WO2009038204A1

WO2009038204A1 - Novel long-chain fatty acid derivative compound and g-protein-coupled receptor agonist containing the compound as active ingredient

Info

Publication number: WO2009038204A1
Application number: PCT/JP2008/067051
Authority: WO
Inventors: Gozoh Tsujimoto; Akira Hirasawa; Yoshiyuki Takahara; Tsutomu Toma; Hidefumi Ozawa
Original assignee: Pharma Frontier Co., Ltd.; Kowa Company, Ltd.
Priority date: 2007-09-17
Filing date: 2008-09-16
Publication date: 2009-03-26

Abstract

It is intended to provide a novel long-chain fatty acid derivative compound having an agonistic activity to GPR120 and GPR40. The long-chain fatty acid derivative compound of the invention is represented by the following general formula (I). In the formula, m+n means an integer of 20 or less, R means a hydrogen atom or an ester residue, Y1 and Y2 mean a halogen atom, the ring Q means a carbocyclic group or a heterocyclic group which may be condensed, X1, X2, and X3 mean a hydrogen atom, a halogen atom, or the like, W means -C(=N-OR1)-, -CH(NR2R3)- or -CH(N3)-. A medicament containing the long-chain fatty acid derivative compound as an active ingredient is effective as an appetite regulating agent, an antiobesity agent, a therapeutic agent for diabetes, a pancreatic beta cell proliferation and differentiation accelerator, a therapeutic agent for metabolic syndrome, a therapeutic agent for gastrointestinal diseases, a therapeutic agent for neuropathy, a therapeutic agent for psychiatric disorder, a therapeutic agent for lung diseases, a therapeutic agent for pituitary hormone deficiency, and a fat flavor seasoning.

Description

Description New long chain fatty acid derivative compounds and G protein-coupled receptor agonists containing these compounds as active ingredients

The present invention relates to a novel long-chain fatty acid derivative compound having an agonistic action on GPR 120 and Z or GPR 40, particularly a 2,2-dihaloalkanecarboxylic acid derivative compound, and these compounds or salts thereof The present invention relates to a G protein-coupled receptor (GPCR) having a fatty acid as an active ingredient as a ligand, more specifically to an agonist of GPR 120 and / or GPR 40, A pharmaceutical composition containing an agonist of type G receptor (GPCR) as an active ingredient, specifically appetite regulator, obesity inhibitor, diabetes therapeutic agent, spleen e-cell differentiation proliferation promoter, metabolic syndrome treatment The present invention relates to agents for treating gastrointestinal diseases, therapeutic agents for neurological disorders, therapeutic agents for mental disorders, therapeutic agents for lung diseases, therapeutic agents for pituitary hormone secretion deficiency, and lipid flavoring seasonings. Background art

GPR 120 and GPR 40 and their related molecules are known as G protein-coupled receptors (GPCR) having fatty acid as a ligand, and GPR 41 and GPR 40 are related molecules. GPR 4 2 etc. are known. The fatty acid receptor G P R 120 is present in the intestinal tract, lungs, brain, etc., and its expression is particularly prominent in the intestinal tract. GPR 1 2 0 is known to have 95% amino acid identity with the 1 4 2 7 3 receptor, which is a G protein-coupled receptor. When cells that have GPR 1 2 0 present in the intestinal tract act on fatty acids as ligands that activate GPR 1 2 0, glucagon-like peptide 1 (GLP-1), collagen tokinin (CCK) It is known to release intestinal hormone peptides such as.

These peptides control physiological functions related to feeding behavior, for example, insulin secretion from knee cells, spleen secretion from the spleen, bile secretion from the gallbladder, It controls appetite suppression. Therefore, by administering to the body a substance that activates the function of GPR 120, prevention and treatment of diabetes due to increased secretion of insulin, treatment of digestive insufficiency by promoting digestive secretion, obesity due to anorectic effect Prevention and treatment of this is conceivable. Furthermore, these peptides are centrally involved in the maintenance of nerve cells. In addition to the intestine, GPR 1 2 0 is present in the lung, pituitary gland, adipocyte and tongue, I am doing. It is presumed that the pituitary gland promotes secretion of pituitary hormones, the fat cells promote fat differentiation, the tongue contributes to taste, and the lungs contribute to lung cell protection.

Furthermore, fatty acid 1 4 2 7 3 (GPR 1 2 0 the same meaning) in I Ri intracellular C a ² + concentration rises to act, the intracellular c AM P generation suppression, activation of MA P kinase, adrenocorticotropic It has been known that suppression of stimulating hormone (AC TH) secretion, suppression of glycerol production from adipocytes, suppression of lipolysis, and the like occur (see, for example, WO 2004Z06 5 9 60). Therefore, it is also expected to be effective as a therapeutic agent for hypersecretion of glucocorticoid (cortisol) and adrenal and adrenal gland secreted by stimulation of ACTH from ACTH hypersecretion or adrenal gland .

Incidentally, the inventors of the present invention have unexpectedly analyzed the function of the GPCR gene GT 0 1 (GPR 1 2 0) polypeptide and identified compounds that act on the peptide. In addition, it is clear for the first time that GT 0 1 polypeptides are distributed on the surface of human intestinal secretory cells and have the function of promoting the secretion of CCK, which functions to control feeding. A compound that is a ligand for GT 0 1 polypeptide has been clarified. More specifically, a compound for a pharmaceutical composition for treating eating disorders is proposed, and examples of such compounds include force phosphonic acid, lauric acid, myristic acid, pentadecanoin. Acid, palmitic acid, stearic acid, araquinic acid, behenic acid, margaric acid, noremic acid, eicosatrienoic acid, elaidic acid, petrocerinic acid, oleic acid, linolenic acid Γ-linolenic acid, homo-γ-linolenic acid, arachidonic acid, eicosagenic acid, eicosatrienic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, eicosatratraic acid, vaccenic acid, etc. Fatty acids were proposed. (For example, see Japanese Patent Laid-Open No. 2 0 0 5-1 5 3 5 8)

— On the other hand, G P R 40 is a 9 9 9

It was discovered in 7 years, and subsequent studies revealed that the receptor was expressed in the kidney and the ligand was fatty acid, and free fatty acids such as oleic acid and linolenic acid acted on GPR 40 It was revealed that insulin secretion from the spleen / 3 cells was promoted. Therefore, a ligand that acts on GPR 40 is expected as a prophylactic / therapeutic agent with a new mechanism of action for diabetes. (See WO 2 0 0 3 0 6 8 9 5 9) On the other hand, the following compounds are known as fatty acid compounds useful as antidiabetic agents.

For example, Inoue et al. Have hypoglycemic action, plasma insulin lowering action, and triglyceride lowering action. Diabetes, diabetic complications, hyperlipidemia or arteriosclerosis The compounds represented by the following general formula, their salts, or their esters are reported to be effective for the prevention and / or treatment of diseases. (Refer to WO 2 0 0 4/1 0 3 9 4 6)

[Wherein m represents an integer from 0 to 4, n represents an integer from 5 to 9, W represents -CH (OR)-(R represents a hydrogen atom or a protecting group for a hydroxyl group) or -C ( = 0) _. In addition, Voss et al. Reported on an antidiabetic drug containing 2,2-dichloroalkanecarboxylic acid represented by the following general formula as an active ingredient. As an example, 12-Prom-2, 2- Dichloro-dodecanoic acid, 16-bromo-2,2-dic-mouth-hexadecanoic acid, 2,2-dichloro-12-cyano-dodecanoic acid, 2,2-dichloro-12-phenoxy-dodecanoic acid, 2 , 2-diglycol -12_ (4-dioxy-phenoxy) -fatty acid compounds such as dodecanoic acid. (See W0 1 9 9 6 Z 1 5 7 8 4)

CI

W-A'-B-A-C-COOH

I

CI

[Wherein A is an alkyl chain having 5 to 20 carbon atoms, A ′ is a covalently bonded biylene or acetylene group, or an alkyl chain having 1 to 10 carbon atoms, B is a covalent bond, A methylene group, sulfur, oxygen or NR ¹ ; W is a hexyl group, a phenyl group or the like which may be substituted with various substituents; ]

The above report has reported fatty acid compounds useful as antidiabetic drugs, and its action mechanism is basically based on PP AR a. It relates to force G protein-coupled receptor (GPCR). There is no description or teaching (Cardiovascular Drug Reviews, Vol.17, No.3, 246-264 (1999)). Disclosure of the invention

Problems to be solved by the invention

As described above, it was known that the secretion of glucagons like peptide-1 (GLP-1) that promotes secretion of insulin by stimulating free fatty acids is mediated by GPR120. However, GLP-1 hormone is degraded in the body in a short time, so it is difficult to use GLP-1 directly for treatment. It was true. Therefore, it is important to search and develop new ligand compounds that stimulate GPR 120 and promote GLP-1 secretion.

Furthermore, the biodistribution, function, and role of GPR 120 and / or GPR 40, which use fatty acids as ligands, have been known, but specific and effective agonist compounds (agonists) have been known. In particular, no agonist compound with excellent activity that can be expected to be put to practical use as a pharmaceutical has been proposed.

Accordingly, an object of the present invention is to provide a compound having excellent agonist activity with respect to GPR 1 20 and Z or GPR 40 having a fatty acid as a ligand, and further, such a compound is effective. Pharmaceutical composition as an ingredient, in particular an agonist, appetite regulator containing the agonist as an active ingredient, obesity inhibitor, diabetes mellitus, spleen J3 cell differentiation and proliferation promoter, metabolic syndrome therapeutic agent It is intended to provide a therapeutic agent for digestive system diseases, a therapeutic agent for neurological disorders, a therapeutic agent for mental disorders, a therapeutic agent for lung diseases or a pituitary hormone deficiency therapeutic agent, and a lipid flavoring seasoning. Means for solving the problem

As a result of searching for a new ligand that acts on GPR 40 that promotes insulin secretion from 3 cells, the present inventors have found that long-chain fatty acid derivative compounds such as aralkylcarboxylic acid compounds have excellent GPR The present invention was completed by finding that it has 40 agonist activity.

In addition, the present inventors have previously described that GPR 1 20 exists in the intestinal tract, lungs, brain, etc., so that cells possessing GPR 1 2 0 present in the intestine act on GPR 1 2 0 by fatty acids. As a result of further research on the basis of these findings, we found that intestinal hormone peptides such as glucagon-like peptide 1 (GLP-1) and collagen tokinin (CCK) are released. The present inventors have succeeded in finding a compound having an active activity and completed the present invention.

Specifically, the present invention provides a long-chain fatty acid derivative compound or a salt thereof such as an aralkyl carboxylic acid compound having excellent agonist activity with respect to GPR 120 and / or GPR 40, and , A pharmaceutical composition containing the compound as an active ingredient, in particular an agonist, and an appetite regulating agent containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient, an obesity suppressor, diabetes treatment Agent, knee i3 cell differentiation / proliferation agent, metabolic syndrome treatment agent, digestive disease treatment agent, neurological disorder treatment agent, mental disorder treatment agent, lung disease treatment agent, pituitary hormone secretion deficiency treatment agent and the compound Alternatively, it provides a lipid-flavored seasoning containing the salt as an active ingredient. Hereinafter, the present invention will be specifically described, but the present invention is not limited thereto.

1. A long-chain fatty acid derivative compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. C00R (I)

[Where

m means an integer from 0 to 6;

n means an integer from 5 to 20;

m + n means an integer of 20 or less;

R represents a hydrogen atom or an ester residue;

Y ¹ and Y ² are the same or different halogen atoms,

Ring Q means a carbocyclic group which may be condensed or a heterocyclic group which may be condensed;

X ^1, X ² and X ³ are the same or different and each is a hydrogen atom, a halogen atom, C ₄ alkyl groups, C〗 - ₄ alkoxy groups, C ₄ alkyl sulfonyl group, a halo C - ₄ alkyl group , a nitro group, an amino group, a hydroxyl group, Shiano group, a mercapto group, - ₄ alkylthio group, sulfonamide de group, Asechirua amino group, C j ₆ alkylamino group, current events ₁ - ₆ alkylamino group, carboxy group, Ariruokishi A group, an aryl group, an aralkyl group, a benzoyl group, a carboxy Ci ₄ alkyl group, an oxo group, a methylenedioxy group, an ethylenedioxy group or an acetoxy group;

W represents —C (= N—OR ¹ ) —, —CH (NR ² R ³ ) — or —CH (N ₃ ) —; R ¹ represents a hydrogen atom or a C ₆ _6 alkyl group ;

R ² and R ³ are the same or different and each is hydrogen atom, C i_ ₈ alkyl group, Ararukiru group, § Rino Rea Honoré Ke group, § reel alkynyl group, SO

₂ R ⁴ (wherein R ⁴ represents an alkyl group, an aryl group or an aralkyl group), C OR ⁵ (R ⁵ represents a C ₆ alkyl group, an aryl group, an aralkyl group or an arylalkylene Or a saturated heterocycle having at least one nitrogen atom formed by R ² and R ³ together with the adjacent nitrogen atom.

Here, the alkyl group may be substituted with 1 to 3 identical or different substituents selected from Group A below. Aralkyl group, The rukenyl group and the allylalkynyl group may be substituted with 1 to 3 identical or different substituents selected from the following group B.

!! Halogen atom, a hydroxyl group, ₆ alkoxy group, amino group, C, _ ₆ alkylamino group, di C - 6 Anorekiruami amino group, a carbonyl group, C - ₆ alkoxy carbonyl group, Shiano group and Ashiru group;

Halogen atom, hydroxyl group, Ji, - ₆ alkoxy groups, C - 6 alkyl group, Amino groups, C i ₆ alkylamino group, current events - ₆ alkylamino group, a carbonyl groups, C〗 ₆ alkoxycarbonyl group, Shiano group and Ashiru Group;

R ² and X ¹ may be combined with the adjacent ring Q to form a condensed ring. 2. Y ¹ and Y ² are both chlorine atoms, and ring Q is an aromatic carbocyclic group that may be condensed, a saturated carbocyclic group that may be condensed, or an aromatic heterocycle that may be condensed. 2. The long-chain fatty acid derivative compound or the pharmaceutically acceptable salt thereof according to 1 above, which is a cyclic group or a saturated heterocyclic group which may be condensed.

3. The long-chain fatty acid derivative according to the above 2, represented by the following general formula (Π), wherein ring Q is a phenyl group or a C _{3 8} cycloalkyl group, and R is a C-6 alkyl group: Its acceptable salt.

2 2) No m (CH ₂ ) _n — C-C00R

(Herein, ring Q ′ means a phenyl group or a C ₃ ₈ cycloalkyl group.) 4. The ring Q is a phenyl group, and R is a hydrogen atom, and is represented by the following general formula (III) 4. The long-chain fatty acid derivative compound or the pharmaceutically acceptable salt thereof according to 3 above, which is a 2,2-dic-mouth alkanecarboxylic acid derivative.

(Here, x means a halogen atom.)

5. The long-chain fatty acid derivative compound or the pharmaceutically acceptable salt thereof according to any one of 1 to 4 above, wherein R ² is a hydrogen atom. m is 0,

n is an integer from 6 to 1 4

W ^{is, - C (= N- OR 1} ) -, - CH (NR 2 R 3) - or - CH (N ₃₎ - a and, R 'force ^s, a hydrogen atom,

R ² is a hydrogen atom,

R ³ is a C ₆ alkyl group, an aralkyl group, an aryl alkenyl group, a C- ₆ alkylsulfonyl group, SO ₂ R ⁴ (where R ⁴ represents a C ₆ alkyl group, an aryl group, or an aralkyl group. Or COR ⁵ (R ⁵ represents a C j ₆ alkyl group, an aryl group, an aralkyl group, or an arylalkenyl group.)

6. The long-chain fatty acid derivative compound or the pharmaceutically acceptable salt thereof according to any one of 1 to 5 above, wherein X ¹ , X ² and X ³ are the same or different and each is a hydrogen atom or a halogen atom .

2. The long-chain fatty acid derivative compound or the pharmaceutically acceptable salt thereof according to 1 above, wherein the long-chain fatty acid derivative compound is a 2,2-diglycol carboxylic acid derivative selected from the following compound group.

