JP5436941B2 - Lactam compound or salt thereof and PPAR activator - Google Patents

Description

  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 resistant diabetes, obesity, etc.).

  Peroxisome proliferators-activated receptor (PPAR) is a nuclear transcription factor that belongs to the nuclear receptor superfamily and regulates transcription in a ligand-dependent manner. In mammals, three subtypes (isoforms) of PPARα, PPARγ, and PPARδ are known, and various studies have been conducted so far.

  PPARα is mainly expressed in tissues that metabolize fatty acids such as liver, myocardium, and small intestine crypts, and regulates fatty acid metabolism. PPARγ 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. PPARδ 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. With regard to fatty acid metabolism, PPARδ 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.

  Thus, PPAR controls various factors related to lipid and carbohydrate metabolism at the gene level. PPAR is also classified as an RXR (retinoic acid X receptor) heterodimeric receptor, forming a heterodimer with RXR, a nuclear receptor for retinoids, and a peroxisome proliferator response sequence (PPRE) of DNA. Combines with and performs its function.

Therefore, 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). For endogenous ligands, long-chain fatty acids act as ligands for all subtypes of PPAR, and ligands for PPARα as eicosanoids, a ligand as 15-deoxy - [delta ^{12, 14} of PPARy ^- although prostaglandin is known, still often elucidated portion not for more information. For exogenous ligands, PPARα ligands (activators) are fibrate hyperlipidemia drugs, phenoxyacetic acids and phenylpropionic acids, PPARγ ligands (activators) are thiazolidinedione (TZD) diabetes drugs (Pioglitazone, rosiglitazone, etc.), non-TZD PPARγ activators (TAK-559 (Takeda Pharmaceutical Co., Ltd.), RG12525 (Aventis), etc.) are known.

  In particular, among PPARδ, PPARδ is delayed in research on its physiological function compared to PPARα and γ, and in recent years, the pharmacology of PPARδ receptor (substance (or activator) having an activating action) has been delayed. Knowledge about activity and pharmaceutical use is being obtained.

  For example, regarding PPAR activator (agonist), WO97 / 28149 (patent document 1) increases the plasma HDL (high density lipoprotein) amount, and is effective in the treatment and prevention of atherosclerotic coronary arteriosclerosis. In addition, there is an effect in the treatment or prevention of atherosclerotic coronary sclerosis when used in combination with an HMG-CoA reductase inhibitor. WO99 / 28115 (Patent Document 2) discloses a therapeutic drug 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). 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 And the like, and WO03 / 8967 (Patent Document 5) show a heat production enhancing action, a mitochondrial uncoupling respiratory enhancing action, a fatty acid β oxidation enhancing action, etc., and an antidiabetic agent, It is disclosed that it is useful as an anti-obesity agent or visceral fat accumulation reducing agent and visceral fat accumulation inhibitor. Furthermore, in Patent Document 4 and Proc. Natl. Acad. Sci., USA, vol. 100, p15924-15929, 2003 (Non-patent Document 1), GW501516 (chemical name: known as a selective PPARδ agonist) is known. 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.

  From the above points, PPARδ 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, such as obesity, insulin resistance It is expected as a prophylactic and / or therapeutic drug for hyperlipidemia, arteriosclerotic diseases (such as atherosclerotic diseases), and metabolic syndrome.

  In WO96 / 30014 (Patent Document 7), as a compound having a farnesyl-protein transferase inhibitory action, and in WO04 / 89897 (Patent Document 8), as a compound having a 5-HT2C activating action, Furthermore, WO05 / 113501 (Patent Document 9) discloses isoindol-1-one derivatives as compounds useful as neuropathic pain control agents, respectively. However, these prior literatures disclose nothing about the binding properties of isoindol-1-one derivatives to PPAR, subtypes of PPAR that can be bound, and the like.

  WO 04/63155 (Patent Document 10) discloses a fused heterocyclic derivative as a PPAR modulator, but does not disclose a compound having a lactam skeleton. Moreover, although the measuring method of PPAR (delta) activation is described, the physiological activity with respect to PPAR (delta) of the said condensed heterocyclic derivative is not disclosed specifically.

  In addition, WO05 / 54176 (Patent Document 11) discloses a diphenyl ether compound as a PPAR agonist. In the examples, 2- {4- [3- (5-chloro-1-oxo-1,3) is disclosed. -Dihydro-isoindol-2-ylmethyl) -5-fluoro-phenoxy] -2-methyl-phenoxy} -2-methyl-propionic acid and 2- {4- [3-fluoro-5- (1-oxo-1) , 3-Dihydro-isoindol-2-ylmethyl) -phenoxy] -2-methyl-phenoxy} -2-methyl-propionic acid is described. However, Patent Document 11 also does not disclose the binding characteristics of the above compounds to PPAR, the subtypes of PPAR that can be bound, and the like.

International Publication No. WO 97/28149 International Publication No. WO 97/28115 International Publication No. WO99 / 4815 International publication WO01 / 603 International Publication WO 03/8967 International Publication WO 06/1092 International Publication WO96 / 30014 International Publication No. WO04 / 89897 International Publication WO05 / 113501 International Publication No. WO04 / 63155 International Publication No. WO05 / 54176

Tanaka et al., Proc. Natl. Acad. Sci., USA, vol. 100, p15924-15929, 2003

  Accordingly, an object of the present invention is to provide a novel lactam compound (isoindoline-1-one derivative) or a salt thereof that is also useful as a PPAR activator (PPARα activator, PPARδ activator, etc.) and the like, and a method for producing the same. There is to do.

  Another object of the present invention is to provide a PPAR activator (agonist) and a pharmaceutical composition capable of effectively activating PPAR (PPARα, PPARδ, etc.).

  Still another object of the present invention includes a lactam compound or a salt thereof and a method for producing the lactam compound or a salt thereof that have a regulated metabolism in the body and can selectively bind to PPAR (PPARα, PPARδ, etc.), and the lactam compound or a salt thereof. It is to provide a pharmaceutical composition and a PPAR activator.

  Another object of the present invention is to provide a preventive and / or therapeutic agent capable of effectively preventing or treating various diseases caused or affected by abnormal metabolism of fatty acids, lipids or sugars and / or excessive intake compared to metabolism. There is to do.

  As a result of intensive studies to achieve the above problems, the present inventors have found that a compound having a benzopyrrolidone skeleton (isoindoline-1-one derivative) selectively binds to PPAR (PPARα, PPARβ and / or PPARδ). Thus, the present inventors have found that the PPAR activity is improved and completed the present invention.

  That is, the lactam compound of the present invention (isoindoline-1-one derivative) is represented by the following formula (1), and the lactam compound of the present invention includes a salt thereof.

[Wherein, R ¹ represents an alkyl group which may have a substituent, an alkoxy group which may have a substituent,
The coefficient a represents an integer of 0 to 5,
R ² represents a halogen atom, an alkyl group which may have a substituent, or an alkoxy group which may have a substituent;
The coefficient b represents an integer of 0 to 4,
X ¹ and X ² each represent an alkylene group or an oxygen atom; when X ¹ is an alkylene group, X ² is an oxygen atom; when X ¹ is an oxygen atom, X ² is an alkylene group;
R ³ represents a hydrogen atom, an alkyl group which may have a substituent,
R ⁴ represents a direct bond or an alkylene group,
R ⁵ represents a hydrogen atom or an optionally substituted alkyl group].

In the compound represented by the formula (1), R ¹ represents a linear or branched C _1-6 alkyl group (for example, a C _1-4 alkyl group), a linear or branched halo C _{1. A -6} alkyl group (eg, a halo C _1-4 alkyl group), a linear or branched C _1-6 alkoxy group (eg, a C _1-4 alkoxy group), or a linear or branched halo C _1-6 alkoxy group (for example, halo _C1-4 alkoxy group) may be sufficient, and the coefficient a may be an integer of 1-3 (for example, 1-2, especially 1). R ² represents a halogen atom, a linear or branched C _1-6 alkyl group (for example, a C _1-4 alkyl group), or a linear or branched C _1-6 alkoxy group (for example, C _{1 -4} alkoxy group), and the coefficient b may be an integer of 0 or 1.

X ¹ and X ² may each be a C _1-4 alkylene group (eg, C _1-3 alkylene group) or an oxygen atom, and X ¹ is a C _1-4 alkylene group (eg, C _1-3). X ² may be an oxygen atom when it is an alkylene group), and X ² may be a C _1-4 alkylene group (for example, a C _1-3 alkylene group) when X ¹ is an oxygen atom.

R ³ may be a hydrogen atom or a C _1-6 alkyl group (eg, a C _1-4 alkyl group), and R ⁴ is a C _1-4 alkylene group (eg, a C _1-3 alkylene group). R ⁵ may be a hydrogen atom; a C _1-6 alkyl group (for example, a linear or branched C _1-4 alkyl group).

  A lactam compound represented by a typical formula (1) can be represented by the following formula (1a).

