JP2013253019A - New piperidine derivative and pharmaceutical containing the same - Google Patents

Abstract

［式中、Ａ及びＢは、一方が窒素原子を示し、他方が窒素原子又はＣＲ⁸を示し、Ｘは、酸素原子、硫黄原子、−（ＣＨ₂）ｎ−Ｎ（Ｒ¹¹）−又は−（ＣＨ₂）ｎ−ＣＨ（Ｒ¹²）−を示し、Ｙが酸素原子又は硫黄原子のとき、Ｚは窒素原子を示し、Ｙが窒素原子のとき、Ｚは酸素原子又は硫黄原子を示し、Ｒ¹〜Ｒ⁷は水素原子、その他の置換基を示す］で表される化合物若しくはその塩、又はそれらの溶媒和物。
【選択図】なしThe present invention provides a novel compound having an action of promoting insulin secretion from pancreatic β cells and useful as a preventive and / or therapeutic agent for diseases caused by hyperglycemia such as diabetes.
The following general formula (1):

[In the formula, one of A and B represents a nitrogen atom, the other represents a nitrogen atom or CR ⁸ , and X represents an oxygen atom, a sulfur atom, — (CH ₂ ) n—N (R ¹¹ ) — or —. (CH ₂ ) n—CH (R ¹² ) —, wherein when Y is an oxygen atom or a sulfur atom, Z represents a nitrogen atom, when Y is a nitrogen atom, Z represents an oxygen atom or a sulfur atom; ^{1 to} R ⁷ represent a hydrogen atom and other substituents] or a salt thereof, or a solvate thereof.
[Selection figure] None

Description

  The present invention relates to a drug having an action of promoting insulin secretion from pancreatic β cells and preventing and / or treating diseases caused by hyperglycemia such as diabetes.

  The pancreas is an endocrine / exocrine gland tissue derived from the endoderm, and is composed of endocrine cells, acinar cells, and duct cells. Pancreatic Langerhans Islet (pancreatic La Islet), which is an endocrine cell, constitutes 1% of the entire pancreas and is mainly classified into four cells. That is, α cells that secrete glucagon, β cells that secrete insulin, δ cells that synthesize and secrete somatostatin, and F cells that synthesize and secrete pancreatic polypeptides. Of these, insulin secreted from β cells has the effect of lowering blood sugar as a main physiological function, and is the only hormone that exhibits a hypoglycemic action. Insulin is secreted by sensing an increase in blood glucose in the pancreatic β cells and released into the portal vein. The released insulin suppresses gluconeogenesis and sugar release in the liver, and promotes glucose uptake in fat and muscle tissues, which are peripheral tissues, thereby maintaining the blood sugar level of the living body.

  Diabetes is a persistent hyperglycemic condition caused by insulin deficiency or by its lack of action. Diabetes mainly leads to insulin-dependent diabetes (IDDM) caused by abnormal pancreatic insulin secretion due to autoimmune diseases, etc., and persistent high insulin status due to insufficient insulin action (insulin resistance), and the insulin secretion ability due to pancreatic exhaustion associated therewith It is divided into two types of non-insulin dependent diabetes mellitus (NIDDM) caused by a decrease. Persistent hyperglycemia due to diabetes causes vascular damage and complications in multiple organs. Typical complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc., and problems such as decreased quality of life (QOL), increased medical costs, decreased survival rate, etc. Yes.

