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WO2012081570A1 - Composé de lactame ou d'un sel de ce dernier, et activateur de ppar - Google Patents

Composé de lactame ou d'un sel de ce dernier, et activateur de ppar Download PDF

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Publication number
WO2012081570A1
WO2012081570A1 PCT/JP2011/078767 JP2011078767W WO2012081570A1 WO 2012081570 A1 WO2012081570 A1 WO 2012081570A1 JP 2011078767 W JP2011078767 W JP 2011078767W WO 2012081570 A1 WO2012081570 A1 WO 2012081570A1
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Prior art keywords
isoindoline
mmol
group
alkyl
ring
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Japanese (ja)
Inventor
知士 青塚
一 金澤
健太郎 熊沢
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Aska Pharmaceutical Co Ltd
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Aska Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a lactam compound or a salt thereof (such as a pharmacologically acceptable salt) useful as a peroxisome proliferator-activated receptor (PPAR) agonist (activator), a compound having a lactam skeleton, or a pharmacological thereof
  • a composition (such as a pharmaceutical composition) containing an acceptable salt, a PPAR activator, fatty acid, lipid or sugar abnormalities and various diseases caused by excessive intake compared to metabolism (eg, arteriosclerosis, cerebral infarction) , Stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes, insulin resistance diabetes, obesity, etc.) and myopathy disorder (eg, muscular dystrophy) About.
  • Peroxisome proliferators-activated receptors belong to the nuclear receptor superfamily and are nuclear transcription factors that regulate transcription in a ligand-dependent manner. In mammals, three subtypes (isoforms) of PPAR ⁇ , PPAR ⁇ , and PPAR ⁇ are known, and various studies have been conducted so far.
  • PPAR ⁇ is mainly expressed in tissues that metabolize fatty acids such as liver, myocardium, and small intestine crypts, and regulates fatty acid metabolism.
  • PPAR ⁇ is highly expressed in adipose tissues, and differentiation of adipocytes, lipoprotein lipase and CD36 It has been clarified that the fatty acid uptake is promoted by inducing and the like, and has a function of storing as neutral fat.
  • PPAR ⁇ is a transcription receptor (regulatory factor) that is not expressed in tissue specificity at the site of expression, is universally expressed in almost all organs, and is involved in fatty acid metabolism.
  • PPAR ⁇ is significantly induced in the regulation of fatty acid metabolism such as fatty acid uptake, transport, oxidation, and uncoupling protein of skeletal muscle and myocardium, and differentiation from monocytes to macrophages. It is known to be involved in lipid metabolism.
  • PPAR peroxisome proliferator response sequence
  • a ligand by binding a ligand to PPAR, it activates PPAR (or heterodimer) to promote binding with PPRE, or inhibits binding of PPAR (or heterodimer) to PPRE to target It becomes possible to regulate gene transcription.
  • the ligands that bind to PPAR include endogenous ligands and non-endogenous ligands (exogenous ligands).
  • long-chain fatty acids act as ligands for all subtypes of PPAR, and ligands for PPAR ⁇ as eicosanoids, a ligand as 15-deoxy - [delta 12, 14 of PPARy - although prostaglandin is known, still often elucidated portion not for more information.
  • PPAR ⁇ ligands are fibrate hyperlipidemia drugs, phenoxyacetic acids and phenylpropionic acids
  • PPAR ⁇ ligands (activators) are thiazolidinedione (TZD) diabetes drugs (Pioglitazone, rosiglitazone, etc.), non-TZD PPAR ⁇ activators (TAK-559 (Takeda Pharmaceutical Co., Ltd.), RG12525 (Aventis), etc.) are known.
  • TZD thiazolidinedione
  • TAK-559 Takeda Pharmaceutical Co., Ltd.
  • RG12525 Aventis
  • PPAR ⁇ is delayed in research on its physiological function compared to PPAR ⁇ and ⁇ , and in recent years, the pharmacology of PPAR ⁇ receptor (substance (or activator) having an activating action) has been delayed. Knowledge about activity and pharmaceutical use is being obtained.
  • WO97 / 28149 increases the plasma HDL (high density lipoprotein) amount, and is effective in the treatment and prevention of atherosclerotic coronary arteriosclerosis. In addition, it is effective in treating or preventing atherosclerotic coronary sclerosis when used in combination with an HMG-CoA reductase inhibitor.
  • WO99 / 28115 Patent Document 2 describes a therapeutic agent for diabetes and It is useful as an anti-obesity drug, WO99 / 4815 (patent document 3) has a serum cholesterol lowering action and LDL (low density lipoprotein) -cholesterol lowering action, WO01 / 603 (patent document 4).
  • HDL-cholesterol raising action includes HDL-cholesterol raising action, fibrinogen lowering action, triglyceride lowering action and insulin level lowering action Dyslipidemia, syndrome X (including metabolic syndrome), heart failure, hypercholesterolemia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity Effective in the prevention or treatment of infectious diseases and the like, and WO03 / 8967 (patent document 5) shows a heat production enhancing action, a mitochondrial uncoupling respiratory enhancing action, a fatty acid ⁇ oxidation enhancing action, etc. It is disclosed that it is useful as an anti-obesity agent or visceral fat accumulation reducing agent and visceral fat accumulation inhibitor. Furthermore, Patent Document 4 and Proc. : Natl.
  • Non-Patent Document 1 have GW501516 (chemical name: known as a selective PPAR ⁇ agonist). 2- ⁇ 2-methyl-4-[( ⁇ 4-methyl-2- [4- (trifluoromethyl) phenyl] -1,3-thiazol-5-yl ⁇ methyl) thio] phenoxy ⁇ acetic acid)
  • the effect of improving obesity and insulin resistance is observed in fat diet-induced obese animals, the improvement of diabetes is observed in genetically obese animals by the action of lowering plasma glucose and blood insulin levels, and WO06 / 1092
  • Patent Document 6 discloses that GW501516 is useful as a glucose-dependent insulin secretagogue that responds to hyperglycemia.
  • the structural formula of GW501516 is represented by the following formula.
  • PPAR ⁇ activators are various diseases caused by or affected by abnormal metabolism of fatty acid or sugar and / or imbalance with metabolism due to excessive intake of fatty acid or sugar (eg obesity, insulin resistance). It is expected as a prophylactic and / or therapeutic drug for hyperlipidemia, arteriosclerotic diseases (such as atherosclerotic diseases), metabolic syndrome) and muscular dystrophy.
  • Patent Document 7 discloses isoindol-1-one derivatives as compounds useful as neuropathic pain control agents, respectively.
  • Patent Document 10 discloses a diphenyl ether compound as a PPAR agonist, and examples include 2- ⁇ 4- [3- (5-chloro-1-oxo-1,3-dihydro -Isoindole-2-ylmethyl) -5-fluoro-phenoxy] -2-methyl-phenoxy ⁇ -2-methyl-propionic acid and 2- ⁇ 4- [3-fluoro-5- (1-oxo-1,3 Synthesis examples of -dihydro-isoindol-2-ylmethyl) -phenoxy] -2-methyl-phenoxy ⁇ -2-methyl-propionic acid are described.
  • Patent Document 11 discloses a lactam compound useful as a PPAR activator.
  • the examples describe synthetic examples such as 4-( ⁇ 2- [4- (carboxymethyl) phenyl] ethyl ⁇ oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one. .
  • Patent Document 11 does not disclose a compound having an effect at a low dose.
  • an object of the present invention is to provide a novel lactam compound (isoindoline-1-one derivative) or a salt thereof useful as a PPAR activator (such as a PPAR ⁇ activator) and a production method thereof.
  • Another object of the present invention is to provide a PPAR activator (agonist) and a pharmaceutical composition capable of effectively activating PPAR (such as PPAR ⁇ ).
  • Still another object of the present invention is to provide a PPAR activator (agonist) and a pharmaceutical composition capable of effectively activating PPAR (such as PPAR ⁇ ) even at a low dose.
  • Another object of the present invention is to provide a lactam compound or a salt thereof that has a regulated metabolism in the body and can selectively bind to PPAR (such as PPAR ⁇ ) and a method for producing the same, and a pharmaceutical composition comprising the lactam compound or a salt thereof. And providing a PPAR activator.
  • PPAR such as PPAR ⁇
  • Still another object of the present invention is to provide a pharmaceutical composition capable of effectively preventing or treating various diseases and myopathy disorders caused or affected by abnormal metabolism of fatty acids, lipids or sugars and / or excessive intake of metabolism. And / or providing a therapeutic agent.
  • a compound having a benzopyrrolidone skeleton selectively binds to PPAR (PPAR ⁇ , PPAR ⁇ and / or PPAR ⁇ ).
  • PPAR activity is remarkably improved by improving PPAR activity, in particular, connecting a specific ring to a benzopyrrolidone skeleton via a specific linker.
  • lactam compound (isoindoline-1-one derivative) of the present invention is represented by the following formula (1), and the lactam compound of the present invention includes a salt thereof.
  • ring Z represents a condensed hydrocarbon ring or a heterocyclic ring; and R 1 is the same or different and has a halogen atom, an alkyl group which may have a substituent, a hydroxyl group, or a substituent.
  • R 2 represents an alkylene group which may have a direct bond or a substituent;
  • R 3 represents the following formula (1a):
  • R 3a represents a hydrogen atom or an alkyl group which may have a substituent
  • the linker X has 1 to 10 atoms whose main chain is selected from a carbon atom (C) and a hetero atom [oxygen atom (O), sulfur atom (S)]; The main chain may have a substituent; Y represents a direct bond, an oxygen atom (O), or a sulfur atom (S); k is an integer of 0 to 5]
  • the linker X may be a linker represented by the following formula (3).
  • linker X may be a linker represented by any of the following formulas (3-1) to (3-5).
  • the bond on the left end of the linker may be ring Z, but the bond on the right end of the linker is ring Z. preferable.
  • the ring Z includes a C 8-16 condensed hydrocarbon ring or at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) as a constituent atom of the ring. It may be a 15-membered heterocycle (monocyclic or fused-ring heterocycle). Further, the ring Z may be a condensed ring including at least a benzene ring, for example, a condensed ring represented by the following formula (2).
  • ring Z 1 represents a benzene ring
  • ring Z 2 represents a non-aromatic or aromatic carbon homocyclic or heterocyclic ring
  • G represents a non-aromatic or aromatic ring Z 2.
  • it represents CH, CH 2 , nitrogen atom (N), NH, oxygen atom (O), or sulfur atom (S), and m is an integer of 1 to 5
  • the dashed line in the ring Z 2 means the ring Z 2 may be either non-aromatic or aromatic.
  • Exemplary rings Z include indane, tetralin, indole, 1,2,3,4-tetrahydroquinoline, benzofuran, coumaran, chroman, benzo (b) thiophene, and 2,3-dihydro. It may be a kind of condensed ring selected from benzo (b) thiophene rings.