[Wherein R ¹ represents a linear or branched C _1-4 alkyl group (for example, C _1-3 alkyl group), a linear or branched fluoro C _1-4 alkyl group (for example, fluoro C _1-3 alkyl group), linear or branched C _1-4 alkoxy group (eg, C _1-3 alkoxy group), or linear or branched fluoro C _1-4 alkoxy group (eg, Fluoro C _1-3 alkoxy group),
X ¹ and X ² each represent a C _1-3 alkylene group (for example, a C _1-2 alkylene group) or an oxygen atom, and X ¹ is a C _1-3 alkylene group (for example, a C _1-2 alkylene group). X ² is an oxygen atom, and when X ¹ is an oxygen atom, X ² is a C _1-3 alkylene group (eg, a C _1-2 alkylene group),
R ³ is a hydrogen atom or a C _1-4 alkyl group (for example, a C _1-3 alkyl group),
R ⁴ is a C _1-4 alkylene group (eg, a C _1-3 alkylene group),
R ⁵ represents a hydrogen atom or a linear or branched C _1-4 alkyl group (for example, a C _1-3 alkyl group).

  The lactam compound (isoindoline-1-one derivative) of the formula (1) or a salt thereof is typically represented by the following formula (3)

[Wherein L ₁ represents a leaving group or a leaving atom, and X ¹ , R ¹ and coefficient a are the same as above]
A compound represented by the formula (lactam compound) or a salt thereof, and the following formula (4):

[Wherein L ₂ represents a leaving atom or leaving group, and R ² , coefficient b, X ² , R ³ , R ⁴ , and R ⁵ are the same as above]
It can manufacture by making the compound or its salt represented by these react.

  In this invention, the manufacturing method of the compound or its salt represented by said Formula (1), for example, following formula (3)

[Wherein L ₁ represents a leaving group or a leaving atom, and X ¹ , R ¹ and coefficient a are the same as above]
A compound represented by the formula (lactam compound) or a salt thereof, and the following formula (4b):

[Wherein L ₂ represents a leaving atom or leaving group, and Z represents the following formula (5a), (5b) or (5c)

(Wherein, Pro represents a protecting group, and R ³ , R ⁴ , and R ⁵ are the same as above), and R ² , coefficient b, and X ² are the same as above]
And a compound represented by the formula (1b)

[Wherein, X ¹ , X ² , R ¹ , coefficients a, R ² , coefficients b, Z are the same as above]
A method for producing a lactam compound represented by the formula:
In the compound represented by the formula (1b) or the formula (4b), when the partial structure Z is a partial structure represented by the formula (5a), the compound represented by the formula (3) or a salt thereof, Reacting the compound represented by 4b) or a salt thereof;
When the partial structure Z is a partial structure represented by the formula (5b), the protecting group Pro of the compound represented by the formula (1b) or the formula (4b) is subjected to a deprotection reaction, and the following formula (6b)

[Wherein X ³ represents a halogen atom, and R ⁴ and R ⁵ are the same as above]
Is reacted with a compound represented by
When the partial structure Z is a partial structure represented by the formula (5c), the compound represented by the formula (1b) or the formula (4b) and the following formula (6c)

[Wherein X ⁴ represents a halogen atom, and R ³ is the same as above]
Is reacted with a compound represented by
A method of producing a compound having the partial structure Z represented by the formula (1b) and represented by the formula (5a) (or forming the partial structure Z represented by the formula (5a)) is also included.

  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 PPARα, PPARγ, and PPARδ.

  The pharmaceutical composition of the present invention contains a lactam compound (isoindoline-1-one derivative) represented by the above formula (1) or a pharmacologically acceptable salt thereof, and contains a carrier. May be. The preventive or therapeutic agent of the present invention comprises (i) a disease caused by abnormal metabolism of fatty acids, lipids (including fats and oils, phospholipids) or sugars, and / or (ii) compared with metabolism of fatty acids, lipids or sugars. , A preventive or therapeutic agent for diseases caused by excessive intake of fatty acids, lipids or sugars, and a lactam compound represented by the formula (1) or a compound having a lactam skeleton represented by the formula (1) And a pharmacologically acceptable salt thereof 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 and obesity Is mentioned.

  The novel lactam compound or a salt thereof of the present invention exhibits high PPAR activity. In addition, since 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. Furthermore, the lactam compound or a salt thereof is regulated in metabolism in the body and can selectively bind to PPAR. In addition, since the prophylactic and / or therapeutic agent of the present invention uses a specific lactam compound or a salt thereof, abnormal metabolism of fatty acids, lipids (including fats and oils, phospholipids) or sugars and / or excessive intake compared to metabolism, etc. Various diseases caused by or affected by can be effectively prevented or treated.

(Lactam compound or salt thereof)
The lactam compound of the present invention is a novel compound and is represented by the following formula (1).

In the compound represented by the formula (1), examples of the alkyl group represented by R ¹ include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, hexyl, Examples thereof include linear or branched C _1-16 alkyl groups such as octyl, decyl and dodecyl groups. The alkyl group is a linear or branched C _1-10 alkyl group, preferably a linear or branched C _1-6 alkyl group, more preferably a linear or branched C _1-4 alkyl group. (For example, a linear or branched _C1-3 alkyl group) in many cases.

Examples of the alkoxy group represented by R ¹ include linear or branched C, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, pentyloxy, hexyloxy and octyloxy groups. Examples thereof include _1-16 alkoxy groups. The alkoxy group is usually a linear or branched C _1-10 alkoxy group, preferably a linear or branched C _1-6 alkoxy group, more preferably a linear or branched C _1-4. In many cases, it is an alkoxy group (for example, a linear or branched C _1-3 alkoxy group).

The alkyl group and alkoxy group may have a substituent. Examples of the substituent include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom and an iodine atom); a linear or branched C _1-4 alkyl group such as a methyl or ethyl group (an alkoxy group represented by R ^1). In contrast, linear or branched C _1-4 alkoxy groups such as a methoxy group and an ethoxy group (relative to the alkyl group or alkoxy group represented by R ¹ ) and the like can be exemplified. Of these substituents, a halogen atom is preferred. That is, R ¹ is preferably a haloalkyl group or a haloalkoxy group. Of the halogen atoms, a fluorine atom, a chlorine atom, and particularly a fluorine atom are preferred.

Examples of such haloalkyl groups include fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, trifluoroethyl, perfluoroethyl, 2,2,3,3,3-pentafluoropropyl, perfluoro Examples thereof include a linear or branched halo C _1-6 alkyl group such as a propyl group. The haloalkyl group is preferably a linear or branched haloalkyl group (especially a fluoro C _1-4 alkyl group), more preferably a halo C _1-3 alkyl group (especially a fluoro C _1-3 alkyl group). is there.

Examples of the haloalkoxy group include fluoromethoxy, chloromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, perfluoroethoxy, 2,2,3,3,3-pentafluoropropyloxy, perfluoropropyl. Examples thereof include a linear or branched halo C _1-6 alkyl group such as an oxy group. The haloalkyl group is preferably a linear or branched haloalkoxy group (particularly a fluoro C _1-4 alkoxy group), more preferably a halo C _1-3 alkoxy group (particularly a fluoro C _1-3 alkoxy group). It is.

The coefficient a 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 substitution position of the substituent R ¹ is not particularly limited, and when the coefficient a is 1, it may be any of 2-, 3- and 4-positions of the benzene ring, and when the coefficient a is 2 or more, The substitution positions of the plurality of substituents R ¹ may be 2,6-position, 2,4-position, 3,5-position, 3,4-position, 3,4,5-position, and the like. When the coefficient a is 1, the substitution position of the substituent R ¹ is often the 4-position.

The halogen atom represented by R ² includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The alkyl group which may have a substituent represented by R ² and the alkoxy group which may have a substituent have the same substituents as those represented by R ^1. Examples thereof may include an alkyl group and an alkoxy group which may have a substituent. R ² is often a halogen atom, a linear or branched C _1-6 alkyl group, or a linear or branched C _1-6 alkoxy group.

The coefficient b is an integer of 0 to 4, preferably an integer of 0 to 2, more preferably an integer of 0 or 1. The coefficient b is usually 0 in many cases. That is, R ² may not be substituted.

X ¹ and X ² each represent an alkylene group or an oxygen atom. Examples of the alkylene group represented by X ¹ and X ² include linear or methylene, ethylene, trimethylene, propylene, dimethylmethylene, tetramethylene, pentamethylene, 3,3-dimethyltrimethylene, hexamethylene groups, and the like. Examples thereof include a branched C _1-10 alkylene group. Preferred alkylene groups are linear or branched C _1-6 alkylene groups (eg, C _1-4 alkylene groups), especially C _1-3 alkylene groups (eg, C _1-2 alkylene groups).

When X ¹ is an alkylene group (for example, a linear or branched alkylene group), X ² is an oxygen atom, and when X ¹ is an oxygen atom, X ² is an alkylene group (for example, a linear group). Or a branched alkylene group).

Examples of the alkyl group which may have a substituent represented by R ³ include an alkyl group which may have the same substituent as R ¹ (for example, a substituent which may have a substituent). Examples thereof include a linear or branched C _1-10 alkyl group. The alkyl group is a linear or branched C _1-6 alkyl group (methyl, ethyl, propyl, isopropyl, butyl group, etc.), preferably a linear or branched C _1-4 alkyl group, particularly a linear chain. Or a branched C _1-3 alkyl group in many cases.

R ³ is usually a hydrogen atom or an alkyl group (such as a C _1-4 alkyl group).