  Treatment of diabetes includes exercise therapy, diet therapy, and drug therapy. Examples of the drug used for drug therapy include a drug that promotes insulin secretion from pancreatic β cells, a drug that improves insulin resistance, a drug that suppresses sugar absorption, and a drug that promotes the use of sugar. Among them, an insulin secretagogue is expected to increase blood insulin concentration and lower blood sugar, and is therefore expected to suppress hyperglycemia and improve diabetes. A sulfonylurea preparation (SU drug), Rapid insulin secretion promoters, DPPIV inhibitors (see Non-Patent Document 1), GLP-1 analogs (see Non-Patent Document 2) and the like are actually used in the field of diabetes treatment. However, the most commonly used SU drug in Japan stimulates pancreatic β-cells and promotes endogenous insulin secretion (see Non-Patent Document 3), but may exhibit hypoglycemia as a side effect, particularly in the elderly, Care should be taken when using this product if the patient has impaired renal function or if the diet is irregular. Also, side effects such as weight gain have been reported. Furthermore, there may be a primary ineffectiveness in which no effect is seen from the initial administration, or a secondary ineffectiveness in which clinical effects are lost during the administration period (see Non-Patent Document 4), and these side effects are reduced, and the insulin secretion ability Development of an insulin secretagogue that reduces the burden on pancreatic β cells is desired.

  Examples of piperidine derivatives having a condensed heterocyclic ring at the 4-position include compounds having an adrenocorticotropic hormone releasing factor antagonistic action (Patent Documents 1, 2, 3, 4, 5), compounds having cell growth inhibitory activity, etc. (Patent Documents) 6) etc. have been reported. Moreover, although the condensed ring compound (patent document 7) related to GPR119 has been reported, the structure is different from the compound of the present invention. On the other hand, compounds having a condensed pyridine or condensed pyrimidine skeleton include compounds having an FXR (Farnesoid X receptor) inhibitory action (Patent Document 8), compounds useful as therapeutic agents for metabolic diseases (Patent Documents 9 and 10), proteins Compounds useful as kinase inhibitors (Patent Documents 11 and 12) and compounds useful as drug resistance therapeutic agents (Patent Document 13) have been reported.

EP 1149583 WO2010 / 058489 pamphlet EP1097709 JP 2001-514260 A JP 2000-109431 A WO2000 / 043394 pamphlet WO2010 / 088518 pamphlet WO2009 / 127321 pamphlet WO2007 / 115822 pamphlet WO2006 / 077401 pamphlet WO2005 / 113560 pamphlet WO2009 / 070524 pamphlet WO2004 / 065389 pamphlet

J Clin Endocrinol Metab, May 2004, 89 (5): 2078-2084. Regul Pept, 2004, 117 (2): 77-88 The Lancet, Aug 31, 1985, 2: 474-475. The Lancet, Sep 12, 1998, 352: 837-853.

  An object of the present invention is to provide a compound having an action of promoting insulin secretion from pancreatic β cells and useful as a prophylactic / therapeutic agent for diseases caused by hyperglycemia such as diabetes.

  As part of research to find a compound having insulin secretion promoting activity, the present inventors searched for a compound that promotes insulin secretion using a hamster pancreatic β cell line HIT-T15 cell. The piperidine derivative represented by (1) was found to have an excellent effect of promoting insulin secretion from pancreatic β cells, and was useful as a therapeutic agent for diabetes, and the present invention was completed.

That is, this invention relates to the invention shown below.
[1] The following general formula (1):