(1) 12-acetamido-2,2-dimethyl mouth-12- (4-chlorophenyl) methyl dodecanoate,

(2) 12-acetamido-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid, (3) 2,2-dichloric acid- 12- (4-distal Mouth phenyl) -12-propanamide methyl dodecanoate,

(4) 2, 2-Dimethyl Mouth -12- (4-Chlorophenyl) -12-propanamide dodecanoic acid,

(5) 12-butanamide-2, 2-dimethyl mouth-12- (4-chlorophenyl) methyl dodecanoate,

(6) 12-butaneamide-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid,

(7) 2,2-dichloro-12- (4-chlorophenyl) -12- (3-methylbutane amide) methyl dodecanoate,

(8) 2,2-dichloro-12- (4-chlorophenyl) -12- (3-methylbutane amide) dodecanoic acid,

(9) 2,2-Dichloro-12- (4-chlorophenyl) -12-ethylaminododecanoate methyl;

(10) 2, 2 -dichloro-12- (4-chlorophenyl) -12-ethylaminododecanoic acid,

(11) 2,2-Dichloro-12- (4-chlorophenyl) -12-propylaminododecanoic acid methyl ester,

(12) 2,2-Dichloro-12- (4-chlorophenyl) -12-propylaminododecanoic acid, (13) 2, 2-dioctyl 12- (4-diphenyl) -12- (3-methylbutylamino) methyl dodecanoate,

(14) 2, 2-Diglycol-12-(4-Dimethyl)-12- (3-Methylbutylamino) dodecanoic acid,

(15) 12-benzamido-2,2-dimethyl oral- 12- (4-chlorophenyl) methyl dodecanoic acid,

(16) 12-Benzamide-2, 2-Dimethyl Mouth- 12- (4-Chlorophenyl) Dodecanoic acid,

(17) 12-Benzylamino-2,2-dimethyl -12- (4-chlorophenyl) methyl dodecanoate,

(18) 12-Benzylamino-2,2-dichloro-12- (4-chlorophenol) Dodecanoic acid,

(19) 12- (4-Chlorophenyl) -2,2-dioxymethyl- 12-cinnamamide methyl dodecanoate,

(20) 12- (4-phenyl) _2,2-dichloro-12- (3-phenylpronamide) methyl dodecanoate,

(21) 12_ (4-Mouth Mouth Feninore) — 2, 2—Dict Mouth Mouth- 12— (3-Fuel Pro-Nano-amide) Dodecanoic acid,

(22) 12- (4-chlorophenyl) -2,2-dichloro-12-methanesulfonamide methyl decanoate,

(23) 12- (4-chlorophenol) -2,2-dichloro-12-methanesulfonamide dodecanoic acid,

(24) 12- (4-mouth mouth phenyl) — 2, 2-dic mouth mouth mouth- 12-hydroxymethyl dodecanoate,

(25) 12- (4-mouth mouth phenyl) -2, 2-dic mouth mouth-12-hydroxyminododecanoic acid,

(26) 12-Azido-12- (4-chlorophenyl) -2, 2_ Dimethyl Methyl dodecanoate,

(27) 12-azido-12- (4-chlorophenyl) -2,2-dichlorododecanoic acid,

(28) 12- (4-chlorophenol) -2, 2-dichloro- 12- (4-tonoleens norephone amide) methyl dodecanoate, and

(29) 12- (4-Neck Mouth Feninore) — 2, 2-Digit Mouth Mouth — 12— (4-Tonoresnorehonamide) Dodecanoic acid.

2, 2-dichloroalkanecarboxylic acid derivatives

(2) 12-acetamide—2, 2-dichloric acid mouth- 12- (4—chlorofluorocarbonic acid) dodecanoic acid, (4) 2,2-dichloro-12- (4-chloroalphing) (Phenyl) -12-propaneamide dodecanoic acid. (6) 12-Butaneamide-2, 2-Dichloromethane-12- (4-Chlorophenyl) dodecanoic acid, (8) 2, 2-Dicyclohexane Mouth-12- (4-chlorophenyl) -12- (3-methylbutanamide) Decanoic acid,

(10) 2,2-Dichloro-12- (4-Clorophenyl) -12-Ethylamino-dodecanoic acid, (12) 2,2-Dichloro-12- (4-Croix Phenyl) -12-propylaminododecanoic acid,

(14) 2,2-Dichloro-12- (4-chlorophenol) -12- (3-methylbutylamino) dodecanoic acid,

(16) 12-benzazamid-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid,

(18) 12-Benzylamino-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid,

(21) 12- (4-Chlorophenyl) -2,2-Dichloro-12— (3-Phenylprono, Namido) Dodecanoic acid,

(23) 12- (4-chlorophenol) -2,2-dichloro-12-methanesulfonamide decanoic acid,

(25) 12- (4-chlorophenol) -2, 2-dichloro-12-hydroxyminododecanoic acid,

(27) 12-Azido- 12- (4-Clorophenyl) -2, 2-Dichlorododecanoic acid, or (29) 12- (4-Clorophenyl) -2, 2- Dike Mouth -12- (4-Toluenesulfonamide) Dodecanoic acid

8. The long-chain fatty acid derivative compound or the pharmaceutically acceptable salt thereof according to 7 above.

2, 2-dichloroalkanecarboxylic acid derivatives

(1) 12-acetamido-2,2-dichloro-12- (4-cyclophenyl) methyl dodecanoate,

(3) 2,2-Dimethyl Mouth- 12- (4-Mix Mouth Phenyl) -12-Propanamide Methyl Dodecanoate,

(5) 12-Butamide-2,2-Dimethyl Mouth-12_ (4-Chlorophenyl) methyl dodecanoate,

(7) 2, 2-Dioctyl chloride-12- (4-Crofolyl) -12- (3-Methylbutaneamide) Methyl dodecanoate,

(9) 2,2-Dimethyl-- 12- (4-Dimethyl-, 2-phenyl) -Methyl 12-ethylamino dodecanoate,

(11) Methyl 2,2-diglycol-12- (4-chlorophenyl) -12-propylaminododecanoate,

(13) 2,2-Dichloro-12- (4-chlorophenyl) -12- (3-methylbutylamino) methyl dodecanoate, (15) 12-benzamide-2,2-dimethyl oral-12- (4-chlorophenyl) methyl dodecanoic acid,

(17) 12-Benzylamino-2,2-dichloro-12- (4-chlorophenol) methyl dodecanoate,

(19) 12- (4-chlorophenol) -2,2-dichloro-12-cinnamamide methyl dodecanoate,

(20) 12- (4-chlorophenyl) -2,2-dichloro-12- (3-phenylpropaneamide) methyl dodecanoate,

(22) 12- (4-chlorophenol) -2,2-dichloro-12-methyl methanesulfonamide dodecanoate,

(24) 12- (4-chlorophenyl) -2,2-dichloro-methyl 12-hydroxyminododecanoate,

(26) 12-Azido-12- (4-chlorophenyl) -2,2-dichlorododecanoic acid methyl ester, or

(28) 12- (4-Clorophenyl) -2,2-dichloro-12- (4-Toluenesulfonamide) Methyl dodecanoate

0. G protein-coupled receptor (GPCR) using as a ligand a fatty acid containing as an active ingredient the long-chain fatty acid derivative compound according to any one of 1 to 9 above or a pharmaceutically acceptable salt thereof ) Agonist.

1. The G protein-coupled receptor agonist according to 10 above, wherein the G protein-coupled receptor (GPCR) force G P R 120 is the same.

2. The G protein-coupled receptor agonist according to the above 10, wherein the G protein-coupled receptor (GPCR) force is GPR 40.

3. A pharmaceutical composition comprising the long-chain fatty acid derivative compound according to any one of 1 to 9 above or a pharmaceutically acceptable salt thereof as an active ingredient.

4. Appetite regulator, anti-obesity agent, diabetes treatment or prevention agent, spleen β-cell differentiation and proliferation promoter, metabolic syndrome treatment agent, digestive system disease treatment or prevention agent, neuropathy treatment or prevention agent, 13. The pharmaceutical composition according to the above item 12, which is a psychiatric disorder therapeutic agent or preventive agent, a pulmonary disease therapeutic agent or prophylactic agent, or a pituitary hormone secretion deficiency therapeutic agent.

5. A lipid flavor seasoning containing the long-chain fatty acid derivative compound or salt thereof according to any one of 1 to 9 as an active ingredient. The invention's effect

The long-chain fatty acid derivative compound of the present invention or a pharmaceutically acceptable salt thereof, in particular, a 2,2-dicycloalkanecarboxylic acid derivative or a pharmaceutically acceptable salt thereof is a G protein conjugate having a fatty acid as a ligand. Has excellent agonist activity against type receptor (GPCR), especially GPR 1 20 and Z or GPR 40. Therefore, the compound of the present invention can release intestinal hormone peptides such as glucagon-like peptide 1 (GLP-1) and collagen tokinin (CCK) by acting on GPR 1 2 0, and an appetite regulating agent. Anti-obesity agent, diabetes treatment agent, spleen i3 cell differentiation and proliferation promoter, metabolic syndrome treatment agent, digestive disease treatment agent, neuropathy treatment agent, mental disorder treatment agent, lung disease treatment agent and pituitary hormone secretion It is effective as a therapeutic agent for insufficiency.

It also has excellent agonist activity against GPR 40, so it is expected to be a prophylactic / therapeutic agent that promotes insulin secretion from kidney β-cells and has a new mechanism of action for diabetes. The

Thus, GPCR agonists having these long-chain fatty acid derivative compounds or pharmaceutically acceptable salts thereof, particularly 2,2-dicycloalkanecarboxylic acid derivative compounds as ligands, more specifically GPR 12 0 agonist, GPR 40 0 agonist is a new device for diseases involving GP R12 0 and / or GPR 40, especially for diseases caused by abnormal physiological functions via GP R12 0 and Ζ or GPR 40 It is expected to be a pharmaceutical product based on the introduction, specifically, appetite regulator, obesity suppressor, diabetes treatment agent, spleen] 3 cell differentiation and proliferation promoter, metabolic syndrome treatment agent, digestive system disease treatment agent, nerve It is effective as a disorder treatment agent, a psychiatric disorder treatment agent, a lung disease treatment agent and a pituitary hormone secretion deficiency treatment agent. In addition, since GPR 1 2 0 is involved in taste, it is expected to be effective as a lipid flavor seasoning.

Brief Description of Drawings

FIG. 1 is a diagram showing the results of a ligand screening of GP R 40 according to ER ツ Atsei in Test Example 1 for the long-chain fatty acid derivative compound according to the present invention.

Figure 1 shows the results of total ERK detection by Western blotting when test compounds were stimulated using cell line TXGPR 40, and Figure 1B shows the results when compounds were stimulated using cell line TXGPR 40. An example of the detection result of phosphorylated ERK by a Western blot is shown, and Fig. 1C shows the result of digitizing and banding the band of Fig. 1B.

Figure 2 shows ERK assembly using cell line TXGPR 40 in Test Example 1. FIG. 5 is a graph showing the results of the GPR 40 screening screen by FIG. 3 is a graph showing the results of comparing the ERK activity of each compound using the cell line TXGPR 1 20. Figure 3A shows an example of the total ERK detection result by Western blotting when stimulating the test compound using the cell line TXGPR 120, and Figure 3B uses the cell line TXGPR 120. Fig. 3C shows an example of the detection result of phosphorylated ERK by Western blotting at the time of stimulation of the test compound. Fig. 3C shows the result of quantifying and graphing the band of Fig. 3B.

FIG. 4 is a graph showing the results of ligand screening of GP R 120 using the ERK assay using the cell line TX GP R 120 in Test Example 1.

BEST MODE FOR CARRYING OUT THE INVENTION

The long-chain fatty acid derivative compound of the present invention has the following structural formula (I):

[Where

m means an integer from 0 to 6;

n means an integer from 5 to 20;

m + n means an integer of 20 or less;

R represents a hydrogen atom or an ester residue;

Y ¹ and Y ² are the same or different halogen atoms,

Ring Q means a carbocyclic group which may be condensed or a heterocyclic group which may be condensed; X ¹ , X ² and X ³ are the same or different and each represents a hydrogen atom, a halogen atom, C!- 4 alkyl group, C〗 - ₄ alkoxy groups, C i ₄ alkylsulfonyl group, Nono b C] ₄ alkyl group, nitro group, amino group, hydroxyl group, Shiano group, Melka script group, C, _ ₄ alkylthio group, Sulfonamide group, acetylamino group,

_ ₆ alkylamino group, di Ci-e alkylamino group, carboxy group, aryloxy group, aryl group, aralkyl group, benzoyl group, carboxy C j

— ₄ means an alkyl group, an oxo group, a methylenedioxy group, an ethylenedioxy group or an acetoxy group;

W ^{is, - C -N- OR 1) -} - CH (NR 2 R 3) - or - CH (N ₃₎ - means; R ¹ is hydrogen atom or a C〗 - means an _alkyl group;

R ² and R ³ are the same or different and each represents a hydrogen atom, a Ci ₈ alkyl group, Aralkyl group, aryl alkenyl group, aryl alkynyl group, one so ₂

R ⁴ (wherein R ⁴ represents a C i- ₆ alkyl group, an aryl group or an aralkyl group),-COR ⁵ (R ⁵ represents.)-6 alkyl group, aryl group, aralkyl group or Or a saturated heterocycle having at least one nitrogen atom formed by R ² and R ³ together with the adjacent nitrogen atom.

Here, the alkyl group may be substituted with 1 to 3 identical or different substituents selected from Group A below. In addition, the aralkyl group, the arylalkylene group, and the arylalkylinyl group may be substituted with 1 to 3 identical or different substituents selected from the following group B.

Halogen atom, hydroxyl group, di-]- ₆ alkoxy group, amino group, C- ₆ alkyl amino group, di-, ₆ alkylamino group, carbonyl group, Ci- ₆ alkoxy carbonyl group, cyano group and acyl group;

Group B>

Halogen atom, hydroxyl group, C - ₆ alkoxy group, 〇〗 - ₆ alkyl group, Amino group, c〗 - ₆ alkylamino amino group, current events ₁ - ₆ alkylamino group, a carbonyl group,

C j — ₆ alkoxycarbonyl group, cyano group and acyl group;

R ² and X ¹ may be combined with the adjacent ring Q to form a condensed ring. In addition, the meaning of terms in the present invention is as follows.

“ _6- alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butinole, isobutinole, s —butinole, t—butinole, pentinore, isopentinole, 2—methinolebutinole, neopenti / les, 1-ethinolepropinore, hexinole, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 Methylenopentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1 monodimethylbutynole, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1 monoethylbutyl Or 2-Ethylbutyl group.

Preferred is a C ₄ _4 alkyl group.

- ₈ alkyl group "means a straight chain or branched alkyl Le group having 1 to 8 carbon atoms, the C, - in addition to the ₆ alkyl group, and the like heptyl or Okuchiru group it can.

The - "C ^ ₄ alkyl group" means a straight chain or branched alkyl Le group having 1 to 4 carbon atoms, e.g., methyl, Echiru, propyl, isopropyl, butyl , Isobutyl, S-butyl or t-butyl group.

The “halogen atom” is a fluorine, chlorine, bromine or iodine atom, preferably a chlorine atom.

The preferred halogen atom in Y] and Y ² is a chlorine atom, and the preferred halogen atom in XX ² and X ^{3 and} the preferred halogen atom in group Α and group B are chlorine, fluorine or bromine atoms.

“Ci- ₆ alkoxy group” means a C _1-6 alkoxy group whose alkyl moiety is a linear or branched “., — 6 alkyl group” as defined above, For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, Hexinoreoxy, 4-methylenopentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethyl Butoxy or 2,3-dimethylbutoxy group.

A C- ₄ alkoxy group is preferred.

The ". Alkoxy group", the alkyl moiety is intended to mean a linear or branched "C] _ ₄ alkyl group" having 1 to carbon atoms is a four Arukiruokishi group as defined above, for example, main butoxy , Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or t-butoxy group.

The - "C! ₄ alkylthio group", the "C -! ₄ alkyl group" represents a binding combined group to a sulfur atom, such as methylthio, Echiruchio, propylthio, iso-propylthio, butylthio, isobutylthio, S - butylthio Or a linear or branched alkylthio group having 1 to 4 carbon atoms such as t-butylthio group.

"Halo C, - ₄ alkyl group" and, 1 to 9, preferably "Ji - ₄ alkyl group" having 1 to 3 of the aforementioned definition of "halogen atom" substituted as defined above is.

