WO2012169571A1 - Novel n-(pyridin-2-yl)alkanamide derivative and ship2 inhibitor containing same as an active ingredient - Google Patents

Abstract

[Problem] To provide a novel N-(pyridin-2-yl)alkanamide derivative and a novel insulin sensitizer containing this derivative as an active ingredient. [Solution] A novel N-(pyridin-2-yl)alkanamide derivative or salt thereof, wherein R¹ and R^2a in the above general formula [1a] represent a hydrogen atom or a halogen atom, and A represents an alkylene group or a bond, has an inhibitory effect on SHIP2, and is useful as an insulin sensitizer by causing an increase in insulin sensitivity.

Description

Novel N- (pyridin-2-yl) alkanamide derivatives and SHIP2 inhibitors containing them as active ingredients

The present invention relates to the use of compounds that increase insulin sensitivity and pharmaceutically acceptable salts thereof.
More specifically, the present invention relates to novel N- (pyridin-2-yl) alkanamide derivatives and SHIP2 inhibitors containing them as active ingredients.

The mechanism of action of new drugs used for the treatment of diabetes under development in the world is roughly divided into insulin resistance improving drugs and insulin secretagogues.
Currently, the development of therapeutic agents for type 2 diabetes is shifting from insulin resistance improving agents represented by glitazones to insulin secretagogues related to inlectins.
Under such circumstances, SHIP2 inhibitors are of interest because they improve central and peripheral insulin resistance in diabetic conditions.
5'-lipid containing inositol 5'-phosphate phatase 2 (SHIP2) has inhibitory control over the phosphatidylinositol 3 kinase (PI3 kinase) system, which plays a central role in the expression of insulin metabolism It is an intracellular factor to be performed (Non-patent Document 1) and is involved in the increase in insulin resistance in type 2 diabetes.
The basis for this is that SHIP2 is highly expressed in skeletal muscles and adipose tissue of db / db mice of type 2 diabetes model animals (Non-patent Document 2), and genetic polymorphisms of type 2 diabetes patients in which SHIP2 expression is enhanced (Non-patent Document 3), and further, it has been shown that insulin resistance and impaired glucose tolerance are induced in SHIP2 overexpressing mice (Non-patent Document 4).
For this reason, the importance of developing SHIP2 inhibitors as next-generation diabetes therapeutic agents has been pointed out (Non-patent Document 5).

SHIP2 inhibitors are being developed all over the world as next-generation diabetes therapeutic agents, but only lead compounds that are not suitable for clinical use have been reported yet.
For example, the compound having a pyrazole skeleton described in Non-Patent Document 6 selectively inhibits the reaction between SHIP2 and a substrate (BODIPY-PIP3) in a test tube, but its action in vivo is unknown.
A compound having a selective inhibitory effect on SHIP2 (AS1949490) described in Non-Patent Document 7 activates insulin signaling molecules, increases sugar uptake activity, and suppresses gluconeogenic activity in cultured skeletal muscle cells and cultured hepatocytes. And improve glucose tolerance in type 2 diabetic db / db mice.
In addition, the related compound exhibits an action of enhancing insulin signal and promoting glucose uptake by insulin in established rat skeletal muscle cells (L6 cells).
However, their efficacy is not high enough and they are not used for the treatment of diabetes.

Based on the structure of a plurality of existing SHIP2 inhibitors, the present inventors performed conformational analysis and molecular superposition calculation by the Ligand-based drug design method, and the pharmacophore (the tertiary of functional groups) that SHIP2 inhibitors should have. Based on the results of molecular superposition calculation, a new compound was designed.
Furthermore, they were synthesized and their medicinal effects were examined using cultured neurons.
As a result, it was confirmed that the synthesized novel N- (pyridin-2-yl) alkanamide derivative had an action to increase insulin sensitivity in vitro, and it was more potent than existing SHIP2 inhibitors. The present inventors have completed the present invention by finding a compound that increases insulin sensitivity.
Hereinafter, the present invention will be described in detail.

In this specification, unless otherwise specified, each term has the following meaning.
A halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an alkyl group is a linear or branched group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl group chain _C 1 _{- 12} alkyl group; a lower alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, straight-chain or branched pentyl and hexyl groups chain _{C 1} - ₆ alkyl group; and the alkylene group include methylene, ethylene, propylene and straight-chain or branched C _1, such as isopropylene group - ₆ alkylene group; and the alkyl group is a halogen atom is substituted, difluoromethyl, Means a halogeno lower alkyl group such as trifluoromethyl;

The present invention provides the following general formula [1]

“Wherein R ¹ represents a hydrogen atom or a halogen atom; R ² represents a halogen atom or an alkyl group which may be substituted with a halogen atom, an optionally substituted phenyl group or a cyclohexyl group; An alkylene group or a bond; m and n each represents an integer of 1 to 3;
A novel N- (pyridin-2-yl) alkanamide derivative represented by the formula:

More specifically, the present invention relates to an N- (pyridin-2-yl) phenylalkanamide derivative of the following general formula [1a] or a salt thereof and an N- (pyridin-2-yl) cyclohexylalkane of the general formula [1b]: An amide derivative or a salt thereof.

"Wherein R ¹ represents a hydrogen atom or a halogen atom; R ^2a represents a halogen atom or an alkyl group optionally substituted with a halogen atom; A represents an alkylene group or a bond; Each represents an integer of ~ 3. "

“Wherein R ¹ represents a hydrogen atom or a halogen atom; R ^2b represents a halogen atom or an alkyl group optionally substituted with a halogen atom; A represents an alkylene group or a bond; Each represents an integer of ~ 3. "

Examples of salts of N- (pyridin-2-yl) alkanamide derivatives of the general formulas [1], [1a] and [1b] include inorganic acids such as hydrochloride, perchlorate, sulfate and nitrate Salt; Organic acid salts such as acetate and methanesulfonate are included.
Preferred salts include pharmacologically acceptable salts.

In the N- (pyridin-2-yl) alkanamide derivatives of the general formulas [1], [1a] and [1b] or salts thereof, isomers (for example, optical isomers, geometric isomers, tautomers, etc.) When present, the present invention includes all such isomers and also includes hydrates, solvates and all crystal forms.

A preferred compound in the present invention is an N- (pyridin-2-yl) phenylalkanamide derivative of the general formula [1a] or a salt thereof.
Further, in the general formula [1a], an N- (pyridin-2-yl) phenylalkanamide derivative or a salt thereof in which n is 1, and m is 1 or 2 is preferable, and a more preferable compound is that A is a methylene group or N- (pyridin-2-yl) phenylalkanamide derivative or a salt thereof which is a bond.

