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WO2015076353A1 - Dérivé 3-alkylpyrazolopyridine - Google Patents

Dérivé 3-alkylpyrazolopyridine Download PDF

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Publication number
WO2015076353A1
WO2015076353A1 PCT/JP2014/080847 JP2014080847W WO2015076353A1 WO 2015076353 A1 WO2015076353 A1 WO 2015076353A1 JP 2014080847 W JP2014080847 W JP 2014080847W WO 2015076353 A1 WO2015076353 A1 WO 2015076353A1
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Prior art keywords
compound
group
trifluoromethyl
ethyl
pyridin
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Japanese (ja)
Inventor
雅巳 荒井
小林　英樹
秀樹 窪田
直生 寺坂
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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    • A61K31/435—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
    • A61K31/4353—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
    • 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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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pyrazolopyridine derivative having a superior lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.
  • LCAT superior lecithin cholesterol acetyltransferase
  • cardiovascular diseases for example, heart disease, cerebrovascular disease, kidney disease, etc.
  • hypertension for example, hypertension, dyslipidemia, diabetes, etc.
  • Antihypertensive drugs, antilipidemia drugs, and antidiabetic drugs are used for the treatment of hypertension, dyslipidemia, and hyperglycemia, respectively.
  • ⁇ and ⁇ blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists are used as antihypertensive agents, and HMG-CoA reductase inhibitors, Insulin, sulfonylureas, metformin, glitazones, DPP4 inhibitors, and the like are used as antidiabetics such as ion exchange resins, nicotinic acid derivatives, probucol, and fibrates.
  • These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels.
  • mortality due to heart disease, cerebrovascular disease and kidney disease has not been greatly improved even by the use of these drugs, and development of better therapeutic agents for these diseases is desired.
  • a direct risk factor for cardiovascular disease is arteriosclerosis accompanied by thickening of the arterial wall, and the cause of the thickening is due to accumulation of oxidized low density lipoprotein (hereinafter referred to as LDL) cholesterol in macrophages in the arterial wall. It is the formation of plaque (Non-Patent Documents 1 and 2). This plaque inhibits blood flow and promotes thrombus formation.
  • LDL oxidized low density lipoprotein
  • Non-Patent Document 3 An increase in the concentration of LDL cholesterol in the blood and a decrease in the concentration of high-density lipoprotein (hereinafter referred to as HDL) cholesterol are both risk factors for coronary artery disease.
  • HDL high-density lipoprotein
  • Peripheral tissue cholesterol is extracted by HDL and esterified by LCAT on HDL to become cholesteryl ester.
  • Increased LCAT activity promotes the withdrawal of cholesterol from macrophages (for example, Non-Patent Documents 4 and 5). Therefore, it is considered that a drug that enhances LCAT activity is useful as a medicament for treating or preventing diseases such as dyslipidemia and arteriosclerosis.
  • Non-patent Document 6 examples of known drugs that enhance LCAT activity include peptide compounds (for example, Non-patent Document 6) and, as small molecules, for example, compounds described in Patent Document 1.
  • Patent Document 2 As the compound having a pyrazolopyridine skeleton, the compound described in Patent Document 2 is known. Patent Document 2 describes an anti-LPA receptor action, but does not describe an LCAT activation action.
  • the present inventors have conducted various synthetic studies aiming at obtaining new anti-arteriosclerotic drugs by having an excellent LCAT activation action and promoting cholesterol withdrawal directly from macrophages. As a result, the present inventors have found that a pyrazolopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and completed the present invention.
  • the present invention provides a pyrazolopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing them.
  • R 2 and R 3 both represent a hydrogen atom, or together with the carbon atom to which they are bonded form a cyclopropyl ring or a cyclobutyl ring, and R 1 represents a group selected from the following group Q1:
  • X represents a single bond, or R 3 represents a hydrogen atom
  • R 1 and R 2 are the same or different and represent a group selected from the following group Q1, X represents a single bond, an oxygen atom, a sulfur atom or a group SO 2 ;
  • Q1 group includes an aryl group, a substituted aryl group, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a heteroaryl group (the heteroaryl may be condensed with a benzene ring), a substituted heteroaryl A group consisting of a group (the heteroaryl may be fused with a benzene ring), a heterocyclyl group and a substitute
  • the substituent is the same or different 1 to 2 substituents selected from the group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group and a C 1 -C 6 alkoxy group) It is.