Specifically, trifluoroleolomethyl, 2-funoleolethyl, 2-chloroethinole, 2-bromoechinole, 3—funoleo oral propinole, 3—black oral propinole, 4 monofluorobutyl, 4 —chlorobutyl, 2, 2, 2—tri Examples include phenol, 3,3,3-trifluoropropyl, 4,4,4 trifluorobutyl, pentafluoroethyl, or 2,2,2-trifluoroleol 1—trifluoromethylethyl, and the like. . Preferred is a trifluoromethyl group. “C _4, —4 alkylsulfonyl group” means a straight or branched anolalkylsulfonyl group having 1 to 4 carbon atoms, such as methylesnorehoninole, ethinolesulphoninole, propinolesnorehoninole, It is a group of ipropronolesnorehoninore, butinolesnorehoninore, isobutinoresnorehoninore, s-butylsenorehoninore or t-butinoresnorehoninore.

The - "C! ₆ alkoxycarbonyl group" means a straight or branched alkoxy group is bonded to a carbonyl group having 1 to 6 defined above carbon atoms, if example embodiment, main butoxycarbonyl, Etoxycanonbonyl, propoxycanonboninole, isopropoxycanonboninole, butoxycarbonyl, isobutoxycarbonyl, s —butoxycanononole, t —butoxycanonbonyl, pentyloxycanolebonyl, isopentyl Xicanolenobonil, 2-Methylbutoxynorebo Ninore, Neopentinorexicanoreboninole, 1—Ethenorepropoxynoreboninore, Hexinorexanoreboninore, 4—Metinorepentinorexinoreboninore , 3 — methylpentyloxycanoleboninole, 2 — methylpentyloxycar Nyl, 1-Methylenopentinorexicanoreboninole, 3, 3 —Dimethenolev Toxicanorepo Ninore, 2,2-Dimethylbutoxycarbonyl, 1,1-Dimethylenobutoxycarbonyl, 1,2-Dimethinolevoxycarbonyl, 1,3 — Dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl or 2-ethylbutoxycarbonyl group. Suitably Ri _ ₄ alkoxycarbonyl der, even more preferably a main butoxycarbonyl or e butoxycarbonyl group. The - "carboxy C ₁ ₄ alkyl group", which carboxy group has been substituted with a linear or branched alkyl group having 1 to 4 carbon defined above carbon, for example, Kano levo alkoxy methylol Honoré, 1—Canoleboxi Chichinole, 2—Forced Boxechinore, 1—Carboxypropyl, 2—Carboxypropyl, 3—Carboxypropyl, 2—Forced Revoloxy 1-Methinoreethinore, 1 1 Carboxybutyl, 2—force noroxybutyl, 3—canoleoxybutyl, 4 monocarboxybutynole, 1—force norboxy 2—methylpropyl, 2—carboxy-1-propyl, 3-carboxy-2-methylpropyl, etc. Can be mentioned.

"C, - ₆ alkylamino amino group" refers to one that is defined above - means "C〗 ₆ alkyl Le group" in the substituted amino group, for example, Mechiruami Roh, Echirua Mi Bruno, pro Pyramino, Isopropyramino, Butylamino, Isobutylamino, s —Butylamino, t-Butylamino, Pentylamino, Isobentilamino, 2 —Methylbutamino, Neopentylamino, 1 —Etenorepro Pyramino, hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino,

1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-di Mono, such as methyl butylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino or 2-ethylbutylamino groups is a ₆ Arukirua amino groups - one C ^. Preferably a mono- C! _ ₄ alkylamino group.

The “di-C ₆ —alkylamino group” means an amino group substituted with two identical or different r C j —e-alkyl groups as defined above, for example, dimethylamino, jetylamino, N 1 -ethylo N-methylamino, dipropylamino, dibutylamino, dipentylamino or dihexylamino groups such as di-Ci- ₆ alkylamino groups. Preferably, di - C - a ₄ alkyl Noreamino group, more preferably a di one C〗 - a ₂ alkylamino group.

“Aryl group” means an aromatic hydrocarbon group having 6 to 14 carbon atoms, for example, phenylol, naphthyl, antrinol, indenolinol, azulenyl, fluorenyl or phenanthryl. Group. Preferably, it is a phenyl group.

And "Ararukiru group", 1 to 3 forces the number 6 to 1 4 of the aforementioned Ariru group having a carbon - group bonded to "C〗 ₆ alkyl group", for example, benzyl, alpha - Nafuchinoremechiru, jS —Naphthylmethinore, Indeninolemethinore, Difueninoremethinore, Trifueninoremethinore, 1 —Fueninore, 2-Fueninore, 1-Naftinoreethinore, 2—Naftinorenocinore, 1_Fueninorepro pinole, — Hue Ninorepro pinole, 3—Phenylpropyl, 1—Naphthinorepro pinole, 2-Naphtinorepro pill, 3-Naphtinorepro pill, 1—Fuenolebutyl, 2-Fuenino levenore, 3-Fuenylbutyl, 4-Fuenylbutynobutyl 2—Naphtyl butyl, 3_Naphtyl butyl, 4—Naphthino butyl, 1 Norre 'pentyl, 2 monounsaturated Eninorepenchiru, 3 - full et two Rupenchiru, 4

—Phenenorepentyl, 5 1-Phenenorepentyl, 1 1-Naphthylpentyl, 2 1-Naphthinolenopentyl, 3 1-Naphthinorepentyl, 4 1-Naphthylpentyl, 5 1-Naphthylpentyl, 1 —Phenino \ xyl, 2 1-Pheninole \ Xyll, 3

—Fueninore \ Xyl, 4 monophenyle \ xil, 5 —Phenyl \ xyl, 6

—Fuenole xyl, 1 naphthinole ^ \ xyl, 2 1 naphthyl \ xyl, 3 1 naphthyl \ xinole, 4 -naphthynole \ xyl, 5 -naphthyl \ xyl, 6 —naphthylhexyl, etc. Preferably, it is a aralkyl group in which the aryl group is a phenyl group or a naphthyl group and the alkyl group is a C- ₄ alkyl group, such as a benzyl group, a naphthylmethyl group, a diphenylmethyl group, or a phenethyl group, and more preferably A benzyl group or a phenethyl group, particularly preferably a benzyl group.

The “aryloxy group” means a group in which the “aryl group” is bonded to an oxygen atom, such as phenyloxy, indenyloxy, naphthyloxy, It is an aromatic hydrocarbon oxy group having 6 to 14 carbon atoms such as phenanthrenelinoxy, anthracenyloxy or phenoleorenyloxy group, and is preferably a phenyloxy or naphthyloxy group.

The "§ reel alkenyl group", the "Ariru group" C ₂ - means a group attached to the ₆ alkenyl group. Here, - a "C ₂ ₆ alkenyl group", Hetu Honoré, 1 - propenyl Ninore, 2-propenyl Ninore, 1 one Buteninore, 2 Buteninore, 3 - butene two shift, 2- Mechinore 1 one pro Peninole, 1 1 Penteninore, 2—Penteninore, 3 —Penteninore, 4 —Penteninore, 3 —Mechinolere _ 2 —Buteninole, 1 Xeninole, 3—Hexeninore, 2, 4 Xagenil or 5 — It means a linear or branched alkenyl group having 2 to 6 carbon atoms having one double bond such as hexenyl. Suitable “aryl alkenyl” groups include, for example, styrinole, 3 — phenenolepronone 1 — 1-nore, 4 — phenenolepronone 3 — hen 1 — inore, 5 — Eninorev. Nonone 4 —Yen1 1 —Yinole, 6 —Fuenore Pro Noh1 5 —Yen1 1 —Inole, Naftinoreetenorre, 3 —Naphthylpropane 1 2 —Yen 1 —Yil, 4 1 Naftino Leprono. Down one 3-E down one 1 - I le, 5 - naphthyl propane one 4 one En 1 I le, 6 - naphthoquinone Chirupuropan one 5 - En 1 - Inore naphthoquinone Chino milled by wet tennis Honoré, 3 Nafuchirupu b Nono ⁰ down one 2 —Yen 1 —Inole, 4 —Naftino Lepro 1 3 —Yen 1 —Nole, 5 —Naftino Leprono ⁰ 4 —Yen 1 —Inole, 6 —Naftino Lepro Non _ 5 _ 1—Inole, anthritol, indenoleureth, azulenyl ethenole, funoleoreno noetule or phenanthrene ethenore group.

The "§ reel alkynyl group", the "Ariru group" force S - means bonded groups in the "C ₂ ₆ alkynyl group". Here, "C ₂ _ ₆ alkynyl group", E Chul, 1 _ pro Bulle, 2-pro Bulle, 1 Buchininore, 2 Buchuru, three to Buchininore, 1 Penchuru, 2 _ pentynyl, 3-pentynyl 4 1-penti 2-norle, 1-hexinole, 2-hexinole, 3-hexinole, 4-hexinole, 5-xinyl, etc., straight or 2 to 6 carbon atoms with one triple bond A branched alkynyl group is meant. Suitable "C ₂ _ ₆ alkynyl group", for example, Hue Nino milled by wet Hee Honoré, 3 - phenylene Norepuropan one 2 - Lee emissions _ 1 - I le, 4 - full Eninorepuro Nokun one 3 - Lee down one 1 Inore , 5 — Huenino Lev. Russia Roh down one 4 - Lee down one 1 - Inore, 6 - Hue two Norepuronoヽ⁰ down one 5 - in one 1 Inore, naphth Noreechininore, 3-Nafuchinorefu. B Nono ° down one 2-i down one 1 Inore, 4 Nafuchinore Puronoヽ⁰ down one 3 - Lee down one 1 - I le, 5 - Nafuchirupuro Nokun one 4 - In one 1 one I le, 6 - Naphthyl Pro None 5 —In 1 Nyl, Intrile Tulle, Indenino Letuenore, Azlenino Leteninore, Funoleoreno Leno Tuenole or Fu Such as the Enantry Rütül group.

The "Ashiru group", saturated or unsaturated hydrocarbon group is optionally branched and bonded to a carbonyl group C ₂ - that means the ₇ aliphatic Ashiru group, or an aromatic Ashiru group. Aliphatic acyl groups include, for example, acetyl, propionyl, butyrinole, isobutyrinole, no-relinole, isonole-relinole, pinole-leunole, hexanoinore, acryloyl, meta-cyl-royl, or cucumber tonoyl. Groups and the like. Aromatic acyl groups include benzoyl, α-naphthoyl, and arylenocarbonyl groups such as 3-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl groups. 1, 4, 4, 6-trimethylbenzoyl or 4 lower toluene alkyl group such as 4-toluoyl group, 4-nitrobenzoyl group, nitrogen such as 2-nitrobenzene group Aryloylcarbonyl group, 2- (methoxycarbonyl) benzoyl group such as aralkoxy carbonyl carbonyl group, aryl carbonyl group such as 4-phenyl benzoyl group, etc. Can be mentioned.

The - "C ₃ ₈ cycloalkyl group", Kishinore number 3 to 8 carbon, and preferably 5 to 7 saturated cycloalkyl group, specifically, cyclopropyl, Shikurobu Chinore, cyclopentyl, cyclohexylene, cycloheteroalkyl Heptyl and cyclooctyl groups. These cycloalkyl groups may contain one or two, preferably one double bond. Examples of such “cycloalkenyl groups” include cyclopropenenole, cyclobuteninole, cyclopenteninole, cyclopenteninole, cyclohexeninole, cyclohexagenyl (2,4-cyclohexanone 1-inore or 2 , 5 -cyclohexadiene 1 -yl group, etc.), cycloheptyl group and cyclooctyl group.

Further, these cycloalkyl groups may be condensed with other cyclic groups such as a benzene ring or a heterocycle, such as indanyl, tetrahydronaphthyl, benzocycloheptyl, or 5, 6, 7, 8 It is a Trahidroy soquinolyl group.

The “carbocyclic group” in “optionally condensed carbocyclic group” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 14 carbon atoms, specifically, the aryl group, A cycloalkyl group and a cycloalkenyl group, and these “carbocyclic groups” may be condensed carbocyclic groups condensed with carbocyclic or heterocyclic rings.

Examples of the “condensed carbocycle” obtained by condensing these “aryl group”, “cycloalkyl group”, and “cycloalkenyl group” include, for example, indenyl, indanyl, 1,4-dihydranaphthyl, 1, 2, 3 , 4 — Tetrahi Dronaftil (1, 2, 3, 4 -tetrahydrone 2-naphthyl, 5,6,7,8 -tetrahydr 2-naphthyl group, etc.) and perhydronaphthyl group.

An aryl group and a cyclyl alkyl group are preferable, and a phenyl group, a biphenyl group, a cyclohexyl group, and the like are more preferable. The “heterocyclic group” in the “heterocyclic group that may be condensed” means at least one selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom, preferably 1 to 4 hetero atoms. Saturated or unsaturated (including partially unsaturated and fully unsaturated) monocyclic 5-membered or 7-membered heterocycles, condensed rings of these heterocycles, or the heterocycles and benzene, It means a condensed ring with a carbocyclic ring selected from cyclopentane and cyclohexane.

Here, “monocyclic saturated heterocyclic group” includes pyrrolidinyl, tetrahydrodrolinole, tetrahydrodrochenyl, imidazolidinyl, virazolidinyl, 1,3-dioxanyl, 1,3-oxathiolanyl , Oxazolidinyl, thiazolidinyl, piperidinyl, piperidino, piperazur, piperazino, tetrahidrobiranyl, tetrahidrothobiranyl, dioxanyl, morpholinyl, thiomorpholinyl, 2-dioxopyridinopi Or 2, 6-dioxopiperidinyl group, etc.

In addition, “unsaturated monocyclic heterocyclic groups” include pyrrolyl, furyl, chenyl, imidazolinole, 1,2-dihydrol-2-oxoyl imidazolyl, virazolinole, diazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, 1, 2, 4 — Triazolyl, 1, 2, 3— Triazolinole, Tetrazolyl, 1, 3, 4, 1 Oxadiazolyl, 1, 2, 4 — Oxadiazolyl, 1, 3, 4 — Thiadiazolyl, 1, 2, 4 — thiadiazolyl, flavanyl, pyridyl, pyrimidinyl, 3, 4-dihydrol 4 — oxopyrimidinyl, pyridazinyl, pyrajul, 1, 3, 5 — triazinyl, imidazolinyl, virazolinyl, oxazolinyl (2 — oxazolinyl, 3-Oxazolinyl, 4-Oxazolinyl group), Isoxazolini , Thiazole Riniru, Lee Sochiazoriniru, Biraniru, 2- Okisobiraniru, 2 Okiso - 2, 5 - dihydric Dorofuraniru or 1, 1 - Jiokiso can be exemplified an 1 H- Isochiazori Le group.

In addition, “heterocyclic group that is a condensed ring” includes indyl (eg, 4-indolyl, 7-indolyl group, etc.), isoindolyl, 1,3-dihydro — 1, 3 —Doxoisoinyl drill, benzofuranyl (eg, 4-benzofuranyl, 7-benzofuranyl group, etc.), indazolinole, isobenzofuranyl, benzothiophenyl (eg, 4-benzothiophenyl, 7-ben Zothiophenyl group and the like. ), Benzoxazolyl (for example, 4-benzoxazolyl, 7-benzoxazolyl group, etc.), benzimidazolyl (for example, 4_benzimidazolyl, 7-benzimidazolyl, etc.), benzothiazolinol (for example, , 4 monobenzothiazolyl, 7—benzothiazolyl group, etc.), indolidinyl, quinolinole, isoquinolinore, 1,2-dihidraw 2 —oxonolinole, quinazolinyl, quinoxalinyl, cinnolinyl, phthaladil, quinolidinyl, Prill, pteridinyl, indolinyl, isindolinyl,

5, 6, 7, 8—Tetrahidroquinolyl, 1, 2, 3, 4—Tetrahidroquino Linole, 2—Oxo 1,2,3,4—Tetrahidroquinolyl, benzo [1,3] Dioxolyl, 2,3-dihydrobenzo [1,4] dioxolinole, 3,4-methylenedioxypyridyl, 4,5-ethylenedioxypyrimidinyl, chromenyl, chromanyl or isochromyl group Can be mentioned.