The N- (pyridin-2-yl) alkanamide derivative of the general formula [1] can be produced, for example, by the following method.
<Production method>

“Wherein R ¹ , R ² , A, m, and n have the same meanings as described above”

The compound of the general formula [1] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [3] in the presence of a condensing agent, a base, a catalyst and the like.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform.
Examples of the condensing agent used in this reaction include carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and N, N-dicyclohexylcarbodiimide (DCC); halogens such as thionyl chloride. A halogenating alkyl ester such as chloroformic acid ethyl ester; an activated amidating agent such as carbonyldiimidazole; and an azidating agent such as diphenylphosphoric acid azide.
The amount of the condensing agent used may be equimolar or more, preferably 1 to 5 times the molar amount of the compound of the general formula [2].
Examples of the base used in this reaction include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, tert-butoxypotassium, sodium carbonate, potassium carbonate and Examples thereof include organic bases and inorganic bases such as sodium hydride, and the amount of the base used may be equimolar or more, preferably 1 to 10-fold mol relative to the compound of the general formula [3].
Examples of the catalyst used as necessary in this reaction include N, N-dimethyl-4-aminopyridine (DMAP) and the like. The amount of the catalyst used is relative to the compound of the general formula [3]. 0.1 to 1 moles.
This reaction is usually carried out at −50 to 200 ° C., preferably −30 to 100 ° C., for 10 minutes to 20 hours.
Although the compound of General formula [2] can be manufactured by the method of a well-known method, For example, the method as described in Bioorganic & Medicinal Chemistry Letters, 19 (20), 5851-5856; 2009 etc. can be mentioned. .
Moreover, in the compound of the general formula [2], when using a compound in which an amino group is protected, the protecting group may be removed in advance.

In the compounds of the general formulas [2] and [3], when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), all these isomers can be used. Hydrates, solvates and all crystalline forms can be used.
These compounds may be used in the next reaction as they are without isolation.

The compound of the general formula [1] thus obtained can be isolated and purified by usual methods such as extraction, crystallization, distillation and column chromatography.

The compound of the present invention comprises an excipient, a binder, a disintegrant, a disintegration inhibitor, a caking / adhesion inhibitor, a lubricant, an absorption / adsorption carrier, a solvent, an extender, an isotonic agent, a solubilizing agent, and an emulsifier. , Suspending agent, thickener, coating agent, absorption accelerator, gelation / coagulation accelerator, light stabilizer, preservative, moisture proofing agent, emulsification / suspension / dispersion stabilizer, anti-coloring agent Oral preparations (tablets) formulated with various pharmaceutical additives such as oxygen / antioxidants, flavoring / flavoring agents, coloring agents, foaming agents, antifoaming agents, soothing agents, antistatic agents, buffering / pH adjusting agents , Capsules, powders, granules, fine granules, pills, suspensions, emulsions, solutions, syrups, etc.), injections, suppositories, external preparations (ointments, patches, etc.), aerosols, etc. It can be a pharmaceutical preparation.

Although the administration method of the said formulation is not specifically limited, It determines suitably according to the form of a formulation, a patient's age, sex, other conditions, and the grade of a patient's symptom.
The dosage of the active ingredient of the preparation of the present invention is appropriately selected according to the usage, patient age, sex, disease form, other conditions, etc., but usually 0.1 to 500 mg per day for an adult. What is necessary is just to divide and administer from 1 time to several times.

Next, the pharmacological action of representative compounds of the present invention will be described.
(Test Example 1)
<Phosphorylation of Ser473 residue of protein kinase B / Akt (part 1)>
1. Primary culture of mouse cerebellar granule cells The cerebellum was removed from C57BL / 6J mice 7 to 8 days after birth, and cell culture containing 25 mM potassium chloride, 2 mM glutamine, 100 U / mL penicillin, 100 μg / mL streptomycin, and 10% fetal bovine serum. The cerebellum was subdivided in basal modified Eagles medium (HK-BME, Invitrogen) and centrifuged at 4 ° C. and 1500 rpm for 3 minutes.
After removing the supernatant, 2 mL of a 0.125% trypsin solution was added to the precipitate and incubated at 37 ° C. for 15 minutes.
Furthermore, 4 mL of HK-BME was added and centrifuged at 4 ° C. and 1500 rpm for 3 minutes to remove the supernatant.
Add 2 mL of deoxyribonuclease I solution [0.004% DNase I, 0.03% trypsin inhibitor] to the precipitate, incubate at 37 ° C for 15 minutes, add 4 mL of HK-BME, and centrifuge at 4 ° C and 1500 rpm for 3 minutes. And the supernatant was removed.
After adding 5 mL of HK-BME to the precipitate and pipetting with a 5 mL and 2 mL sterile glass pipette to suspend the cell mass, the total number of cells was measured with a hemocytometer.
Cerebellar granule cells were seeded at a density of 1.0 × 10 ⁶ cells / mL in a 35 mm culture dish coated with a poly-D-lysine solution (0.05 mg / mL), at 37 ° C., 5% carbon dioxide gas and saturated water vapor. Cultured under.
To remove glial cells coexisting with neurons, on day 1 of culture, the cells were replaced with HK-BME containing 10 μM cytosine arabinoside, and after 16-20 hours, washed twice with phosphate buffered saline. 2 mL of HK-BME was added.
Seven to eight days after the start of culture, the cerebellar granule cells were cultured in a cell culture medium (basal modified Eagles medium: LK-BME) containing 5 mM potassium chloride, 2 mM glutamine, 100 U / mL penicillin, 100 μg / mL streptomycin at 37 ° C., 5%. After incubation for 2 hours under carbon dioxide and saturated water vapor, pretreatment with vehicle (0.1% DMSO), 10 μM of the compound of the present invention or 10 μM of the control compound (AS1949490) for 30 minutes and further stimulation with 0.5 nM of insulin for 10 minutes did.