  • R 1 represents a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, etc.), an alkyl group (a linear or branched C 1-6 alkyl group, etc.), a haloalkyl group (a linear or branched fluoro C 1). -6 alkyl group), an alkoxy group (such as a linear or branched C 1-6 alkoxy group), or a haloalkoxy group (such as a linear or branched fluoro C 1-6 alkoxy group). Also good.
  • R 2 may be an alkylene group (such as a linear or branched C 1-6 alkylene group).
  • R 3a may be a hydrogen atom or an alkyl group (such as a linear or branched C 1-6 alkyl group).
  • Y may be a direct bond, an oxygen atom, or a sulfur atom (particularly a direct bond).
  • a lactam compound represented by a typical formula (1) can be represented by the following formula (4).
  • a representative compound represented by the formula (4) or a salt thereof includes the following compounds: 4- ⁇ [(1-carboxyC 1-4 alkylindan-5-yl) oxy] C 1-4 alkyloxy ⁇ -2- (4-fluoroC 1-4 alkylphenyl) isoindoline-1-one, 4- ⁇ [(1-carboxyC 1-4 alkylindan-5-yl) oxy] C 1-4 alkyloxy ⁇ -2- (4-fluoroC 1-4 alkoxyphenyl) isoindoline-1-one, 4- ⁇ [(1-carboxyC 1-4 alkylindan-5-yl) oxy] C 1-4 alkyl ⁇ -2- (4-C 1-4 alkylphenyl) isoindoline-1-one, 4- ⁇ [(1-carboxyC 1-4 alkylindan-5-yl) oxy] C 1-4 alkyl ⁇ -2- (4-C 1-4 alkylphenyl) isoindoline-1-one, 4- ⁇ [
  • the prodrug form refers to, for example, a group (biologically equivalent group) in which the carboxyl group in the compound is metabolized in vivo to form a carboxyl group, such as an alkoxycarbonyl group, a carbamoyl group.
  • a group biologically equivalent group
  • An N-substituted carbamoyl group for example, an N-alkylcarbamoyl group, an N-acylcarbamoyl group, etc.
  • These compounds may be optically active, for example, (R) or (S) based on the substitution position of the group —R 2 —C ( ⁇ O) —R 3. .
  • the present invention also includes a PPAR activator containing a lactam compound represented by the formula (1) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the PPAR activator may be an activator for activating at least one selected from PPAR ⁇ , PPAR ⁇ , and PPAR ⁇ .
  • the pharmaceutical composition of the present invention may contain a lactam compound (isoindoline-1-one derivative) represented by the above formula (1) or a pharmacologically acceptable salt and carrier thereof.
  • the preventive or therapeutic agent of the present invention comprises (i) a disease caused by abnormal metabolism of fatty acid, lipid (including fat and oil, phospholipid) or sugar, (ii) fatty acid compared to metabolism of fatty acid, lipid or sugar, A disease caused by excessive intake of lipids or sugars, and / or (iii) a preventive or therapeutic agent for myopathy, which is represented by the lactam compound represented by the formula (1) or the formula (1) A compound having a lactam skeleton or a pharmacologically acceptable salt thereof is contained as an active ingredient.
  • the disease is selected from the group consisting of arteriosclerosis, cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes, insulin resistant diabetes, obesity and muscular dystrophy Diseases.
  • the novel lactam compound of the present invention or a salt thereof exhibits high PPAR activity.
  • the PPAR activator or the pharmaceutical composition is composed of a specific lactam compound or a salt thereof, it can be selectively bound to PPAR to effectively activate PPAR.
  • the lactam compound of the present invention or a salt thereof can remarkably activate PPAR (such as PPAR ⁇ ) even at a low dose.
  • the lactam compound or a salt thereof regulates metabolism in the body and can selectively bind to PPAR.
  • the prophylactic and / or therapeutic agent of the present invention uses a specific lactam compound or a salt thereof, it is caused by abnormal metabolism of fatty acids, lipids (including fats and oils, phospholipids) or sugar and / or excessive intake of metabolism. Or various affected diseases can be effectively prevented or treated.
  • the compound represented by the formula (1) is a compound in which a ring Z is connected to a benzopyrrolidone skeleton via a specific linker X.
  • the nitrogen atom of the benzopyrrolidone skeleton is substituted with a phenyl group which may have a substituent R 1 .
  • the halogen atom represented by R 1 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • alkyl group represented by R 1 examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, hexyl, octyl, decyl, dodecyl group and the like. And a linear or branched C 1-10 alkyl group.
  • Preferred alkyl groups are linear or branched C 1-6 alkyl groups, more preferably linear or branched C 1-4 alkyl groups (eg, linear or branched C 1-3 alkyl groups). ).
  • alkoxy group represented by R 1 examples include a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy, octyloxy group
  • examples thereof include a linear or branched C 1-16 alkoxy group.
  • Preferred alkoxy groups are linear or branched C 1-10 alkoxy groups (eg, linear or branched C 1-6 alkoxy groups), more preferably linear or branched C 1-4 alkoxy groups. It may be a group (for example, a linear or branched C 1-3 alkoxy group).
  • the alkyl group and alkoxy group may have a substituent.
  • substituents include methyl, ethyl such as halogen atom (fluorine atom, chlorine atom, bromine atom, etc.); C 1-4 alkoxy C 1-4 alkyl group, C 1-4 alkoxy C 1-4 alkoxy group, etc.
  • a linear or branched C 1-4 alkyl group such as a group (relative to the alkoxy group represented by R 1 ); a linear or branched C 1-4 alkoxy group such as a methoxy or ethoxy group ( And an alkyl group represented by R 1 or an alkoxy group).
  • a halogen atom particularly a fluorine atom
  • the alkyl group and alkoxy group having a substituent are preferably a haloalkyl group or a haloalkoxy group.
  • haloalkyl group examples include a linear or branched halo C 1-6 alkyl group such as a fluoromethyl group (such as a trifluoromethyl group), a fluoroethyl group (a 2,2,2-trifluoroethyl group).
  • a fluoromethyl group such as a trifluoromethyl group
  • a fluoroethyl group a 2,2,2-trifluoroethyl group
  • mono to perfluoro C 1-6 alkyl groups preferably mono to perfluoroethyl groups
  • fluoropropyl groups 3,3,3,2,2-pentafluoropropyl groups, perfluoropropyl groups, etc.
  • perfluoro C 1-4 alkyl groups examples include perfluoro C 1-4 alkyl groups) and chloroalkyl groups corresponding to these fluoroalkyl groups.
  • haloalkoxy group examples include a linear or branched haloC 1-6 alkoxy group such as a fluoromethoxy group (such as a trifluoromethoxy group), a fluoroethoxy group (2,2,2-trifluoroethoxy group, Mono to perfluoro C 1-6 alkoxy groups (preferably mono to perfluoro) such as fluoroethoxy groups), fluoropropoxy groups (3,3,3,2,2-pentafluoropropoxy groups, perfluoropropoxy groups, etc.) C 1-4 alkoxy group), and chloroalkoxy groups corresponding to these fluoroalkoxy groups.
  • a linear or branched haloC 1-6 alkoxy group such as a fluoromethoxy group (such as a trifluoromethoxy group), a fluoroethoxy group (2,2,2-trifluoroethoxy group, Mono to perfluoro C 1-6 alkoxy groups (preferably mono to perfluoro) such as fluoro
  • R 1 represents a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, etc.), an alkyl group (for example, a linear or branched C 1-6 alkyl group, particularly a linear or branched C 1-4 alkyl group) Group), a haloalkyl group (for example, a linear or branched fluoro C 1-6 alkyl group, in particular, a linear or branched fluoro C 1-4 alkyl group), an alkoxy group (for example, linear or A branched C 1-6 alkoxy group, in particular a linear or branched C 1-4 alkoxy group), a haloalkoxy group (eg a linear or branched fluoro C 1-6 alkoxy group, in particular In many cases, it is a linear or branched fluoro C 1-4 alkoxy group).
  • an alkyl group for example, a linear or branched C 1-6 alkyl group, particularly a linear or
  • the coefficient k may be an integer of 0 to 5, preferably an integer of 1 to 3, more preferably 1 or 2 (for example, 1). That is, preferred compounds have at least one substituent R 1 .
  • the coefficient k is 2 or more, the types of the radicals R 1 may be the same or different from each other.
  • the substitution position of the substituent R 1 is not particularly limited, and when the coefficient k is 1, it may be any of 2-, 3-, 4-position of the benzene ring, but when the coefficient k is 1, The substitution position of the substituent R 1 is often the 4-position.
  • the substitution positions of the plurality of substituents R 1 are 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position, It may be 3,4,5-position, etc.
  • the condensed hydrocarbon ring represented by ring Z may be a non-aromatic or aromatic condensed hydrocarbon ring.
  • a C 8-20 condensed cyclic hydrocarbon ring eg, C 8-16 condensed cyclic hydrocarbon ring
  • a C 9-14 condensed cyclic carbon ring examples thereof include a hydrogen ring, more preferably a C 9-12 condensed cyclic hydrocarbon ring.
  • C 9-14 arene rings such as indene and naphthalene, or hydrogenated rings thereof [for example, hydrogenated rings of indene (such as indane), hydrogenated rings of naphthalene (1,4-dihydronaphthalene, tetralin) Etc.) etc.].
  • indene such as indane
  • naphthalene 1,4-dihydronaphthalene, tetralin
  • the heterocycle represented by the ring Z may be a non-aromatic heterocycle or an aromatic heterocycle, and may be a non-fused heterocycle (monocyclic heterocycle) or a fused heterocycle.
  • the heterocyclic ring represented by ring Z is not particularly limited, and for example, at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) is used as a constituent atom of the ring. It may be a heterocyclic ring.
  • the number of heteroatoms is not particularly limited, and may be, for example, about 1 to 4, preferably 1 to 3, and more preferably about 1 to 2 (particularly 1).
  • the heterocyclic ring represented by the ring Z is, for example, a 5- to 15-membered heterocyclic ring, preferably a 6- to 14-membered heterocyclic ring, more preferably an 8- to 13-membered heterocyclic ring. It may be a ring (eg, a 9-12 membered heterocycle).
  • non-condensed heterocycle represented by ring Z examples include a 5- to 8-membered heterocycle, preferably a 5- to 7-membered heterocycle, and more preferably a 5- or 6-membered heterocycle.
  • a typical non-fused heterocycle is a non-fused ring containing at least one (for example, 1 to 3, preferably 1 or 2) heteroatom selected from N, O and S as a member atom of the ring.
  • Heterocycles for example, 5- or 6-membered rings containing nitrogen atoms as heteroatoms such as pyrrole, imidazole, pyrazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine; Or a 6-membered ring; a 5- or 6-membered ring containing a sulfur atom such as thiophene as a heteroatom; a 5- or 6-membered ring containing a nitrogen atom and an oxygen atom such as oxazole, isoxazole or oxazine as a heteroatom; thiazole, isothiazole, 5- or 6-membered rings containing nitrogen and sulfur atoms as heteroatoms, such as thiazine; And addition ring can be exemplified.
