WO2007142217A1 - Dérivé de 1-phénylpyridone - Google Patents

Dérivé de 1-phénylpyridone Download PDF

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WO2007142217A1
WO2007142217A1 PCT/JP2007/061333 JP2007061333W WO2007142217A1 WO 2007142217 A1 WO2007142217 A1 WO 2007142217A1 JP 2007061333 W JP2007061333 W JP 2007061333W WO 2007142217 A1 WO2007142217 A1 WO 2007142217A1
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group
azetidine
methyl
fluoro
phenol
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PCT/JP2007/061333
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Japanese (ja)
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Hiroyuki Kishino
Yuji Haga
Sayaka Mizutani
Minoru Moriya
Norikazu Otake
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Banyu Pharmaceutical Co., Ltd.
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Publication of WO2007142217A1 publication Critical patent/WO2007142217A1/fr

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Definitions

  • the present invention relates to a novel 1-furubiridone derivative.
  • the derivative acts as a melanin aggregation hormone receptor antagonist and is used as a preventive or therapeutic agent for various cardiovascular diseases, nervous system diseases, metabolic diseases, reproductive diseases, respiratory diseases, gastrointestinal diseases and the like.
  • MCH Melanin Concentrating Hormone
  • MCH is thought to be responsible for various central functions in the body.
  • the hypothalamic lateral cortex has long been known as a feeding center, and in recent years, much molecular biological 'pharmacological knowledge has been accumulated that suggests the involvement of MCH in energy homeostasis control. ing. That is, it has been reported that mRNA expression of MCH precursor is increased in the brain of obZob mice, dbZdb mice, AyZa mice, Zucker fatty rats and fasted mice, which are genetic obesity model animals [Nature, Vol. 380, 243 (1996); Diabetes, Vol. 47, 294 (1998); Biochemical and Biophysical Research Communications, Vol. 268, 88 (2000); Molecular Brain Research, Vol. 92, 43 (2001) reference].
  • MCH is an important factor in the formation of obesity, and that it is involved in metabolic disorders and respiratory diseases in which obesity is also a risk factor.
  • MCH is known to cause anxiety, acupuncture, memory 'learning, diuresis, sodium / potassium excretion, oxytocin secretion, and reproductive' sexual function [Peptides, Vol. 17 , 171 (1996); Peptides, Vol. 18, 1095 (1997); Pe ptides, Vol. 15, 757 (1994); Journal of Neuroendocrinology, Vol. 8, 57 (1996); Critical Reviews in Neurobiology, Vol. 8 , 221 (1994)].
  • MCH induces various pharmacological actions mainly through MCH receptors present in the central nervous system.
  • type 1 receptors MCH-1R or SLC-1
  • type 2 receptors MCH-2R or SLT
  • Biochemical and Biophysical Research Communications Vol. 261, 622 (1999); Nature Cell Biology, Vol. 1, 267 (1999); FEBS Letters , Vol. 457, 522 (1999); Biochemical and Biophysical Research Communications, vol. 283, 10 13 (2001); The Journal of Biological Chemistry, Vol. 276, 20125 (200 1); Proceedings of the National Academy of Sciences of the Unite d States of America, Vol.
  • MCH-1R deficiency is known to increase activity in mice [see Proceedings of the National Academy oi sciences oi the United states of America, Vol. 99, 3240 (2002)]. It is also strongly implicated in central diseases with abnormalities, such as attention deficit / hyperactivity disorder, schizophrenia depression [Molecular Medicine Today, Vol. 6, 43 (2000); Trends in Neuroscience, Vol, 24, 527 (2001)].
  • MCH The function of MCH is expressed by binding of MCH to the MCH receptor. Therefore, inhibition of MCH receptor binding can block the expression of MCH action. Therefore, substances that antagonize receptor binding to MCH are various diseases involving MCH, such as obesity, diabetes, hormone secretion abnormalities, hyperlipidemia, gout, fatty liver, and other metabolic diseases; Symptom, acute depressive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte disorders, etc .; for example, bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, integration Central and peripheral nervous system diseases such as ataxia, attention deficit / hyperactivity disorder, memory impairment, sleep disorder, cognitive impairment, motor impairment, sensory abnormalities, olfactory disturbance, morphine tolerance, drug addiction, alcoholism; Life such as infertility, premature birth, sexual dysfunction It is expected to be useful as a prophylactic or therapeutic agent for reproductive diseases; gastrointestinal tract diseases, respiratory diseases, cancer or skin pigmentation
  • Patent Document 1 or 2 discloses compounds having an MCH receptor antagonistic action, but they do not have a pyridone ring.
  • Patent Document 3 discloses certain pyridone derivatives having P38 MAP kinase activity, but does not describe MCH receptor antagonism.
  • Patent Document 4 discloses a wide range of compounds including the compound of the present invention. However, in this publication, there is no specific disclosure for specific compounds having a azetidinyl group! /.
  • Patent Document 1 PCT International Publication WO01Z21577 Pamphlet
  • Patent Document 2 PCT International Publication WO02Z02744 Pamphlet
  • Patent Document 3 PCT International Publication WO03Z68230 pamphlet
  • Patent Document 4 PCT International Publication WO05Z085200 Pamphlet
  • Az optionally has a substituent and may represent a azetidyl group
  • L represents a single bond or optionally a substituent, and may represent a C1-C2 alkylene group, provided that , When L is a single bond, L is not bonded at the 1- or 2-position of the azetidyl group, and when L is a L-alkylene group, L is not bonded at the 1-position of the azetidinyl group.