R ⁴ is a direct bond or an alkylene group, and the alkylene group represented by R ⁴ is a linear or branched alkylene group similar to the alkylene group represented by X ¹ and X ² (linear Or a branched _C1-10 alkylene group) can be illustrated. Preferred alkylene groups are linear or branched C _1-6 alkylene groups (eg, linear or branched C _1-4 alkylene groups), especially linear or branched C _1-3 alkylene groups. (For example, a C _1-2 alkylene group such as a methylene group).

As the alkyl group which may have a substituent represented by R ⁵ , an alkyl group which may have the same substituent as R ¹ (for example, linear or branched C _{1- 10} alkyl groups). R ⁵ is often a hydrogen atom or an alkyl group (for example, a linear or branched C _1-6 alkyl group), particularly a hydrogen atom or a linear or branched C _1-4 alkyl group ( Methyl, ethyl, propyl, isopropyl, butyl group, etc.). The alkyl group may be a linear or branched C _1-3 alkyl group.

Preferred R ⁵ is a hydrogen atom, a linear or branched C _1-6 alkyl group.

  A preferred lactam compound can be represented by the following formula (1a).

(Wherein R ¹ , X ¹ , X ² , R ³ , R ⁴ and R ⁵ are the same as above).

  The lactam compound may form a salt with an acid or a base. 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 oxalic acid, succinic acid, maleic acid, fumaric acid 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 The salt of the lactam compound and the acid may be a mixed acid salt (for example, hydrochloric acid-sulfate, etc.) The base capable of forming a salt with the lactam compound is an organic base. (Amines such as monoamine to trialkylamines such as methylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and diisopropylethylamine; alkanolamines such as ethanolamine; alkylene polyamines such as ethylenediamine and diethylenetriamine), inorganic bases [Metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, iron hydroxide, and aluminum hydroxide (such as alkali metal or alkaline earth metal hydroxide); sodium carbonate, sodium bicarbonate, potassium carbonate, Carbonic acid Alkali metal carbonates such as bidium and cesium carbonate, ammonia, etc.] The lactam compound may form a salt with one of these bases, or may form a salt with two or more types of bases. May be.

  The lactam compound or a salt thereof may be a solvate (such as an organic solvate such as a hydrate or an organic solvent such as ethanol) or an anhydride. The lactam compound or a salt thereof includes a tautomer, an optically active form having an asymmetric carbon atom ((R) form, (S) form, diastereomer, etc.), a racemate, or a mixture thereof. . In addition, the lactam compound or a salt thereof may be a prodrug or an active metabolite that is modified in the functional group of the compound or the salt and exhibits an activity in vivo.

(Method for producing lactam compound)
Reaction step (A):
The compound represented by formula (1) or a salt thereof is a reaction step (A) in which a compound represented by formula (3) or a salt thereof is reacted with a compound represented by formula (4) or a salt thereof. ).

Wherein L ₁ and L ₂ each represent a leaving group or a leaving atom, and X ¹ , R ¹ , coefficient a, R ² , coefficient b, X ² , R ³ , R ⁴ , and R ⁵ are Same as)
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 (particularly a bromine atom and an iodine atom) are preferable.

Examples of the combination of L ₁ and L ₂ include (i) a combination of a halogen atom and a hydroxyl group [specifically, (i-1) the leaving atom L ₁ is a halogen atom, and the leaving atom L ₂ Is a hydrogen atom of a hydroxyl group, (i-2) a combination in which a leaving atom L ₁ is a hydrogen atom of a hydroxyl group and a leaving atom L ₂ is a halogen atom], (ii) a hydroxyl group and a hydroxyl group [Specifically, (ii-1) a combination in which the leaving group L ₁ is a hydroxyl group and the leaving atom L ₂ is a hydrogen atom of the hydroxyl group, and (ii-2) a leaving atom L ₁ is A combination of a hydrogen atom of a hydroxyl group and a leaving group L ₂ being a hydroxyl group] can be exemplified.

  The reaction between the compound represented by formula (3) and the compound represented by formula (4) can be selected according to the combination of the leaving group and the leaving atom.

Reaction step (A-1): When the combination of L ₁ and L ₂ is a combination of a halogen atom and a hydroxyl group (the embodiment (i)), the compound represented by the formula (3) and the formula (4) Is reacted in the presence of a base to obtain a compound of the formula (1).

Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate. These bases can be used alone or in combination of two or more. As the base, alkali metal carbonates such as cesium carbonate and potassium carbonate are often used. The amount of the base to be used, relative to 1 mole of the compound having a halogen atom _{(L 1} or _{L 2),} can be selected from the range of about 0.9 to 10 moles, usually 1 to 5 moles (e.g., 1.05 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, cyclic ethers such as 1,4-dioxane and tetrahydrofuran (THF)), esters (such as ethyl acetate), ketones (such as acetone and methyl ethyl ketone), nitriles (such as acetonitrile and propionitrile), amides (such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAA) and the like), sulfoxides such as dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like can be exemplified. These 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 not higher 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.

Reaction step (A-2): When the combination of L ₁ and L ₂ is a combination of a hydroxyl group and a hydroxyl group (the embodiment (ii)), the compound represented by the formula (3) and the formula (4) The target compound represented by the formula (1) can be obtained by reacting the compound represented by) under Mitsunobu reaction conditions. 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. it can. Examples of azodicarboxylic acid esters include azodicarboxylic acid alkyl esters such as diethyl azodicarboxylate (DEAD), and examples of triphenylphosphines 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 (3) (or the compound represented by the formula (4)), 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 (DMF, DMAA, hexamethylphosphate triamide, etc.), sulfoxides (DMSO, etc.), N-methylpyrrolidone (NMP), tertiary amines such as pyridine, trimethyl phosphate, etc. Examples thereof include phosphate esters. These 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 not higher 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.

  In addition, the compound represented by the said Formula (1) or its salt can also be obtained by the following reaction process formula, for example. That is, a compound represented by the following formula (3) (lactam compound) or a salt thereof is reacted with a compound represented by the following formula (4b) or a salt thereof, and the lactam compound represented by the formula (1b) or In a method for producing the salt,

[Wherein Z represents the following formula (5a), (5b) or (5c)

(Wherein, Pro represents a protecting group, R ³ , R ⁴ , and R ⁵ are the same as above), L ₁ , L ₂ , X ¹ , X ² , R ¹ , coefficient a, R ² , and coefficient b are the same as above]
(A) When the partial structure Z of the formula (1b) or the formula (4b) is a partial structure represented by the formula (5a), the compound represented by the formula (3) or a salt thereof, and the following formula (4b) [Reaction step (A)]
(B) When the partial structure Z is a partial structure represented by the formula (5b), the protecting group Pro of the compound represented by the formula (1b) or the formula (4b) is deprotected, and the following formula (6b)

[Wherein X ³ represents a halogen atom, and R ⁴ and R ⁵ are the same as above]
[Reaction step (B)],
(C) When the partial structure Z is a partial structure represented by the formula (5c), the compound represented by the formula (1b) or the formula (4b) and the following formula (6c)

[Wherein X ⁴ represents a halogen atom, and R ³ is the same as above]
[Reaction step (C)],
A method of producing a compound having the partial structure Z represented by the formula (1b) and represented by the formula (5a) is also included.

  The reaction of the compound represented by the formula (3) and the compound represented by (4b) can be performed in the same manner as in the reaction step (A).

  The reaction steps (B) and (C) can be represented by the following reaction formula, and the partial structure Z represented by the formula (5a) is formed by these reactions.

[Wherein R ³ , R ⁴ and R ⁵ , X ³ , X ⁴ and Pro are the same as above]
The halogen atom represented by X ³ and X ⁴ includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among the halogen atoms, a chlorine atom, a bromine atom and an iodine atom (particularly a bromine atom and an iodine atom) Is preferred.

Reaction step (A):
In the compound of the formula (1b) or the formula (4b), when the partial structure Z is a partial structure represented by the formula (5a), the compound represented by the formula (3) or a salt thereof, and the following formula (4b) In the same manner as in the reaction step (A-1) or (A-2), depending on the leaving group or the combination of the leaving atoms L ₁ and L _2. Can be reacted. In addition, for the preparation of a compound in which the partial structure Z is represented by the formula (5a), the following Synthesis Example 2, WO 2001/00603, WO 1997/23216 and the like can be referred to.

Reaction step (B):
When the partial structure Z is a partial structure represented by the formula (5b) (partial structure having a protecting group Pro), the protecting group Pro of the compound represented by the formula (1b) or the formula (4b) is deprotected. And reacting with the compound represented by the formula (6b) to form a partial structure Z in the compound represented by the formula (1b) or the formula (4b). In the partial structure represented by the formula (5b), R ³ is usually an alkyl group.

The compound (4b) having the partial structure (5b), wherein R ³ is an alkyl group and L ₂ is a halogen atom (such as a bromine atom) can be obtained by a known method, for example, J. Med. Chem., 2009 , 52 (1), pp 33-47, WO 2006/104280, etc. or can be easily prepared with reference to these methods. Further, a compound (4b) having a partial structure (5b), wherein R ³ is an alkyl group and L ₂ is a hydroxyl group can also be obtained by a known method such as J. Med. Chem., 2009, 52 (1). , pp 33-47, WO 2002/006189 and the like, or can be easily prepared with reference to these methods.

