WO2005108399A1 - イミダゾピリジン化合物 - Google Patents
イミダゾピリジン化合物 Download PDFInfo
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- WO2005108399A1 WO2005108399A1 PCT/JP2005/008819 JP2005008819W WO2005108399A1 WO 2005108399 A1 WO2005108399 A1 WO 2005108399A1 JP 2005008819 W JP2005008819 W JP 2005008819W WO 2005108399 A1 WO2005108399 A1 WO 2005108399A1
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Definitions
- the present invention relates to imidazopyridine compounds useful in the field of medicine.
- This compound acts as a melanin-concentrating hormone receptor antagonist and is useful as a preventive or therapeutic agent for various cardiovascular, nervous, metabolic, reproductive, respiratory, and gastrointestinal disorders. It is.
- MCH Melanin Concentrating Hormone
- MCH is responsible for various central functions in living organisms. It is considered that there is.
- the hypothalamic lateral area has long been known as the feeding center, and in recent years, a great deal of molecular biological and pharmacological knowledge has been accumulated suggesting that MCH is involved in the regulation of energy homeostasis. That is, ob / ob mice, which are genetically obese model animals, dbZdb mice, Ay / a mice, and Zuckerfatty rats have been reported to increase the expression of mRNA for MCH precursors in the brain of fasted mice [Nature, 380 vol. 243 (1996); Diabetes, 47, 294 (1998); Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) Vol. 268, p. 88 (2000); Molecular. Brain Research, Vol. 92, p. 43 (2001)].
- mice deficient in the MCH precursor gene have reduced food intake and increased oxygen consumption per body weight compared to wild-type mice, and low body weight due to a decrease in body fat has been observed [Nature (Nature), 396 volumes, 670 pages (1998)].
- transgenic mice overexpressing the MCH precursor exhibit obesity and insulin resistance associated with binge eating [The Journal of Obliteration].
- MCH is an important factor in obesity formation, and is suggested to be involved in metabolic disorders and respiratory diseases where obesity is a risk factor.
- MCH is known to have anxiety-producing effects, epilepsy, memory and learning, diuretic effects, sodium and potassium excretion, oxitocin secretion, and involvement in reproductive and sexual functions.
- MCH elicits a variety of pharmacological effects, primarily through MCH receptors located in the central nervous system.
- MCH receptors at least two types of receptors, type 1 receptor (MCH-1R or SLC-11) and type 2 receptor (MCH-2R or SLT), are known [Nachia (Na ture), 400, 261 (1999); Nature, 400, 265 (1999); Biochemical and Biophysical Research Communications (B 1 och emica 1 and Biop hy sicai Research Communications), 261, 622 (1999); Nature Celle Biology, 1st. 267 (1999) FEBSL Letters, N 457, 522 (1999); Biochemical 'and' biofission power, Nore Research Communications, Inc., Omm unications, 2 Vol.
- substances that antagonize MCH receptor binding include various diseases associated with MCH, such as obesity, diabetes, hormonal secretion, hyperlipidemia, gout, fatty liver, hepatitis, metabolic diseases such as cirrhosis, Cardiovascular diseases such as angina, acute depressive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, and electrolyte abnormalities, such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia , Schizophrenia, attention deficit hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, paresthesia, olfactory disorder, morphine tolerance, drug dependence, alcohol dependence, etc. It is useful as a prophylactic or therapeutic agent for diseases such as reproductive diseases such as infertility, premature birth, and sexual dysfunction, as well as gastrointestinal diseases, respiratory diseases,
- WO 01/82925 discloses a compound of the following formula as a melanin-concentrating hormone receptor antagonist.
- Patent Document 2 International Publication WO 01 21 577
- the present invention provides an imidazopyridine compound having an action of antagonizing the binding of MCH to MCH-1R, and uses the compound to obtain obesity, diabetes, abnormal hormonal secretion, hyperlipidemia, gout, Metabolic diseases such as fatty liver, hepatitis, cirrhosis, etc., e.g. angina pectoris, acute / congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte disorders, etc., e.g.
- bulimia Affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, paresthesia, olfactory disorder, morphine tolerance, narcotics
- Central and peripheral nervous system diseases such as addiction and alcoholism, for example, reproductive diseases such as infertility, premature birth, and sexual dysfunction, and other preventive agents for gastrointestinal diseases, respiratory diseases, cancer, and skin pigmentation Or
- An object of the present invention is to provide a ⁇ .
- the present inventors have conducted intensive studies to develop compounds that inhibit the binding of MCH to MCH-1R! /, Specific substituents at positions 2, 3, and 6 of the imidazopyridine skeleton It has been found that an imidazopyridine compound characterized by having the following is a novel substance not described in the literature, and that the compound is effective as an MCH-1R antagonist. Reached.
- 1 ⁇ and 1 2 are each independently
- R 1 and R 2 together form a 5- to 8-membered carbocyclic ring optionally substituted with R 6 together with the carbon atom to which they are attached,
- R 3 represents a hydrogen atom, a halogen atom, a 6 alkyl group or a 6 alkyloxy group
- R 4 represents a hydrogen atom or an alkyl group
- R 5 represents a halogen atom, Shiano group, a hydroxyl group, an amino group may optionally be substituted with fluorine atom or hydroxyl - fluorinated alkyl group, mono ⁇ preparative 6 alkyl Ruamino group, di-alkylamino group, optionally An optionally substituted C 6 alkyloxy group, C 6 alkyloxy C 6 alkyl group, C 6 alkyloxycarbonyl group, alkyloxycarbonylamino group,
- (c ⁇ 6 alkyl) represents a substituent selected from the group consisting of an amino group
- R 6 represents R 5 or an oxo group
- n and n are each independently an integer from 0 to 10, satisfying 0 ⁇ m + n ⁇ 10,
- yl represents 0, 1 or 2
- y 2 represents 0 or 1
- ⁇ ⁇ ⁇ is a divalent substituent
- R 5 optionally substituted with R 5 , a 1- or 2-cyclic 3- to 8-membered aromatic or aliphatic heterocyclic group, or
- Ar 2 represents a 5- to 6-membered aromatic carbocyclic group optionally having a substituent or a 5- to 6-membered aromatic heterocyclic group optionally having a substituent. You. ] Or a pharmaceutically acceptable salt thereof.
- Ar 1P is optionally represents an A ri may have a protecting group
- Ar 2P is optionally represents an A r 2 may have a protecting group
- Alpha gamma iota, Te 2 E to iX are the same as above.
- R 1P is optionally represents an R 1 which may have a protecting group
- R 2P is if the represents an R 2 may have a protecting group
- RR 2 and R 3 The above is the same.
- a reproductive disease typified by infertility, premature birth and sexual dysfunction; a gastrointestinal tract disease; a respiratory disease; a preventive or therapeutic agent for cancer or skin pigmentation.
- halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- the “rC ⁇ e alkyl group” means an alkyl group having 1 to 6 carbon atoms, that is, a linear or branched alkyl group having 1 to 6 carbon atoms.
- C 3 - 6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms, specifically, consequent opening propyl, consequent opening heptyl group, is a cyclohexyl group consequent opening pentyl Moto ⁇ Pi consequent opening No.
- “Okiso group” means a group forming a carbonylation Le group together with the carbon atom in an organic compound, for example, in the case of R 5, and two R 5 and the carbon atoms to which they are attached force It refers to the case of forming a luponyl group.
- C i _ 6 alkyl group substituted with fluorine atom specific examples of the alkyl group substituted with the latter fluorine atom Specific examples include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a 1,2-difluoroethyl group.
- alkyl group which may be substituted with a hydroxyl group optionally Ji ⁇ C Bok 6 alkyl group in which some of the hydrogen atoms have been substituted with a hydroxyl alkyl group or a C Bok 6 alkyl groups are included, the latter Specific examples of the alkyl group substituted with a hydroxyl group include a hydroxymethyl group, a 2-hydroxylethyl group, and a 3-hydroxypropyl group.
- the group C 6 alkyl Le group to an oxygen atom is substituted with a C ⁇ 6 alkyl group or a fluorine atom is bonded is included
- Specific examples of the ⁇ ⁇ 6 alkyloxy group include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n_butyloxy group, an isobutoxy group, a tert-butoxy group and an n-pentyloxy group.
- 6- alkyloxy group substituted with a fluorine atom examples include a fluoromethyoxy group, a difluoromethyoxy group, a trifluoromethyoxy group, and a 1,2-difluoroethoxy group.
- a “monoalkylamino group” is a group in which one of the hydrogen atoms of an amino group is substituted with an alkyl group, and specifically, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group , Sec-butylamino group, tert-butylamino group and the like.
- a “dialkylamino group” is a group in which two hydrogen atoms of an amino group are substituted with a C 6 alkyl group, and specifically, a dimethylamino group, a getylamino group, an ethylmethylamino group, a di (n-propyl) amino group And a methylpropylamino group, a diisopropylamino group and the like.
- re — 6- alkyloxy C-ealkyl group is a group in which one of the hydrogen atoms of an alkyl group has been replaced with a C-i-alkyloxy group. And a ethoxymethyl group, a propyloxymethyl group, an ethoxymethyl group, and an ethoxyxyl group.
- the “ 6- alkyloxycarboyl group” is a group in which a C i-e alkyloxy group is bonded to a carbonyl group, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propyloxycarbonyl group. Group, isopropyloxycarbonyl group, n-butyloxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, n -pentyloxycarbonyl group and the like.
- the “(C i-6 alkyloxycarbonyl) amino group” is a group in which an alkyloxycarbonyl group is bonded to an amino group, specifically, a methoxycarbonylamino group, an ethoxycarbonylamino group, —Propoxycarbonylamino group Isopropyloxycarbonylamino group, n-butoxycarbonylamino group, isobutoxycarbonylamino group, tert-butoxycarbonylamino group, n-pentyloxycarbonylamino group And the like.
- the “(C 6 alkyloxycarbonyl) C 6 alkylamino group” is a group in which a C i-e alkyloxycarbonyl group is bonded instead of a hydrogen atom on a nitrogen atom of a mono C-6 alkylamino group, Specific examples include a (methoxycarbonyl) methylamino group, a (ethoxycarbonyl) methylamino group, and a (n-propyloxycarbonyl) methylamino group.