[Where:
One of A and B represents a nitrogen atom and the other is a nitrogen atom or CR ⁸ (where R ⁸ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, or Nitro group)
D represents a nitrogen atom or CR ⁹ (wherein R ⁹ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group or a nitro group);
E represents a nitrogen atom or CR ¹⁰ (wherein R ¹⁰ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group or a nitro group);
X is an oxygen atom, a sulfur atom, — (CH ₂ ) n—N (R ¹¹ ) — or — (CH ₂ ) n—CH (R ¹² ) — (wherein R ¹¹ and R ¹² are each a hydrogen atom; Or a C _1-6 alkyl group, and n represents 0 or 1);
When Y is an oxygen atom or a sulfur atom, Z represents a nitrogen atom;
When Y is a nitrogen atom, Z represents an oxygen atom or a sulfur atom;
R ¹ and R ³ each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group or a nitro group,
Alternatively, R ¹ and R ¹¹ or R ¹ and R ¹² may be combined to form a heterocycle;
R ² is a hydrogen atom, —S (O) R ¹³ , —S (O) ₂ R ¹⁴ , —CO ₂ R ¹⁵ or —CONR ¹⁶ R ¹⁷ , an aryl group, a heteroaryl group (where R ¹³ and R ¹⁴ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, an optionally substituted C _6-10 aryl group, an amino group, respectively. A mono (C _1-6 alkyl) amino group or a di (C _1-6 alkyl) amino group, R ¹⁵ represents a C _1-6 alkyl group, and R ¹⁶ and R ¹⁷ are each independently A hydrogen atom or a C _1-6 alkyl group which may have a substituent);
R ⁴ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group or an amino group;
R ⁵ and R ⁶ each independently represent a hydrogen atom or a C _1-6 alkyl group;
R ⁷ is a C _1-6 alkyl group, —C (O) R ¹⁸ , —C (S) R ¹⁹ , —S (O) ₂ R ²⁰ , an optionally substituted C _6-10 aryl group Or a 5- to 10-membered heteroaryl group which may have a substituent (wherein R ¹⁸ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _6-10 aryl C _1-6 alkoxy group, A 5- to 10-membered heteroaryl group or mono (C _1-6 alkyl) amino group which may have a substituent, wherein R ¹⁹ and R ²⁰ are a C _1-6 alkyl group and a halo C _1-6 alkyl, respectively; Group, C _3-8 cycloalkyl group, mono (C _1-6 alkyl) amino group, _optionally substituted C _6-10 aryl group or _optionally substituted 5-10 membered heteroaryl Show group)]
Or a salt thereof, or a solvate thereof.

[2] A heterocycle formed by combining R ¹ and R ¹¹ or R ¹ and R ¹² together has the following formula:

[Where:
R ²¹ is a hydrogen atom, a C _1-6 alkyl group, —C (O) R ²² or —S (O) ₂ R ²³ (where R ²² and R ²³ are each a C _1-6 alkyl group, C _{3- 8 represents a} cycloalkyl group, and the wavy line represents an aromatic ring constituted by D and E].
The compound according to [1] or a salt thereof, or a solvate thereof, selected from the group consisting of:

[3] The following compound group:
tert-Butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate, 3- (1- (5- Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indolin-1-yl) isoxazolo [4,5-d] pyrimidine, and 3- (1- (5-ethylpyrimidine) 2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine [1] or [2] Or a salt thereof, or a solvate thereof.

[4] A pharmaceutical composition comprising the compound according to any one of [1] to [3] or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

[5] An insulin secretion promoter comprising the compound or salt thereof according to any one of [1] to [3] or a solvate thereof as an active ingredient.

[6] A hypoglycemic agent comprising the compound according to any one of [1] to [3] or a salt thereof, or a solvate thereof as an active ingredient.

[7] A preventive and / or therapeutic agent for diabetes comprising the compound according to any one of [1] to [3] or a salt thereof, or a solvate thereof as an active ingredient.

[8] A method for promoting insulin secretion, comprising administering an effective amount of the compound according to any one of [1] to [3] or a salt thereof, or a solvate thereof.

[9] A method for lowering blood glucose, comprising administering an effective amount of the compound according to any one of [1] to [3] or a salt thereof, or a solvate thereof.

[10] A method for preventing and / or treating diabetes, comprising administering an effective amount of the compound or salt thereof according to any one of [1] to [3] above, or a solvate thereof.

[11] The compound according to any one of the above [1] to [3] or a salt thereof, or a solvate thereof, for promoting secretion of insulin.

[12] The compound according to any one of the above [1] to [3] or a salt thereof, or a solvate thereof, for lowering blood glucose.

[13] The compound according to any one of the above [1] to [3] or a salt thereof, or a solvate thereof, for preventing and / or treating diabetes.

