JP2010132590A - Oxadiazole compound - Google Patents

Abstract

A compound useful as an anti-obesity drug is provided.
The inventors of the present invention have studied compounds having a DGAT1 inhibitory action, confirmed that the oxadiazole compounds of the present invention have an excellent DGAT1 inhibitory action, and completed the present invention. The oxadiazole compound of the present invention has a DGAT1 inhibitory action, and can be used as a preventive and / or therapeutic agent for obesity, type II diabetes, fatty liver, and their peripheral diseases. The compound of formula (I) has structural features in that the amino group at position 5 of 1,3,4-oxadiazole is substituted with at least one sp ³ carbon, and the ring structure of the benzene ring It is not substituted with sp ² carbon, including carbon.
[Selection figure] None

Description

  The present invention relates to an oxadiazole compound useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating obesity.

  Obesity is a condition in which the balance between energy intake and energy consumption is lost in the living body, and excess energy accumulates excessively as triglycerides, mainly triglycerides in adipose tissue. Insulin resistance, diabetes, arteriosclerosis, non-alcoholic fatty He is deeply involved in the onset and progression of diseases such as hepatitis or hypertension. It is also known that accumulation of excess triglycerides in the liver, muscle and the like other than adipose tissue causes dysfunction in those tissues. In recent years, the number of obese patients has increased with changes in lifestyle habits, but the treatment methods for them are limited, and the development of new anti-obesity drugs is desired.

  DGAT is an enzyme involved in the final step of the triglyceride biosynthetic pathway, that is, a reaction for generating triglyceride from diacylglycerol and fatty acyl-CoA, and subtypes of DGAT1 and DGAT2 have been reported. DGAT1 has low amino acid sequence homology with DGAT2 and high homology with ACAT (Proc. Nat. Acad. Sci. 95: 13018-13023, 1998; J. Biol. Chem. 276: 38870). -38876, 2001). As a phenotype of DGAT1 knockout mice, resistance to obesity induced by a high fat diet, improved insulin resistance, increased leptin sensitivity, decreased liver fat mass, increased energy consumption, etc. have been reported (Nature Genetics 25: 87-90, 2000; J. Clin. Invest. 109: 1049-1055, 2002). DGAT1 hetero knockout mice show intermediate phenotype between wild type and homo-deficient mice (Arterioscler. Thromb. Vasc. Biol. 25; 482-486, 2005), DGAT1 inhibition is obese, type II diabetes It is considered promising as a target for pharmacotherapy of fatty liver and surrounding diseases.

［式中、R¹は置換されていてもよいアリール若しくはヘテロアリールを示す。その他の記号は当該公報を参照のこと。］ For example, it has been reported that a compound represented by the following formula has a DGAT1 inhibitory action (Patent Document 1).

[Wherein, R ¹ represents an optionally substituted aryl or heteroaryl. For other symbols, see the publication. ]

［式中の記号は当該公報を参照のこと。］ In addition, it has been reported that a compound represented by the following formula has a DGAT1 inhibitory action (Patent Document 2).

[See the official gazette for symbols in the formula. ]

［式中の記号は当該公報を参照のこと。］ Further, it has been reported that a compound represented by the following formula has a DGAT1 inhibitory action (Patent Document 3).

[See the official gazette for symbols in the formula. ]

［式中の記号は当該公報を参照のこと。］ In addition, a compound represented by the following formula has been reported to have a DGAT1 inhibitory action, and a compound having a structure common to that of the oxadiazole compound according to the present invention is disclosed as a production intermediate (patent) Reference 4).

[See the official gazette for symbols in the formula. ]

  However, none of the above documents disclose or suggest the oxadiazole compound according to the present invention.

International Publication No. WO 2006/064189 Pamphlet International Publication No. WO 2007/138311 Pamphlet International Publication No. WO 2007/138304 Pamphlet International Publication No. WO 2007/141517 Pamphlet

  Provided is an oxadiazole compound useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating obesity.

（式中、
R^1Aは、
（１）群Zより選択される１つ以上の基で置換されていてもよいC_2-10アルキル、
（２）群Zより選択される１つ以上の基で置換されていてもよいC_3-10シクロアルキル、又は、
（３）-X¹-R^1Cで示される基であり、
群Zは、ハロゲン、-R⁰、-O-R⁰、シアノ、-OH、-SO₂-C_1-6アルキル、-O-SO₂-C_1-6アルキル、及びC_3-8シクロアルキルからなる群であり、
R⁰は、-OH、-O-C_1-6アルキル、-SO₂-C_1-6アルキル、及びハロゲンからなる群より選択される１つ以上の基で置換されていてもよいC_1-6アルキルであり、
X¹は、C_1-6アルキレン、C_2-3アルキレン-O-C_0-3アルキレン、C_3-6シクロアルカンジイル、又はC_3-6シクロアルカンジイル-O-C_0-3アルキレンであり、
R^1Cは、
（１）群Zより選択される１つ以上の基で置換されていてもよいC_3-10シクロアルキル、
（２）群Zより選択される１つ以上の基で置換されていてもよいC_6-14アリール、又は、
（３）群Zより選択される１つ以上の基で置換されていてもよい芳香族ヘテロ環であり、
R^1Bは、-H、又はC_1-6アルキルであり、
X²は、結合、又はC_1-6アルキレンであり、
R^2Aは、-CO₂H、-CO₂-C_1-6アルキル、又は-CONH₂であり、
R^2Bは、-H、又はC_1-6アルキルであり、
R¹¹、R¹²、R¹³、及びR¹⁴は、同一又は異なって、-H、C_1-6アルキル、又はハロゲンである。）
なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。 As a result of intensive studies on a compound having a DGAT1 inhibitory action, the present inventors have found that the oxadiazole compound of the present invention has a DGAT1 inhibitory action and completed the present invention.
That is, the present invention relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof, and a pharmaceutically acceptable excipient.

