WO2002014277A1 - Composes de biphenylcarboxamidoisoindoline, procedes de preparation de ceux-ci et produits intermediaires destines a la synthese de ceux-ci - Google Patents

Composes de biphenylcarboxamidoisoindoline, procedes de preparation de ceux-ci et produits intermediaires destines a la synthese de ceux-ci Download PDF

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WO2002014277A1
WO2002014277A1 PCT/JP2001/006844 JP0106844W WO0214277A1 WO 2002014277 A1 WO2002014277 A1 WO 2002014277A1 JP 0106844 W JP0106844 W JP 0106844W WO 0214277 A1 WO0214277 A1 WO 0214277A1
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group
substituted
unsubstituted
lower alkyl
ring
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PCT/JP2001/006844
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English (en)
Japanese (ja)
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Harutami Yamada
Akira Ando
Hiroyuki Kawanishi
Koichi Nagata
Mikiko Yasuhara
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Tanabe Seiyaku Co., Ltd.
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Priority to AU2001277728A priority Critical patent/AU2001277728A1/en
Publication of WO2002014277A1 publication Critical patent/WO2002014277A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C07D401/06—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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

Definitions

  • the present invention relates to a novel biphenylcarboxamide isoindoline compound having an excellent apolipoprotein B (ApoB) secretion inhibitory effect and a serum lipid lowering effect, and being useful as a medicament, a process for producing the same, and a synthetic intermediate thereof.
  • ApoB apolipoprotein B
  • WO 96/40640 discloses 4,1-trifluoromethyl-piphenyl-l-carboxylic acid [2- (thiophen-l-yl-l-acetyl) l 1,2,3, 4-tetrahydroisoquinoline-1-6-yl] one amide, 4,1-trifluoromethyl-pyphene-2-lu-2-carboxylic acid [2- (pyridine-12-yl-1-acetyl) 1-1,2,3 , 4-tetrahydroisoquinoline-1-6-yl] -amide and the like, and WO Patent Publication No.
  • WO98 / 23953 disclose 4,1-trifluoromethyl-1-biphenyl-2-fluoro-2-carboxylic acid [ 2- (2- (pyridine-1-yl) ethyl) -1,2,3,4-tetrahydroisoquinoline-16-yl] -amide, etc. has ApoB secretion inhibitory activity, It has been suggested that it can be used as a lipid lowering agent.
  • the present invention provides a novel biphenylcarboxamide isoindoline compound having an excellent apolipoprotein B secretion inhibitory action and a serum lipid lowering action. Further, the present invention also provides a method for producing such a novel compound and a synthetic intermediate thereof. Disclosure of the invention
  • the present inventors have conducted intensive studies and as a result, have found a novel biphenylcarpoxamido soindrin compound having an apolipoprotein B secretion inhibitory action and a serum lipid lowering action, and completed the present invention.
  • ring A is a substituted or unsubstituted benzene ring
  • ring B is a substituted or unsubstituted benzene ring
  • Q is one CO— or one CH 2 —
  • R is a substituted or unsubstituted lower alkyl group, substituted Or an unsubstituted lower alkenyl group, a substituted or unsubstituted radical group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group;
  • Examples of the substituent on the ring A in the target compound [I] of the present invention include:
  • cyano group an unsubstituted rubamoyl group, or a labamoyl group substituted with a group selected from a lower alkyl group, a lower alkoxy lower alkyl group, a halogeno lower alkyl group, and an aryl lower alkyl group;
  • Ring A may be substituted with 1 to 3 identical or different groups selected from the above (1) to (10).
  • Examples of the substituent on ring B in the target compound [I] of the present invention include, for example,
  • an unsubstituted amino group or (i) a lower alkanol group substituted with 1 to 3 identical or different groups selected from a lower alkoxy group, an amino group, a lower alkylamino group and a lower alkoxycarbonyl group A group selected from (ii) an amino-protecting group, (iii) an unsubstituted lower alkyl group, or a pyridyl group, or a lower alkyl group substituted with a lower alkylamino group, and (i V) a pyridylcarbonyl group.
  • Substituted amino group or (i) a lower alkanol group substituted with 1 to 3 identical or different groups selected from a lower alkoxy group, an amino group, a lower alkylamino group and a lower alkoxycarbonyl group A group selected from (ii) an amino-protecting group, (iii) an unsubstituted lower alkyl group, or a pyridy
  • Ring B may be substituted with 1 to 3 identical or different groups selected from the above (1) to (9).
  • R in the target compound [I] of the present invention is a substituted or unsubstituted lower alkyl group
  • the substituent on the lower alkyl group is
  • an unsubstituted aryl or unsubstituted fluorenyl group or a lower alkyl group an unsubstituted amino group or a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, or a lower alkylaminocarbonyl
  • An amino group substituted with a halogeno lower alkylaminocarboyl group, a lower alkanoyl group, or a halogeno lower alkanoyl group a lower alkoxy group; an aryl lower alkoxy group; a benzyloxy lower alkoxy group; a lower alkylamino lower alkoxy group; A hydroxyl group or a protected hydroxyl group; a lower alkyl group rubamoyl group; a halogeno lower alkyl group rubamoyl group; An aryl group or a fluorenyl group substitute
  • V i i an amino group substituted with an unsubstituted amino group or an amino-protecting group, a lower alkyl group, a pyridyl group, or a pyrimidinyl group;
  • the lower alkyl group for R may be substituted with the same or different 1 to 3 groups selected from the above (i) to (iX).
  • R in the target compound [I] of the present invention is a substituted or unsubstituted lower alkenyl group
  • substituent on the lower alkenyl group include an aryl group.