[14] A compound or a salt thereof according to any one of [1] to [3], or a solvate thereof, for producing an insulin secretion promoter, a hypoglycemic agent, or a preventive and / or therapeutic agent for diabetes. use.

  The piperidine derivative of the present invention or a salt thereof, or a solvate thereof is an orally administrable low-molecular compound having an action of strongly promoting insulin secretion from pancreatic β cells, and is caused by hyperglycemia in mammals including humans. It is useful as a preventive and / or therapeutic agent for a disease that occurs, such as diabetes.

  In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Examples include n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n-hexyl group and the like.

In the present specification, "halo C _1-6 alkyl group", a C _1-6 alkyl group substituted by the same or different 1 to replaceable maximum halogen atoms, for example, monofluoromethyl Examples thereof include a methyl group, a difluoromethyl group, a trifluoromethyl group, a monochloromethyl group, a dichloromethyl group, a trichloromethyl group, a monobromomethyl group, a monoiodomethyl group, and a 2,2,2-trifluoroethyl group.

In the present specification, examples of the “C _3-8 cycloalkyl group” include monocyclic, polycyclic or condensed cyclic cycloalkyl groups having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Examples of such a cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

In the present specification, examples of the “C _2-6 alkenyl group” include a vinyl group, a prop-1-en-1-yl group (propenyl group), and a prop-2-en-1-yl group (allyl group). , Isopropenyl group, but-1-en-1-yl group, but-2-en-1-yl group (crotyl group), but-3-en-1-yl group, 2-methylprop-2-ene- 1-yl group, 1-methylprop-2-en-1-yl group, penta-1-en-1-yl group, penta-2-en-1-yl group, penta-3-en-1-yl group Penta-4-en-1-yl group, 3-methylbut-2-en-1-yl group, 3-methylbut-3-en-1-yl group, hexa-1-en-1-yl group, hexa 2-ene-1-yl group, hexa-3-en-1-yl group, hexa-4-en-1-yl group, Examples include a hexa-5-en-1-yl group and a 4-methylpent-3-en-1-yl group.

In the present specification, examples of the “C _2-6 alkynyl group” include ethynyl group, prop-1-yn-1-yl group, prop-2-yn-1-yl group (propargyl group), but-1 -In-1-yl group, but-3-yn-1-yl group, 1-methylprop-2-in-1-yl group, penta-1-in-1-yl group, penta-4-in-1 -Yl group, hexa-1-in-1-yl group, hexa-5-in-1-yl group and the like.

In the present specification, examples of the “C _1-6 alkoxy group” include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. N-pentoxy group, isopentoxy group, neopentoxy group, n-hexyloxy group, isohexyloxy group and the like.

In this specification, examples of the “C _1-6 alkylthio group” include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, and a tert-butylthio group. Group, n-pentylthio group, isopentylthio group, neopentylthio group, n-hexylthio group, isohexylthio group and the like.

In the present specification, the “mono (C _1-6 alkyl) amino group” means a group in which the alkyl group is bonded to a nitrogen atom, for example, a methylamino group, an ethylamino group, a propylamino group, Examples include isopropylamino group, butylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group, neopentylamino group, n-hexylamino group, and isohexylamino group. .

In the present specification, the “di (C _1-6 alkyl) amino group” means a group in which two alkyl groups are the same or different and bonded to a nitrogen atom, for example, a dimethylamino group, a methylethylamino group , Diethylamino group, methylpropylamino group, ethylpropylamino group, dipropylamino group, diisopropylamino group, dibutylamino group and the like.

In the present specification, examples of the “C _6-10 aryl group” include a phenyl group, a naphthyl group, an azulenyl group, and the like.

