WO2006041046A1 - ピリジン誘導体 - Google Patents
ピリジン誘導体 Download PDFInfo
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- WO2006041046A1 WO2006041046A1 PCT/JP2005/018669 JP2005018669W WO2006041046A1 WO 2006041046 A1 WO2006041046 A1 WO 2006041046A1 JP 2005018669 W JP2005018669 W JP 2005018669W WO 2006041046 A1 WO2006041046 A1 WO 2006041046A1
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- pharmacologically acceptable
- methyl
- otatanylamino
- methoxypyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
Definitions
- the present invention relates to a pyridine derivative having an excellent inhibitory action of an acylchoenzyme 'cholesterol' acyltransferase (hereinafter abbreviated as ACAT), a pharmacologically acceptable salt thereof, and a pharmacologically acceptable salt thereof. And other pharmacologically acceptable derivatives thereof.
- ACAT acylchoenzyme 'cholesterol' acyltransferase
- Atherosclerosis occupies the most important position.
- the main cause of atherosclerosis is the accumulation of cholesterol ester in the foam cells under the vascular endothelial cells.
- ACAT inhibitors inhibit cholesterol ester synthesis in these foam cells, reduce cholesterol ester accumulation, and suppress the formation and development of rod-shaped lesions due to cholesterol ester accumulation.
- Atherosclerosis is correlated with hypercholesterolemia.
- Cholesterol in food is absorbed by intestinal mucosal cells as free cholesterol, esterified by ACAT, and transferred to the blood. Therefore, ACAT inhibitors suppress the elevation of blood cholesterol by inhibiting the transfer of cholesterol in food to the blood.
- compounds having an ACAT inhibitory action are useful as therapeutic agents for hyperlipidemia or arteriosclerotic diseases and as Z or preventive agents.
- R 1 represents an alkyl group or xanthanyl methyl group
- R 2 represents a hydrogen atom or an alkyl group
- R 3 represents an alkyl group or an alkylthio group
- R 4 represents a cycloalkyl group or an alkyl group
- n represents 0 or 1.
- ACAT inhibitors see Patent Document 1.
- the compound (a) has a basic skeleton in which R 1 is an alkyl group or a xanthenylmethyl group.
- the compound having the general formula (I) of the present invention has a corresponding basic pyridine ring. In a certain point, it is different from the compound (a).
- the compound having the general formula (I) of the present invention is also different from the above compound (a) in that it has a carboxy group on the benzene ring bonded to the amide.
- R la is a C alkyl group
- R lb is a hydrogen atom or the same group as R la
- R 2a , R 2b and R 2e are
- R 3 is C ⁇
- R 4 is A 1 — R 5 group (A 1 is C-alkylene group, R 5 is halogen atom, C ⁇
- a 3 — R 5 group (A 2 is a C alkylene group, etc., X is an oxygen atom, sulfur atom or imino group, etc.
- a 3 represents a single bond or a C alkylene group. However, the sum of the carbon numbers of A 2 and A 3 is 1
- N 0 or 1.
- ACAT inhibitors see Patent Document 2.
- R la is a C alkyl group or cycloalkyl alkyl group
- R lb is the same as a hydrogen atom or R la
- R a , R z and are the same or different and are a hydrogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C alkyl group, an alkyl group substituted with a fluorine atom, C
- R 3 is C alkyl group
- R 4 is a hydroxyalkyl group
- n 0 or 1.
- ACAT inhibitors see Patent Document 3).
- R 1 is a C alkyl group!
- T a , R 2b , R 2e and R 2d are a hydrogen atom, a C alkyl group, 1 to
- R 3 is C
- R 4 represents an aminocarbonyl group or an aminocarbonylmethyl group.
- R 1 is an alkyl group
- R 2a , R 2b , R 2e and R 2d are hydrogen atoms, halogen atoms, substitutable alkyl groups, alkoxy groups, alkylthio groups, alkylsulfier groups, alkylsulfo groups,
- R 3 is an alkyl group
- A is a single bond or an alkylene group
- B is an alkylthio group, Al Kirusurufieru group, an alkyl A sulfol group, a sulfamoyl group, a monoalkylsulfamoyl group, a dialkylsulfamoyl group, a sulfamoylamino group, a monoalkylsulfamoylamino group or a dialkylsulfamoylamino group, n represents 0 or 1; Are known as ACAT inhibitors (see Patent Document 5).
- R la is a hydroxyl group, R lb and R or a hydrogen atom or an alkyl group (where one of R lb and R le is an alkyl group), R 2 is an alkyl group, R 3 is a saturated heterocyclyl group, a heteroaryl group, a hetero group.
- ACAT inhibitors see Patent Document 6).
- the compounds (b) to (f) essentially have a substituted phenyl group at one end in the basic skeleton, but the compound having the general formula (I) of the present invention has a corresponding group. It is different from the above compounds (b) to (f) in that it is a pyridine ring.
- Patent Document 7 a compound having the general formula (g) having an apolipoprotein A-1 secretion promoting action as a therapeutic or preventive agent for arteriosclerotic diseases such as myocardial infarction, Disclosure.
- R 1 is an alkyl group
- R 2a , R 2b , R 2e and R 2d are hydrogen atoms, halogen atoms, substitutable alkyl groups, substitutable alkoxy groups, alkoxyiminomethyl groups, alkylthio groups, alkylsulfur groups.
- R 3 represents an alkyl group
- A represents a single bond or alkylene.