  • Ar may optionally have a substituent, may be a phenol group or may optionally have a substituent, and may represent a pyridyl group]
  • the present invention provides:
  • Metabolic diseases including obesity, diabetes, hormone secretion abnormalities, hyperlipidemia, gout, fatty liver, hepatitis, and cirrhosis, which contain the compound represented by formula (I) as an active ingredient; narrow Cardiomyopathy, acute congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, and cardiovascular disease represented by electrolyte abnormalities; bulimia, affective disorder, depression, anxiety, epilepsy, delirium, Dementia, schizophrenia, attention deficit ⁇ hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory abnormalities, olfactory disturbance, morphine tolerance, narcotic dependence and alcohol dependence Nervous system diseases; reproductive diseases represented by infertility, premature birth and sexual dysfunction; gastrointestinal diseases; respiratory diseases; preventive or therapeutic agents for cancer or skin pigmentation
  • the present invention provides:
  • a method for preventing or treating a disease caused by melanin-concentrating hormone which comprises administering an effective amount of the compound represented by formula (I) to a mammal, particularly a human,
  • the compound of the present invention has MCH-1R antagonism, and obesity, diabetes, Metabolic disorders such as abnormal secretion, hyperlipidemia, gout, fatty liver, hepatitis, cirrhosis, such as angina, acute, congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte abnormalities Cardiovascular diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory Central and peripheral nervous system diseases such as abnormalities, olfactory disturbance, morphine tolerance, narcotic addiction, alcoholism, reproductive system diseases such as infertility, premature birth, sexual dysfunction, etc. It is useful as a prophylactic or therapeutic agent for cancer or skin pigmentation, particularly as a prophylactic or therapeutic agent for obesity.
  • Metabolic disorders such as abnormal secretion, hyperlipidemia, gout, fatty liver,
  • FIG. 1 is a graph showing the spontaneous food intake of mice up to 24 hours after oral administration of the compound of the present invention to mice with dietary obesity.
  • the term “lower” means that the group or compound to which the word is attached has 6 or less carbon atoms, preferably 4 or less.
  • the "lower alkyl group” includes a C1-C6 linear or C3-C6 branched alkyl group, and specifically includes, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group.
  • the C1-C4 alkyl group includes a C1-C4 straight chain or C
  • “Lower cycloalkyl group” includes C3-C6 cycloalkyl groups, and specifically includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. Group.
  • the "lower alkylene group” includes a C1-C6 linear or C3-C6 branched alkylene group, and specifically includes, for example, a methylene group, an ethylene group, a propylene group, a butylene. Group, pentylene group, hexylene group and the like.
  • the C1-C2 alkylene group means an alkylene group having 1 or 2 carbon atoms in the main chain.
  • “optionally substituted may be an azetidyl group”, “optionally substituted !, may be a C1-C2 alkylene group”, “optionally substituted.
  • substituent in the phenyl group or the pyridyl group optionally having a substituent include, for example, a halogen atom, a cyano group, a hydroxyl group, and optionally a fluorine atom.
  • it may be substituted with a hydroxyl group, or a lower alkyl group, optionally substituted with a fluorine atom or a hydroxyl group, or a lower cycloalkyl group, optionally substituted with a fluorine atom.
  • Lower alkyloxy group lower alkyloxy lower alkyl group, lower alkyloxy carbonyl group, lower alkylcarbonyl group, lower alkylcarbonyloxy group, rubamoyloxy group, mono-lower alkyl group Examples thereof include rubamoyloxy group, di-lower alkylcarbamoyloxy group, lower alkylsulfol group, sulfamoyl group, mono-lower alkylsulfamoyl group, di-lower alkylsulfamoyl group, etc.
  • the “C1-C2 alkylene group”, “phenyl group” or “pyridyl group” may be substituted by one or more of these substituents.
  • halogen atom examples include a fluorine atom, a chlorine atom, an iodine atom, and an iodine atom.
  • lower alkyl group optionally substituted with a fluorine atom or a hydroxyl group some or all of the hydrogen atoms of the lower alkyl group or the lower alkyl group are substituted with a fluorine atom or a hydroxyl group.
  • the lower alkyl group substituted with a fluorine atom or a hydroxyl group include, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, 1, 2 —Difluoroethyl group, 2-hydroxyethyl group, 1,2-dihydroxyethyl group and the like can be mentioned.
  • the "lower cycloalkyl group optionally substituted with a fluorine atom or a hydroxyl group” may include a part of hydrogen atoms of the lower cycloalkyl group or the lower cycloalkyl group. Includes a lower cycloalkyl group which is entirely substituted with a fluorine atom or a hydroxyl group.
  • Examples of the lower cycloalkyl group substituted with the latter fluorine atom or hydroxyl group include a fluorocyclopropyl group, Fluorocyclobutyl group, Fluorocyclopentyl group, Fluorocyclohexyl group, Difluorocyclopropyl group, 1,2-Difluorocyclopropyl group, Hydroxycyclopropyl group, Hydroxycyclobutyl group, Hydroxycyclopentyl group, Examples thereof include a hydroxycyclohexyl group and a 1,2-dihydroxycyclopropyl group.
  • the “lower alkyloxy group optionally substituted with a fluorine atom” includes a group in which a lower alkyl group or a lower alkyl group substituted with a fluorine atom is bonded to an oxygen atom.
  • the lower alkyloxy group include a methoxy group, an ethoxy group, an n propyloxy group, an isopropyloxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, and an n-pentyloxy group.
  • the substituted lower alkyloxy group include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1,2-difluoroethoxy group, and the like.