2. Western blot method Lysis buffer [20 mM Tris (pH = 7.4), 5 mM EDTA (pH = 8.0), 10 mM disodium phosphate, 100 mM sodium fluoride, 1% polyethylene (9) Octylphenyl ether, 10 μg / mL aprotinin, 10 μg / mL leupeptin, 1 mM phenylmethylsulfonyl fluoride, 2 mM sodium orthovanadate] was added, followed by centrifugation at 14,000 rpm for 15 minutes to obtain a cell lysate.
A Remli solution containing dithiothreitol was added to a cell lysate having a constant protein amount by Bradford method, and boiled for 5 minutes.
Next, the protein was separated by molecular weight size using SDS-polyacrylamide gel electrophoresis and transferred to a polyvinylidene fluoride membrane.
The polyvinylidene fluoride membrane was blocked with 5% non-fat milk solution or 2.5% bovine serum albumin at 25 ° C. for 1.5 hours, and then anti-Ser473 phospho-Akt antibody and anti-Akt 1 at 4 ° C., 16-20 Incubated for hours.
Further, after washing the polyvinylidene fluoride membrane, horseradish peroxidase-anti-mouse (or anti-rabbit) IgG conjugate (GE Healthcare) was allowed to act at 25 ° C. for 1 hour, and then ECL western blotting detection reagents ( Bands were detected with a lumino image analyzer (LAS-4000, Fujifilm) by chemiluminescence using GE Healthcare.
Bands were quantified by Scion image (Frederick).

As a result, regarding phosphorylation of Ser473 residue of Akt by insulin, under the above conditions, AS1949490 did not show an increase in insulin action, but the compound of the present invention showed an increase in insulin action. .
For example, compound 17 is 1.47 times, compound 18 is 1.05 times, compound 20 is 1.02 times, compound 22 is 1.33 times, and compound 23 is 1.27 times. The compound 24 was increased 1.33 times, respectively.

(Test Example 2)
<Phosphorylation of Ser473 residue of protein kinase B / Akt (part 2)>
1. Primary culture of rat cerebral cortical cells Fetal 17-18 day old fetuses were removed from pregnant Sprague-Dawley rats, whole brain was collected, washed with phosphate buffered saline (PBS (-)), and cerebral cortex was isolated. Released.
The cerebral cortex is subdivided in a cell culture medium (Dulbecco's modified Eagle's medium: DMEM) containing 0.01 g / L kanamycin sulfate, 1.5 g / L sodium bicarbonate, 3.5 g / L glucose, 10% fetal bovine serum. And centrifuged at 1500 rpm for 3 minutes at 25 ° C.
After removing the supernatant, 2 mL of a 0.125% trypsin solution was added to the precipitate and incubated at 37 ° C. for 15 minutes.
Furthermore, 4 mL of DMEM was added and centrifuged at 25 ° C. and 1500 rpm for 3 minutes to remove the supernatant.
Add 2 mL of deoxyribonuclease I solution [0.004% DNase I, 0.03% trypsin inhibitor] to the precipitate, incubate at 37 ° C for 15 minutes, add 4 mL of DMEM, and centrifuge at 25 ° C and 1500 rpm for 15 minutes. Qing was removed.
After adding 5 mL of DMEM to the precipitate and pipetting with a sterile glass pipette to suspend the cell mass, the total number of cells was measured with a hemocytometer.
Cerebral cortical cells are seeded at a density of 2.0 × 10 ⁶ cells / mL in a 35 mm culture dish pre-coated with 0.05 mg / mL poly-D-lysine solution, at 37 ° C. under 10% carbon dioxide and saturated water vapor. In culture.
The medium was replaced with serum-free DMEM on the 3rd and 5th days of culture.
On the 6th day of culture, the cells were treated with DMEM containing 10 μm of the solvent (0.1% DMSO), the compound of the present invention or 10 μm of the control compound (AS1949490) for 15 minutes, and then stimulated with 1 nM of insulin for 5 minutes.

2. Western blotting The same method as in Test Example 1 was used.

As a result, phosphorylation of Ser 473 of Akt by insulin in rat cerebral cortical cells under the above conditions, AS1949490 enhanced insulin action by 1.16 times.
In contrast, the compound of the present invention, for example, compound 1.25 times, compound 9 1.45 times, compound 10 1.38 times, compound 11 1.69 times, compound 12 1.72 times Compound 17 increased 1.69 times, Compound 22 increased 1.36 times, Compound 23 increased 1.31 times, and Compound 24 increased 1.70 times.

(Test Example 3)
<Phosphorylation of Thr308 residue of protein kinase B / Akt>
1. Culture of 3T3-L1 adipocytes Mouse-derived 3T3-L1 preadipocytes contain 10% donor bovine serum (DBS) (Dulbecco's Modified Eagle Medium: (DMEM; 100 U / mL penicillin and 100 μg / mL streptomycin) , Life Technology Co., Ltd.), seeded on a 10 cm culture dish, and cultured under conditions of 37 ° C. and 10% carbon dioxide gas.
After culturing to 70% confluence, the cells were seeded in a 6-well culture dish, grown to 100% confluent, and cultured in DMEM containing 10% DBS for 3 days.
Further, for induction of differentiation into adipocytes, the cells were cultured for 3 days in DMEM containing 10% fetal bovine serum (FBS), 0.5 mM 3-isobutyl-1-methylxanthine, 1 μM dexamethasone, and 1 μM insulin. The medium was replaced with DMEM containing FBS and 0.8 μM insulin, and further cultured for 3 days to be differentiated into adipocytes.
Thereafter, the cell culture medium was changed every 3 days with DMEM containing 10% -FBS until it was used in the experiment.
On days 10-12 after differentiation induction, 3T3-L1 adipocytes were washed with phosphate buffered saline (PBS (−)), replaced with serum-free medium, and 20 μg / mL tumor necrosis factor. -α: TNF-α) and incubated at 37 ° C. under 10% carbon dioxide for 16 hours.
Furthermore, after pretreatment for 15 minutes with 10 μM of the compound of the present invention or a control compound (10 μM AS1949490), stimulation was performed for 120 minutes with 17 nM of insulin.

2. Western blotting The cells obtained above were lysed with Lysis buffer (20 mM Tris (pH = 7.4), 140 mM NaCl, 1% Nonidet P-40, 1 mM EDTA, 1 mM EGTA, 2.5 mM sodium pyrophosphate, 1 mM β-glycerophosphate, 2 mM Na3VO4, 50 mM sodium fluoride, 0.62% aprotinin, 1 mM phenylmethylsulfonyl fluoride], and the cells were detached using a cell scraper.
The cell lysate was gradually dissolved on ice for 20 minutes, and then centrifuged at 4 ° C. and 14000 rpm for 10 minutes to remove insoluble components, and the supernatant was used as a cell lysate.
The cell lysate was mixed with a Remli solution containing dithiothreitol, stirred with a vortex mixer, and boiled for 5 minutes.
This sample was subjected to SDS-polyacrylamide gel electrophoresis to separate proteins according to molecular weight size and transferred to a polyvinylidene fluoride membrane.
This polyvinylidene fluoride membrane was blocked with 5% non-fat milk solution at 25 ° C. for 1 hour, and then anti-Thr308 phospho-Akt antibody (Cell Signaling Technology, MA, USA) and anti-Akt1 antibody were combined with 4 ° C., 16-20 Reacted for hours.
Further, after washing the polyvinylidene fluoride membrane, it was reacted with a horseradish peroxidase-labeled anti-mouse (or anti-rabbit) IgG antibody at 25 ° C. for 1 hour, and a lumino image was obtained by chemiluminescence using ECL Western blotting detection reagents (GE Healthcare). Detection was performed with an analyzer (LAS-4000, Fujifilm).