- the group n represents 0 or 1; Is known as a compound having apolipoprotein A-1 secretion promoting action! (See Patent Document 7).
- the compound (g) essentially has a substituted phenyl group at one end in the basic skeleton, but the compound having the general formula (I) of the present invention has a corresponding basic pyridine ring. In this respect, the structural properties are completely different from the above compound (g).
- Patent Document 1 JP-A-7-0021
- Patent Document 2 JP-A-8-92222
- Patent Document 3 JP-A-8-325218
- Patent Document 4 JP-A-9-143137
- Patent Document 5 Japanese Patent Laid-Open No. 10-316648
- Patent Document 6 Japanese Patent Laid-Open No. 11 158133
- Patent Document 7 JP-A-10-316641 Disclosure of the invention
- the present inventors aimed at the development of a compound with low toxicity and excellent ACAT inhibitory activity, and as a result of intensive studies over many years on the synthesis of various pyridine derivatives and their pharmacological activity, they were excellent.
- a novel compound having an ACAT inhibitory activity and having a therapeutic effect or a preventive effect (especially a therapeutic effect) on arteriosclerotic diseases was discovered, thus completing the present invention.
- the object of the present invention is to provide a novel pyridine derivative having low toxicity and excellent ACAT inhibitory activity, a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof or a pharmaceutically acceptable salt thereof. It is to provide other derivatives.
- the present invention will be specifically described.
- the pyridine derivative of the present invention has the following general formula (I) or general formula (la).
- R 1 is a group arbitrarily selected from a halogen atom, a C—C alkyl group, and a substituent group a.
- R 2 is arbitrarily selected from a hydrogen atom, a halogen atom, a C—C alkyl group, and a substituent group a.
- R 3 is a C—C alkyl group, substituted with 1 to 3 groups arbitrarily selected from the substituent group a.
- R 4 s are the same or different and are optionally selected from a halogen atom, a C—C alkyl group, and a substituent group a.
- C represents a arylthio group
- n an integer of 0 to 2
- Substituent group a is a halogen atom, amino group, C—C alkoxy group, C—C alkylthio
- Substituent group b is a C—C alkyl group or a group arbitrarily selected from substituent group a and 1
- the present invention provides a pyridine derivative having the general formula (I), a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof or other pharmacologically acceptable derivatives thereof.
- R 1 is a C—C alkyl group, a C—C alkoxy group, a phenol group, or a C—C alkyl group.
- R 3 is C 1 -C alkyl substituted with C 1 -C alkyl, C—C cycloalkyl
- R 4 is the same or different and is a halogen atom, C—C alkyl group, C—C alkoxy group
- R 1 is a C—C alkyl group, a C—C alkoxy group, a phenol group, or a C—C alkyl group.
- R 2 is a hydrogen atom or a C—C alkyl group
- R 3 is a C—C alkyl substituted with a C—C alkyl group or a C—C cycloalkyl group.
- R 4 is the same or different and is a halogen atom, C—C alkyl group, C—C alkoxy group
- n an integer of 0 to 2.
- the present invention provides a pyridine derivative having the general formula (la), a pharmacologically acceptable salt thereof, a pharmaceutically acceptable ester thereof or other pharmacologically acceptable derivative thereof.
- a pyridine derivative having the general formula (la) a pharmacologically acceptable salt thereof, a pharmaceutically acceptable ester thereof or other pharmacologically acceptable derivative thereof.
- suitable compounds are shown below.
- R 4 is the same or different and is a halogen atom, a methylthio group or a methoxy group, a pyridine derivative, a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof or other pharmacologically acceptable derivative thereof,
- the pyridine derivative according to any one of (1) to (14), its pharmaceutically acceptable salt, its pharmacologically acceptable ester, or its pharmacologically acceptable other Provided is a therapeutic or prophylactic agent for arteriosclerotic diseases comprising a derivative as an active ingredient.
- the present invention provides:
- the pyridine derivative according to any one of (1) to (14), its pharmacologically acceptable salt, its pharmacologically acceptable ester, or other pharmacologically acceptable derivative thereof is effective.
- a method for treating or preventing arteriosclerotic diseases by administering a pharmaceutical composition as a component.
- the pyridine derivatives having the general formulas (I) and (la) of the present invention and pharmacologically acceptable salts thereof have excellent ACAT inhibitory activity with low toxicity, and the general formulas (I) and A pharmaceutical composition containing as an active ingredient a compound having Z or (Ia), a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof or other pharmacologically acceptable derivative thereof is an arteriosclerotic agent. It is useful as a prophylactic or therapeutic agent (preferably a therapeutic agent) for a disease.
- BEST MODE FOR CARRYING OUT THE INVENTION [0045] The present invention will be specifically described.
- the pyridine derivative of the present invention has the following general formulas (I) and (la).
- halogen atom in the definition of R 4 or substituent group a is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.
- alkyl group means, for example,
- c-c alkyl group represents a group bonded to an oxygen atom, such as a methoxy group
- C—C aryl group in the definition of R 1 or R 4 is, for example, a phenol group.
- aromatic hydrocarbon group having 6 to 10 carbon atoms such as an indenyl group and a naphthyl group, preferably a phenyl group.
- C—C alkyl group in the definition of R 3 is, for example, the above “C—C alkyl group”.
