WO2002098872A1 - Isoindolines et procede d'elaboration - Google Patents

Isoindolines et procede d'elaboration Download PDF

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WO2002098872A1
WO2002098872A1 PCT/JP2002/005357 JP0205357W WO02098872A1 WO 2002098872 A1 WO2002098872 A1 WO 2002098872A1 JP 0205357 W JP0205357 W JP 0205357W WO 02098872 A1 WO02098872 A1 WO 02098872A1
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group
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phenyl
substituted
compound
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Naoyuki Harada
Michihisa Yato
Hiroshi Kamaya
Koichi Nagata
Hidenori Iwai
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Tanabe Seiyaku Co., Ltd.
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/06—Antihyperlipidemics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D401/14—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 three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel isoindoline compound which has an excellent apolipoprotein B (ApoB) secretion inhibitory action and a serum lipid lowering action and is useful as a medicament, and a method for producing the same.
  • ApoB apolipoprotein B
  • WO096Z40640 discloses that 4,1-trifluoromethyl-piphenyl-2-carboxylic acid [2- (thiophen-2-ylacetylacetyl) _1,2,3,4-tetrahydroisoquinoline-16-yl] —Amide, 4′-Trifluoromethyl-piphenyl—2-carboxylic acid [2- (pyridine-2-yl-acetyl) -1,2,3,4-tetrahydroisoquinoline-1-6-yl] —amide
  • WO 98/23593 discloses that 4'-trifluoromethyl-piphenyl-1-carboxylic acid [2- (2- (pyridine-1-yl) ethyl) -1 1,2 It has been suggested that 2,3,4-tetrahydroisoquinoline-6-yl] -amide and the like have an inhibitory effect on ApOB secretion and can be used as a serum lipid-lowering agent.
  • amide compounds described therein are compounds having a biphenyl structure in the carboxylic acid portion and a tetrahydroisoquinoline ring in the amine portion, and the nitrogen-containing carboxylic acid portion such as the compound of the present invention.
  • Compounds having an aliphatic heterocyclic monophenyl group No compounds having an isodolin ring in the amine moiety are described.
  • the present invention provides a novel isoindoline compound having excellent apolipoprotein B secretion inhibitory action and serum lipid lowering action. Further, the present invention provides The present invention also provides a method for producing such a novel compound.
  • the present invention provides a compound represented by the general formula [I]:
  • ring A is an optionally substituted nitrogen-containing aliphatic heterocyclic group
  • Q is —CO— or —CH 2 —
  • R represents a lower alkyl group substituted with an optionally substituted heterocyclic group
  • the present invention further provides a compound represented by the general formula [3]:
  • ⁇ is a halogen atom
  • Q and R have the same meaning as described above.
  • the present invention also provides a compound represented by the following general formula [5]:
  • the present invention further provides a compound of the general formula [I-a]:
  • the present invention further provides a compound of the general formula [5]:
  • R has the same meaning as described above, and X represents a leaving group.
  • the present invention further provides a compound of the general formula [5]:
  • Examples of the substituent on the ring A in the target compound [I] of the present invention include:
  • a lower alkyl group which may be substituted with an aryl group or a lower alkoxy group, (2) an aryl group optionally substituted with a lower alkyl group or a cyano group,
  • lower alkanol group (10) lower alkanol group; aryl lower alkanol group; aryl carbonyl group; lower alkoxy carbonyl group; aryl lower alkoxy carbonyl group; aryl carbonyl group; aryl sulfonyl group; lower alkyl sulfonyl.
  • R 3 and R 4 may be the same or different and each is a group selected from a hydrogen atom, an alkyl group, an aryl lower alkyl group, a pyridyl lower alkyl group, a pyridyl group, and an aryl group.
  • Equation (12) Wherein n is an integer from 0 to 3,
  • Ring A may be substituted with 1 to 3 identical or different groups selected from the above substituents.
  • nitrogen-containing aliphatic heterocyclic group in ring A examples include, for example, one or two And a 3- to 8-membered aliphatic heterocyclic group containing a hydrogen atom.
  • Specific examples include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a morpholino group, a azepanyl group, and a diazepanyl group.
  • substituent on the heterocyclic group for R in the target compound [I] of the present invention include, for example,
  • the heterocyclic group for R may be substituted with the same or different 1 to 3 groups selected from the above substituents.