  • R in the target compound [I] of the present invention is a substituted or unsubstituted rubamoyl group
  • substituent on the rubamoyl group include a lower alkyl group, a halogeno lower alkyl group, and a benzothiazolyl group.
  • the substituted or unsubstituted carbamoyl group includes a compound represented by the formula: In the formula, m represents an integer of 0 to 4,
  • R in the target compound [I] of the present invention is a substituted or unsubstituted heterocyclic group
  • substituent on the heterocyclic group include a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, and an amino group.
  • the heterocyclic group for R may be substituted with the same or different 1 to 3 groups selected from the above substituents.
  • the heterocyclic group includes, for example, at least one heterocyclic group selected from nitrogen, oxygen, and sulfur. And monocyclic, bicyclic, or tricyclic heterocyclic groups containing a term atom.
  • R in the target compound [I] of the present invention is a substituted or unsubstituted aryl group
  • substituent on the aryl group include a lower alkyl group, a lower alkoxy group, a lower alkyl group, a lubamoyl group, and a halogeno lower alkyl group.
  • substituent on the aryl group include a rubamoyl group, a morpholinyl group, an amino group, a lower alkylamino group, a hydroxyl group or protected water, and a protected amino group.
  • the aryl group in R may be substituted with 1 to 3 identical or different groups selected from the above substituents.
  • R in the target compound [I] of the present invention is a substituted or unsubstituted aryl group
  • specific examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, and a phenanthryl group.
  • the protective group for the amino group include a substituted or unsubstituted lower alkoxy carbonyl group, a lower alkenyloxycarbonyl group, an acyl group, a substituted or unsubstituted aryl group substituted lower alkyl group, a lower alkenyl group and the like.
  • Specific examples thereof include those substituted with a halogen atom such as an ethoxycarbonyl group, a methoxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group, or a non-substituted halogen atom.
  • a lower alkyl group substituted or unsubstituted with a lower alkoxy group such as a benzyl group or a 4-methoxybenzyl group, a lower alkenyl group such as an aryl group, and a 9-fluorenylmethoxycarboxy group are also exemplified.
  • a substituted or unsubstituted lower alkoxycarbonyl group specifically, a benzyloxycarbonyl group and a tert-butoxycarbonyl group.
  • the protected amino group also includes, for example, a case where a phthalimid group is formed together with the protected amino group.
  • the protective group for the hydroxyl group may be a substituted or unsubstituted aryl lower alkyl group, an acyl group, a substituted or unsubstituted lower alkoxycarbonyl group.
  • protecting groups such as trialkylsilyl groups.
  • unsubstituted aryl aryl lower alkyl groups such as benzyl group, phenethyl group, etc., formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, benzoyl group, etc., methoxycarbonyl group.
  • Ring B has the formula:
  • R is the formula:
  • p 1 or 2
  • Ring C is a pyridine, pyrrol, thiazole, pyrimidine, pyrazole, triazole, or tetrazole ring,
  • R 3 and R 4 may be the same or different, and are each selected from a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a nitro group, a lower alkoxycarbonyl group, a carboxyl group, a cyano group, or an amino group Group,
  • Ring B has the formula:
  • R 3 and R 4 may be the same or different and each represents a hydrogen atom, A group selected from alkyl, cyano, or amino;
  • Ring B has the formula:
  • R is the formula:
  • R 3 and R 4 may be the same or different, and each is a group selected from a hydrogen atom, a cyano group, or an amino group;
  • Ring B has the formula:
  • R 2 is a hydrogen atom, a lower alkoxy group, a lower alkylamino lower alkoxy group, a pyridyl lower alkoxy group, a (lower alkylamino) phenyl lower alkoxy group, a pyrrolidino lower alkoxy group, a hydroxy lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkyl Rbamoyl lower alkoxy group, lower alkylamino lower alkanoylamino group, pyridylcarbonylamino group, lower alkylamino lower alkylamino group, or lower alkoxycarbonyl group, R is selected from the following (1) to (3) Lower alkyl group substituted with a group: (1) selected from unsubstituted pyrazolyl group or lower alkyl group or nitro group A pyrazolyl group substituted with a group
  • R 1 is a trifluoromethyl group or a lower alkanoyl group
  • Ring B is an unsubstituted benzene ring or a group selected from a lower alkoxy group, a (lower alkylamino) lower alkanoylamino group, a lower alkylamino lower alkoxy group, a lower alkyl group, a rubamoyl group and a lower alkoxycarbonyl group; Substituted benzene ring,
  • R is a lower alkyl group substituted by a group selected from the following (1) to (5):
  • Ring B is a benzene ring
  • particularly preferred compounds include, for example, 2- (1H-pyrazole-111-yl) acetyl- 15- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline ,
  • the target compound [I] of the present invention can exist as an optical isomer based on the asymmetric atom.
  • the present invention includes any of these optical isomers and mixtures thereof. It is.
  • the target compound [I] of the present invention or a pharmacologically acceptable salt thereof has an inhibitory effect on apolipoprotein B secretion and has an excellent serum lipid lowering effect.
  • the target compound [I] of the present invention or a pharmacologically acceptable salt thereof includes hyperlipidemia, ischemic heart disease, atherosclerosis, coronary atherosclerosis, hypercholesterolemia, hypertriglyceride.
  • Blood, familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary arteriosclerosis, coronary heart disease, ischemic brain disease, stroke, circulatory and microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute Prevention of hemorrhagic inflammation, obesity, steatosis, constipation, etc.-It can be applied to treatment.
  • the target compound [I] of the present invention has the characteristics of low toxicity and high safety as a medicine.