- 1 8 1 6 kill group or heptyl group, 5-methylhexyl group, 4 methylhexyl group, 3-methylhexyl group, 2 methylhexyl group, 4, 4 dimethylpentyl group, 3, 3 dimethyl Pentyl group, 2,2 dimethylpentyl group, octyl group, 6 methylheptyl group, 5-methylheptyl group, 4 methylheptyl group, 3 methylheptyl group, 2 methylheptyl group, 5,5-dimethylhexyl group, It may be a linear or branched alkyl group having 1 to 8 carbon atoms such as 4,4-dimethylhexyl group, 3,3-dimethylhexyl group, 2,2 dimethylhexyl group, and preferably Is an alkyl group having 4 to 8 carbon atoms, more preferably a pentyl group or a 4-methylpentyl group.
- the “cycloalkyl group” in the definition of R 3 can be, for example, a cyclic alkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. Preferably, it is a cyclopropyl or cyclobutyl group.
- "5- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and Z or nitrogen atoms" in the definition of R 3 or substituent group b is, for example, a furyl group , Chenyl group, Pyrrolyl group, Azepinyl group, Pyrazolyl group, Imidazolyl group, Oxazolyl group, Isoxazolyl group, Thiazolyl group, Isothiazolyl group, 1, 2, 3 Oxadiazolyl group, Triazolyl group, Tetrazolyl group, Thiadiazolyl group, Biranyl group, Aromatic heterocyclic group such as pyridyl group, pyridazinyl group, pyrimidyl group, birazinyl group and morpholinyl group, thiomorpholinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazoliny
- a partially or completely reduced group preferably a 5- to 7-membered heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom, such as a pyrrolyl group , Azepinyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, 1, 2, 3 oxadiazolyl group, triazolyl group, tetrazolyl group, thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, Corresponds to aromatic heterocyclic groups such as pyraduryl groups and morpholinyl groups, thiomorpholinyl groups, pyrrolidinyl groups, pyrrolinyl groups, imidazolidinyl groups, imidazolinyl groups, virazolidinyl groups, virazolyl groups,
- C—C aryloxy group in the definition of R 4 is the above “C—C alkyl group”.
- 6 10 6 10 group is a group bonded to an oxygen atom, for example, an aromatic hydrocarbon oxy group having 6 to 10 carbon atoms such as a phenoxy group, an indenyloxy group, or a naphthyloxy group. Preferred is a phenyl group.
- C—C alkylthio group in the definition of R 4 or substituent group a is the above “
- C C alkyl group is a group bonded to a sulfur atom, for example, methylthio group, ethyl
- C—C arylthio in the definition of R 4 is the above “C—C aryl”.
- ⁇ 6 10 6 10 group '' is a group bonded to a sulfur atom, for example, an aromatic hydrocarbon thio group having 6 to 10 carbon atoms such as a phenylthio group, an indenylthio group, or a naphthylthio group. Is a phenolthio group.
- the "pharmacologically acceptable salt” in the above is a compound having the general formula (I) or (la) of the present invention having a carboxy group and an amino group or a pyridine group, Alternatively, it can be converted into a basic salt or an acid salt by reacting with an acid, and the salt is shown.
- Alkali metal salts such as sodium salt, potassium salt and lithium salt; Alkaline earth metal salts such as magnesium salt and calcium salt; N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, Organic bases such as dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline or glycine, lysine, arginine, ornithine, glutamate, aspartic acid An amino acid salt such as a salt, and preferably an alkali metal salt.
- Hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate; methanesulfone Acid, lower alkanesulfonates such as trifluoromethanesulfonate, ethanesulfonate
- Benzene sulfonate, p aryl sulfonate such as toluene sulfonate, acetate, malate, fumarate, succinate, kenate, ascorbate, tartrate, oxalate, Organic acid salts such as maleate; and amino acid salts such as glycine salt, lysine salt, algin salt, ornithine salt, glutamate salt, and aspartate, and most preferably Acid salt.
- the "ester” in the above refers to an ester of the compound having the general formula (I) or (la) of the present invention, and can be an ester.
- “General protecting group” refers to a protecting group that can be cleaved by a kinetic method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis. As the “general protecting group” in the above, specifically,
- pentyl, 2-methylpentyl, 1-methylpentyl, 3,3 dimethylbutyl, 2,2 dimethylbutyl, 1,1-dimethylbutyl, 1,2 dimethylbutyl, 1,3 dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl “Lower alkyl group”;
- lower alkyl such as 2 hydroxyethyl, 2, 3 dihydroxypropyl, 3 hydroxypropyl, 3, 4 dihydroxybutyl, 4-hydroxybutyl; “aliphatic acyl” such as acetylmethyl, “lower alkyl” ;
- Trimethylsilyl Triethylsilyl, Isopropyldimethylsilyl, t-Butyldimethylsilyl, Methyldiisopropylsilyl, Methyldi-butylsilyl, Triisopropylsilyl, Methyldiphenylsilyl, Isopropyldiphenylsilyl, Butyldiphenylsilyl, Phenyl
- Protecting group that can be cleaved in vivo by a biological method such as hydrolysis refers to an ester that is hydrolyzed in the human body to produce a free acid or a salt thereof.