  • heterocyclic group for R examples include a monocyclic or bicyclic heterocyclic group containing 1 to 4 nitrogen atoms. Specifically, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl, virazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, isoquinolyl, benzimidazolyl And the like.
  • Examples of the aryl group in ring A include one to three ring aryl groups, and specific examples include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
  • examples of the protecting group for the amino group include a lower alkoxycarbonyl group, an optionally substituted lower alkoxycarbonyl group, and the like; Specifically, an ethoxycarbonyl group, a methoxycarbonyl group, a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, an aryloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a tert-butoxycarbonyl group , 2,2,2-trichloroethyloxycarbonyl group, formyl group, acetyl group, propionyl group, butylyl group and the like.
  • a benzyl group, a 4-methoxybenzyl group, an aryl group and the like can also be mentioned.
  • a lower alkoxycarbonyl group which may be substituted may be mentioned, 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 phthalimide group is formed together with the protected amino group.
  • the protecting group for the hydroxyl group may be an optionally substituted aryl lower alkyl group, an acyl group, or an optionally substituted lower alkoxy group.
  • Common protecting groups such as a carbonyl group and a trialkylsilyl group can be exemplified. Of these, preferred are, for example, unsubstituted aryl aryl lower alkyl groups such as benzyl group and phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryl group such as acryloyl group and benzoyl group, and methoxycarbonyl.
  • R 1 is (1) a hydrogen atom
  • R 3 and R 4 may be the same or different and each represents a group selected from a hydrogen atom, an alkyl group, a phenyl lower alkyl group, a pyridyl lower alkyl group, a pyridyl group and a phenyl group.
  • ⁇ is an integer from 0 to 3
  • R 2 represents a hydrogen atom or a lower alkoxy lower alkyl group, and is a group represented by
  • R is the formula:
  • n an integer of 1 to 3
  • W represents a pyrazolyl group optionally substituted with a group selected from:
  • ring A has the formula:
  • R 1 is (1) a hydrogen atom
  • Equation (9) — CONR 3 R 4
  • R 3 and R 4 may be the same or different, and each represents a group selected from an alkyl group and a phenyl group;
  • ⁇ is 1 or 2
  • R is the formula:
  • ring A has the formula:
  • R 1 is (1) a phenyl lower alkyl group
  • R 3 and R 4 may be the same or different, and each represents a group selected from an alkyl group;
  • R is the formula:
  • ring A has the formula:
  • R 1 is (1) a phenyl lower alkyl group
  • lower alkylsulfonyl group (7) a phenylcarbonyl group; a lower alkoxycarbonyl group; a phenyl lower alkoxycarbonyl group; a phenyloxycarbonyl group; and an amino group which may be substituted with a group selected from a lower alkyl group;
  • R 3 and R 4 may be the same or different and each represents a group selected from an alkyl group, a phenyl group, and a phenyl lower alkyl group.
  • n 1 or 2
  • R 1 is (1) a phenyl lower alkyl group
  • Equation (6) — C ⁇ NR 3 R 4 NN RI
  • R 3 and R 4 may be the same or different and each represents a group selected from an alkyl group and a phenyl group.
  • R is the formula:
  • particularly preferred compounds include 2-[(1H-pyrazole-1-yl) acetyl] -5- [2- [4-(N-methyl-N-n-butyl- 1-yl] benzoylamino] -iso Indoline, 2-[(1H-pyrazole-1-yl) acetyl] -1-5- [2- (4-dimethylcarbamoylbiperidine-1-1-yl) benzoylamino] -isoindolin, or their pharmacologically Acceptable salts are included.
  • the target compound [I] of the present invention may exist as an optical isomer based on the asymmetric atom when the ring A, the substituent on the ring A and / or the group R has an asymmetric atom. And optically isomers and mixtures thereof.
  • the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof has an apolipoprotein B secretion inhibitory action and exhibits an excellent serum lipid lowering action.
  • the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof is preferably hyperlipidemia, ischemic heart disease, atherosclerosis, coronary atherosclerosis, hypercholesterolemia, hypertriglyceridemia.
  • Familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary atherosclerosis, coronary heart disease, ischemic brain disease, stroke, circulatory and microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute hemorrhagic It can be applied to the prevention and treatment of Tengitis, 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 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 hydrobromide, acetate, fumarate, oxalate, and the like.