  • the "lower alkyloxy lower alkyl group” is a lower alkyl group substituted with a lower alkyloxy group. Specifically, for example, a methoxymethyl group, an ethoxymethyl group, an n-propyloxymethyl group, isopropyl Examples include an oxymethyl group, a 1-methoxyethyl group, and a 2-methoxy group.
  • “Lower alkyloxycarbonyl group” is a group in which a lower alkyloxy group is bonded to a carbo group (one CO 2), and includes C1-C6 alkyloxycarbol groups, Specifically, for example, a methoxy carbo ol group, an ethoxy carbo ol group, an n propyloxy carbonyl group, an isopropyloxy carbo ol group, an n-butoxy carbo ol group, an isobutoxy carbo ol group, a tert Examples thereof include a butoxycarbonyl group and an n-pentyloxycarbonyl group.
  • the “lower alkylcarbonyl group” is a group in which a lower alkyl group is bonded to a carbo group (one CO 2), and includes a C1-C6 alkylcarbol group. Acetyl group, propionyl group, ptylyl group, isoptylyl group, valeryl group, isovaleryl group, bivaloyl group and the like.
  • the "lower alkylcarboxoxy group” is a group in which a lower alkylcarbo yl group is bonded to an oxygen atom, and specifically includes, for example, an acetoxy group, a propio- loxy group, a valeryloxy group, an isovaleryl group. Examples include a ruoxy group and a bivalyloxy group.
  • One of these is a group substituted with a lower alkyl group.
  • a methylcarbamoyl group, an ethylcarbamoyl group, an npropyl carbamoyl group, an isopropylcarbamoyl group, an n-butylcarbamoyl group, sec -A butylcarbamoyl group, a tert butylcarbamoyl group, etc. are mentioned.
  • the "di-lower alkyl force ruberamoyl group” means two hydrogens of force rubermoyl group (one CONH).
  • each atom is a group substituted with a lower alkyl group.
  • a dimethyl group a rubamoyl group, a jetylcarbamoyl group, an ethylmethylcarbamoyl group, a di (n-propyl) rubamoyl group, a methyl ( (n-propyl) strong rubermoyl group, diisopropylcarbamoyl group and the like.
  • “Mono-lower alkyl strength ruberamoyloxy group” is a group in which a mono-lower alkylcarbamoyl group is bonded to an oxygen atom, and specifically includes, for example, methylcarbamoyloxy group, ethylcarbamoyloxy group, n Examples thereof include propyl group ruberamoyloxy group, isopropyl group ruberamoyloxy group, n-butylcarbamoyloxy group, sec butylcarbamoyloxy group, tert-butylcarbamoyloxy group and the like.
  • the “di-lower alkyl strength ruberamoyloxy group” is a group in which a di-lower alkylcarbamoyl group is bonded to an oxygen atom. Specifically, for example, a dimethylcarbamoyloxy group, a jetylcarbamoyloxy group Ethylmethylcarbamoyloxy group, di (n propyl) force ruberamoyloxy group, methyl (n propyl) force ruberamoyloxy group, diisopropyl force ruberamoyloxy group and the like.
  • “Lower alkylsulfonyl group” is a lower alkyl group bonded to a sulfonyl group (SO 2).
  • methylsulfol group ethylsulfol group, n-propylsulfol group, isopropylsulfol group, n-butylsulfol group, sec-butylsulfol group, Examples thereof include a tert-butylsulfol group.
  • “Mono-lower alkylsulfamoyl group” is a hydrogen atom of a sulfamoyl group (one SO NH). One of the children is a group substituted with a lower alkyl group. Specifically, for example, monomethylsulfamoyl group, monoethylsulfamoyl group, mono (n-propyl) sulfamoyl group, monoisopropylsulfamoyl group, mono (N-Butyl) sulfamoyl group, mono (sec-butyl) sulfamoyl group, mono (tert-butyl) sulfamoyl group and the like can be mentioned.
  • Di-lower alkylsulfamoyl group refers to two waters of a sulfamoyl group (one SO NH).
  • Each of the elementary atoms is a group substituted with a lower alkyl group.
  • the "pharmaceutically acceptable salt thereof" of the compound represented by the formula (I) includes a pharmaceutically acceptable ordinary salt, and includes an amino group and a tertiary of the compound of the formula (I). Examples include acid addition salts in amines and acid addition salts in nitrogen-containing heterocycles.
  • Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate, maleate, fumarate, tartrate, citrate and ascorbate. And organic acid salts such as trifluoroacetate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate, maleate, fumarate, tartrate, citrate and ascorbate.
  • organic acid salts such as trifluoroacetate
  • sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.
  • Az represents an azetidyl group optionally having a substituent.
  • the substituent in Az is preferably a hydroxyl group, an oxo group, a C1-C4 alkyl group optionally substituted with a fluorine atom or a hydroxyl group, optionally substituted with a fluorine atom or a hydroxyl group, However, C3-C4 cycloalkyl groups, C1-C4 alkoxy groups, sulfonyl groups, etc.
  • hydroxyl group for example, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group
  • examples include a cyclopropyl group, a cyclobutyl group, a fluoromethyl group, a 2-fluoroethyl group, etc., and in particular, a C1-C4 alkyl group optionally substituted with a fluorine atom or a hydroxyl group, or optionally a fluorine atom or a hydroxyl group.
  • a C3-C4 cycloalkyl group is recommended.
  • these substituents may have 1 to 3, preferably 1 to 2, with respect to Az. Unsubstituted Az is also recommended.
  • Az can also contain azetidine N-oxide.