  • the target compound [I] of the present invention can be used in a free form or in the form of a pharmaceutically acceptable salt for pharmaceutical use.
  • Pharmaceutically acceptable salts of compound [I] include, for example, inorganic salts such as hydrochloride, sulfate, phosphate or bromide hydrochloride, acetate, fumarate, oxalate Organic salts such as citrate, methanesulfonate, benzenesulfonate, tosylates or maleates may be used.
  • a salt with a base for example, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt
  • the target compound [I] of the present invention or a salt thereof includes any of its inner salts and adducts, solvates and hydrates thereof.
  • the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and tablets, granules, capsules, powders, injections, inhalants, etc. It can be used as a conventional pharmaceutical preparation such as an agent.
  • the dosage of the compound of interest [I] of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, age of the patient, weight and condition. 0.01 to 5 mg / kg, especially about 0.1 to 3 mgZkg, for oral preparation, usually about 0.1 to per day; L 00 mg / kg, especially about 0.1 to 5 Omg / kg Is preferred.
  • the target compound [I] can be produced by the following (Method A) to (Method H), but is not limited thereto.
  • the biphenylcarpo and xamidoisoindoline compounds represented by the target compound [I] of the present invention have the general formula [5]:
  • the compound can be produced by reacting a compound represented by the formula (I) or a salt thereof.
  • This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, in the presence or absence of a base group.
  • the solvent may be any solvent that does not adversely affect the reaction, for example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, benzene, 1,2-dichloroethane And 1-methylpyrrolidinone.
  • condensing agent examples include dicyclohexyl carpoimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carpoimide “hydrochloride (WS C ⁇ HC 1), diphenylphosphoryl azide ( DPPA), carbonyldiimidazole (CDI), getylcyanophosphonate (DEPC), diisopropylcarboimide (DIPCI), benzotriazole-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (PvBOP) ), 2, 4, 6-triclo-mouth benzoyl chloride.
  • DCC dicyclohexyl carpoimide
  • WS C ⁇ HC 1 1-ethyl-3- (3-dimethylaminopropyl) carpoimide “hydrochloride
  • DPPA diphenylphosphoryl azide
  • CDI carbonyldiimidazole
  • DEPC gety
  • Examples of the activator include 1-hydroxybenzotriazole (HOB t), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy xy 7-azabenzotriazole (HOAt), Hydroxyphthalimid (HOPht), pentafluorophenol (Pfp-OH) and the like.
  • Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-indene (DBU) and the like.
  • the amount of the condensing agent to be used is 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [5] or compound [6].
  • the amount of the activating agent to be used is 1 to; L equivalent, preferably 1 to 2 equivalent, relative to compound [5] or compound [6]. This reaction can be carried out, for example, at 0 to 100 ° C, preferably at 0 to 50 ° C.
  • compound [I] can also be obtained by converting compound [6] to a reactive derivative such as acid chloride or mixed acid anhydride and then reacting with compound [5] in the presence of a base.
  • a reactive derivative such as acid chloride or mixed acid anhydride
  • the biphenylcarboxamidoisoindoline compound represented by the target compound [I] of the present invention also has the general formula [15]:
  • X 1 represents a leaving group, and other symbols have the same meanings as described above, or a salt thereof, and a compound represented by the general formula [16]:
  • M is a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group,
  • a metal which may be coordinated by the same or different group (s) selected from a group selected from the group consisting of a hydroxyl group, a lower alkoxy group, an alkylenedioxy group, an aryloxy group, an arylenedioxy group and an arylthio group.
  • the other symbols have the same meanings as above.
  • This reaction can be carried out in a solvent, in the presence of a catalyst / in the presence or absence of a base, in the presence or absence of an additive.
  • the solvent may be any solvent that does not adversely affect the reaction, for example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, xylene, water, 1-methylpyrrolidinone , Dimethoxyethane, dioxane, getylamine, triethylamine and the like.
  • the metal of M include boron, tin, silicon, zinc, magnesium, aluminum, lithium, nickel, and the like.
  • Examples of the catalyst include, for example, palladium acetate, tetrakistriphenylphosphine palladium, bistriphenylphosphinepalladium dichloride, bis (dibenzylideneacetone) palladium, bisbenzonitrile palladium dichloride and the like.
  • Examples of the base include sodium carbonate, potassium carbonate, potassium phosphate, triethylamine, diisopropylethylamine and the like.
  • Examples of additives include triphenylphosphine, tri-tolylphosphine, tri-n-butylphosphine, copper [I] bromide, copper iodide [I], triphenylarsine, and tri (2-furyl).
  • the amount of compound [16] to be used is 1 to 5 equivalents, preferably 1 to 1.5 equivalents, relative to compound [15].
  • the amount of the catalyst to be used is 0.001 to 0.5 equivalent, preferably 0.05 to 0.2 equivalent, relative to compound [15].
  • the amount of the base to be used is 1-20 equivalents, preferably 1-5 equivalents, relative to the compound [15].
  • the amount of the additive to be used may be 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [15].
  • the reaction is For example, it can be carried out at 0 to 150 ° C, preferably 30 to 120 ° C.
  • the leaving group X 1 include a fluorine atom, a chlorine atom, a halogen atom such as a bromine atom or an iodine atom, and a trifluoromethanesulfonyloxy group.
  • This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activating agent, in the presence or absence of a base group.
  • the solvent may be any solvent that does not adversely affect the reaction, and for example, those exemplified as the solvent that can be used in the reaction of the above (Method A) can be used as appropriate.
  • Base or activity As the agent, for example, those exemplified in the reaction of the above (Method A) can be used as appropriate.