Preferable examples of these “aromatic heterocyclic groups” include furyl (eg, 2-furyl, 3-furyl), chenyl (eg, 2-chenyl, 3-chenyl), pyridyl. (Eg, 2 —pyridyl, 3 —pyridyl, 4 monopyridyl), pyrimidinyl (eg, 2 —pyrimidinyl, 4 _pyrimidinyl, 5 —pyrimidyl, 6 —pyrimidinyl), pyridazinyl (eg, 3 —Pyridazinyl, 4-pyridazinyl), birazinyl (eg, 2-pyrazinyl), pyrrolinole (eg, 1 —pyrrolinole, 2—pyrrolinole, 3_pyrrolyl), imidazolyl (eg, 1 1 imidazolyl, 2 — imidazolyl, 4 1 imidazolyl, 5 — imidazolyl), virazolinole (eg, 1 — virazolinole, 3-pyrazolyl, 4 monopyrazolyl), oxazolyl (eg, 2 — oxazolyl) Lu, 4-oxazo Lyl, 5-oxazolyl), isoxazolinol, thiazolyl (eg, 2 —thiazolinol, 4 —thiazolyl, 5 —thiazolyl), isothiazolyl, oxadiazolyl (eg, 1, 2, 4 — oxaziazole) 5 —Yl, 1, 3, 4 —oxadiazole—2 —yl), thiadiazol (eg, 1, 3, 4 —thiadiazole—2 —yl), triazolinol (eg, 1, 2, 4 — Triazonole 1 — Fil, 1, 2, 4 — Triazol 3 — Fil, 1, 2, 3_ Triazole 1 — Fil, 1, 2, 3 — Triazonole 2 — Fil , 1, 2, 3 — Triazol 4 —yl), Tetrazolyl (eg, Tetrazol 1 —yl, Tetrazol 1 —yl), Quinolinol (eg, 2 —Quinolyl, 3-quinoline, 4-quinolyl), quinazolinole (eg, 2_ Quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2 — quinoxalinole), benzofurinole (eg, 2 — benzofurinole, 3 — benzofurinole), benzo cheninole column, 2 — benzochelinole, 3 — benzochelinole ), Benzoxazols (eg, 2_benzoxazolyl), benzothiazolyl (eg, 2— Benzothiazolyl), benzui midazolinole (eg, benzui midazol roe 1 — yl, benzui midazol 1 — yl), indole nore (eg, indole 1 yl, indole 1 3 yl) ), 1 H-indazolinole (eg, 1 H-indazol_ 3 -yl), 1 H-pyro mouth [2,3-b] birazinyl (eg, 1 H-pyro mouth [2,3, b] pyrazine 1 H-pyrophylpyridinyl (eg, 1 H —pyro mouth [2, 3-b] pyridine 1 6 —yl), 1 H —Imidazopyridinyl (eg, 1 H —Imidazo [4, 5— b] Pyridine 1 2 —yl, 1 H—Imidazo [4,5— c] Pyridine 1 2 —yl, 1 H—Imidazolopyrazinyl (eg, 1 H —Imidazo [4,5-b] pyrazine 1- 2-yl), triazinyl, isoquinolyl, benzoxaziazolyl, benzothi Zia Zoriru, mention may be made of Benzuto Riazoriru group, and the like.

The “ester residue” means a modifying group of a carboxyl group, and means a group that can be chemically or metabolically hydrolyzed to be chemically changed to a carboxy group. Specifically, in addition to the C i — ₆ alkyl group, bivalyloxymethyl, 1 — (acetyloxy) ethyl, 1 (ethoxycarbonyloxy) ethyl, 1 (cyclohexyl) (Oxyxanolenobonyloxy) ethynole, carboxymethyl, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl, phenyl or o-tolyl group. Preferred is a C- ₄ alkyl group.

“It may be substituted with 1 to 3 identical or different substituents” means that it may be substituted with 1 to 3 identical or different substituents. It should be noted that even if the number of substituents is not specifically described, it means that “substituents may be substituted with one or more substituents”.

“Saturated heterocycle” in “saturated heterocycle having at least one nitrogen atom formed together with an adjacent nitrogen atom” means, for example, at least one ring atom other than a carbon atom. Means a 5- to 7-membered nitrogen-containing heterocycle containing a nitrogen atom and further containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms, such as pyrrolidine, i Midazolidin, virazolidin, piperidine, piperazine, morpholine or thiomorpholine.

“R ² and X ¹ may be combined with the adjacent ring Q to form a condensed ring”. Specifically, for example, R ² and X ¹ are combined together to form a methylene group, an ethylene group It may be formed.

“Long chain” in the “long chain fatty acid derivative compound” means a carboxylic acid compound having 8 to 23 carbon atoms.

Other groups that are not specifically defined here are those that are usually used. Follow.

The “pharmaceutically acceptable salt thereof” may be any salt that forms a non-toxic salt with the compound represented by the above general formula.

The acid that can be used to prepare a pharmaceutically acceptable acid addition salt is a pharmaceutically acceptable acid addition salt (ie, a pharmaceutically acceptable anion). Salt), for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate Salt, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, dulconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzene Sulfonate, p-Toluene sulfonate, and acid forming pamoate.

Chemical bases that can be used to prepare pharmaceutically acceptable base salts are bases that form non-toxic base salts with the compound. The non-toxic base salts include, but are not limited to, pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earths. Base salts, ammonium or water-soluble amine addition salts derived from metal-like cations (eg calcium and magnesium), eg N-methyldalkamine (medalmine), and lower alkanolamines and pharmacology Mention may be made of other basic salts of organic amines which can be tolerated. The compounds of the present invention include all stereoisomers (eg, cis and trans isomers) and all optical isomers (eg, R and S enantiomers) of the compound represented by formula (I), and racemates. , Diastereomers, and mixtures thereof.

The compounds of the invention may also exist in various tautomeric forms. The present invention includes all tautomers of the compound represented by the formula (I). The compounds of the present invention may contain double bonds such as olefins. When such a double bond is present, the compound of the present invention includes a cis configuration, a trans configuration, and a mixture thereof.

The “pharmaceutical composition” includes, in addition to a so-called “composition” composed of an active ingredient and a compounding agent as a medicine, a combination with other drugs and the like. Needless to say, the pharmaceutical composition may be used in combination with any other drug within a range that is acceptable in the medical field. Therefore, the pharmaceutical composition is for use in combination with other drugs. It can also be said to be a pharmaceutical composition.

m means an integer of 0 to 6, preferably an integer of 0 to 4, particularly preferably 0.

n represents an integer of 5 to 20, preferably an integer of 5 to 15 and preferably an integer of 8 to 15.

m + n represents an integer of 20 or less, preferably an integer of 5 to 15 and particularly preferably an integer of 8 to 15.

Ring Q means a condensed which may be carbocyclic or heterocyclic group, preferably Ariru group such as phenylene Le group; C _3, such as a cyclohexyl group consequent opening - ₈ consequent opening alkyl group; Pi lysyl group An aromatic heterocyclic group such as a saturated heterocyclic group such as a pyrrolidinyl group. Particularly preferred are a phenyl group and a cyclohexyl group, and more preferred is a phenyl group.

X ^1, X ² and X ³ are the same or different and each is a hydrogen atom, a halogen atom, C j - ₄ Anorekinore group, - ₄ alkoxy group, c! — ₄ alkylsulfonyl group, halo C i — ₄ alkyl group, nitro group, amino group, hydroxyl group, cyano group, mercapto group, alkylthio group, sulfonamido group, acetylamino group,

C j - e alkylamino amino group, di C i - e alkylamino group, a carboxy group, § Rinoreokishi group, Arinore group, Ararukinore group, Benzoinore group, force Norebokishi C j - ₄ alkyl group, Okiso group, Mechirenjiokishi group, Echirenjiokishi group Or means an acetoxy group.

Preferably, a hydrogen atom, a halogen atom, an alkyl group, a C — ₄ alkoxy group, C! - ₄ alkylsulfonyl group, Bruno, mouth C - ₄ alkyl group, a hydroxyl group, Shiano group, Asechiruamino group, a carboxy group, Ariruokishi group, Araru kill group or a carboxy C, - an _alkyl group, particularly preferably, X ¹及X ² is a hydrogen atom, X ³ is a halogen atom, and further a chlorine atom.

Y ¹ and Y ² each represent the same or different halogen atom, preferably Y ¹ and Y ² are the same halogen atom, and more preferably Y ¹ and Y ² are both chlorine atoms.

R represents a hydrogen atom or an ester residue, preferably a hydrogen atom, ethyl, pivalloynoroxymethyl, 1- (acetyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (cyclohexyl) Oxycarbonyloxy) ethyl, carboxymethyl, (5-methyl-1-2-oxo-1,3-dioxo-4-yl) methyl, phenyl, o-tolyl, etc., particularly preferably a hydrogen atom or C, - an _alkyl group, most preferably a hydrogen atom. Note that compounds in which R is an ester residue, in particular a C ₄ -4 alkyl group, In addition to being useful as an intermediate compound for producing a compound in which R is a hydrogen atom, it itself has an agonist activity and is also useful as a prodrug.

W ^{is, - C (= N- OR 1} ) -, - CH (NR 2 R 3) - or - CH (N ₃₎ - means. R 'is a hydrogen atom or C, it means a _ ₆ alkyl group, preferably a hydrogen atom also Haji i ₄ alkyl group, particularly preferably a hydrogen atom.

R ² and R ³ are the same or different and each is hydrogen atom, - ₈ alkyl group, Ararukiru group, § reel § Honoré en Honoré group, § reel alkynyl group, - SO 2 R ⁴ (where, R ⁴ is C j ₆ alkyl group, allyl group or aralkyl group.), COR ⁵ (R ⁵ means C ₂₆ alkyl group, aralkyl group, aralkyl group or aralkyl group), or R A saturated heterocycle having at least one nitrogen atom formed by ² and R ³ together with the adjacent nitrogen atom.

Here, the alkyl group, particularly the alkyl group in R ² and R ³ , may be substituted with 1 to 3 identical or different substituents selected from the following dulpe A. In addition, the aralkyl group, the aralkyl alkenyl group, and the aralkyl alkynyl group, particularly the aralkyl group, the aralkyl alkenyl group, and the final alkynyl group in R ² and R ³ are 1 to 3 identical or different substituents selected from the following group B: It may be substituted with a group.

Halogen atom, hydroxyl group, C i ₆ alkoxy group, amino groups, C] - ₆ alkylamino group, current events - ₆ alkylamino amino group, a carbonyl groups, C ₆ alkoxy carbonyl group, Shiano group and Ashiru group;

Halogen atom, a hydroxyl group, - ₆ alkoxy groups, C ₆ alkyl group, Amino groups, C〗 - ₆ alkylamino group, current events ₁ - ₆ alkylamino group, a carbonyl group,

C! _ ₆ alkoxycarbonyl group, Shiano group and Ashiru group;

R ² is preferably a hydrogen atom or a C 6-6 alkyl group, particularly preferably a hydrogen atom or a C- ₄ alkyl group, and more preferably a hydrogen atom. R ³ represents a hydrogen atom, a C ₈ alkyl group, an aralkyl group, an allyl alkenyl group, an allyl alkynyl group, S 0 ₂ R ⁴ , — COR ⁵ , but preferably, 〇 — ₈ alkyl group, aralkyl The group SO ₂ R ⁴ or one COR ⁵ . Aralkyl groups suitable as R ³ are aralkyl groups in which the aryl group such as benzyl, naphthylmethyl, diphenylmethyl or phenethyl group is a phenyl group or a naphthyl group, and the alkyl group is a C j ₄ alkyl group. Preferred is a benzyl or phenethyl group, and particularly preferred is benzyl. It is a group.

R ² and R ³ together with the adjacent nitrogen atom form a saturated heterocyclic ring such as pyrrolidine, imidazolidine, virazolidin, piperidine, piperazine, morpholine, thiomorpholine May be.

R ⁴ is 〇] - ₆ alkyl group, means a Ariru group or Ararukiru group, the good Mashiku is C, ₄ alkyl group or a C, _ ₄ alkyl which may be substituted § Li Lumpur group with a group .

R ⁵ represents a Ci ₆ alkyl group, an aryl group, an aralkyl group or an arylalkyl group, preferably a C ₆ alkyl group; a phenyl group; a benzyl group, a naphthylmethyl group, a diphenylmethyl group and a phenyl: An aralkyl group selected from a group; an arylalkenyl group substituted with a phenyl group such as a styryl group;

R ² and X ¹ may combine together to form a methylene group or an ethylene group, and together with the adjacent ring Q to form a condensed ring. The novel GPCR agonist having a fatty acid as a ligand of the present invention, particularly GPR 120 agonist and / or GPR 40 agonist, contains the long-chain fatty acid derivative compound as an active ingredient. Our studies have revealed that these compounds activate (enhance) the functions of GPR 120 and Z or GPR 40.

Specifically, in the GPCR agonist of the present invention, these compounds act on intestinal hormone-secreting cells to release intestinal hormones, and these hormones (specifically CCK and GLP-1) are received by target cells. It is based on a new mechanism that acts on the body (CCK receptor or GLP-1 receptor) and exhibits various medicinal effects.

The target disease and efficacy of the present invention are based on an increase in C CK concentration in the blood or target organ and an increase in GLP-1 concentration in the blood or target organ. According to the present invention, GP C R is activated, and a wide range of treatments with an increase in the concentration of C C K or G L P-1 in the blood or the target organ is possible.

For example, the following can be mentioned as therapeutic agents for target diseases associated with increased C C K concentrations.

(i) Promotion of digestive activity;

These include promotion of secretion of secretion, promotion of secretion of gastric juice, promotion of bile secretion, retention of food retention in the stomach, promotion of intestinal motility, and prevention of reflux due to contraction of the lower esophageal sphincter. Therefore, it is possible to treat diseases with insufficient digestive activity by increasing C C K.

(i i) appetite suppression effect;

Increasing CCK gives a feeling of fullness and suppresses appetite. therefore, It is possible to suppress diseases related to food, such as obesity, and to treat bulimia nervosa.

(iii) promotion of differentiation and proliferation of cells in the gastric mucosa;

By promoting the differentiation and proliferation of cells in the gastric mucosa, it can be used as a therapeutic agent for gastric wall disorders.

(iv) promotion of insulin secretion;

It can be used as a therapeutic agent for diabetes by promoting insulin secretion from spleen i3 cells.

(V) nerve repair, maintenance action;

It can be used as a neuropathy treatment by repairing and maintaining nerves. It should be noted that the subject of the present invention is not limited to the above, and it can be easily understood that the entire treatment for diseases associated with increased C CK concentration can be the subject.

On the other hand, examples of the therapeutic agent for the target disease associated with an increase in the concentration of GLP-1 include the following.

(i) Promotion of insulin secretion from spleen / 3 cells;

By promoting the secretion of insulin from knee cells, it can be used as a therapeutic agent for diabetes.

(ii) Promotion of differentiation and proliferation of knee 3 cells;

Spleen) It can be used as an anti-diabetic agent for preventing the transition from hyperglycemia, insulin resistance, obesity, etc. to diabetes by promoting the differentiation and proliferation of 8 cells. Furthermore, it can be used as a medicament for improving the survival rate of transplanted cells at the time of 3 cell transplantation.

(iii) suppression of gastric acid secretion;

It can be used as a therapeutic agent for gastric hyperacidity by suppressing gastric acid secretion.

(iv) Intestinal motility suppression;

It can be used as a therapeutic agent for diarrhea by suppressing intestinal motility.

(V) maintenance of nerve plasticity and survival;

It can maintain neuronal plasticity and survival and can be used as a therapeutic agent for diseases caused by neuropathy. Also,

(vi) appetite suppression effect;

It can be used as an anti-obesity treatment by suppressing appetite.

It should be noted that the subject of the present invention is not limited to the above, and it can be easily understood that the entire treatment of the disease associated with the increased concentration of 0-1 can be the subject.

The long-chain fatty acid derivative compound of the present invention simultaneously releases CCK and GLP-1 In many cases, both of them exhibit similar efficacy, but they appear to compete with each other in digestive activity. In fact, both cooperate smoothly to perform digestive activity, and the simultaneous release of CCK and GLP-1 is a more physiologically rational therapeutic agent.

Therefore, the long-chain fatty acid derivative compound of the present invention is

Examples of treatments in which C C K and G L P-1 are released and these effectively act on the target organ are as follows.

(i) coordinated promotion of digestive activity, treatment of digestive activity disorder,

(ii) obesity prevention treatment by appetite suppression, bulimia treatment,

(iii) Knee] Prevention of diabetes by promoting secretion of insulin from 3 cells or by promoting differentiation and proliferation of 3 cells or their precursor cells. Or] a therapeutic effect promoter for 3 cell or progenitor cell transplantation treatment,

(iv) Nerve cell plasticity, nerve transplantation by viability maintenance action, treatment promoting agent at the time of nerve junction or Alzheimer's disease treatment for diseases caused by nerve cell damage,

(V) treatment of abnormal intestinal motility during enteritis due to normalization of intestinal motility,

(vi) Inhibition of damage to intestinal cells or damage to nerve cells present in the intestinal tract.