  Examples of the protecting group include amino group (or imino group) protecting groups such as t-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Z), p-methoxybenzyloxycarbonyl group (Z (OMe)), 9 -Fluorenylmethoxycarbonyl group (Fmoc), 3-nitro-2-pyridinesulfenyl group (Npys) and the like can be exemplified. For deprotection of the protecting group, a conventional method such as acid treatment (anhydrous hydrogen fluoride, trifluoromethanesulfonic acid, trifluoroacetic acid, etc.) can be used. Specifically, hydrochloric acid-1,4-dioxane, hydrochloric acid It can be carried out using a solvent system such as ethyl acetate, acetyl chloride-methanol, trifluoroacetic acid-thiophenol, trifluoroacetic acid-dichloromethane, sulfuric acid-dioxane, trimethylsilyl-chloroform iodide, trimethylsilyl-iodide iodide. For protecting groups and elimination of the protecting groups, reference can be made to “protective group in organic synthesis” (JOHN WILEY & SONS, INC).

  Deprotection of the protecting group is usually carried out in a solvent, and examples of the solvent include conventional solvents such as halogenated hydrocarbons (dichloromethane and the like), ethers (chain ethers such as diethyl ether and diisopropyl ether, 1 , 4-dioxane, cyclic ethers such as tetrahydrofuran (THF), esters (such as ethyl acetate), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, propionitrile, etc.), amides (N, N— Examples thereof include dimethylformamide (DMF), N, N-dimethylacetamide (DMAA), sulfoxides (dimethylsulfoxide (DMSO), etc.) The deprotection reaction of the protecting group can be carried out by heating (for example, 30 to 100 ° C.) or room temperature. (For example, 15 to 25 ° C.).

  Reaction of deprotected compound represented by formula (1b) or formula (4b) (a compound in which protecting group Pro is a hydrogen atom) and a compound represented by formula (6b) (such as bromoacetate) In the same manner as in the reaction step (A), for example, the reaction can be performed in a solvent (acetonitrile, DMF, acetone, etc.) in the presence of a base (cesium carbonate, potassium carbonate, etc.).

As the compound (6b), haloalkane carboxylic acid or ester thereof, for example, bromo C _1-10 alkane carboxylic acid such as bromoacetic acid or ester thereof, bromopropionic acid or ester thereof, bromobutyric acid or ester thereof, bromoisobutyric acid or ester thereof, etc. Or the ester (For example, halo _C1-6 alkanecarboxylic acid or its ester) can be illustrated.

Reaction step (C):
When the partial structure Z is a partial structure represented by the formula (5c), the compound represented by the formula (1b) or the formula (4b) is reacted with the compound represented by the formula (6c) (alkyl halide). The partial structure Z is formed in the compound represented by formula (1b) or formula (4b). In the partial structure represented by the formula (5c), the hydrogen atom of the imino group (═N—H) is protected with a protective group in the same manner as the deprotection of the protective group in the reaction step (B). It may also be generated by deprotecting the imino group.

As the compound (6c), an alkyl halide, for example, linear or branched such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, propyl iodide, isopropyl iodide, butyl iodide, isobutyl iodide, etc. Examples thereof include a chain C _1-10 alkyl halide (for example, a linear or branched C _1-6 alkyl halide).

  The reaction of the compound represented by the formula (1b) or the formula (4b) and the compound represented by the formula (6c) (alkyl halide) is carried out in the same manner as in the reaction step (A), for example, a base (carbonic acid). In the presence of cesium, potassium carbonate, etc.) in a solvent (acetonitrile, DMF, acetone, etc.).

In the compound, a compound in which R ⁵ is a hydrogen atom can be prepared by subjecting a compound in which R ⁵ is an alkyl group to a conventional hydrolysis reaction to liberate it to a carboxyl group. Hydrolysis can be performed by a conventional method, for example, using a base, and is usually performed in a solvent. As the base, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates and the like are generally used. Solvents include water, alcohols (methanol, ethanol, isopropanol, etc.), water-soluble ethers (1,4-dioxane, tetrahydrofuran, etc.), water-soluble ketones (acetone, etc.), nitriles (acetonitrile, propionitrile, etc.) ), Amides (DMF, DMAA, etc.), sulfoxides (DMSO, etc.) and the like. Usually, a mixed solvent of water and a water-soluble solvent may be used.

  The obtained lactam compound and its salt can be converted into each other. For example, 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 (3), compound (4) or (4a) as an intermediate can be prepared by a known conventional method or a similar method, and can be purchased as a commercial product. Moreover, the following total examples can also be referred for preparation of an intermediate body to these.

For example, in the compound (3) in which -X ¹ -L ₁ is an alkoxycarbonyl group, reaction of 2-methylisophthalic acid dialkyl ester with a halogen source (such as bromosuccinimide (NBS) or N-chlorosuccinimide) is started. 2-halomethylisophthalic acid dialkyl ester is prepared by halogenation with an agent (radical source such as azobisisobutyronitrile (AIBN) or benzoyl peroxide), and the 2-halomethylisophthalic acid dialkyl ester and aniline are prepared. It can be prepared by reacting with a derivative and cyclization. As the solvent for the halogenation reaction, carbon tetrachloride, benzene or the like can be used, and the reaction temperature is often carried out under heating conditions, preferably under reflux conditions. 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.

  In addition, 2-methylisophthalic acid dialkyl ester hydrolyzes 2,6-dicyanotoluene with an acid or an 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 See the section on the synthesis of esters from carboxylic acids, such as “Chemical Lecture 4th Edition, Experimental Chemistry Lecture 5th Edition”, “protective group in organic synthesis” (JOHN WILEY & SONS, INC), etc.].

In the compound (3), a compound in which —X ¹ -L ₁ is a carboxyl group can be prepared by hydrolyzing a compound in which —X ¹ -L ₁ is an alkoxycarbonyl group in the presence of an alkali. Hydrolysis can be performed in a solvent at room temperature to under heating. As the solvent, water, a mixed solvent of water and a water-soluble organic solvent [alcohol (methanol, ethanol), dioxane, etc.] can be used.

A compound in which —X ¹ -L ₁ is a carboxyl group can be derived into a compound in which —X ¹ -L ₁ is a hydroxymethyl group by reduction using a reducing agent by a conventional method. For details of the reducing agent, for example, “MARCH'S ADVANCED ORGANIC CHEMISTRY” (JOHN WILEY & SONS) can be referred to. Examples of the reducing agent include sodium borohydride-aluminum chloride, borane-THF complex, borane-dimethylsulfide 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 performed, 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 to the extent.

A compound in which —X ¹ -L ₁ is a hydroxymethyl group can be derived by halogenation by a conventional method to derive a compound in which —X ¹ -L ₁ is a halomethyl group. As the halogenation conditions, a general method can be adopted, and for example, the section of halides such as New Experimental Chemistry Course (Maruzen Co., Ltd.), Experimental Chemistry Course 4th Edition, Experimental Chemistry Course 5th Edition can be referred to. Examples of the halogenating agent 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 carried out in a solvent (for example, methylene chloride, chloroform, carbon tetrachloride, carbon tetrabromide, THF, etc.), and the reaction temperature can be carried out, for example, at 0 ° C. to room temperature.

(PPAR activator and pharmaceutical composition)
The compound having a lactam skeleton represented by the formula (1) or a salt thereof has a high binding property to PPAR (PPARα, PPARγ and / or PPARδ), and 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).

  In addition, the pharmaceutical composition of the present invention can be composed of a compound having a lactam skeleton represented by the above formula (I) or a pharmacologically acceptable salt thereof and, if necessary, a carrier.

  The compound represented by the formulas (1) and (1a) or a pharmaceutically acceptable salt thereof can activate at least one selected from PPARα, PPARγ and PPARδ, preferably PPARα and / or PPARδ. (In particular, it has high activity against PPARδ).

  In the pharmaceutical composition constituting the PPAR activator and the pharmaceutical composition of the present invention, the carrier is appropriately selected according to the form (ie, dosage form), dosage form, use, etc. of the pharmaceutical composition (or formulation). Is done. 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. Furthermore, the preparation may be a preparation with controlled drug release rate (sustained release preparation, immediate release preparation). In aerosols used for inhalants and the like, the aerosol generation method is not particularly limited. For example, the same sealed container is filled with a pharmaceutically active ingredient and a propellant such as an alternative fluorocarbon and sprayed. Alternatively, 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. Furthermore, the preparation may be an oral administration preparation or a parenteral administration preparation (nasal drops, inhalants, transdermal preparations, etc.). Furthermore, 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).

  Examples of the carrier 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. For example, as 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.

  Examples of the excipient 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. . Examples of disintegrants include calcium carbonate, carboxymethylcellulose or salts 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.

  Examples of the coating agent 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, or methyl methacrylate- (meth) acrylic acid copolymer, and 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.

  Among oil carriers, 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. Examples of the aqueous carrier 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.

  In the preparation, known additives can be appropriately used depending on the administration route and dosage form. Examples of such 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), pH adjusters or buffers (citric acid-sodium citrate buffer, etc.), stabilizers, preservatives or preservatives (parabens, such as methylparaben and butylparaben), bactericides 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. These additives can be used alone or in combination of two or more.

  For example, in an injection, a solubilizer, a solubilizer, a suspending agent, a buffer, a stabilizer, a preservative and the like are usually used as the additive. In addition, in the powder injection for use by dissolving or suspending at the time of administration, conventional additives used in powder injection can be used.