  • Organic salts such as citrate, methanesulfonate, benzenesulfonate, tosylate or maleate are listed.
  • 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 compound of interest [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and tablets, granules, capsules, powders, It can be used as conventional pharmaceutical preparations such as propellants and inhalants.
  • the dose 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 mg / kg, for oral preparation, usually about 0.1 to per day: L 0 Omg / kg, especially about 0.1 to 5 OmgZkg It is preferable to set the degree.
  • the target compound [I] is prepared by the following [Method A] to
  • the isindrin compound represented by the target compound [I] of the present invention has the general formula [1]:
  • 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, Examples include benzene, 1,2-dichloroethane, 1-methyl-1-pyrrolidinone, and the like.
  • condensing agent examples include dicyclohexylcarboimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide * hydrochloride (WSC ⁇ HC 1), diphenylphosphoryl azide (DPPA), Lupernidimidazole (CD I), getylcyanophosphonate (DEPC), diisopropylpyrcalopimide (DIPC I), benzotriazo-1-yl 1-yloxy-1-trispirolidinophosphonium hexafluorophosphate (PyBOP) And the like.
  • DCC dicyclohexylcarboimide
  • WSC ⁇ HC 1 hydrochloride
  • DPPA diphenylphosphoryl azide
  • CD I Lupernidimidazole
  • DEPC getylcyanophosphonate
  • DIPC I diisopropylpyrcalopimide
  • PyBOP benzotriazo-1-yl
  • the activator examples include 1-hydroxybenzotriazole (HOB t), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), and 1-hydroxy-7-azabenzotriazole (HO At). And hydroxyphenylimide (HOPht), penfluorophenol (Pfp-OH) and the like.
  • the base for example, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicycline [5.4.0] _7-indene (DBU) and the like can be mentioned.
  • the amount of the condensing agent to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [1] or [2].
  • the amount of the activator to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [1] or [2].
  • the amount of the base to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [1] or [2].
  • This reaction can be carried out at 0 to 100 t, preferably 0 to 50. Further, the compound [1] may be once converted to a reactive derivative such as an acid chloride or a mixed acid anhydride, and then reacted with the compound [2] in the presence of a base.
  • a reactive derivative such as an acid chloride or a mixed acid anhydride
  • the isoindoline compound represented by the target compound [I] of the present invention has the general formula [3]:
  • Y represents a halogen atom, and other symbols have the same meanings as described above, and a compound represented by the formula or a salt thereof, and a compound represented by the general formula [4]:
  • This reaction can be carried out in a solvent, in the presence or absence of a base, or in the presence or absence of an activator.
  • the solvent may be any solvent that does not adversely affect the reaction.
  • the base include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate and cesium carbonate.
  • the activator include copper (I) iodide, copper powder, palladium acetate and the like.
  • the amount of the base to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [3] or [4].
  • the amount of the activator to be used may be 001 to 0.5 equivalent, preferably 0.05 to 0.2 equivalent, relative to compound [3] or [4].
  • This reaction can be carried out at 0 to 15 O :, preferably at 0 to 80.
  • 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.
  • those exemplified as solvents that can be used in the reaction of compound [1] with compound [2] in the above [Method A] may be appropriately used.
  • the activator for example, the activator exemplified in the above [Method A] can be appropriately used.
  • the amount of the condensing agent to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [5] or [6].
  • the amount of the activator used is compound [5] or
  • This reaction can be carried out at a temperature of 0 to 100, preferably 0 to 50.
  • the compound [6] may be once converted into a reactive derivative such as an acid chloride or a mixed acid anhydride, and then reacted with the compound [5] in the presence of a base.
  • 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 monoethyl borofluoride triethyl ether complex, lithium aluminum hydride, aluminum hydride, lithium borohydride, polan-dimethyl sulfide complex, and poran-tetrahydrofuran complex And the like.
  • the amount of the reducing agent to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [I-a].
  • This reaction can be carried out at -30 to 100, preferably 0 to 50. Law
  • the isoindoline compound represented by the general formula [I-b] includes a compound represented by the general formula [5] or a salt thereof, and a compound represented by the general formula [7]: R-CH 2 -X [7]
  • X represents a leaving group, and other symbols have the same meanings as described above, and can also be produced by reacting with a compound represented by the following formula or a salt thereof.