- Ji 6 alkylcarboxy El group is a group in which the C ⁇ 6 alkyl group to a carbonyl group bound, specifically Asechiru group, a propionyl group, Puchiriru group, Isopuchi Lil group, Pareriru group, isovaleryl group, pivaloyl group And the like.
- the “rc ⁇ ealkylcarbonyloxy group” is a group in which an —6 alkylcarbonyl group is bonded to an oxygen atom, and specifically, an acetooxy group, a propionyloxy group, a valeryloxy group, an isovaleryloxy group, a bivaloyloxy group C "0 ⁇ 6 alkylcarbonylamino" is one of the hydrogen atoms of the amino group
- 6 is a group substituted with an alkylcarbonyl group, and specific examples include an acetamido group, a propioylamino group, an isobutyrylamino group, a palerylamino group, an isovalerylamino group, and a vivaloylamino group.
- (C i-6 alkyl-carbonyl) alkylamino group is mono C 6 ⁇ Hydrogen atoms on the nitrogen atom of Rukiruamino group is a group substituted with C _ 6 alkylcarbonyl group, (methylcarbonyl) Mechiruamino group, (E chill carbonyl) methylcarbamoyl Ruamino group, etc. (n- propyl carbonyl) Mechiruamino group No.
- a “mono-6 alkyl rubamoyl group” is a group in which one of the hydrogen atoms of a rubamoyl group has been replaced with an alkyl group, specifically, a methylcarbamoyl group, an ethylcarbamoyl group, an n-propyl Isopropyl rubamoyl, n-butynolecanolebamoinole, sec-butylcarbamoinole, tert-butylcarbamoyl and the like.
- a “diC i -e alkyl carbamoyl group” is a group in which two hydrogen atoms of a carbamoyl group are substituted with an alkyl group, and specifically, a dimethylcarbamoyl group, a dimethylcarbamoyl group, and a methylmethylcarbamoyl group. And a di (n-propyl) carnomoyl group, a methylpropyl group and a diisopropyl group.
- “Mono C — 6 alkyl rubamoylamino group” is a group in which one of the hydrogen atoms of the amino group is substituted with an alkyl rubamoylamino group, specifically, methylcarbamoylamino, ethylcarbamoylamino, n-propyl Carbamoylamino, isopropylcarbamoylamino, ⁇ -butylcarbamoylamino, sec-butylcarbamoylamino, tert-butylcarbamoylamino, and the like.
- Di C 6 alkyl force Rubamoiruamino group one of the hydrogen atoms of the Amino group but a group substituted with di-ci _ 6 alkyl force Rubamoiru group include dimethyl Cal Bamoiruamino group, Jefferies Chi carbamoyl ⁇ amino group, Di- (n-propyl) -functional vamoylamino group, diisopropyl-functional valmoylamino group, di (n-butyl) carbamoylamino group, di (sec-butyl) -functional valmomoylamino group, di (tert-butynole) carbamoylamino group, etc. No.
- “Mono-dialkyl alkyl group 6- alkyl) amino group” means mono C
- a hydrogen atom on the nitrogen atom of the “6 alkylamino group” is a group in which a monoalkylcarbamoyl group has been substituted, specifically, a monomethylcarbamoyl (methyl) amino group and a monoethylcarbamoyl (methyl) amino group.
- Di C - 6 alkyl force Rubamoiru alkyl) amino group include mono C - 6 hydrogen atoms on the nitrogen atom of Arukiruamino group "is a group obtained by substituting a di C i _ 6 alkyl force Rubamoiru group, specifically Examples include a dimethylcarbamoyl (methyl) amino group, a getylcarbamoyl (methyl) amino group, and a di (n-propyl) dirubamoyl (methyl) amino group.
- a “monoalkyl rubamoyloxy group” is a group in which a C- 6 alkyl rubamoyl group is bonded to an oxygen atom. Specific examples include a methylcarbamoyloxy group, an ethylcarbamoyloxy group, an n-propyl rubamoyloxy group, and isopropylamine. Examples include a rucarbamoyloxy group, an n-butynole group, a rubamoyloxy group, a sec-butylinole group, and a tert-butyl carbamoyloxy group.
- Di one 6 alkyl force Rubamoiruokishi group is a group in which oxygen atom, varies alkyl force Rubamoiru groups bonded, specifically dimethylcarbamoyl O alkoxy group.
- C alkylsulfonyl group is a group in which a C 6 alkyl group is bonded to a sulfonyl group. Specifically, a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an isopropylsulfonyl group, an n-butyl Examples thereof include a sulfonyl group, a sec-butylsulfonyl group, and a tert-butylsulfonyl group.
- r C ⁇ e alkylsulfonyl ⁇ amino group "is one is 6 alkylsulfonyl group and substituted groups of the hydrogen atoms of the Amino group include methylsulfonyl amino group, E chill sulfonyl ⁇ amino group, n- Examples include a propylsulfonylamino group, an isopropylsulfonylamino group, an n-butylsulfonylamino group, a sec-butylsulfonylamino group, and a tert-butylsulfonylamino group.
- Ji ⁇ alkylsulfonyl (C - 6 alkyl) amino group is a group in which a hydrogen atom on the nitrogen atom of the "C i one 6 Al Kiruamino group” is substituted with C 6 alkylsulfonyl group, specifically Methylsulfonyl (methyl) amino group, ethylsulfonyl (methyl) amino group, (n-propyl) sulfonyl (methyl) amino group, etc. I can get lost.
- a “monoalkylsulfamoyl group” is a group in which an alkyl group is bonded to a sulfamoyl group, and specifically, a monomethylsulfamoyl group, a monoethynolesnorefamoyl group, a mono (n-propynole) snorefamoy And a mono (n-butyl) sulfamoyl group, a mono (sec-butinole) sulfamoyl group, a mono (tert-butyl) sulfamoyl group, and the like.
- dialkylsulfamoyl group is a group in which a dialkyl group is bonded to a sulfamoyl group, and specifically, a dimethylsulfamoyl group, a getyls-norefamoyl group, a di (n-propynole) sulfamoinole group, a diisopropino group Resinole famoyl group, di (n-butyl) sulfamoyl group, di (sec-butyl) sulfamoyl group, di (tert-butynole) sulfamoinole group and the like.
- (Mono- 6- alkylsulfamoyl) amino group is a group in which one of the hydrogen atoms of the amino group is substituted with a mono-Ci- 6- alkylsulfamoyl group, specifically (monomethylsulfamoyl) Amino group, (monoethylsulfamoyl) amino group, [mono (n-propyl) sulfamoyl] amino group, (monoisopropylsulfamoyl) amino group, [mono (n-butyl) sulfamoyl] amino group,
- (DiC- 6 alkylsulfamoyl) amino group is a group in which one of the hydrogen atoms of an amino group is substituted with a dialkylsulfamoyl group.
- Rufamoyl) amino group examples include an amino group, [di (n-propyl) sulfamoyl] amino group, (methylpropylsulfamoyl) amino group, and (diisopropylsulfamoyl) amino group.
- “Mono - 6 alkylsulfamoyl - 6 alkyl) amino group” is a group in which a hydrogen atom on the nitrogen atom is substituted with mono-alkylsulfamoyl Famoiru group "mono ⁇ ⁇ 6 Arukiruamino group", specifically, Monomethylsulfamoyl (methylol) amino group, monoethylsulfamoyl (methyl) amino group, mono (n-propyl) sulfamoyl (methyl) amino group and the like.
- the “di-6 alkylsulfamoyl (C- 6 alkyl) amino group” is a group in which a hydrogen atom on the nitrogen atom of the “mono-6 alkylamino group” is substituted with a di- 6 alkylsulfamoyl group.
- Specific examples include a dimethylsulfamoyl (methyl) amino group, a getylsulfamoyl (methyl) amino group, and a di (n-propyl) sulfamoyl (methyl) amino group.
- Examples of the "3- to 8-membered heterocycloalkyl group” include azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrobilanyl group, morpholinyl group, and 1-thiazole 4-azocyclocyclo group.
- the “pharmaceutically acceptable salt” of the imidazopyridine compound represented by the formula [I] means a pharmaceutically acceptable conventional salt, and includes an acid addition salt at an amino group or an acid at a nitrogen-containing heterocycle. Examples thereof include addition salts and base addition salts in the carboxyl group having a carboxyl group.
- Examples of the acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate, maleate, fumarate, tartrate, citrate, ascorbate, and trifluoro.
- Organic acid salts such as acetate, methanesulfonate, isethionate, benzenesulfonate, and sulfonates such as p-toluenesulfonate are exemplified.
- the base addition salt examples include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, and ethanol.
- alkali metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as calcium salt and magnesium salt
- ammonium salt trimethylamine salt
- triethylamine salt triethylamine salt
- dicyclohexylamine salt examples of the base addition salt
- examples thereof include amine salts, diethanolamine salts, triethanolamine salts, procaine salts, and organic amine salts such as N, N, and dibenzylethylenediamine salts.
- R 1 and R 2 are each independently
- R 1 and R 2 together form a 5- to 8-membered carbocycle optionally substituted with R 6 together with the carbon atom to which they are attached.
- the R 5, a halogen atom, Shiano group, a hydroxyl group, an amino group, optionally fluorine atom or a hydroxyl group in the optionally substituted CI_ 6 alkyl group, mono-6 ⁇ alkylamino group, di-alkylamino group, optionally fluorine atom 6 alkyloxy, C 6 alkyloxy C 6 alkyl, C i-e alkyloxycarbonylamino, C 6 alkyloxycarbonyl
- R 5 is preferably a hydroxyl group, a cyano group, a dimethylamino group, a fluorine atom, a methoxy group, a methoxycarbonyl group, an ethoxycarbonyl group, or the like.
- R 6 represents R 5 or an oxo group, preferably a hydroxyl group, a fluorine atom, a methyl group, a methoxy group, a methoxycarbonyl group, an ethoxycarbonyl group, an oxo group, or the like.
- R 1 and R 2 a 3-8 membered heterocycloalkyl-C.
- a 3-8 membered heterocycloalkyl-C Preferably as your Keru heterocycloalkyl moiety _ 4 alkyl, Tetorahi Dorofuraniru, Tet Rahidorobiraniru, preferably morpholinyl, as c R 1 to pyrrolidinyl or piperidinyl is exemplified, C - 6 alkyl group, C 3 - 8 cycloalkyl one C .