As a result, AS1949490 enhanced insulin action by 1.2-fold under the above conditions in phosphorylation of Akt Thr308 residue by insulin in 3T3-L1 adipocytes.
On the other hand, the compound of the present invention is, for example, 1.37 times for compound 11, 1.20 times for compound 14, 1.22 times for compound 15, 1.26 times for compound 16, and 1.27 times for compound 18. Compound 20 increased 1.29 times, Compound 21 increased 1.21 times, and Compound 28 increased 1.30 times.

(Test Example 4)
<Glucose tolerance test in mice>
Male 8-week-old C57BL / 6J or BKS.Cg- + Leprdb / + Leprdb / Jcl (db / db) mice were treated with AS1949490 or compound 11 (300 mg / kg) suspended in 0.5% methylcellulose 2 times a day. Orally administered twice.
On the 10th day after administration, body weight and food intake were measured.
On the 13th day (C57BL / 6J) or 10th day (db / db) after administration, a glucose tolerance test was performed under fasting for 6 hours.
In the glucose tolerance test, D-glucose (2 g / kg) was intraperitoneally administered to 7-8 mice in a group, and blood was collected from the tail vein after 0, 15, 30, 60 and 120 minutes, and blood glucose level was measured. The area under the blood concentration time curve (AUC) was determined.
The blood glucose level was measured using Nipro FS blood glucose sensor light (Nipro).
The result is shown in FIG.

The N- (pyridin-2-yl) alkanamide derivative of the present invention exhibits an action of increasing insulin signal (protein kinase B / Akt phosphorylation) in mouse cerebellar granule cells and rat cerebral cortical cells.
This effect was more remarkable than AS1949490, which is a known compound that selectively inhibits SHIP2.
In addition, the N- (pyridin-2-yl) alkanamide derivative of the present invention exhibits an action of increasing insulin signal (protein kinase B / Akt phosphorylation) in 3T3-L1 adipocytes.
This effect was more remarkable than AS1949490, which is a known compound that selectively inhibits SHIP2.
In addition, the N- (pyridin-2-yl) alkanamide derivative of the present invention does not exhibit a significant hypoglycemic effect in normal mice, but exhibits a significant hypoglycemic effect in diabetic model mice.

It is a figure explaining SHIP2 and this invention compound. SHIP2 negatively regulates insulin signal by dephosphorylating PI (3,4,5) P3 to PI (3,4) P2 in the insulin target tissue. FJ compounds enhance insulin signal by inhibiting SHIP2. It is a figure which shows the blood glucose level and AUC in the glucose tolerance test in a mouse | mouth.

Next, although a reference example and an example explain the present invention, the present invention is not limited to these.
(Reference Example 1)
tert-Butyl [4- (4-chlorobenzyloxy) pyridin-2-yl] amine

Under argon gas atmosphere, 4- (4-Chlorobenzyloxy) pyridine 1-oxide (0.236 g, 1.0 mmol) in methylene chloride (10 mL) at 0 ° C. with tert-butylamine (0.53 mL, 5.0 mmol) and tosyl chloride (0.381 g, 2.0 mmol) was sequentially added and stirred for 10 minutes.
Further, tert-butylamine (0.1 mL, 1.0 mmol) and tosyl chloride (0.095 g, 0.5 mmol) were added and stirred for 10 minutes. Further, tert-butylamine (0.1 mL, 1.0 mmol) and tosyl chloride ( 0.095 g, 0.5 mmol) was sequentially added and stirred for 10 minutes.
After confirming the completion of the reaction, saturated sodium bicarbonate water is added with stirring until the aqueous layer shows basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3), the combined methylene chloride is dried over potassium carbonate, and the solvent is distilled off.
The obtained residue was purified using silica gel chromatography (eluent: methylene chloride + trimethylamine) to give 0.273 g of tert-Butyl [4- (4-chlorobenzyloxy) pyridin-2-yl] amine crystals (yield 94). %).

Melting point: 88-90 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 7.91 (1H, d, J = 5.9 Hz), 7.35 (4H, m), 6.21 (1H, dd, J = 8.1 Hz, J = 2.2 Hz), 5.98 ( 1H, d, J = 2.0 Hz), 5.01 (2H, s), 4.53 (1H, br), 1.22 (9H, s)

The following compounds were synthesized in the same manner.
・ Tert-Butyl [4- (4-fluorobenzyloxy) pyridin-2-yl] amine

Melting point: 83-85 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 7.90 (1H, dd, J = 9.3 Hz, J = 3.7 Hz), 7.38-7.36 (2H, m), 7.15-7.04 (2H, m), 6.22 (1H , dd, J = 5.9 Hz, J = 2.2 Hz), 5.99 (1H, s), 4.98 (2H, s), 4.56 (1H, br), 1.38 (9H, s)

N- [4- (4-Chlorobenzyloxy) pyridin-2-yl] -3-phenylpropionamide [Compound 5]

To a solution of tert-Butyl- [4- (4-chloro-benzyloxy) -pyridin-2-yl] -amine (0.177 g, 0.82 mmol) in methylene chloride (15 mL) under an argon gas atmosphere, trifluoroacetic acid 2 0.0 mL was added and heated to reflux for 2 days.
After completion of the reaction, a 10% aqueous sodium hydroxide solution is added with stirring until the aqueous layer shows basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3), and the combined methylene chloride is dried over potassium carbonate.
The crystals obtained by distilling off the solvent were dissolved in a methylene chloride (5 mL) solution under an argon gas atmosphere, phenylpropionic acid (0.123 g, 0.82 mmol), EDC hydrochloride (0.173 g, 0.90 mmol), DMAP (0.01 g, 0.082 mmol) was sequentially added and stirred overnight at room temperature.
After confirming the completion of the reaction, saturated multistory water is added with stirring until the aqueous layer shows basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3), and the combined methylene chloride layer is dried over potassium carbonate, and then the solvent is distilled off.
The obtained residue was purified using silica gel chromatography (eluent: hexane: acetone = 8: 1) to give crystals of N- [4- (4-Chlorobenzyloxy) pyridin-2-yl] -3-phenylpropionamide (0 159 g, 53%).