  • 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 includes, for example, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethanol, isopropyl alcohol, and acetonitrile.
  • Bases include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, and the like.
  • Additives include sodium iodide, copper iodide (1), Examples thereof include tetra (lower) alkyl ammonium halides such as copper (II) iodide, copper powder, potassium iodide, tetrabutylammonium chloride, and tetraethylammonium chloride.
  • tetra (lower) alkyl ammonium halides such as copper (II) iodide, copper powder, potassium iodide, tetrabutylammonium chloride, and tetraethylammonium chloride.
  • the leaving group X includes, for example, a fluorine atom, a chlorine atom, a halogen atom such as a bromine atom or an iodine atom, a p_toluenesulfonyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group and the like.
  • a Mitsunobu reagent such as triphenylphosphine-diethylazodicarboxylate or triphenylphenyl-diisopropylazodicarboxylate can be used.
  • the amount of the base to be used may be 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to compound [5] or [7].
  • the amount of the additive to be used may be 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [5] or [7].
  • This reaction can be carried out at from ⁇ 30 to 150, preferably from 0 to 80.
  • the isoindoline compound represented by the general formula [I-b] includes a compound represented by the general formula [5] or a salt thereof, and a general formula [8]:
  • 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, getyl 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, sodium sodium triacetoxyborohydride, palladium hydrogen monocarbon, sodium borohydride monoacetic acid, and the like.
  • the amount of the base to be used may be 1-20 equivalents, preferably 1-5 equivalents, relative to compound [5] or [8].
  • the amount of the reducing agent to be used may be 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [5] or [8].
  • the reaction of the compounds [5] and [8] can be carried out at a temperature of 0 to 100, preferably 0 to 50, and the reduction reaction of the reaction product is performed at a temperature of 30 to 100T, preferably 0 to 50T.
  • the condensation reaction and the reduction reaction can be continuously performed in the same reaction vessel as a reductive amination reaction.
  • the target compound [I] of the present invention is obtained by further converting the substituent and / or the group R on the ring A of the compound obtained as described above to another desired substituent by a conventional method. Can also be manufactured.
  • the method for converting such a substituent is as follows. What is necessary is just to select suitably according to the kind of objective substituent, For example, it can implement as (method a)-(j method).
  • the corresponding compound [I], which is a substituent, and a lower alkyl halide (eg, methyl iodide, benzyl bromide) which may be substituted with an aryl group are reacted with a base (eg, sodium hydride, potassium carbonate). It can be produced by reacting in the presence.
  • a base eg, sodium hydride, potassium carbonate
  • the target compound [I] in which the substituent on the ring A in the general formula [I] is a substituent having a lower alkylamino group is a corresponding compound in which the substituent on the ring A is a substituent having an amino group. It can be produced by reacting [I] with a lower alkyl halide (eg, methyl iodide, benzyl bromide) in the presence of a base (eg, sodium hydride, potassium carbonate).
  • a lower alkyl halide eg, methyl iodide, benzyl bromide
  • the target compound in which the substituent on ring A in the general formula [I] is a substituent containing an amino group substituted with a lower alkyl group or an aryl lower alkyl group (for example, a dimethylamino group, a acetylamino group, a benzylamino group) [ I] is the corresponding compound [I] in which the substituent on ring A is a substituent containing an amino group, and a lower alkanal or aryl lower alkanal (for example, formaldehyde, benzaldehyde) and a reducing agent ( For example, it can be produced by reacting in the presence of sodium borohydride and sodium triacetoxyborohydride.
  • the target compound [I] containing an imino group in which ring A is substituted by a lower alkyl group or an aryl lower alkyl group in the ring is an imino group.
  • the corresponding compound [I] containing a group (one NH—) and a lower alkanal or aryl lower alkanal (eg, formaldehyde, benzaldehyde) are reduced with a reducing agent (eg, sodium borohydride, tria hydride). It can be produced by reacting in the presence of sodium (cetoxyboron).
  • the substituent on ring A in the general formula [I] contains a lower alkoxycarbonylamino group (for example, tert-butoxycarbonylamino group).