- R 1 is more preferably a methyl group, an ethyl group, an n-propyl group, Pill, n-butyl, t-butyl, hydroxymethyl, 1-hydroxyl, 1-methyl-1-hydroxyethyl, cyclopropyl, N-methylacetaminomethyl, 2-ethoxycarbo -Ru 2-propyl group, 1H-pyridin-12-onylmethyl group, pyrrolidone-12-onylmethyl group, N-methyl-1-methylsulfonylaminomethyl group, morpholine-4-ylmethyl group, tetrahydrofuran-13- Yl, tetrahydrofuran-1-yl, 2-methylcyclopropyl, 1-methylcyclopropyl, 3-methoxycyclobutyl, 3-hydroxycyclobutyl, 3-oxocyclobutyl, Methoxymethyl group.
- Pyrrolidine-1-ylmethyl group pyrrolidine-1-ylpropyl group, dimethylaminomethyl group, 3-morpholine 4-ylpropyl group, 3-hydroxypropyl group, 3-hydroxypropene 1-1-yl group, 3-hydroxy-3-methylpropyl group, 3- (3-fluoropyrrolidine-1-1) Propyl group, 3- (3: 3-difluoropyrrolidine-1-yl) propyl group, 3- (1H-pyrazole-11-yl) propyl group, (2-pyrrolidine-1-1-ylethoxy) methyl group Butyl group, 3-methoxycyclobutyl group, 3-hydroxy-13-methylcyclobutyl group, and the like, and more preferably, methynole group, ethyl group, isopropyline group, t-butyl group, hydroxymethyl group, Methyl 1-hydroxyethyl group, cyclopropyl group.
- R 2 a hydrogen atom, an alkyl group, C 3 _ 6 cycloalkyl group, 3-8 membered the heterocycloalkyl one C. — 4 alkyl group is exemplified, wherein any hydrogen atom of the alkyl moiety may be optionally substituted by R 5 , and any hydrogen atom of the cycloalkyl moiety or the heterocycloalkyl moiety is It may be optionally substituted by R 6 .
- Examples of the carbocycle when R 1 and R 2 are taken together to form a 5- to 8-membered carbocycle together with the carbon atom to which they are bonded are as follows.
- R 6 which may be bonded to these carbocycles, a halogen atom (particularly a fluorine atom), a hydroxyl group, a d_ 6 alkyl group or a C 6 alkyloxy group is preferably exemplified.
- R 3 examples include a hydrogen atom, a halogen atom, an alkyl group, and a Ci-6 alkyloxy group.
- R 4 represents a hydrogen atom or an alkyl group, and specific examples thereof include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group. Etc. are recommended.
- any hydrogen atom in the alkylene moiety of each of the substituted leathers from a) to i) may be optionally substituted with R 5 ,
- n and n are each independently an integer from 0 to: L 0, and 0 m + n ⁇
- y 1 represents 0, 1 or 2
- y 2 represents 0 or 1.
- R 5 which may be substituted with alkylene in W include a methyl group, an ethyl group, a hydroxyl group, a fluorine atom, a cyclohexyl group, a _butoxycarbonyl group, and the like.
- a fluorine atom, a methyl group, etc. are recommended.
- C) includes one CH 2 —one, -CH (CH 3 ) one, one 0_CH 2 —, -O—, one CH 2 _0—CH 2 _,-(CH 2 ) 2 — O— Etc. are exemplified,
- d) includes: O—CH 2 —0—, -0- (CH 2 ) 2—0—, -0- (CH 2 ) 3 —O—, -0- (CH 2 ) 4 — 0— Is exemplified,
- Examples of g) include one CH 2 —C (O) —NH— and one C (O) _NH—, and examples of h) include one CH 2 —NH_C (O) one, -NH-C (O ) Is exemplified, and i) is exemplified by 1 CH 2 —NH—.
- Ar is a divalent substituent
- an aromatic 3-8 membered to may be 1 or bicyclic substituted with R 5 or an aliphatic heterocyclic group, or,
- b) optionally represents an aromatic or aliphatic carbocyclic group having 3 to 8 membered are optionally may one or bicyclic be substituted with R 5.
- a ri is a group obtained by removing two hydrogen atoms from a monocyclic or bicyclic 3- to 8-membered aromatic or aliphatic heterocyclic ring, or a mono- or bicyclic 3- to 8-membered aromatic group. Or a group in which two hydrogen atoms have been removed from an aliphatic carbon ring.
- Examples of the aromatic or aliphatic heterocycle in a) include aziridine, oxaziridine, 2H-azirine, diaziridine, azetidine, furan, isoxazole, oxazole, isothiazole, thiazole, 1H-imidazole, 1H- [12, 4] Triazole, 2H— [1,2,3] triazole, 1H—pyrazole 1H—pyrrole, [1,3,4] thiadiazole, [1,2,4] thiadiazol, [1,3,4] oxadiazole , [1,2,4] oxadiazole, 2H-tetrazole, thiophene, pyridine, pyrimidine, pyrazine, pyridazine [1,2,4] triazine, [1,2,4,5] tetrazine, 2H—1,4— Oxazine, 1,2-dihydropyridine, 1,6-dihydropyrida
- Examples of the aromatic or aliphatic carbocycle in b) include cyclopropane, cyclobutane, cyclopentane, cyclohexane, hexaheptane And benzene, indene, naphthalene and the like.
- R 5 be A r is substituted, a halogen atom, a hydroxyl group, an amino group, Okiso group, triflate Ruo Russia methyl, human Dorokishi alkyl group, Ji 6 alkyl group, C ⁇ 6 Arukiruokishi, C ⁇ Examples thereof include a 6- alkyloxy Ci- 6 alkyl group.
- Ar is preferably a furan-2,4-diyl group, a thiophene-1,4-diyl group, an isoxazole-3,5-diyl group, an oxazole-2,4-diyl group, an oxazole-1,2,5-diyl group, Thiazole_3,5-diyl group, thiazole-2,4-diyl group, thiazole_2,51-diyl group, 2H— [1,2,3] triazole-12,5-diyl group, 1H-pyrazole-1, 4 _diyl group, 1H-pyrazole-1,3 _diyl group, 1H-pyrrole-1,3-diyl group, [1,2,4] thiadiazole-3,5-diyl group, [1,2,4] triazi 1,3,6-diyl group, benzoxazole-1,2,6-diyl group, benzofuran
- Ar 2 represents a 5- to 6-membered aromatic carbocyclic group optionally having a substituent or a 5- to 6-membered aromatic heterocyclic group optionally having a substituent .
- Examples of the optional substituent to which Ar 2 may bind include a halogen atom such as a chlorine atom and a fluorine atom; a C 6 alkyl group such as a methyl group, an ethyl group, an n-propyl group and an isopropyl group; group, Jifuruoromechiru group, d_ 6 alkyl group substituted with a fluorine atom such as Torifuruoromechi Le group; main butoxy group, an ethoxy group, d_ 6 Arukiruokishi groups such as isopropyl O alkoxy group;.
- a halogen atom such as a chlorine atom and a fluorine atom
- a C 6 alkyl group such as a methyl group, an ethyl group, an n-propyl group and an isopropyl group
- Jifuruorome butoxy group Torifuruorome butoxy fluoride such groups Alkoxy substituted with atoms Group; methylsulfonyl group, Echirusuruhoniru group; cyclopropyl group, Shikuropuchi Le group, c 3, such as cyclopentyl group - 6 cycloalkyl group; cyclopropyl O alkoxy group, c 3 _ 6 cycloalkyl, such as cyclobutyl O alkoxy group Substituted with a hydroxyl group such as a hydroxymethyl group, a 2-hydroxylethyl group, a 1-hydroxyl-l-methylethyl group, etc.
- a hydroxyl group such as a hydroxymethyl group, a 2-hydroxylethyl group, a 1-hydroxyl-l-methylethyl group, etc.
- a 6-alkyl group such as a dimethylamino group and a getylamino group
- methylsulfinyl Group methylsulfanyl group, nitrile group, etc., and among them, a chloro group, a fluoro group, a promo group, a methinole group, an ethynole group, an isopropyl group, a 1-hydroxyl-1-methylethyl group, a difluoromethyl group, a trifluoromethyl group
- Ziff Ruorome butoxy group Torifuruorome butoxy group, cyclopropyl group, Shikuropuropi Noreokishi group, methylsulfonyl group, methylsulfinyl group, Mechirusurufa two Honoré group, Echirusuruhoniru group, nitrile group,
- Ar 2 include a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-phenylenoyl group, a 4-chlorophenyl group, a 3-phenylphenyl group, 2-chlorophenyl, 3,4-difluorophenyl, 3,4-dichloropheninole, 2,4-difluorophenyl, 2-triphenylenomethylphenyl, 3-trifluoromethylphenyl Enyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-methylsulfonylphenyl, 4-methylsulfenylphenyl, 4-methylthiophenyl, 3-fluoro-4-methyl Toxylphenyl, 4-hydroxyphenyl, pyridine_2-yl, pyridin-3-yl, 4-cyclopropylpyridine-12-yl, 5-cyclopropylpyridine_2-yl , 6—
- Ar 2 is preferably a pyrroyl-1-yl group, a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, or a 3,4-diphnole group.
- the compound represented by the formula [I] can be produced, for example, by appropriately combining the methods described in the following production methods 1 to 3.
- halogen atom such as a chlorine atom, a bromine atom, an iodine atom, etc .
- an aryloneresolenonyloxy group such as a p-toluenesnolephonyloxy group, a benzenesolenohonyloxy group, methyl
- sulfo Nino Les oxy group a leaving group Torifunoreo port methane Sno Reho sulfonyl O carboxymethyl like alkanesulfonyl O alkoxy group, R 1P, R 2P, RR 2, R 3, R 4, Ar 1P, Ar have W, 1: 21 ) And 1 " 2 are the same as above.
- Step 1-1 a step of amidating the compound represented by the formula [II] and the compound represented by the formula [III] in a solvent to obtain a compound represented by the formula [], 2: optionally condensing the compound represented by the formula [1 '] with the compound represented by the formula [IV], and
- Step 13 The step of deprotecting the protective group, if necessary, if necessary.
- Step 11-1 The amidation condensation reaction is carried out using a conventionally known amino acid used in the peptide synthesis method.