  In addition, in 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. .

  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. 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. Can be prepared by a conventional formulation method, for example, a production method described in the 15th revision Japanese Pharmacopoeia or a method according to this production method.

  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.

(Preventive and / or therapeutic agent)
The compound represented by the formula (1) or (1a) or a pharmacologically acceptable salt thereof exhibits specific binding characteristics to PPAR and can effectively activate PPAR. Metabolism of lipids (including fats and oils, phospholipids) and / or sugars can be promoted. Therefore, the compound having the lactam skeleton or a pharmacologically acceptable salt thereof (or the PPAR activator or the pharmaceutical composition) is (i) a disease caused by abnormal metabolism of fatty acid, lipid or sugar, and And / or (ii) It is effective as a preventive or therapeutic agent for diseases caused by excessive intake of fatty acids, lipids or sugars compared to metabolism of fatty acids, lipids or sugars. In addition, such a preventive or therapeutic agent usually contains the compound having the lactam skeleton or a pharmacologically acceptable salt thereof as an active ingredient.

  Examples of the diseases (i) and (ii) include arteriosclerosis, cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes, insulin resistance Examples include diseases selected from the group consisting of diabetes and obesity.

  In the PPAR activator, pharmaceutical composition, preventive and / or therapeutic agent, 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 PPAR activator, pharmaceutical composition, prophylactic and / or therapeutic agent can be administered once or multiple times (about 2 to 6 times) per day.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Synthesis Example 1 (Synthesis of methyl N- (4-hydroxyphenyl) aminoacetate)

A solution of N- (4-hydroxyphenyl) glycine (1.67 g, 10.0 mmol) in hydrochloric acid-methanol (50 mL) was heated to reflux overnight. An aqueous sodium hydrogen carbonate solution was added and the solvent was distilled off, followed by extraction with dichloromethane to obtain crystals of methyl N- (4-hydroxyphenyl) aminoacetate (1.55 g, 85%).
¹ H NMR (CDCl ₃ ) δ: 3.77 (3H, s), 3.87 (2H, s), 6.50-6.56 (2H, m), 6.68-6.74 (2H, m).

Synthesis Example 2 ( Synthesis of N- (4-hydroxyphenyl) -N-methylaminoacetic acid ethyl acetate)
(I) Synthesis of ethyl N- (4-methoxyphenyl) -N-methylaminoacetate

To a solution of 4-methoxy-N-methylaniline (137 mg, 1.00 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (44 mg, 1.10 mmol), and the mixture was stirred at room temperature for 20 minutes. Ethyl bromoacetate (184 mg, 1.10 mmol) was added and stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain oily N- (4-methoxyphenyl) -N-methylaminoethyl acetate (142 mg, 64%).
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 3.02 (3H, s), 3.75 (3H, s), 4.00 (2H, s) 4.16 (2H, q, J = 7.3 Hz), 6.65-6.71 (2H, m), 6.80-6.86 (2H, m).

  (Ii) Synthesis of ethyl N- (4-hydroxyphenyl) -N-methylaminoacetate

Under ice cooling, a boron tribromide dichloromethane solution (5 mL) was added to a solution of N- (4-methoxyphenyl) -N-methylaminoethyl acetate (130 mg, 0.58 mmol) obtained in (i) above in dichloromethane (5 mL). 0.58 ml, 0.58 mmol) was added, and the mixture was stirred at room temperature for 1 day. Further, boron tribromide dichloromethane solution (0.58 ml, 0.58 mmol) was added, and the mixture was stirred at room temperature for 1 day. After neutralizing with triethylamine and evaporating the solvent, the residue was purified by silica gel column chromatography to obtain ethyl N- (4-hydroxyphenyl) -N-methylaminoacetate (53 mg, 44%).
¹ H NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.3 Hz), 3.00 (3H, s), 3.99 (2H, s), 4.16 (2H, q, J = 7.3 Hz), 4.40 (1H, brs), 6.59-6.65 (2H, m), 6.71-6.77 (2H, m).

Synthesis Example 3 ( Synthesis of N- (4-hydroxyphenyl) -N-methylaminoacetic acid ethyl ester)

  To a solution of 4- (methylamino) phenol sulfate (5.00 g, 14.5 mmol) in acetonitrile (100 mL), sodium hydrogen carbonate (4.88 g, 58.1 mmol) and ethyl bromoacetate (4.85 g, 29.0 mmol) And stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain ethyl N- (4-hydroxyphenyl) -N-methylaminoacetate (4.60 g, 76%).

Synthesis Example 4 ( Synthesis of 4 -bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 2-methylisophthalic acid

To a suspension of 2,6-dicyanotoluene (2.84 g, 20.0 mmol) in ethylene glycol (20 mL) was added 14N aqueous sodium hydroxide solution (7 mL, 0.10 mol), and the mixture was stirred at 150 ° C. overnight. Concentrated hydrochloric acid was added, and the resulting crystals were collected by filtration and dried to obtain crystals of 2-methylisophthalic acid (3.61 g, quant).
¹ H NMR (DMSO-d ₆ ) δ: 2.58 (3H, s), 7.35 (1H, t, J = 7.9 Hz), 7.80 (2H, d, J = 7.9 Hz), 13.14 (2H, brs).

  (Ii) Synthesis of dimethyl 2-methylisophthalate

A suspension of 2-methylisophthalic acid (3.59 g, 19.9 mmol) obtained in (i) above in hydrochloric acid-methanol (40 mL) was heated to reflux overnight. An aqueous sodium hydrogen carbonate solution was added, and the resulting crystals were collected by filtration and dried to obtain crystals of dimethyl 2-methylisophthalate (3.61 g, 87%).
¹ H NMR (CDCl ₃ ) δ: 2.69 (3H, s), 3.91 (6H, s), 7.29 (1H, t, J = 7.9 Hz), 7.87 (2H, d, J = 7.9 Hz).

  (Iii) Synthesis of 4-methoxycarbonyl-2- (4-trifluoromethylphenyl) isoindoline-1-one

  To a solution of dimethyl 2-methylisophthalate (1.67 g, 8.00 mmol) obtained in (ii) above in carbon tetrachloride (25 mL), bromosuccinimide (1.42 g, 8.00 mmol) and benzoyl peroxide (75 % In Water, 143 mg) was added, and the mixture was heated to reflux for 8 hours. After standing to cool, insolubles were filtered off and the solvent was distilled off to obtain dimethyl 2-bromomethylisophthalate.

A solution of dimethyl 2-bromomethylisophthalate and 1-amino-4- (trifluoromethyl) benzene (1.29 g, 8.00 mmol) in dimethylformamide (25 mL) is stirred at 60 ° C. for 2 hours and 120 ° C. for 1.5 hours. did. After allowing to cool, the obtained crystals were collected by filtration and dried to give 4-methoxycarbonyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (1.84 g, 69%). .
¹ H NMR (CDCl ₃ ) δ: 4.02 (3H, s), 5.22 (2H, s), 7.65 (1H, t, J = 7.6 Hz), 7.70 (2H, d, J = 8.9 Hz), 8.10 (2H, d, J = 8.9 Hz), 8.14 (1H, d, J = 7.6 Hz), 8.28 (1H, d, J = 7.6 Hz) ).

  (Iv) Synthesis of 4-carboxy-2- (4-trifluoromethylphenyl) isoindoline-1-one

To a suspension of 4-methoxycarbonyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (671 mg, 2.00 mmol) obtained in (iii) above in methanol (10 mL) and water (2 mL) 2N aqueous sodium hydroxide solution (1.5 mL, 3.00 mmol) was added, and the mixture was heated to reflux for 70 minutes. 1N Hydrochloric acid was added, and the resulting crystals were collected by filtration and dried to give 4-carboxy-2- (4-trifluoromethylphenyl) isoindoline-1-one (604 mg, 94%).
¹ H NMR (DMSO-d ₆ ) δ: 5.32 (2H, s), 7.72 (1H, t, J = 7.6 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.07 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.17 (2H, d, J = 8.9 Hz), 8.23 (1H, dd, J = 1.0 Hz, 7. 6 Hz), 13.60 (1H, br).

  (V) Synthesis of 4-hydroxymethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one

Borane-tetrahydrofuran complex was added to a solution of (iv) 4-carboxy-2- (4-trifluoromethylphenyl) isoindoline-1-one (574 mg, 1.79 mmol) obtained above in tetrahydrofuran (35 mL) under ice-cooling. (2.16 mL, 2.14 mmol) was added dropwise and stirred at 0 ° C. for 45 minutes and at room temperature overnight. Further, borane-tetrahydrofuran complex (0.90 mL, 0.90 mmol) was added, and the mixture was stirred at room temperature for 4 hours and a half. Methanol was added and the solvent was distilled off. Water was added, and the mixture was extracted with dichloromethane to obtain crystals of 4-hydroxymethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (520 mg, 95%).
¹ H NMR (CDCl ₃ ) δ: 1.98 (1H, t, J = 5.6 Hz), 4.90 (2H, d, J = 5.6 Hz), 4.97 (2H, s), 7. 48 (1H, t, J = 7.3 Hz), 7.53 (1H, dd, J = 1.0 Hz, 7.3 Hz), 7.68 (2H, d, J = 8.9 Hz), 7.85 (1H, dd, J = 1.0 Hz, 7.3 Hz), 8.05 (2H, d, J = 8.9 Hz).