  • the condensed heterocyclic ring represented by ring Z may be a condensed ring of a heterocyclic ring and a heterocyclic ring, or a condensed ring of a hydrocarbon ring and a heterocyclic ring.
  • a condensed heterocyclic ring containing at least 5 to 8 membered monocyclic heterocyclic ring for example, 5 to 7 membered monocyclic heterocyclic ring, preferably 5 or 6 membered monocyclic heterocyclic ring
  • exemplary fused heterocycles include fused heterocycles containing at least one (eg, 1 or 2) heteroatom selected from N, O, and S as members of the ring.
  • Such rings include fused heterocyclic rings including 5 or 6-membered monocyclic heterocycles [eg, indole, indoline, isoindole, isoindoline, indolizine, indazole, benzimidazole, benzotriazole, purine, quinoline, isoquinoline.
  • fused heterocyclic rings including 5 or 6-membered monocyclic heterocycles [eg, indole, indoline, isoindole, isoindoline, indolizine, indazole, benzimidazole, benzotriazole, purine, quinoline, isoquinoline.
  • a condensed heterocyclic ring containing a benzene ring for example, a benzene ring and a heterocyclic ring containing at least one heteroatom selected from N, O, and S (for example, a 5- to 8-membered monocyclic ring)
  • it is a condensed ring with a formula heterocycle, preferably a 5- to 7-membered monocyclic heterocycle, more preferably a 5- or 6-membered monocyclic heterocycle.
  • Preferred ring Z is a condensed ring including a benzene ring [a benzene ring and a 5- to 10-membered monocyclic hydrocarbon ring or a monocyclic heterocycle (for example, a 5- or 6-membered monocyclic hydrocarbon ring or a monocyclic ring).
  • a condensed ring represented by the following formula (2).
  • ring Z 1 represents a benzene ring
  • ring Z 2 represents a non-aromatic or aromatic hydrocarbon ring or heterocyclic ring
  • G represents a non-aromatic or aromatic group of ring Z 2 .
  • CH represents CH, CH 2 , N, NH, O, or S
  • m is an integer of 1 to 5 (especially 1 to 3).
  • the dashed line in the ring Z 2 means the ring Z 2 may be either non-aromatic or aromatic.
  • non-aromatic or aromatic hydrocarbon ring represented by ring Z 2
  • examples of the non-aromatic or aromatic hydrocarbon ring (carbon allocyclic ring) represented by ring Z 2 include cycloalkene rings (for example, C 5-8 cyclohexene rings such as cyclopentene ring and cyclohexene ring), arenes Ring (for example, C 6-10 arene ring such as benzene ring) and the like.
  • non-aromatic or aromatic heterocycle represented by ring Z 2 include at least one heteroatom selected from the monocyclic heterocycles exemplified as ring Z, for example, N, O, and S.
  • a member atom of the ring for example, furan, thiophene, pyran, pyrrole, pyridine, hydrogenated rings thereof [for example, 2,3-dihydrofuran, 2,3-dihydrothiophene, 2,3 A 5- or 6-membered monocyclic heterocycle such as dihydropyran, pyrroline (such as 2-pyrroline), 1,2,3,4-tetrahydropyridine, and the like.
  • G can be exemplified by CH, CH 2 , N, NH, O, and S depending on the non-aromaticity or aromaticity of ring Z 2 . Of these G, CH, CH 2 , O, and S are often used.
  • the coefficient m (the number of repeating units of the methylene chain) can be appropriately selected according to the number of constituent atoms of the ring Z 2 , and is, for example, 1 to 5, preferably 1 to 4, more preferably 1 to 3 (particularly 1 Or it may be about 2).
  • rings Z represented by the formula (2) indane ring, tetralin ring, indole ring, 1,2,3,4-tetrahydroquinoline ring, benzofuran ring, coumaran ring, chroman ring, benzo (b) thiophene ring And a condensed ring selected from 2,3-dihydrobenzo (b) thiophene rings.
  • the linker X may be substituted with the ring Z 2 , but is usually substituted with the ring Z 1 .
  • the substitution position of the linker X may be, for example, any of the 1-, 2-, 3-, and 4-positions, preferably the 2-, 3-position, and more preferably the 2-position.
  • the group [—Y—R 2 —C ( ⁇ O) —R 3 ] may be substituted on ring Z 1 , but is usually substituted on ring Z 2 .
  • the substitution position of the group [—YR 2 —C ( ⁇ O) —R 3 ] is, for example, 1′- (G is relative to CH or N), 2′-, or 3′-position. It may be 1'-, 3'-position, more preferably 3'-position.
  • the ring Z represented by the formula (2) may be, for example, a condensed ring represented by the following formula (2a) or (2b).
  • G 1 represents CH, CH 2 , N, NH, O, or S depending on the non-aromaticity or aromaticity of ring Z 2 ;
  • G 2 represents CH or N;
  • m is an integer of 1 to 5 (especially 1 to 3);
  • ring Z 1 and ring Z 2 are the same as above]
  • G 1 is the same as G, and CH, CH 2 , O, and S are preferable.
  • G 2 is preferably CH or N.
  • the condensed ring represented by the formula (2a) is preferable.
  • the condensed ring (or divalent condensed ring group) represented by the formula (2a) include a 1,5-indane-diyl group, a 2,6-tetralin-diyl group, a 1,5-indole-diyl group, 1,6- (1,2,3,4-tetrahydroquinoline) -diyl, 3,6-benzofuran-diyl group, 3,6-coumaran-diyl group, 2,6-chroman-diyl group, 3,6- A benzo (b) thiophene-diyl group and a 3,6- (2,3-dihydrobenzo (b) thiophene) -diyl group are preferred.
  • the alkylene group (including the alkylidene group) represented by R 2 includes methylene, ethylene, propylene, ethylethylene And linear or branched C 1-20 alkylene groups such as trimethylene, dimethylmethylene (isopropylidene), 1,4-butylene, hexamethylene, 1,8-octylene and 1,10-decylene groups.
  • a preferred alkylene group may be a linear or branched C 1-10 alkylene group, more preferably a linear or branched C 1-6 alkylene group (eg, a C 1-4 alkylene group).
  • the alkylene group represented by R 2 may have a substituent.
  • substituents include a halogen atom, a hydroxyl group, an alkoxy group, an acyl group, a carboxyl group, and an alkoxycarbonyl group.
  • R 2 is often a linear or branched C 1-4 alkylene group (a linear or branched C 1-3 alkylene group such as a methylene, ethylene, or propylene group).
  • R 3 is usually a group represented by the following formula (1a) (a hydroxyl group or an alkoxy group which may have a substituent).
  • R 3a represents a hydrogen atom or an alkyl group which may have a substituent
  • the alkyl group that may have a substituent represented by R 3a is an alkyl group that may have a substituent similar to R 1 [for example, a substituent]
  • a linear or branched C 1-10 alkyl group which may have for example, a linear or branched C 1-6 alkyl group, a linear or branched halo C 1-6 alkyl group Etc.] etc. can be illustrated.
  • R 3a is a hydrogen atom, an alkyl group [for example, a linear or branched C 1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, and butyl groups linear or branched C 1- 4 alkyl groups, especially straight-chain or branched C 1-3 alkyl groups)].
  • alkyl group for example, a linear or branched C 1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, and butyl groups linear or branched C 1- 4 alkyl groups, especially straight-chain or branched C 1-3 alkyl groups)].
  • Y is often a direct bond, an oxygen atom, or a sulfur atom (particularly a direct bond).
  • the ring Z may have a substituent other than the group [—Y—R 2 —C ( ⁇ O) —R 3 ], if necessary.
  • substituents include a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, an acyl group, an acyloxy group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a sulfonic acid group, a sulfamoyl group, and an amino group.
  • the alkyl group and the alkoxy group may be further substituted with a substituent (for example, a halogen atom) as necessary to form a haloalkyl group, a haloalkoxy group, or the like.
  • a substituent for example, a halogen atom
  • acyl group examples include a formyl group; a linear or branched C 1-10 alkyl-carbonyl group such as acetyl, propionyl, butyryl group (preferably a C 1-6 alkyl-carbonyl group, more preferably C 1-4 alkyl-carbonyl group); C 3-10 cycloalkyl-carbonyl group such as cyclohexylcarbonyl group (preferably C 5-6 cycloalkyl-carbonyl group); C 6-10 aryl-carbonyl group such as benzoyl group; Examples thereof include C 6-10 aryl-C 1-4 alkyl-carbonyl groups such as benzylcarbonyl group.
  • acyloxy group examples include linear or branched C 2-6 acyloxy groups such as acetoxy, propionyloxy, and butyryloxy groups.
  • alkoxycarbonyl group examples include linear or branched methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, and t-butoxycarbonyl groups. Examples thereof include a C 1-6 alkoxy-carbonyl group.
  • Ring Z may have one or more of these substituents.
  • the kind thereof may be the same or different.
  • the main chain of the linker X linking the benzopyrrolidone skeleton and the ring Z is 1 to 10 (for example, 1 to 1) selected from a carbon atom (C) and a hetero atom [oxygen atom (O), sulfur atom (S)]. 8, preferably 1 to 5, more preferably 1 to 3) atoms. Further, the main chain may have 5 or less (for example, 0 to 4, preferably 0 to 2, more preferably 0 or 1) heteroatoms. Furthermore, in the linker X, the carbon atom of the main chain may have a substituent (or a side chain). Examples of the substituent include a halogen atom, a hydroxyl group, an alkoxy group, an acyl group, a carboxyl group, and an alkoxycarbonyl group.
  • linker X examples include a divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent, an oxo group (—O—), a thio group (—S—), or a combination thereof. And the like.
  • the divalent saturated or unsaturated aliphatic hydrocarbon group may be either an alkylene group (including an alkylidene group), an alkenylene group, an alkynylene group [linear or branched chain such as ethynylene or propynylene group].
  • Alkynylene group preferably C 2-6 alkynylene group etc.
  • dienylene group preferably C 3-6 alkadienylene such as butadiene diyl group which may be either linear or branched Group, etc.
  • alkylene group, an alkenylene group, and the like are preferable.
  • alkylene group examples include linear or branched C 1-6 alkylene groups such as methylene, ethylene, propylene, ethylethylene, trimethylene, dimethylmethylene (isopropylidene), 1,2-butylene and 1,4-butylene. Can be illustrated.
  • Preferred alkylene groups are linear or branched C 1-4 alkylene groups (eg, C 1-2 alkylene groups).
  • alkenylene group examples include linear or branched C 2-6 alkenylene groups such as vinylene, propenylene, butenylene (such as 2-butenylene), 2-pentenylene, and 4-propyl-2-pentenylene.
  • Preferred alkenylene groups are linear or branched C 2-4 alkenylene groups (eg, C 2-3 alkenylene groups).