- a conventionally known amino acid used in the peptide synthesis method for example, “Basics and experiments of peptide synthesis” (Nobuo Izumiya, Maruzen Co.,
- This reaction is usually carried out in an inert solvent, for example, halogenated hydrocarbons such as methylene chloride, chloroform, and the like; getyl ether, tetrahydrofuran (hereinafter, referred to as “THFJ”), 1,4-dioxane (hereinafter, referred to as “THFJ”). And dioxane); acetonitrile, dimethylformamide (hereinafter, referred to as “DMF”), dimethylsulfoxide (hereinafter, referred to as “DMS ⁇ ”), pyridine and the like, and a mixed solvent thereof. .
- an inert solvent for example, halogenated hydrocarbons such as methylene chloride, chloroform, and the like
- dioxane ace
- the amidation reaction is preferably carried out in the presence of a condensing agent.
- a condensing agent examples include N, N, 1-hexylhexylcarbodiimide, and 2-chloro-1,3-dimethyl-1-2.
- the amount of the condensing agent to be used is usually from 1 mol to an excess mol per 1 mol of the compound represented by the formula [II], and preferably 1 mol to 1.5 mol is recommended.
- the reaction temperature is usually from 50 ° C to 100 ° C, preferably from -20 ° C to 50 ° C.
- the reaction time is usually 30 minutes to 7 days, preferably 1 hour to 24 hours.
- the compound represented by the formula [I] is also reacted. It can also be manufactured.
- a reactive derivative of the carboxylic acid represented by the formula [II] for example, an acid halide, a mixed acid anhydride, an active ester, an active amide and the like are used. These reactive derivatives are described in the “Peptide Synthesis Fundamentals and Experiments” (Nobuo Izumiya et al., Maruzen Co., Ltd.,
- the acid halide of the compound represented by the formula [II] can be obtained by reacting the compound represented by the formula [II] with a halogenating agent according to a conventionally known method.
- a halogenating agent include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, and phosgene.
- the mixed acid anhydride of the compound represented by the formula [II] can be prepared by a conventionally known method, for example, in the presence of an amine such as triethylamine in the presence of the compound represented by the formula [II] and ethyl ethyl carbonate, Can be obtained by reacting with an alkyl carbonate such as isobutyl carbonate or the like; an aliphatic carboxylic acid chloride such as piperoyl chloride ( an active ester of the compound represented by the formula [II] is The compound represented by the formula [II] is converted into a condensing agent according to a conventionally known method, for example, N, N'-dicyclohexylcarbodiimide, 11- (3-dimethylaminopropyl) -31-ethylcarbodiimide, etc.
- N-hydroxy compounds such as N-hydroxysuccinimide, N-hydroxyphthalimid, 1-hydroxybenzotriazole (hereinafter referred to as “HOB t”) in the presence of 4-nitrophenol , 2, 4-di-nitrophenol, 2, 4, 5-trichloro port Fuenonore, can be obtained by reacting a phenol compound such as pentachlorophenol Hue no Honoré.
- the active amide of the compound represented by the formula [II] can be obtained by subjecting the compound represented by the formula [II] to, for example, one equivalent of 1,1,1-carbonyldiimidazole or 1,1′-monomer according to a conventionally known method. It can be obtained by reacting with carbonylbis (2-methylimidazole) and the like.
- the amount of the reactive derivative of the compound represented by the formula [II] is typically 0.5 mol to an excess mol per 1 mol of the compound represented by the formula [III], and preferably 1 mol. Molar to 1.5 mole is recommended.
- the amidation reaction proceeds in the absence of a base, but is preferably performed in the presence of a base group in order to promote the reaction smoothly. It is preferred to work in the presence of a group.
- organic bases such as triethylamine, diisopropylethylamine, pyridine, etc.
- Inorganic bases such as sodium hydrogencarbonate and the like can be used.
- the amount of the base to be used is, for example, 1 mol to excess mol per 1 mol of the compound represented by the formula [III], preferably 1 mol to 4 mol, and when the base is a liquid.
- the base may be used as both a solvent and a base.
- a basic catalyst such as dimethylaminopyridine can be used as a catalyst for promoting the reaction.
- the amount of the catalyst to be used is, for example, 0.1 mol to 5 mol, preferably 0.1 mol to 0.5 mol, per 1 mol of the reactive derivative.
- the reaction temperature is typically in the range of 150 ° C to 100 ° C, preferably in the range of 120 ° C to 50 ° C.
- reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 24 hours.
- Step 1-2 When R 4 is other than a hydrogen atom, the compound represented by the formula [1 ′] is reacted with the compound represented by the formula [IV] in a solvent in the presence of a base to obtain a compound represented by the formula [IV]: It can be a compound represented by [IP]. Specifically, after stirring the compound represented by the formula [1 '] and a base in a solvent under ice-cooling for about 10 to 60 minutes, the compound represented by the formula [IV] is added to the obtained reaction solution. The reaction may be performed for 1 to 20 hours.
- solvent examples include ethers such as getyl ether, THF, and dioxane; DMF, DMSO, and the like.
- Examples of the base include sodium hydride, potassium hydride and the like, and examples of the compound represented by the formula [IV] include methyl iodide, methyl iodide, methyl p-toluenesulfonate and the like.
- Step 1_3 When the compound represented by the formula [IP] has a protecting group, the compound represented by the formula [I] can be obtained by removing the protecting group.
- the deprotection method includes the type of protecting group and the stability of the compound represented by the formula [IP].
- the method described in the literature [Protective Group's Organic Synthesis (Trot Greene), TW Green (TW Greene), John Wiley & Sons (1981)] or a method analogous thereto, for example, solvolysis using an acid or a base, that is, for example, from 0.01 mol to a large excess of an acid, preferably trifluoroacetic acid, formic acid,
- a method of reacting hydrochloric acid or the like, or an equimolar to large excess of a base preferably potassium hydroxide, calcium hydroxide, or the like; chemical reduction using a metal hydride complex or a palladium-one carbon catalyst, a Raney nickel catalyst It is carried out by catalytic reduction or the like using, for example.
- the compound represented by the formula [III] can be prepared by the method described in Production Method 2 using commercially available reagents.
- Production method 2 is a method for producing the compound represented by the formula [III]. Reaction formula
- T s represents a p-toluenesulfonyl group
- X R 1P , R 2P and R 3 are the same as above.
- Solvents include, for example, benzene, toluene, acetone, ethyl acetate; ethers such as dioxane, THF, and getyl ether; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride. And the like.
- the base include inorganic bases such as sodium carbonate, sodium hydrogencarbonate and calcium carbonate; and organic bases such as pyridine and triethylamine.
- the amount of p-toluenesulfonyl chloride used is, for example, 0.9 to 1.5 mol, preferably 1 to 1.2 mol, and preferably 1 to 1.2 mol, based on 1 mol of the compound II.
- the amount to be used is, for example, 1 to an excess mol per 1 mol of the compound II, and preferably 1 to 5 mol is recommended.
- Examples of the solvent include THF, DMF, ethanol, DMSO and the like.
- Examples of the base include an inorganic base such as sodium hydride; and an organic base such as diisopropylpropylethylamine and triethylamine.
- the amount of the compound A to be used is, for example, 1 mol to 10 mol per 1 mol of the compound, and preferably 1 mol to 5 mol is recommended.
- the amount of the base used is, for example, 1 mol to 1 mol of the compound ⁇ J, preferably 1 mol to 5 mol, preferably 1 mol to 5 mol.
- solvent examples include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride.
- Examples of the acid anhydride include acetic anhydride, trifluoroacetic anhydride and the like.
- the amount of the acid anhydride to be used is, for example, 1 mol to excess mol per 1 mol of compound A, and preferably 1 mol to 5 mol is recommended.
- the nitro group of the compound is reduced to obtain a compound represented by the formula [III].
- the reduction method for example, the method described in WO 02/40019 can be used.
- Compound I or Compound A can be a commercially available reagent, or can be prepared by the method described in Production Examples.
- Production method 3 is a method for producing the compound represented by the formula [II]. According to the following method, various types of compounds can be prepared.
- compound and compound: L are condensed in a solvent in the presence of a base to obtain compound A.
- the reaction solvent include acetone, methanol, ethanol, benzene, toluene, 1,2-dichloroethane, THF, DMF and a mixed solvent thereof with water.
- the base examples include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, silver carbonate, potassium fluoride, and sodium hydroxide; and organic bases such as disopropylethylamine, sodium methoxide, and sodium methoxide. Bases are exemplified.
- a reaction accelerator such as sodium iodide, potassium iodide, 18-chloro-6, tetraethylammonium iodide and tetrabutylammonium iodide may be added. .
- the amount of compound (1) used is, for example, 1 mol to excess mol per mol of compound, and preferably 1 mol to 1.5 mol is recommended.
- the amount of the reaction accelerator used is, for example, 0.1 mol to 0.5 mol per 1 mol of the compound.
- the reaction temperature is, for example, from room temperature to 150 ° C, preferably from room temperature to 100 ° C.
- compound 8 has an ester group (COOR 9 ) or a cyano group
- This compound can be hydrolyzed by a conventionally known method to give a compound.
- a commercially available reagent can be used for the compound.
- a commercially available reagent can be used for the compound ⁇ , and the method described in Production Examples can be used. Can be prepared.
- R represents a lower alkyl group having 1 to 4 carbon atoms
- nl and ml are the same or different and represent an integer of 1 to 3
- 81: and 211 are the same as described above. It is. ]
- an organic phosphorus compound such as dialkylazodicarboxylate and triarylphosphine or trialkylphosphine in a reaction solvent.
- compound 12 (12a or 12b) Subsequently, compound (13a or 13b) can be obtained by hydrolyzing the ester portion of compound 12 with carohydrate.
- Dialkyl azodicarboxylates include dimethyl azodicarboxylate Tert-butyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipyridine, and the like.
- triarylphosphine include trif.
- Examples include enylphosphine and tritolylphosphine, and examples of trialkylphosphine include triethylphosphine, tributylphosphine, and trioctylphosphine. Among them, a combination of diisopropyl azodicarboxylate and triphenylphosphine, or a combination of 1,1 '-(azodicarbonyl) dipiperidide and triptylphosphine is recommended.
- the amount of the compound 11 to be used is, for example, 1 mol to 3 mol, preferably 1 mol to 1.5 mol, per 1 mol of the compound 10.
- Examples of the amount of the organic phosphorus compound such as dialkylazodicarboxylate and triarylphosphine or trialkylphosphine used include 1 mol to 3 mol of dialkylazodicarboxylate per 1 mol of compound 10. Preferably, 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 10, and preferably 1 mol to 1.5 mol is recommended. .