  (Vi) Synthesis of 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one

To a solution of 4-hydroxymethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (2.00 g, 6.51 mmol) obtained in (v) above in methylene chloride (30 mL) was added N-bromosuccinate. Acid imide (1.74 g, 9.76 mmol) and triphenylphosphine (2.56 g, 9.76 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, methanol (2 mL) was added and stirred at room temperature for 20 minutes. The 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%).
¹ H NMR (CDCl ₃ ) δ: 4.60 (2H, s), 4.97 (2H, s), 7.53 (1H, d, J = 9.1 Hz), 7.61 (1H, dd, J = 1.2 Hz, 7.5 Hz), 7.70 (2H, d, J = 8.7 Hz), 7.91 (1H, dd, J = 1.2 Hz, 7.5 Hz), 8.07 (2H , D, J = 8.7 Hz).

Synthesis Example 5 ( Synthesis of 4-bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
(I) Synthesis of 4-methoxycarbonyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one

  Bromosuccinimide (4.27 g, 24.01 mmol) and benzoyl peroxide were added to a solution of dimethyl 2-methylisophthalate (5.00 g, 8.00 mmol) obtained in Synthesis Example 4 (ii) in carbon tetrachloride (75 mL). (75% in Water, 400 mg) was added and heated to reflux for 2 hours. After standing to cool, insolubles were filtered off and the solvent was distilled off to obtain dimethyl 2-bromomethylisophthalate.

A solution of dimethyl 2-bromomethylisophthalate and 1-amino-4- (trifluoromethoxy) benzene (4.25 g, 24.01 mmol) in dimethylformamide (75 mL) at 60 ° C. for 1.5 hours and at 120 ° C. for 1.5 hours. Stir. After allowing to cool, the reaction solution was diluted with methanol and then with water. The obtained crystals were collected by filtration, washed with water, and dried to give 4-methoxycarbonyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (7.17 g, 85%).
¹ H NMR (CDCl ₃ ) δ: 4.01 (3H, s), 5.19 (2H, s), 7.30 (2H, d, J = 9.1 Hz), 7.64 (1H, t, J = 7.5 Hz), 7.98 (2H, d, J = 9.1 Hz), 8.13 (1H, dd, J = 0.8 Hz, 7.5 Hz), 8.27 (1H, dd, J = 0.8 Hz, 7.5 Hz).

  (Ii) Synthesis of 4-carboxy-2- (4-trifluoromethoxyphenyl) isoindoline-1-one

To a solution of 4-methoxycarbonyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (7.11 g, 20.23 mmol) obtained in (i) above in dioxane (50 mL), 2N aqueous sodium hydroxide solution (15.2 mL, 30.4 mmol) was added, and the mixture was stirred at room temperature for 17 hours. 1N Hydrochloric acid (30.4 mL) was added to the reaction mixture, diluted with ice water, and the resulting crystals were collected by filtration. The obtained crystals were washed with water and dried to give 4-carboxy-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (6.63 g, 97%).
¹ H NMR (DMSO-d ₆ ) δ: 5.28 (2H, s), 7.48 (2H, d, J = 9.2 Hz), 7.71 (1H, t, J = 7.6 Hz), 8.00-8.10 (3H, m), 8.22 (1 H, d, J = 7.6 Hz), 13.57 (1 H, br).

  (Iii) Synthesis of 4-hydroxymethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one

To a solution of 4-carboxy-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (4.00 g, 11.86 mmol) obtained in (ii) above in tetrahydrofuran (250 mL) under ice-cooling, Tetrahydrofuran complex (38.8 mL, 41.13 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 17.5 hours. Methanol was added to the reaction solution under ice cooling, and the solvent was distilled off. Water was added to the residue and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether-hexane to obtain crystals of 4-hydroxymethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (3.32 g, 87%).
¹ H NMR (CDCl ₃ ) δ: 2.05 (1H, t, J = 5.2 Hz), 4.88 (2H, d, J = 5.2 Hz), 4.92 (2H, s), 7. 25-7.32 (3H, m), 7.42-7.53 (2H, m), 7.83 (1H, dd, J = 1.5 Hz, 7.1 Hz), 7.88-7.96 (2H, m).

  (Iv) Synthesis of 4-bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one

To a solution of 4-hydroxymethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (1.29 g, 4.00 mmol) obtained in (iii) above in dichloromethane (24 mL) under ice-cooling. Phenylphosphine (1.57 g, 6.00 mmol) and N-bromosuccinimide (1.07 g, 6.00 mmol) were added, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 50 minutes. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 4-bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (1.48 g, 96%) crystals.
¹ H NMR (CDCl ₃ ) δ: 4.58 (2H, s), 4.93 (2H, s), 7.28-7.31 (2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.58 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.88 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.91-7.97. (2H, m).

Synthesis Example 6 ( Synthesis of 4-bromomethyl-2- (4-methylphenyl) isoindoline-1-one)
(I) Synthesis of 4-methoxycarbonyl-2- (4-methylphenyl) isoindoline-1-one

  Bromosuccinimide (1.71 g, 9.61 mmol) and benzoyl peroxide were added to a solution of dimethyl 2-methylisophthalate (2.00 g, 9.61 mmol) obtained in Synthesis Example 4 (ii) in carbon tetrachloride (30 mL). (75% in Water, 150 mg) was added, and the mixture was heated to reflux for 3.5 hours. After standing to cool, insolubles were filtered off and the solvent was distilled off to obtain dimethyl 2-bromomethylisophthalate.

A solution of dimethyl 2-bromomethylisophthalate and 1-amino-4-methylbenzene (1.03 g, 9.61 mmol) in dimethylformamide (30 mL) was stirred at 60 ° C. for 3 hours and 120 ° C. for 2 hours. After allowing to cool, the reaction solution was diluted with methanol and then with water. The obtained crystals were collected by filtration, washed with water, and dried to give 4-methoxycarbonyl-2- (4-methylphenyl) isoindoline-1-one (2.14 g, 79%).
¹ H NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 3.95 (3H, s), 5.22 (2H, s), 7.27 (2H, d, J = 8. 6 Hz), 7.72 (1 H, t, J = 7.7 Hz), 7.81 (2 H, d, J = 8.6 Hz), 8.05 (1 H, dd, J = 1.0 Hz, 7.7 Hz) ), 8.22 (1H, dd, J = 1.0 Hz, 7.7 Hz).

  (Ii) Synthesis of 4-carboxy-2- (4-methylphenyl) isoindoline-1-one

To a solution of 4-methoxycarbonyl-2- (4-methylphenyl) isoindoline-1-one (2.00 g, 7.11 mmol) obtained in (i) above in dioxane (20 mL), 2N aqueous sodium hydroxide solution (5 3 mL, 10.6 mmol) was added, and the mixture was stirred at room temperature for 17 hours. 1N Hydrochloric acid (5.3 mL) was added to the reaction mixture, diluted with ice water, and the resulting crystals were collected by filtration. The obtained crystals were washed with water and dried to give 4-carboxy-2- (4-methylphenyl) isoindoline-1-one (1.84 g, 97%).
¹ H NMR (DMSO-d ₆ ) δ: 2.32 (3H, s), 5.22 (2H, s), 7.27 (2H, d, J = 8.6 Hz), 7.72 (1H, t, J = 7.7 Hz), 7.81 (2H, d, J = 8.6 Hz), 8.05 (1H, dd, J = 1.0 Hz, 7.7 Hz), 8.22 (1H, dd) , J = 1.0 Hz, 7.7 Hz).

  (Iii) Synthesis of 4-hydroxymethyl-2- (4-methylphenyl) isoindoline-1-one

Borane-tetrahydrofuran complex was added to a solution of 4-carboxy-2- (4-methylphenyl) isoindoline-1-one (1.30 g, 4.86 mmol) obtained in (ii) above in tetrahydrofuran (100 mL) under ice-cooling. (6.9 mL, 7.30 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 25.5 hours. Methanol was added to the reaction solution under ice cooling, and the solvent was distilled off. Water was added to the residue and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether-hexane to obtain crystals of 4-hydroxymethyl-2- (4-methylphenyl) isoindoline-1-one (1.01 g, 82%).
¹ H NMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 4.69 (2H, d, J = 5.5 Hz), 5.00 (2H, s), 5.39 (1H, t, J = 5.5 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.52 (1H, t, J = 7.4 Hz), 7.64 (2H, t, J = 7) .4 Hz), 7.80 (2H, d, J = 8.4 Hz).

  (Iv) Synthesis of 4-bromomethyl-2- (4-methylphenyl) isoindoline-1-one

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%).
¹ H NMR (CDCl ₃ ) δ: 2.37 (3H, s), 4.58 (2H, s), 4.91 (2H, s), 7.23-7.26 (2H, m), 7 .50 (1H, t, J = 7.6 Hz), 7.56 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.73-7.78 (2H, m), 7.88 ( 1H, dd, J = 1.3 Hz, 7.6 Hz).