  • Az is azetidine 1-yl group, azetidine 3-yl group, N-methylazetidine 3-yl group, N-ethylazetidine 3-yl group, N- (n-propyl) azetidine 3- Group, N-isopropylazetidine 3-yl group, N cyclopropylzetidine 3-yl group, N-cyclobutylazetidine-3-yl group, N- (2-fluoroethyl) azetidine 3- Group, azetidine-2-yl group, N-methylazetidine-2-yl group, N-ethylazetidine 2-yl group, N- (n-propyl) azetidine-2-yl group, N-isopropylase Examples thereof include tidin-2-yl group, N-cyclobutylazetidine-2-yl group and the like, more preferably N-ethylazetidine 3-yl group, N-
  • L represents a single bond or an optionally substituted C1-C2 alkylene group.
  • the substituent in the "optionally substituted, optionally C1-C2 alkylene group” is preferably, for example, a hydroxyl group, a fluorine atom, or optionally a fluorine atom.
  • C1-C6 alkyl group, optionally substituted with a fluorine atom, C1-C6 alkyloxy group and the like are exemplified, and more preferably, optionally substituted with a fluorine atom!
  • C1-C4 alkyl groups are recommended.
  • L may be bonded at any of the 1, 2 and 3 positions of the azetidyl group, but when L is a single bond, L is bonded at the 1-position (nitrogen atom) or 2-position of the azetidinyl group.
  • L-butylene group L cannot be bonded at the 1-position (nitrogen atom) of the azetidinyl group! / ⁇ .
  • L is an ethylene group, it is not particularly limited. Therefore, the following O-L-Az bonding modes are recommended. (Here, the substituents in L and Az are omitted.)
  • Ar may optionally have a substituent, and may be a phenyl group or an optionally substituted group, and may represent a pyridyl group.
  • substituents in the "optionally substituted phenyl group” or “optionally substituted pyridyl group” of Ar preferably a halogen atom, C1-C6
  • substituents in the "optionally substituted phenyl group” or “optionally substituted pyridyl group” of Ar preferably a halogen atom, C1-C6
  • examples thereof include an alkyloxy group, a C1-C6 alkyl group which may be optionally substituted with a fluorine atom, and more preferably a fluorine atom and a chlorine atom.
  • substituents may have 1 to 3, preferably 1 to 2, with respect to Ar.
  • Ar is a phenyl group, a 3-fluorophenol group, a 4-fluorophenol group, a 3-chlorophenol group, a 4-cyclophenol group, or 3,4-difluoro.
  • examples include a phenol group, a 5-chloropyridine-2-yl group, a 5-trifluoromethylpyridine-2-yl group, and a 5-fluoropyridin-2-yl group.
  • a 4-fluorophenyl group, 4-clonal phenyl groups, 3,4-difluorophenyl groups, 5-chromic pyridine 2-yl groups, etc. are recommended.
  • the compound represented by the formula (I) can be prepared, for example, by the following production method or the method shown in Examples. However, the production method of the compound of the present invention is not limited to these examples.
  • Manufacturing Method 1 The compound represented by the formula (I) can be produced by reacting the compound represented by the formula ( ⁇ ) with the compound represented by the formula ( ⁇ ).
  • the reaction between the compound represented by the formula ( ⁇ ) and the compound represented by the formula ( ⁇ ) is usually performed by condensing both in an organic solvent in the presence of a base. This can be done.
  • Examples of the leaving group in J include a bromine atom, a chlorine atom, a benzenesulfonyloxy group, a p-toluenesulfo-oxy group, and a methanesulfo-oxy group.
  • organic solvent examples include halogenated carbons such as methylene chloride, chloroform, and dichloroethane; aliphatic hydrocarbons such as n heptane and n-hexane; aromatic hydrocarbons such as benzene, toluene, and xylene.
  • halogenated carbons such as methylene chloride, chloroform, and dichloroethane
  • aliphatic hydrocarbons such as n heptane and n-hexane
  • aromatic hydrocarbons such as benzene, toluene, and xylene.
  • Ethers such as jetyl ether, tetrahydrofuran (hereinafter referred to as “THF”), 1,4 dioxane (hereinafter referred to as “dioxane”), ethylene glycol dimethyl ether; esters such as methyl acetate and ethyl acetate; Examples include acetonitrile, N, N-dimethylformamide (hereinafter referred to as “DMF”), dimethyl sulfoxide (hereinafter referred to as “DMS Oj t”), and mixed solvents thereof.
  • THF tetrahydrofuran
  • dioxane 1,4 dioxane
  • ethylene glycol dimethyl ether esters such as methyl acetate and ethyl acetate
  • esters such as methyl acetate and ethyl acetate
  • Examples include acetonitrile, N, N-dimethylformamide (hereinafter referred to as “DMF”), dimethyl
  • Examples of the base include organic amines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine; sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, carbonate Inorganic amines such as cesium, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like are exemplified, and potassium carbonate, cesium carbonate and the like are recommended.
  • organic amines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine
  • Inorganic amines such as cesium, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like are exemplified, and potassium carbonate, cesium carbonate and the like are recommended.
  • the amount of the compound represented by the formula ( ⁇ ) to be used is, for example, 0.9 mol to 2.0 mol, preferably 1.1 mol, per 1 mol of the compound represented by the formula ( ⁇ ). To 1.5 moles is recommended.
  • the amount of the base used is, for example, 1 mol to 10 mol, preferably 2 mol to 3 mol per mol of the compound represented by the formula ( ⁇ ).
  • the reaction temperature is, for example, 20 ° C to 150 ° C, preferably 60 ° C to 100 ° C is recommended, and the reaction is usually completed in 1 to 3 hours.
  • Examples of the azo compound include dimethylazodicarboxylate, jetylazodicarboxylate, diisopropylazodicarboxylate, 1,1 '(azodicarbol) dipiperidide, and the like, and triarylphosphine
  • Examples of the trialkylphosphine include triphenylphosphine and tributylphosphine.