  • Examples of the group selected from a divalent saturated or unsaturated aliphatic hydrocarbon group, an oxo group, and a thio group include, for example, a combination of a divalent saturated or unsaturated aliphatic hydrocarbon group and an oxo group.
  • a group for example, a linear or branched alkyleneoxy group such as a methyleneoxy group (—CH 2 O—), an ethyleneoxy group (—C 2 H 4 O—) (for example, a C 1-6 alkyleneoxy group, Preferably a C 1-4 alkyleneoxy group); a methylenedioxy group (—O—CH 2 —O—), an ethylenedioxy group (—O—C 2 H 4 —O—), 1,3-propylenedioxy
  • a linear or branched alkylenedioxy group such as a group (—O—C 3 H 6 —O—), a 1,4-butylene dioxy group (—O—C 4 H 8 —O—) (for example, C 1-6 alkylenedioxy group, preferably a C 1-4 Ruki dioxy group)]
  • a divalent saturated or unsaturated aliphatic hydrocarbon group and a combination of groups of thio groups e.g., methylenethio group (-CH
  • the divalent saturated or unsaturated aliphatic hydrocarbon group may have a substituent, and examples of the substituent include a halogen atom, a hydroxyl group, an alkoxy group, an acyl group, a carboxyl group, and an alkoxycarbonyl group. .
  • the linker X may be a linker represented by the following formula (3), for example.
  • n1 and X 2 are the same or different and represent a direct bond, an oxygen atom, or a sulfur atom, n1 is 0 or 1, n2 is an integer of 0 to 5, and a carbon atom is required
  • n1 and X 2 are a direct bond, at least one of n 1 and n 2 is not 0.
  • the coefficient n1 represents the number of repeating units of the vinylene chain and is 0 or 1.
  • the coefficient n2 indicates the number of repeating units of the methylene chain, and may be, for example, about 0 to 5, preferably 0 to 4, more preferably about 0 to 3 (eg, 0 to 2, particularly 0 or 1). . Note that when both the coefficients n1 and n2 is 0, at least one of X 1 and X 2 is often a direct bond.
  • the linker X is usually a linker represented by any of the following formulas (3-1) to (3-5).
  • a preferred coefficient a is about 1 to 6 (eg, 1 to 4, preferably 1 to 3), and a preferred coefficient b is about 0 to 6 (eg, 0 to 4, preferably 0 to 2, especially 0 or 1).
  • the preferable coefficient c is about 0 to 6 (for example, 0 to 4, preferably 0 to 2), the preferable coefficient d is about 1 to 6 (for example, 1 to 4), and the preferable coefficient e is 0. About 6 (for example, 0 to 4, preferably 0 to 2).
  • the left end of the linker may be connected to the ring Z, but the right end of the linker is preferably connected to the ring Z.
  • linkers represented by formulas (3-2) to (3-5) [for example, linkers represented by formulas (3-2) to (3-4), in particular, formula (3-3) -2) or (3-3)] is preferred.
  • the linker X may be bonded to any of the 3-, 4-, 5-, 6- and 7-positions of the isoindoline-1-one skeleton, but preferably 4-, 5-, 6-, It may be bonded to the 7-position, more preferably the 4-position.
  • a preferred lactam compound can be represented by the following formula (4).
  • X is a linker represented by the formula (3-2)
  • R 1 represents a linear or branched halo C 1-4 alkyl group (such as a fluoro C 1-4 alkyl group), or a linear or branched halo C 1-4 alkoxy group (fluoro C 1-4 alkoxy group).
  • R 2 is a linear or branched C 1-4 alkylene group
  • X is a linker represented by the formula (3-3),
  • R 1 is a linear or branched C 1-4 alkyl group, a linear or branched halo C 1-4 alkyl group (such as a fluoro C 1-4 alkyl group), or a linear or branched chain
  • a halo C 1-4 alkoxy group such as a fluoro C 1-4 alkoxy group [particularly a linear or branched C 1-4 alkyl group]
  • R 2 is a linear or branched C 1-4 alkylene group,
  • a compound in which R 3 is a hydroxyl group, a linear or branched C 1-4 alkoxy group: 4- ⁇ [(1-carboxyC 1-4 alkylindan-5-yl) oxy] C 1-4 alkyl ⁇ -2- (4-C 1-4 alkylphenyl) iso
  • X is a linker represented by the formula (3-3),
  • R 1 is a linear or branched C 1-4 alkyl group, a linear or branched halo C 1-4 alkyl group (such as a fluoro C 1-4 alkyl group), or a linear or branched chain
  • a halo C 1-4 alkoxy group such as a fluoro C 1-4 alkoxy group
  • R 2 is a linear or branched C 1-4 alkylene group,
  • X is a linker represented by the formula (3-3)
  • R 1 is a linear or branched C 1-4 alkyl group, a linear or branched halo C 1-4 alkyl group (such as a fluoro C 1-4 alkyl group), or a linear or branched chain
  • a halo C 1-4 alkoxy group such as a fluoro C 1-4 alkoxy group
  • R 2 is a linear or branched C 1-4 alkylene group
  • a compound in which R 3 is a hydroxyl group, a linear or branched C 1-4 alkoxy group: 4- ⁇ [(5-CarboxyC 1-4 alkyl-5,6,7,8-
  • X is a linker represented by the formula (3-3)
  • R 1 is a linear or branched C 1-4 alkyl group, a linear or branched halo C 1-4 alkyl group (such as a fluoro C 1-4 alkyl group), or a linear or branched chain
  • a halo C 1-4 alkoxy group such as a fluoro C 1-4 alkoxy group
  • R 2 is a linear or branched C 1-4 alkylene group
  • a compound in which R 3 is a hydroxyl group, a linear or branched C 1-4 alkoxy group: 4- ⁇ [(3-CarboxyC 1-4 alkyl-2,3-dihydrobenzo (b) thiophen-6-yl) oxy] C 1-4 alkyl ⁇ -2- (4-C
  • X is a linker represented by the formula (3-4)
  • R 1 represents a linear or branched halo C 1-4 alkyl group (such as a fluoro C 1-4 alkyl group), or a linear or branched halo C 1-4 alkoxy group (fluoro C 1-4 alkoxy group).
  • R 2 is a linear or branched C 1-4 alkylene group
  • the lactam compound may form a salt with an acid.
  • Acids that can form salts with lactam compounds include organic acids [organic carboxylic acids (eg, alkane carboxylic acids such as acetic acid, propionic acid, butyric acid; alkene carboxylic acids such as (meth) acrylic acid; tartaric acid, citric acid, lactic acid] Hydroxycarboxylic acids such as gluconic acid, malic acid, succinic acid, salicylic acid, phenolphthaline, and tannic acid; haloalkane carboxylic acids such as trichloroacetic acid and trifluoroacetic acid; and a variety of oxalic acid, succinic acid, maleic acid, fumaric acid, etc.
  • organic carboxylic acids eg, alkane carboxylic acids such as acetic acid, propionic acid, butyric acid; alkene carboxylic acids such as (meth) acrylic acid; tartaric acid, citric acid,
  • Divalent carboxylic acids Divalent carboxylic acids; organic sulfonic acids (alkane sulfonic acids such as methane sulfonic acid, arene sulfonic acids such as benzene sulfonic acid, toluene sulfonic acid, diphenyl disulfonic acid; amino acids such as aspartic acid), inorganic acids (for example, hydrochloric acid, odor Hydrohalic acids such as hydrofluoric acid; sulfuric acid, glass And phosphoric acid).
  • organic sulfonic acids alkane sulfonic acids such as methane sulfonic acid, arene sulfonic acids such as benzene sulfonic acid, toluene sulfonic acid, diphenyl disulfonic acid
  • amino acids such as aspartic acid
  • inorganic acids for example, hydrochloric acid, odor Hydrohalic acids such as hydrofluoric acid; sulfuric acid, glass And phospho
  • the lactam compound usually forms a salt with a base.
  • Bases capable of forming salts with lactam compounds include organic bases (amines such as mono- to trialkylamines such as methylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, diisopropylethylamine; alkanols such as ethanolamine).
  • the lactam compound may form a salt with one of these bases, or may form a salt with two or more bases.
  • the lactam compound or salt thereof of the present invention may be an anhydride or hydrate, and may be a solvate (such as a solvate with an organic solvent such as ethanol).
  • the compound of the present invention or a salt thereof includes not only a hydrate or a solvate but also an isolated crystal (such as a polymorphic substance).
  • the lactam compound of the present invention or a salt thereof includes a tautomer, an optically active substance having an asymmetric carbon atom ((R) form, (S) form, diastereomer, etc.), a racemic form, or a combination thereof. Mixtures and the like are also included.
  • the compound of the formula (4) has an asymmetric carbon atom (for example, a carbon atom substituted by a group [—Y—R 2 —C ( ⁇ O) —R 3 ]), and thus is an optically active substance. May be.
  • the optical purity of the optically active substance may be, for example, an enantiomeric excess (ee) of 80% or more (preferably 90% or more).
  • ee an enantiomeric excess
  • the lactam compound or a salt thereof may be a prodrug (or active metabolite) in which the functional group of the compound or salt is modified and the activity is expressed in vivo.
  • prodrug form examples include compounds that exhibit activity by metabolism such as hydrolysis, oxidation, reduction, transesterification (eg, ester form, ether form, alcohol form, amide form, etc. of the compound of formula (1)). Is mentioned.
  • the lactam compound of the present invention or a salt thereof has high safety.
  • the compound represented by the formula (1) or a salt thereof is prepared by a conventional method, for example, a compound represented by the following formula (5) or a salt thereof, and a compound represented by the following formula (6) or a salt thereof. It can be obtained by the reaction step (A) to be reacted.
  • X 3 and X 4 each represent a group or an atom that can be linked to each other to form a linker X, and ring Z, R 1 , R 2 , R 3 , X, Y, and k are the same as above
  • X 3 and X 4 are a group (or a precursor group of the linker X) or an atom that can be linked to each other to form the linker X.
  • the precursor group of the linker X include an unsaturated aliphatic hydrocarbon group (such as an alkenylene group).
  • the precursor group of the linker X (for example, unsaturated aliphatic hydrocarbon) can be converted into a saturated aliphatic hydrocarbon group as the linker X by, for example, a known hydrogenation reaction.
  • the hydrogenation reaction may be performed, for example, in the presence of a catalyst (such as activated carbon-palladium) in a hydrogen atmosphere.
  • the reaction may be carried out in the presence of a solvent [for example, alcohols (C 1-4 alkanols such as ethanol), ethers (cyclic ethers such as 1,4-dioxane), etc.].
  • Examples of the leaving group include a hydroxyl group and an alkylsulfonyloxy group which may have a substituent.
  • Examples of the leaving atom include a hydrogen atom and a halogen atom.