Example 1 (Synthesis of 4- {4- [N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethylphenyl) isoindoline-1-one)

4-Bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (1.36 g, 3.66 mmol) obtained in Synthesis Example 4 and N- (4-hydroxy) obtained in Synthesis Example 1 were used. To a suspension of methyl phenyl) aminoacetate (730 mg, 4.03 mmol) in acetonitrile (40 mL) was added cesium carbonate (1.31 g, 4.03 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added, and the resulting crystals were recrystallized from 1,4-dioxane, dried and 4- {4- [N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethylphenyl). ) Crystals of isoindoline-1-one (1.19 g, 69%) were obtained.
¹ H NMR (CDCl ₃ ) δ: 3.78 (3H, s), 3.89 (2H, s), 4.10 (1H, br), 4.97 (2H, s), 5.17 (2H) , S), 6.57-6.63 (2H, m), 6.85-6.91 (2H, m), 7.54 (1H, t, J = 7.6 Hz), 7.61 (1H) , Dd, J = 1.3 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.91 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8. 04 (2H, d, J = 8.6 Hz).

Example 2 (Synthesis of 4- {4- [N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one)

4-Bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (3.00 g, 7.77 mmol) obtained in Synthesis Example 5 and N- (4-hydroxyphenyl) obtained in Synthesis Example 1 ) Cesium carbonate (2.78 g, 8.55 mmol) was added to a suspension of methyl aminoacetate (1.41 mg, 7.77 mmol) in acetonitrile (60 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered to remove insolubles, and the solvent was distilled off under reduced pressure to obtain a yellow solid residue. The residue is purified by silica gel column chromatography, washed with methanol, and dried to give 4- {4- [N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl). Crystals of isoindoline-1-one (0.50 g, 13%) were obtained.
¹ H NMR (CDCl ₃ ) δ: 3.78 (3H, s), 3.89 (2H, s), 4.11 (1H, br), 4.94 (2H, s), 5.16 (2H) , S), 6.56-6.63 (2H, m), 6.84-6.91 (2H, m), 7.27-7.32 (2H, m), 7.50-7.62. (2H, m), 7.88-7.95 (3H, m).

Example 3 Synthesis of 4- {4- [N- (ethoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethylphenyl) isoindoline-1-one

To a solution of ethyl N- (4-hydroxyphenyl) -N-methylaminoacetate (169 mg, 0.81 mmol) obtained in Synthesis Example 2 in acetonitrile (15 mL) with cesium carbonate (254 mg, 0.78 mmol) and Synthesis Example 4 The obtained 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (222 mg, 0.60 mmol) was added and stirred overnight at room temperature. Water was added, and the obtained crystals were recrystallized from ethanol and dichloromethane, dried and dried by 4- {4- [N- (ethoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoro). Crystals of methylphenyl) isoindoline-1-one (177 mg, 59%) were obtained.
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 3.03 (3H, s), 4.02 (2H, s), 4.17 (2H, q, J = 7.3 Hz), 4.97 (2H, s), 5.17 (2H, s), 6.65-6.71 (2H, m), 6.88-6.94 (2H, m) 7.53 (1H, t, J = 7.6 Hz), 7.61 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.67 (2H, d, J = 8.6 Hz), 7.90 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8.04 (2H, d, J = 8.6 Hz).

Example 4 Synthesis of 4- {4- [N- (methoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethylphenyl) isoindoline-1-one

4- {4- [N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (188 mg, 0.40 mmol) obtained in Example 1 To a dimethylformamide (7 mL) solution were added potassium carbonate (61 mg, 0.44 mmol) and methyl iodide (62 mg, 0.44 mmol), and the mixture was stirred at 50 ° C. overnight. Furthermore, potassium carbonate (111 mg, 0.80 mmol) and methyl iodide (113 mg, 0.80 mmol) were added, and the mixture was stirred at 50 ° C. for 8 hours. Water was added, and the resulting crystals were purified by silica gel column chromatography to obtain 4- {4- [N- (methoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethylphenyl). Crystals of isoindoline-1-one (86 mg, 44%) were obtained.
¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.71 (3H, s), 4.04 (2H, s), 4.97 (2H, s), 5.17 (2H) , S), 6.65-6.71 (2H, m), 6.88-6.95 (2H, m), 7.54 (1H, t, J = 7.6 Hz), 7.61 (1H , Dd, J = 1.3 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.91 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8. 04 (2H, d, J = 8.6 Hz).

Example 5 (Synthesis of 4- {4- [N- (methoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one)

4- {4- [N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (300 mg, 0.62 mmol) obtained in Example 2 To a dimethylformamide (6 mL) solution were added potassium carbonate (128 mg, 0.93 mmol) and methyl iodide (262 mg, 1.85 mmol), and the mixture was stirred at 60 ° C. overnight. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow solid residue. The residue was washed with methanol and dried to give 4- {4- [N- (methoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1- On (129 mg, 42%) crystals were obtained.
¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.71 (3H, s), 4.04 (2H, s), 4.94 (2H, s), 5.17 (2H , S), 6.65-6.71 (2H, m), 6.88-6.93 (2H, m), 7.27-7.32 (2H, m), 7.50-7.62. (2H, m), 7.88-7.95 (3H, m).

Example 6 (Synthesis of 4- {4- [N- (ethoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one)

4-Bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (1.00 g, 2.59 mmol) obtained in Synthesis Example 5 and N- (4-hydroxyphenyl) obtained in Synthesis Example 3 Cesium carbonate (1.10 g, 3.37 mmol) was added to a suspension of ethyl N-methylaminoacetate (0.596 g, 2.85 mmol) in acetonitrile (20 mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was filtered to remove insolubles, and the solvent was distilled off under reduced pressure to obtain a brown solid residue. The residue was washed with ethanol and dried to give 4- {4- [N- (ethoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1- On (1.03 g, 77%) crystals were obtained.
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1 Hz), 3.03 (3H, s), 4.02 (2H, s), 4.17 (2H, q, J = 7.1 Hz), 4.94 (2H, s), 5.17 (2H, s), 6.65-6.72 (2H, m), 6.87-6.95 (2H, m) 7.27-7.33 (2H, m), 7.50-7.62 (2H, m), 7.87-7.96 (3H, m).

Example 7 Synthesis of 4- {4- [N- (ethoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-methylphenyl) isoindoline-1-one

4-Bromomethyl-2- (4-methylphenyl) isoindoline-1-one (316 mg, 1.00 mmol) obtained in Synthesis Example 6 and N- (4-hydroxyphenyl) -N obtained in Synthesis Example 3 -To a suspension of ethyl methylaminoacetate (251 mg, 1.20 mmol) in acetonitrile (20 mL) was added cesium carbonate (391 mg, 1.20 mmol), and the mixture was stirred overnight at room temperature. Water was added, and the resulting crystals were collected by filtration and dried to give 4- {4- [N- (ethoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-methylphenyl) isoindoline- Crystals of 1-one (392 mg, 88%) were obtained.
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 2.36 (3H, s), 3.03 (3H, s), 4.01 (2H, s) 4.17 (2H, q, J = 7.3 Hz), 4.92 (2H, s), 5.15 (2H, s), 6.65-6.71 (2H, m), 6.87. -6.94 (2H, m), 7.21-7.25 (2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.58 (1H, dd, J = 1. 3 Hz, 7.6 Hz), 7.71-7.76 (2 H, m), 7.89 (1 H, dd, J = 1.3 Hz, 7.6 Hz).

Example 8 Synthesis of 4- {4- [N-ethyl-N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethylphenyl) isoindoline-1-one

4- {4- [N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (282 mg, 0.60 mmol) obtained in Example 1 To a dimethylformamide (8 mL) solution were added potassium carbonate (124 mg, 0.90 mmol) and ethyl iodide (140 mg, 0.90 mmol), and the mixture was stirred at 60 ° C. for 6 hours and at 80 ° C. for 2 hours. Further, ethyl iodide (187 mg, 1.20 mmol) was added, and the mixture was stirred at 60 ° C. overnight. Water was added, and the obtained crystals were purified by silica gel column chromatography to give 4- {4- [N-ethyl-N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethylphenyl). Crystals of isoindoline-1-one (120 mg, 40%) were obtained.
¹ H NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.3 Hz), 3.42 (2H, q, J = 7.3 Hz), 3.73 (3H, s), 4. 00 (2H, s), 4.97 (2H, s), 5.17 (2H, s), 6.62-6.68 (2H, m), 6.87-6.93 (2H, m) 7.54 (1H, t, J = 7.6 Hz), 7.61 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.91 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.04 (2H, d, J = 8.6 Hz).

Example 9 Synthesis of 4- {4- [N-ethyl-N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one

4- {4- [N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (250 mg, 0.51 mmol) obtained in Example 2 To a dimethylformamide (5 mL) solution were added potassium carbonate (428 mg, 3.10 mmol) and ethyl iodide (480 mg, 3.08 mmol), and the mixture was stirred at 60 ° C. overnight. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow solid residue. The residue was washed with methanol and dried to give 4- {4- [N-ethyl-N- (methoxycarbonylmethyl) amino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1- On (166 mg, 63%) crystals were obtained.
¹ H NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.1 Hz), 3.42 (2H, q, J = 7.1 Hz), 3.73 (3H, s), 3. 99 (2H, s), 4.94 (2H, s), 5.16 (2H, s), 6.62-6.67 (2H, m), 6.87-6.92 (2H, m) 7.25-7.31 (2H, m), 7.50-7.62 (2H, m), 7.88-7.95 (3H, m).