Melting point: 117-123 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.04 (1H, d, J = 5.9 Hz), 7.95 (1H, d, J = 2.2 Hz), 7.93 (1H, br), 7.41-7.20 (9H, m ), 6.62 (1H, dd, J = 8.1 Hz, J = 2.3 Hz), 5.11 (2H, s), 3.05 (2H, t, J = 7.8 Hz), 2.69 (2H, t, J = 7.8 Hz)
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 172.19, 166.33, 153.46, 148.25, 140.37, 134.14, 134.08, 128.93, 128.82, 128.51, 128.19, 126.27, 108.22, 99.58, 69.09, 39.11, 31.11

In the same manner as in Example 1, the following compounds were obtained.
N- [4- (4-Chlorobenzyloxy) pyridin-2-yl] -2-phenylacetamide [Compound 6]

Melting point: 124-129 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 169.69, 166.29, 152.89, 148.49, 134.17, 134.11, 133.77, 129.43, 129.21, 128.94, 128.86, 127.72, 108.44, 99.19, 69.11, 44.97

・ N- (4-Benzyloxypyridin-2-yl) -2-phenylacetamide [Compound 7]

Melting point: 100-123 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 169.90, 166.49, 153.33, 148.11, 135.45, 134.01, 129.17, 128.84, 128.52, 128.19, 127.52, 127.29, 108.35, 99.61, 69.81, 44.45

・ N- (4-Benzyloxypyridin-2-yl) -3-phenylpropionamide [Compound 8]

Melting point: 95-97 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 171.18, 166.63, 153.37, 148.09, 140.40, 135.57, 128.64, 128.52, 128.31, 128.22, 127.66, 126.26, 108.25, 99.63, 69.94, 39.15, 31.14

N- [4- (4-Chlorobenzyloxy) -pyridin-2-yl] -2- (4-fluorophenyl) acetamide [Compound 9]

Melting point: 153-156 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 169.51, 166.35, 162.23 (d, J = 246.5 Hz), 152.94, 148.45, 134.19, 134.05, 130.99 (d, J = 8.3 Hz), 129.59 (d, J = 3.3 Hz), 128.93, 128.86, 115.99 (d, J = 21.5 Hz), 108.52, 99.34, 69.13, 43.86

N- (4-Benzyloxypyridin-2-yl) -2- (4-fluoro-phenyl) acetamide [Compound 10]

Melting point: 103-110 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 169.51, 166.63, 162.20 (d, J = 244.0 Hz), 152.94, 148.34, 135.54, 130.98 (d, J = 8.3 Hz), 129.65 (d, J = 3.3 Hz ), 128.66, 128.34, 127.64, 115.96 (d, J = 21.5 Hz), 108.55, 99.47, 69.97, 43.83

N- [4- (4-Chlorobenzyloxy) -pyridin-2-yl] -2- (2,6-difluorophenyl) acetamide [Compound 11]

Melting point: 122-125 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 167.70, 166.40, 161.48 (dd, J = 256.4, J = 7.86 Hz), 153.31, 148.18, 134.13, 134.01, 129.33 (t, J = 9.9 Hz), 128.90, 128.81, 111.32 (dd, J = 24.8, J = 5.8 Hz), 110.58 (t, J = 13.7 Hz), 108.70, 99.53, 69.09, 30.98

・ N- (4-Benzyloxypyridin-2-yl) -2- (2,6-difluorophenyl) acetamide [Compound 12]

Melting point: 118-121 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.05 (1H, br), 7.96 (1H, d, J = 5.9 Hz), 7.96 (1H, d, J = 2.2 Hz), 7.42-7.25 (6H, m ), 6.96 (1H, t, J = 7.8 Hz), 6.65 (2H, dd, J = 4.8 Hz, J = 2.4 Hz), 5.10 (1H, s), 3.82 (1H, s)

N- [4- (4-Fluorobenzyloxy) pyridin-2-yl] -3-phenylpropionamide [Compound 13]

Melting point: 112-119 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 171.36, 166.33, 162.50 (d, J = 246.5 Hz), 153.68, 147.95, 140.35, 131.26 (d, J = 3.3 Hz), 129.46 (d, J = 8.3 Hz ), 128.36, 128.08, 126.12, 115.46 (d, J = 22.3 Hz), 108.09, 99.69, 69.09, 38.82, 31.03

N- [4- (4-Fluorobenzyloxy) pyridin-2-yl] -2-phenylacetamide [Compound 14]

Melting point: 107-108 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 169.97, 166.28, 162.46 (d, J = 247.3 Hz), 153.40, 148.10, 134.03, 131.21 (d, J = 2.5 Hz), 129.41 (d, J = 8.3 Hz ), 129.11, 128.76, 127.23, 115.42 (d, J = 21.5 Hz), 108.30, 99.53, 69.06, 44.32

N- [4- (4-Fluorobenzyloxy) pyridin-2-yl] -2- (4-fluorophenyl) acetamide [Compound 15]

Melting point: 50-54 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 169.74, 166.41, 162.57 (d, J = 247.3 Hz), 162.036 (d, J = 246.3 Hz), 153.27, 148.19, 131.23 (d, J = 3.3 Hz), 130.79 (d, J = 7.4 Hz), 129.74, 129.49 (d, J = 8.3 Hz), 115.73 (d, J = 19.0 Hz), 115.53 (d, J = 21.5 Hz), 108.49, 99.59, 69.19, 43.49

2- (2,6-Difluorophenyl) -N- [4- (4-fluoro-benzyloxy) pyridin-2-yl] acetamide [Compound 16]

Melting point: 50-59 ° C
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 167.89, 166.39, 162.45 (d, J = 247.3 Hz), 161.39 (dd, J = 248.1, J = 7.4 Hz), 153.58, 147.95, 131.21 (d, J = 3.3 Hz), 129.39 (d, J = 8.3 Hz), 129.04 (t, J = 10.3 Hz), 115.39 (d, J = 21.5 Hz), 111.06 (dd, J = 24.8, J = 5.8 Hz), 110.51, (t, J = 20.3 Hz), 108.51, 99.66, 69.06, 30.58

(Reference Example 2)
・ 4- (4-Chlorobenzyloxymethyl) pyridine

Under an argon gas atmosphere, lithium aluminum hydride (0.113 g, 3 mmol) was added to a solution of ethyl isonicotinate (0.274 mL, 2 mmol) in tetrahydrofuran (10 mL) at 0 ° C., and the mixture was heated to reflux for 7 hours.
After cooling, a 10% aqueous sodium hydroxide solution was added to the reaction solution with stirring until the reaction solution was all white.
Further, after extraction with ethyl acetate (10 mL × 3) while heating, the combined ethyl acetate is dried over potassium carbonate, and the solvent is distilled off.
Sodium hydride (0.088 g, 2.2 mmol) was added to a 5 mL solution of the obtained solid dimethylformamide at 0 ° C. in an argon gas atmosphere, and the mixture was stirred at room temperature for 30 minutes.
P-Chlorobenzyl chloride (0.256 mL, 2 mmol) was added again at 0 ° C., and the mixture was stirred at room temperature for 2.5 hours.
10 mL of water is added to the reaction mixture, and the aqueous layer is extracted with ethyl acetate (10 mL × 3).
The obtained residue was purified by silica gel column chromatography (eluent; hexane: acetone = 10: 1) to obtain a pale yellow oily substance (0.228 g, 49%).