- Methoxymethyl 1 ethoxyethyl, 1-methyl-1-methoxyethyl, 1 (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1 dimethyl-1-methoxymethyl, ethoxymethyl, n -propoxymethyl, isopropoxymethyl, n-butoxymethyl, t Lower alkoxy lower alkyl group such as butoxymethyl, lower alkoxylated lower alkoxy lower alkyl group such as 2-methoxymethoxymethyl, phenoxymethyl Such as “aryl” oxy “lower alkyl group”, halogenated lower alkoxy lower alkyl groups such as 2,2,2-trichlorodiethylethoxy, bis (2-cyclodiethyl) methyl, etc. ";
- “Lower alkyl” thiomethyl groups such as methylthiomethyl and ethylthiomethyl
- aryl thiomethyl groups such as phenylthiomethyl and naphthylthiomethyl
- halogen such as 2-methanesulforuethyl, 2-trifluoromethanesulfolethyl, “lower alkyl” sulfone “lower alkyl group”;
- Aryl sulfonyl “lower alkyl” such as 2-benzenesulfo-ruethyl, 2-toluenesulfo-ruethyl;
- Phthalidyl groups such as phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl
- aryl groups such as phenol and indanyl
- a “carboxyalkyl group” such as carboxymethyl
- the “other derivative” in the above has a compound power carboxy group having the general formula (I) or (la) of the present invention, and therefore other than the above “pharmacologically acceptable salt” and the above “ester”. Since it can be a derivative, its derivative is shown.
- Such derivatives include, for example, methylamine, ethenoreamine, propylamine, isopropylamine, butynoleamine, isobutinorea on the carboxy group of the compound having the general formula (I) or (la).
- the compound having the general formula (I) or (la) of the present invention and a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof or other pharmacologically acceptable derivative thereof are left in the atmosphere.
- the water may be absorbed and adsorbed water may be attached or a hydrate may be formed, and such a hydrate is also included in the present invention.
- the compound having the general formula (I) or (la) of the present invention and a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof, or other pharmacologically acceptable derivatives thereof are contained in the molecule. Since it has an asymmetric carbon atom, optical isomers exist.
- the present invention includes all optical isomers and mixtures containing optical isomers in an arbitrary ratio.
- the compound having the general formula (I) of the present invention is preferably
- Illustrative compound number 17 4 t-butyl 3- [3- (2-methoxypyridine 3-yl) otatanylamino] benzoic acid,
- Illustrative compound number 86 4 t-butyl-3- [3- (2-methoxypyridine 3 yl) 7 methyl otatanylamino] benzoic acid,
- the compound having the general formula (I) of the present invention can be produced according to the method described below.
- Method A is a method for producing a compound having the general formula (I).
- R ⁇ R 2 , R 3 , R 4 and n have the same meaning as described above, and R 5 represents a protecting group for a carboxy group.
- the "protecting group” of the “carboxyl protecting group” in the definition of R 5 is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of organic synthetic chemistry. It is a CC alkyl group, preferably a methyl group or an ethyl group.
- Step A1 is a step of producing a compound having the general formula (IV).
- the carboxyl group of the compound having the general formula (II) is converted to an acid halide, etc.
- a method carried out by reacting with a compound having (III), or (ii) a compound having the general formula ( ⁇ ) and a compound having the general formula ( ⁇ ) in an inert solvent in the presence of a condensing agent There is a method carried out by reacting in the presence or absence of a base group.
- the inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and examples thereof include dichloromethane, chlorophenol, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene.
- Halogenated hydrocarbons such as jetyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; or formamide, N, N dimethylformamide, N, N dimethylacetamide, Amides such as oxamethyl phosphate triamide, preferably halogenated hydrocarbons, more preferably dichloromethane [0081]
- the base used in the above reaction is not particularly limited.
- Organic bases such as octane (DABCO), 1,8 diazabicyclo [5. 4. 0] undek-7en (DBU), preferably triethylamine, diisopropylethylamine.
- the reaction temperature varies depending on the raw material compound, the reagent used, the type of the solvent, and the like, but is usually 20 ° C to 60 ° C, and preferably 20 ° C to 30 ° C.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 24 hours, and preferably 1 to 12 hours.
- the target compound of this step is collected from the reaction mixture according to a conventional method.
- the reaction mixture is neutralized as appropriate, and if insoluble matter is present, it is removed by filtration, and then the reaction solution is extracted with an organic solvent that is not miscible with water, such as ethyl acetate, and washed with water or the like.
- the target compound is obtained by drying the organic layer containing the target compound over anhydrous magnesium sulfate, anhydrous sodium sulfate or the like and distilling off the solvent.
- the obtained target compound is optionally prepared by a conventional method such as recrystallization, reprecipitation, or a method commonly used for separation and purification of ordinary organic compounds (for example, silica gel, alumina, magnesium-silica gel system).
- HPLC high performance liquid chromatography
- Halogenated hydrocarbons such as jetyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; or formamide, N, N dimethylformamide, N, N dimethylacetamide, Amides such as oxamethylphosphoric triamide, preferably dichloromethane, tetrahydrofuran, N, N dimethylformamide or a mixed solvent thereof.
- the condensing agent used in the above reaction is not particularly limited, but examples thereof include azodicarboxylic acid di-lower alkyl ester-triphenylphosphine such as azodicarboxylic acid jetyl ester-triphenylphosphine.
- Carbodiimide derivatives such as N, N, -dicyclohexylcarbodiimide (DCC), 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide (EDCI); 2-halo, such as 2-chloro 1-methylpyridum-muzide; 1 Lower alkyl pyridinium halides; Diaryl phosphoryl azides such as diphenylphosphoryl azide (DPPA); Chloroleic acid esters such as chloroethyl formate and isobutyl black formate; such as jetyl phosphoryl chloride Phosphoryl chlorides; N, N,-Imidazoles such as carbodiimidazole (CDI) Conductor; O— (7-azabenzotriazole 1-yl) N, N, ⁇ ', ⁇ , monotetramethyl oxafluorphosphate (HATU), (1H-benzotria Benzol triazole derivatives such as sol-1-yloxy) tripyrrolidin
- the base used in the above reaction is not particularly limited.