  • the target compound [I] as a substituent is prepared by reacting the corresponding compound [I] in which the substituent on ring A is a substituent having a carboxyl group with diphenylphosphoric acid azide in the presence of a base (for example, triethylamine). It can be produced by reacting to an isocyanate and reacting it with a lower alcohol (for example, tert-butyl alcohol).
  • the lower alkoxyl ruponylamino group can be further converted to a free amino group by a conventional deprotection reaction of an amino group.
  • the target compound [I] which is a substituent containing a compound (I), is a compound corresponding to the compound (I) in which the substituent on ring A is a substituent containing an amino group, and a corresponding halide (eg, 2-bromo Pyrimidine) in the presence of a base (eg, triethylamine).
  • a base eg, triethylamine
  • a substituent on ring A in the general formula [I] is a lower alkanoyl group; an aryl lower alkanol group; an aryl carbonyl group; a lower alkoxyl propyl group; an aryl lower alkoxyl propyl group; an aryloxy carbonyl group; Substituted with a group selected from an arylsulfonyl group; and a lower alkylsulfonyl group.
  • the target compound [I], which is a substituent having an amino group, is the same as the corresponding compound [I], wherein the substituent on ring A is a substituent having an amino group, and the corresponding acylating agent and the like (for example, Dimethylcarbamoyl chloride, benzyloxycarbonyl chloride, benzenesulfonyl chloride) in the presence of a base (for example, triethylamine, carbonate carbonate).
  • a base for example, triethylamine, carbonate carbonate
  • R 1G represents a lower alkoxycarbonyl group optionally substituted with a formyl group or an aryl group, a lower alcohol group optionally substituted with an aryl group, an arylsulfonyl group, or a lower alkylsulfonyl group.
  • the ring A has the formula:
  • a compound or a salt thereof which is a group represented by the following formula:
  • X 1 represents a halogen atom, and the other symbols have the same meanings as described above.
  • the compound can be produced by reacting with a compound represented by the following formula in the presence of a base (eg, triethylamine).
  • a base eg, triethylamine
  • the target compound [I] which is a substituent containing a carbamoyl group in which the substituent on ring A may be substituted, is a substituted compound in which the substituent on ring A contains a carboxyl group.
  • the compound can be produced by reacting the corresponding compound [I] which is a group with a corresponding amine compound (eg, dimethylamine, N-methyl-Nn-butylylamine) in the same manner as in the above [Method A].
  • the target compound [I] in which the substituent on the ring A in the general formula [I] is a substituent containing an ester group (for example, benzyl ester) is a substituted compound in which the substituent on the ring A contains a carboxyl group.
  • the compound can be produced by reacting the corresponding compound [I] as a group with a corresponding alcohol compound (for example, benzyl alcohol) in the same manner as in the above [Method A].
  • the target compound [I] of the present invention obtained as described in the above [Method A] to [Method F] or [Method A] to [Method j] may be converted into a pharmacologically 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.
  • Starting compound [1] can be produced, for example, according to the following method.
  • R 5 represents a lower alkyl group or a benzyl group, and other symbols have the same meanings as described above.
  • reaction for producing compound [11] from compound [9] and compound [10] can be carried out in the same manner as in the above [Method B].
  • the reaction to produce compound [1] from compound [11] can be carried out under conventional hydrolysis reaction conditions (for example, sodium hydroxide / hydrogen) or hydrogenolysis reaction conditions (palladium / carbon / hydrogen). can do.
  • hydrolysis reaction conditions for example, sodium hydroxide / hydrogen
  • hydrogenolysis reaction conditions palladium / carbon / hydrogen
  • reaction to produce compound [13] from compound [12] and compound [10] It can be carried out in the same manner as described in [Method B].
  • the reaction for producing the compound [1] from the compound [13] can be carried out under conventional hydrolysis reaction conditions (for example, concentrated hydrochloric acid, concentrated sulfuric acid).
  • the reaction for producing the compound [11] from the compound [13] can be carried out under conventional solvolysis conditions (for example, concentrated sulfuric acid and ethanol).
  • Starting compound [2] ([2-a] and [2-b]) can be produced, for example, according to the following method.
  • the reaction for producing compound [15] from dichloro compound [18] and compound [19] 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 tetra lower alkyl ammonium halides such as tetrabutylammonium chloride and tetraethylammonium chloride.
