WO2002014276A1 - Composes a base de benzoylaminoisoindoline, leurs procedes de preparation et produits intermediaires utilises dans leur synthese - Google Patents

Composes a base de benzoylaminoisoindoline, leurs procedes de preparation et produits intermediaires utilises dans leur synthese Download PDF

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Publication number
WO2002014276A1
WO2002014276A1 PCT/JP2001/006843 JP0106843W WO0214276A1 WO 2002014276 A1 WO2002014276 A1 WO 2002014276A1 JP 0106843 W JP0106843 W JP 0106843W WO 0214276 A1 WO0214276 A1 WO 0214276A1
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group
substituted
unsubstituted
lower alkyl
compound
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PCT/JP2001/006843
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English (en)
Japanese (ja)
Inventor
Harutami Yamada
Akira Ando
Hiroyuki Kawanishi
Koichi Nagata
Mikiko Yasuhara
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Tanabe Seiyaku Co., Ltd.
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Priority to AU2001277727A priority Critical patent/AU2001277727A1/en
Publication of WO2002014276A1 publication Critical patent/WO2002014276A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to a novel benzoylaminoisoindoline compound which has excellent apolipoprotein B (ApoB) secretion inhibitory activity and serum lipid lowering effect and is 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-2-carboxylic acid [2- (thiophen-1-yl-1-acetyl) -1,1,2,3,4-tetrahydroisoquinoline 1-6-yl] 1-amide, 4,1-trifluoromethyl-1-biphenyl-12-carboxylic acid [2- (pyridine-1-2-ylua cetyl) -1,2,3,4-tetrahydroisoquinoline-1-6-yl ] -Amid et al.
  • WO 98/23593 disclose 4,1-trifluoromethyl-1-biphenyl-12-carboxylic acid [2- (2- (pyridine-12-yl) ethyl) -1 It has been suggested that 1,2,3,4-tetrahydroisoquinoline-1-6-yl] -amide and the like have an inhibitory effect on ApoB secretion and can be used as a serum lipid-lowering agent.
  • the present invention provides a novel benzoylaminoisoindoline 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 an intermediate for synthesizing the same. Is what you do. Summary of the Invention
  • the present inventors have conducted intensive studies and, as a result, have found a novel benzoylaminoisoindoline compound having an apolipoprotein B secretion inhibitory action and a serum lipid lowering action, and completed the present invention. .
  • the present invention provides a compound represented by the general formula [I]:
  • ring ⁇ is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group
  • ring B is a substituted or unsubstituted benzene ring
  • Q is one C ⁇ or _CH 2 —
  • R represents a substituted or unsubstituted lower alkyl group, a substituted or 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 ring A in the target compound [I] of the present invention include: (1) a trifluoromethyl group,
  • a lower alkoxy group such as a ruponyl group.
  • Ring A may be unsubstituted or substituted with 1 to 3 identical or different groups selected from the above (1) to (10).
  • Ring A includes, for example, a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur atoms.
  • Specific examples include a pyridyl group, a pyrimidinyl group, a virazinyl group, a pyridazinyl group, a furyl group, a phenyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an imidazolyl group, and a pyrazolyl group.
  • Examples of the substituent on ring B in the target compound [I] of the present invention include: (1) a nitro group,
  • unsubstituted amino group or (i) lower alkoxy group, amino group, lower alkyl group A lower alkanoyl group substituted with 1 to 3 identical or different groups selected from a kill group, an amino group and a lower alkoxycarbonyl group, (ii) a protecting group for an amino group, (iii) an unsubstituted lower alkyl group, or pyridyl A lower alkyl group substituted with a group or a lower alkylamino group, and (iV) a pyridylcarbonyl group, an amino group substituted with a group selected from the group consisting of:
  • Ring B may be unsubstituted or 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 alkanol group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, or a lower alkylaminocarboxy group
  • n an integer of 0 to 4
  • the lower alkyl group for R may be unsubstituted or substituted with one to three identical or different 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
  • the substituent on the rubamoyl group may be a lower alkyl group or a halogeno group. Examples include a lower alkyl group and a benzothiazolyl group.
  • the substituted or unsubstituted carbamoyl group includes a compound represented by 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
  • the substituent on the heterocyclic group may be a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, And an amino group, a lower alkylamino group, a hydroxyl group, a protected hydroxyl group, a protected amino group and the like.
  • the heterocyclic group for R may be unsubstituted or 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 heterocyclic group
  • examples of the heterocyclic group include a pyridyl group, an indolyl group, a thiazolyl group, an imidazolyl group, and a pyrrolyl group.