In the present specification, the “substituted sulfonyl group” means “C _1-6 alkylsulfonyl group” in which an alkyl group is bonded via sulfonyl (—SO ₂ —), and “halo” in which a haloalkyl group is bonded via a sulfonyl group. C _1-6 alkylsulfonyl group ", a C _3-8 cycloalkyl group" C _3-8 cycloalkyl sulfonyl group attached through a sulfonyl ", C _2-6 alkenyl group bonded through a sulfonyl" C _{2 -6} alkenylsulfonyl group ", C _2-6 alkynyl group bonded through a sulfonyl" C _2-6 alkynylsulfonyl group ", an amino group is bonded through a sulfonyl" sulfamoyl group ", mono (C _1-6 alkyl) amino group or a di (C _1-6 alkyl) amino group is bonded through a sulfonyl "mono (C _1-6 alkyl) sulfamoyl group" or "di (C _1-6 alkyl) Surufamo Le group ", the aryl group means or the like attached through a sulfonyl" C _6-10 arylsulfonyl group ".

In the present specification, examples of the “C _1-6 alkylsulfonyl group” include, for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butyl. Sulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, 2-methylbutylsulfonyl group, 1-methylbutylsulfonyl group, 1-ethylpropylsulfonyl group, 2,2- Dimethylpropylsulfonyl group, n-hexylsulfonyl group, 4-methylpentylsulfonyl group, 3-methylpentylsulfonyl group, 2-methylpentylsulfonyl group, 1-methylpentylsulfonyl group, 3,3-dimethylbutylsulfonyl group, 2, 2 -Dimethylbutylsulfonyl group, 1,1-dimethylbutylsulfonyl group, 1,2-dimethylbutylsulfonyl group, 1,3-dimethylbutylsulfonyl group, 2,3-dimethylbutylsulfonyl group, 1-ethylbutylsulfonyl group, 2 -An ethyl butyl sulfonyl group etc. are mentioned.

In the present specification, examples of the “halo C _1-6 alkylsulfonyl group” include a fluoromethylsulfonyl group, a difluoromethylsulfonyl group, a trifluoromethylsulfonyl group, a chloromethylsulfonyl group, a bromomethylsulfonyl group, and an iodomethylsulfonyl group. 2,2,2-trifluoroethylsulfonyl group and the like.

In the present specification, examples of the “C _3-8 cycloalkylsulfonyl group” include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, a cycloheptylsulfonyl group, and a cyclooctylsulfonyl group. Can be mentioned.

In the present specification, examples of the “C _2-6 alkenylsulfonyl group” include a vinylsulfonyl group, a propenylsulfonyl group, an allylsulfonyl group, a crotylsulfonyl group, and the like.

In the present specification, examples of the “C _2-6 alkynylsulfonyl group” include an ethynylsulfonyl group, a propargylsulfonyl group, and the like.

In the present specification, examples of the “mono (C _1-6 alkyl) sulfamoyl group” include a methylsulfamoyl group, an ethylsulfamoyl group, a propylsulfamoyl group, an isopropylsulfamoyl group, and a butylsulfamoyl group. Group, sec-butylsulfamoyl group, tert-butylsulfamoyl group, pentylsulfamoyl group, hexylsulfamoyl group and the like.

In the present specification, examples of the “di (C _1-6 alkyl) sulfamoyl group” include dimethylsulfamoyl group, methylethylsulfamoyl group, diethylsulfamoyl group, dipropylsulfamoyl group, diisopropylsulfamoyl group. A moyl group, a dibutylsulfamoyl group, etc. are mentioned.

In the present specification, examples of the “C _6-10 arylsulfonyl group” include a phenylsulfonyl group, a toluenesulfonyl group, a naphthylsulfonyl group, an azulenylsulfonyl group, and the like.

  In the present specification, the “heterocycle” means a 5-membered or 6-membered saturated or unsaturated heterocycle optionally having at least one nitrogen atom, oxygen atom or sulfur atom, for example, Pyrrolidine, pyrroline, pyrrole, pyrrolidinone, pyrrolinone, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, piperidine, piperidinone, dihydropyridine, dihydropyridinone, pyridine, morpholine, pyrimidine, thiophene, furan and the like.