  • Examples of the alkylsulfonyloxy group which may have a substituent include halogen atoms such as a methanesulfonyloxy group (CH 3 SO 3 —), a fluoromethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and an ethanesulfonyloxy group.
  • Examples thereof include a C 1-6 alkylsulfonyloxy group which may have a substituent, and a C 1-4 alkylsulfonyloxy group or a halo C 1-4 alkylsulfonyloxy group is particularly preferable.
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among the halogen atoms, a chlorine atom, a bromine atom and an iodine atom are preferable.
  • L 1 and L 2 for example, (i) a combination of a halogen atom and a hydroxyl group (or a mercapto group) [specifically, one of L 1 and L 2 is a halogen atom and the other is a hydroxyl group A combination that is a hydrogen atom of a group (or a mercapto group)], (ii) a combination of a hydroxyl group and a hydroxyl group [specifically, one of L 1 and L 2 is a hydroxyl group, and the other is a hydrogen atom of a hydroxyl group A combination of a halogen atom and an alkenyl group [specifically, a combination in which one of L 1 and L 2 is a halogen atom and the other is a hydrogen atom of an alkenyl group], (iv) an alkyl in combination [details of sulfonyloxy group and the alkenyl group is one alkylsulfonyl
  • reaction between the compound represented by the formula (5) and the compound represented by the formula (6) can be selected according to the combination of the leaving group and the leaving atom.
  • the compound represented by the formula (1) can be obtained by reacting the compound represented by the formula (5) with the compound represented by the formula (6) in the presence of a base. .
  • the base may be an organic base (such as a tertiary amine), but is usually an inorganic base.
  • inorganic bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate (including alkali metal hydrogen carbonates). And the like. These bases can be used alone or in combination of two or more.
  • alkali metal carbonates such as cesium carbonate and potassium carbonate are often used.
  • the amount of the base used can be selected from a range of about 0.9 to 10 moles with respect to 1 mole of the compound having a halogen atom (L 1 or L 2 ), and usually 1 to 5 moles (for example, 1.05 to 5 moles), more preferably about 1 to 3 moles (for example, 1.1 to 2 moles).
  • the reaction may be performed in the absence of a solvent, but is usually performed in a solvent.
  • Solvents include various organic solvents inert to the reaction, for example, hydrocarbons (aliphatic hydrocarbons such as hexane and cyclohexane, aromatic hydrocarbons such as toluene), ethers (chains such as diethyl ether and diisopropyl ether).
  • Ethers such as 1,4-dioxane, tetrahydrofuran (THF), esters (ethyl acetate, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, propionitrile, etc.), amides ( Examples thereof include N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAA) and the like, sulfoxides such as dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like.
  • solvents can be used alone or in combination.
  • the solvent is often an aprotic solvent (for example, aprotic polar solvents such as ketones, nitriles, and amides).
  • the reaction can be performed in an inert atmosphere or air, and can be performed at a temperature lower than the reflux temperature of the reaction system, for example, under heating (for example, about 30 to 100 ° C.) or at room temperature (for example, 15 to 25 ° C.). .
  • the reaction may be performed under normal pressure, reduced pressure, or increased pressure.
  • the compound represented by the formula (1) is reacted with the compound represented by the formula (6) under Mitsunobu reaction conditions to obtain the target compound represented by the formula (1).
  • Obtainable for Mitsunobu reaction, reference can be made to literature: SYNTHESIS, 1981, 1 (1981).
  • the Mitsunobu reaction can be performed in the presence of an activating component for activating the hydroxyl group, such as azodicarboxylic acid esters and triphenylphosphine, or in the presence of a (cyanomethylene) phosphorane reagent.
  • an activating component for activating the hydroxyl group such as azodicarboxylic acid esters and triphenylphosphine
  • a (cyanomethylene) phosphorane reagent e.g., a (cyanomethylene) phosphorane reagent.
  • azodicarboxylic acid esters include azodicarboxylic acid alkyl esters such as diethyl azodicarboxylate (DEAD), and examples of triarylphosphines include triphenylphosphine (PPh 3 ).
  • Examples of the (cyanomethylene) phosphorane reagent include (cyanomethylene) trimethylphosphorane, (cyanomethylene) triethylphosphorane, (cyanomethylene) tributylphosphorane, and the like. These components can be used alone or in combination of two or more. The use amount of these activating components is selected from a range of about 0.7 to 5 moles with respect to 1 mole of the compound represented by the formula (5) (or the compound represented by the formula (6)), for example. In general, it may be about 1 to 2.5 mol (for example, 1 to 1.5 mol).
  • the reaction may be performed in the absence of a solvent, but is usually performed in a solvent.
  • Solvents are various organic solvents that are inert to the reaction, such as hydrocarbons (aliphatic hydrocarbons such as hexane and cyclohexane, aromatic hydrocarbons such as benzene and toluene), halogenated hydrocarbons (such as dichloromethane), and the like.
  • Ethers chain ethers such as diethyl ether and diisopropyl ether, cyclic ethers such as 1,4-dioxane and THF
  • esters such as ethyl acetate
  • ketones such as acetone and methyl ethyl ketone
  • nitriles acetonitrile, Propionitrile, etc.
  • amides DF, DMAA, hexamethylphosphate triamide, etc.
  • sulfoxides DMSO, etc.
  • NMP N-methylpyrrolidone
  • tertiary amines such as pyridine, trimethyl phosphate, etc. Examples thereof include phosphate esters.
  • solvents can be used alone or in combination.
  • the solvent is often a hydrocarbon (such as toluene) or an aprotic solvent (for example, an aprotic polar solvent such as ketones, nitriles or amides).
  • the reaction can be performed in an inert atmosphere or air, and can be performed at a temperature lower than the reflux temperature of the reaction system, for example, under heating (for example, about 30 to 100 ° C.) or at room temperature (for example, 15 to 25 ° C.). .
  • the reaction may be performed under normal pressure, reduced pressure, or increased pressure.
  • the embodiment (iii) is represented by the formula (1) by reacting the compound represented by the formula (5) with the compound represented by the formula (6) in the presence of a base and a catalyst.
  • Target compound can be obtained.
  • the base may be an inorganic base (such as an alkali metal salt), but is usually an organic base.
  • organic base include aliphatic amines [eg, aliphatic tertiary amines such as tri-C 1-4 alkylamine (triethylamine, diethylmethylamine, diisopropylethylamine, tri-n-propylamine, tributylamine, etc.)], Examples thereof include aromatic amines (for example, aromatic tertiary amines such as N, N-dimethylaniline), heterocyclic amines and the like. These bases can be used alone or in combination of two or more.
  • tri-C 1-4 alkylamine such as triethylamine is often used.
  • the amount of the base used can be selected from a range of about 0.9 to 10 moles with respect to 1 mole of the compound having a halogen atom (L 1 or L 2 ), and usually 1 to 5 moles (for example, 1.05 to 5 moles), more preferably about 1 to 3 moles (eg, 1.1 to 3 moles).
  • Heck reaction catalyst such as palladium complex [Pd (OCOCH 3 ) 2 , Pd (OCOCH 3 ) 2 -PPh 3 , PdCl 2 (PPh 3 ) 2 , (CH 3 CN) 2 PdCl 2 , Pd 2 ( dba) 3 etc.] is widely used. These catalysts can be used alone or in combination of two or more. These catalysts may be used in combination with phosphine ligands (triarylphosphine such as triphenylphosphine and tolylphosphine, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene) as required. May be.
  • phosphine ligands triarylphosphine such as triphenylphosphine and tolylphosphine, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene
  • the catalyst is used in an amount of 0.001 to 0.5 mol, preferably 0.005 to 0.3 mol, more preferably 0.01 to 1 mol of the compound having a halogen atom (L 1 or L 2 ). It may be about 0.1 mol.
  • the reaction may be performed in the absence of a solvent, but is usually performed in a solvent.
  • the solvent is the same solvent (for example, aprotic polar solvents such as ketones, nitriles and amides) and ethers (such as cyclic ethers such as 1,4-dioxane) as in the reaction of the embodiment (i). There are many cases.
  • the reaction can be performed in an inert atmosphere or air, and can be performed at a temperature lower than the reflux temperature of the reaction system, for example, under heating (for example, about 30 to 150 ° C.) or at room temperature (for example, 15 to 25 ° C.). .
  • the reaction may be performed under normal pressure, reduced pressure, or increased pressure.
  • reaction of a combination of a halogen atom and an alkenyl group may be referred to as a Heck reaction. Details of the Heck reaction can be referred to, for example, literature (4th edition, Experimental Chemistry Course 19, Organic Synthesis I, Hydrocarbon / Halogen Compounds, edited by The Chemical Society of Japan, p123-132, issued on June 5, 1992).
  • the obtained lactam compound and its salt can be converted into each other.
  • a lactam compound can be formed by subjecting a lactam compound to an acid treatment with an organic acid or an inorganic acid, or a base treatment with an organic base or an inorganic base, and the salt of the lactam compound can be converted into a strong base such as sodium hydroxide.
  • Bases or acids (strong acids such as hydrochloric acid, sulfuric acid, hydrofluoric acid, etc.) can be used to liberate salts to produce lactam compounds.
  • the obtained lactam compound represented by the formula (1) or a salt thereof may be separated by a conventional separation or purification (or isolation) method, for example, filtration, phase transfer, salting out, distillation, solvent removal, precipitation, It may be separated or purified by crystallization, recrystallization, decantation, extraction, drying, washing, chromatography, and combinations thereof.
  • the compound (5) and the compound (6) as intermediates can be prepared by known conventional methods or similar methods, and can be purchased as commercial products. The following synthesis examples can also be referred to for the preparation of these intermediates.
  • the compound (5) in which the group —X 3 -L 1 is an alkoxycarbonyl group is obtained by reacting 2-methylisophthalic acid dialkyl ester with a halogen source (bromosuccinimide (NBS), N-chlorosuccinimide, etc.)
  • 2-halomethylisophthalic acid dialkyl ester was prepared by halogenation with an initiator (radical source such as azobisisobutyronitrile (AIBN) or benzoyl peroxide), and the 2-halomethylisophthalic acid dialkyl ester and It can be prepared by reacting an aniline derivative with cyclization.
  • halogenated hydrocarbons carbon tetrachloride, etc.
  • aromatic hydrocarbons benzene, etc.
  • the cyclization reaction can be performed in a solvent (DMF or the like), and is performed by heating and stirring at an appropriate temperature, for example, room temperature to 200 ° C. [preferably about 100 to 150 ° C. (for example, around 120 ° C.)]. be able to.
  • 2-methylisophthalic acid dialkyl ester is obtained by hydrolyzing 2,6-dicyanotoluene with an acid or alkali to produce a dicarboxylic acid [for example, New Experimental Chemistry Course (Maruzen Co., Ltd.), Experimental Chemical Course 4th Edition , See the synthesis of carboxylic acids by hydrolysis from nitriles, such as Experimental Chemistry Course 5th edition], and can be obtained by esterifying the produced dicarboxylic acid [for example, New Experimental Chemistry Course (Maruzen Co., Ltd.), experiment “Protective ⁇ group in organic synthesis” (No. 4) (Chemical Lecture 4 edition (November 30, 1992), Experimental Chemistry Lecture 5 edition (March 31, 2005)) 3rd edition, see JOHN WILEY & SONS, INC., New York, 1991)].