In addition to the intestinal tract, GPR 1 2 0 is known to occur in the lungs, pituitary gland, fat cells, and tongue. Therefore,

(vii) Improvement of lung function in the lung, for example, treatment of lung diseases such as C O P D (chronic obstructive pulmonary disease) by promoting surfactant secretion,

(viii) pituitary hormone secretion promoting action from the pituitary gland,

(ix) obesity treatment or prevention by promoting lipid differentiation in adipocytes,

(X) Improvement of taste and flavor of lipids.

Furthermore, it is known to suppress the secretion of the adrenal corticotropic hormone ACTH through the GPR 1 2 0 receptor expressed in the pituitary gland. It is expected to be effective as a therapeutic agent for hypersecretion of glucocorticoid (cortisol) and adrenal androgen secreted by TH stimulation.

The long-chain fatty acid derivative compound of the present invention had an agonistic action on G P R 40 and / or G P R 120.

GPR40 is present in knee β cells, and insulin secretion is promoted by activation of GPPR40. Therefore, the G P R 40 agonist compound is

(i) Antidiabetic drug by promoting insulin secretion from spleen i3 cells,

(ii) It can be used as an anti-diabetic agent for preventing the transition from hyperglycemia, insulin resistance, obesity, etc. to diabetes by promoting the differentiation and proliferation of i3 cells or their progenitor cells. In addition, to improve the survival rate of transplanted cells when transplanting 3 cells It can also be used as a pharmaceutical.

The GPCR agonist containing the long-chain fatty acid derivative compound of the present invention as an active ingredient has the above-mentioned medicinal effects, and can be formulated, for example, as follows.

The GPCR agonist of the present invention is formulated to be compatible with a therapeutically appropriate route of administration, including intravenous and oral administration. Solutions or suspensions used for intravenous administration include, but are not limited to, sterile diluents such as water for injection, saline solution, non-volatile oil, polyethylene glycol, glycerin, propylene Lenglycol, or other synthetic solvents, preservatives such as benzyl alcohol or other methylbaraben, anti-oxidants such as ascorbic acid or sodium hydrogen sulfite, soothing agents such as benzalkonium chloride, pro-power-in hydrochloride, A chelating agent such as ethylenediaminetetraacetic acid (EDTA), a buffer such as acetate, citrate, or phosphate, or a drug for osmotic pressure adjustment such as sodium chloride or dextrose. May be included.

pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Non-diameter preparations are stored in ampoules, glass or plastic disposable syringes or multidose vials.

To make the preparation suitable for injection, it is a sterile injectable solution or dispersion medium, a sterile aqueous solution (water-soluble) or dispersion medium to prepare at the time of use, and a sterilized powder (freeze-dried). Protein, nucleic acid, etc.). For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, CR EMO P HOR EL (registered trademark, BASF, Parasippany, NJ), or phosphate buffered saline (PBS ) Is included. When used as an injection, GPCR agonists must be sterilized and maintain sufficient fluidity to be administered using a syringe. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures. For example, when a coating agent such as lectin is used, the required particle size is maintained in a dispersion medium, and an appropriate fluidity is maintained by using a surfactant. Various antibacterial and antifungal agents can be used to prevent microbial contamination, such as parabens, chlorobutanol, fenore, asconolevic acid, and thimerosal. In addition, polyalcohols such as sugar, mannitol, sorbitol, and agents that maintain isotonicity such as sodium chloride may be included in the composition. Compositions that can delay adsorption include agents such as aluminum monostearate and gelatin. Sterile injectable solutions are prepared by adding the required ingredients alone or in combination with the other ingredients, then adding the required amount of the active compound in a suitable solvent and sterilizing. Generally, a dispersion medium is prepared by incorporating the active compound into a sterile medium that contains a basic dispersion medium and the other necessary ingredients described above. Sterile powder preparation methods for the preparation of sterile injectable solutions include vacuum drying and lyophilization to prepare a powder containing the active ingredient and any desired ingredients derived from the sterile solution. It is.

In the case of an oral preparation, an inert diluent or a carrier that does not cause harm when taken into the body is included. Oral preparations are, for example, contained in gelatin capsules or compressed into tablets. For oral treatment, the active compound is incorporated with excipients and used in the form of tablets, troches, or capsules. Oral preparations can also be prepared using a flowable carrier. In addition, pharmaceutically compatible binders, and or adjuvant materials may be included.

Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds with similar properties. Excipients such as microcrystalline cellulose, binders such as arabic gum, tragacanth or gelatin; swelling agents such as starch or lactose, alginic acid, PRI MO GEL, or corn starch; lubricants such as magnesium stearate or STRROTES Agents; lubricants such as colloidal silicon oxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylic acid or orange flavor.

When a preparation for systemic administration is used, it can be transmucosally or transdermally. For transmucosal or transdermal administration, penetrants that can penetrate the target barrier are selected. Transmucosal penetrants include surfactants, bile salts, and fusidic acid derivatives. Nasal sprays or suppositories can be used for transmucosal administration. For transmucosal administration, the active compound is formulated in entiments, ointments, jewels or creams.

The pharmaceutical compositions of the invention can also be prepared in the form of suppositories (eg, with bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In the case of a controlled-release preparation, it can be prepared using a carrier that can prevent immediate removal from the body. For example, biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polydalicolic acid, collagen, polyorthoesters, and polylactic acid. Such materials are ALZAC orporation (Mountain V i ew, CA) and NOVA P harmaceutica 1 s, Inc. (Lake Elsinore, CA) and can also be readily prepared by one skilled in the art. Ribosome suspensions can also be used as pharmaceutically acceptable carriers. Useful ribosomes are not limited, but are suitable for use as a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derived phosphatidylethanol (PEG-PE) to be of a size suitable for use. Prepared through a pore size filter and purified by reverse phase evaporation. For example, an antibody Fab ′ fragment or the like may be bound to a ribosome via a dysnoden exchange reaction (Martin and Papahadjopoulos, 1 9 8 2). See, for example, the description in E ppstein et al., 1 985; Hwang et al., 1980 for detailed preparation methods.

The dose of the GPCR agonist of the present invention depends on the condition of the patient (human) or animal to be administered, the administration method, etc. in the treatment or prevention of a specific disease. It is possible to

For example, in the case of injection administration, for example, it is preferable to administer about 0.1 μg / kg to 50 O mg Z kg per patient's body weight per day, generally administered in one or more divided doses. You will get. Preferably, the dosage level is from about 0.1 μg kg force to about 2500 mg Zkg per day, more preferably from about 0.5 to about 100 mg Zkg per day.

For oral administration, it is preferably provided in the form of a tablet containing 1.0 to 1 O 2 O O mg of active ingredient. Preferably, the dosage of the active ingredient for the patient (human) or animal to be treated is between 0.001 and 100 mg mg. The compound is administered on a regimen of 1 to 4 times a day, preferably once or twice a day.

Further, as a means for screening the long-chain fatty acid derivative compound of the present invention, by measuring the operability to GPR 120 and GPR 40, it is possible to deal with the above-mentioned target diseases whose application is expanded. You can screen for better drugs. Next, an example of a typical production method of the long-chain fatty acid derivative compound represented by the above general formula, particularly (I) will be described, but the production method of the compound of the present invention is not limited thereto. It can be easily produced by appropriately combining or applying known or known methods.

1. Production of a long-chain fatty acid derivative compound in which W is —CH (NR ² R ³ ) —; (1) Production of a compound in which R ³ is — COR ⁵ ;

In the following, the case where R ² is a hydrogen atom will be described. However, for R ^{2 other} than a hydrogen atom, for example, by using R ⁵ CONHR ² instead of R ⁵ CONH ₂ , the target compound can be similarly obtained. Obtainable.

(Where X ¹ , X ² , X ³ , m, n, Y ′, Y ² , Q and R ⁵ are the same as above, and R ′ is a carboxy protecting group such as a lower alkyl group such as methyl Means a group.)

[Process 1]

Step 1 is a step of producing a compound having the general formula (2), and the compound having the general formula (1) that can be produced by the method described in W0 0 4/1 0 3 9 4 6 This is achieved by subjecting the nitrile compound to the Ritter reaction. This reaction can be carried out in a solvent in the presence or absence of an acid.

The solvent is not particularly limited. For example, an acid such as acetic acid or sulfuric acid that uses a reacting nitrile compound can be used.

The acid is not particularly limited, but sulfuric acid, hydrochloric acid, acetic acid, trifluoroacetic acid, nitrosonium (NO BF ₄ , NOPF ₆ ) and the like can be used. The reaction conditions vary depending on the raw materials used, but in general, the reaction is carried out at −20 to 100 ° C., preferably 50 to 100 ° C. for 5 minutes to 2 days, preferably 5 hours to 24 hours. Thus, a compound having the general formula (2) can be produced.

Also, the compound having the general formula (1) can be reacted with an amide compound (R ⁵ C ONH ₂ or R ⁵ C ONHR ² ) in a solvent in the presence of a catalyst to have the general formula (2). The production of the compound can be achieved.

As the catalyst, hafnium (IV) triflate can be used. The solvent is not particularly limited, but ditromethane or the like can be used.

The reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 to 24 hours. To produce a compound having the general formula (2).

[Process 2]

Step 2 is a step of producing a compound having the general formula (3), and is achieved by subjecting the compound having the general formula (2) obtained in [Step 1] to a normal hydrolysis reaction. This reaction, _fa can be conducted in the presence of a solvent, base or acid

The solvent is not particularly limited, and for example, tetrahydrofuran, dioxane, methanol, ethanol, water and the like can be used alone or in combination.

The acid is not particularly limited, but inorganic acids such as sulfuric acid and hydrochloric acid, and organic acids such as acetic acid and trifluoroacetic acid can be used.

The base is not particularly limited. For example, lithium hydroxide, sodium hydroxide, metal hydroxides such as lithium hydroxide, lithium carbonate, sodium carbonate, carbonate Umum, cesium carbonate, etc. can be used.

The reaction conditions vary depending on the raw materials used, but in general, the reaction is carried out at −20 to 100 ° C., preferably 15 to 50 ° C. for 5 minutes to 1 day, preferably 30 minutes to 12 hours. To produce a compound having the general formula (3).

(2) R ³ is, C, _ ₈ alkyl group, the preparation of the compounds is Ararukiru group or the like; hereinafter, although described when R ² is hydrogen atom, R ² is the compounds other than hydrogen atom, the step 'R ⁵ in place of the C ONH _2' in 1 R ⁵ By using the compound (2) obtained by using CONHR ² where W is one CH (NR ² COR ⁵ ) —, the target compound can be similarly obtained.

Process 3 Process 4

(Where X ¹ , X ² , X ³ , m, n, Y Υ ² and Q are the same as above, R ′ means a protecting group for a carboxy group such as a lower alkyl group, such as a methyl group, R ⁵ 'means a C i _ ₆ alkyl group, an aryl group, an aralkyl group or an arylalkyl group.

[Process 3]

Step 3 is a step of producing a compound having the general formula (4), and subjecting the compound having the general formula (2) obtained in [Step 1] to a selective reduction reaction of an amide group. Is achieved. The reaction can be performed in a solvent in the presence of a catalyst.

Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, a dioxane, etc. can be used individually or in combination.

Examples of the catalyst include a borane / tetrahydrofuran complex.

The reaction conditions vary depending on the raw materials used, but in general, the reaction is carried out at −20 to 100 ° C., preferably 10 to 25 ° C. for 1 minute to 1 day, preferably 1 hour to 12 hours. To produce a compound having the general formula (4) Can do.

[Process 4]

Step 4 is a step of producing a compound having the above general formula (5), and the compound having the general formula (4) obtained in [Step 3] is subjected to normal hydrolysis as in the above [Step 2]. This is achieved by reacting. The solvent, base group or acid used in this reaction, and the reaction conditions are the same as those described in [Step 2].

(3) R ³ is (wherein, R ⁴ is - ₆ alkyl group means a § aryl group or Ararukiru group.) In one S_〇 ₂ R ⁴ production of those compounds;

Hereinafter, the case where R ² is a hydrogen atom will be described. For compounds in which R ² is other than a hydrogen atom, R ⁴ S 0 ₂ NHR ² is used instead of R ⁴ S 0 ₂ NH ₂ in Step 5, The target compound can be obtained in the same manner.

(1)

Process 6

(Wherein X ¹ , X ² , X m, n Y ¹ , Y ² and Q are the same as above, R ′ means a protecting group for a carboxy group such as a lower alkyl group, for example, a methyl group, R ⁴ Represents a C- ₆ alkyl group, an aryl group or an aralkyl group.) [Step 5]

Step 5 is a step of producing a compound having the general formula (6). This is achieved by reacting a compound having the general formula (1) with a sulfonamide compound in a solvent in the presence of a catalyst.

The reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 hours to 24 hours. To produce a compound having the general formula (2).

[Process 6]

Step 6 is a step of producing a compound having the above general formula (7), and the compound having the general formula (6) obtained in [Step 5] is subjected to normal hydrolysis in the same manner as in the above [Step 2]. This is achieved by reacting. The solvent, base group or acid used in this reaction, and the reaction conditions are the same as those described in [Step 2]. Production of a compound in which W is -〇 (= ^ -01 ^)-(where R ¹ represents a hydrogen atom or a Ci ₆ alkenyl group);

(8)

Process 8

(Ten)

(Where XX ² , X ³ , m, n, YY ² and Q are the same as above, and R ′ means a protecting group for a carboxy group such as a lower alkyl group, such as a methyl group. R ¹ represents a hydrogen atom or a C ₆ „ ₆ alkyl group.)

[Process 7]

Step 7 is a step of producing a compound having the general formula (9), and can be produced by a method similar to the method described in the W0 0 4 Z 1 0 3 9 4 6 brochure. It is achieved by reacting a compound having 8) with a hydroxylamine compound or a C, ₆ alkyloxyamine compound in a solvent in the presence of a catalyst.

As the catalyst, sodium acetate, sodium carbonate, ammonia or the like can be used.

The reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 hours to 24 hours. To produce a compound having the general formula (9).

[Process 8]

Step 8 is a step for producing a compound having the above general formula (10), and the compound having the general formula (9) obtained in [Step 7] is converted into a conventional hydrolyzate as in the above [Step 2]. This is achieved by a decomposition reaction. The solvent, base or acid used in this reaction, and the reaction conditions are the same as those described in [Step 2]. Preparation of compounds wherein W is -CH (N ₃ )-and -CH (NH ₂ )-;

(1)

COOR,

(11)

COOH

(12)

(Where X ¹ , X ² , X ³ , m, n, Y ¹ _N Y ² , Q and R ′ are the same as above)

[Process 9]

Step 9 is a step of producing a compound having the general formula (11), and is achieved by subjecting the compound having the general formula (1) and an azidating agent to a Mitsunobu reaction. This reaction can be carried out in a solvent in the presence of a phosphine reagent and an azodicarboxylic acid derivative.

Examples of the azide glaze include hydrogen azide and diphenyl phosphate azide.

Examples of the phosphine reagent include triphenyl phosphine, triethyl phosphine, and the like.

Examples of the azodicarboxylic acid derivative include dialkyl esters of azodicarboxylic acid such as jetyl azodicarboxylate or diisopropyl azodicarboxylate, and azodicarboxylic acid amide.

The solvent is not particularly limited, and for example, methylene chloride or tetrahydrofuran can be used.

The reaction conditions vary depending on the raw materials used, but are generally 0 to 100 ° C, preferably 0 to 50 ° C for 5 minutes to 2 days, preferably 1 to 24 hours. To produce a compound having the general formula (11).

[Process 1 0]

Step 10 is a step of producing a compound having the general formula (1 2).

The compound having the general formula (1 1) obtained in [Step 9] can be subjected to the usual hydrolysis reaction similar to the above [Step 2] to obtain the carboxylic acid compound of the general formula (1 1). . The solvent, base or acid used in this reaction, and the reaction conditions are [Step

It is the same as described in 2].

By subjecting the obtained carboxylic acid compound to a reduction reaction, production of the compound of the general formula (12) is achieved. Examples of the reduction reaction include catalytic reduction, metal reduction using a hydride-based reducing reagent, and reduction using an organic phosphorus compound.

Reductants include palladium-carbon and hydrogen for catalytic reduction, combinations of Raney nickel and hydrogen, and hydride-based reducing reagents such as lithium aluminum hydride, dichloroborane dimethylsulfide complex, and hydrogen. An example of the organic phosphorus compound reducing agent such as a combination of sodium borohydride and cobalt chloride is triphenylphosphine.