(Where
R ^1A is
(1) C _2-10 alkyl optionally substituted with one or more groups selected from group Z;
(2) C _3-10 cycloalkyl optionally substituted with one or more groups selected from group Z, or
(3) a group represented by -X ¹ -R ^1C
Group Z consists of halogen, -R ⁰ , -OR ⁰ , cyano, -OH, -SO ₂ -C _1-6 alkyl, -O-SO ₂ -C _1-6 alkyl, and C _3-8 cycloalkyl. A group,
R ⁰ is, -OH, -OC _1-6 alkyl, -SO ₂ -C _1-6 alkyl, and one or more C _1-6 alkyl optionally substituted with a group selected from the group consisting of halogen And
X ¹ is C _1-6 alkylene, C _2-3 alkylene-OC _0-3 alkylene, C _3-6 cycloalkanediyl, or C _3-6 cycloalkanediyl-OC _0-3 alkylene,
R ^1C
(1) a C _3-10 cycloalkyl optionally substituted with one or more groups selected from group Z;
(2) C _6-14 aryl optionally substituted with one or more groups selected from group Z, or
(3) an aromatic heterocycle optionally substituted with one or more groups selected from group Z;
R ^1B is -H or C _1-6 alkyl;
X ² is a bond or C _1-6 alkylene;
R ^2A is -CO ₂ H, -CO ₂ -C _1-6 alkyl, or -CONH ₂ ;
R ^2B is -H or C _1-6 alkyl;
R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are the same or different and are —H, C _1-6 alkyl, or halogen. )
Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol indicates the same meaning.

The present invention also relates to a pharmaceutical composition for treating obesity comprising a compound of formula (I) or a salt thereof. This pharmaceutical composition includes a therapeutic agent for obesity containing the compound of formula (I) or a salt thereof.
The present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of obesity, and the administration of an effective amount of a compound of formula (I) or a salt thereof to a patient. Relates to a method for treating obesity.

The compound of formula (I) has structural features in that the amino group at position 5 of 1,3,4-oxadiazole is substituted with at least one sp ³ carbon, and the ring structure of the benzene ring It is not substituted with sp ² carbon, including carbon.

  The compound of formula (I) or a salt thereof has a DGAT1 inhibitory action and can be used as an agent for preventing and / or treating obesity.

Hereinafter, the present invention will be described in detail.
In the present specification, “alkyl” is linear or branched alkyl; “C _2-10 alkyl” is linear or branched alkyl having 2 to 10 carbon atoms, for example, Ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decanyl and the like, and in another embodiment, ethyl, isobutyl, neopentyl; “C _1-6 alkyl” is linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc. In another embodiment, methyl, ethyl, propyl, and isopropyl are used. In another embodiment, methyl and ethyl are used. It is methyl.
“Alkylene” is linear or branched alkylene; “C _0-3 alkylene” is linear or branched alkylene having 0 to 3 carbon atoms, such as a bond, methylene, Ethylene, trimethylene, methylmethylene, methylethylene, and the like. In another embodiment, they are a bond, methylene, and ethylene; “C _2-3 alkylene” is a linear or branched carbon having 2 to 3 carbon atoms. For example, ethylene, trimethylene, methylmethylene, methylethylene, etc., and in another embodiment, is ethylene; “C _1-6 alkylene” is a linear or branched carbon number of 1 to 6 alkylene, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, methylethylene, Methyl ethylene, ethyl ethylene, etc., in another embodiment, methylene, ethylene, methylmethylene, ethyl methylene, dimethyl methylene, methyl ethylene, in a further aspect methylene, ethylene.
“Cycloalkyl” is a saturated hydrocarbon ring group, the cyclohexyl may have a bridge, may be condensed with a benzene ring, and one or two elements constituting the ring are O, It may be replaced with a heteroatom selected from N and S. Accordingly, “C _3-8 cycloalkyl” is a saturated hydrocarbon ring group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. “C _3-10 cycloalkyl” is a saturated hydrocarbon ring group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecanyl, norbornyl, Bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [4.1.0] heptyl, bicyclo [3.2.1] octyl, adamantyl, 1,2,3,4-tetrahydronaphthyl, indanyl, tetrahydropyranyl , Tetrahydrothiopyranyl and the like.
“C _3-6 cycloalkanediyl” is a divalent group of a cycloalkyl having 3 to 6 carbon atoms in the above cycloalkyl, such as cyclopropane-1,1-diyl, cyclopropane-1,2- Diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, cyclopentane-1,3 -Diyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl and the like. Diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, and in another embodiment, cyclopropane-1,1-diyl Diyl and cyclopropane-1,2-diyl.
“C _6-14 aryl” is a monocyclic to tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms, for example, phenyl or naphthyl, and in another embodiment, phenyl.
The “aromatic heterocycle” is a monocyclic to bicyclic aromatic heterocyclic group containing one or more heteroatoms selected from O, N, and S as ring-constituting atoms, such as furyl, Examples include pyrrolyl, thienyl, imidazolyl, oxazolyl, thioxazolyl, oxadiazolyl, thiooxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, and another embodiment is pyridyl.
“Halogen” means —F, —Cl, —Br, —I. In another embodiment, it is —F, —Cl, —Br, and in another embodiment, it is —F, —Cl. In still another embodiment, -F.