- Organic bases such as octane (DABCO), 1,8 diazabicyclo [5. 4. 0] undek-7en (DBU), preferably triethylamine, diisopropylethylamine.
- the reaction temperature varies depending on the raw material compound, the condensing agent, the type of the solvent, etc., but is usually carried out at -20 ° C to 100 ° C, preferably 0 ° C to 80 ° C, more preferably Is between 20 ° C and 50 ° C.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 24 hours, and preferably 1 to 24 hours.
- Step A2 is a step of producing a compound having the general formula (I), and is performed by hydrolyzing the compound having the general formula (IV) with a base in an inert solvent.
- the inert solvent used in the above reaction is not particularly limited as long as it is used in a normal hydrolysis reaction.
- the base used in the above reaction is not particularly limited as long as it is usually used as a base and does not inhibit the reaction.
- an alkali metal such as lithium carbonate, sodium carbonate, or potassium carbonate is used.
- the reaction temperature varies depending on the raw material compound, the reagent used, the type of solvent, etc., but is usually carried out at 0 ° C to 100 ° C, preferably 0 ° C to 60 ° C, more preferably. Is between 20 ° C and 60 ° C.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 24 hours, and preferably 1 to 24 hours.
- the target compound can be separated and purified by the same method as described in Method A, Step A1, if necessary.
- Method B is a method for producing a compound having the general formula ( ⁇ ).
- R 3 , R 4 and n are as defined above, and R ° and R 7 are C—C
- R 16 represents an alkyl group
- R 8 represents a protecting group for a carboxy group
- R 9 represents a C—C alkyl group
- Met is an alkyl metal or alkyl earth metal halide
- C—C alkyl group in the definition of R 6 , R 7 and R 9 is the above “C—C alkyl group”.
- the “protecting group for carboxyl group” in the definition of R 8 is the same as the definition of the “protecting group for carboxyl group”, and is, for example, a C—C alkyl group, and preferably an ethyl group. "C-C ⁇ in the definition of R 9
- the “6 6 10 reel group” is the same as the definition of the “c C aryl group” described above.
- Alkali metal in the definition of Met is lithium, sodium, potassium, rubidium, cesium, francium, and preferably lithium.
- Alkaline earth metal of “alkali earth metal halide” in the definition of Met is an ordinary alkaline earth metal, for example, beryllium, magnesium, calcium, strontium, norlium, radium, and preferably Is magnesium and “halide” is the above “norogen atom”.
- Step B1 is a step of producing a compound having the general formula (VI), and is performed by reacting a compound having the general formula (V) with HNR 6 (OR 7 ).
- the condensing agent used in the above reaction is the same as in Step A1, but is particularly preferably E
- Step B2 is a step for producing a compound having the general formula (VIII) and is carried out in an inert solvent.
- the reaction is carried out by reacting the compound having the general formula (VI) with the organometallic reagent (VII).
- the inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction.
- aliphatic carbonization such as hexane, heptane, lignin, and petroleum ether.
- tetrahydrofuran is preferably ethers It is.
- tetrahydrofuran is tetrahydrofuran.
- the reaction temperature varies depending on the raw material compound, the reagent used, the type of solvent, and the like, but is usually carried out at 78 ° C to 50 ° C, preferably 20 ° C to 50 ° C, more preferably It is 0 ° C to 40 ° C.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 24 hours, and preferably 1 hour to 24 hours. .
- the target compound can be separated and purified by the same method as described in Method A, Step A1, if necessary.
- Step B3 is a step for producing a compound having the general formula (X), and reacting a compound having the general formula (VIII) with a compound having the general formula (IX) in the presence of a base in an inert solvent. It is done from Yuko.
- the solvent used in the above reaction does not inhibit the reaction and dissolves the starting material to some extent
- the aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, black benzene and dichlorobenzene; Ethers such as til ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran; tolyls such as acetonitrile, isobutyric-tolyl; formamide, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, Amides such as oxamethyl phosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane, and ethers are preferred. Most preferred is tetrahydrofuran.
- the base used in the above reaction is not particularly limited as long as it is used as a base in a normal reaction.
- alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate are used.
- Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate
- alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride
- sodium hydroxide sodium hydroxide
- Alkali metal hydroxides such as potassium, hydroxide, barium, lithium hydroxide
- inorganic bases such as sodium fluoride, alkali metal fluorides such as lithium fluoride; sodium methoxide , Sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tertoxide, lithium methoxide Lucari metal alkoxides; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclo
- the reaction temperature varies depending on the raw material compound, the reagent used, the type of the solvent, etc., but is usually -20 ° C to 100 ° C, preferably 0 ° C to 60 ° C, more preferably 20 ° C to 60 ° C.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 24 hours, and preferably 1 to 24 hours.
- the target compound can be separated and purified by the same method as described in Method A, Step A1, if necessary.
- Step B4 is a step for producing general formula (XI), and is carried out by reducing compound (X) in the presence of a reducing agent in an inert solvent.
- the solvent used in the above reaction is not particularly limited.