The solvent is not particularly limited, and for example, methanol, ethanol, n-propanol, jetinoreethenole, tetrahydrofuran, dichloromethane, ethyl acetate, water and the like can be used.

The reaction conditions vary depending on the raw materials used, but are generally 0 to 10 ° C., preferably 0 to 50 ° C. for 5 minutes to 2 days, preferably 1 to 24 hours. It is possible to produce a compound having the general formula (1 2). Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

[Example 1]

12-acetoamide -2,2-dichloro-12- (4-chlorophenyl) Production of methyl dodecanoate;

2,2-dichloro mouth-12- (4-chlorophenyl) -12-hydroxydodecanoic acid methyl ester (200 mg, 0.49 mmol) (WO 0 4 ノ 1 0 3 9 4 6 ノ, ° Fret) and acetonitrile (200 mg, 4.88 mmol), acetic acid 60 / L are mixed and stirred. After making the solution, sulfuric acid was added and stirred at 70 ° C for 15 hours.

The reaction solution was cooled, chloroform and water were added, and the organic layer was separated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent hexane-ethyl acetate = 10: 1) to give the desired product (278 mg, 100% yield) as a yellow oil. Obtained.

1H-NMR (270MHz, CDC1 ₃ ) δ: 1.28 (12H, ra), 1.61 (2Η, m), 1.80 (2H, m), 2.05 (3H, s), 2.39 (2H, m), 3.88 (3H, s), 4.88 (1H, q, J = 7.6Hz), 5.79 (1H, d, J = 8.4Hz), 7.30 (4H, m).

[Example 2]

12-acetoamide— 2, 2—_ Distilled mouth mouth 12- (4—Chlorophenyl) Production of dodecanoic acid

12-acetamido-2,2-dichloro-12- (4-chlorophenyl) methinole dodecanoate (40 mg, 0.089 mmol) was dissolved in 1 raL of methanol and 2 mol / L Water A 0.1 mL aqueous lithium oxide solution was added, and the mixture was stirred at room temperature for 1 hour.

Add 2 mol / L hydrochloric acid to the reaction solution, adjust the pH to about 2, 10 ml of chloroform, add 5 raL of water, separate the organic layer, concentrate it under reduced pressure, and use the resulting residue as a silica gel column chromatography. Purification by chromatography (eluent hexane-ethyl acetate = 5: 1) gave the desired product (18 mg, 46% yield) as a colorless oil.

1H-NR (270MHz, CDC1 ₃ ) δ: 1.25 (12H, m), 1.56 (2H, m), 1.80 (2H, m), 2.06 (3H, s), 2.45 (2H, m), 4.96 (1H, q, J = 7.6Hz), 6.02 (1H, d, J = 8.4Hz), 7.30 (4H, m).

[Example 3]

2, 2—Dioctane — 12— (4 – Digestive Full)-1 ² -Production of Propanami_Dododecanoic Acid Methyl; ■ y X 'OMe

The target product (yield 100%) was obtained as a colorless oil by using the same method as in Example 1 except that propiononitol was used instead of HN and 0-acetonitol.

1H-NMR (270MHz, CDC1 ₃ ) δ: 1.10—1.40 (12H, m), 1.17 (3Η, t, J = 7.3Hz), 1.46-1.64 (2Η, m), 1.67-1.82 (2Η, m), 2.14-2.27 (2H, m), 2.32-2.45 (2H, m), 3.89 (3H, s), 4.81 (1H, q, J = 7.6Hz), 5.56 (1H, d, J = 8.4Hz), 7.18 -7.34 (4H, m).

[Example 4]

Jiku Mouth-12- (4-Mixed Mouth-Fuenyl) -12-Propanamide Dodecanoic Acid

12-acetamido-2,2-dichloro _12- (4-chlorophenyl) 2,2-dichloro-12- (4-chlorophenyl) -12-prono instead of methyl dodecanoate The target product (yield 73%) was obtained as a colorless oil by using methyl amide decanoate in the same manner as in Example 2.

1H-NMR (270 MHz, CDC1 ₃ ) δ: 1.10-1.94 (14H, m), 1.17 (3H, t, J = 7.6Hz), 2.31 (2H, m), 2.49 (2H, m), 5.02 (1H, m), 5.76 (1H, m), 7.17-7.37 (4H, ra).

[Example 5]

12-butane amide -2,2-dichloro -12- (4-chlorophenol) Preparation of methyl dodecanoate;

The target product (yield 100%) was obtained as a colorless oil by using the same method as in Example 1 except that butyronitrile was used instead of acetonitrile.

1H-NMR (400MHz, CDC1 ₃ ) δ: 0.92 (3Η, t, J = 7.5Hz), 1.17-1.78 (18H, m), 2.15 (2H, t, J = 7.5Hz), 2.33-2.52 (2H, m), 3.89 (3H, s), 4.92 (1H, q, J = 7.5Hz), 5.58 (1H, m), 7.20 (2H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.6 Hz).

[Example 6]

12-Butamide-2,2-Diglycol -_12- (4_Chlorophenyl) Production of dodecanoic acid;

12-butaneamide-2,2-dichloro-12- (4-chlorophenyl) 12-butaneamide-2,2-dichloro-12- (4-chlorophenyl) in place of methyl dodecanoate The target product (yield 73%) was obtained as a colorless oil by using methyl decanoate in the same manner as in Example 2.

1H-NMR (270MHz, CDC1 ₃ ) δ: 0.93 (3H, t, J = 7.6Hz), 1.17-2.40 (20H, m), 2.49 (2H, m), 5.02 (1H, q, J = 6.8Hz) , 5.74 (1H, m), 7.22 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.6Hz). [Example 7]

2,2-Dichloro-12- (4-chlorophenyl) -12- (3-methylbutane amide) e

The target product (yield 34%) was obtained as a colorless oil by using the same method as in Example 1 using isovaleritol instead of acetonitrile.

1H-NMR (270MHz, CDC1 ₃ ) δ 0.99 (6H, d, J = 6.5Hz), 1.11-1.62 (16H, m), 1.74 (1H, ra), 2.00-2.22 (2H, m), 2.31-2.46 (2H, m), 3.89 (3H, s), 4.92 (1H, q, J = 7.8Hz), 5.52 (1H, m), 7.20 (2H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.6Hz).

[Example 8]

2,2-dichloro-12- (4-chlorophenyl) -12 -_ (3-methylbutane amide) dodeca

12-Butaneamide-2,2-Dichloromethane -12- (4-Chlorophenyl) Instead of methyl dodecanoate, 2, 2-Dichloromethane-12- (4-Dichlorophenyl)-12 -(3-Methylbutaneamide) Using methyl dodecanoate and using the same method as in Example 2, the target product (yield 66%) was obtained as a colorless oil.

[Example 9]

2,2—Dichloro-12— (4-—Methyl chloride) -Methyl 12-ethylamino dodecanoate

12-acetamido-2,2-dichloro-12- (4-chlorophenyl) methyl dodecanoate (100 mg, 0.22 mmol) was dissolved in 2 mL of tetrahydrofuran (THF), Under an air stream, the mixture was cooled to 0 ° C and stirred for 5 minutes. Thereafter, borane · THF complex (2.1 mL, 2.22 mmol) was slowly added dropwise, and after completion of the addition, the mixture was stirred at 0 ° C for 10 minutes and then at 50 ° C for 3 hours.

Methanol was added to the reaction solution under ice cooling to decompose excess borane · THF complex, followed by concentration under reduced pressure. Chloroform and water were added to the residue, the organic layer was separated, and the residue obtained after concentration under reduced pressure was purified by silica gel gel chromatography (eluent: hexane-ethyl acetate = 2: 1) The desired product (23 mg, 24% yield) was obtained as a colorless oil.

1H-NMR (400MHz, CDC1 ₃ ) δ 1.04 (3H, t, J = 7. OHz), 1.29 (12H, ra), 1.56-1.98 (4H, m), 2.19 (2H, m), 2.45 ( 2H, m), 3.54 (1H, t, J = 6.5Hz) 3.88 (3H, s), 7.30 (4H, m). [Example 10]

2, 2-diethyl -12- (4-chlorophenyl) -12-ethylamino-dodecanoic acid production;

12-acetamido-2,2-dichloro-12- (4-chlorophenyl) 2,2-dichloro-12- (4-chlorophenyl) -12-ethylamine instead of methyl dodecanoate Using methyl decanoate and using the same method as in Example 2, the desired product (yield 81%) was obtained as a colorless oil.

_{1H-NMR (400MHz, CDC1 3} ) δ: 1.16-1.66 (12H, m), 1.39 (2H, t, J = 7.2Hz), 2.18 (2H, m), 2.41 (2H, t, J two 7.4 Hz) , 2.75 (2H, m), 3.95 (3H, m), 7.42 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz).

[Example 1 1]

2,2-Dioctyl chloride-12- (4-Chlorophenyl) -12-propylaminonodecanoic acid methyl ester production;

12-acetamido-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid The target product (yield 51%) was obtained by using the same method as in Example 9 using 2,2-dichloro-12- (4-chlorophenyl) -12-pronounamidododecanoate methyl instead of tinole. ) Was obtained as a colorless oil.

1H-NMR (270MHz, CDC1 ₃ ) δ 0.86 (3H, m), 1.10-1.76 (18H, m), 2.19 (2H, m), 2.37 (2H, m), 3.53 (1H, t, J = 7.8Hz) 3.90 (3H, s), 7.21-7.29 (4H, m).

[Example 1 2]

2, 2-dioctylamine-12- (4-diphenyl) -12-propylaminododecanoic acid production;

12-acetamido-2,2-dichlorine mouth-12- (4-chlorophenyl) 2,2-dichloro-12- (4-chlorophenyl) -12-propynoleamino instead of methinole dodecanoate The target product (yield> 100%) was obtained as a white solid using methyl dodecanoate in the same manner as in Example 2.

1H-NMR (400MHz, CDC1 ₃ ) δ: 0.88 (3H, t, J = 7.4Hz), 1.04-2.01 (18H, m), 2.19 (2H, ra), 2.59 (2H, m), 3.94 (1H, m), 7.43 (2H, d, J = 8.6Hz), 7.56 (2H, d, J = 8.6Hz). [Example 1 3]

2,2-Dichloro-12- (4-chlorophenyl) -12- (3-methylbutylamino) Production of methyl dodecanoate

12-acetoamide -2, 2-dichloro-12- (4-chlorophenyl) 2, 2-dichloro-12- (4-chlorophenyl) -12 instead of methyl dodecanoate -(3-Methylbutanamide) Using methyl dodecanoate and using the same method as in Example 9, the target product (yield 34%) was obtained as a colorless oil. 1H-NMR (400MHz, CDC1 ₃ ) δ: ..86 (6H, m), 1.04-1.96 (18H, m), 2.13-2.25 (3H, m), 2.31-2.45 (2H, m), 3.52 (2H , t, J = 7.8Hz) 3.90 (3H, s), 7.21 (2H, d, J = 8.4Hz), 7.29 (2H, d, J = 8.4Hz).

[Example 1 4]

2,2-dioctyl chloride-12- (4-chlorophenyl) -12- (3-methylbutylamino) Production of dodecanoic acid;

12-acetoamide-2,2-dichloro-12- (4-chlorophenyl) 2,2-dichloro-12- (4-chlorophenyl) instead of methyl methacrylate ) -12-(3-Methylbutylamino) The target product (yield 98%) was obtained as a colorless oil by using methyl dodecanoate in the same manner as in Example 2.

_{1H-NMR (400MHz, CDC1 3} ) δ: 0.81 (6Η, m), 0.83-2.27 (20H, m), 2.54 (2H, ra), 2.70 (1H, m), 3.99 (1H, m), 7.41 ( 2H, d, J = 8.6Hz), 7.54 (2H, d, J = 8.6Hz).

[Example 1 5]

12-benzamide 12- (4-chlorophenenole) -2,2-di-octahydrate Manufacture of methyl dodecanoate; αΤ ι 〜 ^^ 、人〇

CI 'CI. _Me

2,2-Dichloro-12- (4-chlorophenyl) -12-hydroxydodecanoic acid methylolate (500 mg, 1.22 mmol), benzamide (256 'mg, 2.11 mmol), hafnium (IV) Triflate (20 mg, 0.026 mmol) and nitromethane 10 mL were mixed and stirred at 70 ° C for 12 hours.

The reaction solution is cooled, jet ether and water are added, the organic layer is separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by force gel chromatography (eluent hexane-ethyl acetate = 10: 1) gave the desired product (580 mg, 93% yield) as a yellow oil.

1H-NMR (270MHz, CDC1 ₃ ) δ 1.15—1.48 (12H, m), 1.48—1.68 (4H, m), 1.87 (2H, m), 2.38 (2H, m), 2.05 (3H, s) , 3.88 (3H, s), 5.11 (1H, q, J = 7.6 Hz), 6.31 (1H, d, J = 7.6 Hz), 7.21-7.55 (7H, m), 7.75 (2H, m)

[Example 1 6]

12-benzamide -2, 2-dioctyl chloride- 12- (4-diphenyl) production of dodecanoic acid;

12-acetamido-2,2-diglycol 12- (4-chlorophenyl) 12-benzamido-2,2-diglycol 12- (4-chlorophenyl) in place of methyl dodecanoate The target product (yield 100%) was obtained as a colorless oil by using methyl decanoate in the same manner as in Example 2.

_{1H-NMR (270MHz, CDC1 3} ) δ: 1.16-1.44 (12H, m), 1.44-1.66 (4H, m), 1.89 (2H, m), 2.44 (2H, ra), 3.88 (3H, s), 5.16 (1H, q, J = 7.6Hz), 6.43 (1H, d, J = 8.1Hz), 7.22-7.55 (7H, m), 7.74 (2H, m).

[Example 1 7]

12-Benzylamino-2, 2-dioctylamine-12- (4-dioctylol) production of methyl dodecanoate;

12-acetamido-2,2-dichloro-12- (4-chlorophenyl) 12-bensamide-2,2-dichloric acid mouth instead of methyl dodecanoate 12- (4-chlorophenyl) Dode The crude target product (yield 26%) was obtained as a colorless oil using the same method as in Example 9 using methyl quinoate, and used in the next reaction without further purification. did.

[Example 1 8]

12-Benzenorea Mino-2,2-Dichloro—12— (4-chlorophenyl) Made of dodecanoic acid

12-acetamido-2,2-dichloro-12- (4-chlorophenyl) Crude 12-benzylamino-2-2,2-dichloro-12- (in place of methyl dodecanoate) Using 4-chlorophenyl) dodecanoate and using the same method as in Example 2, the target product (yield 57%) was obtained as a colorless oil.

1H-NMR (400MHz, CDC1 ₃ ) δ: 1. 13-1.90 (16H, ra), 2.20 (2 (, m), 3.90 (2Η, s), 4.65 (2H, t, J = 7. 2Hz), 7. 20-7. 36 (9H, m). [Example 1 9]

12- (4-Chlorophenyl) -2,2-diglycol Mouth- Manufacture of 12-cinnamamide methyl dodecanoate

The target product (yield 34%) was obtained as a yellow oil by using cinnamamide instead of benzamide and using the same method as in Example 15.

1H-NMR (270MHz, CDC1 ₃ ) δ: 0.79-1.88 (16H, m), 2.40 (2H, m), 3.88 (3H, s), 5.05 (1H, q, J = 7.6 Hz), 5.88 (1H, d, J = 8.1 Hz), 6.39 (1H, d, J = 15.7 Hz), 7. 21-7.51 (9H, m), 7. 61 (1H, d, J = 15.7Hz). [Example 2 0]

12 1 (4 1 mouthpiece) 2-2-mouth mouth -12- (3-Phenylpronamine) Production of methyl dodecanoate;

.

12- (4-chlorophenyl) -2,2-dichloro-12-cinnamamide dodecanoic acid 45 mg (0.083 mM) in 1 mL methanolate was dissolved in 10% A carbon catalyst was added and stirred at room temperature for 30 minutes in a hydrogen atmosphere.

The residue obtained by concentrating the reaction solution under reduced pressure was purified by flash column chromatography (eluent hexane-ethyl acetate = 10: 1) to give the desired product (34 mg, 75% yield) as a yellow oil. Obtained.