In the present specification, “optionally substituted” means unsubstituted or substituted with 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.
One embodiment of “Group Z” is a group consisting of halogen, —R ⁰ , —OR ⁰ , cyano, and —OH, and in another embodiment, halogen may be substituted with one or more halogens. A group consisting of C _1-6 alkyl and cyano, and in yet another embodiment, a group consisting of halogen and C _1-6 alkyl _optionally substituted with one or more halogens. In the case where R ^1A is C _4-10 alkyl optionally substituted with one or more groups selected from group Z, one embodiment of group Z is a group consisting of halogen and —OR ^0. There, in another embodiment a group consisting of halogen, and one or more good -OC _1-6 alkyl optionally substituted by halogen, in a further aspect halogen, and -OC _1-6 alkyl It is a group.

Certain embodiments of the compound of formula (I) are shown below.
(1) The compound wherein R ^1A is C _3-10 cycloalkyl optionally substituted with one or more groups selected from group Z. In another embodiment, R ^1A is a group represented by -X ¹ -R ^1C , X ¹ is methylene, methylmethylene, ethylene, 1-methylethylene, or 2-methylethylene, and R ^1C is from group Z A compound which is C _3-10 cycloalkyl optionally substituted with one or more selected groups, or phenyl optionally substituted with one or more groups selected from group Z.
(2) The compound wherein R ^1B is —H. In another embodiment, the compound wherein R ^1B is methyl.
(3) The compound wherein R ¹¹ is —H. In another embodiment, the compound wherein R ¹¹ is methyl. In yet another embodiment, the compound in which R ¹¹ is fluoro.
(4) The compound wherein R ¹² is —H. In another embodiment, the compound wherein R ¹² is methyl. In yet another embodiment, the compound in which R ¹² is fluoro.
(5) The compound wherein R ¹³ is —H. In another embodiment, the compound wherein R ¹³ is methyl. In yet another embodiment, the compound wherein R ¹³ is fluoro.
(6) The compound wherein R ¹⁴ is —H. In another embodiment, the compound wherein R ¹⁴ is methyl. In yet another embodiment, the compound in which R ¹⁴ is fluoro.
(7) A compound in which X ² is a bond. In another embodiment, the compound wherein X2 is methylene.
(8) The compound wherein R ^2A is —CO ₂ H. In another embodiment, the compound wherein R ^2A is —CO ₂ —C _1-6 alkyl. In yet another embodiment, the compound in which R ^2A is —CONH ₂ .
(9) The compound wherein R ^2B is —H. In another embodiment, the compound wherein R ^2B is methyl.
(10) A compound which is a combination of two or more of the groups described in (1) to (9) above.

Examples of specific compounds included in the present invention include the following compounds.
Trans-4- [4-({[5- (cyclohexylamino) -1,3,4-oxadiazol-2-yl] carbonyl} amino) phenoxy] cyclohexanecarboxylic acid,
Cis-4- (4-{[(5-{[4- (trifluoromethyl) benzyl] amino} -1,3,4-oxadiazol-2-yl) carbonyl] amino} phenoxy) cyclohexanecarboxylic acid,
Cis-4- {4-[({5-[(2,4,6-trifluorobenzyl) amino] -1,3,4-oxadiazol-2-yl} carbonyl) amino] phenoxy} cyclohexanecarboxylic acid ,
Cis-4- (4-{[(5-{[(2S) -2-phenylpropyl] amino} -1,3,4-oxadiazol-2-yl) carbonyl] amino} phenoxy) cyclohexanecarboxylic acid,
Cis-4- (4-{[(5-{[4- (trifluoromethyl) cyclohexyl] amino} -1,3,4-oxadiazol-2-yl) carbonyl] amino} phenoxy) cyclohexanecarboxylic acid,
Cis-4- {4-[({5-[(2-cyclohexylethyl) amino] -1,3,4-oxadiazol-2-yl} carbonyl) amino] phenoxy} cyclohexanecarboxylic acid.

In the compound of the formula (I), tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
In addition, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

  Furthermore, this invention also includes the pharmaceutically acceptable prodrug of the compound shown by a formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.

  The salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.

  Furthermore, the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

(Production method)
The compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
Moreover, the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate, or reacts further using the obtained compound of the formula (I) in the same manner as the protecting group. Can be manufactured. The reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference literature attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.

(First manufacturing method)

  This production method is a method for producing the compound of the present invention by adding an aminocarbonyl group to compound 1-a and cyclizing the resulting compound 1-b. In addition, these processes can isolate | separate a product after the process 1, and can also perform the process 2, and the process 1 and the process 2 can also be performed continuously.

(Process 1)
This step is a step of adding an aminocarbonyl group to compound 1-a.
When amine HN (—R ^1A ) (— R ^1B ) is used, carbonyldiimidazole, phosgene, triphosgene or the like can be used as the carbonyl source. This reaction is carried out by stirring in a solvent inert to the reaction or in the absence of a solvent, usually at 0 ° C. to heating, preferably at room temperature to heating, usually for 1 hour to 120 hours. At this time, a base such as triethylamine, diisopropylethylamine, or pyridine may be added in order to facilitate the reaction. The solvent used here is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane. Aprotic polar solvents such as dimethylformamide (DMF), dimethylacetamide, and dimethylsulfoxide (DMSO);
When R ^1B is —H, isocyanate R ^1A —N═C═O can be used. In this case, the reaction is carried out in a solvent inert to the reaction or in the absence of a solvent at room temperature to It is usually carried out by stirring for 1 hour to 120 hours under heating, preferably under heating. Although the solvent used here is not specifically limited, Ethers; Halogenated hydrocarbons; Aprotic polar solvents; In addition, isocyanate can also be produced | generated and used in a reaction system by the Curtius rearrangement using a corresponding carboxylic acid and diphenylphosphoric acid azide, for example.