- alcohols such as methanol, ethanol, and isopropanol; jetyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; esters such as ethyl acetate and propyl acetate; Suitably alcohols.
- the reducing agent used in the above reaction is not particularly limited as long as it is usually used in a catalytic reduction reaction.
- palladium carbon palladium black, acid platinum, platinum black Rhodium-aluminum oxide, triphenylphosphine-rhodium chloride (Wilkinson complex), rhodium-barium sulfate, raney nickel, and preferably rhodium carbon.
- the pressure is not particularly limited, but is usually 1 to 10 atm.
- reaction temperature varies depending on the raw material compound, the reagent used, the type of solvent, etc.
- 0 ° C to 50 ° C preferably 0 ° C to 30 ° C.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent, and the type of the solvent used, but is usually 10 minutes to 24 hours, and preferably 1 to 12 hours.
- the target compound can be separated and purified by the same method as described in Method A, Step A1, if necessary.
- Step B5 is a process for producing a compound having the general formula ( ⁇ ) and has the general formula (XI).
- the compound to be obtained is hydrolyzed with a base in an inert solvent.
- Method C is another method of Method B for producing a compound having the general formula ( ⁇ ).
- R 3 R 4 R 8 and n are as defined above.
- Step C1 is a step for producing a compound having the general formula ( ⁇ ).
- the compound having the general formula (V) has the general formula (XII) in an inert solvent in the presence of a base or an acid catalyst. This is done by reacting with a compound.
- the solvent used in the above reaction is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, dichloroethane, black benzene, dichlorobenzene and the like.
- Halogenated hydrocarbons such as jetyl ether, di-propyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; -tolyls such as acetonitrile, isobutyoxy-tolyl; formamide, N Amides such as, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane Yes, preferably aromatic carbonization Hydrogens.
- ethers such as jetyl ether, di-propyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether
- -tolyls such as acetonitrile, isobutyoxy-tolyl
- formamide N Am
- the base used in the above reaction is not particularly limited.
- alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate; sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, and the like.
- Alkali metal hydrogen carbonates alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium Alkali metal alkoxides such as ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide; methyl mercaptaphorine, jetylamine, dipropylamine, dibutylamine, diisopropylamine, piperidine, pyrrolidine, N-methylmorpholine, triethyl Amine
- DBN nona 5 hen
- 1, 4 Organic bases such as diazabicyclo [2. 2. 2] octane (DABCO), 1,8 diazabicyclo [5. 4. 0] deca 7-en (DBU), or lithium diisopropylamide
- lithium Organometallic bases such as bis (trimethylsilyl) amide, preferably secondary amines such as morpholine, jetylamine, dipropylamine, dibutylamine, diisopropylamine, piperidine and pyrrolidine, and more preferably Are piperidine and pyrrolidine.
- the acid used in the above reaction is not particularly limited, but for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid; acetic acid, formic acid, oxalic acid, benzoic acid Bronsted acids such as acids, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc .; zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, A Lewis acid such as boron tribromide; or an acid ion-exchange resin, preferably an organic acid, and more preferably a carboxylic acid such as acetic acid or benzoic acid.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid
- the reaction temperature varies depending on the raw material compound, the reagent used, the type of the solvent, etc., but is usually 20 ° C to 150 ° C, preferably 70 ° C to 120 ° C.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of the solvent used, but is usually 10 minutes to 48 hours, preferably 2 to 36 hours, more preferably In Is 12 to 24 hours.
- the target compound can be separated and purified by the same method as described in Method A, Step A1, if necessary.
- Step C2 is a step for producing a compound having the general formula (XIV) in an inert solvent.
- the reaction is carried out by reacting the compound having the general formula ( ⁇ ) with the organometallic reagent (VII).
- the yield may be improved by adding copper (I) halide (preferably copper bromide or copper iodide).
- the solvent used in the above reaction is not particularly limited.
- aromatic hydrocarbons such as benzene, toluene, and xylene
- methylene chloride dichloroethane, black benzene, dichlorobenzene, and the like.
- Halogenated hydrocarbons such as jetyl ether, di-propyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether, and preferably ethers.
- ethers such as jetyl ether, di-propyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether, and preferably ethers.
- tetrahydrofuran is tetrahydrofuran.
- reaction temperature varies depending on the starting compound, the reagent used, the type of solvent, etc.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 12 hours, preferably 10 minutes to 4 hours. .
- the target compound can be separated and purified by the same method as described in Method A, Step A1, if necessary.
- Step C3 is a step for producing a compound having the general formula (XV), and is performed by hydrolyzing the compound having the general formula (XIV) with a base in an inert solvent.
- Step C4 is a step for producing a compound having the general formula ( ⁇ ), and is performed by heating the compound having the general formula (XV) in an inert solvent.
- the solvent to be used is not particularly limited, and examples thereof include hexane, heptane, ligroyl.
- Aliphatic hydrocarbons such as petroleum ether, petroleum ether; Aromatic hydrocarbons such as benzene, toluene, xylene; Halogens such as methylene chloride, black form, carbon tetrachloride, dichloroethane, black benzene, dichlorobenzene Hydrocarbons; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and jetyl carbonate; ethers such as jetyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and jetylene glycol dimethyl ether ; methanol, ethanol, n - flop propanol, isopropanol, n- butanol, isobutano
- reaction temperature varies depending on the raw material compound, the reagent used, the type of solvent, etc.