- reaction solvent Shioi ⁇ methylene, chloride port Holm, Jikuroroetan, carbon tetrahalide such charcoal chloride arsenide; n - heptane, aliphatic hydrocarbons cyclohexane and the like n-; benzene, toluene, and xylene Aromatic hydrocarbons; ethers such as getyl ether, THF, dioxane, and ethylene glycol dimethyl ether; esters such as methyl acetate and ethyl acetate; and solvents such as DMF and DMSO.
- the reaction temperature is, for example, 0 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., and the reaction is usually completed in 2 hours to 2.4 hours.
- Compound 13a or compound 13b can be obtained by hydrolyzing the obtained compound 12a or compound 12b by a conventionally known method using a sodium hydroxide solution or the like.
- compound 10a for compound 10a, compound 10b, compound 11a and compound 11b, commercially available reagents can be used, and they can be prepared by the method described in Production Examples. It is.
- x 2 represents a halogen atom or a trifluoromethanesulfonyloxy group, and R, Ar 1P , and! ! ! Is the same as above.
- Compound 14 and compound 15 are condensed in a solvent in the presence of a palladium catalyst and a base catalyst to obtain compound 16 (Heck reaction: Ziegler, CB, Heck, RF, J. Org. Chem. , 43, 2941 (1 978).
- the solvent include DMF, p-xylene, toluene, acetonitrile, N-methyl 2-pyridone, dioxane, N, N-dimethylacetamide and the like.
- palladium acetate in some cases, it can be used with a ligand such as triphenylphosphine, tri-10-trinolephosphine, tri'-n-butylphosphine, tricyclohexylphosphine, etc.), bis ( Dibenzylideneacetone) palladium (possibly with tri- and can be used with ligands such as 1-tolylphosphine), dichlorobis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) phene Mouth] paradigm and the like.
- a ligand such as triphenylphosphine, tri-10-trinolephosphine, tri'-n-butylphosphine, tricyclohexylphosphine, etc.
- bis Dibenzylideneacetone
- the base examples include inorganic bases such as sodium acetate, carbonated carbonate, sodium carbonate, calcium carbonate, sodium hydrogencarbonate, and cesium carbonate; and organic bases such as triethylamine and triptylamine.
- the amount of the palladium catalyst used is, for example, 0.01 equivalent to 0.5 equivalent relative to 1 equivalent of compound 14, and the amount of base used is 1 equivalent to 1 equivalent of compound 14. Five equivalents are illustrated.
- a ligand when used in combination with a palladium catalyst, 1 mol to 5 mol is exemplified for the palladium complex, and preferably 1 mol to 2 mol is recommended.
- the reaction temperature is, for example, room temperature to 130 ° C., preferably 80 ° C. to 130 ° C.
- the compound i ⁇ is hydrogenated and reduced in a solvent to obtain a compound i_L, and the ester site of the compound 17 is hydrolyzed to lead to a corresponding carboxylic acid.
- Hydrogenation is carried out for 1 to 5 hours at room temperature under a stream of hydrogen using palladium carbon, Raney nickel, iridium black or the like as a catalyst.
- the amount of the catalyst used is, for example, 5 to 200 parts by weight based on 100 parts by weight of the compound 16.
- Examples of the hydrogenation solvent include methanol, ethanol, tert-butanol, benzene, THF, and the like.
- Compounds 14 and 15 can be prepared using commercially available reagents or by the methods described in Examples.
- R ' represents a halogen atom, ⁇ Bok 6 alkyl group, an alkyl group that is substituted with a fluorine atom, Arukiruokishi groups, C WINCH 6 Arukiruokishi group substituted by fluorine atoms, methylsulfonyl group, Echirusuruhoniru groups, C 3 _ 6 consequent opening alkyl groups, C 3 _ 6 cycloalkyl O alkoxy groups, C substituted with a hydroxyl group 6 Represents an alkyl group, a dialkynoleamino group, a methylsulfinyl group, a methylsulfanyl group, a nitrile group or the like, and R and Arlp are the same as above. ]
- Compound ___ is obtained by condensing compound 18 and compound 19 in a solvent in the presence of an acid or base catalyst.
- Compound 20 can be converted to compound 21 by hydrolysis by a conventionally known method.
- solvent examples include acetic anhydride, benzoic anhydride, toluene, DMF, acetonitrile. Nitrobenzene, methanol, ethanol and the like.
- Examples of the acid include acetic acid, p-toluenesulfonic acid and the like
- examples of the base include sodium methoxide, sodium methoxide, sodium hydride, piperidine, sodium acetate, potassium acetate and the like.
- the amount of the acid used is, for example, 100 parts by weight to 100 parts by weight with respect to 100 parts by weight of the compound 18, and the amount of the base used is 100 parts by weight of the compound. For example, 10 parts by weight to 100 parts by weight with respect to 18.
- a catalyst is not particularly required.
- the reaction temperature is, for example, 100 ° C. to 250 ° C., preferably 160 ° C. to 250 ° C., and the reaction is usually completed in 4 hours to 24 hours.
- compound 21 can be converted to compound 22 by hydrogenating compound 21 as necessary.
- Hydrogenation is completed by carrying out the reaction in a solvent in the presence of a catalyst such as palladium carbon, platinum dioxide, Raney nickel, iridium black and the like under a stream of hydrogen for 1 hour to 5 hours.
- a catalyst such as palladium carbon, platinum dioxide, Raney nickel, iridium black and the like under a stream of hydrogen for 1 hour to 5 hours.
- the amount of the catalyst used is, for example, 5 to 200 parts by weight based on 100 parts by weight of the compound 21.
- Examples of the solvent for hydrogenation include methanol, ethanol, tert-butanol, benzene, THF, and the like.
- Compound 18 and compound 19 can be prepared by the methods described in Production Examples in addition to commercially available reagents.
- the corresponding compound 24a or 24b can be prepared, for example, by the following method.
- E t represents Echiru group, the P h, iota R and Alpha gamma, the same as above.
- the reaction of arylbenzylbumamide having a carboxyl group with triethyl phosphite in toluene Japanese Patent Application Laid-Open No. 11-60537) or with triphenyl phosphine in acetone (R. Broos, D. Tavernier, M. Anteunis, J. Chem. Educ., 55, 813 (1978)) You can get 24.
- Production method 3-6 is a production method when W in the formula (1) is one (CH 2 ) m —C ⁇ _NH— or one NH—CO— (CH 2 ) n —.
- Compound 29 (compound 29a or 29b) is obtained by amidating compound 27 (compound 27a or 27b) and 28 (compound 27a or 27b).
- Compound 30 (compound 30a or 30b) is obtained by hydrolyzing the ester group of the obtained compound.
- the amidation can be carried out according to Steps 11-1.
- Compound 27a, compound 27b, compound 28a and compound 28b can all be commercially available reagents, and can be prepared by the method described in Production Examples. Manufacturing method 3-7
- reaction solvent examples include acetonitrile, methanol, getyl ether, THF, DMSO, acetone and the like
- base examples include potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium hydride and the like.
- Preferred combinations of solvent and base include acetate nitrile Z carbonate, methanol sodium methoxide, DMSO or DMF / hydrogen sodium, and the like.
- the amount of compound 11b used is, for example, 1 equivalent to 2 equivalents to 1 equivalent of compound 31, and the amount of base used is 1 equivalent to 1 equivalent to 1 equivalent of compound.
- the reaction temperature is, for example, room temperature to 150 ° C., preferably 70 ° C. to 100 ° C., and the reaction is usually completed in 2 hours to 12 hours.
- potassium iodide may be added to the reaction system for the purpose of accelerating the reaction.
- the amount of use at this time is, for example, 0.01 equivalent to 0.5 equivalent relative to 1 equivalent of compound 31.
- Compound 32 is hydrolyzed by a known method to give compound 33. Can do.
- Compound 31 can be prepared by a commercially available reagent or by the method described in Examples.
- Protecting group for amino group includes benzyl group, p-methoxybenzyl group, 3,
- Aralkyl groups such as dimethoxybenzinole, o-nitrobenzinole, p-nitrobenzinole, benzylhydryl, and trityl; lower alkanols such as formyl, acetyl, propionyl, petyryl, and piperoyl Groups; benzoyl groups; arylalkanol groups such as phenylacetyl group and phenoxyacetyl group; lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group and tert-butoxycarbonyl group; benzyloxy Aralkyloxycarbonyl groups such as carbonyl group, p-nitrobenzoyloxycarbonyl group and phenethyloxycarbonyl group; lower alkylsilyl groups such as trimethylsilinole group and tert-butyldimethylsilyl group Acetyl group, bi Royle group,
- hydroxyl protecting group examples include lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group; lower alkyl silyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; A lower alkoxymethyl group such as a toxicoxymethyl group and a 2-methoxyethoxymethyl group; a tetrahydroviranyl group; for example, a trimethylsilylethoxymethyl group; a benzyl group, a p-methoxybenzyl group, a 2,3-dimethoxybenzyl group, and an o-2 Aralkyl groups such as trobenzyl group, p-nitrobenzyl group and trityl group; and acyl groups such as formyl group and acetyl group. Particularly, methyl group, methoxymethyl group, tetrahydroviranyl group, Tyl, trimethyls
- Examples of the “protecting group for carboxyl group” include lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group; lower haloalkyl groups such as 2,2,2-trichloroethyl group; A lower alkenyl group such as a propenyl group; an aralkyl group such as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group, and a trityl group; particularly, a methyl group, an ethyl group; Tert-butyl, 2-propenyl, benzyl, p-methoxybenzyl, benzylhydryl, etc. are recommended.
- Examples of the “protecting group for oxo group or carbonyl group” include acetals such as ethylene ketal, trimethylene ketal, and dimethyl ketal, and ketals.
- the method of removing the protecting group depends on the kind of the protecting group and the stability of the compound represented by the formula [I].
- the method described in the literature [Protective group-syn-organic.
- an acid or a base may be prepared according to a method described in Synthesis Global Organic Synthesis, TW Greene, by John Wiley & Sons (1981), or a method analogous thereto.
- the solvolysis used that is, for example, the reaction of 0.01 mol to a large excess of an acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid, or the like, or an equimolar to a large excess of a base, preferably, potassium hydroxide, calcium hydroxide, etc.