Example 10 Synthesis of 4- {4- [N- (carboxymethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one

4- {4- [N- (Ethoxycarbonylmethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 6 (0.100 g , 0.19 mmol) in dioxane (5 mL) was added 1 mol / L aqueous sodium hydroxide solution (1.5 mL) and stirred at room temperature for 7 hours. 1N HCl aqueous solution (1.5 mL) was added to the reaction solution, and then diluted with water. The resulting crystals were collected by filtration, washed with water and dried to give 4- {4- [N- (carboxymethyl) -N-methylamino] phenoxy} methyl-2- (4-trifluoromethoxyphenyl) isoindoline-1- On (0.086 g, 91%) crystals were obtained.
¹ H NMR (DMSO-d ₆ ) δ: 2.92 (3H, s), 4.02 (2H, s), 5.12 (2H, s), 5.21 (2H, s), 6.62 (2H, d, J = 8.9 Hz), 6.95 (2H, d, J = 8.9 Hz), 7.47 (2H, d, J = 8.9 Hz), 7.58 (1H, t, J = 7.5 Hz), 7.75 (1H, d, J = 7.5 Hz), 7.76 (1H, d, J = 7.5 Hz), 8.05 (2H, d, J = 8.9 Hz) ).

Test Example 1 (PPAR screening method: measurement of PPARα, PPARγ or PPARδ 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. This solution is mixed with a receptor plasmid pBIND-hPPARα (or γ or δ) for expressing a fusion protein of a DNA binding domain of the transcription factor Gal4 of yeast and a PPARα (or γ or δ) ligand binding domain and a reporter plasmid pG5-Luc. After standing, the whole amount was added to a 100 mm plate. 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.

  The induction ratio of the test substance was determined as follows. That is, the luciferase activity of the test substance non-administered group is a1, the luciferase activity of the test substance of the control drug is a2, and the luciferase activity of the test substance at the concentrations shown in Table 1 (30, 10, 3, and 1 μg / mL) is a3. Fold ratio A2 (A2 = a2 / a1) of the luciferase activity a2 of the control drug and the concentrations shown in Table 1 (30, 10, 3, and 1 μg / mL) with respect to the luciferase activity a1 of the test substance non-administered group ) The ratio A3 (A3 = a3 / a1) of the luciferase activity a3 of the test substance is calculated, and the ratio R [R = (A3 / A2) of the test substance magnification A3 at each concentration with respect to the control drug magnification A2 × 100] was calculated as the induction ratio R of the test substance.

  PPARα activity: The compounds of Examples showing PPARα activity stronger than the addition of the control drug fenofibric acid (standard addition concentration 100 μM) were as follows for the addition concentrations of each test substance.

Test substance 30 μg / mL: Examples 5 and 6
Test substance 10 μg / mL: Example 5
PPARγ activity: The compounds of Examples showing PPARγ activity stronger than the addition of the control drug triglitazone (standard addition concentration 10 μM) were as follows for the addition concentrations of each test substance.

Test substance 30 μg / mL: Example 5
PPARδ activity: GW501516 (standard addition concentration 100 nM) was used as a control drug, and the PPARδ 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 Table 1. In addition, the compound of the Example which showed PPAR (delta) activity stronger than control drug GW501516 (standard addition density | concentration of 100 nM) addition is a compound which showed the numerical value of 100% or more in Table 1.

Formulation Example 1 (tablet)
Tablets were obtained according to the known methods described in the General Rules for Preparations of JP XIV for the following formulations.

Formulation example in one tablet:
50 mg of the compound of Example 3
Crystalline cellulose 100mg
Lactose 20mg
Corn starch 28mg
Magnesium stearate 2mg
Total amount 200mg
Formulation Example 2 (Capsule)
Capsules were 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:
50 mg of the compound of Example 3
Lactose 100mg
Corn starch 28mg
Magnesium stearate 2mg
Total amount 200mg
Formulation Example 3 (granule and tablet)
Hydroxypropyl methylcellulose 2910 aqueous solution (HPMC, solid content 13 parts by weight) was added to a mixture of 30 parts by weight of the compound of Example 3, lactose 20 parts by weight and crystalline cellulose 50 parts by weight, kneaded, extruded and granulated. Granulate, dry and sieve to obtain granules. To 100 parts by weight of the obtained granules, 65 parts by weight of crystalline cellulose and 2 parts by weight of magnesium stearate were added, mixed, and tableted to obtain tablets having the following composition.

30 mg of the compound of Example 3
Lactose 20mg
Hydroxypropyl methylcellulose 2910 13mg
Crystalline cellulose 115mg
Crospopidone 20mg
Magnesium stearate 2mg
Total amount 207mg

  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 (PPARα, PPARγ and / or PPARδ), and activates PPAR. Therefore, it is useful as a PPAR activator (such as a PPARα activator, a PPARγ activator and / or a PPARδ 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. , Cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes that may be insulin resistant, obesity, etc.) . That is, the said compound or its pharmacologically acceptable salt is useful as a medicinal component of a pharmaceutical composition.

Claims (10)

A lactam compound represented by the following formula (1) or a salt thereof.

[Wherein, R ¹ represents an alkyl group which may have a substituent, an alkoxy group which may have a substituent,
The coefficient a represents an integer of 0 to 5,
R ² represents a halogen atom, an alkyl group which may have a substituent, or an alkoxy group which may have a substituent;
The coefficient b represents an integer of 0 to 4,
X ¹ and X ² each represent an alkylene group or an oxygen atom; when X ¹ is an alkylene group, X ² is an oxygen atom; when X ¹ is an oxygen atom, X ² is an alkylene group;
R ³ represents a hydrogen atom or an alkyl group which may have a substituent,
R ⁴ represents a direct bond or an alkylene group,
R ⁵ represents a hydrogen atom or an optionally substituted alkyl group]. R ¹ is a linear or branched C _1-6 alkyl group, a linear or branched halo C _1-6 alkyl group, a linear or branched C _1-6 alkoxy group, or a linear chain Or a branched halo C _1-6 alkoxy group, the coefficient a is an integer of 1 to 3,
R ² is a halogen atom, a linear or branched C _1-6 alkyl group, or a linear or branched C _1-6 alkoxy group, and the coefficient b is an integer of 0 or 1,
X ¹ and X ² are each a C _1-4 alkylene group or an oxygen atom; when X ¹ is a C _1-4 alkylene group, X ² is an oxygen atom; and when X ¹ is an oxygen atom, X ^{1 2} is a C _1-4 alkylene group,
R ⁴ is a C _1-4 alkylene group,
R ³ is a hydrogen atom or a C _1-6 alkyl group,
The lactam compound or a salt thereof according to claim 1, wherein R ⁵ is a hydrogen atom or a C _1-6 alkyl group. The lactam compound represented by the formula (1) is represented by the following formula (1a)

Wherein R ¹ is a linear or branched C _1-4 alkyl group, a linear or branched fluoro C _1-4 alkyl group, a linear or branched C _1-4 alkoxy group. Or a linear or branched fluoro C _1-4 alkoxy group,
X ¹ and X ² each represent a C _1-3 alkylene group or an oxygen atom, and when X ¹ is a C _1-3 alkylene group, X ² is an oxygen atom, and when X ¹ is an oxygen atom, X 2 ² is a C _1-3 alkylene group,
R ³ represents a hydrogen atom or a C _1-4 alkyl group,
R ⁴ represents a C _1-4 alkylene group,
R ⁵ represents a hydrogen atom or a linear or branched C _1-4 alkyl group)
The lactam compound according to claim 1 or 2, or a salt thereof. R ¹ is a linear or branched C _1-3 alkyl group, a linear or branched fluoro C _1-3 alkyl group, a linear or branched C _1-3 alkoxy group, or a linear chain Or branched fluoro _C1-3 alkoxy group,
X ¹ and X ² are each a C _1-2 alkylene group or an oxygen atom; when X ¹ is a C _1-2 alkylene group, X ² is an oxygen atom; and when X ¹ is an oxygen atom, X 2 ² is a C _1-2 alkylene group;
R ³ is a hydrogen atom or a C _1-3 alkyl group,
R ⁴ is a C _1-3 alkylene group,
The lactam compound or a salt thereof according to claim 3, wherein R ⁵ is a hydrogen atom or a linear or branched C _1-3 alkyl group. Following formula (3)

[Wherein, L ₁ represents a leaving group or a leaving atom, and X ¹ , R ¹ and coefficient a are the same as described in claim 1]
And a lactam compound represented by the following formula (4):

[Wherein L ₂ represents a leaving atom or leaving group, and R ² , coefficient b, X ² , R ³ , R ⁴ , and R ⁵ are the same as described in claim 1]
The method of manufacturing the lactam compound or its salt of Claim 1 by making the compound or its salt represented by these react.   A PPAR activator comprising the lactam compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.   The PPAR activator according to claim 6, which is an activator for activating at least one selected from PPARα, PPARγ, and PPARδ.   A pharmaceutical composition comprising the lactam compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof.   Prevention or treatment of diseases caused by abnormal metabolism of fatty acids, lipids or sugars and / or (ii) diseases caused by excessive intake of fatty acids, lipids or sugars compared to metabolism of fatty acids, lipids or sugars A preventive or therapeutic agent comprising the lactam compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.   The disease is a disease selected from the group consisting of arteriosclerosis, cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes, insulin resistant diabetes and obesity The preventive or therapeutic agent according to claim 9.