- the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent, and the type of the solvent used, but is usually 10 minutes to 12 hours, and preferably 1 to 6 hours.
- the target compound can be separated and purified by the same method as described in Method A, Step A1, if necessary.
- Method D is a method for producing optically active general formulas (Ila) and (lib) from a compound having general formula (XI).
- Step D1 is carried out by separation from a racemic compound having the general formula (XI) by a general chromatographic method for separation of optically active substances (adsorption chromatography using a column having an optically active solid support). This is a method for obtaining a compound having (Xla) and (Xlb).
- Step D2 hydrolysis
- Step D2 is a process for producing a compound having the general formula (Ila) or (lib), and hydrolyzing the compound having the general formula (Xla) or (Xlb) with a base in an inert solvent. It is done from Kotoko.
- Example 2 [1- (2-Methoxypyridine-3-yl) hexyl] malonic acid di prepared in lb Ethyl (2.24 g, 6.4 mmol) was dissolved in ethanol (15 mL), 10% aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at 50 ° C. for 5 hr.
- Methyl 3-amino-4-t-butylbenzoate (7.69 g, 39.8 mmol) described in J. Chem. Soc. 1961, 611 was dissolved in methylene chloride (150 mL) under a nitrogen atmosphere, and pyridine ( 16. lmL, 199mmol) was added, and a solution of the above acid chloride in methylene chloride (50mL) was added dropwise and stirred at room temperature for 3 hours.
- a saturated aqueous solution of ammonium chloride is added to the reaction solution, the aqueous phase is extracted with methylene chloride, and the resulting organic phase is washed with an aqueous sodium hydrogen sulfate solution and saturated brine, and then is added with anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. The resulting crude product was purified using silica gel column chromatography (hexane: ethyl acetate, 9: 1 to 3: 1) to give the title compound (1 2.95 g, 74%).
- Example 1 4-N-butyl 3- [3- (2-methoxypyridine-1-yl) otatanylamino] benzoate (198 mg, 0.45 mmol) prepared in Id was dissolved in methanol (3 mL), and 1N Sodium hydroxide aqueous solution (2 mL) was added, and the mixture was stirred at room temperature for 18 hours.
- Example 3-(2-Methoxypyridine-1-yl) octanoic acid (180 mg, 0.7 2 mmol) and methyl 3-amino-4-methoxybenzoate (123 mg, 0.68 mmol) prepared in lc were used in Example Id.
- the title object compound (153 mg, 52%) was obtained according to the method described.
- Example 2a Using the 4-methoxy-1-3- [3- (2-methoxypyridine-1-3-yl) otatanylamino] benzoate methyl (130 mg, 0.31 mmol) prepared in Example 2a, the method described in Example le was used. Therefore, the title object compound (91 mg, 73%) was obtained.
- Methyl 5-amino 2 bromo 4-t-butylbenzoate (4.5 lg, 15.8 mmol) prepared in Example 3a was dissolved in 1,4-dioxane (40 mL) containing 10% water, and trimethylboroxine (1.98 g, 15.8 mmol), palladium [1, ⁇ -bis (diphenylphosphino) ferrocene] dichloride (1.28 g, 0.16 mmol), cesium carbonate (15.4 g, 47.4 mmol), and at 110 ° C for 2 hours under nitrogen atmosphere Stir.
- Example Id was prepared using 3- (2-methoxypyridine-3-yl) octanoic acid (179 mg, 0.7 lmmol) and 5 amino-4 methyl benzoate (126 mg, 0.68 mmol) prepared in lc.
- the title object compound (218 mg, 77%) was obtained according to the method described.
- IR (CHC1) vmax 2955, 2859, 1722, 1585, 1464, 1416, 1295, 1255, 1
- Example le using 4-chloro-methyl 3- [3- (2-methoxypyridine-1-yl) otatanylamino] benzoate (193 mg, 0.46 mmol) prepared in Example 4a According to the method, the title object compound (97 mg, 52%) was obtained.
- Example le Described in Example le using 2- [3- (2-methoxypyridine-1-yl) otatanylamino] -4-biphenylcarboxylate (303 mg, 0.66 mmol) prepared in Example 5a. According to the method described above, the title object compound (268 mg, 91%) was obtained.
- Example 3- (2-Methoxypyridine-3-yl) octanoic acid (200 mg, 0.8 Ommol) prepared in lc and 2-amino4 described in Bioorg. Med. Chem. Lett. 2002, 12, 2065, —The title object compound (281 mg, 75%) was obtained using methyl biphenyl 4-carboxylate (250 mg, 1. Ommol) according to the method described in Example Id.
- Example Id was prepared using 3- (2 ethoxypyridine 1-yl) octanoic acid (200 mg, 0.75 mmol) and methyl 3-amino-4-t-butylbenzoate (188 mg, 0.91 mmol) prepared in Example 7e. According to the method described, the title object compound (31 lmg, 91%) was obtained.
- Example le Described in Example le using 4-t-butyl-3- [3- (2-ethoxypyridine-3-yl) otanoylamino] benzoate (298 mg, 0.66 mmol) prepared in Example 7f.
- the title target compound (227 mg, 79%) was obtained according to the above method.
- Example le Described in Example le using 3- [3- (2-Ethoxypyridine-1-yl) otatanylamino] -4-methoxybenzoate (265 mg, 0.62 mmol) prepared in Example 8a. According to the method, the title object compound (221 mg, 86%) was obtained.