  • Examples of the trialkylphosphine include triethylphosphine and tributyphosphine. Of these, the combination of diisopropyl azodicarboxylate and triphenylphosphine, or the combination of 1,1,-(azodicarbol) dipiperidide and tributylphosphine is recommended.
  • the amount of the compound represented by the formula (III) is 1 to 10 mol, preferably 1 to 1.5 mol per 1 mol of the compound represented by the formula ( ⁇ ). Recommended.
  • the use amount of the azo compound and the organophosphorus compound is exemplified by 1 mol to 3 mol of the azo compound per 1 mol of the compound represented by the formula ( ⁇ ), preferably 1 1 mol to 1.5 mol is recommended, and 1 mol to 3 mol of the organic phosphorus compound is exemplified with respect to 1 mol of the compound represented by the formula ( ⁇ ), preferably 1 mol to 1.5 mol. Recommended.
  • reaction solvent examples include halogenated carbons such as methylene chloride, chloroform, dichloroethane, and carbon tetrachloride; aliphatic hydrocarbons such as n heptane and n-hexane; benzene, toluene, and xylene.
  • Aromatic hydrocarbons such as: ethers such as jetyl ether, THF, dioxane, and ethylene glycol dimethyl ether; esters such as methyl acetate and ethyl acetate; acetonitrile, N-methylpyrrolidone (hereinafter referred to as “NMP”) ), DMF, DMSO Or a mixed solvent thereof.
  • the reaction temperature is, for example, 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C is recommended, and the reaction is usually completed in 2 hours to 24 hours.
  • the compound represented by the formula ( ⁇ ) can be produced, for example, by the method described in International Publication WO2005Z085200.
  • the compound represented by the formula (III) can be prepared by the method described in the Examples, as well as Chemical and Pharmaceutical Bulletin, Vol. 22, 1490 (1974), Journal of Hetero cyclic Chemistry, Vol. 24, 255. (1987) and JP-A-2000-143622, etc., or a method analogous thereto.
  • the protecting group for the amino group is not particularly limited as long as it has the function, and examples thereof include a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, and a trityl group.
  • the protecting group for the hydroxyl group is not particularly limited as long as it has the function thereof, for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group; a trimethylsilyl group, a tert-butyldimethylsilyl group Lower alkylsilyl group such as methoxymethyl group, 2-alkoxymethyl group such as 2-methoxyethoxymethyl group, etc .; tetrahydrovinyl group; trimethylsilylethoxymethyl group; benzyl group, p-fluorobenzoyl group, p- Examples thereof include aralkyl groups such as methoxybenzyl group, 2,3-dimethoxybenzyl group and trityl group; and acyl groups such as formyl group and acetyl group.
  • a lower alkyl group such as a methyl group, an ethyl group, a propyl group
  • the compound represented by the formula (1-1) can be produced by reacting the compound represented by the formula (IV) with the compound represented by the formula (V).
  • X represents a leaving group, formyl group or oxo group
  • Az p represents an azetidyl group which may be protected
  • Azl represents an azetidyl group
  • R optionally represents fluorine.
  • a lower alkyl group that may be substituted with an atom or a hydroxyl group, or a lower cycloalkyl group that may optionally be substituted with a fluorine atom or a hydroxyl group is shown, and Ar and L are as defined above.
  • the amount of the compound represented by the formula (IV) and the compound represented by the formula (V) is usually used by using equimolar amounts of either or a small excess of either one.
  • Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, zinc biscianoborohydride, nickel biscianoborohydride and the like.
  • the amount of the reducing agent to be used is, for example, 1 mol to excess mol per mol of the compound represented by the formula (IV), and preferably 1 mol to 5 mol is recommended.
  • organic solvents examples include alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, THF, and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloromethane; benzene, toluene, Aromatic hydrocarbons such as black benzene and xylene; solvents such as DMF and acetonitrile, or mixed solvents thereof.
  • alcohols such as methanol, ethanol, and propanol
  • ethers such as diethyl ether, THF, and dioxane
  • halogenated hydrocarbons such as methylene chloride, chloroform, and dichloromethane
  • benzene, toluene Aromatic hydrocarbons such as black benzene and xylene
  • solvents such as DMF and acetonitrile, or mixed solvents thereof.
  • the reaction temperature is usually 20 ° C to 100 ° C, preferably 0 ° C to room temperature, and the reaction time is usually 5 minutes to 7 days, preferably 1 Time 6 to 6 hours.
  • the compound represented by the formula (V) includes alkyl halides such as methyl iodide, iodide til, and propyl bromide; lower alkyl aldehydes such as formaldehyde and acetoaldehyde; acetone, cyclobutanone, and the like. And lower alkyl carbo yl and the like.
  • a compound represented by the formula (I2) can be produced by reacting a compound represented by the formula (VII) with a compound represented by the formula (VIII).
  • the compound represented by the formula (VII) can be produced by reacting the compound represented by the formula ( ⁇ ) and the compound represented by the formula (VI) according to the production method 1. it can.
  • This reaction can be carried out according to production method 1.
  • a compound represented by the formula (I-2) can be obtained by performing a reaction according to Production Method 1.
  • Examples of the compound represented by the formula (VI) include 1, 2 dibromoethane, 2 bromoethanol, (2R) -2- (tetrahydro-1-2H-pyran-2-yloxy) propyl methanesulfonate, (2S)- Examples include 2- (tetrahydro-1,2H-pyran-1,2-yloxy) propyl methanesulfonate and the like.