  • the compound [I-a] can also be obtained by converting the compound [2] to a reactive derivative such as an acid chloride or a mixed acid anhydride and then reacting the compound [13] with a compound [13] in the presence of a base. it can.
  • a reactive derivative such as an acid chloride or a mixed acid anhydride
  • the biphenylcarboxamidoisoindoline compound represented by the formula can be produced by subjecting a compound represented by the general formula Cl-al or a salt thereof to a reduction reaction.
  • the reduction reaction can be carried out in a solvent in the presence of a suitable reducing agent.
  • the solvent may be any solvent that does not adversely affect the reaction, and examples thereof include tetrahydrofuran, getyl ether, dioxane, and dimethoxetane.
  • Suitable reducing agents include, for example, sodium boroborodiethyl borotriethyl ether complex, lithium aluminum hydride, aluminum hydride, lithium borohydride, diborane-dimethyl sulfide complex, diborane-tetrahydrofuran complex And the like.
  • the amount of the reducing agent to be used is 1 to 10 equivalents, preferably 1 to 2 equivalents, per 1 mol of the compound [Ia]. This reaction can be carried out, for example, at 130 to 100 ° C, preferably 0 to 50 ° C.
  • the carboxamide isoindoline compound may also be a compound represented by the general formula [13] or a salt thereof, and a compound represented by the general formula [17]:
  • the above condensation reaction can be carried out in a solvent in the presence or absence of a base, and the subsequent reduction reaction can be carried out in the presence of a reducing agent.
  • the solvent used for the condensation reaction or the reduction reaction may be any solvent that does not adversely affect the reaction, for example, methylene chloride, tetrahydrofuran, dioxane, dimethyl ether, methanol, ethanol, isopropyl alcohol, 1 , 2-dichloroethane, water and the like.
  • the base include triethylamine, diisopropylethylamine, 4-methylmorpholine and the like.
  • the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, triacetate, sodium borohydride, sodium palladium carbon and sodium borohydride. include acetate force s.
  • the amount of compound [17] to be used is 1 to 5 equivalents, preferably 1 to 1.5 equivalents, relative to compound [13].
  • the amount of the base to be used is 1-20 equivalents, preferably 1-5 equivalents, relative to compound [13].
  • the amount of the reducing agent to be used is 1-; 0 equivalent, preferably 1-5 equivalent, relative to compound [13].
  • the reaction is carried out, for example, at a temperature of from 30 to 100 ° C, preferably from 0 to 100 ° C.
  • the above condensation reaction and reduction reaction can also be carried out in one pot as a reductive amination reaction.
  • the biphenyl carboxamide doisoindolini conjugate represented by the general formula [I-b] is also compounded with the compound represented by the general formula [13] or a salt thereof, General formula [18]: R—CH 2 —X 2 [1′8]
  • X 2 represents a leaving group, and the other symbols have the same meanings as described above.
  • This reaction can be carried out in a solvent, in the presence of a base, in the presence or absence of an additive.
  • the solvent may be any solvent that does not adversely affect the reaction, and examples include tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethanol, isopropyl alcohol, and acetonitrile.
  • examples include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide and the like.
  • Additives include sodium iodide, copper iodide [I] Examples thereof include copper iodide (11), copper powder, potassium iodide, tetrabutylammonium chloride, and tetra-lower alkylammonium chloride such as tetraethylammonium chloride.
  • the amount of compound [18] to be used is 1 to 5 equivalents, preferably 1 to 1.5 equivalents, relative to compound [13].
  • the amount of the base to be used is 1-20 equivalents, preferably 1-5 equivalents, relative to compound [13].
  • the amount of the additive to be used may be 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [13]. This reaction can be carried out, for example, at a temperature of from 30 to 150 ° C, preferably from 0 to • 80 ° C.
  • the leaving group X 2 is, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, a methanesulfonyloxy group And trifluoromethansulfonyloxy group, hydroxyl group and the like.
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • a trifluoromethanesulfonyloxy group such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • a trifluoromethanesulfonyloxy group such as a fluorine atom, a chlorine atom, a bromine atom or an
  • a Mitsunobu reagent such as triphenylphenylphosphine-diethylazodicarboxylate and triphenylphenylphosphine-diisopropylazodicarboxylate can also be used.
  • P represents a protecting group for a hydroxyl group, and other symbols have the same meanings as described above.
  • biphenylcarpoxamide isoindoline compound represented by the general formula [13] or a salt thereof is represented by the general formula [19]:
  • This reaction can be carried out in a solvent, in the presence of a base, in the presence or absence of an additive.
  • the solvent may be any solvent that does not adversely affect the reaction, and examples thereof include methanol, ethanol, isopropyl alcohol, dimethylformamide, and acetoniryl.
  • Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine and the like.
  • As the additive for example, salt ammonium, yowidani tin (II) and the like can be mentioned.
  • 5 represents a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted aryl group, and other symbols have the same meanings as described above.
  • biphenylcarboxamidoisoindoline compound represented by the general formula [13] And a salt thereof, or a salt thereof, and a general formula [20]:
  • This reaction can be carried out in a solvent, in the presence or absence of a base or acid.
  • the solvent may be any solvent that does not adversely affect the reaction, and examples include methanol, ethanol, and propanol.
  • Examples of the base include triethylamine, diisopropylamine and the like.
  • Examples of the acid include acetic acid, formic acid, p-toluenesulfonic acid and the like.
  • the target compound [I] of the present invention is obtained by converting the substituent on the ring A, the substituent on the ring B and / or the group R of the compound obtained as described above to another desired substituent. Can also be manufactured. Such a method for converting a substituent may be appropriately selected according to the type of the desired substituent, and may be carried out, for example, as in (method a) to (method k).