(Process 2)
This step is a step of producing the compound of the present invention by cyclizing compound 1-b.
The reaction is carried out in an inert solvent or in the absence of a solvent, an activator such as p-toluenesulfonyl chloride, phosphoryl chloride, thionyl chloride, 2-chloro-1,3-dimethylimidazolium chloride; an acid such as polyphosphoric acid; or Dehydrating agent such as Burgess reagent; or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or its salt, and triethylamine, diisopropylethylamine, pyridine when isothiocyanate is used instead of isocyanate in Step 1 In the presence of a base such as room temperature to heating, preferably under heating, usually by stirring for 1 hour to 120 hours. Although the solvent used here is not specifically limited, Ethers; Halogenated hydrocarbons; Aprotic polar solvents;

The compound of the present invention produced by this production method can be derived into another compound of the present invention by subjecting it to a method well known to those skilled in the art, such as hydrolysis reaction, amidation reaction and esterification reaction. Can do. For example, a compound in which R ^2A is —CO ₂ —C _1-6 alkyl can be derived into a compound in which R ^2A is —CO ₂ H by subjecting it to a hydrolysis reaction. Further, the if R ^2A is face down in the amidation reaction of a compound is a -CO ₂ H to a compound R ^2A is -CONH _2, R ^2A is -CO ₂ -C be face down in the esterification reaction _1-6 It can be derived into another compound that is alkyl.

  In addition, compound 1-a, which is a raw material compound, is produced by a known method (for example, see Patent Document 1 described above) or a method according thereto, or a method described in Production Examples or a method analogous thereto. be able to.

The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances. The salt of the compound of the formula (I) can be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

  The pharmacological activity of the compound of formula (I) was confirmed by the following test.

Test Example 1 DGAT1 Inhibitory Activity Test (1) Preparation of Bacmid-hDGAT1 The base sequence encoding human DGAT1 (hDGAT1) (1467 bases of CDS in Genbank Accession No. NM_012079) was cloned and ligated to pFastBac ^TM 1 (Invitrogen). PFastBac1-hDGAT1 was prepared. From this plasmid, a recombinant baculovirus solution (Bacmid-hDGAT1) was prepared using Bac-to-Bac (registered trademark) Baculovirus Expression System (Invitrogen).

(2) Preparation of Sf9 cell-derived DGAT1-expressing microsomal fraction
Sf9 cells were seeded on 225cm ² Flask Angled Neck (CORNING) to 80% confluency, and statically cultured in a constant temperature incubator at 27 ° C using EX-CELL ^TM 420 INSECT SERUM-FREE MEDIUM (SAFC Biosciences) did. 24 hours later, the culture solution was removed, and 1.67 mL of recombinant baculovirus solution (Bacmid-hDGAT1) diluted with EX-CELL ^TM 420 INSECT SERUM-FREE MEDIUM 3.33 mL was added. Cultured with shaking for 1 hour. Thereafter, 25 mL of EX-CELL ^™ 420 INSECT SERUM-FREE MEDIUM was added and cultured at 27 ° C. for 72 hours in a constant temperature incubator. Infected cells were collected and suspended in 1.5 mL of Buffer A (100 mM Sucrose, 40 mM phosphate buffer (pH 7.2) containing 50 mM KCl) containing Complete Protease Inhibitor Cocktail (Roche Diagnostics KK), and SONIFER 250 (BRANSON) ) Was used for sonication. This suspension was centrifuged at 10,000 × g for 5 minutes, and the supernatant was recovered. The supernatant obtained by centrifuging the supernatant at 100,000 × g for 60 minutes was dissolved in 600 μL of buffer A, and sonicated again to prepare a suspension. This suspension was used as hDGAT1-expressing Sf9 cell microsomes.

(3) DGAT1 activity measurement
DGAT1 activity is 100 mM Tris-HCl (pH 8.0), 2 mM MgCl ₂ , 0.01% BSA, test substance dissolved in dimethyl sulfoxide (DMSO) (DMSO final concentration 2%), and hDGAT1-expressing Sf9 cell microsome 200 μM dioleoyl glycerol or dipalmitoyl glycerol, 8.9 μM [ ¹⁴ C] oleoyl-CoA, 1.68% acetone was added to phospholipid FlashPlate (PerkiElmer Life Science). After carrying out the reaction at 30 ° C. for 60 minutes, the reaction was stopped by adding twice the amount of the reaction solution (100 μL) of isopropyl alcohol: 0.1 M carbonate buffer (pH 9.0) = 1: 1. The next day, counts were measured with a top count microplate scintillation counter (PerkinElmer Life Science).
The count when no test substance was added was used as a control (TG when DMSO was added). The blank TG was counted when the test substance and microsome were not added. The DGAT1 inhibition rate of the test substance was calculated by the following formula.
Inhibition rate (%) = (TG when the test substance is added-Blank TG) ÷ (TG when DMSO is added-Blank TG) x 100
The DGAT1 inhibition rate was calculated when the concentration of the test substance in the reaction solution was 1, 10, 100, or 1000 nM. Using the obtained inhibition rate, linear regression was performed, and the test substance concentration (IC ₅₀ ) required to inhibit DGAT1 activity by 50% was determined using SAS 8.2 software package (SAS Institute Japan, Ltd., Tokyo, Japan). Calculated.