  • Examples of the compound represented by the formula (VIII) include azetidine, 3-hydroxyazetidine, 2-methylazetidine, 3-methylazetidine, and the like.
  • the compound represented by the formula (I) obtained by force, the compound represented by the formula (I 1) or the compound represented by the formula (I 2) can be obtained by conventional separation means, for example, solvent extraction. It can be easily isolated and purified by recrystallization, column chromatography, preparative thin layer chromatography or the like. [0100] These compounds can be converted into pharmaceutically acceptable salts by a conventional method, and vice versa.
  • conversion to a salt-free compound can also be performed according to a conventional method.
  • MCH 1R-expressing cells were obtained by transfection with CHO-K1 (American Type ⁇ Collection ⁇ Collection).
  • Experiment f row 2 (Eating test of mice in a boat) C Feeding high fat diet to male C57BLZ6 mice (10-12 weeks old) to form dietary obesity I let you. Various amounts of the compound of Example 18 were suspended in 0.5% aqueous methylcellulose solution and orally administered 1-2 hours before the start of the dark period. Subsequently, mice were fed with a high fat diet, and spontaneous food intake was measured up to 24 hours after administration.
  • FIG. 1 is a graph showing spontaneous food intake of mice up to 24 hours after oral administration of 30 mgZkg of the compound of the present invention to mice with dietary obesity. That is, 1) when the compound of Example 18 is not administered, and 2) when 30 mg Zkg of the compound of Example 18 is administered, the spontaneous food intake (g) of mice for 24 hours is shown.
  • the compound of the present invention significantly suppressed the spontaneous food intake of mice that had formed dietary obesity in a dose-dependent manner.
  • the amount of food consumed when only a 0.5% aqueous solution of methylcellulose was administered instead of the compound of the present invention was used as a control.
  • the present invention relates to metabolic diseases such as obesity, diabetes, abnormal hormone secretion, hyperlipidemia, gout, fatty liver, hepatitis, cirrhosis, such as angina pectoris, acute congestive heart failure, myocardial infarction.
  • metabolic diseases such as obesity, diabetes, abnormal hormone secretion, hyperlipidemia, gout, fatty liver, hepatitis, cirrhosis, such as angina pectoris, acute congestive heart failure, myocardial infarction.
  • Circulatory system diseases such as atherosclerosis, hypertension, kidney disease, electrolyte abnormalities, such as bulimia, emotional disorder, depression, anxiety, hemorrhoids, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder, Central and peripheral nervous system diseases such as memory disorders, sleep disorders, cognitive disorders, motor disorders, sensory abnormalities, olfactory disorders, morphine tolerance, narcotic addiction, alcoholism, such as infertility, premature birth, sexual dysfunction It can be used for preventive or treatment of systemic diseases, gastrointestinal diseases, respiratory diseases, cancer or skin pigmentation.
  • electrolyte abnormalities such as bulimia, emotional disorder, depression, anxiety, hemorrhoids, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder
  • Central and peripheral nervous system diseases such as memory disorders, sleep disorders, cognitive disorders, motor disorders, sensory abnormalities, olfactory disorders, morphine tolerance, narcotic addiction, alcoholism, such as infertility, premature birth, sexual dysfunction It can be used
  • the compound of the present invention can be administered orally or parenterally, and by formulating it into a form suitable for its administration, obesity, diabetes, abnormal hormone secretion, hyperlipidemia, gout, fatty liver, hepatitis , Metabolic diseases such as cirrhosis, such as angina pectoris, acute congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte abnormalities, such as bulimia, affective disorders, Depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory abnormality, olfactory disturbance, morphine tolerance, drug dependence, alcohol Serve as a preventive or therapeutic agent for central and peripheral nervous system diseases such as addiction, for example, reproductive system diseases such as infertility, premature birth, sexual dysfunction, and other diseases, gastrointestinal diseases, respiratory diseases, cancer be able to.
  • Metabolic diseases such as cirrhosis, such as angina pe
  • a pharmaceutically acceptable carrier for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn Starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, cured Castor oil, polybulurpyrrolidone, magnesium stearate, light anhydrous key acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol Le,
  • Examples of dosage forms formulated as a mixture of these carriers and the compound of the present invention include solid preparations such as tablets, capsules, granules, powders or suppositories; or, for example, syrups and elixirs.
  • solid preparations such as tablets, capsules, granules, powders or suppositories; or, for example, syrups and elixirs.
  • liquid preparations such as injections can be mentioned, and these can be prepared according to conventionally known methods in the field of preparations.
  • a liquid preparation it may be dissolved or suspended in water or other appropriate medium at the time of use.
  • physiological saline or glucose solution in the case of injections, it may be dissolved or suspended in physiological saline or glucose solution as necessary, and a buffer or preservative may be added.
  • These preparations can contain the compound of the present invention in a proportion of 1.0 to: LOO wt%, preferably 1.0 to 60 wt% of the entire pharmaceutical composition,
  • the above-acceptable carrier can be contained in an amount of 0 to 99.0% by weight, preferably 40 to 99.0% by weight.
  • These preparations may contain other therapeutically effective compounds such as a therapeutic agent for diabetes, a therapeutic agent for hypertension, a therapeutic agent for arteriosclerosis and the like.
  • the dosage and frequency of administration are the patient's sex, age, weight, degree of symptom, and type of desired therapeutic effect.
  • the dose is usually from 0.001 to 50 mg / kg body weight per day, and can be administered in single or multiple doses.
  • the dosage is preferably about 0.01 to about 25 mg Zkg per day, about 0.05 to about 25 per day. 1 Omg / kg is more preferred!