  • the group R is a substituent containing an unsubstituted lower alkylamino group or a substituted lower alkylamino group (for example, a dimethylamino group). It can be produced from the corresponding compound [I], which is a substituent containing a primary or secondary amino group, and the corresponding aldehyde compound (for example, formaldehyde) by treating in the same manner as in the above (Method E). 'it can.
  • the target compound [I] in which the substituent on the ring A in the general formula [I] is an oxime-containing substituent is a corresponding compound in which the substituent on the ring A is a carboxy-containing substituent. It can be produced by reacting [I] with hydroxylamine.
  • the target compound [I] wherein R is a substituent containing a substituted or unsubstituted carbamoyl group, the substituent on ring A, the substituent on ring B, and / or the group R contains a carboxyl group It can be produced by treating the corresponding compound [I] which is a substituent and the corresponding primary or secondary amine compound in the same manner as in the above (Method A).
  • the target compound [I] in which the substituent on the ring A, the substituent on the ring B, and / or the group R is a substituent containing an acylamino group is a substituent on the ring A
  • the group R is a substituted or unsubstituted nitrogen-containing heterocyclic group-substituted lower alkyl group (eg, 1-pyrazolylmethyl group) or lower alkylamino lower alkyl group (eg, dimethylaminomethyl group)
  • the group R is a lower alkyl group (for example, a chloromethyl group) substituted with a nitrogen atom, and a corresponding substituted or unsubstituted nitrogen-containing heterocycle (for example, , Pyrazole) or a primary or secondary lower alkylamine (eg, dimethylamine) in the presence of a base.
  • the base examples include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium hydroxide, sodium borohydride, and the like. Is mentioned.
  • the target compound [I] in which the substituent on the ring A, the substituent on the ring B, and / or the group R is a substituent containing an amino group is a compound on the ring A
  • R is a substituent containing a two-terminal group
  • Compound [I] can be produced by reacting in the presence of a reducing agent (for example, palladium hydrogen-carbon).
  • the target compound [I] in which the group R in the general formula [I] is a substituent containing an acetyl group, is the same as the corresponding compound [I] in which the group R is a substituent containing a nodogen atom, and a tri-lower alkyl (1 —Lower alkoxyvinyl) It can be produced by reacting tin with a catalyst (for example, bis triphenylphosphine, radium dichloride, palladium acetate, etc.) and then decomposing it with caro water.
  • a catalyst for example, bis triphenylphosphine, radium dichloride, palladium acetate, etc.
  • the objective conjugate [I] in which the substituent and / or the group R on the ring A in the general formula [I] is a hydroxyl group-containing substituent, is characterized in that the substituent on the ring A and / or the group R Manufactured by treating the corresponding compound [I], which is a substituent containing a rupolyl group, with a conventional reducing agent (eg, sodium borohydride, lithium aluminum hydride, lithium borohydride, etc.) can do.
  • a conventional reducing agent eg, sodium borohydride, lithium aluminum hydride, lithium borohydride, etc.
  • the compound [I] in which the group R in the general formula [I] is a substituent containing an amino lower alkyl group (eg, an aminomethyl group) is a lower alkyl group in which the group R is substituted with a halogen atom (eg, chloromethyl).
  • a halogen atom eg, chloromethyl
  • the corresponding compound [I], which is a substituent containing the group (I) is reacted with an azidating agent, and then subjected to a reduction reaction to produce the compound (I).
  • the azidating agent include sodium azig, sodium thimethyltrimethylsilane, triptyltin azide and the like.
  • the reducing agent include hydrogen Z palladium monocarbon, triphenylphosphine monohydrate, zinc monoacetic acid, and hydrosulfite sodium.
  • the target compound [I] in which the substituent on ring A and the substituent on Z or ring B are a substituent containing an acyloxy group or a substituted or unsubstituted lower alkoxy group The corresponding compound [I], wherein the substituent on ring A and the substituent on Z or ring B are a substituent containing a hydroxyl group, and an acylating agent (for example, Phenyl acetyl chloride) or a substituted or unsubstituted lower alkyl halide (eg, 2-methoxethyl chloride) in the presence of a base (eg, potassium carbonate, cesium carbonate). can do.
  • an acylating agent for example, Phenyl acetyl chloride
  • a substituted or unsubstituted lower alkyl halide eg, 2-methoxethyl chloride
  • a base eg, potassium carbonate, cesium carbonate
  • the target compound wherein the substituent on ring A and the substituent on ring A or ring B in the general formula [I] are a substituent containing a substituted or unsubstituted lower alkylamino group
  • [I] is a corresponding conjugate [I] wherein the substituent on ring A and / or the substituent on ring B is a substituent containing a substituted or unsubstituted lower alkanoylamino group.
  • a reducing agent for example, borane-dimethylsulfide complex.
  • the desired compound [I] of the present invention obtained as described in the above (Method A) to (Method H) or (Method a) to (Method k) may be converted into a pharmaceutically acceptable salt, if desired. It can also be converted. Conversion to a pharmaceutically acceptable salt may be performed according to methods known to those skilled in the art.
  • the starting compound [5] ([5-a] and [5-b]) can be produced, for example, according to the following method.
  • reaction for producing compound [3] from isoindoline [1] and carboxylic acid compound [2] can be carried out in the same manner as in the above (Method A).
  • the reaction for producing compound [3] from dichloro compound [7] and compound [8] can be carried out in the presence of a base, in the presence or absence of an additive.
  • a base include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, and the like.
  • the additive include tetrabutylammonium chloride and tetraethylammonium chloride. And tetra-lower alkyl ammonium halides such as muchloride.