  • 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, a protected water rooster, a protected amino group, and the like.
  • the aryl group in R may be unsubstituted or 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 phenanthrenyl group.
  • examples of the protecting group for the amino group include a substituted or unsubstituted lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, and acyl group. And a substituted or unsubstituted aryl group-substituted lower alkyl group, lower alkenyl group and the like. Specific examples include an ethoxycarbonyl group, a methoxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloromethyl group.
  • Substituted or unsubstituted with a halogen atom such as a thioloxycarbonyl group, or substituted or unsubstituted with a lower alkoxy group such as a lower alkoxycarbonyl group, a benzyloxycarbonyl group, or a 4-methoxybenzyloxycarbonyl group.
  • Ashiru groups such Puchiriru group.
  • a lower alkoxy group such as a benzyl group or a 4-methoxybenzyl group, or an unsubstituted aryl group substituted with a lower alkyl group, a lower alkenyl group such as an aryl group, or a 9-fluorenyl methoxycarbonyl group And the like.
  • a substituted or unsubstituted lower alkoxycarbonyl group is preferred, and specific examples thereof include 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 protecting 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.
  • common protecting groups such as trialkylsilyl group and the like.
  • aryl aryl lower alkyl groups such as benzyl group and phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, benzoyl group, etc., methoxycarbonyl group, Ethoxycarbonyl group, etc.
  • lower alkoxy groups such as trialkylsilyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.
  • a triphenylmethyl group, a 2-cyanoethyl group and the like can be mentioned.
  • target compounds [I] of the present invention preferred compounds are those wherein ring A has the formula:
  • R 1 is a trifluoromethyl group or a lower alkynyl group
  • Ring B is substituted with an unsubstituted benzene ring or a group selected from a lower alkoxy group, a (lower alkylamino lower alkanol) amino group, a lower alkylamino lower alkoxy group, a lower alkyl group and a lower alkoxycarbonyl group Benzene ring,
  • Q is CO— or one CH 2 —
  • R is a lower alkyl group substituted by a group selected from the following (1) to (4):
  • Ring B is a benzene ring
  • R is an unsubstituted pyrazolylmethyl group or a virazolylmethyl group substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group, and a hydroxy lower alkyl group.
  • target compound [I] of the present invention include, for example, 2- (1H-pyrazol ⁇ "l_1_yl) acetyl-1 5-[2-(5-trifluoromethyl) Pyridine-1-yl) benzoylamino] -isoindoline, 2- (1H-pyrazole_1-yl) acetyl-5- [2- (5-trifluoromethyl-pyridine-12-yl) -1-3-methoxy Carboel benzoylamino] one isoindoline,
  • the target compound [I] of the present invention can exist as an optical isomer based on the asymmetric atom.
  • the present invention includes both of these optical isomers and mixtures thereof.
  • the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof has an apolipoprotein B secretion inhibitory effect and exhibits an excellent serum lipid lowering effect.
  • the objective compound [I] of the present invention or a pharmaceutically acceptable salt thereof is hyperlipidemia, ischemic heart disease, atherosclerosis, coronary atherosclerosis, hypercholesterolemia, hypertriglyceridemia.
  • Disease familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary arteriosclerosis, coronary artery disease, ischemic brain disease, stroke, circulatory and microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute bleeding It is useful for the prevention and treatment of sexually transmitted inflammation, obesity, steatosis, constipation, etc.
  • 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 may be in a free form or a pharmacologically acceptable salt. Can also be used for pharmaceutical applications.
  • Pharmaceutically acceptable salts of compound [I] include, for example, inorganic salts such as hydrochloride, sulfate, phosphate or bromide hydrochloride, acetate, fumarate, oxalate
  • organic acid salts such as citrate, methanesulfonate, benzenesulfonate, tosylate and maleate.
  • 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
  • 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 thereof, and salts 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, B It can be used as conventional pharmaceutical preparations such as fillers.
  • 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 SmgZkg, especially about 0.1 to 3 mg / kg, 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 benzoylaminoisoindoline compound represented by the target compound [I] of the present invention has the general formula [5]:
  • 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.
  • a solvent may be used as long as it does not adversely affect the reaction.
  • Examples of the condensing agent include dicyclohexyl carpoimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide 'hydrochloride (WS C ⁇ HC 1), diphenyl phosphoryl azide (DPPA) , Carbonyldiimidazole (CDI), getylcyanophosphonate (DEPC), diisopropylcarboimide (DIPCI), benzotriazole-111-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), etc. No.
  • Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), and 1-hydroxy-7-azabenzotriazole (HOB).
  • HOA t hydroxyphthalimid
  • P fp-OH pentafluorophenol
  • Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazavic mouth [5.4.0] -7-pandacene (DBU) and the like.
  • the amount of the condensing agent to be used is 1 to 10 equivalents, preferably,; with respect to compound [5] or compound [6]; ⁇ 2 equivalents can be used.
  • the amount of the activating agent to be used is 1 to: 0 equivalent, preferably 1 to 2 equivalent, relative to compound [5] or compound [6]. Can be. This reaction can be carried out, for example, at 0 to L 0 ° C, preferably at 0 to 50 ° C.
  • Compound [I] can also be obtained by converting compound [6] to a reactive derivative such as an acid chloride or a mixed acid anhydride and then reacting with compound [5] in the presence of a base.
  • a reactive derivative such as an acid chloride or a mixed acid anhydride
  • the benzoylaminoisoindoline 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 general formula [16]:
  • M is selected from a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group, an aryl group, a lower alkoxy group, an alkylenedioxy group, an aryloxy group, an arylenedioxy group and an arylthio group.
  • This reaction can be carried out in a solvent, in the presence of a catalyst, in the presence or absence of a base, or 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.
  • metal of M for example, Examples include boron, tin, silicon, zinc, magnesium, aluminum, lithium, nickel, and the like.
  • Examples of the catalyst include palladium acetate, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium 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.
  • Additives include, for example, triphenylphosphine, tri0-tolylphosphine, tri-n-butylphosphine, copper (I) bromide, copper (I) iodide, triphenylenylsine, tri (2-furyl)
  • Examples include phosphine, diphenylphosphinophenol (dppf), diphenylphosphinobutane (dppb), 2,6-ditert-butyl-4-cresol, and the like.
  • 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 used amount of ⁇ ⁇ can be 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 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]. This reaction can be carried out, for example, at 0 to 150 ° C, preferably at 30 to 120 ° C.
  • a fluorine atom a chlorine atom, a halogen atom such as a bromine atom or an iodine atom, Ru triflumizole Ruo b methanesulfonyl O carboxymethyl group and the like.
  • 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, 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.
  • the base or the activating agent for example, those exemplified in the reaction of the above (Method A) can be used as appropriate.
  • compound [Ia] can be obtained by converting compound [2] to a reactive derivative such as an acid chloride or a mixed acid anhydride and then reacting with compound [13] in the presence of a base.
  • a reactive derivative such as an acid chloride or a mixed acid anhydride
  • the benzoylaminoisoindoline compound represented by the general formula [Ia] or a salt thereof can be produced by subjecting the compound 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 dimethoxyethane.
  • Suitable reducing agents include, for example, sodium borohydride sodium borotriethyl diethyl 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, relative to compound [I-a].
  • This reaction is, for example, _30 to 100. C, preferably at 0-50 ° C.
  • the benzoylaminoisoindoline compound represented by the general formula [I-b] is also 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, such as methylene chloride, tetrahydrofuran, dioxane, getyl ether, methanol, ethanol, isopropyl alcohol, and the like. 1,2-dichloroethane, water and the like.
  • Bases include, for example, triethylamine, diisopropyl Luethylamine, 4-methylmorpholine and the like.
  • the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, monoparadium hydrogen hydrogen, sodium borohydride-acetic acid, and the like.
  • 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 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 30 to 100 ° C, preferably 0 to 50 ° C.
  • the above condensation reaction and reduction reaction can also be carried out in one pot as a reductive amination reaction.
  • the benzoylaminoisoindoline compound represented by the general formula [I-b] is also a compound represented by the general formula [13] or a salt thereof, and the general formula [18]:
  • 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 of the base include potassium carbonate, sodium carbonate, triethylamine, disopropylethylamine, pyridine, and hydroxy [arsenic acid, potassium hydroxide, and the like.
  • Additional additive include sodium iodide and iodide.
  • 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
  • Mitsunobu reagents such as triphenylphenylphosphine-diethylazodicarboxylate and triphenylphenylphosphine-diisopropylazodioxycarbonylate can be used.
  • P represents a hydroxyl-protecting group, and 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 thereof include methanol, ethanol, isopropyl alcohol, dimethylformamide, and acetoniryl.