  • R 2 and R 3 are both hydrogen atoms
  • X is a single bond
  • R 1 is a benzyl group.
  • R 2 and R 3 both represent a hydrogen atom
  • R 1 represents a group selected from the following group Q2
  • X represents a single bond
  • R 3 represents a hydrogen atom
  • R 1 and R 2 are the same or different and represent a group selected from the following group Q2, X represents a single bond, an oxygen atom, a sulfur atom or a group SO 2
  • Group Q2 is a group consisting of a substituted aryl group, a C 1 -C 6 alkyl group and a substituted heterocyclyl group
  • the substituent in the Q2 group is a substituted heteroaryl group (the substituent on the heteroaryl is a group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, and a C 1 -C 6 alkoxy group)
  • a pharmacologically acceptable salt thereof according to (1) which is the same or different 1 or 2
  • Or therapeutic agent (10) A preventive agent for a disease caused by a decrease in the concentration of HDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof.
  • Or therapeutic agent (11) An LCAT activator comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient, (12) a reversible LCAT activator comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient, (13) An anti-arteriosclerosis agent comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient, (14) A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof, (15) A method for preventing or treating a disease, comprising administering to a human an effective amount of the compound according to any one
  • a method for the prevention or treatment of the disease caused (20) The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis, (21) The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia, (22) The compound according to any one of (1) to (4) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood Acceptable salts, and (23) The compound according to any one of (1) to (4) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by a decrease in the concentration of HDL cholesterol in the blood It is an acceptable salt.
  • Compound (I) of the present invention is a compound represented by formula (I) or a tautomer thereof.
  • the compound (I) containing any tautomer is represented by the structural formula of the formula (I) and the corresponding chemical name.
  • any isomer of the other tautomer (amide-imidic acid) of the compound (I) of the present invention is contained in the present compound (I).
  • the compound (I ) Is also represented by the structural formula represented by formula (I) and the corresponding chemical name.
  • the “C 3-7 cycloalkyl group” is a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms (C 3-6 cycloalkyl group) is preferable, and a cyclopropyl group is more preferable.
  • the “aryl group” is, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group.
  • the “C 1-6 alkyl group” is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, It may be an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group, or a hexyl group, and is preferably a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms ( C 1-4 alkyl group), more preferably a methyl group.
  • the “heteroaryl group (the heteroaryl may be condensed with a benzene ring)” is, for example, a pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, furyl group, thienyl group.
  • Benzofuryl group benzothienyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, pyrrole group, pyrazolyl group, imidazolyl group, triazolyl group, benzoxazolyl group or benzothiazolyl group, preferably 5 members Or a 6-membered heteroaryl group (the heteroatoms on the heteroaryl ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) (“heteroaryl More preferably a pyridyl group, pyrazinyl group, pyrimidyl group, Group, a thienyl group, a thiazolyl group or a pyrazolyl group.
  • the “heterocyclyl group” is a monocyclic or bicyclic 3 to 10 member containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • a saturated or unsaturated heterocyclic group such as aziridinyl group, azetidinyl group, pyrrolidinyl group, morpholinyl group, pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isothiazolyl group, pyranyl group, Pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, benzimidazolyl group, benzoxazolyl group, quinolyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyridyl group, tetrahydropyridyl group, etc. Or a 6-membered heterocyclyl group, more preferably Enyl group, a pyridyl group, a tetrahydropyranyl group, an isoxazo
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
  • the “C 1-6 haloalkyl group” is the above “C 1-6 alkyl group” substituted with the same or different 1 to 3 “halogen atoms”, for example, , Fluoromethyl group, chloromethyl group, bromomethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group or 2,2,2-trifluoroethyl group, preferably A C 1-3 alkyl group substituted with 1 to 3 chlorine atoms or 1 to 3 fluorine atoms, and more preferably a trifluoromethyl group.