  • a compound in which the group -X 3 -L 1 is a carboxyl group is prepared by hydrolyzing a compound in which the group -X 3 -L 1 is an alkoxycarbonyl group in the presence of an alkali. it can. Hydrolysis can be performed in a solvent at room temperature to under heating.
  • a solvent water, a mixed solvent of water and a water-soluble organic solvent [alcohol (methanol, ethanol, etc.), dioxane, etc.] can be used.
  • a compound in which the group -X 3 -L 1 is a carboxyl group can be reduced to a compound in which the group -X 3 -L 1 is a hydroxymethyl group by reduction using a reducing agent by a conventional method.
  • a reducing agent for example, “MARCH'S ADVANCED ORGANIC CHEMISTRY” (4th edition, JOHN WILEY & SONS, INC., New York, 1992) can be referred to.
  • Examples of the reducing agent include sodium borohydride-aluminum chloride, borane-THF complex, borane-dimethyl sulfide complex, 9-borabicyclo [3.3.1] nonane, lithium aluminum hydride, sodium aluminum hydride, trimethoxyhydrogen. Examples include lithium aluminum hydride and diisobutylaluminum hydride. Preferred reducing agents include borane-THF complex and the like.
  • the reaction can be carried out, for example, in a solvent (diethyl ether, tetrahydrofuran, toluene, n-hexane or a mixed solvent thereof), and the reaction temperature is, for example, ⁇ 100 ° C. to heating (preferably 0 ° C. to room temperature). ) Can be done at a degree.
  • a compound in which the group -X 3 -L 1 is a halomethyl group can be derived.
  • Conventional methods and general methods can be used for the halogenation conditions. For example, see the section on halides such as New Experimental Chemistry Course (Maruzen Co., Ltd.), Experimental Chemistry Course 4th Edition, Experimental Chemistry Course 5th Edition. it can.
  • halogenating agent examples include “triphenylphosphine and N-bromosuccinimide or N-chlorosuccinimide”, “triphenylphosphine and carbon tetrachloride or carbon tetrabromide”, “thionyl chloride and DMF or pyridine”, “Lithium chloride, lithium bromide, zinc chloride or zinc bromide under Mitsunobu conditions” and the like.
  • the reaction can be performed in a solvent (eg, methylene chloride, chloroform, carbon tetrachloride, carbon tetrabromide, THF, etc.), and the reaction temperature is, for example, ⁇ 100 ° C. to 100 ° C. (eg, 0 ° C. to room temperature). Can be done.
  • the compound (6) in which the group —X 4 -L 2 is a hydroxyl group can be prepared by a known method depending on the kind of the ring Z.
  • a compound in which ring Z is an indane ring for example, (5-hydroxyindan-1-yl) ethyl acetate and the like] is prepared according to the method described in the literature: J. Med. Chem., 50, 984-1000 (2007).
  • Compounds that can be prepared and in which ring Z is an indole ring are described in literature: Bioorganic. Med. Chem. Lett., 17, 3630-3635 (2007).
  • the compound (6) in which the group -X 4 -L 2 is a haloalkyloxy group includes a compound in which the group -X 4 -L 2 is a hydroxyl group and a dihaloalkane (1-bromo-2-chloroethane, 1-bromo-3- It can be prepared by reacting with bromo-chloroalkanes such as chloropropane. In addition, you may perform this reaction on the conditions similar to the reaction of the said aspect (i).
  • a compound in which the group -X 4 -L 2 is an alkenyl group is obtained by combining a compound in which the group -X 4 -L 2 is a hydroxyl group with a haloalkanesulfonic acid (such as trifluoromethanesulfonic anhydride) in a solvent (such as pyridine).
  • a haloalkanesulfonic acid such as trifluoromethanesulfonic anhydride
  • a compound in which the group —X 4 -L 2 is a haloalkanesulfonyloxy group is prepared by reacting in the presence, and this compound and an alkenylating agent (dialkyl vinylboronate, trialkyl (vinyl) tin, etc.) are mixed with a solvent (Water, tetrahydrofuran, dimethylformamide, etc.), alkali metal salts (carbonates such as sodium carbonate, hydrochlorides such as lithium chloride), and catalysts (such as palladium complexes such as bis (triphenylphosphine) palladium (II) dichloride) It can obtain by making it react in presence of.
  • an alkenylating agent dialkyl vinylboronate, trialkyl (vinyl) tin, etc.
  • a solvent Water, tetrahydrofuran, dimethylformamide, etc.
  • alkali metal salts carbonates such as sodium carbonate, hydrochlorides such as lithium chloride
  • a compound in which the group —X 4 -L 2 is an alkenyl group can be obtained by a similar operation even when the compound is a halogen atom.
  • a compound in which the group -X 4 -L 2 is a mercapto group is obtained by reacting a compound in which the group -X 4 -L 2 is a halogen atom with a thiocyanate (such as sodium thiocyanate) to react with the group -X 4 -L
  • a thiocyanate such as sodium thiocyanate
  • a reducing agent such as dithiothreitol
  • a solvent such as methanol
  • a phosphate such as potassium dihydrogen phosphate
  • Ring Z compound is a fused ring represented by the following formula (2c) or (2d), the enantioselective the condensed ring Z is represented by the following formula (2e) (the unsaturated bonds of the ring Z 2) It can be obtained by adding hydrogen to (asymmetric hydrogenation reaction).
  • asymmetric hydrogenation reaction For details of the reaction, refer to, for example, JP-T-2009-542580.
  • ring Z 1 , ring Z 2 , G 1 and m are the same as above
  • a mixture containing a compound, a base and a catalyst can be obtained by subjecting to a hydrogen atmosphere.
  • the base examples include alkali metal hydroxide, alkali metal alkoxide (for example, alkali metal C 1-4 alkoxide such as sodium methoxide), alkali metal thioalkoxide (for example, alkali metal thio C 1-4 alkoxide such as sodium thiomethoxide) ), And combinations thereof. Of these bases, alkali metal C 1-4 alkoxides such as sodium methoxide are preferred.
  • the ratio of the base may be, for example, about 0.01 to 100 mol, preferably about 0.1 to 10 mol, per 1 mol of the compound represented by the formula (2e).
  • the catalyst is not particularly limited as long as it can promote the formation reaction of a specific optically active substance, and is usually a catalyst containing a transition metal and a ligand (for example, a complex or a coordination compound).
  • a transition metal complex may be formed in the reaction system or before being subjected to the reaction.
  • transition metals include Group 8 elements (such as iron and ruthenium) and Group 9 elements (such as cobalt and rhodium).
  • a ligand having at least optical activity a ligand having at least optical activity
  • the asymmetric ligand may be, for example, an amine ligand (such as diphenyl C 2-6 alkanediamine such as 1,2-diphenyl-1,2-ethanediamine).
  • a scale is used.
  • phosphine ligand examples include a ligand having a dicycloalkylphosphino group [for example, bis (dicyclohexylphosphino) biC 6-10 aryl and the like], a ligand having a diarylphosphino group [for example, Bis (diphenylphosphino) C 2-6 alkane; bis (diphenylphosphino) bi C 5-10 cycloalkane; bis (diphenylphosphino) bi C 6-10 aryl (eg, 2,2′-bis (diphenylphosphine) Fino) -1,1′-binaphthyl etc.); bis (diphenylphosphino) paracyclophane; bis (diphenylphosphino) pyrrolidine; bis (diphenylphosphino) ferrocene etc.], ligands having phosphorano groups [eg Bisphosphorano C 2-6 alkanes (eg, bis
  • a typical catalyst includes a catalyst containing rhodium and an asymmetric phosphine ligand.
  • a rhodium complex eg, (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate, bis (1,5 -Rhodium complexes coordinated with asymmetric ligands (such as cycloalkadiene) such as cyclooctadiene) rhodium tetrafluoroborate] and asymmetric phosphine ligands [eg bisphosphorano C 2-6 alkane, bis ( DiC 1-4 alkylphosphonato) ferrocene etc.] is often used in combination.
  • the ratio of the catalyst is not particularly limited, and is, for example, about 0.00001 to 0.1 mol, preferably about 0.0001 to 0.05 mol part per 1 mol of the compound represented by the formula (2e). May be.
  • the asymmetric hydrogenation reaction may be performed in the presence of a solvent.
  • the solvent include aliphatic hydrocarbons, aromatic hydrocarbons, alcohols (such as methanol and ethanol), ethers, nitriles, amides, sulfoxides, and mixed solvents thereof.
  • the proportion of the solvent may be about 0.1 to 200 parts by weight, preferably about 1 to 150 parts by weight with respect to 1 part by weight of the compound represented by the formula (2e).
  • the reaction temperature may be ⁇ 30 ° C. to heating, preferably room temperature to 100 ° C. (for example, about 20 to 50 ° C.).
  • the hydrogen pressure (partial pressure) of the reaction system may be, for example, about 0.1 to 10 MPa, preferably about 0.2 to 1 MPa.
  • the optical purity of the compound in which ring Z is represented by formula (2c) or (2d) may be improved by optical resolution.
  • the optical resolution method is not particularly limited, and for example, a compound in which ring Z is represented by the formula (2c) or (2d) (or a racemate) and a base having optical activity [for example, p- (1-aminoethyl) )) ( ⁇ -amino C 2-4 alkyl) (C 1-4 alkyl) C 6-10 arenes etc.] such as toluene is reacted to form a salt, and the salt is purified by crystallization, recrystallization, etc. The method of doing is mentioned.
  • the compound having a lactam skeleton represented by the formula (1) or a salt thereof has a high binding property or selective binding property to PPAR, and activates at least one selected from PPAR ⁇ , PPAR ⁇ and PPAR ⁇ . And preferably has high activity against PPAR ⁇ and / or PPAR ⁇ (particularly PPAR ⁇ ).
  • the lactam compound or a salt thereof is useful as a PPAR activator.
  • the PPAR activator of the present invention may contain at least the lactam compound represented by the formula (1) or a pharmacologically acceptable salt thereof, and the lactam compound or the pharmacologically acceptable salt thereof. You may comprise independently.
  • the PPAR activator usually contains the lactam compound or a pharmacologically acceptable salt thereof as an active ingredient.
  • the PPAR activator of the present invention is a combination of the compound having a lactam skeleton or a pharmacologically acceptable salt thereof and a carrier (such as a pharmacologically or physiologically acceptable carrier) as desired. Or a pharmaceutical composition (or preparation).
  • composition of the present invention can be composed of a compound having a lactam skeleton represented by the above formula (1) or a pharmacologically acceptable salt thereof and, if necessary, a carrier.