As a result, some of the compounds of formula (I) showed DGAT1 inhibitory action with IC ₅₀ values of 50 nM or less in the above test. Table 1 shows the results in this test for some compounds of formula (I).

Test Example 2 Inhibition of plasma triglyceride (TG) elevation by fat administration
10-week-old male C57BL / 6J mice were fasted for 18 hours, and 1 mg / kg of the test substance was orally administered. The test substance was suspended in a 0.5% methylcellulose solution and administered. One hour later, fat (intralipid 20%, Terumo (Frezenius), 10 mL / kg) was orally administered. Blood was collected from the tail vein immediately before fat administration and 2 hours later to obtain plasma. For the measurement of plasma TG, triglyceride E test Wako (Wako Pure Chemical Industries, Ltd.) was used, and the plasma TG increase value by fat administration was calculated. Using the 0.5% methylcellulose administration group as a control, the plasma TG elevation value was used as a control to determine the TG elevation inhibition rate when the test substance was administered.

  As a result, some of the compounds of formula (I) showed a significant inhibitory action on plasma TG elevation relative to the control group, and some of the compounds of formula (I) showed an inhibitory action on plasma TG elevation of more than 80%. It was.

Test Example 3 Anti-obesity effect in DIO mice
High-fat diet (Research Diet D12492, 60 kcal% fat) was fed to 9-week-old male C57BL / 6J mice. From the 4th week, the solvent used in the test was administered for the purpose of acclimatization of mice. From the 5th week, the test substance was orally administered once or twice a day. The test substance was suspended in a 0.5% methylcellulose solution and administered. Repeated administration for 4 weeks was performed, and the body weight change by test substance administration was observed.

  As a result, some compounds of formula (I) showed an inhibitory effect on weight gain caused by a high fat diet.

  As a result of the above test, it was confirmed that the compound of the formula (I) has an anti-obesity action in a dietary obesity model. Therefore, it can be used for the prevention and / or treatment of obesity, type II diabetes, fatty liver and the like.

A pharmaceutical composition containing one or more of the compounds of formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. Can be prepared by a commonly used method.
Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, or a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

  Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

  External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.

  Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

  In general, in the case of oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. In the case of intravenous administration, the daily dose is appropriately about 0.0001 to 10 mg / kg per body weight, and is administered once a day or divided into multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

  The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

  Hereinafter, based on an Example, the manufacturing method of the compound of a formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is shown to a manufacture example. Further, the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.

Moreover, the following abbreviations may be used in Examples, Production Examples, and Tables below.
Rf: Production example number, Ex: Example number, Structure: Chemical structural formula (Me: methyl, Et: ethyl, iPr: isopropyl, tBu: tert-butyl, nPen: normal pentyl. The configuration is shown. Among the compounds, those with “*” attached to the production example number or the example number indicate that they are optically active substances.), Syn: production method (the compound is described in the column) Indicates that the compound was produced by the same production method as the compound of Example No.), Rsy: production method (the compound was produced by the same production method as the compound of the production example number described in the column) ), Data: physical data (showing the following data for the compound: NMR1: δ (ppm) of the peak in ¹ H-NMR in DMSO-d _6; NMR 2: ¹ H in CDCl ₃ -Δ (ppm) of peak in NMR, ESP: ESI-MS [M + H] ⁺ , ESN: ESI-MS [MH] ⁻ .)

Production Example 1
To a mixture of 1,4-dioxaspiro [4.5] decan-8-ol (6.3 g), 1-fluoro-4-nitrobenzene (5.1 g) and DMF (51 ml) was added 60% oily sodium hydride (1.6%) under ice-cooling. g) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the resulting solid was collected by filtration and washed with hexane to obtain a pale yellow solid (9.5 g). To a mixture of this solid (9.5 g) and THF (70 ml), 1M hydrochloric acid (40 ml) was added at room temperature, and the mixture was stirred at 70 ° C. (oil bath temperature) for 14 hours. Thereafter, the reaction mixture was allowed to cool, and then THF was distilled off under reduced pressure. The solid that emerged was collected by filtration, washed successively with water and diisopropyl ether, and washed with 4- (4-nitrophenoxy) cyclohexanone as a yellow solid. 7.1 g was obtained.

Production Example 2
To a mixture of sodium hydride (660 mg) and THF (44 ml) was added ethyl diethylphosphonoacetate (3.3 ml) dropwise over 10 minutes under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. 4- (4-Nitrophenoxy) cyclohexanone (3.7 g) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1M hydrochloric acid (200 ml), and liquid separation was performed using ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5-50: 50) to obtain 3.9 g of colorless solid ethyl [4- (4-nitrophenoxy) cyclohexylidene] acetate.

Production Example 3
To a mixture of ethyl [4- (4-nitrophenoxy) cyclohexylidene] acetate (2 g) and THF (40 ml), 10% palladium on activated carbon (800 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) at room temperature. Stir for hours. The reaction mixture was filtered through Celite, washed with THF, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 to 10:90) to give oily ethyl [trans-4- (4-aminophenoxy) cyclohexyl] acetate (Production Example 3). 390 mg and 560 mg of oily ethyl [cis-4- (4-aminophenoxy) cyclohexyl] acetate (Production Example 6) were obtained.