  • the “C 1-6 alkoxy group” is an oxygen atom to which the “C 1-6 alkyl group” is bonded.
  • a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group Preferably, it is an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, and more preferably a methoxy group.
  • the “aryloxy group” is an oxygen atom to which the “aryl group” is bonded, and may be, for example, a phenoxy group or a naphthyloxy group, and is preferably a phenoxy group.
  • the “aralkyl group” is the “C 1-6 alkyl group” substituted with the “aryl group”, for example, a benzyl group or a phenethyl group, preferably , A phenyl-C 1-3 alkyl group, and more preferably a benzyl group.
  • “pharmacologically acceptable salts” include, for example, hydrohalides such as hydrofluoric acid salts, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates.
  • Inorganic salts such as sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salts; organic acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate, maleate; and amino acid salts such as ornithate, glutamate, aspartate Can be mentioned.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention. Is done.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may be taken out from the solvent and become a solvate by leaving it in a solvent, and such a solvate is also encompassed in the present invention. Is done.
  • Compound (I) of the present invention has an optical isomer based on an asymmetric center in the molecule. Unless otherwise specified, in the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.
  • Compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound may be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activating action, and is arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (heart failure). , Including myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), lipid abnormalities It is useful as an active ingredient of a therapeutic or prophylactic agent for renal disease, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease, particularly an anti-arteriosclerotic agent.
  • Production method 1 is a method for producing compound (I) of the present invention from compound (II).
  • X, R 1 , R 2 , and R 3 are as defined above, and R 4 represents a methyl group or an ethyl group.
  • Compound (II) includes compound (IIx) which is a tautomer.
  • compound (II) includes all isomers of tautomers. That is, the compound (II) includes all of the compound (II), the compound (IIx), and a mixture of the compound (II) and the compound (IIx) in an arbitrary ratio.
  • the compound represented by the compound name of compound (II) includes all of compound (II), compound (IIx), and a mixture of compound (II) and compound (IIx) in an arbitrary ratio.
  • This step is a step for producing compound (I) by condensing compound (III) with compound (II) by heating in a solvent inert to the reaction or in the absence of a solvent.
  • Solvents used in this step include organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid; diethyl ether, diisopropyl ether , Tetrahydrofuran, dioxane, dimethoxyethane, or ethers such as tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2 Alcohols such as methoxyethanol, diethylene glycol or glycerol; aromatic hydrocarbons such as benzene, toluene or xylene; or It is a
  • the reaction temperature in this step is usually 40 ° C. to 150 ° C., preferably 50 ° C. to 130 ° C., more preferably 60 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is usually 5 minutes to 72 hours, preferably 15 minutes to 24 hours, and more preferably 30 minutes to 3 hours.
  • Manufacturing method 2 The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
  • R 5 is an alkoxy group, a chlorine atom or an oxazolidinone auxiliary group
  • the oxazolidinone auxiliary group is, for example, 2-oxo A -4-substituted-1,3-oxaloridin-3-yl group, preferably a chiral-2-oxo-4-isopropyl-1,3-oisazolidin-3-yl group, and so on.
  • R a has one or more amino groups (the amino group is a primary or secondary amino group, including a cyclic amino group) or a carbonyl group, and is converted to R 1 by Step 2-3. Represents a group.
  • Compound (IV), which is a starting material for this step may be a commercially available product, or can be produced by esterifying, amidating, or acidifying a known benzoic acid compound by a conventional method. .
  • compound (IV) is produced by reacting compound (IV) with acetonitrile in an inert solvent using a base. It is a process.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably sodium hydride or n-butyllithium.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 0 ° C., and more preferably ⁇ 78 ° C. to ⁇ 40 ° C.
  • the reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.
  • this step is a step of producing compound (V) by reacting compound (IV) with cyanoacetic acid using a base in an inert solvent when R 5 is a chlorine atom. is there.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably n-butyllithium.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 0 ° C., and more preferably ⁇ 78 ° C. to ⁇ 40 ° C.
  • the reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.