  • the compound of the present invention is a drug effective for hypertension, hypertension related to obesity, hypertension related diseases, cardiac hypertrophy, left ventricular hypertrophy, metabolic disease, obesity, obesity related diseases, etc. (hereinafter referred to as “combination drug”). ) Can be used in combination. Such drugs can be administered simultaneously, separately or sequentially in the prevention or treatment of the disease.
  • the compound of the present invention is used at the same time as one or more concomitant drugs, it can be a pharmaceutical composition in a single dosage form.
  • the composition containing the compound of the present invention and the concomitant drug may be administered to the administration subject in different packages simultaneously, separately or sequentially. They may be administered with a time lag.
  • the dose of the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease, combination, etc., in accordance with the clinically used dose.
  • the administration form of the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include: 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) separate administration of the compound of the present invention and the concomitant drug.
  • Simultaneous administration of two preparations obtained by formulation in the same administration route 3) Time difference in the same administration route of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug 4) Simultaneous administration of two kinds of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, 5) Compound of the present invention and the concomitant drug Administration of two different preparations obtained by separate formulation in different routes of administration (e.g. compound of the invention; administration in concomitant order of drugs or in reverse order) Administration).
  • the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • concomitant drug used in the present invention examples include “diabetes therapeutic drug”, “hyperlipidemic therapeutic drug”, “hypertension therapeutic drug”, “anti-obesity drug” and the like. Two or more of these concomitant drugs may be used in combination at an appropriate ratio.
  • Specific drugs include simvastatin; mepastatin (mevastatin) Ezetimibe; atorvastatin; sitagliptin; metformin; sibutramine; onorlistat, orlist at; knexa; topiramate; phen Theremin (phentermine); oral sartan; combination of losartan and hydrothiazia thiazide; or rimonabant, N— [3— (4 chlorophenol) 2 (S) —felue 1 ( S) Methyl propyl] — 2— (4 trifluoromethyl— 2 pyrimidyloxy) —2—methylpropanamide, N— [(IS, 2S) —3— (4—black mouth) 2— (3— Cyanophylol) 1 1-Methylpropyl] 2 Methyl 2— ⁇ [5 (Trifluoromethyl) pyridine— 2yl] oxy ⁇ propanamide, N— [3— (4 Closures) 2—
  • the above combination drug can be obtained by using one or more of the compound of the present invention and the above combination drug in combination.
  • the above combination drug is useful for prevention or treatment of metabolic diseases by combining with one or more drugs selected from the group power consisting of antidiabetic drugs and hyperlipidemia drugs.
  • combinations containing antihypertensive drugs and antihypertensive drugs are useful for the prevention or treatment of metabolic diseases with a synergistic effect by adding antidiabetic drugs and Z or hyperlipidemia drugs.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound (208 g, 85%) as a yellow solid.
  • the reaction mixture was diluted with ethyl acetate (2000 ml) and poured into a 13% aqueous solution of ammonium chloride (1500 ml), and the precipitate was filtered through Celite. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (333 g, 87 %) Was obtained as a colorless solid.
  • tert Butyl 3 (hydroxymethyl) azetidine 1 To a solution of carboxylate (184 mg, 0.98 mmol) in THF (10 ml) was added triethylamine (150 1, 1.08 mmol) and methanesulfonyl chloride (76 1, 0.98 mmol). The mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate.
  • Example 1 [0122] In the following, the same procedure as in Example 1 was carried out except that (5-closed pyridine-2-yl) methyl methanesulfonate in Example 1- (7) was replaced with the following compounds.
  • Example 4 The same operation as in Example 1 was carried out using fluorinated bendyl bromide to obtain the title compound (30 mg) as a colorless solid.
  • Example 4 The same operation as in Example 1 was performed using black-opened benyl bromide to obtain the title compound (lOOmg) as a colorless solid.
  • L-tartaric acid 81.2 g, 0.54 mol was dissolved in hot methanol (800 ml) with heating, and then palladium hydroxide (15. Og) was added to the resulting residue. The mixture was stirred for 2 days at 50 ° C under a hydrogen atmosphere (1 atm). Water (400 ml) was added to the reaction solution to dissolve the precipitated crystals, and then the reaction solution was filtered and concentrated under reduced pressure. Methanol (1000 ml) was added to the resulting residue, heated under reflux for 1 hour, and stirred overnight at room temperature. The precipitated crystals were filtered to obtain azetidine 3ol 'monotartrate (70. lg, 58%) as colorless crystals.
  • Example 9 The same operation as in Example 9 was carried out except that the formalin aqueous solution was replaced with acetonitrile (0.1 ml) to obtain the title compound (46.9 mg, 87%) as a colorless solid.
  • Example 9 The same operation as in Example 9 was carried out except that the formalin aqueous solution was changed to cyclobutanone (0.1 ml) in Example 9, and the title compound (52.3 mg, 90%) was obtained as a colorless solid.
  • 'HNMR 400MHz, CDC1, 6ppm: 1.62—2.08 (6 ⁇ , m), 3.16—3.31 (3
  • Example 13 4 [(4 Fluorobenzyl) oxy] 1— ⁇ 4— [(1-Isopropylazetidine-1-3-yl) oxy] phenol ⁇ pyridin-2 (1H) —one
  • Example 8 4-[(4 fluorobenzyl) oxy] — 1- (4 hydroxyphenol) pyridin 2 (1H) -one was replaced with the corresponding compound, and the same procedure was followed. The title compound (737 mg, 75%) was obtained as a colorless solid.
  • Example 15 The same operation as in Example 15 was carried out using propionaldehyde to give the title compound (49 mg, 63%) as a colorless solid.