Production Example 4
To a mixture of ethyl [trans-4- (4-aminophenoxy) cyclohexyl] acetate (390 mg), N, N-diisopropylethylamine (0.538 ml), methylene chloride (20 ml) at 0 ° C. with ethyl chloroglyoxylate (0.17 ml) And stirred at room temperature for 1 hour. The reaction mixture was added to 1M hydrochloric acid, and liquid separation was performed using chloroform. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and yellow. A solid was obtained. To a mixture of this solid and ethanol (35 ml) was added hydrazine monohydrate (0.136 ml) at room temperature, and the mixture was stirred at room temperature for 2 hours. Thereafter, a solid was collected from the reaction mixture by filtration, washed with ethanol (EtOH), dried under reduced pressure, and colorless solid ethyl [trans-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexyl. ] 350 mg of acetate was obtained.

Production Example 5
To a mixture of N-cyclobutyl-1H-imidazole-1-carboxamide (47 mg) and THF (2 ml), ethyl [cis-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexyl] acetate (100 mg) And THF (1 ml) and acetic acid (0.016 ml) were added and stirred at 40 ° C. overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol (MeOH) = 95: 5), and oily ethyl cis-4- [4-({[2- (cyclobutylcarbamoyl) hydrazino] (oxo) 120 mg of (acetyl} amino) phenoxy] cyclohexanecarboxylate were obtained.

Example 1
Ethyl trans-4- [4-({[5- (benzylamino) -1,3,4-oxadiazol-2-yl] carbonyl} amino) phenoxy] cyclohexanecarboxylate (183 mg), EtOH (5 ml), To a mixture of THF (5 ml) was added 1M aqueous sodium hydroxide solution (2 ml) at room temperature, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. Thereafter, a 10% aqueous citric acid solution was added until the pH reached 3, and the solid that appeared was collected by filtration. EtOH was added to this solid while heating, and the mixture was allowed to cool and stir, and then the solid was collected by filtration to give colorless solid trans-4- [4-({[5- (benzylamino) -1,3,4- 87 mg of oxadiazol-2-yl] carbonyl} amino) phenoxy] cyclohexanecarboxylic acid were obtained.

Example 2
Trans-4- [4-({[5- (cyclohexylamino) -1,3,4-oxadiazol-2-yl] carbonyl} amino) phenoxy] cyclohexanecarboxylic acid (85 mg) and DMF (3 ml) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride (49 mg) and 1-hydroxybenzotriazole monohydrate (35 mg) were added, and the mixture was stirred at room temperature for 30 minutes, and then ammonium chloride ( 13 mg) and triethylamine (0.036 ml) were sequentially added, and the mixture was stirred at room temperature for 18 hours. Thereafter, water was added to the reaction mixture, and the solid that appeared was collected by filtration. EtOH was added to the solid while heating, and the mixture was allowed to cool and stir. The solid was collected by filtration, and colorless solid N- {4-[(trans-4-carbamoylcyclohexyl) oxy] phenyl} -5- (cyclohexyl) 25 mg of amino) -1,3,4-oxadiazole-2-carboxamide was obtained.

Example 3
Trans-4- [4-({[5- (cyclohexylamino) -1,3,4-oxadiazol-2-yl] carbonyl} amino) phenoxy] cyclohexanecarboxylic acid (1 g) and MeOH (40 ml) To the mixture was added concentrated sulfuric acid (0.025 ml), and the mixture was heated to reflux for 24 hours. After air cooling, after concentration under reduced pressure to about half amount, add the reaction mixture in chloroform and saturated aqueous sodium hydrogen carbonate solution, perform liquid separation operation with chloroform, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, 558 mg of colorless solid methyl trans-4- [4-({[5- (cyclohexylamino) -1,3,4-oxadiazol-2-yl] carbonyl} amino) phenoxy] cyclohexanecarboxylate was obtained.

Example 4
Ethyl trans-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexanecarboxylate (100 mg), chloroform (10 ml) was mixed with (R)-(+)-isocyanic acid-α- at room temperature. After adding methylbenzyl (0.06 ml), the mixture was stirred at 60 ° C. (oil bath temperature) for 4 hours. Thereafter, p-toluenesulfonyl chloride (60 mg) and triethylamine (0.1 ml) were sequentially added to the reaction mixture, and the mixture was stirred at 60 ° C. (oil bath temperature) for 24 hours. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution, and liquid separation was performed using chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether, and colorless solid ethyl trans-4- (4-{[(5-{[(1R) -1-phenylethyl] amino} -1,3,4-oxadiazole was obtained. 108 mg of -2-yl) carbonyl] amino} phenoxy) cyclohexanecarboxylate were obtained.

Example 5
To a mixture of cyclopropanamine (0.06 ml), N, N-diisopropylethylamine (0.35 ml) and chloroform (20 ml), triphosgene (85 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. (4-{[Hydrazino (oxo) acetyl] amino} phenoxy) cyclohexanecarboxylate (200 mg) was added, and the mixture was stirred at 60 ° C. (oil bath temperature) for 2 hours. Thereafter, p-toluenesulfonyl chloride (120 mg) and triethylamine (0.2 ml) were successively added to the reaction mixture, followed by stirring at 60 ° C. (oil bath temperature) for 14 hours. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution, and liquid separation was performed using chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with ether, and colorless solid ethyl trans-4- [4-({[5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] carbonyl} amino) 123 mg of phenoxy] cyclohexanecarboxylate was obtained.