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.64 (2H, dd J = 4.4, J = 1.7 Hz), 7.36-7.26 (6H, m), 4.56 (2H, s), 4.56 (2H, s)
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 149.90, 147.13, 136.09, 133.67, 129.00, 128.67, 121.76, 71.93, 70.41

Similarly, the following compounds were synthesized.
・ 4- (4-Fluorobenzyloxymethyl) pyridine

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.58 (2H, dd, J = 4.5 Hz, J = 1.6 Hz), 7.36-7.26 (4H, m), 7.08-7.04 (2H, m), 4.56 (2H , s), 4.56 (2H, s)

(Reference Example 3)
・ Tert-Butyl- [4- (4-chlorobenzyloxymethyl) pyridin-2-yl] amine

Under an argon gas atmosphere, metachloroperbenzoic acid (0.561 g, 2 mmol) was added to a solution of 4- (4-Chloro-benzyloxymethyl) -pyridine (0.228 g, 0.98 mmol) in methylene chloride (5 mL) at 0 ° C. After the addition, the mixture was returned to room temperature and stirred overnight.
After confirming the completion of the reaction, a 10% aqueous sodium hydroxide solution was added with stirring until the aqueous layer showed basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3), the combined methylene chloride is dried over potassium carbonate, and the solvent is distilled off.
To a solid methylene chloride (10 mL) solution thus obtained, tert-butylamine (0.62 mL, 5.9 mmol) and tosyl chloride (0.450 g, 2.36 mmol) were sequentially added at 0 ° C. under an argon gas atmosphere for 10 minutes. Stir.
Furthermore, tert-butylamine (0.12 mL, 1.18 mmol) and tosyl chloride (0.112 g, 0.59 mmol) were added and stirred for 10 minutes, and then tert-butylamine (0.12 mL, 1.18 mmol) and tosyl chloride ( 0.112 g, 0.59 mmol) was sequentially added and stirred for 10 minutes.
After confirming the completion of the reaction, saturated sodium bicarbonate water is added with stirring until the aqueous layer shows basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3), the combined methylene chloride is dried over potassium carbonate, and the solvent is distilled off.
The obtained residue was purified by silica gel chromatography (eluent: methylene chloride + triethylamine) to obtain crystals (0.316 g, 97%).

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.02 (1H, d, J = 5.1 Hz), 7.34-7.28 (4H, m), 6.49 (1H, d, J = 5.4 Hz), 6.44 (1H, s ), 4.53 (2H, s), 4.53 (2H, s), 4.51 (1H, br), 1.42 (9H, s)

Similarly, the following compounds were synthesized.
・ Tert-Butyl (4-benzyloxymethylpyridin-2-yl) amine

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.02 (1H, d, J = 5.4 Hz), 7.37-7.28 (5H, m), 6.50 (1H, d, J = 5.1 Hz), 6.46 (1H, s ), 4.57 (2H, s), 4.44 (2H, s), 4.53 (1H, br), 1.42 (9H, s)

・ Tert-Butyl [4- (4-fluoro-benzyloxymethyl) pyridin-2-yl] amine

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.02 (1H, d, J = 5.4 Hz), 7.34-7.26 (2H, m), 7.05 (2H, d, J = 8.7 Hz), 6.49 (1H, d , J = 5.4 Hz), 6.44 (1H, s), 4.52 (2H, s), 4.48 (1H, br), 4.43 (2H, s), 1.42 (9H, s)

N- [4- (4-Chlorobenzyloxymethyl) pyridin-2-yl] -2- (2,6-difluorophenyl) acetamide [Compound 17]

Under an argon gas atmosphere, trifluoroacetic acid (2.4 mL) was added to a methylene chloride (15 mL) solution of tert-Butyl [4- (4-chlorobenzyloxymethyl) pyridin-2-yl] amine (0.286 g, 0.94 mmol). In addition, the mixture was heated to reflux for 2 days.
After completion of the reaction, a 10% aqueous sodium hydroxide solution is added with stirring until the aqueous layer shows basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3).
The combined methylene chloride is dried with potassium carbonate.
The crystals obtained by distilling off the solvent were converted into a methylene chloride (5 mL) solution under an argon gas atmosphere, and 2,6-difluorophenylacetic acid (0.143 g, 0.83 mmol), EDC hydrochloride (0.176 g, 0.92 mmol) and DMAP (0.01 g, 0.083 mmol) were sequentially added, and the mixture was stirred overnight at room temperature.
After confirming the completion of the reaction, saturated multistory water is added with stirring until the aqueous layer shows basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3).
The combined methylene chloride is dried with potassium carbonate.
The residue obtained by distilling off the solvent was purified using silica gel chromatography (eluent; hexane: acetone = 8: 1) to obtain crystals (0.213 g, 63%).