  • Example 15 The same operation as in Example 15 was carried out using acetone to obtain the title compound (28 mg, 53%) as a colorless solid.
  • Example 15 The same operation as in Example 15 was performed using cyclobutanone to give the title compound (30 mg, 53%) as a colorless solid.
  • the title compound (17 mg) was obtained as a colorless solid by performing the same operation as in Example 12 using a formalin aqueous solution.
  • the title compound (6m) was prepared by carrying out the same operation as in Example 12 using acetaldehyde. g) was obtained as a colorless solid.
  • Example 9 The same operation as in Example 9 was carried out using acetone to obtain the title compound (26 mg) as a colorless solid.
  • Example 9 The same operation as in Example 9 was performed using cyclobutanone to obtain the title compound (21 mg) as a colorless solid.
  • the compound of the present invention has MCH-1R antagonistic activity, excellent metabolic stability, high safety, excellent in vivo anti-obesity activity, and excellent balance as a medicine. Therefore, metabolic diseases such as obesity, diabetes, hormone secretion abnormalities, hyperlipidemia, gout, fatty liver, hepatitis, cirrhosis, such as angina pectoris, acute congestive heart failure, myocardial infarction, cyclic arteriosclerosis Circulatory system diseases such as hypertension, hypertension, kidney disease, electrolyte abnormalities such as bulimia, affective disorder, depression, anxiety, hemorrhoids, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder, memory impairment, sleep Disorders, cognitive impairments, movement disorders, sensory abnormalities, olfactory disturbances, morphine tolerance, narcotic addiction, alcohol dependence, and other central and peripheral nervous system diseases such as infertility, premature birth, reproductive system diseases such as sexual dysfunction, etc. It is useful as a prophylactic or therapeutic agent for

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Abstract

La présente invention concerne un composé représenté par la formule (I) qui peut être utilisé en tant que matière active : (I) dans laquelle Az représente un groupe azétidinyle qui peut porter un substituant ; L représente une liaison simple ou un groupe alkylène en C1-C2 qui peut facultativement porter un substituant ; et Ar représente un groupe phényle qui peut facultativement porter un substituant ou un groupe pyridyle qui peut facultativement porter un substituant. Le composé peut être utilisé en tant qu'antagoniste d'un récepteur de l'hormone de concentration de la mélanine et il est donc utilisable en tant qu'agent pharmaceutique pour une maladie du système nerveux central, une maladie cardiovasculaire ou une maladie métabolique.
PCT/JP2007/061333 2006-06-07 2007-06-05 Dérivé de 1-phénylpyridone WO2007142217A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010104830A1 (fr) 2009-03-09 2010-09-16 Bristol-Myers Squibb Company Analogues de pyridone utiles comme antagonistes du récepteur 1 de l'hormone concentrant la mélanine
WO2010104818A1 (fr) 2009-03-09 2010-09-16 Bristol-Myers Squibb Company Analogues d'azapyridone utiles comme antagonistes du récepteur 1 de l'hormone concentrant la mélanine
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
JP2011509937A (ja) * 2008-01-11 2011-03-31 アルバニー モレキュラー リサーチ， インコーポレイテッド Ｍｃｈ拮抗薬としての（１−アジノン）置換ピリドインドール類
WO2011127643A1 (fr) * 2010-04-12 2011-10-20 Merck Sharp & Dohme Corp. Dérivés de pyridone
US20120316200A1 (en) * 2010-04-12 2012-12-13 Merck Sharp & Dohme Corp. Pyridone derivatives
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US9434695B2 (en) 2012-07-18 2016-09-06 Sunshine Lake Pharma Co., Ltd Nitrogenous heterocyclic derivatives and their application in drugs
US9902712B2 (en) 2013-12-19 2018-02-27 Sunshine Lake Pharma Co., Ltd. Nitrogenous heterocyclic derivatives and their application in drugs

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Cited By (20)

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US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
JP2011509937A (ja) * 2008-01-11 2011-03-31 アルバニー モレキュラー リサーチ， インコーポレイテッド Ｍｃｈ拮抗薬としての（１−アジノン）置換ピリドインドール類
US9650378B2 (en) 2008-01-11 2017-05-16 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9296743B2 (en) 2008-01-11 2016-03-29 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
JP2014129417A (ja) * 2008-01-11 2014-07-10 Albany Molecular Research Inc Ｍｃｈ拮抗薬としての（１−アジノン）置換ピリドインドール類
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
WO2010104830A1 (fr) 2009-03-09 2010-09-16 Bristol-Myers Squibb Company Analogues de pyridone utiles comme antagonistes du récepteur 1 de l'hormone concentrant la mélanine
WO2010104818A1 (fr) 2009-03-09 2010-09-16 Bristol-Myers Squibb Company Analogues d'azapyridone utiles comme antagonistes du récepteur 1 de l'hormone concentrant la mélanine
US8278316B2 (en) 2009-03-09 2012-10-02 Bristol-Myers Squibb Company Aza pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
US8563583B2 (en) 2009-03-09 2013-10-22 Bristol-Myers Squibb Company Pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US20120316200A1 (en) * 2010-04-12 2012-12-13 Merck Sharp & Dohme Corp. Pyridone derivatives
WO2011127643A1 (fr) * 2010-04-12 2011-10-20 Merck Sharp & Dohme Corp. Dérivés de pyridone
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US9434695B2 (en) 2012-07-18 2016-09-06 Sunshine Lake Pharma Co., Ltd Nitrogenous heterocyclic derivatives and their application in drugs
US9902712B2 (en) 2013-12-19 2018-02-27 Sunshine Lake Pharma Co., Ltd. Nitrogenous heterocyclic derivatives and their application in drugs

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