  • Step 2-2 This step is a step for producing compound (II) by reacting compound (V) with a hydrazine compound in an inert solvent.
  • Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably alcohols, more preferably ethanol.
  • the hydrazine compound used in this step is anhydrous hydrazine, hydrazine monohydrate, hydrazine hydrochloride, hydrazine acetate, hydrazine sulfate, hydrazine nitrate, hydrazine hydrobromide, hydrazine oxalate, or hydrazine phosphate.
  • Preferred is hydrazine monohydrate or hydrazine acetate.
  • the reaction temperature in this step is preferably 20 ° C. to 120 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 10 minutes to 24 hours, and more preferably 1 hour to 5 hours.
  • Step 2-3 This step is a step of producing compound (IV) by reacting compound (VI) with a heteroarylating agent in the presence of a base in an inert solvent when R a has an amino group. is there.
  • Solvents used in this step include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Alcohols; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; or ketones such as acetone.
  • Examples of the base used in this step include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Potassium.
  • the reaction temperature in this step is preferably ⁇ 30 ° C. to 100 ° C., and more preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is preferably 30 minutes to 24 hours, and more preferably 1 hour to 10 hours.
  • the heteroarylating agent used in this step is a compound having the formula R b —Cl, the formula R b —Br or the formula R b —I, preferably the formula R b —Br or the formula R b —I (R b represents a heteroaryl group or a substituted heteroaryl in the Q1 group).
  • R a of compound (VI) has a carbonyl group
  • compound (VI) is reduced by reducing compound (VI) in an inert solvent or in the absence of a solvent. Is a process of manufacturing.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol , Tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or alcohols such as glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, Or amides such as hexamethylphosphorotriamide; ketones such as acetone; or dichloromethane, dichloroethane, chloroform Alkyl halides can be mentioned a, preferably, ethers, amides,
  • Examples of the combination of reagents used in this step include palladium-carbon and hydrogen, aluminum chloride and lithium aluminum hydride, or triethylsilane and trifluoroacetic acid, and preferably triethylsilane and trifluoroacetic acid.
  • the reaction temperature in this step is preferably ⁇ 30 ° C. to 50 ° C., and more preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is preferably 30 minutes to 48 hours, and more preferably 5 hours to 24 hours.
  • Production method 3 is a method for producing compound (I) of the present invention from compound (V).
  • Step 3-1 This step is a step for producing compound (IIa) by reacting compound (V) with a diphenylmethylhydrazine compound in an inert solvent.
  • Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably alcohols, more preferably ethanol.
  • the diphenylmethyl hydrazine compound used in this step can be anhydrous diphenylmethyl hydrazine, diphenylmethyl hydrazine hydrochloride, diphenylmethyl hydrazine acetate, etc., and is preferably diphenylmethyl hydrazine hydrochloride or diphenylmethyl hydrazine acetate.
  • the reaction temperature in this step is preferably 20 ° C. to 120 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 10 minutes to 24 hours, and more preferably 1 hour to 5 hours.
  • Step 3-2 In this step, compound (Ia) is produced by condensing compound (III) with compound (III) by heating in a solvent inert to the reaction or in the absence of a solvent.
  • This step can be performed under the same conditions as in step 1.
  • Step 3-3 This step is a step for producing compound (I) by removing the diphenylmethyl group of compound (Ia) in an inert solvent.
  • Examples of the reagent used for removing the diphenylmethyl group in the compound (IIa) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like, which can remove the trityl group described in the above.
  • Solvents used in this step are preferably alcohols such as methanol or ethanol: ethers such as tetrahydrofuran or 1,4-dioxane; alkyl halides such as dichloromethane or chloroform; ethyl acetate Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.
  • alcohols such as methanol or ethanol: ethers such as tetrahydrofuran or 1,4-dioxane; alkyl halides such as dichloromethane or chloroform; ethyl acetate Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.
  • the reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, more preferably trifluoroacetic acid, and a compound called a cation scavenger such as triethylsilane, anisole or thioanisole as an additive. It may be used.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.
