R3, R4, et R5 sont chacun indépendamment un atome d'hydrogène, un alkyle substitué ou non, ou autre).
PCT/JP2012/061033 2011-04-27 2012-04-25 Dérivé de benzimidazole ayant une action antagoniste sur les récepteurs de npy y5 Ceased WO2012147765A1 (fr)

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US10123994B2 (en) 2014-10-28 2018-11-13 Shionogi & Co., Ltd. Heterocyclic derivative having AMPK-activating activity

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WO2007125952A1 (fr) * 2006-04-28 2007-11-08 Shionogi & Co., Ltd. Derive amine ayant une activite antagoniste du recepteur y5 du npy
WO2009054434A1 (fr) * 2007-10-25 2009-04-30 Shionogi & Co., Ltd. Dérivé d'amine présentant une activité antagoniste du récepteur npy y5 et son utilisation

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WO2007125952A1 (fr) * 2006-04-28 2007-11-08 Shionogi & Co., Ltd. Derive amine ayant une activite antagoniste du recepteur y5 du npy
WO2009054434A1 (fr) * 2007-10-25 2009-04-30 Shionogi & Co., Ltd. Dérivé d'amine présentant une activité antagoniste du récepteur npy y5 et son utilisation

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