- Example 9a Using the N-methoxy-1-N-methyl-2-phenoxynicotinamide (730 mg, 2.8 mmol) prepared in Example 9a, the title compound (414 mg, 54%) was prepared according to the method described in Example 7b. Obtained.
- Example 7c The title compound was prepared according to the method described in Example 7c using 1- (2-phenoxypyridine-1-yl) hexan-1-one (39 lmg, 1.5 mmol) prepared in Example 9b. (4 91 mg, 100%) was obtained. MS (FAB) m / z: 340 (M + H).
- Example 7d The title compound (450 mg) was prepared according to the method described in Example 7d using 3- (2 phenoxypyridine 1-yl) 2-octaenoate (479 mg, 1.4 mmol) prepared in Example 9c. , 93%).
- Example 9e Performed using 3- (2 phenoxypyridine-l-yl) octanoic acid (148 mg, 0.47 mmol) and 3 amino-4-tert-butylbenzoic acid methyl ester (117 mg, 0.57 mmol) prepared in Example 9e. According to the method described in Example Id, the title object compound (218 mg, 92%) was obtained.
- Example 3 Using 3- (2 phenoxypyridine-1-yl) octanoic acid (152 mg, 0.49 mmol) and methyl 3-amino-4-methoxybenzoate (106 mg, 0.58 mmol) prepared in Example 9e The title object compound (219 mg, 94%) was obtained according to the method described in Id. IR (KBr) vmax 3415, 2948, 2855, 1722, 1594, 1534, 1431, 1263, 121 2cm;
- Example 10a As described in Example le using 4-methoxy-1-3- [3- (2-phenoxypyridine-1-yl) otatanylamino] benzoate (200 mg, 0.42 mmol) prepared in Example 10a. According to the method, the title object compound (173 mg, 89%) was obtained.
- Example 1 The title target compound (1.62 g, 2 steps 70%) was obtained according to the method described in Example lb, using 2- (2 methylsulfurpyridine-3-ylmethylene) malonate jetyl prepared in la. .
- Example 2- [1- (2-Methylsulfurylpyridine-3-yl) hexyl] manufactured in lib using ethyl malonate (1.60 g, 4.4 mmol) and following the procedure described in Example lc. To give the title object compound (807 mg, 70%).
- Example 1 Using 3- (2 methylsulfurylpyridine-3-yl) octanoic acid (192 mg, 0.72 mmol) and methyl 3-amino-4-tert-butylbenzoate (178 mg, 0.8 6 mmol) prepared in lc, The title object compound (286 mg, 87%) was obtained according to the method described in Example Id.
- Example 1 Performed using 3- (2 methylsulfurylpyridine-3-yl) octanoic acid (192 mg, 0.72 mmol) and methyl 3-amino-4-methoxybenzoate (156 mg, 0.86 mmol) prepared in lc The title object compound (284 mg, 92%) was obtained according to the method described in Example Id.
- Example 1 e Using methyl 4-methoxy-1- [3- (2-methylsulfurpyridine-1-3-yl) otatanylamino] benzoate (267 mg, 0.61 mmol) prepared in Example 12a The title compound (179 mg, 70%) was obtained according to the method described in 1.
- Example 13a Using the N-methoxy-N-methylnicotinamide (1.86 g, 11.2 mmol) prepared in Example 13a and according to the method described in Example 7b, the title object compound (1.78 g, 90%) was obtained.
- Example 13b Using the 1-pyridin-3-ylhexan-1-one (1.78 g, 10. Om mol) prepared in Example 13b and following the procedure described in Example 7c, the title compound (2.44 g, 98 %).
- Example 7d The title compound (2.36 g, 96%) was prepared according to the method described in Example 7d using 3 pyridine-3-yl-2-octaenoate (2.43 g, 9.8 mmol) prepared in Example 13c. Obtained.
- the title object compound (1.97 g, 94%) was obtained according to the method described in Example 7e by using 3 pyridine-3-yloctanoate (2.35 g, 9.4 mmol) prepared in Example 13d.
- Example 13e Following the procedure described in Example Id using 3 pyridine-3-yloctanoic acid (203 mg, 0.92 mmol) and 3 amino-4-tert-butylbenzoate (213 mg, 1. lmmol) prepared in Example 13e. To give the title object compound (166 mg, 44%).
- Example 14a 4-methoxy-1- (3-pyridine-3-ylotatanylamino) prepared in Example 14a Using the methyl benzoate and following the procedure described in Example le, the title compound (132 mg, 2 steps 56% )
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JPH10316562A (ja) * | 1997-03-14 | 1998-12-02 | Sankyo Co Ltd | 抗動脈硬化剤 |
JP2000502708A (ja) * | 1995-12-29 | 2000-03-07 | スミスクライン・ビーチャム・コーポレイション | ビトロネクチン受容体拮抗物質 |
US6310095B1 (en) * | 1995-11-06 | 2001-10-30 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
WO2003030889A1 (en) * | 2001-10-03 | 2003-04-17 | Bayer Healthcare Ag | Para-amino benzoic acids as integrin antagonists |
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US6310095B1 (en) * | 1995-11-06 | 2001-10-30 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
JP2000502708A (ja) * | 1995-12-29 | 2000-03-07 | スミスクライン・ビーチャム・コーポレイション | ビトロネクチン受容体拮抗物質 |
JPH10316562A (ja) * | 1997-03-14 | 1998-12-02 | Sankyo Co Ltd | 抗動脈硬化剤 |
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