Melting point: 67-70 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.23 (1H, d, J = 5.1 Hz), 8.18 (1H, s), 8.03 (1H, br), 7.34-7.26 (6H, m), 7.09 (1H , d, J = 4.2 Hz), 6.96 (1H, t, J = 7.8 Hz), 4.53 (2H, s), 4.53 (2H, s), 3.83 (2H, s)
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 167.48, 161.43 (dd, J = 255.6, J = 7.4 Hz), 151.60, 150.17, 147.54, 136.05, 133.48, 129.26 (t, J = 9.9 Hz), 128.98, 128.53, 118.14, 112.47, 111.24 (dd, J = 24.8, J = 5.8 Hz), 110.41 (t, J = 20 Hz), 71.86, 70.56, 30.85

The following compounds were synthesized in the same manner as Example 3.
N- [4- (4-Chlorobenzyloxymethyl) pyridin-2-yl] -2-phenylacetamide [Compound 18]

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.34 (1H, br), 8.21 (1H, s), 8.17 (1H, d, J = 5.1 Hz), 7.38-7.26 (9H, m), 7.06 (1H , d, J = 4.9 Hz), 4.53 (2H, s), 4.53 (2H, s), 3.74 (2H, s)

N- (4-Benzyloxymethylpyridin-2-yl) -2-phenylacetamide [Compound 19]

Melting point: 54-57 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.18 (1H, d, J = 7.6 Hz), 8.17 (1H, s), (7.82 (1H, br), 7.39-7.26 (10H, m), 7.04 ( 1H, d, J = 4.4 Hz), 4.59 (2H, s), 4.55 (2H, s), 3.76 (2H, s)
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 169.55, 151.34, 150.33, 147.69, 137.58, 133.92, 129.37, 129.11, 128.44, 127.80, 127.75, 127.59, 118.20, 112.05, 72.72, 70.50, 44.82

N- [4- (4-Chlorobenzyloxymethyl) -pyridin-2-yl] -3-phenylpropionamide [Compound 20]

Melting point: 56-63 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.21 (1H, s), 8.19 (1H, d, J = 4.9 Hz), 8.18 (1H, br), 7.37-7.19 (9H, m), 7.07 (1H , d, J = 5.4 Hz), 4.56 (2H, s), 4.56 (2H, s), 3.05 (2H, t, J = 7.7 Hz), 2.70 (2H, t, J = 7.68 Hz)

N- (4-Benzyloxymethylpyridin-2-yl) -3-phenylpropionamide [Compound 21]

Melting point: 57-60 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.50 (1H, br), 8.20 (1H, s), 8.18 (1H, d, J = 5.1 Hz), 7.38-7.09 (11H, m), 4.60 (2H , s), 4.56 (2H, s), 3.04 (2H, t, J = 7.7 Hz), 2.69 (2H, t, J = 7.8 Hz)
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 170.62, 151.28, 150.34, 147.85, 140.36, 137.63, 128.63, 128.51, 128.31, 127.87, 127.83, 126.39, 118.14, 111.96, 72.81, 70.59, 39.41, 31.19

N- [4- (4-Chloro-benzyloxymethyl) pyridin-2-yl] -2- (4-fluorophenyl) acetamide [Compound 22]

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.20 (1H, d, J = 5.1 Hz), 8.18 (1H, s), 7.81 (1H, br), 7.35-7.26 (7H, m), 7.08 (1H , t, J = 8.5 Hz), 4.55 (2H, s), 4.55 (2H, s), 3.73 (2H, s)
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 169.40, 162.15 (d, J = 246.5 Hz), 151.42, 150.15, 147.68, 136.05, 133.56, 130.92 (d, J = 8.3 Hz), 129.70 (d, J = 4.1 Hz), 115.88 (d, J = 21.5 Hz), 112.16, 71.93, 70.57, 43.70

N- (4-Benzyloxymethylpyridin-2-yl) -2- (4-fluoro-phenyl) acetamide [Compound 23]

Melting point: 88-92 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.19 (1H, d, J = 5.37), 8.18 (1H, s), 7.86 (1H, br), 7.37-7.26 (7H, m), 7.08 (2H, t, J = 8.7 Hz), 4.59 (2H, s), 4.55 (2H, s), 3.27 (2H, s)

N- (4-Benzyloxymethylpyridin-2-yl) -2- (2,6-difluorophenyl) acetamide [Compound 24]

Melting point: 84-86 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.22 (1H, d, J = 5.4 Hz), 8.17 (1H, s), 7.96 (1H, br), 7.36 (1H, d, J = 4.4 Hz), 7.33-7.28 (6H, m), 7.12 (1H, d, J = 4.4 Hz), 6.96 (2H, t, J = 7.8 Hz), 4.58 (2H, s), 4.54 (2H, s), 3.83 (2H , s)
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 167.53, 161.41 (dd, J = 256.4, J = 8.3 Hz), 151.66, 150.51, 147.39, 137.48, 129.15 (t, J = 10.3 Hz), 128.35, 127.72, 127.67, 118.14, 112.58, 111.16 (dd, J = 24.8, J = 5.8 Hz), 110.476 (t, J = 19.4 Hz), 72.64, 70.38, 30.73

・ N- [4- (4-Fluorobenzyloxymethyl) pyridin-2-yl] -3-phenylpropionamide [Compound 25]

Melting point: 56-59 ° C
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.21 (1H, d, J = 5.1 Hz), 8.19 (1H, s), 7.97 (1H, br), 7.37-7.26 (8H, m), 7.06 (2H , t, J = 8.8), 4.56 (2H, s), 4.56 (2H, s), 3.06 (2H, t, J = 7.8 Hz), 2.70 (2H, t, J = 7.8 Hz)
¹³ C-NMR (100 MHz CDCl ₃ ) δ: 171.04, 162.34 (d, J = 245.6 Hz), 151.80, 150.21, 147.42, 140.38, 133.31 (d, J = 3.3 Hz), 129.50 (d, J = 8.3 Hz ), 128.44, 128.16, 126.20, 117.86, 115.26 (d, J = 21.5 Hz), 112.44, 71.97, 70.46, 38.96, 31.08

2- (2,6-Difluorophenyl) -N- [4- (4-fluorobenzyloxymethyl) pyridin-2-yl] acetamide [Compound 26]

Add trifluoroacetic acid (2.4 mL) to a methylene chloride (15 mL) solution of tert-Butyl [4- (4-fluorobenzyloxymethyl) pyridin-2-yl] amine (0.288 g, 1 mmol) in an argon gas atmosphere. Heat to reflux for days.
After completion of the reaction, a 10% aqueous sodium hydroxide solution is added with stirring until the aqueous layer shows basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3), the combined methylene chloride is dried over potassium carbonate, and the solvent is distilled off.
The obtained crystals were made into a methylene chloride (5 mL) solution under an argon gas atmosphere, and 2,6-difluorophenylacetic acid (0.115 g, 0.67 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (0.141 g, 0.74 mmol) and N, N-dimethyl-4-aminopyridine (0.008 g, 0.067 mmol) are sequentially added and stirred at room temperature overnight.
After completion of the reaction, the solvent is distilled off.
The obtained residue was purified by silica gel chromatography (eluent; hexane: acetone = 8: 1) to obtain crystals (0.053 g, 20%).