  • the carrier is appropriately selected depending on the form (ie, dosage form), dosage form, use, etc. of the pharmaceutical composition (or formulation).
  • the dosage form is not particularly limited, and is a solid preparation (powder, powder, granule (granule, fine granule, etc.), pill, pill, tablet, capsule, dry syrup, suppository, etc., semi-solid preparation (cream) Agents, ointments, gels, gummi, etc.), liquids (solutions, suspensions, emulsions, syrups, elixirs, lotions, injections, etc.). Also included are sprays such as the powders and / or liquids, aerosols and the like.
  • the capsule may be a liquid-filled capsule or a capsule filled with a solid agent such as a granule.
  • the preparation may be a lyophilized preparation.
  • the preparation may be a preparation with controlled drug release rate (sustained release preparation, immediate release preparation).
  • the aerosol generation method is not particularly limited.
  • the same sealed container is filled with a pharmaceutically active ingredient and a propellant such as an alternative fluorocarbon and sprayed.
  • it may be a method in the form of a nebulizer or an atomizer using a compressed gas such as carbon dioxide or nitrogen filled in a separate container from the active pharmaceutical ingredient.
  • the preparation may be an oral administration preparation or a parenteral administration preparation (nasal drops, inhalants, transdermal preparations, etc.).
  • the preparation may be a topical preparation (solutions such as injections (aqueous injections, non-aqueous injections, etc.), suspensions, ointments, patches, cataplasms, etc.).
  • the preparation of the present invention is often a solid preparation (especially an orally administered preparation).
  • the carrier examples include, in addition to the pharmacopoeia, (1) Pharmaceutical Additive Handbook, Maruzen Co., Ltd., (1989), (2) “Pharmaceutical Additives Dictionary 2000” (Pharmaceutical Daily Report, published in March 2002), (3) “Pharmaceutical Additives Dictionary 2005” (Pharmaceutical Daily Report, published in May 2005), (4) Pharmacy, Revised 5th Edition, Nanedo (1997), and (5) Pharmaceutical Additives Standard 2003 Among the components (for example, excipients, binders, disintegrants, lubricants, coating agents, etc.) listed in (Pharmaceutical Daily, August 2003), depending on the route of administration and formulation application, as appropriate You can choose.
  • a carrier for a solid preparation at least one carrier selected from excipients, binders and disintegrants is often used, and additives such as lipids may be used.
  • excipient examples include sugars such as lactose, sucrose, glucose, sucrose, mannitol, sorbitol or sugar alcohols; starch such as corn starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose); Examples thereof include silicon oxides such as acids and synthetic aluminum silicates or silicates.
  • Binders include soluble starches such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as agar, gum arabic, dextrin, sodium alginate, tragacanth gum, xanthan gum, hyaluronic acid, sodium chondroitin sulfate; polyvinylpyrrolidone, polyvinyl alcohol, carboxy Synthetic polymers such as vinyl polymer, polyacrylic acid polymer, polylactic acid, and polyethylene glycol; and cellulose ethers such as methyl cellulose, ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. .
  • disintegrants examples include calcium carbonate, carboxymethylcellulose or a salt thereof (carmellose, carmellose sodium, carmellose calcium, croscarmose sodium, etc.), cross-linked polyvinyl pyrrolidone (polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone (crospovidone), croscopovidone, etc. ), Low-substituted hydroxypropylcellulose and the like. These carriers can be used alone or in combination of two or more.
  • the coating agent examples include saccharides, cellulose derivatives such as ethyl cellulose and hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, Eudragit (meta Acrylic acid / acrylic acid copolymer).
  • the coating agent may be an enteric component such as cellulose phthalate, hydroxypropylmethylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, or a polymer containing a basic component such as dialkylaminoalkyl (meth) acrylate ( Gastric soluble components composed of Eudragit etc.).
  • the preparation may also be a capsule containing these enteric components and gastric components in the skin.
  • oily carriers include animal and vegetable oils (vegetable oils such as jojoba oil, olive oil, palm oil, and cottonseed oil; animal oils such as squalane) and mineral oils (liquid paraffin, silicone oil, etc.) Etc. can be exemplified.
  • aqueous carrier examples include water (purified or sterile water, distilled water for injection, etc.), physiological saline, Ringer's solution, glucose solution, water-soluble organic solvents [lower aliphatic alcohols such as ethanol and isopropanol; (poly) alkylene glycols ( Ethylene glycol, diethylene glycol, polyethylene glycol and the like); glycerin and the like], dimethylisosorbide, dimethylacetamide and the like.
  • the semi-solid carrier may be selected from the solid pharmaceutical carrier and / or the liquid carrier. Furthermore, the carrier of the semi-solid preparation may contain a lipid.
  • Lipids include waxes (beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.), long chain fatty acid esters (saturated or unsaturated fatty acid alkyl esters, fatty acids and polyhydric alcohols [poly C 2-4 alkylene glycol, glycerin or Polyglycerin, etc.), hardened oils, higher alcohols (saturated fatty alcohols such as stearyl alcohol, unsaturated aliphatic alcohols such as oleyl alcohol), higher fatty acids (linoleic acid, linolenic acid, Stearic acid, oleic acid and the like), metal soaps (for example, fatty acid metal salts such as sodium coconut oil fatty acid and calcium stearate) and the like.
  • waxes beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.
  • long chain fatty acid esters saturated or unsaturated fatty acid alkyl esters
  • additives can be appropriately used depending on the administration route, dosage form and the like.
  • additives include lubricants (for example, talc, magnesium stearate, polyethylene glycol 6000), disintegration aids, antioxidants or antioxidants, and emulsifiers (for example, nonionic surfactants).
  • Surfactants dispersants, suspending agents, solubilizers, solubilizers, thickeners (water-soluble polymers such as carboxyvinyl polymer, polyvinyl alcohol, carrageenan, gelatin; cellulose such as carboxymethylcellulose) Ethers, etc.), pH adjusters or buffers (citric acid-sodium citrate buffer, etc.), stabilizers, preservatives or preservatives (parabens, such as methylparaben and butylparaben), fungicides or antibacterial agents (benzoic acid) Benzoic acids such as sodium acid), antistatic agents, flavoring agents or masking agents (for example, Etc.
  • Taste agents coloring agents (such as dyes and pigments such as red iron oxide), such as flavoring agents, or perfumes (fragrances), fresheners, defoamers, isotonic agents, soothing agents.
  • coloring agents such as dyes and pigments such as red iron oxide
  • perfumes fragments
  • fresheners such as peppers and peppers
  • isotonic agents such as sodium tartrate
  • soothing agents such as sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium stearate, sodium stearate, sodium stearate, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stearate, sodium stearate, sodium steacetate
  • a solubilizer, a solubilizer, a suspending agent, a buffering agent, a stabilizer, a preservative, etc. are usually used as the additive.
  • a solubilizer, a solubilizer, a suspending agent, a buffering agent, a stabilizer, a preservative, etc. are usually used as the additive.
  • conventional additives used in powder injection can be used.
  • topical administration agents such as inhalants and transdermal absorption agents, dissolution aids, stabilizers, buffers, suspending agents, emulsifiers, preservatives and the like are usually used as the above additives. .
  • drugs In addition to the compound having the lactam skeleton or a pharmacologically acceptable salt thereof, if necessary, one or more other substances that do not adversely affect the effects for the purpose of enhancing the action, reducing the dose, reducing side effects, etc. These drugs may be used in combination.
  • the drugs that can be used in combination may be small molecules (for example, small molecule drugs), polypeptides, antibodies, vaccines, and the like.
  • drugs for example, “diabetes treatment drugs”, “diabetes complication treatment drugs”, “anti-obesity” Drugs, hypertension drugs, hyperlipidemia drugs, diuretics, antithrombotic drugs, Alzheimer's disease drugs, antidepressants, antianginal drugs, “Antiarrhythmic agents”, “vasodilators”, “anti-inflammatory agents”, “antitumor agents” and the like can be mentioned.
  • the PPAR activator and the pharmaceutical composition of the present invention are each a compound having a lactam skeleton represented by the above formula (I) or a pharmacologically acceptable salt thereof, a carrier component, and an additive if necessary.
  • the PPAR activator and pharmaceutical composition of the present invention are highly safe and are human and non-human animals, usually mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys). Etc.), especially for humans.
  • the dosage of the PPAR activator and the pharmaceutical composition of the present invention includes the subject to be administered, age, weight, sex and condition (general condition, medical condition, presence / absence of complications, etc.), administration time, dosage form, administration It can be appropriately selected depending on the method or the like. Similarly, the administration method can be selected in consideration of these requirements.
  • the compound represented by the above formula (1) or a pharmacologically acceptable salt thereof exhibits specific binding characteristics to PPAR and can effectively activate PPAR. Therefore, fatty acids, lipids (oils and fats, Metabolism) such as phospholipids and / or sugars.
  • the compound having the lactam skeleton or a pharmacologically acceptable salt thereof is (i) a disease caused by abnormal metabolism of fatty acid, lipid or sugar, ii) It is effective as a prophylactic or therapeutic agent for diseases caused by excessive intake of fatty acids, lipids or sugars and / or (iii) myopathy disorders as compared with metabolism of fatty acids, lipids or sugars.
  • a preventive or therapeutic agent normally contains the compound having the lactam skeleton or a pharmacologically acceptable salt thereof as an active ingredient.
  • the diseases (i), (ii) and (iii) include, for example, arteriosclerosis, cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes Examples thereof include diseases selected from the group consisting of insulin-resistant diabetes, obesity and muscular dystrophy.
  • the dose of the compound having a lactam skeleton or a pharmacologically acceptable salt thereof to a human is usually 0.01 to 1 per day. It can be selected from a range of about 1000 mg, preferably about 0.1 to 750 mg, more preferably about 0.1 to 500 mg (for example, 0.1 to 300 mg).
  • the lactam compound or a salt thereof of the present invention has an extremely high PPAR activation ability and is therefore effective even at a low dose.
  • the PPAR activator, pharmaceutical composition, prophylactic and / or therapeutic agent can be administered once or multiple times (about 2 to 6 times) per day.
  • reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography to obtain crystals of 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (2.00 g, 83%).
  • Triphenylphosphine was added to a suspension of 4-hydroxymethyl-2- (4-methylphenyl) isoindoline-1-one (963 mg, 3.80 mmol) obtained in (iii) above in dichloromethane (40 mL) under ice cooling. (1.50 g, 5.70 mmol) and N-bromosuccinimide (1.01 g, 5.70 mmol) were added, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 2 hours. Water was added, extracted with dichloromethane, and purified by silica gel column chromatography to obtain crystals of 4-bromomethyl-2- (4-methylphenyl) isoindoline-1-one (650 mg, 54%).