  • the reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
  • X, R 1 and R 2 are as defined above, and R 6 represents a hydroxyl group, an alkoxy group, or an oxazolidinone auxiliary group.
  • This step is a step for producing compound (IVa) by reacting compound (VII) with an alkylating agent using a base in an inert solvent.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide, n-butyllithium, lithium diisopropyl It can be an organometallic base such as amide, lithium hexamethylene disilazide, sodium hexamethylene disilazide or potassium hexamethylene disilazide, more preferably lithium diisopropylamide or lithium hexamethylene disilazide.
  • the alkylating agent used in this step can be preferably methyl iodide, ethyl iodide or dimethyl sulfate, and more preferably methyl iodide.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 0 ° C., and more preferably ⁇ 78 ° C. to 5 ° C.
  • the reaction time in this step is preferably 30 minutes to 5 hours, and more preferably 30 minutes to 2 hours.
  • the compound represented by the formula (IVb) can be produced, for example, by the following method.
  • R 1 is as defined above, R 7 is a methyl group or an ethyl group, R 8 is a hydrogen atom, a methyl group, or an ethyl group, X a is a chlorine atom, a bromine atom, And an iodine atom.
  • Step 5-1 This step is a step for producing compound (X) by reacting compound (VIII) with malonic ester compound (IX) using a palladium catalyst.
  • Step 5-2 This step is a step of producing compound (IVb) from compound (X) under acidic conditions or basic conditions.
  • the solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an aromatic hydrocarbon such as toluene; or a mixture thereof. It is a solvent, more preferably an alcohol or an ether, and still more preferably ethanol or 1,4-dioxane.
  • the reagent used in this step is preferably hydrochloric acid or a sodium hydroxide aqueous solution.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 20 ° C. to 70 ° C.
  • the reaction time in this step is preferably 1 hour to 10 hours, and more preferably 2 minutes to 6 hours.
  • R 1 is as defined above, R 7 represents a methyl group or an ethyl group, and X b represents a chlorine atom, a bromine atom, or an iodine atom.
  • Step 6 This step is a step for producing compound (IVc) by reacting compound (XI) with compound (XII) in the presence of a base in an inert solvent.
  • Solvents used in this step include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Alcohols; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; or ketones such as acetone.
  • Examples of the base used in this step include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Cesium.
  • the reaction temperature in this step is preferably ⁇ 30 ° C. to 150 ° C., and more preferably 20 ° C. to 100 ° C.
  • the reaction time in this step is preferably 30 minutes to 24 hours, and more preferably 1 hour to 10 hours.
  • R 2 and R 3 are as defined above, and X 1 is a chlorine atom, a bromine atom, an iodine atom, or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
  • R 9 represents an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group in the Q1 group
  • X 2 represents B (OH) 2 , a bromine atom, or Indicates an iodine atom.
  • Step 7 a halogenated compound (IIb) in which X 1 is a chlorine atom, a bromine atom, or an iodine atom is converted into an organoboron compound in which X 2 is B (OH) 2 by a Suzuki-Miyaura reaction using a palladium catalyst.
  • compound (IIc) is produced by reacting with halogenated compound (XIII) wherein X 2 is bromine atom or iodine atom by Suzuki-Miyaura reaction.
  • the palladium catalyst, ligand, base and reaction conditions used in this step are not particularly limited as long as they are reagents and conditions used in the usual Suzuki-Miyaura reaction. Miyaura, A .; Suzuki, Chem. Rev. 1995, volume 95, p. 2457 and the like.
  • Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; water; or a mixed solvent thereof And is preferably a mixed solvent of ethers and water, and more preferably a mixed solvent of 1,4-dioxane and water.
  • the palladium catalyst used in this step is preferably tetrakistriphenylphosphine palladium or [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate, or an organic metal base such as sodium tert-butoxide or potassium tert-butoxide. More preferably, it is potassium carbonate.
  • Manufacturing method 8 is a method for producing compounds (Ic) and (Id) of the present invention from compound (XIV).
  • R x represents an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group in the Q1 group, and Boc is tert. -Represents a butoxycarbonyl group.
  • Step 8-1 This step is a step of producing compound (Ic) by removing the Boc group in compound (XIV).