  • the reaction for producing compound [4] from compound [3] can be carried out in the presence of a suitable nitrating agent.
  • suitable nitrating agents include, for example, concentrated nitric acid / concentrated sulfuric acid, potassium nitrate / concentrated sulfuric acid, potassium nitrate Z-trifluoroacetic acid and the like.
  • the reaction for producing compound [9] from compound [1] can be carried out in the same manner as the reaction for producing compound [4] from compound [3].
  • reaction for producing the compound [4] from the compound (9) and the carboxylic acid compound [2] can be carried out in the same manner as in the above (Method A).
  • the reaction for producing compound [5-a] from compound [4] can be carried out in the presence of a suitable reducing agent.
  • a suitable reducing agent include hydrogen / palladium monocarbon, lithium aluminum hydride, zinc monoacetic acid, iron (II) chloride—hydrochloric acid, tin (II) chloride—hydrochloric acid, iron monohydrochloride, iron monochloride ammonium, ammonium formate / Palladium-single carbon and the like.
  • reaction for producing compound [5-b] from compound [5-a] can be carried out in the same manner as in the above (Method D).
  • the reaction for producing compound [5-b] from compound [9] is the same as the reaction (N-alkylation) in the same manner as in the above (Method F), followed by the reaction for producing compound [5-a] from compound [4].
  • R is a lower alkyl group having a nitrogen atom
  • various nucleophiles are reacted in the presence or absence of a base.
  • a substituent can be introduced on the alkyl group.
  • the halogen atom include a halogen atom such as a chlorine atom, a bromine atom, and an iodine atom.
  • nucleophiles examples include Imida Examples include a nitrogen-containing heterocyclic group such as sol, virazole, pyrrole, indole, and triazole, and a primary or secondary lower alkylamino group such as dimethylamine, getylamine, ethylamine, morpholine, piperidine, and pyrrolidine.
  • the base include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, cesium fluoride, sodium hydroxide, potassium hydroxide and the like.
  • Starting compound [6] can be produced, for example, according to the following method.
  • X. represents a hydrogen atom, a halogen atom or a trifluoromethanesulfonyloxy group
  • Y represents a lower alkoxycarbonyl group or a (mono- or di-) lower alkylamino group
  • X 3 represents a leaving group
  • X 4 represents a leaving group
  • reaction for producing compound [24] from compound [23] can be carried out as follows.
  • a compound represented by the formula: M—X 3 or M—M is reacted in a solvent, in the presence of a base, in the presence or absence of an additive. And, if necessary, treatment with an acid.
  • the solvent include tetrahydrofuran, dioxane, dimethyl ether, dimethoxetane and the like.
  • the base include n-butyllithium, sec-butyllithium and the like.
  • the additive include tetramethylethylenediamine, hexamethylphosphoric triamide, and the like.
  • the acid include hydrochloric acid, sulfuric acid, sodium chloride and the like.
  • the reaction can be carried out by reacting a compound represented by MM and, if necessary, treating with an acid.
  • the solvent include dimethoxetane, water, ethanol, toluene, dimethylformamide, acetonitrile, dioxane, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, and a mixed solvent thereof.
  • Examples of the catalyst include palladium severe acid, tetrakistriphenylphosphine palladium, bis (diphenylphosphinophene phenyl) dichloropalladium, and the like.
  • Examples of the base include potassium acetate, potassium carbonate, sodium carbonate and the like.
  • As additives for example, triphenylphosphine, tree 0-tolylphosphine, tree n-butylphosphine, diphenylphosphineophene benzene (dppi), diphenylphosphineobutane (dppb), 2,6-ditert Monobutyl 4-cresol and the like.
  • Examples of the acid include hydrochloric acid, sulfuric acid, and ammonium chloride.
  • the reaction to produce compound [28] from compound [24] and compound [25] is performed in a solvent, in the presence of a catalyst, in the presence or absence of a base, in the presence or absence of an additive.
  • a solvent include dimethoxetane, water, ethanol, toluene, dimethylformamide, acetonitrile, dioxane, tetrahydrofuran, and a mixed solvent thereof.
  • the catalyst include palladium acetate, bistriphenylphosphine palladium dichloride, tetrakistriphenylphosphine palladium, and bistriphenylphosphine.
  • Examples include impalladium dichloride, bis (dibenzylideneacetone) palladium, and bisbenzonitrile palladium dichloride.
  • Examples of the base include lium carbonate, sodium carbonate, potassium phosphate and the like.
  • the additives include, for example, triphenylphosphine, tri-n-butylphosphine, tri-10-tolylphosphine, diphenylphosphinophenephenic acid (dppf), diphenylphosphinobutane (dppb), 2,6 —Gee tert—Butyl-4-taresol, etc.
  • the leaving group X 3 e.g., chlorine, bromine, halogen atom such as iodine, lower alkoxy group, Shiano group, triflate Ruo b methanesulfonyl two Ruokishi group, and the like.
  • M—X 3 Specific examples of the compound represented by the formula: M—X 3 include tri-n-butyltin sulfide, tri- ⁇ -butyltin trifluoromethanesulfonate, and tri-lower alkoxyborane.
  • ⁇ — ⁇ examples include bispinacolato diboron, biscatecholate diboron, pistria ⁇ -butyltin, and the like.
  • the leaving group X 4 in the compound [25] or compound [27] for example, chlorine, bromine, halogen atom such as iodine, triflate Ruo b methanesulfonyl two Ruokishi group, and the like.
  • reaction for producing compound [16] from compound [26] can be carried out in the same manner as the reaction for producing compound [24] from compound [23].