Example 6
To a mixture of cyclopentylacetic acid (0.054 ml) and toluene (1 ml) were added triethylamine (0.068 ml) and diphenylphosphoric acid azide (0.099 ml) at room temperature, and the mixture was stirred at room temperature for 30 minutes and then at 90 ° C. for 10 minutes. The reaction mixture was returned to room temperature, chloroform (9 ml) and ethyl cis-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexanecarboxylate (100 mg) were added, and the mixture was stirred at 60 ° C. for 6 hr. Thereafter, p-toluenesulfonyl chloride (60 mg) and triethylamine (0.1 ml) were added to the reaction mixture returned to room temperature, and stirred at 60 ° C. for 18 hours. The mixture was diluted with chloroform, washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15 to 65:35) to give colorless solid ethyl cis-4- {4-[({5-[(cyclopentylmethyl) amino]- 65 mg of 1,3,4-oxadiazol-2-yl} carbonyl) amino] phenoxy} cyclohexanecarboxylate was obtained.

Example 7
Carbonyldiimidazole (84 mg) was added to a mixture of ethyl cis-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexanecarboxylate (100 mg) and THF (5 ml), and the mixture was stirred at room temperature overnight. 2- (Aminomethyl) pyridine (0.075 ml) was added to the reaction mixture and stirred for 2 hours. Thereafter, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure and diluted with chloroform. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chloroform (10 ml), p-toluenesulfonyl chloride (142 mg) and triethylamine (0.14 ml) were sequentially added to the resulting residue, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 to chloroform). : Methanol = 90: 10) to obtain a brown solid of ethyl cis-4- {4-[({5-[(pyridin-2-ylmethyl) amino] -1,3,4-oxadiazole- 61 mg of 2-yl} carbonyl) amino] phenoxy} cyclohexanecarboxylate were obtained.

Example 8
Carbonyldiimidazole (51 mg) was added to a mixture of 2,4,5-trifluorobenzylamine (51 mg) and THF (5 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, chloroform (10 ml) was added, ethyl cis-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexanecarboxylate (100 mg) was added, and the mixture was stirred at 60 ° C. overnight. did. Thereafter, reagents were prepared in the same manner as described above using 2,4,5-trifluorobenzylamine (135 mg) and carbonyldiimidazole (135 mg), added to the reaction mixture, and then stirred at 60 ° C. overnight. Thereafter, the reaction mixture returned to room temperature was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chloroform (10 ml) was added to the residue, and then p-toluenesulfonyl chloride (60 mg) and triethylamine were added. (0.1 ml) was added and stirred at 60 ° C. overnight. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 65: 35), and colorless solid ethyl cis-4- {4-[({5-[(2,4,5-trifluorobenzyl) 61 mg of [amino] -1,3,4-oxadiazol-2-yl} carbonyl) amino] phenoxy} cyclohexanecarboxylate were obtained.

Example 9
A mixture of ethyl cis-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexanecarboxylate (100 mg), benzyl isocyanate (0.041 ml), chloroform (8 ml) at 60 ° C. (oil bath temperature) Stir for 2 hours. Thereafter, p-toluenesulfonyl chloride (60 mg) and triethylamine (0.088 ml) were sequentially added to the reaction mixture, and the mixture was stirred at 60 ° C. (oil bath temperature) overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and a liquid separation operation was performed using chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: MeOH = 100: 0 to 90:10) to give a colorless solid. To a mixture of this solid, EtOH (2 ml) and THF (3 ml) was added 1M aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. Thereafter, 10% aqueous citric acid solution was added until the pH reached 3, and the resulting solid was collected by filtration and washed with diisopropyl ether to give a colorless solid cis-4- [4-({[5- (benzylamino)- 54 mg of 1,3,4-oxadiazol-2-yl] carbonyl} amino) phenoxy] cyclohexanecarboxylic acid were obtained.

Example 10
To a mixture of ethyl [cis-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexyl] acetate (150 mg), DMF (7 ml) was added cyclohexyl isothiocyanate (0.067 ml) at room temperature, Stir at 65 ° C. for 1 hour. Thereafter, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride (95 mg) was added to the reaction mixture, and the mixture was stirred at 85 ° C. for 6 hours. The reaction mixture was returned to room temperature, water was added, and the solid that appeared was collected by filtration. This solid was washed with ether to obtain a solid. This was dissolved in 1M aqueous sodium hydroxide solution (1.2 ml), THF (2.5 ml), EtOH (2.5 ml) and stirred (refrigerated at night). Thereafter, the reaction mixture was concentrated under reduced pressure, a 10% aqueous citric acid solution was added until the pH reached 3, and the solid that appeared was collected by filtration. This was dissolved in EtOH by heating, returned to room temperature, and the resulting solid was collected by filtration to give a colorless solid {cis-4- [4-({[5- (cyclohexylamino) -1,3,4-oxadi 44 mg of Azol-2-yl] carbonyl} amino) phenoxy] cyclohexyl} acetic acid was obtained.