_{1H-NMR (400MHz, CDC1 3} ) δ: 1.03-2.06 (16H, m), 2.36-2.55 (4H, m), 2.94 (2H, t, J = 7.6Hz), 3.89 (3H, s), 4.86 ( 1H, q, J = 7.6Hz), 5.49 (1H, m), 7.07 (2H, d, J = 8.4Hz), 7.01-7.30 (7H, m).

[Example 2 1]

12- (4-chlorophenyl) -2,2-dichloro-12- (3-phenylpropaneamide)

12-acetamido-2,2-dichloro-12- (4-chlorophenyl) 12- (4-diphenyl) -2,2-diglycol instead of methyl dodecanoate -12- (3-Felpronamide) Using methyl dodecanoate and using the same method as in Example 2, the target product (yield 64%) was obtained as a colorless oil. _{1H-NMR (270MHz, CDC1 3} ) δ: 1.05-2.09 (16H, m), 2.34-2.68 (4H, m), 2.94 (2H, t, J = 7.6Hz), 4.92 (1H, m), 5.67 ( 1H, 'm)', '7.04 (' 2ΗΓ J = 8.6Hz), 6.96-7.28 (7H, m). [Example 2 2]

Production of 12- (4-chlorophenyl) -2,2-dichloro-12-methanesulfonamide methyl dodecanoate;

I

The target product (yield 71%) was obtained as a brown oil by using methanesulfonic acid amide instead of benzamide and using the same method as in Example 15.

1H-NMR (270MHz, CDC1 ₃ ) δ: 1.13-1.88 (16H, m), 2.40 (2Η, m), 2.59 (3H, s), 3.88 (3H, s), 4.41 (1H, q, J = 7.3 Hz), 4.85 (1H, m), 7.24 (1H, d, J = 8.6Hz), 7.35 (1H, d, J = 8.6Hz). [Example 2 3]

12- (4-Chlorophenyl) -2, 2-dioctyl chloride-Production of 12-methanesulfonamide dodecanoic acid;

12-acetoamide-2,2-dichloro-12- (4-chlorophenyl) 12- (4-chlorophenyl) -2, 2- in place of methyl dodecanoate The target product (yield 68%) was obtained as a colorless oil by using methyl dichloro-12-methanesulfonamide dodecanoate in the same manner as in Example 2.

1H-NMR (270 MHz, CDC1 ₃ ) δ: 1.16-1.82 (16H, m), 2.35-2.51 (2H, m), 2.61 (3H, s), 4.43 (1H, m), 5.39 (1H, m), 7.25 (2H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.6 Hz).

[Example 2 4]

12- (4-chlorophenol) -2, 2-dichloro-mouth mouth -12-hydroxy minododecanoic acid Chill production;

2,2-dichloro-12- (4-chlorophenyl) -12-methyl dodecanoate (550 mg, 1.35 mmol) (WO 0 4 no 1 0 3 9 4 6 no ), Hydroxyamine hydrochloride (103 mg, 1.48 mM), and sodium acetate (188 mg, 2.29 ra) were placed in an eggplant flask, and 4 mL of ethanol and 1 mL of water were added and heated to reflux for 4 hours. .

After cooling the reaction solution to room temperature, water and chloroform were added to separate the organic layer, which was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired product (525 mg, 92% yield) as pale yellow Obtained as an oil.

1H-NMR (400MHz, CDC1 ₃ ) δ 1.15-1.67 (14H, m), 2.40 (2H, m), 2.78 (2H, t, J = 8.0Hz), 3.89 (3H, s), 7.36 (2H , d, J = 8.6Hz), 7.52 (2H, d, J = 8.6Hz).

[Example 2 5]

12- (4-mouth mouth phenyl)-2, 2-di- mouth mouth mouth -12-production of hydroxymino-dodecanoic acid;

12-acetoamide-2,2-dichloro-12- (4-chlorophenyl) Instead of methyl dodecanoate 12- (4-chlorophenyl) -2, 2- The target product (yield 83%) was obtained as a colorless oil by using methyl dichloro-12-hydroxyminododecanoate in the same manner as in Example 2.

1H-NMR (270 MHz, CDC1 ₃ ) δ: 1.18-1.66 (14H, m), 2.44 (2H, m), 2.84 (2H, t, J = 7.8 Hz), 7.34-7.54 (4H, m).

[Example 2 6]

12-Azido-12- (4-chlorophenyl) -2,2-dioxy

Was obtained as a yellow oil.

1H-NMR (400MHz, CDC1 ₃ ) δ: 1.16-1.86 (16H, m), 2.41 (2H, m), 3.89 (3H, s), 4.39 (1H, t, J = 7.4Hz), 7.23 ( 2H, d, J = 6.6Hz), 7.35 (2H, d, J = 6.6Hz).

[Example 2 7]

12-Azido-12- (4-Chlorophenyl) -2,2-diglycol _Production of dodecanoic acid;

12-acetamido-2,2-dichloro-2-12- (4-phenyl) 12-azido-12- (4-chlorophenyl) -2,2-dichlorine dodecane instead of methyl dodecanoate Using methyl acid and the same method as in Example 2, the target product (yield 90%) was obtained as a colorless oil.

[Example 2 8]

12- (4-chlorophenol) — 2, 2-dichloro mouth-12— (4-tonoreens norephone amide) Production of methyl dodecanoate;

Instead of benzamide, 4-toluenesulfonic acid amide was used. The target product (yield 31%) was obtained as yellow crystals by using the same method. [Example 2 9]

12-(4-chlorophenol)-2, 2-dimethyl _Mouth —12— (4-Toluenesulfonamide) Production of dodecanoic acid

12-acetoamide-2, 2-dichloro 12- (4-chlorophenyl) 12- (4-cyclophenyl) instead of methyl dotecanate -2, 2-dichloro Mouth-12- (4-Tonoleenesulfonamide) Using methyl dodecanoate in the same manner as in Example 2, the target product (yield 72%) was obtained as a colorless oil. Next, various tests were performed using these compounds.

Test 1 ： Ligand screening of G PR 40 and GP R 120 by extracellular signal-regulated kinase (ERK) Atsey

The materials and methods used in Test 1 are as follows.

1. Protein recovery

(1) In this experiment, cell lines T XGPR 40 and TXGPR 120 were used for seeding in a 35 ram dish so that the cell number was 5 X 105 / dish. After confirming colonization in Dish, Doxycycline treatment (10 μg Doxycycl in was released from Itoda solution) and Starvation (replaced with FBS (-) Medium) was performed 28 hours before, and 20 hours later I was an

T X G P R 4 0 and T X G P R 1 2 0 are the

0 (h G P R 40) or human G P R 120 (h G P R 120) gene

It means a cell line that stably introduces GPR40 or GPR120 protein by introducing a plasmid incorporated into an expression vector that is expressed by doxycycline treatment.

(2) The ligand used is the long chain fatty acid derivative compound according to the present invention.

These were prepared by dissolving in DMSO and diluted 10-fold with Medium to make a total volume of 100 μ 1. In addition, DMS was used as a negative control, and PMA (Phorbol 12-myristate-13-acetate) was used as a positive and control. (3) Medium was removed from the dish of cells, and the total volume was 0.9 ml.

(4) Ligand solution was dripped from above the cell solution, and the dish was gently shaken to diffuse and allowed to react at room temperature.

(5) After the reaction for 5 minutes, the medium was discarded, and the medium remaining in the d i sh was removed on ice with an aspirator.

(6) 150 // 1 Lysis buffer (50mM HEPES (pH7.0), 150mM NaCl, 10% glycerol, 1% NonidetP- 40, 2mM MgCl 2, ImM EDTA, lOOm NaF, lOmM Sodiumphosphate, ImM Na 3 V0 4, 20 mM β-glycerophosphate, Proteinase Inhibitor) and the cells were collected with Cell Scraper.

(7) The collected liquid is mixed with 150 1 (equal volume) of 1 X SDS Sample Buffer (0.1M Tris-HCl (pH6.8), 4% SDS, 12% Mercaptoethanol, 20% glycerol, BPB) Used for Western Blotting below or stored at -20 ° C. . SDS-PAGE

(1) The crude enzyme solution mixed with SDS Sample Buffer was sonicated using a sonifier and then incubated at 90 ° C for 5 min.

(2) Centrifugation (15,000 rpm, 5 min, 4 ° C) with vortexing.

(3) Fill the electrophoresis tank with 1X SDS-PAGE Rising Buffer (25mM Tris, 0.2M Glycine, 1% SDS), set two 7.5% acrylamide gels, and remove the supernatant after centrifugation of the sample. Applied. Electrophoresis was performed at a constant current of 40 mA. (Approximately 80 to 90 min)

Blotting (Semi-Dry method)

(1) PVDF membrane f Size of genore lying together, soak in methanol ί cocoon for 15 sec, then transfer buffer C solution (25raM Tris, 0.02% SDS, 2% methanol, 40 mM 6-aminohexanoic acid) in Swelled for 15 min. The filter paper used for Blotting was cut to a size of lOcmX 10cm.

(2) Two filter papers soaked in A solution (0.3M Tris, 0.02% SDS, 2% methanol) in a Blotting device, and two filter papers soaked in B solution (25m Tris, 0.02% SDS, 2% methanol). I put a membrane on it. Furthermore, the gel after electrophoresis was placed thereon, and finally two filter papers soaked in C solution were overlaid and covered.

(3) Transfer was performed at 15 V for 30 minutes.

. Blocking

(1) The following operations are all performed at room temperature. After completion of the transfer, the membrane was transferred to a case containing 1 XTTBS (0.2 Tris, 1.5M NaCl, 0.2% Tween20) and washed for 15 minutes.

(2) Excluding TTBS, add about 10 ml of Block Ace and shake for 1 hour to block. did.

5. —Next antibody

(1) Primary antibodies (p44 / 42 MAP Kinase Antibody and Phospho-p44 / 42 MAP Kinase Antibody) were each diluted 1000 times with TTBS.

(2) After completion of Blocking, the Block Ace solution was removed, the primary antibody solution was added, and the reaction was carried out by shaking for 2 hours.

6. Secondary antibody

(1) The secondary rod (Anti-rabbit Ig, Horseradish Peroxidase linked F (ab) 2 fragment) was diluted 5000 times with TTBS.

(2) —The next antibody solution was removed and washed in TTBS for 5-10 minutes with shaking. Wash 3 times.

(3) TTBS was removed and the secondary antibody solution was added and shaken for 1 hour.

7. Detection

(1) 2 ml each of Detection Reagent 1 and Detection Reagent 2 in ECL kit were mixed on ice.

(2) The secondary antibody solution was removed from the membrane after the completion of the secondary antibody reaction, and the membrane was shaken in TTBS for 5 minutes and washed. Wash 3 times.

(3) The membrane was drained with force and placed in the knock, and 2 ml of Detection Reagent mixture was applied to one membrane.

(4) The membrane and film were brought into contact with each other for 5 minutes in the cassette and developed with an automatic processor.

8. Analysis

(1) Scan the film and import it to a computer, and digitize the band using the “Image J” application —————————————————————————————————————————————————————————————————— .

(2) Normalize by DMS0 and PMA, and compare the drug straightness. The test results for each ligand compound are shown in Figs. 1 to 4 and Table 1.

With respect to the long-chain fatty acid derivative compound according to the present invention, ligand screening of GP R 40 by the ER K assembly in Test Example 1 was performed. Among them, the results of the representative compounds of Examples 16, 6, 21, 2, 3, 25, 27, and 29 are shown in FIG.

Here, DM means DMS0 as a negative control, PMAί or positive, and Phorbol-12-myri state-13-ace tattoo as a control. LA means cis-phosphoric acid as a positive target. FIG. 1A shows a test compound using the cell line TXGPR 40. Examples 1 6, 2 1, 2 3, 2 9, 2 7, 2 5. Concentration 10 μM and 100 μ μ. FIG. 4 is a diagram showing an example of the total ERK detection result using a western blot during stimulation.

Fig. 1B shows test compounds using cell line TXGPR 40 (Examples 16, 2, 1, 2, 3, 29, 27, 25, concentrations 10 μΜ and 100 μΜ). FIG. 6 is a diagram showing an example of the detection result of phosphorylated ER による by a catalyst.

Fig. 1C shows the result of quantifying and graphing the band in Fig. 1 and shows E R Κ activity induced by compound stimulation of T XG P R 40. Specifically, the Phospho ERK / Total E RK values (vertical axis) at the concentrations of 10 and 100 μΜ of each of the compounds of Examples 16, 6, 21, 2, 3, 29, 27, 25. is there.

FIG. 2 is a graph showing the results of GPR 40 screening by ERK assembly using the cell line TXG PR 40 in Test Example 1. The vertical axis represents phospho E RK I total E RK. Normalize with DMS O and PMA and compare values between drugs. The concentration of the test compound is 10 μM and 100 / iΜ.

TXCONT without GPCR gene integration and cells not treated with Doxycycline (Dox (-)) are arranged as negative controls and treated with Doxycycline (Dox (+)). ERK activity of the compound Were compared. When GPR 40 protein is expressed in cell line TXGPR 40, Examples 4, 6, 8, 1 6, 2 1, 2 3, 2 5, 2 7, 2 9 strongly activated ERK .

FIG. 3 is a graph showing the results of comparison of ERK activity of each compound using the cell line T XGPR 120. Here, DM means DMS0 as a negative control, and PMA means Phorbo 12-myristate-13-acetate as a positive control. LA means cis-a-linolenic acid as a positive target.

Fig. 3A shows test compounds using cell line TXGPR 120 (with Doxycycline stimulation) (Examples 16, 2, 1, 2, 3, 2, 9, 27, 25, 8. Concentrations of 10 μM and 100 M.) It is a figure showing an example of the detection result of total ERK by Western blot at the time of stimulation.

FIG. 3B shows a test compound using the cell line TXGPR 1 2 0 (Examples 16, 2, 1, 23, 29, 27, 25, 8. Concentrations 10 / x M and 100 M ₀ ) FIG. 6 is a diagram showing an example of the detection result of phosphorylated ERK by a wet stamp slot during stimulation. FIG. 3C shows the result of numerically graphing the band of FIG. 3B, and shows the ERK activity induced by the compound stimulation of T XG PR 1 20. Specifically, Phospho ER at 10 M and 100 μM concentrations of Examples 1, 6, 21, 23, 29, 27, 25, 8 K / TotalE RK value (vertical axis).

FIG. 4 is a graph showing the results of comparing the ERK activity of each compound using the cell line T XGPR 120. Normalized by DMS O and PMA and compared values between drugs.

TXC ON T without GPR integration and cells not treated with Doxycycline (Dox (-)) are arranged as negative controls and treated with Doxycycline (Dox (+ )) The ERK life of the compounds was compared. The concentration of the test compound is 10 μM and 100 // Μ.

As a result, when GPR 1 2 0 protein was expressed in cell line Τ XGPR 1 2 0, Examples 4, 6, 8, 1 6, 2 1, 2 3, 2 5 and 2 9 were strongly ER Κ Activated. The above results are summarized in Table 1.

It means full. From this result, the compounds of Examples 4, 6, 8, 1 6, 2 1, 2 3, 2 5, 2 7 and 29, especially those of Examples 1 6, 2 1, 2 3, 2 7 and 29 The effectiveness of the compound as an agonist for GPR 40 was confirmed, and the compounds of Examples 4, 6, 8, 16, 2 1, 2 3, 25, and 29 were agonists for GPR 120 As a result, its effectiveness was confirmed. Further, from the viewpoint of selectivity, it was confirmed that the compound of Example 27 was effective as a selective agonist for GPR 40, and Examples 4, 6, 8, and It was confirmed that 25 compounds have efficacy as selective agonists for GPR 1 20. Furthermore, the compounds of Examples 16, 21, 21, 3 and 29 were confirmed to be effective as agonists against both GPR 120 and GPR 40. Industrial applicability

GPR 1 2 0 is a cell that possesses GPR 1 2 0 cells as described in papers and patents (Nature Medicine, 11 (1), 90-94, 2005 and JP 2 0 5 — 1 5 3 5 8). Promotes the release of GLP-1 or CCK from the body, coordinated promoter of digestive activity, therapeutic agent of digestive activity disorder; anti-obesity therapeutic agent by appetite suppression, therapeutic agent of bulimia; promotion of differentiation and proliferation of knee cells Diabetes preventive and therapeutic agents, especially therapeutic effect promoters when transplanting β cells or their progenitor cells; nerve cell plasticity, nerve transplantation by viability maintenance, therapeutic accelerators during nerve junction, or Alzheimer's disease It is effective as a therapeutic agent for intestinal motility during enteritis due to normalization of intestinal motility; a therapeutic agent for lung diseases such as COPD (chronic obstructive pulmonary disease) by promoting surfactant secretion in the lung; Is that It is clear from the following paper.