  • reagents used for removing Boc in compound (XIV) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like which can remove Boc described in the above.
  • the solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an alkyl halide such as dichloromethane or chloroform; Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.
  • an alcohol such as methanol or ethanol
  • an ether such as tetrahydrofuran or 1,4-dioxane
  • an alkyl halide such as dichloromethane or chloroform
  • Esters such as toluene
  • aromatic hydrocarbons such as toluene
  • a mixed solvent thereof more preferably alkyl halides, and still more preferably dichloromethane.
  • the reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.
  • the reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
  • Step 8-2 This step is a step for producing compound (Id) by reacting compound (Ic) with an arylating agent or heteroarylating agent.
  • This step can be performed under the same conditions as in step 2-3 (i).
  • the product of each of the above steps is a free compound or a salt thereof, after completion of the reaction, if necessary, a conventional method, for example, (1) a method of concentrating the reaction solution as it is, or (2) filtering insoluble matter such as a catalyst. (3) A method in which water and a solvent immiscible with water (for example, dichloroethane, diethyl ether, ethyl acetate, toluene, etc.) are added to the reaction solution, and the product is extracted (4) )
  • the crystallized or precipitated product can be isolated from the reaction mixture, such as by filtration.
  • the isolated product can be purified by a conventional method such as recrystallization, reprecipitation, various chromatographies and the like, if necessary.
  • the product of each step can be used in the next step without isolation or purification.
  • Compound (I) of the present invention is isolated and purified as a free compound, a pharmacologically acceptable salt, hydrate, or solvate thereof.
  • the pharmacologically acceptable salt of the compound (I) of the present invention can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.
  • Various isomers can be separated by utilizing differences in physicochemical properties between isomers.
  • a racemic mixture can be converted to an optically pure isomer, such as by fractional crystallization leading to a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column.
  • the diastereo mixture can be separated by fractional crystallization or various chromatographies.
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • Examples of the administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration by tablet, granule, powder, capsule or syrup, or injection or suppository. Parenteral administration, and the like, and can be administered systemically or locally.
  • Examples of the oral pharmaceutical form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, Examples include syrups and elixirs.
  • Examples of pharmaceutical forms for parenteral use include injections, ointments, gels, creams, patches, sprays, inhalants, sprays, eye drops, and suppositories. These forms of pharmaceuticals are pharmaceutically acceptable, such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffering agents, or wetting agents.
  • the additive can be prepared according to a conventional method using additives appropriately selected as necessary.
  • the dosage of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is as follows: symptoms, body weight, age, administration method of the administered person (warm-blooded animal, eg, human) Varies depending on etc.
  • the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). It is desirable to administer one to several times a day depending on the symptoms.
  • the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). Is preferably administered one to several times per day depending on the symptoms.
  • hexane represents n-hexane
  • THF represents tetrahydrofuran
  • IPA 2-propanol
  • DMF represents N, N′-dimethylformamide
  • DMSO dimethyl sulfoxide
  • n-butyllithium (2.69 M hexane solution, 100 mL, 0.269 mol) was added dropwise at ⁇ 78 ° C. and stirred for 15 minutes. Further, at the same temperature, a solution of the crude product obtained in the above operation in anhydrous THF (100 mL) was added dropwise and stirred for 1 hour. 2M hydrochloric acid was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • N-Butyllithium (2.69 M hexane solution, 32.6 mL, 87.7 mmol) was added dropwise at ⁇ 78 ° C. to a solution of anhydrous acetonitrile (4.60 mL, 87.9 mmol) in anhydrous THF (200 mL) at the same temperature. After stirring for 30 minutes, a solution of methyl 2- (4-chlorophenyl) propionate (1.01 g, 4.76 mmol) in anhydrous THF (200 mL) was added dropwise at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 45 minutes.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • reaction solution was allowed to cool to room temperature and filtered, and then the solvent of the filtrate was distilled off under reduced pressure.