Example 11
Ethyl cis-4- [4-({[2- (cyclobutylcarbamoyl) hydrazino] (oxo) acetyl} amino) phenoxy] cyclohexanecarboxylate (120 mg), chloroform (10 ml), p-toluenesulfonyl chloride (56 mg) , Triethylamine (0.082 ml) was added, and the mixture was stirred at 60 ° C. overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was separated using chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: MeOH = 100: 0 to 90: 1) to obtain a colorless solid (76 mg). To a mixture of this solid (76 mg), EtOH (2 ml) and THF (3 ml) was added 1M aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and a 10% aqueous citric acid solution was added until pH 3. Thereafter, the solid that appeared was collected by filtration and washed with diisopropyl ether to give a colorless solid cis-4- [4-({[5- (cyclobutylamino) -1,3,4-oxadiazole-2]. 6 mg of -yl] carbonyl} amino) phenoxy] cyclohexanecarboxylic acid were obtained.

Example 12
To a mixture of 4,4-difluorocyclohexaneamine hydrochloride (73 mg), N, N-diisopropylethylamine (0.02 ml) and chloroform (10 ml), a solution of triphosgene (42 mg) in THF (2 ml) was slowly added at 0 ° C. After stirring at 45 ° C., ethyl trans-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexanecarboxylate (100 mg) and chloroform (8 ml) were added, and 2 at 60 ° C. (oil bath temperature). Stir for hours. Thereafter, p-toluenesulfonyl chloride (60 mg) and triethylamine (0.1 ml) were sequentially added to the reaction mixture, followed by stirring at 60 ° C. (oil bath temperature) for 14 hours. The reaction mixture was added to water and subjected to liquid separation using chloroform-MeOH (= 10: 1). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: MeOH = 100: 0 to 90:10) to obtain an oily substance. To a mixture of this oily substance, EtOH (2 ml) and THF (2 ml) was added 1M aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and 10% aqueous citric acid solution was added until pH 4-5. Thereafter, the solid that emerged was collected by filtration, washed with isopropanol, and colorless solid trans-4- {4-[({5-[(4,4-difluorocyclohexyl) amino] -1,3,4- 49 mg of oxadiazol-2-yl} carbonyl) amino] phenoxy} cyclohexanecarboxylic acid was obtained.

Example 13
Carbonyldiimidazole (170 mg) was added to a mixture of ethyl cis-4- (4-{[hydrazino (oxo) acetyl] amino} phenoxy) cyclohexanecarboxylate (200 mg) and THF (10 ml), and the mixture was stirred at room temperature for 2 hours. Neopentylamine (0.18 ml) was added to the reaction mixture and stirred overnight. Thereafter, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure and diluted with chloroform. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thereafter, chloroform (20 ml), p-toluenesulfonyl chloride (284 mg) and triethylamine (0.28 ml) were sequentially added to the residue, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 to chloroform). : MeOH = 90: 10) to obtain a colorless solid (145 mg). To a mixture of this solid (145 mg), EtOH (3 ml) and THF (3 ml) was added 1M aqueous sodium hydroxide solution (1.4 ml), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and 10% aqueous citric acid solution was added until pH 4-5. Thereafter, the solid that appeared was collected by filtration and washed with ether. This solid was heated and dissolved in a mixed solvent of EtOH-water, and then allowed to stand at room temperature. The solid that emerged was collected by filtration and further washed with EtOH to give a colorless solid cis-4- {4-[({ 85 mg of 5-[(2,2-dimethylpropyl) amino] -1,3,4-oxadiazol-2-yl} carbonyl) amino] phenoxy} cyclohexanecarboxylic acid was obtained.

Table 2 below shows the chemical structural formulas of the production example compounds. Tables 3 to 17 below show chemical structural formulas of the example compounds.
In addition, Table 18 below shows the production methods and physical data of the production example compounds. Moreover, the manufacturing method and physical data of an Example compound are shown in the following Tables 19-23.
Tables 24 to 39 below show the structures of other compounds of the compound of formula (I). These can be easily produced by using the above-described production methods and the methods described in the Examples, methods that are obvious to those skilled in the art, or variations thereof.

  The compound of the formula (I) or a salt thereof has a DGAT1 inhibitory action, and can be used as a preventive and / or therapeutic agent for obesity, type II diabetes, fatty liver, and their peripheral diseases.

Claims (1)

A compound of formula (I) or a salt thereof.

(Where
R ^1A is
(1) C _2-10 alkyl optionally substituted with one or more groups selected from group Z;
(2) C _3-10 cycloalkyl optionally substituted with one or more groups selected from group Z, or
(3) a group represented by -X ¹ -R ^1C
Group Z consists of halogen, -R ⁰ , -OR ⁰ , cyano, -OH, -SO ₂ -C _1-6 alkyl, -O-SO ₂ -C _1-6 alkyl, and C _3-8 cycloalkyl. A group,
R ⁰ is, -OH, -OC _1-6 alkyl, -SO ₂ -C _1-6 alkyl, and one or more C _1-6 alkyl optionally substituted with a group selected from the group consisting of halogen And
X ¹ is C _1-6 alkylene, C _2-3 alkylene-OC _0-3 alkylene, C _3-6 cycloalkanediyl, or C _3-6 cycloalkanediyl-OC _0-3 alkylene,
R ^1C
(1) a C _3-10 cycloalkyl optionally substituted with one or more groups selected from group Z;
(2) C _6-14 aryl optionally substituted with one or more groups selected from group Z, or
(3) an aromatic heterocycle optionally substituted with one or more groups selected from group Z;
R ^1B is -H or C _1-6 alkyl;
X ² is a bond or C _1-6 alkylene;
R ^2A is -CO ₂ H, -CO ₂ -C _1-6 alkyl, or -CONH ₂ ;
R ^2B is -H or C _1-6 alkyl;
R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are the same or different and are —H, C _1-6 alkyl, or halogen. )