  • Examples of the base include, for example, triethylamine, disodium, and the like. Examples include propylethylamine, 4-methylmorpholine, etc.
  • the additive include ammonium chloride, tin (II) iodide, and the like.
  • R 2 represents a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group, and other symbols have the same meanings as described above.
  • 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 includes, for example, methanol, ethanol, propanol, etc.
  • Examples of the base include triethylamine, disopropylamine, 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 converts the substituent on ring A, the substituent on ring B and / or the group R of the compound obtained as described above to another desired substituent. Can also be produced.
  • the method for converting such a substituent is described in What is necessary is just to select suitably according to the kind of substituent which is a target, For example, it can implement as (method a)-(method i).
  • the target compound [I] in which the group R in the general formula [I] is a substituent containing a substituted or unsubstituted lower alkylamino group (eg, a dimethylamino group) is a primary or secondary compound in which the group R is not protected. It can be produced from the corresponding compound [I], which is a substituent containing a secondary amino group, and the corresponding aldehyde compound (eg, formaldehyde) by treating in the same manner as in the above (Method E).
  • 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.
  • [I] can be produced by reacting hydroxylamine with a conventional method.
  • 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 a substituted or unsubstituted carbamoyl group is represented by a ring A
  • the substituent on the ring B, and / or the corresponding compound [I] in which the group R is a substituent containing a carboxyl group (Method A) It can be manufactured by treating in the same manner as described above.
  • 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 corresponding compound [I] in which the substituent on the ring B and / or the group R is a substituent containing an amino group and a corresponding acylating agent (for example, picolinic acid, dimethylaminoglycine) can be obtained by the above-mentioned (Method A). )).
  • the group R is a substituted or unsubstituted nitrogen-containing heterocyclic group-substituted lower group
  • the compound [I] which is an alkyl group (for example, 1-pyrazolylmethyl group) or a lower alkylamino lower alkyl group (for example, dimethylaminomethyl group) is a lower alkyl group in which the group R is substituted with a halogen atom (for example, , A chloromethyl group) and a corresponding substituted or unsubstituted nitrogen-containing heterocycle (eg, virazole) or a primary or secondary lower alkylamine (eg, dimethylamine). It can be produced by reacting in the presence.
  • the base examples include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, 7] potassium oxide, cesium fluoride, and sodium hydrogen carbonate. 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
  • the reaction is carried out by reacting the corresponding compound [I], wherein the substituent on B and / or the group R is a substituent containing a nitro group, in the presence of a reducing agent (for example, hydropalladium-carbon).
  • a reducing agent for example, hydropalladium-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 halogen atom. It can be produced by reacting with (lower alkoxyvinyl) tin in the presence of a catalyst (for example, bis triphenylphenylphosphine palladium dichloride, palladium acetate, etc.) and then hydrolyzing.
  • a catalyst for example, bis triphenylphenylphosphine palladium dichloride, palladium acetate, etc.
  • the target compound [I] in which the substituent on the ring A and / or the group R in the general formula [I] is a substituent containing a hydroxyl group is a compound having the substituent on the ring A and Z or the group R is a compound having a hydroxyl group.
  • the corresponding compound [I], which is a substituent containing a group can be produced by treating with a conventional reducing agent (for example, sodium borohydride, lithium aluminum hydride, lithium borohydride, etc.). it can. (Method i: azidation and reduction reaction)
  • 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 azide, trimethylsilane azide, triptyltin azide and the like.
  • the reducing agent include hydrogen / palladium monocarbon, triphenylphosphine-water, zinc-acetic acid, hydrosulfite sodium and the like.
  • the target compound [I] in which the substituent on the ring A and / or the substituent on the ring B in the general formula [I] is a substituent containing an acyloxy group or a substituted or unsubstituted lower alkoxy group
  • the corresponding compound [I] wherein the substituent on A and / or the substituent on ring B is a hydroxyl-containing substituent, and a acylating agent (eg, phenyl acetyl chloride) or a substituted or unsubstituted lower It can be produced by reacting with an alkyl halide (for example, 2-methoxethyl chloride) in the presence of (for example, potassium carbonate or cesium carbonate).
  • the substituent on ring A, and / or the substituent on ring B is a substituent containing a substituted or unsubstituted lower alkylamino group.
  • 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. Next, a method for adjusting the raw material mixture used in the above method will be described below.
  • 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 compound [3] is produced from a dichloro compound [7] and a compound [8].
  • the reaction can be carried out in the presence of a base, in the presence or absence of an additive.