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.22 (1H, d, J = 5.1 Hz), 8.18 (1H, s), 8.06 (1H, br), 7.34-7.31 (2H, m), 7.23 (1H , t, J = 7.6 Hz), 7.08 (1H, d, J = 5.1 Hz), 7.06-6.93 (4H, m), 4.56 (4H, s), 3.83 (2H, s)

2- (3,5-Difluorophenyl) -N- [4- (4-fluorobenzyloxymethyl) pyridin-2-yl] acetamide [Compound 27]

White crystals
¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.22 (1H, d, J = 5.1 Hz), 8.18 (1H, d, J = 1.3 Hz), 7.84 (1H, br), 7.36-7.32 (1H, m ), 7.10 (1H, dd, J = 5.1, J = 1.3 Hz), 7.08-6.87 (6H, d, m), 4.54 (4H, s), 3.89 (2H, s)

N- [4- (4-Chlorophenoxymethyl) pyridin-2-yl] -2- (2-trifluoromethylphenyl) acetamide [Compound 28]

In an argon gas atmosphere, tert-Butyl- [4- (4-chlorobenzyloxy) pyridin-2-yl] amine (0.169 g, 0.58 mmol) in methylene chloride (10 mL) solution, trifluoroacetic acid (1.2 ml) And reflux with heating for 2 days.
After completion of the reaction, a 10% aqueous sodium hydroxide solution is added with stirring until the aqueous layer shows basicity.
The separated aqueous layer is extracted with methylene chloride (10 mL × 3), the combined methylene chloride is dried over potassium carbonate, and the solvent is distilled off.
The obtained crystals were made into a methylene chloride (5 mL) solution under an argon gas atmosphere, and 2- (trifluoromethyl) phenylacetic acid (0.092 g, 0.45 mmol), 1-ethyl-3- (3-dimethylaminopropyl) was obtained. Carbodiimide hydrochloride (0.173 g, 0.90 mmol) and N, N-dimethyl-4-aminopyridine (0.005 g, 0.045 mmol) are sequentially added, and the mixture is stirred at room temperature overnight.
After completion of the reaction, the solvent is distilled off.
The obtained residue was purified by silica gel chromatography (eluent; hexane: acetone = 8: 1) to obtain crystals (0.116 g, 61%).

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.00 (1H, d, J = 5.9 Hz), 7.90 (1H, d, J = 2.2 Hz), 7.80 (1H, br), 7.70 (1H, d, J = 7.8 Hz), 7.57 (1H, t, J = 7.8 Hz), 7.48 (1H, d, J = 7.8 Hz), 7.70 (1H, t, J = 7.8 Hz), 7.35-7.21 (4H, m), 6.60 (1H, dd, J = 5.9, 2.2 Hz), 5.05 (2H, s), 3.91 (2H, s)

N- [4- (4-Chlorophenoxymethyl) pyridin-2-yl] -2- (3-trifluoromethylphenyl) acetamide [Compound 29]

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.00 (1H, d, J = 5.9 Hz), 7.94 (1H, br), 7.90 (1H, d, J = 2.2 Hz), 7.56-7.47 (4H, m ), 7.34-7,25 (4H, m), 6.62 (1H, dd, J = 5.9, 2.2 Hz), 5.05 (2H, s), 3.77 (2H, s)

N- [4- (4-Chlorophenoxymethyl) pyridin-2-yl] -2-o-tolylacetamide [Compound 30]

¹ H-NMR (400 MHz CDCl ₃ ) δ: 7.97 (1H, d, J = 5.9 Hz), 7.95 (1H, d, J = 2.7 Hz), 7.34-7.22 (4H, m), 6.62 (1H, dd , J = 5.9, 2.7 Hz), 5.07 (2H, s), 3.75 (2H, s), 2.32 (3H, s)

N- [4- (4-Chlorophenoxymethyl) pyridin-2-yl] -2-m-tolylacetamide [Compound 31]

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.18 (1H, br), 7.97 (1H, d, J = 5.9 Hz), 7.95 (1H, d, J = 2.4 Hz), 7.34-7.32 (4H, m ), 7.16-7.09 (4H, m), 6.59 (1H, dd, J = 5.9, 2.4 Hz), 5.06 (2H, s), 3.68 (2H, s), 2.33 (3H, s)

N- [4- (4-Chlorophenoxymethyl) pyridin-2-yl] -2-cyclohexylacetamide [Compound 32]

¹ H-NMR (400 MHz CDCl ₃ ) δ: 8.05 (1H, br), 8.02 (1H, d, J = 5.8 Hz), 7.96 (1H, d, J = 2.4 Hz), 7.35-7.34 (4H, m ), 6.60 (1H, dd, J = 5.8, 2.4 Hz), 5.08 (2H, s), 2.23 (2H, d, J = 7.1 Hz), 1.89-0.94 (11H, m)

The compound of the present invention exhibited an insulin signal enhancing action in mouse cerebellar granule cells, mouse-derived adipocytes, rat cerebral cortex cells, etc., and further exhibited a blood glucose lowering action in diabetes model mice. The compounds are useful as novel therapeutic agents for type 2 diabetes.
In addition, it is considered that the effect of neurotrophic factor can be enhanced by inhibiting SHIP2 in the cranial nervous system, and the compound of the present invention is expected to be used as an agent for improving central degenerative diseases such as Alzheimer's dementia.

Claims (6)

1. The following general formula [1]
   

   

   “Wherein R ¹ represents a hydrogen atom or a halogen atom; R ² represents a halogen atom or an alkyl group which may be substituted with a halogen atom, an optionally substituted phenyl group or a cyclohexyl group; An alkylene group or a bond; m and n each represents an integer of 1 to 3;
   Or an N- (pyridin-2-yl) alkanamide derivative represented by the formula:
2. ^2. The N- (pyridin-2-yl) alkanamide derivative according to claim 1, wherein R ² is a halogen atom or an optionally substituted phenyl group and an optionally substituted phenyl group. salt.
3. ^2. The N- (pyridin-2-yl) alkanamide derivative according to claim 1, wherein R ² is a halogen atom or an optionally substituted cyclohexyl group with a halogen atom or an alkyl group optionally substituted with a halogen atom. salt.
4. The N- (pyridin-2-yl) alkanamide derivative or a salt thereof according to any one of claims 1 to 3, wherein n is 1 and m is 1 or 2.
5. The N- (pyridin-2-yl) alkanamide derivative or a salt thereof according to any one of claims 1 to 4, wherein A is a methylene group or a bond.
6. A SHIP2 inhibitor comprising the N- (pyridin-2-yl) alkanamide derivative or a salt thereof according to any one of claims 1 to 5 as an active ingredient.

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