  • the reaction for producing compound [16] from compound [15] can be carried out in the presence of a suitable nitrating agent.
  • suitable nitrating agents include, for example, concentrated nitric acid Z concentrated sulfuric acid, potassium nitrate concentrated sulfuric acid, potassium nitrate trifluoroacetic acid and the like.
  • the reaction for producing compound [17] from compound [14] can be carried out in the same manner as the reaction for producing compound [16] from compound [15].
  • the reaction for producing compound [16] from compound [17] and carboxylic acid compound [6] can be carried out in the same manner as in the above-mentioned [Method A].
  • the reaction for producing compound [2-a] from compound [16] can be carried out in the presence of a suitable reducing agent.
  • a suitable reducing agent include palladium hydrogen monocarbon, lithium aluminum hydride, zinc-acetic acid, iron (II) chloride monochloride, tin chloride (II) monohydrochloride, iron chloride, iron chloride ammonium, and ammonium formate Z. Palladium monocarbon and the like.
  • the reaction for producing compound [2-b] from compound [2-a] can be carried out in the same manner as in the above [Method D].
  • the compound [2-a] is converted from compound [16] after treatment (N-alkylation) in the same manner as in the above [Method E]. It can be carried out by treating (reducing the nitro group) in the same manner as in the production reaction.
  • Starting compound [3] can be produced, for example, according to the following method.
  • reaction for producing compound [3] from compound [2] and compound [20] can be carried out in the same manner as in the above [Method A].
  • Starting compound [5] can be produced, for example, according to the following method.
  • Boc a tert-butoxycarbonyl group, in which the symbols have the same meanings as described above.
  • the reaction for producing the compound [21] from the compound [17] in a solvent can be carried out in the presence, in the presence of a base or absence of di tert one Petit dicarbonate (Bo c 2 ⁇ ).
  • a base or absence of di tert one Petit dicarbonate (Bo c 2 ⁇ ).
  • the solvent include tetrahydrofuran, methylene chloride, 1,2-dichloroethane, dioxane, ethyl acetate and the like.
  • Examples of the base include triethylamine, potassium carbonate, sodium carbonate, diisopropylethylamine, sodium hydrogen carbonate, 4-dimethylaminopyridine and the like.
  • reaction for producing compound [22] from compound [21] can be carried out in the same manner as the reaction for producing compound [2-a] from compound [16].
  • reaction for producing compound [23] from compound [22] and compound [1] is as described above.
  • the reaction for producing the compound [5] from the compound [23] can be carried out in the presence of a deprotecting agent for an amino group protected by a Boc group.
  • a deprotecting agent for example, examples thereof include hydrochloric acid-dioxane, ethyl acetate monohydrochloride, trifluoroacetic acid, and chlorotrimethylsilane.
  • each intermediate compound is not limited to the one shown in the chemical reaction formula, and if it does not participate in the reaction, its salt may be used. Alternatively, 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, diisopropylethylamine; 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 And salts with organic acids such as trifluoroacetic acid.
  • organic bases such as pyridine, triethylamine, diisopropylethylamine
  • hydrochloric acid sulfuric acid, nitric acid, hydrobromic acid
  • Salts with inorganic acids such as phosphoric acid, acetic acid, oxalic acid, citric acid,
  • an appropriate protecting group for each functional group may be obtained by a conventional method of synthetic chemistry. And protecting groups may be appropriately removed when unnecessary.
  • examples of the alkyl group include linear or branched ones having 1 to 16 carbon atoms, and particularly those having 1 to 10 carbon atoms.
  • the lower alkyl group or lower alkoxy group includes straight or branched ones having 1 to 6 carbon atoms, particularly those having 1 to 4 carbon atoms.
  • a lower alkanoyl group is a straight-chain or branched-chain one having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms
  • a cycloalkyl group is 3 to 20 carbon atoms, especially Those having 3 to 12 carbon atoms are exemplified.
  • the cyclo-lower alkyl group includes those having 3 to 8 carbon atoms, particularly 3 to 6 carbon atoms.
  • the alkenyl group includes a linear or branched chain having 2 to 16 carbon atoms, especially 2 to 10 carbon atoms, and the lower alkenyl group includes 2 to 8 carbon atoms, particularly 2 carbon atoms. ⁇ 4 are listed.