- Method Chemical reduction using a metal hydride complex or catalytic reduction using a palladium-carbon catalyst, Raney nickel catalyst or the like.
- the compound represented by the formula [I] obtained by the above method can be easily isolated and purified by a conventionally known separation means.
- separation means include solvent extraction, recrystallization, column chromatography, liquid chromatography, preparative thin-layer chromatography, and the like.
- the compound of the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of the substituents. It includes all stereoisomers, tautomers and mixtures thereof.
- a membrane preparation prepared from the cells expressing MCH-1R was used for the test compound and 5
- Atsushi buffer 50 mM Tris buffer containing 10 mM magnesium chloride, 2 mM ethylenediaminetetraacetic acid, 0.01% bacitracin and 0.2% ⁇ serum albumin
- OpM [ 125 I] MCH (NEN) 50 mM Tris buffer containing 10 mM magnesium chloride, 2 mM ethylenediaminetetraacetic acid, 0.01% bacitracin and 0.2% ⁇ serum albumin
- the 50% inhibitory concentration (IC 5 value) of the test compound for 125 I] MCH binding was determined.
- Table 7 shows the results. Table 7.
- the compound of the present invention strongly inhibited the binding of MCH-1R to MCH-1R and acted as an MCH-1R antagonist.
- the compound of the present invention has MCH-1R antagonistic activity, and is used for metabolic diseases such as obesity, diabetes, hormonal secretion, hyperlipidemia, gout, fatty liver, hepatitis, and cirrhosis.
- Cardiovascular diseases such as angina pectoris, acute and depressive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, and electrolyte abnormalities, such as bulimia, affective disorders, depression, anxiety, epilepsy, delirium, and dementia , Schizophrenia, attention deficit hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, paresthesia, olfactory disorder, morphine tolerance, drug dependence, alcohol dependence, etc.
- Diseases for example, reproductive diseases such as infertility, premature birth, and sexual dysfunction, as well as prophylactic or therapeutic agents for gastrointestinal diseases, respiratory diseases, cancer or skin pigmentation, especially for obesity Useful as
- the compound of the present invention can be administered orally or parenterally.
- Metabolic diseases such as hepatitis and cirrhosis, such as angina pectoris, acute and congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, and electrolyte disorders such as electrolyte abnormalities
- Patients for example bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, paresthesia, olfactory disorder, Central and peripheral nervous system diseases such as morphine tolerance, drug dependence, and alcoholism, such as reproductive diseases such as infertility, premature birth, and sexual dysfunction, etc., gastrointestinal diseases, respiratory diseases, cancer, skin pigmentation, etc. And especially as a prophylactic or therapeutic agent for obesity.
- a pharmaceutically acceptable carrier can be added thereto in accordance with the dosage form, and then administered after various formulations.
- various additives conventionally known in the pharmaceutical field can be used, for example, gelatin, milk bran, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, canoleboxoxy Methynoresenorelose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, calcium phosphate anhydrous, cunic acid, trisodium citrate, hydroxypropyl pill cellulose, sorbitol, sorbitan fatty acid ester, polysorbate, Sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light caffeic anhydride, talc, vegetable oil, benzyl anolecol, gum arabic, propylene glycol Lumpur, poly Anore
- Dosage forms formulated as a mixture of these carriers and the compounds of the present invention include, for example, solid preparations such as tablets, capsules, granules, powders or suppositories; or, for example, syrups, elixirs or injections And the like, and these can be prepared according to a conventionally known method in the field of pharmaceuticals.
- solid preparations such as tablets, capsules, granules, powders or suppositories; or, for example, syrups, elixirs or injections And the like, and these can be prepared according to a conventionally known method in the field of pharmaceuticals.
- liquid preparations they may be dissolved or suspended in water or other appropriate medium before use.
- it may be dissolved or suspended in a physiological saline solution or a glucose solution as needed, and a buffer or a preservative may be added.
- preparations may contain the compound of the present invention at a ratio of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the whole pharmaceutical composition, and may be pharmaceutically acceptable.
- the carrier may be contained in an amount of 0 to 99.0% by weight, preferably 40 to 99.0% by weight.
- preparations contain other therapeutically effective compounds, such as It may contain an agent for treating blood pressure, an agent for treating arteriosclerosis, and the like.
- the dose and frequency of administration are determined by the sex, age, weight, degree of symptoms and the type and range of the intended therapeutic effect of the patient.
- the dose is usually 0.001 to 5 O mg per day lg, and can be administered in single or multiple doses.
- the dosage is preferably from about 0.01 to about 25 mg / kg per day, more preferably from about 0.05 to about 10 mg / kg per day.
- the compound of the present invention is a drug effective for hypertension, hypertension related to obesity, hypertension-related disease, cardiac hypertrophy, left ventricular hypertrophy, metabolic disease, obesity, obesity-related disease (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. When the compound of the present invention is used contemporaneously with one or more concomitant drugs, it can be made into a pharmaceutical composition as a single dosage form. However, in combination therapy, the composition containing the compound of the present invention and the concomitant drug may be administered to the subject in different packages, simultaneously, separately or sequentially. They may be administered at staggered times.
- the dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration target, administration route, disease, combination and the like.
- 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.
- Such administration forms include, for example, 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and 2) separate preparation of the compound of the present invention and the concomitant drug. 3) Simultaneous administration of the two preparations obtained by the same route of administration, and 3) the time difference between the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug.
- concomitant drug used in the present invention examples include a "diabetic drug”, a “hyperlipidemic drug”, a “hypertensive drug”, an “antiobesity drug” and the like. Two or more of these concomitant drugs may be used in combination at an appropriate ratio.
- glidazones eg, glitazones
- glitazones eg, ciglitazone (ciglitazone), dalglitazone (darglitazone), engridazone (englitazone), isagridazone (isaglitazone) (MCC-555), etc.
- Glitazone pioglitazone
- rosiglitazone rosiglitazone
- troglitazone troglitazone
- PPAR gamma agonist 2) methonoremin (formin) ), Buformin, phenformin, and other biguanides; 3) protein-inlet oral synphosphatase-IB inhibitor; 4) acethexamine, chlorpropamide, diabinese, glibenclamide ), Glipizide, glyburide; glimepiride, dalikladi (Gliclazide), sulphonylurea such as dalipentide (glipentide), glyquidone (gliquidone), darisolamide (glisolamide), tolazamide, tolptamide; 5) repaglinide, nateglinide (nateglinide), etc.
- hypolipidemic agent examples include: 1) cholesterylamine, colesevelem, colestipol ⁇ colestipol, dialkylaminoalkyl derivative of cross-dextran, Colestid registered trademark, LoCholest registered trademark, Questran Bile acid absorption promoters such as registered trademarks; 2) atorvastatin (atorvastatin), itavastatin (itavastatin), fluvastatin (fluvastatin), oral vasstatin (lovastatin), pravastatin (pravastatin), rivastatin (rivastatin), rosastatin HMG-CoA reductase inhibitors such as rosuvastatin, simvastatin, ZD-4522; 3) HMG-CoA synthesis inhibitor; 4) snatol esters, Cholesterol absorption inhibitors such as sitosterol, sterol darcoside, ezetimibe, etc .; 5) avasimibe, Esluc
- CETP inhibitor 7) squalene synthesis inhibitor; 8) antioxidant such as probucol; 9) beclofibrate, benzafibrate, ciprofibrate, clofibrate, ethibrate, fenofibrate, gemcabene ), PPAR CK agonists such as gemfibrozil, GW-7647, BM-170744, LY-518674, fibric acid derivatives (for example, Atromid®, Lopid®, Tricor®, etc.); 10) GW-4064 FXR receptor antagonists, such as SR-103912; 11) LXR receptor agonists, such as GW3965, T9013137, XTC0-179628; 12) Lipo, such as niacin Rotein synthesis inhibitor; 13) renin one angiopathy O Tianjin System inhibitors; 14) microsomal triglyceride transport inhibitors; 15) bile acid reabsorption inhibitors such as BARA1453,
- hypotensive agent examples include: 1) Clothiardidone such as clothiazide, chlorothiazide, dichlorophenamide, hydrofluorothiazide, indapamide (indapamide), and hydroclothiazide; bumetanide Diuretics such as loop systems such as esacrynic acid, furosemide and torsemide; sodium systems such as amide mouth and triamterene; aldosterone antagonists such as spironolatane and epilenone; 2) acebutolol.
- Clothiardidone such as clothiazide, chlorothiazide, dichlorophenamide, hydrofluorothiazide, indapamide (indapamide), and hydroclothiazide
- bumetanide Diuretics such as loop systems such as esacrynic acid, furosemide and torsemide
- sodium systems such as amide mouth and triamterene
- betazolonore (betaxolol), benon tronore (bevantolol), bisoprolonore (bisoprolol), bopindolonore (bopindolol), power deoteoronore (carteolol), canolebejironore (carvediléro) esm olol), intenoronole, indenolol, metaprolol, nadolol, nebipolol, nebutolol, penbutolol, pindolonole, propanolol, sotalol, tarolol —Adrenaline blockers; 3) amlodipine, aranidipine, azelnidipine, barenidipine, benidipine, bepridini pine, bepridini pine, bepridinpine, bepridine , Diltia
- Angiotensin converting enzyme rat inhibitor (5) such as sigma purinole (perindropri), cannif, quanipril, spirapril, tenocapril, tendracapril, trandolapril, zofenopril, etc .; omapatrilat), cadoxatril.
- Neutral endopeptidase inhibitors such as ecadrill, fosidotril, sampatrilat, AVE7688 and ER4030; 6) Tezosentan (tezosentan), endothelin antagonists such as A308165, YM62899; 7) Vasodilators such as hydralazine, clonidine, minoxidil, nicotinyl alcohol, etc .; 8) Potassartan, eprosartan, irbesartan, mouth sultan, pratosartan, tasosartan, tenoret 5; Angiotensin II antagonists such as sanoretan (telmisartan), valsartan, EXP-3137, FI6828K, RNH6270; 9) ZJS adrenaline blockers such as dipradilol, arotinolol, and amosulalol;
- anti-obesity drug examples include: 1) 5HT (serotophen) such as paroxetine (paroxetine), fluoxetine (fluoxetine), fenfluramine (fenfluramine), fluvoxamine (fluvoxamine), senoletraline (sertraline), and imipramine.