  • triphenylphosphine was added to a solution of 2- (4-bromophenyl) -4-hydroxymethylisoindoline-1-one (2.257 g, 7.09 mmol) obtained in (iii) above in dichloromethane (50 mL). (2.791 g, 10.64 mmol) and N-bromosuccinimide (1.894 g, 10.64 mmol) were added, and the mixture was stirred at room temperature for 22 hours. Further, triphenylphosphine (0.931 g, 3.55 mmol) and N-bromosuccinimide (0.631 g, 3.55 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 6 hours and a half.
  • Triethylsilane (0.48 mL, 3.00 mmol) was added to a solution of methyl (6-hydroxybenzo (b) thiophen-3-yl) acetate (222 mg, 1.00 mmol) obtained in Synthesis Example 18 in trifluoroacetic acid (5 mL). And heated to reflux for 6 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain the oily title compound (205 mg, 91%).
  • Tributyl (vinyl) tin (1) was added to a solution of [6- (trifluoromethylsulfonyloxy) benzofuran-3-yl] ethyl acetate (1.60 g, 4.53 mmol) obtained in (i) above in dimethylformamide (30 mL). .98 mL, 6.79 mmol), lithium chloride (1.92 g, 45.28 mmol), bis (triphenylphosphine) palladium (II) dichloride (318 mg, 0.45 mmol) were added, and the mixture was stirred at 80 ° C. overnight.
  • triphenylphosphine (437 mg, 1.66 mmol) was added to a solution of ethyl (6-hydroxymethylbenzofuran-3-yl) ethyl acetate (260 mg, 1.11 mmol) obtained in (v) above in dichloromethane (8 mL), N-bromosuccinimide (296 mg, 1.66 mmol) was added, and the mixture was stirred at 0 ° C. for 20 minutes and at room temperature for 2.5 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the oily title compound (288 mg, 87%).
  • resorcinol (8.81 g, 80.0 mmol) was added to a concentrated sulfuric acid (30 mL) solution of ethyl 4-chloroacetoacetate (11.56 mL, 85.0 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added, and the resulting crystals were collected by filtration and dried to give the title compound (14.42 g, 86%) as crystals.
  • Example 31 4- ⁇ [(3-Carboxymethyl-2,3-dihydrobenzo (b) thiophen-6-yl) oxy] methyl ⁇ -2- (4-trifluoromethoxyphenyl) isoindoline-1-one Synthesis (i) 4- ⁇ [(3-methoxycarbonylmethyl-2,3-dihydrobenzo (b) thiophen-6-yl) oxy] methyl ⁇ -2- (4-trifluoromethoxyphenyl) isoindoline-1- On composition
  • Triethylamine (0.13 mL, 0.91 mmol) was added to a solution of 4-bromo-2- (4-methylphenyl) isoindoline-1-one (212 mg, 0.70 mmol) obtained in Synthesis Example 11 in dimethylformamide (9 mL).
  • Tris (dibenzylideneacetone) dipalladium (0) 64 mg, 0.07 mmol
  • tri-o-tolylphosphine 43 mg, 0.14 mmol
  • 6-vinylbenzofuran-3-yl Ethyl acetate (161 mg, 0.70 mmol) was added and stirred at 110 ° C. overnight.
  • Example 54 4- ⁇ [(5-Carboxymethyl-5,6,7,8-tetrahydronaphthalen-2-yl) oxy] methyl ⁇ -2- (4-trifluoromethoxyphenyl) isoindoline-1-one Synthesis (i) 4- ⁇ [(5-Ethoxycarbonylmethyl-5,6,7,8-tetrahydronaphthalen-2-yl) oxy] methyl ⁇ -2- (4-trifluoromethoxyphenyl) isoindoline-1- On composition
  • Example 61 4-( ⁇ [(3S) -3-carboxymethyl-2,3-dihydrobenzofuran-6-yl] oxy ⁇ methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Synthesis (i) 4-( ⁇ [(3S) -3-methoxycarbonylmethyl-2,3-dihydrobenzofuran-6-yl] oxy ⁇ methyl) -2- (4-trifluoromethylphenyl) isoindoline-1- On composition
  • Example 62 4-( ⁇ [(3R) -3-carboxymethyl-2,3-dihydrobenzofuran-6-yl] oxy ⁇ methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Synthesis (i) 4-( ⁇ [(3R) -3-methoxycarbonylmethyl-2,3-dihydrobenzofuran-6-yl] oxy ⁇ methyl) -2- (4-trifluoromethylphenyl) isoindoline-1- On composition
  • Test Example 1 (Measurement of PPAR ⁇ agonist activity) Twenty-four hours before transfection, 0.6 ⁇ 10 6 cells of CHO cells were seeded on 100 mm plates. TransIT LT-1 (transfection reagent, manufactured by Miras) was added to RPMI 1640 (medium, manufactured by IWAKI), mixed using a vortex mixer, and allowed to stand. Into this solution, the receptor plasmid pBIND-hPPAR ⁇ for expressing the fusion protein of the DNA binding domain of the transcription factor Gal4 of yeast and the PPAR ⁇ ligand binding domain and the reporter plasmid pG5-Luc were mixed and allowed to stand. Added. After 24 hours, cells were harvested and seeded in 96 well plates. Next, a solution (test substance concentration 1% by weight) in which the test substance was dissolved in dimethyl sulfoxide (DMSO) was added, and the luciferase activity 24 hours after the drug addition was measured.
  • DMSO dimethyl sulfoxide
  • the ratio R [R (A3 /
  • GW501516 standard addition concentration 100 nM
  • the PPAR ⁇ activity of the test substance was evaluated by the relative value (percentage) of the induction ratio relative to the control drug.
  • the results are shown in Tables 1-6.
  • the test substance shows PPAR ⁇ activity stronger than that of the control drug GW501516 (reference addition concentration 100 nM) at each measured concentration, it is shown as a numerical value of 100% or more in Tables 1 to 6.
  • the activity was less than 50% or not measured, it was expressed as “ ⁇ ”.
  • Formulation Example 1 (tablet) A tablet is obtained in accordance with the known method described in the General Rules for Preparations of JP XIV for the following formulation.
  • Formulation example in one tablet Compound of Example 31 50 mg Crystalline cellulose 100mg Lactose 20mg Corn starch 28mg Magnesium stearate 2mg Total amount 200mg
  • Formulation Example 2 (Capsule) Capsules are obtained in accordance with known methods described in the General Rules for Preparations of JP XIV for the following formulations.
  • Formulation example in one capsule Compound of Example 47 50 mg Lactose 100mg Corn starch 48mg Magnesium stearate 2mg Total amount 200mg
  • the novel lactam compound of the present invention or a salt thereof (such as a pharmacologically acceptable salt) has a high binding property to PPAR (PPAR ⁇ , PPAR ⁇ and / or PPAR ⁇ ), and activates PPAR. Therefore, it is useful as a PPAR activator (such as a PPAR ⁇ activator, a PPAR ⁇ activator and / or a PPAR ⁇ activator). Therefore, the compound or a pharmacologically acceptable salt thereof is various diseases (for example, arteriosclerosis) caused by abnormal intake of fatty acids, lipids (including fats and oils, phospholipids) or sugar and excessive intake compared to metabolism.
  • diseases for example, arteriosclerosis

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Abstract

Cette invention concerne un composé de lactame ou d'un sel de ce dernier représenté par la formule (1), lequel composé possède un squelette de lactame ou d'un sel de lactame et convient comme activateur de PPAR. [Dans cette formule, le noyau Z correspond à un noyau hydrocarboné condensé ou un noyau hétérocyclique ; R1 désigne des atomes d'halogène identiques ou différents, des groupes alkyle pouvant avoir un groupe substitué, des groupes hydroxyle, ou des groupes alkoxy pouvant avoir un groupe substitué ; R2 désigne un groupe alkylène pouvant avoir une liaison directe ou un groupe substitué ; R3 désigne un groupe alkoxy pouvant avoir un groupe hydroxyle ou un groupe substitué ; le lieur (X) compte 1-10 atomes dans la chaine principale pris dans des atomes de carbone et des hétéro atomes, et la chaîne principale peut avoir un groupe substitué ; Y désigne une liaison directe, un atome d'oxygène ou un atome de soufre ; et k est un entier compris entre 0 et 5.]
PCT/JP2011/078767 2010-12-14 2011-12-13 Composé de lactame ou d'un sel de ce dernier, et activateur de ppar Ceased WO2012081570A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015153410A1 (fr) * 2014-03-31 2015-10-08 The Trustees Of Columbia University In The City Of New York Activateurs d'histone acétyltransférase et utilisation desdits activateurs
CN106977478A (zh) * 2017-04-21 2017-07-25 山东大学 一种2‑（6‑羟基‑2,3‑二氢苯并呋喃‑3‑基）乙酸甲酯的手性拆分方法

Families Citing this family (1)

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CN112480047B (zh) * 2020-12-01 2023-06-02 云南省第二人民医院 一种具有降糖调脂作用的化合物及其制剂与应用

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WO2005056522A2 (fr) * 2003-12-04 2005-06-23 National Health Research Institutes Composes indoles
JP2006516254A (ja) * 2003-01-06 2006-06-29 イーライ・リリー・アンド・カンパニー Ｐｐａｒモジュレータとしての縮合ヘテロ環誘導体
JP2006524220A (ja) * 2003-04-17 2006-10-26 ワーナー−ランバート カンパニー リミティド ライアビリティー カンパニー Ｐｐａｒ活性を変調する化合物及び製造法
WO2009072581A1 (fr) * 2007-12-05 2009-06-11 Aska Pharmaceutical Co., Ltd. Composé lactame ou sel de celui-ci, et activateur du ppar

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JP2006516254A (ja) * 2003-01-06 2006-06-29 イーライ・リリー・アンド・カンパニー Ｐｐａｒモジュレータとしての縮合ヘテロ環誘導体
JP2006524220A (ja) * 2003-04-17 2006-10-26 ワーナー−ランバート カンパニー リミティド ライアビリティー カンパニー Ｐｐａｒ活性を変調する化合物及び製造法
WO2005056522A2 (fr) * 2003-12-04 2005-06-23 National Health Research Institutes Composes indoles
WO2009072581A1 (fr) * 2007-12-05 2009-06-11 Aska Pharmaceutical Co., Ltd. Composé lactame ou sel de celui-ci, et activateur du ppar

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015153410A1 (fr) * 2014-03-31 2015-10-08 The Trustees Of Columbia University In The City Of New York Activateurs d'histone acétyltransférase et utilisation desdits activateurs
US11191768B2 (en) 2014-03-31 2021-12-07 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and uses thereof
CN106977478A (zh) * 2017-04-21 2017-07-25 山东大学 一种2‑（6‑羟基‑2,3‑二氢苯并呋喃‑3‑基）乙酸甲酯的手性拆分方法
CN106977478B (zh) * 2017-04-21 2019-04-09 山东大学 一种2-(6-羟基-2,3-二氢苯并呋喃-3-基)乙酸甲酯的手性拆分方法

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