  • reaction for producing compound [28] from compound [16] and compound [27] can be carried out in the same manner as the reaction for producing compound [28] from compound [24] described above.
  • the reaction for producing the compound [6] from the compound [28] can be carried out by treating the compound with an acid or m3 ⁇ 4.
  • the acid include concentrated hydrochloric acid and sulfuric acid.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydroxide and hydrogen peroxide.
  • Starting compound [13] can be produced, for example, according to the following method.
  • Boc represents a tert-butoxycarbonyl group, and other symbols have the same meanings as described above.
  • the reaction for producing the compound [10] from the compound [9] in a solvent, di-tert. - presence Petit dicarbonate (Bo c 2 0), can be carried out in the presence or absence of a base.
  • a solvent include tetrahydrofuran, methylene chloride, 1,2-dichloroethane, dioxane, ethyl acetate and the like.
  • the base include triethylamine, potassium carbonate, sodium carbonate, diisopropylethylamine, sodium hydrogen carbonate, 4-dimethylaminopyridine and the like.
  • reaction for producing compound [11] from compound [10] can be carried out in the same manner as the reaction for producing compound [5-a] from compound [4].
  • reaction for producing compound [12] from compound [11] and compound [6] can be carried out in the same manner as in the above (Method A).
  • the reaction for producing compound [13] from compound [12] can be carried out in the presence of a Boc group deprotecting agent.
  • the deprotecting agent for the B 0 c group include hydrochloric acid-dioxane, ethyl acetate monohydrochloride, trifluoroacetic acid, and odotrimethylsila. And the like.
  • the starting compound [15] can be produced, for example, according to the following method
  • reaction for producing the compound [15] from the compound [5] and the compound [14] can be carried out in the same manner as in the above (method).
  • each intermediate compound is only the one shown in the above chemical reaction formula.
  • a salt or a reactive derivative thereof can be appropriately used as long as the reaction is not adversely affected.
  • the salt include metal salts such as sodium, potassium, lithium, calcium, and magnesium; organic compounds such as pyridine, triethylamine, and diisopropylethylamine; salts with ⁇ 3 ⁇ 4, hydrochloric acid, sulfuric acid, nitric acid, and bromide water.
  • Salts with inorganic acids such as basic acid and phosphoric acid, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, cunic acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluene
  • inorganic acids such as basic acid and phosphoric acid, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, cunic acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluene
  • organic substances such as sulfonic acid and trifluoroacetic acid.
  • each functional group may be prepared by a conventional method of synthetic chemistry in addition to the above.
  • an appropriate protecting group may be introduced into the compound, and the protecting group may be appropriately removed when unnecessary.
  • examples of the alkyl include a linear or branched alkyl having 1 to 16 carbon atoms, and in particular, an alkyl having 0.1 to 8 carbon atoms.
  • Lower alkyl or lower alkoxy is a straight or branched chain having 1 to 6 carbon atoms. And especially those having 1 to 4 carbon atoms.
  • the lower alkanoyl includes linear or branched ones having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms, and cycloalkyl means 3 to 20 carbon atoms, especially 3 carbon atoms. ⁇ 12.
  • Cyclo-lower alkyl includes those having 3 to 8 carbon atoms, especially 3 to 6 carbon atoms.
  • Alkenyl includes linear or branched ones having 2 to 16 carbon atoms, especially 2 to 10 carbon atoms, and lower alkenyl means 2 to 8 carbon atoms, especially 2 to 4 carbon atoms.
  • Alkylene includes linear or branched ones having 1 to 16 carbon atoms, especially 1 to 10 carbon atoms, and lower alkylene includes 1 to 8 carbon atoms, particularly 1 to 6 carbon atoms. Linear or branched ones are mentioned.
  • Halogen atoms include fluorine, chlorine, bromine or iodine.
  • the heterocyclic group include a monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom atom selected from nitrogen, oxygen, and sulfur.
  • the aryl group include a phenyl group, a naphthyl group, an anthranyl group, and a phenanthryl group.
  • the organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated food, and then dried over anhydrous sodium sulfate.
  • Example 1 The corresponding starting compound was treated in the same manner as in Example 1 (1) or Example 1 (1) (2) to give the compounds shown in Table 1.
  • the unit of the measured value of MS or IR in the table is “mZz” or “cm—, respectively. The same applies hereinafter.)
  • Example 37 2- (2-chloro-1--2-phenylacetyl) -1-5- [2- (4-trifluoromethylphenyl) benzoylamino] .- isoindoline (compound obtained in Example 13) 1 50 mg, 50% dimethylamine An aqueous solution (1 ml) and a solution of 46 mg of sodium iodide in ethanol (6 ml) were heated and stirred at 50 for 3 hours. After cooling to room temperature, the reaction solution was concentrated. Dilute aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate.
  • Example 39 2- [2- (4-benzyloxyphenyl) acetyl] -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (compound obtained in Example 18) To a solution of 1.36 g of ethanol (5 ml) was added 5% palladium / carbon 30 Omg, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 day. After removing the catalyst by filtration and concentrating the filtrate, a mixed solution of getyl ether and n-hexane was added to the residue, and the precipitated powder was collected by filtration to obtain 2- [2- (4-hydroxyphenyl) acetyl. ] — 5— [2- (4-Trifluoromethylphenyl) benzoylamino] -isoindoline (1.02 g) was obtained as a colorless powder.
  • reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate).
  • a 4M hydrochloric acid-dioxane solution was added to the crude ethyl acetate solution, and the precipitate was collected by filtration. 44 mg of (2-dimethylaminoethyl) oxy] phenyl] acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindrin hydrochloride was obtained as a colorless powder.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, and then dried over anhydrous sodium sulfate.