  • N-Butyllithium (2.69 M hexane solution, 5.80 mL, 15.6 mmol) was added dropwise at ⁇ 78 ° C. to a solution of anhydrous acetonitrile (0.85 mL, 16.2 mmol) in anhydrous THF (25 mL) at the same temperature. After stirring for 30 minutes, a solution of ethyl 2- (1-benzofuran-2-yl) propionate (1.13 g, 5.18 mmol) prepared in Reference Example 45 in anhydrous THF (25 mL) was added dropwise at ⁇ 78 ° C. And stirred for 45 minutes at the same temperature.
  • reaction solution was allowed to stand at room temperature, water was added, extraction was performed with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure.
  • Potassium carbonate (2.70 g, 19.5 mmol) was added to a mixed solution of the crude product obtained in the above operation in ethanol (50 mL) and water (25 mL), and stirred for 18 hours while heating under reflux. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the carboxylic acid compound Got.
  • Test Example 1 Measurement of LCAT activity (in vitro) A density gradient centrifugation was performed to obtain a fraction composed of HDL3 (1.125 ⁇ specific gravity ⁇ 1.210 g / mL) from plasma of a healthy person. The obtained fraction was dialyzed with phosphate buffered saline (pH 7.4) and used as an enzyme source and acceptor of LCAT. The test drug was prepared by dissolving in dimethyl sulfoxide.
  • the radioactivity of the portion corresponding to cholesterol oleate was measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Samples to which no test drug was added were similarly processed and measured. Using the following equation, compared with no addition of test drug was calculated EC 50 values of LCAT activation. The results are shown in Table 1.
  • X represents the logarithm of the concentration of the test drug
  • Y represents the response of the test drug (LCAT activity)
  • Top indicates the maximum value (maximum plateau)
  • Bottom indicates a minimum value (minimum flat area);
  • EC 50 indicates a 50% effective concentration.
  • the compound of the present invention has an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.
  • Test Example 2 Measurement of LCAT activity (plasma) Human, cynomolgus monkey or human LCAT transgenic mouse plasma is used as an enzyme source and acceptor for LCAT.
  • the test drug is prepared by dissolving in dimethyl sulfoxide. [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin was added to 5 ⁇ L of each plasma and 45 ⁇ L of PBS. Add the test drug at a concentration to make the total volume 80 ⁇ L. After incubating this mixture at 37 ° C.
  • X represents the logarithm of the concentration of the test drug
  • Y represents the response of the test drug (LCAT activity)
  • Top indicates the maximum value (maximum plateau)
  • Bottom indicates a minimum value (minimum flat area);
  • EC 50 indicates a 50% effective concentration.
  • DTNB Ielman's reagent, final concentration 0.26 mM
  • mercaptoethanol final concentration 2 mM
  • bovine serum albumin 0.6% bovine serum albumin
  • the radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Compared with the LCAT activity before administration, the rate of change in LCAT activation at each time point is calculated.
  • Test Example 4 Cynomolgus monkey efficacy test
  • the test drug was propylene glycol (Sigma-Aldrich) -Tween 80 (Sigma-Aldrich) mixed solution [4/1 (v / v)] or 0.5% (w / v) Dissolve in aqueous methylcellulose and administer orally to cynomolgus monkeys for 1 or 7 days. Blood is collected before and after administration on the 1st or 7th day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.
  • HDL cholesterol content plasma cholesterol content ⁇ (HDL cholesterol peak area / sum of each peak)
  • non-HDL cholesterol content plasma cholesterol content ⁇ (peak area of non-HDL cholesterol / sum of each peak)
  • the increase rate (%) of HDL after a single administration of 10 mg / kg as compared to before administration was determined from AUC before administration and 24 hours after administration, and the results are shown in Table 2.
  • Test Example 5 Human LCAT transgenic mouse drug efficacy test The test drug was dissolved in polypropylene glycol-Tween 80 mixed solution [4/1 (v / v)] or 0.5% (w / v) methylcellulose aqueous solution, Human LCAT transgenic mice are orally administered for 1, 4 or 7 days. Blood is collected before and after administration on the first, fourth or seventh day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.