  • a base for example, sodium hydroxide, hydroxylating water, sodium hydride, potassium hydride, sodium methoxide and the like can be mentioned.
  • the additive include tetra-lower alkyl ammonium halides such as tetrabutylammonium chloride and tetraethylammonium chloride.
  • this process for example, for example,
  • 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 / 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-carbon, lithium aluminum hydride, zinc monoacetic acid, chloridite (II) —hydrochloric acid, tin (II) chloride—hydrochloric acid, iron monohydrochloride, iron monochloride ammonium, and formic acid. Ammonia / palladium-single carbon.
  • 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] (Reduction of nitro group)
  • R is a lower alkyl group having a halogen atom
  • a substituent can be introduced on the alkyl group by reacting various nucleophiles in the presence or absence of a base.
  • the halogen atom include a halogen atom such as a chlorine atom, a bromine atom, and an iodine atom.
  • nucleophilic agent examples include a nitrogen-containing heterocyclic group such as imidazole, pyrazole, pyrrole, indole, and triazole; or a primary or secondary lower group such as dimethylamine, getylamine, ethylamine, morpholine, piperidine, and pyrrolidine.
  • examples include an alkylamino group and the like.
  • the base examples include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, potassium, cesium fluoride, sodium hydroxide, potassium hydroxide and the like.
  • Starting compound [6] can be produced, for example, according to the following method.
  • X. I a hydrogen atom, a halogen atom or a trifluoromethanesulfonyloxy group
  • Y is a lower alkoxycarbonyl group or a mono- or di-lower alkylamino group
  • X 3 is a leaving group
  • X 4 is 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-butyl lithium, sec_butyl lithium and the like.
  • the additive include tetramethylethylenediamine, hexamethylphosphoric triamide, and the like.
  • the acid include hydrochloric acid, sulfuric acid, and salted ammonium.
  • X 0 is a halogen atom or a trifluoromethanesulfonyloxy group
  • 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 formula: M—X 3 or The reaction can be carried out by reacting the compounds 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 sulphate, tetrakistriphenylphosphine palladium, bis (diphenylphosphinophenocene) dichloropalladium and the like.
  • Examples of the base include acetic acid potassium, lithium carbonate, sodium carbonate and the like.
  • the additives include, for example, triphenylphosphine, tri-tolylphosphine, tri-n-butylphosphine, diphenylphosphinophene benzene (dppf), diphenylphosphinobutane (dppb), 2, 6 —Gee tert-butyl-1-4-cresol;
  • 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 or a mixed solvent thereof.
  • the catalyst include palladium acetate, bistriphenyl and the like.
  • Phosphine palladium dichloride tetrakistriphenylphosphine, radium, bistriphenylphosphine Palladium dichloride, bis (dibenzylideneacetone) ino, "radium, bisbenzonitrile palladium dichloride and the like.
  • the base include potassium carbonate, sodium carbonate and potassium phosphate. Is, for example, triphenylphosphine, tri-n-butylphosphine, tri-10-tolylphosphine, diphenylphosphinophenocene (dppf). Diphenylphosphineobutane (dppb), 2,6-di-tert. —Butyl 4-cresol and the like.
  • 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-n-butyltin trifluoromethanesulfonate, and tri-lower alkoxyborane.
  • MM examples include bispinacolato diboron, biscatecholate diboron, bistri-n-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.
  • the reaction for producing the compound [16] from the compound [26] can be carried out in the same manner as the reaction for producing the compound [24] from the compound [23].
  • reaction for producing compound [28] from compound [16] can be carried out in the same manner as the reaction for producing compound [28] from compound [24] described above.
  • the reaction for producing compound [6] from compound [28] can be carried out by treating the compound with an acid or a base.
  • 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 [1 0] from the compound [9] in a solvent, di- tert - can presence Petit dicarbonate (Bo c 2 0), carried out the presence or absence of a base.
  • a solvent include tetrahydrofuran, methylene chloride, 1,2-dichloroethane, dioxane, ethyl acetate and the like.
  • Bases include, for example, triethylamine, potassium carbonate, sodium carbonate, diisopropylethylamine, sodium carbonate, and 4-dimethylaminopyri. Gin 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].
  • 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 Boc group include hydrochloric acid-dioxane, ethyl acetate monohydrochloride, trifluoroacetic acid, and pseudotrimethylsilane.
  • the starting compound [15] can be produced, for example, according to the following method.
  • reaction for producing compound [15] from compound [5] and compound [14] can be carried out in the same manner as in the above (Method A).