(i) Cooperative promoter of digestive activity, therapeutic agent for digestive activity disorder;

Nutrition 2001; 17 (3): 230-5, Best Pract Res Clin Endocrinol Metab 2004; 18 (4): 569-86, Dig Dis Sc i .2004; 49 (3): 36 to 9, Endocrinology

2004; 145 (6): 2653-9, Pharmacol Toxicol 2002; 91 (6): 375-81, Gastroenterology 2004; 127 (3): 957 69, Best Pract Res Clin Endocrinol Metab 2004; 18 (4): 569- 86, Med Res Rev. 2003; 23 (5): 559-605, Med Res Rev. 2003; 23 (5): 559-605, Horm Metab Res 2004; 36 (l 1-12): 842-5, Horm Metab Res 2004; 36 (11-12): 842-5, Am J Phyusiol Endcrinol Metab

2004; 287 (6): E1209-15, Dig Dis Sci 1998; 43 (4): 799-805,

(ii) anti-obesity therapeutic agent by appetite suppression, bulimia therapeutic agent;

Physiol Behav. 2004; 83 (4): 617-21, Best Pract Res Cli Endocrinol Metab. 2004; 18 (4): 569-86, Trends Endcrinol Metab.2004; 15 (6): 259-63 Cuur Drug Target CNS Neurol disord 2004; 3 (5): 379-88

(iii) Spleen β-cell differentiation / proliferation-promoting agent by promoting the differentiation / proliferation of β-cells, especially the therapeutic effect-promoting agent during β-cell or its precursor cell transplantation treatment;

Diobetology, 2005; 48 (9): 1700-13, Diabetes 2004; 53suppl 3: S225-32, Hormone Metab Res. 2004 (11_12): 766-70, Hormone Metab Res. 2004, 36 (11-12): 846 -51

(iv) Nerve plasticity, nerve transplantation by viability maintenance action, treatment promoting agent at the time of nerve junction or treatment for diseases caused by neuronal disorders such as Alzheimer's disease; Curr Drug Target CNS Neurol Disord 2002; 1 (5): 495 -510, Curr Drug Targets. 2004; 5 (69: 565-71, Curr Alzheimer Res 2005, 2 (3): 377-85 (v) a therapeutic agent for intestinal motility abnormalities during enteritis due to normalization of intestinal motility;

Drug 2003; 63 (12): 1785-97, Br J Pharmacol. 2004; 141 (8): 1275-84, (vi) Lung disease therapeutic agents such as COPD (chronic obstructive pulmonary disease) by promoting surfactant secretion in the lung;

Endocrinology. 1998; 139 (5): 2363-8. Am J Respir Crit Care Med. 2001; 163 (4): 840-6.

In addition, as described above, GPR 40 agonist is a therapeutic agent for diseases involving GPR 40, particularly diseases caused by abnormal physiological functions via GPR 40, specifically diabetes caused by promotion of insulin secretion. Therapeutic or preventive agent; Knee β-cell differentiation and proliferation promoter;] Improving the survival rate of transplanted cells at the time of 3-cell transplantation; Preventing the transition from hyperglycemia, insulin resistance, obesity, etc. to diabetes Diabetes preventive agent: Effective as a preventive or therapeutic agent for metabolic syndrome.

In addition, a compound having agonist activity for GPR 40 and GPR 120 is a disease associated with GPR 40 and / or GPR 120, particularly G GR 40 and 及び or GPR 120. Therapeutic or prophylactic agent for the above-mentioned diseases caused by abnormal physiological functions, for example, antidiabetic agent or prophylactic agent by promoting insulin secretion; spleen] 3-cell differentiation and proliferation promoting agent; hyperglycemia, insulin It is effective as a prophylactic or therapeutic agent for metabolic syndrome, which prevents the transition from resistance and obesity to diabetes.

Claims

The scope of the claims

1. A long-chain fatty acid derivative compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. COOR (I)

[Where

m means an integer from 0 to 6;

'n means an integer from 5 to 20;

m + n means an integer of 20 or less;

0 R represents a hydrogen atom or an ester residue;

Y ¹ and Y ² are the same or different halogen atoms,

Ring Q means a carbocyclic group which may be condensed or a heterocyclic group which may be condensed; X ¹ , X ² and X ³ are the same or different and each represents a hydrogen atom, a halogen atom, a _4- alkylene; Group, C ₄ -anoloxy group, C] — _4- anoloxy sulfonyl group, halo C, ₄ alkyl group, nitro group, amino group, hydroxyl group, cyan group, mercapto group, — alkylthio group, sulfonamido Group, acetylamino group, C ₆ alkylamino group, di. — ₆ alkylamino group, carboxy group, aryloxy group, aryl group, aralkino group, benzoyl group, carboxy Ci ₄ alkyl group, oxo group, methylenedioxy group, ethyloxydioxy group or acetoxy group;

W represents —C (═N—OR ¹ ) —, —CH (NR ² R ³ ) — or —CH (N ₃ ) —; R ¹ represents a hydrogen atom or a C ₆ , ₆ alkyl group. ;

1 ² and 1¾ ³ are the same or different and each represents a hydrogen atom, a C _8, an alkyl group, an aralkyl group, an aryl alkenyl group, an aryl alkynyl group, S O5 ₂ R (where R ⁴ is a C ₆ alkyl Group, aryl group or aralkyl group),-COR ⁵ (R ⁵ means ₆ alkyl group, aralkyl group, aralkyl group or aralkyl group), or R ² and R ³ Means a saturated heterocycle having at least one nitrogen atom formed together with an adjacent nitrogen atom.

Here, the alkyl group may be substituted with 1 to 3 identical or different substituents selected from Group A below. In addition, the aralkyl group, the aralkylalkenyl group, and the aralkylalkynyl group are selected from the following group B 1 To 3 identical or different substituents may be substituted.

Halogen atom, ^^ acid group,. ] -6 alkoxy groups, amino groups,

Noreamino group, di-C ₆ alkylamino group, carbonyl group,

A xoxycarbonyl group, a cyano group and an acyl group;

Halogen atom, hydroxyl group, ₆ alkoxy group, C, ₆ anolalkyl group, amino group, C! — 6 alkylamino group, dizyl] — ₆ alkylamino group, carbonyl group, C〗 ₆ alkoxycarbonyl group, cyano A group and an acyl group; R ² and X ¹ may be combined with an adjacent ring Q to form a condensed ring. 2. Y ¹ and Y ² are both chlorine atoms, and ring Q is an aromatic carbocyclic group that may be condensed, a saturated carbocyclic group that may be condensed, or an aromatic heterocycle that may be condensed. The long-chain fatty acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a cyclic group or a saturated heterocyclic group which may be condensed.

3. The long-chain fatty acid derivative compound or pharmaceutical according to claim 2, which is represented by the following general formula (II), wherein ring Q is a phenyl group or a C _{3 8} cycloalkyl group, and R is a —6 alkyl group. Its acceptable salt.

-C00R (II)

(Here, ring Q ′ means a phenyl group or a C _3-8 cycloalkyl group.) 4. Ring Q is a funil group, and R is a hydrogen atom. 4. The long-chain fatty acid derivative compound according to claim 3, which is a 2,2-dichloroalkanecarboxylic acid derivative, or a pharmaceutically acceptable salt thereof. 2) _m W (CH ₂ ) — C-COOH (III)

(Here, X means a halogen atom.)

5. The long-chain fatty acid derivative compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ² is a hydrogen atom.

6. m is 0,

n is an integer from 6 to 1 4

W is -C (= N_OR ¹ )-, — CH (NR ² R ³ )-or -CH (NJ- R ¹ is a hydrogen atom,

R ² is a hydrogen atom,

R ³ is C ₂ - ₆ alkyl group, Ararukiru group, § Li Ruarukeniru group, C -! 6 alkylsulfonyl group, - S_〇 ₂ R ⁴ (where, R ⁴ is, C] - ₆ alkyl group, Ariru group or An aralkyl group.) Or — COR ⁵ (R ⁵ is

C, means a _6- alkyl group, an aryl group, an aralkyl group, or an arylalkenyl group. ) And

X ¹ , X ² and X ³ are the same or different and each is a hydrogen atom or a halogen atom

The long-chain fatty acid derivative compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. The long-chain fatty acid derivative compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the long-chain fatty acid derivative compound is a 2,2-dialkyl carboxylic acid derivative selected from the following compound group.

(1) 12-acetoamide -2, 2-dichloro-12- (4-chlorophenyl) methyl dodecanoate,

(2) 12-acetamido-2,2-diglycol -12- (4-chlorophenyl) dodecanoic acid,

(3) 2,2-Dioxy-Methyl-12- (4-Mixical Methyl) -12-Methyl dodecanoate,

(4) 2,2-Dichloro-12- (4-chlorophenol) -12-propanamide dodecanoic acid,

(5) 12-butaneamide-2,2-dichloro-12- (4-phenyl) methyl dodecanoate,

(6) 12-butane amide -2, 2-diglycol oral -12- (4-chlorophenyl) dodecanoic acid,

(7) 2, 2-Dimethyl Mouth- 12- (4-Chlorophenyl) -12- (3-Methylbutaneamide) Methyl dodecanoate,

(8) 2, 2-Dimethyl Mouth- 12- (4-Chlorophenyl) -12- (3-Methylbutaneamide) Dodecanoic acid,

(9) 2,2-Dichloro-12- (4-chlorophenyl) -12-ethylaminomethyl dodecanoate,

(10) 2,2-Dichloro-12- (4-chlorophenyl) -12-ethylaminododecanoic acid,

(12) 2,2-dichloro-12- (4-chlorophenol) -12-propylamino dodecanoic acid,

(13) 2,2-Dichloro-12- (4-chlorophenol) -12- (3-methylbutinoreamino) methyl dodecanoate,

(14) 2, 2-Dimethyl Mouth-12- (4-Mix Mouth Phenyl) -12- (3-Methylbutylamino) Dodecanoic acid,

(15) 12-benzamide-2,2-dimethyl mouth mouth-12- (4-chlorophenyl) methyl dodecanoate,

(16) 12-Benzamide-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid,

(17) 12-Benzylamino-2,2-dioxymethyl- 12- (4-chlorophenyl) methyl dodecanoate,

(18) 12-Benzenorea Mino-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid,

(19) 12- (4-Clorophenyl) -2,2-Dichloro-methyl 12-cinnamamide dodecanoate,

(20) 12— (4-Mouth-Phenol) —2, 2-Di-Cut Low 12— (3-Phenyl Promamide) Methyl Dodecanoate,

(21) 12- (4-click throat Hue sulfonyl) - 2, 2-dichloroethylene B B - 12- (3-Fuenirupuronoヽ⁰ Nami de) dodecanoic acid,

(22) 12- (4-chlorophenol) -2-2,2-dichloro-12-methansenorephone amide methyl decanoate,

(23) 12- (4-chlorophenol) — 2, 2—Dichloro-12-methansolephone amide dodecanoic acid,

(24) 12- (4-chlorophenol) -2,2-dichloro-12-hydroxymethyl dodecanoate,

(25) 12- (4-chlorophenyl) -2,2-dichloro-12-hydroxyminododecanoic acid,

(26) 12-azido-12- (4-chlorophenyl) -2,2-dioctylmethyl dodecanoate,

(27) 12-Azido-12- (4-chlorophenyl) -2,2-dichlorododecanoic acid,

(28) 12- (4-chlorophenyl) -2,2-dichloro-12- (4-toluenesulfonamide) methyl dodecanoate, and

(29) 12— (4-Mouth Mouth Feninore) — 2, 2—Dict Mouth Mouth — 12— (4-Tonorenore Noramide) Dodecanoic acid.

2, 2-dichloroalkanecarboxylic acid derivatives

(2) 12-acetoamide -2, 2-dichloro-12- (4-chlorophenyl) dodecanoic acid, (4) 2, 2 -dichloro- 12- (4-chloro (Phenyl) -12-propaneamide dodecanoic acid, (6) 12-butaneamide -2, 2-dichloric acid -12- (4-chlorophenyl) dodecanoic acid, (8) 2, 2-dichloromethane B-12- (4-chlorophenol) -12- (3-methinolevbutaneamide) dodecanoic acid,

(10) 2,2-dichloro-12- (4-chlorophenyl) -12-ethylaminododecanoic acid, (12) 2,2-dichloro-12- (4-chlorophenyl) -12-propylaminododecanoic acid,

(14) 2, 2-Dimethyl Mouth- 12- (4-Mouth Mouth Phenyl) -12- (3-Methylbutylamino) Dodecanoic acid

(16) 12-Benzamido-2,2-dichloro-12- (4-chlorophenol) dodecanoic acid, (18) 12-benzylamino-2,2-dichloro-12 (4-chlorophenyl) dodecanoic acid,

(21) 12— (4-mouth mouth phenyl) — 2, 2— Dike mouth mouth— 12- (3-phenylprono ヽ. Amide) dodecanoic acid,

(23) 12- (4-Chlorophenyl) -2, 2-Dichloro-12-methansnorephone amide dodecanoic acid,

(25) 12- (4-Chlorophenyl) -2,2-Diglycolate mouth-12-Hydroxyminododecanoic acid

(27) 12-Azido-12- (4-chlorophenyl) -2,2-dichlorododecanoic acid, or (29) 12- (4-chlorophenyl) -2,2-dichloro- 12- (4-Toluenesulfonamide) Dodecanoic acid

The long-chain fatty acid derivative compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. 2, 2-Dichloroalkanecarboxylic acid derivative

(1) 12-acetamido-2,2-dichloro-12- (4-chlorophenyl) methyl dodecanoate,

(3) 2,2-dichloro-12- (4-chlorophenyl) -12-propanamide methyl dodecanoate,

(5) 12-butaneamide-2,2-dichloro-12- (4-chlorophenyl) methenole dodecanoate,

(7) 2,2-Dimethyl--12- (4-Dimethyl) -12- (3-methylbutanamide) methyl dodecanoate,

(9) 2,2-dichloro-12- (4-chlorophenyl) -12-ethylamino dodecanoic acid methylol,

(13) 2,2-Dichloro-12- (4-chlorophenyl) -12- (3-methylbutylamino) methyl dodecanoate,

(15) 12-benzamide-12- (4-chlorophenol) -2,2-dichlorododecanoic acid methinole,

(17) 12-Benzylamino-2, 2-Dimethyl Mouth-12- (4-Chlorophenyl) Dodecane Methyl acid,

(19) 12- (4-Chlorophenyl) -2,2-dioxymethyl- 12-cinnamamide methyl dodecanoate,

(20) 12- (4-diphenyl) -2, 2-diglycol- 12- (3-phenylpronamide) methyl dodecanoate,

(22) 12- (4-chlorophenyl) -2,2-dichloro-12-methanesulfonamide methyl decanoate,

(24) 12- (4-Chlorophenyl) -2,2-dioxy -12-hydroxymethyl minododecanoate,

(26) 12-Azide _12- (4-Clorophenyl) -2,2-Dichloromethyl dodecanoate, or

(28) 12- (4-diphenyl) -2, 2-diglycol- 12- (4-toluenesulfonamide) methyl dodecanoate

10. A G protein-coupled receptor comprising, as a ligand, a fatty acid containing as an active ingredient the long-chain fatty acid derivative compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof. (GPCR) agonist.

1 1. The G protein-coupled receptor agonist according to claim 10, wherein the G protein-coupled receptor (GPCR) force G P R 1 2 0 is used.

1. The G protein-coupled receptor agonist according to claim 10, wherein the G protein-coupled receptor (GPC R) force is G P R 40.

1 3. A pharmaceutical composition comprising the long-chain fatty acid derivative compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient.

1 4. Appetite regulating agent, anti-obesity agent, diabetes treatment or prevention agent, knee] 3 cell differentiation and proliferation promoter, metabolic syndrome treatment agent, digestive system disease treatment agent or prevention agent, neuropathy treatment agent The pharmaceutical composition according to claim 12, which is a prophylactic agent, a psychiatric disorder therapeutic agent or prophylactic agent, a pulmonary disease therapeutic agent or prophylactic agent, or a pituitary hormone secretion deficiency therapeutic agent.

1 5. A lipid-flavored seasoning containing the long-chain fatty acid derivative compound or salt thereof according to any one of claims 1 to 9 as an active ingredient.