  • HDL cholesterol content plasma cholesterol content ⁇ (HDL cholesterol peak area / sum of each peak)
  • non-HDL cholesterol content plasma cholesterol content ⁇ (peak area of non-HDL cholesterol / sum of each peak)
  • Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
  • Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and in particular, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease.
  • arteriosclerosis arteriosclerotic heart disease
  • coronary heart disease including acute coronary syndrome, heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorders and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (peripheral arterial disease, Treatment of diabetic vascular complications), dyslipidemia, LCAT deficiency, low HDL cholesterolemia, high LDL cholesterolemia, diabetes, hypertension, metabolic syndrome, Alzheimer's disease, corneal opacity, or renal disease or It is useful as an active ingredient of prophylactic agents, particularly anti-arteriosclerotic agents.

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Abstract

　L'invention concerne un composé représenté par la formule (dans la formule, R2 et R3 représentent tous les deux des atomes d'hydrogène ou forment un cycle cyclopropyle ou un cycle cyclobutyle conjointement aux atomes de carbone qui les lient, R1 représente un groupe sélectionné parmi le groupe Q1, et X représente une simple liaison; ou R3 représente un atome d'hydrogène, et R1 et R2 sont identiques ou différents et représentent des groupes sélectionnés parmi le groupe Q1), le composé ayant un effet d'activation exceptionnel de la LCAT et étant utile comme principe actif d'un agent de traitement ou de prévention de l'artériosclérose, de la cardiopathie due à l'artériosclérose, de l'insuffisance coronaire (comprenant l'insuffisance cardiaque, l'infarctus du myocarde, l'angine de poitrine, l'ischémie cardiaque, les troubles cardiovasculaires, et la resténose consécutive à l'angioplastie), la maladie cérébrovasculaire (comprenant l'accident vasculaire cérébral et l'infarctus cérébral), la maladie vasculaire périphérique (comprenant les complications vasculaires associées au diabète), la dyslipidémie, le faible taux de cholestérol HDL, ou l'insuffisance rénale, et spécialement étant utile comme agent anti-artériosclérotique.
PCT/JP2014/080847 2013-11-25 2014-11-21 Dérivé 3-alkylpyrazolopyridine Ceased WO2015076353A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12054479B1 (en) 2022-03-14 2024-08-06 Slap Pharmaceuticals Llc Multicyclic compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56108712A (en) * 1980-01-31 1981-08-28 Dai Ichi Seiyaku Co Ltd Lecithin cholesterol acyl transferase activator
JPH02142728A (ja) * 1988-08-25 1990-05-31 Merrell Dow Pharmaceut Inc 抗アテローム性動脈硬化症剤及び抗過コレステリン血症剤としてのピラゾロピリジン誘導体
US5478830A (en) * 1992-05-29 1995-12-26 The Du Pont Merck Pharmaceutical Company Fused-ring heterocycles for the treatment of atherosclerosis
JP2013536807A (ja) * 2010-09-02 2013-09-26 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｌｐａ受容体アンタゴニストとしてのピラゾロピリジノン誘導体
WO2013187462A1 (fr) * 2012-06-14 2013-12-19 第一三共株式会社 Dérivé de pipéridinylpyrazolopyridine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56108712A (en) * 1980-01-31 1981-08-28 Dai Ichi Seiyaku Co Ltd Lecithin cholesterol acyl transferase activator
JPH02142728A (ja) * 1988-08-25 1990-05-31 Merrell Dow Pharmaceut Inc 抗アテローム性動脈硬化症剤及び抗過コレステリン血症剤としてのピラゾロピリジン誘導体
US5478830A (en) * 1992-05-29 1995-12-26 The Du Pont Merck Pharmaceutical Company Fused-ring heterocycles for the treatment of atherosclerosis
JP2013536807A (ja) * 2010-09-02 2013-09-26 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｌｐａ受容体アンタゴニストとしてのピラゾロピリジノン誘導体
WO2013187462A1 (fr) * 2012-06-14 2013-12-19 第一三共株式会社 Dérivé de pipéridinylpyrazolopyridine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12054479B1 (en) 2022-03-14 2024-08-06 Slap Pharmaceuticals Llc Multicyclic compounds

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