  • each intermediate compound has an adverse effect on the reaction as well as the one shown in the above chemical reaction formula. If it does not affect, a salt thereof or a reactive derivative thereof can also be used as appropriate.
  • the salt examples include metal salts such as sodium, potassium, lithium, calcium, and magnesium, salts with organic bases such as pyridine, triethylamine, disopropylethylamine, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, Salts with inorganic acids such as phosphoric acid, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, citric acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoro Salts with organic acids such as acetic acid O
  • organic bases such as pyridine, triethylamine, disopropylethylamine, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid
  • Salts with inorganic acids such as phosphoric acid, acetic acid, oxalic acid, citric acid,
  • the starting compound or each of the intermediates has a functional group in the production of the target compound of the present invention and the raw material conjugate
  • the raw material compound or each of the intermediates may be appropriately applied to each functional group by a conventional method of synthetic chemistry in addition to the above.
  • Such protecting groups may be introduced as appropriate, and if unnecessary, those protecting groups may be appropriately removed.
  • examples of the alkyl include a linear or branched alkyl having 1 to 16 carbon atoms, and particularly an alkyl having 1 to 8 carbon atoms.
  • the lower alkyl or lower alkoxy includes linear or branched ones having 1 to 6 carbon atoms, particularly those having 1 to 4 carbon atoms.
  • lower alkanoyl includes linear or branched ones having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms
  • cycloalkyl includes 3 to 20 carbon atoms, particularly 3 to 12 'are mentioned.
  • 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, particularly 2 to 16 carbon atoms.
  • Alkylene includes linear or branched ones having 1 to 16 carbon atoms, especially 1 to 10 carbon atoms.
  • Lower alkylenes include 1 to 8 carbon atoms, particularly 1 to 6 carbon atoms.
  • 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.
  • reaction solution was cooled to room temperature, diluted with ethyl acetate, further added with 15 ml of a 10% aqueous potassium fluoride solution, and stirred.
  • the insoluble material was filtered through celite, the organic layer of the filtrate was separated, washed with water and saturated food, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • 1-yl) acetyl-5- [2- (3-pyridyl) -benzoylamino] -isoindolin 57 mg was obtained.
  • the saturated sodium bicarbonate washing solution was acidified with 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of methanol and water to give 76 mg of methyl 2- (5-trifluoromethyl-pyridine-12-yl) isophthalate (Compound 12 (3b)). Obtained as colorless needles.
  • a novel benzoylaminoisoindolin compound having a clear lipid lowering effect and useful as a medicament, a process for producing the same, and a synthetic intermediate thereof are provided.

Abstract

L'invention concerne des composés à base de benzoylaminoisoindoline utiles comme médicaments, ou des sels pharmaceutiquement acceptables de ces composés ; des procédés de préparation de ces composés ou de ces sels ; ainsi que des produits intermédiaires utilisés dans leur synthèse. Ces composés sont représentés par la formule générale (I), dans laquelle A représente un groupe hétérocycle aromatique à 5 ou 6 chaînons, substitué ou non ; B représente un noyau benzénique substitué ou non ; Q représente CO- ou CH2- ; R représente un alkyle inférieur substitué ou non, un alcényle inférieur substitué ou non, un carbamoyle substitué ou non, un groupe hétérocycle substitué ou non, ou un aryle substitué ou non.
PCT/JP2001/006843 2000-08-10 2001-08-09 Composes a base de benzoylaminoisoindoline, leurs procedes de preparation et produits intermediaires utilises dans leur synthese WO2002014276A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2002098872A1 (fr) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Isoindolines et procede d'elaboration

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GB989917A (en) * 1963-05-15 1965-04-22 Dresden Arzneimittel New amides of isoindolinyl-2-acetic acid
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EP0587180A2 (fr) * 1992-09-11 1994-03-16 E.R. SQUIBB & SONS, INC. Dérivés d'aryl urées (thiourées) et cyanoguanidines
WO1994009000A1 (fr) * 1992-10-13 1994-04-28 Warner-Lambert Company Derives de quinoxalinedione utiles comme antagonistes d'acides amines excitateurs
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WO1997041111A1 (fr) * 1996-04-30 1997-11-06 Pfizer Inc. Procedes et intermediaires pour la preparation de [2-(2h-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolein-6-yl]-amide d'acide 4'-trifluoromethylbiphenyl-2-carboxylique
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WO2002098872A1 (fr) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Isoindolines et procede d'elaboration

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