  • the alkylene group includes a linear or branched one having 1 to 16 carbon atoms, particularly 1 to 10 carbon atoms, and a lower alkylene group includes 1 to 8 carbon atoms. Particularly, a linear or branched one having 1 to 6 carbon atoms can be mentioned.
  • the halogen atom includes fluorine, chlorine, bromine or iodine.
  • reaction solution was poured into a dilute aqueous solution of sodium hydrogencarbonate, and extracted with chloroform.
  • the organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, and then dried over anhydrous sodium sulfate.
  • Example 42 2-[(1H-pyrazole-1-yl) acetyl] -1-5- [2- (piperazin-1-yl) benzoylamino] -isoindoline trihydrochloride (compound obtained in Example 37) 20
  • methylene chloride 15 ml
  • a solution of 200 mg of triethylamine and 6 Omg of dimethylcarbamoyl chloride in methylene chloride (5 ml) under ice-cooling.
  • the reaction mixture was warmed to room temperature and stirred for 20 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate.
  • the 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 water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and then dried over anhydrous sodium sulfate.
  • the organic layer was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and then dried over anhydrous sodium sulfate.
  • Benzyl 2- (4-ethoxycarbonylbiperidine-11-yl) benzoate (compound obtained in Reference Example 4) 5.37 g and 2.5 g of 5% palladium-carbon were added to ethanol (100 ml). The suspension was stirred under a hydrogen atmosphere at room temperature and normal pressure for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated to give 4.08 g of 2- (4-ethoxycarboxylbiperidine-11-yl) benzoic acid as a colorless solid.
  • reaction solution was poured into ice water, the precipitated powder was collected by filtration, dried, and recrystallized from a mixed solution of chloroform and methanol to give 5-nitro-12- (1H-pyrazole-11-acetyl) acetyl —5.31 g of isoindoline were obtained as colorless crystals.
  • a novel isindolin compound which has an excellent apolipoprotein B secretion inhibitory action and a serum lipid lowering action and is useful as a medicament, and a method for producing the same.

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Abstract

La présente invention concerne des isoindolines représentées par la formule générale (I) ou certains de leurs sels pharmacologiquement admis. L'invention concerne également un procédé d'élaboratio correspondant. Dans cette formule, A est un groupe hétérocyclique aliphatique azoté substituable; Q est -CO- ou -CH2-; enfin, R est un alkyle inférieur substitué avec un groupe hétérocyclique éventuellement substitué.
PCT/JP2002/005357 2001-06-01 2002-05-31 Isoindolines et procede d'elaboration WO2002098872A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0765878A1 (fr) * 1995-09-29 1997-04-02 Bayer Ag Amides de l'acide aryl-, alkyl- et cycloalkyl-acétique hétérocyclique
EP0779279A1 (fr) * 1995-12-15 1997-06-18 Bayer Ag Hétérocycles bicycliques
WO2000005201A1 (fr) * 1998-07-21 2000-02-03 Novartis Ag Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments
WO2000061556A1 (fr) * 1999-04-09 2000-10-19 Meiji Seika Kaisha, Ltd. Composes heterocycliques contenant de l'azote et composes de benamide et medicaments contenant ces composes
WO2002014276A1 (fr) * 2000-08-10 2002-02-21 Tanabe Seiyaku Co., Ltd. Composes a base de benzoylaminoisoindoline, leurs procedes de preparation et produits intermediaires utilises dans leur synthese

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0765878A1 (fr) * 1995-09-29 1997-04-02 Bayer Ag Amides de l'acide aryl-, alkyl- et cycloalkyl-acétique hétérocyclique
EP0779279A1 (fr) * 1995-12-15 1997-06-18 Bayer Ag Hétérocycles bicycliques
WO2000005201A1 (fr) * 1998-07-21 2000-02-03 Novartis Ag Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments
WO2000061556A1 (fr) * 1999-04-09 2000-10-19 Meiji Seika Kaisha, Ltd. Composes heterocycliques contenant de l'azote et composes de benamide et medicaments contenant ces composes
WO2002014276A1 (fr) * 2000-08-10 2002-02-21 Tanabe Seiyaku Co., Ltd. Composes a base de benzoylaminoisoindoline, leurs procedes de preparation et produits intermediaires utilises dans leur synthese

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