  • the crude product was dissolved in methanol, and a 10% hydrochloric acid-methanol solution was added under ice-cooling.
  • Examples 53 and 54 were obtained by treating the corresponding starting compounds in the same manner as in Example 46 (2), and then separating the resulting mixture by silica gel column chromatography.
  • reaction solution was poured into a dilute aqueous sodium hydrogen carbonate solution, and extracted with a black hole form.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and then dried over anhydrous sodium sulfate.
  • Example 76 To a solution of 6.03 g of 2-pyridylacetonitrile and 13.22 g of 1,4-dibromobutane in 13.2 g of dimethyl sulfoxide (150 ml) was added 4.29 g of sodium amide under cooling with water. Stirred for hours. The reaction solution was poured into ice water and extracted with dimethyl ether. The organic layer was washed next with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; chromate form) to give 5.79 g of 1- (2-pyridyl) -11-cyclopentane-potanol. Obtained as a yellow liquid. MS (A PC I) m / z; 173 (M + H), IR (Ne at) cm " 1 : 22
  • Example 77 The compound obtained in Example 77 was treated in the same manner as in Example 39 to give 2- (3-hydroxy-12,2-dimethylpropanol) -1- [2- (4-trifluoromethyl). Phenyl) benzoylamino] -isoindoline was obtained as colorless crystals.
  • the compound shown in Table 5 was obtained by treating the corresponding raw material (danied product) in the same manner as in Example 81.
  • the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
  • Example 122 (1) The compound obtained in Example 122 (1) and morpholine were treated in the same manner as in Example 122 (2) to give the compounds described in Table 8.
  • Example 106 The compound obtained in Example 106 was treated in the same manner as in Example 124 to give the compounds described in Table 9. Table 9
  • Example 134 The compound obtained in Example 134 and the corresponding starting compounds were treated in the same manner as in Example 122, to give compounds as shown in Table 11.
  • reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate.
  • the starting compound N- (2-methoxyethyl) -12-chloro-5- (trifluoromethyl) benzoic acid amide can be produced as follows. — (Trifluoromethyl) benzoyl chloride 1. A solution of 25 g of dichloromethane (15 ml) was cooled in an ice bath, and a solution of 9-39 mg of 2-methoxyethylamine in dichloromethane (5 ml) was added dropwise. The reaction solution was brought to room temperature, diluted with chloroform, and washed with water, dilute hydrochloric acid, saturated aqueous solution of sodium carbonate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate.
  • Methyl 2- (4-formylphenyl) benzoate (Compound obtained in Reference Example 28 (1)) To a solution of 35 Omg of acetone (15 ml) was added 345 mg of potassium permanganate in water (10 ml). ) The solution was added dropwise. After stirring at room temperature for 2 hours, react The solution was filtered through celite. Acetone was distilled off from the filtrate, and 10% hydrochloric acid was added to the obtained aqueous layer, followed by extraction with ethyl acetate.
  • N, N-dimethyl-4-monobromobenzoic acid amide 1144 mg, bis (pinacolato) diboron 1430 mg, potassium acetate 148 0 mg, [1,1'-bis (diphenylphosphino) phenacene ]
  • a mixture of 123 mg of dichloropalladium methylene chloride complex and 30 ml of dimethylformamide was stirred at 80 ° C for 2.5 hours.
  • Ethyl acetate and water were added to the reaction solution, and insolubles were removed by filtration using Celite.
  • the organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • N, N-dimethyl-4-monobromobenzoic acid amide 227 mg, bis (pinacolato) dipolone 286 mg, potassium acetate 297 mg, [1,1'-bis (diphenylphosphino) phenol [Sen] dichloropalladium chloride methylene complex 24.3 mg of a dimethylformamide 5 ml mixture was stirred at 80 ° C for 2.5 hours.
  • a novel biphenylcarboxamido soindolin compound having an excellent apolipoprotein B (ApoB) secretion inhibitory action and a serum lipid lowering action, and useful as a medicament, a method for producing the same, and a synthetic intermediate thereof Is provided.
  • ApoB apolipoprotein B

Abstract

L'invention concerne des nouveaux composés de biphénylcarboxamidoisoindoline de formule générale (I), utilisés comme médicaments, ou des sels acceptables sur le plan pharmaceutique de ceux-ci, ainsi que des procédés de préparation des composés ou des sels et des produits intermédiaires destinés à la synthèse de ceux-ci, dans laquelle A représente un noyau benzénique substitué ou non substitué; B représente un noyau benzénique substitué ou non substitué; Q représente CO- ou CH2-; et R représente un alkyle inférieur substitué ou non substitué, un alkylène inférieur substitué ou non substitué, un carbamoyle substitué ou non substitué, un groupe hétérocyclique substitué ou non substitué, un aryle substitué ou non substitué ou analogues.
PCT/JP2001/006844 2000-08-10 2001-08-09 Composes de biphenylcarboxamidoisoindoline, procedes de preparation de ceux-ci et produits intermediaires destines a la synthese de ceux-ci WO2002014277A1 (fr)

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WO2014100734A1 (fr) * 2012-12-21 2014-06-26 Epizyme, Inc. Inhibiteurs de prmt5 et leurs utilisations
US8906900B2 (en) 2012-12-21 2014-12-09 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8940726B2 (en) 2012-12-21 2015-01-27 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8993555B2 (en) 2012-12-21 2015-03-31 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9365555B2 (en) 2012-12-21 2016-06-14 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10653693B2 (en) 2014-08-04 2020-05-19 Epizyme, Inc. PRMT5 inhibitors and uses thereof

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