- 5HT serotophen
- paroxetine praroxetine
- fluoxetine fluoxetine
- fenfluramine fenfluramine
- fluvoxamine fluvoxamine
- senoletraline senoletraline
- imipramine examples include: 1) 5HT (serotophen) such as paroxetine (paroxetine), fluoxetine (fluoxetine), fenfluramine (fenfluramine), fluvoxamine (fluvoxamine), senoletraline (sertraline), and imipramine.
- Transporter inhibitor 2) Norepinephrine transporter inhibitor such as GW320659, desipramine, talsuprara, nomifensin; 3) Rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo) BAY—65— 2520 (Bayer), SLV-319 (Sonorebee), Other USP5, 532, 237, USP4, 973, 587, USP5, 013, 837, USP5 '081, 122, USP5, 112, 820, USP5, 292, 736 , USP5, 624, 941, USP6, 028, 084, W096 / 33159, W098 / 33765, W098 / 43636, W098 / 43635, W001 / 09120 W001 / 96330, W098 / 31227, W098 / 41519, W098 / 37061, W000 / Compounds disclosed in 10967
- CNTF ciliary neu 17
- axokine (Regeneron)
- other CNTF derivatives such as compounds disclosed in W094 / 09134, W098 / 22128, and W099 / 43813; 18) NN703, hexarelin, MK-0677, SM -130686, CP-424, 391, L-692, 429, L-163, 255.USP6358951, US Patent Application No.
- acylestrogens such as the compounds disclosed in 35; darcocorticoid doantagonist; 36) BVT3498, BVT2733, others W001 / 90091, W001 / 90090, 11-hydroxysteride dehydrogenase type 1 inhibitors such as compounds disclosed in W001 / 90092; 37) stearyl co-A desaturase 1 inhibitor (stearoyl-CoA desaturase-1); 38) isoleucine thiazolidide, Linpyrrolidide (valine pyrrolidide), NVP- DPP728, AF237, P93 / 01, TSL225, TMC-2A / 2B / 2C, FE999011 P9310 / K364, VIP0177, SDZ274-444, others W003 / 004498, W003 / 004496, EP1258476, W002 / 08
- the combination drug can be obtained by using one or more of the compound of the present invention and the combination drug in combination.
- the combination drug is useful for preventing or treating a metabolic disease by combining it with one or more drugs selected from the group consisting of a drug for treating diabetes and a drug for treating hyperlipidemia.
- a combination containing a therapeutic agent for hypertension and an anti-obesity agent is useful for preventing or treating a synergistic reversible disease by adding a therapeutic agent for diabetes and / or a therapeutic agent for hyperlipidemia.
- the title compound (46 mg) was obtained by performing the same operation as in Production Example 1-2 except that the compound (110 mg) obtained in Production Example 4-2 and ethanol (4 mL) were used as a solvent.
- the title compound (2.2 g) was obtained using 2-amino-5-fluoropyridine (1.5 g) according to the method described in International Publication WOO 3Z05088.
- the title compound (1.2 g) was obtained in the same manner as in Production Example 2.1 using the compound (2.2 g) obtained in Production Example 5-1.
- the title compound (240 mg) was obtained by performing the same operation as in Production Example 1-2 using the compound (274 mg) obtained in Production Example 5-4.
- the title compound (142 mg) was obtained by performing the same operation as in Production Example 2-2 using the compound (238 mg) obtained in Production Example 6-1.
- the title compound (1.5 g) was obtained by performing the same operation as in Production Example 6-1 using 6-fluoropyridine_2-carboxylic acid (1.6 g).
- the title compound (1.1 g) was obtained by performing the same operation as in Production Example 2-2 using the compound (1.5 g) obtained in Production Example 7-1.
- the title compound (1.4 g) was obtained by performing the same operation as in Production Example 11-11 using the compound (806 mg) obtained in Production Example 7-3.
- the title compound (1.2 g) was obtained by performing the same operation as in Production Example 1-2 using the compound (1.3 g) obtained in Production Example 7-4.
- the title compound (625 mg) was obtained by performing the same operation as in Production Example 2-3 using the compound (500 mg) obtained in Production Example 8-1 and 2-hydroxymethylpyridine (27 Omg).
- the title compound (205 mg) was obtained by performing the same operation as in Production Example 1-2 using the compound (24 Omg) obtained in Production Example 8-2.
- the title compound (141 mg) was obtained by performing the same operation as in Production Example 1-2 using the compound (165 mg) obtained in Production Example T-1.
- the title compound (3.8 g) was obtained by performing the same operation as in Production Example 1-2 using the compound (4.4 g) obtained in Production Example 11-12.
- the title compound was obtained (75 mg) by performing the same reaction as in Production Example 1-2 except that the compound (85 mg) obtained in Production Example 13-1 and methanol as a solvent were used.
- the title compound was obtained by the same procedure as in Production Example 1-2 except that the compound (2.0 g) obtained in Production Example 16-1 and a mixed solvent of methanol and THF were used as the solvent.
- the compound (2.0 g) obtained in Production Example 16-1 and a mixed solvent of methanol and THF were used as the solvent.
- the title compound (94 Omg) was obtained in the same manner as in Production Example 1_2 except that the compound (1.0 g) obtained in Production Example 17-1 and a mixed solvent of methanol and THF were used as a solvent. Obtained.
- the title compound (11 Omg) was obtained by performing the same operation as in Production Example 1-2 using the compound (140 mg) obtained in Production Example 18-2.
- a 4 N aqueous solution of sodium hydroxide (1.OmL) was added to a mixed solution of the compound (400 mg) obtained in Production Example 191-2 in methanol (8. OmL) and tetrahydrofuran (4. lmL), and the mixture was stirred at room temperature for 2 days. After adjusting the pH of the mixed solution to about 3 using 6 N hydrochloric acid at 0 ° C, the mixed solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated under reduced pressure to obtain the title compound (362 mg).
- a THF solution (5 OmL) of diisopropylamine (12.6 mL) was cooled to 0 ° C, a solution of 2.6 M n-butyllithium in hexane (33 mL) was added, and the mixture was stirred at the same temperature for 10 minutes. Then, the mixture was cooled to ⁇ 78 ° C., and a THF solution (15 mL) of 4-monomethylbenzenecarboxylic acid (2.3 g) was added dropwise. After stirring the reaction solution at 140 ° C for 2.5 hours, a THF solution (4 mL) of methyl picolinate (2.0 g) was added dropwise. The reaction solution was warmed to room temperature and stirred for 24 hours.
- the title compound was obtained in the same manner as in Production Example 1-2 except that the compound (300 mg) obtained in Production Example 26-1 and a mixed solvent of methanol and THF (1: 1, 5 mL) were used as the solvent. (250 mg) was obtained.
- the compound (200.Omg) obtained in Production Example 27_1 was dissolved in methanol (0.5 mL) and acetone (0.5 mL), and a 4 N aqueous sodium hydroxide solution (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 5 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL). The aqueous layer was acidified (pH 3) with a 10% aqueous hydrochloric acid solution, and the resulting precipitate was collected by filtration and dried to give the title compound (135.6 mg) as a colorless solid.
- the title compound (284.Omg) was obtained in a light brown color by performing the same operation as in Production Example 28-1 to 28-4 using 2-chloro-3-ditropyridine (500.Omg). Obtained as a colored solid.
- the aqueous layer was acidified (pH 3) with a 10% aqueous hydrochloric acid solution, and the resulting precipitate was collected by filtration and dried to give the title compound (698.4 mg) as a colorless solid.
- the title compound (640 mg) was obtained by performing the same operation as in Production Example 28-1 using 4-hydroxybenzenecarboxylic acid ethyl ester (558 mg) and 2,5-dichloropyridazine (500 mg).
- the title compound (1.1 g) was obtained in the same manner as in Production Example 1-2 except that the compound obtained in Production Example 36-1 (1.28 g) and ethanol (2 OmL) were used as a solvent. Got.
- the title compound (3.6 g) was obtained by performing the same operation as in Production Example 1-2 using the compound (4.4 g) obtained in Production Example 37-1.
- the compound (7.61 g) obtained in Production Example 38-4 was dissolved in dichloroethane (75 mL), and trifluoroacetic anhydride (5.3 mL) was added dropwise under ice-cooling, followed by stirring at room temperature for 24 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate (15 OmL) to the reaction solution, the mixture was extracted three times with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, concentrated, and the obtained yellow solid was suspended in a mixed solvent of ethyl ethyl isopropyl ether acetate and filtered. The title compound (3.8 g) was obtained as a yellow solid.
- the compound (3.77 g) obtained in Production Example 38_5 was dissolved in methanol (4 OmL), 10% palladium on carbon (434 mg) was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere (1 atm). . After filtering the reaction solution, the filtrate was concentrated, and the residue was dissolved in ethyl acetate (10 OmL). A solution of 4 N hydrochloric acid in ethyl acetate (8 mL) was added, and the resulting brown precipitate was filtered off to give the title compound. (4.34 g) was obtained as a brown solid.
- a methanol solution (7 OmL) of the compound (7.lg) obtained in Production Example 39-3 was The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere in the presence of radium carbon (10%, 1.0 g). After filtering off the palladium carbon, a 4 N solution of ethyl acetate monohydrochloride (2 OmL) was added to the filtrate, which was then concentrated to obtain the title compound (7.79 g).
- the title compound was obtained by the same procedures as in Production Example 38-6 using the compound obtained in Production Example 40-3.
- the title compound was obtained by performing the same operation as in Production Example 38-6 using 2-cyclopropyl-1-methyl-6-nitroimidazo [1,2-a] pyridine synthesized according to JP-A-2003-207632. Was.
- Production Example 43 The title compound was obtained by performing the same operations as in Production Example 38-6 using the trans compound obtained in 3-8.
- a methanol solution of the compound obtained in Production Example 44 _ 3 (6. 80 g) (7 OmL), was added dropwise and at room temperature, bromine (3. OML) Oyutsukuri. After stirring for 1.5 hours, water (10 OmL) was added, and the mixture was stirred overnight. After the methanol was distilled off, the mixture was extracted with getyl ether, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. The organic layer was dried and concentrated. To the obtained residue were added THF (10 OmL), the compound (10.2 g) obtained in Production Example 38_3, and diisopropylethylamine (12.2 mL), and the mixture was stirred at room temperature overnight.
- the title compound was obtained by the same procedures as in Production Example 38-6 using the compound obtained in Production Example 44-6.
- the compound (7 Omg) obtained in Production Example 47-7 was suspended in a mixed solvent of methanol and water (1: 1, 4 mL), and iron powder (83.8 mg) and ammonium chloride (160 mg) were added at room temperature. . After heating to 90 ° C and stirring for 4 hours, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
- 2,3-Dimethyl-6-troimidazo [1,2-a] pyridine (1.5 g) synthesized according to JP-A-2003-207632 was dissolved in chloroform (50 mL), and N-bromosuccinimide was dissolved. (Hereinafter referred to as “NBS”) and stirred at room temperature for 1 hour. After concentrating the reaction solution, it was dissolved in methanol (50 mL), and a methanol solution of 25% sodium methoxide (2. OmL) was added at 0 ° C., followed by stirring at room temperature for 30 minutes.
- the title compound was obtained by the same procedures as in Production Example 38-6 using the compound obtained in Production Example 49-11.
- the title compound (42.3 mg) was obtained by performing the same operation as in Example 1 using the compound (57.lmg) obtained in Production Example 43-9 and the compound (50.lmg) obtained in Production Example 3-2. mg) as a white solid.
- the title compound (67.7 mg) was obtained by performing the same operation as in Example 1 using the compound (53 mg) obtained in Production Example 41-1 and the compound (46 mg) obtained in Production Example 4-13. Got.
- the title compound (79 mg) was obtained by performing the same operation as in Example 1 using the compound (68 mg) obtained in Production Example 40-4 and the compound (49 mg) obtained in Production Example 5-5. Obtained.
- the title compound (38) was obtained by performing the same operation as in Example 1 using the compound (35 in g) obtained in Production Example 4 2-1 and the compound (3 Omg) obtained in Production Example 6-4. 2 mg).
- the title compound (35) was obtained by performing the same operation as in Example 1 using the compound (50 mg) obtained in Production Example 39-4 and the compound (55 mg) obtained in Production Example 7-5. 4 mg) was obtained.
- the title compound (53 mg) was obtained as a pale orange by performing the same operation as in Example 1 using the compound (64 mg) obtained in Production Example 39- and the compound (64 mg) obtained in Production Example T-12. As obtained.
- Production Example 4 The title compound was obtained by performing the same operation as in Example 1 using the compound (31.5 mg) obtained in 1-1 and the compound (3 Omg) obtained in Production Example 10-2. (48 mg) was obtained.
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Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/579,570 US7566781B2 (en) | 2004-05-10 | 2005-05-09 | Imidazopyridine compound |
EP05739029A EP1748048A4 (en) | 2004-05-10 | 2005-05-09 | IMIDAZOPYRIDINE COMPOUND |
CA002566184A CA2566184A1 (en) | 2004-05-10 | 2005-05-09 | Imidazopyridine compound |
JP2006513053A JPWO2005108399A1 (ja) | 2004-05-10 | 2005-05-09 | イミダゾピリジン化合物 |
AU2005240942A AU2005240942B2 (en) | 2004-05-10 | 2005-05-09 | Imidazopyridine compound |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004139909 | 2004-05-10 | ||
JP2004-139909 | 2004-05-10 |
Publications (1)
Publication Number | Publication Date |
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WO2005108399A1 true WO2005108399A1 (ja) | 2005-11-17 |
Family
ID=35320177
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/008819 WO2005108399A1 (ja) | 2004-05-10 | 2005-05-09 | イミダゾピリジン化合物 |
Country Status (7)
Country | Link |
---|---|
US (1) | US7566781B2 (ja) |
EP (1) | EP1748048A4 (ja) |
JP (1) | JPWO2005108399A1 (ja) |
CN (1) | CN1950372A (ja) |
AU (1) | AU2005240942B2 (ja) |
CA (1) | CA2566184A1 (ja) |
WO (1) | WO2005108399A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010536839A (ja) * | 2007-08-17 | 2010-12-02 | アストラゼネカ アクチボラグ | 化合物979 |
US8431593B2 (en) | 2006-11-27 | 2013-04-30 | H. Lundbeck A/S | Heteroaryl amide derivatives |
RU2502737C2 (ru) * | 2009-09-24 | 2013-12-27 | Ф. Хоффманн-Ля Рош Аг | Производные имидазопиридина или имидазопиримидина в качестве ингибиторов фосфодиэстеразы 10а |
WO2020116662A1 (ja) | 2018-12-06 | 2020-06-11 | 第一三共株式会社 | シクロアルカン−1,3−ジアミン誘導体 |
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EP1867341A4 (en) * | 2005-03-29 | 2009-07-29 | Banyu Pharma Co Ltd | THERAPEUTIC AGENT FOR NON-ALCOHOLIC HEPATIC ADPATIVE DISEASE, AND METHOD FOR SELECTING MEDICAMENTAL CANDIDATE COMPOUND FOR THE TREATMENT OR PREVENTION OF NON ALCOHOLIC HEPATIC ADAPTIVE DISEASE |
WO2007002701A2 (en) * | 2005-06-27 | 2007-01-04 | Amgen Inc. | Anti-inflammatory aryl nitrile compounds |
JPWO2007018248A1 (ja) * | 2005-08-10 | 2009-02-19 | 萬有製薬株式会社 | ピリドン化合物 |
EP1921065B1 (en) | 2005-08-24 | 2010-10-20 | Banyu Pharmaceutical Co., Ltd. | Phenylpyridone derivative |
AR064491A1 (es) | 2006-12-22 | 2009-04-08 | Astex Therapeutics Ltd | Derivados de imidazo[1, 2-a]pirimidina, un proceso para su preparacion, una composicion farmaceutica que los comprende y su uso en el tratamiento de enfermedades mediadas por las quinasas fgfr. |
CA2672213C (en) | 2006-12-22 | 2016-02-16 | Astex Therapeutics Limited | Bicyclic amine derivatives as protein tyrosine kinase inhibitors |
MX2009013169A (es) * | 2007-06-03 | 2010-04-30 | Univ Vanderbilt | Moduladores alostericos positivos del mglur5 benzamida y metodos de elaboracion y uso de los mismos. |
US8853392B2 (en) | 2007-06-03 | 2014-10-07 | Vanderbilt University | Benzamide mGluR5 positive allosteric modulators and methods of making and using same |
US20100324049A1 (en) * | 2007-09-27 | 2010-12-23 | Makoto Ando | Diaryl ketimine derivative having antagonism against melanin-concentrating hormone receptor |
GB0720038D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New compounds |
GB0720041D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New Compounds |
GB0810902D0 (en) | 2008-06-13 | 2008-07-23 | Astex Therapeutics Ltd | New compounds |
WO2009154132A1 (ja) * | 2008-06-19 | 2009-12-23 | 萬有製薬株式会社 | スピロジアミン-ジアリールケトオキシム誘導体 |
GB0906472D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
GB0906470D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
JP5685203B2 (ja) | 2009-05-29 | 2015-03-18 | ラクオリア創薬株式会社 | カルシウムチャネル遮断薬またはナトリウムチャネル遮断薬としてのアリール置換カルボキサミド誘導体 |
US9309238B2 (en) * | 2009-11-05 | 2016-04-12 | University Of Notre Dame Du Lac | Imidazo [1,2-a]pyridine compounds, synthesis thereof, and methods of using same |
WO2013130935A1 (en) * | 2012-03-02 | 2013-09-06 | Genentech, Inc. | Amido-benzyl sulfoxide derivatives |
IL257743B (en) | 2015-09-17 | 2022-08-01 | Marvin J Miller | Heterocyclic compounds containing benzyl amine and preparations useful against mycobacterial inflammation |
GB201904375D0 (en) * | 2019-03-29 | 2019-05-15 | Galapagos Nv | Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
GB201904374D0 (en) * | 2019-03-29 | 2019-05-15 | Galapagos Nv | Novel compunds and pharmaceutical composistions thereof for the treatment of inflammatory disorders |
KR102666156B1 (ko) * | 2019-06-18 | 2024-05-16 | 주식회사 엘지에너지솔루션 | 리튬 이차 전지용 전해질 및 이를 포함하는 리튬 이차 전지 |
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2005
- 2005-05-09 CN CNA2005800150099A patent/CN1950372A/zh active Pending
- 2005-05-09 EP EP05739029A patent/EP1748048A4/en not_active Withdrawn
- 2005-05-09 JP JP2006513053A patent/JPWO2005108399A1/ja active Pending
- 2005-05-09 WO PCT/JP2005/008819 patent/WO2005108399A1/ja active Application Filing
- 2005-05-09 CA CA002566184A patent/CA2566184A1/en not_active Abandoned
- 2005-05-09 US US11/579,570 patent/US7566781B2/en not_active Expired - Fee Related
- 2005-05-09 AU AU2005240942A patent/AU2005240942B2/en not_active Ceased
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US8431593B2 (en) | 2006-11-27 | 2013-04-30 | H. Lundbeck A/S | Heteroaryl amide derivatives |
JP2010536839A (ja) * | 2007-08-17 | 2010-12-02 | アストラゼネカ アクチボラグ | 化合物979 |
RU2502737C2 (ru) * | 2009-09-24 | 2013-12-27 | Ф. Хоффманн-Ля Рош Аг | Производные имидазопиридина или имидазопиримидина в качестве ингибиторов фосфодиэстеразы 10а |
WO2020116662A1 (ja) | 2018-12-06 | 2020-06-11 | 第一三共株式会社 | シクロアルカン−1,3−ジアミン誘導体 |
US11236106B2 (en) | 2018-12-06 | 2022-02-01 | Daiichi Sankyo Company, Limited | Cycloalkane-1,3-diamine derivative |
US12060365B2 (en) | 2018-12-06 | 2024-08-13 | Daiichi Sankyo Company, Limited | Cycloalkane-1,3-diamine derivative |
Also Published As
Publication number | Publication date |
---|---|
AU2005240942B2 (en) | 2010-08-05 |
US20070249659A1 (en) | 2007-10-25 |
EP1748048A1 (en) | 2007-01-31 |
CN1950372A (zh) | 2007-04-18 |
AU2005240942A1 (en) | 2005-11-17 |
EP1748048A4 (en) | 2010-05-26 |
JPWO2005108399A1 (ja) | 2008-03-21 |
US7566781B2 (en) | 2009-07-28 |
CA2566184A1 (en) | 2005-11-17 |
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