  In the present specification, the “5-10-membered heteroaryl group” means a 5- to 10-membered monocyclic, polycyclic, or 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Fused cyclic aromatic heterocyclic group means, for example, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group , Tetrazolyl group, pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, benzofuranyl group, isobenzofuranyl group, benzothienyl group, indolyl group, isoindolyl group, indazolyl group, benzoimidazolyl group, benzoxazolyl group, benzoisoxa Zolyl group, benzothiazolyl group, benzoiso Azolyl group, benzooxadiazolyl group, benzothiadiazolyl group, benzotriazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, pteridinyl group, phlopyridyl group , Thienopyridyl group, pyrrolopyridyl group, oxazolopyridyl group, thiazolopyridyl group, imidazopyridyl group and the like.

In the present specification, the “C _6-10 aryl C _1-6 alkoxy group” means a group in which the C _1-6 alkoxy group is bonded to a phenyl group, a naphthyl group, an azulenyl group or the like. Examples thereof include a phenyl-C _1-6 alkoxy group, a naphthyl-C _1-6 alkoxy group, and an azulenyl-C _1-6 alkoxy group. More specifically, a benzyloxy group, a phenethyloxy group, a naphthylmethyl group, and the like can be given.

In this specification, examples of the “substituent” in the C _1-6 alkyl group which may have a substituent include a halogen atom, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group, a mono ( C _1-6 alkyl) amino group, di (C _1-6 alkyl) amino group, di (C _2-6 alkenyl) amino group, mono (C _3-8 cycloalkyl) amino group, C _2-7 alkoxycarbonyl group Amino group, carboxyl group, cyano group, carbamoyl group, sulfamoyl group, hydroxyl group, nitro group and the like. You may have 1-4 of these substituents. In addition, the carbon number (C _2-7 ) of the alkoxycarbonyl group indicates a number including the carbonyl carbon.

In this specification, examples of the “substituent” in the C _6-10 aryl group which may have a substituent and the 5-10 membered heteroaryl group which may have a substituent include a halogen atom, C _1-6 alkyl group, C _3-8 cycloalkyl group, halo C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, mono (C _1-6 alkyl) ) Amino group, di (C _1-6 alkyl) amino group, di (C _2-6 alkenyl) amino group, mono (C _3-8 cycloalkyl) amino group, dioxaboranyl group, morpholino group, piperidino group, oxadiazolyl group, C _2-7 alkoxycarbonyl group, amino group, carboxyl group, cyano group, carbamoyl group, sulfamoyl group, hydroxyl group, nitro group and the like can be mentioned. You may have 1-4 of these substituents. Moreover, these substituents may further have a substituent.

R ¹ and R ³ are preferably a hydrogen atom, a halogen atom, or a C _1-6 alkyl group, and particularly preferably a hydrogen atom, a halogen atom, or a C _1-4 alkyl group. Among these, R ¹ is more preferably a halogen atom or a C _1-6 alkyl group, and R ³ is more preferably a hydrogen atom.

In general formula (1), the halogen atom in R ¹ and R ³ is preferably a fluorine atom.

In the general formula (1), the C _1-6 alkyl group in R ¹ and R ³ is preferably a C _1-4 alkyl group, and more preferably a methyl group.

In general formula (1), R ² is preferably a hydrogen atom, —S (O) R ¹³ , —S (O) ₂ R ¹⁴ , —CO ₂ R ¹⁵ or —CONR ¹⁶ R ¹⁷ , preferably a hydrogen atom, — S (O) R ¹³ and —S (O) ₂ R ¹⁴ are more preferable.

In general formula (1), R ⁴ , R ⁵ and R ⁶ are preferably hydrogen atoms.

In general formula (1), as R ⁷ , —C (O) R ¹⁸ , —C (S) R ¹⁹ , —S (O) ₂ R ²⁰ , optionally substituted C _6-10 aryl 5-10 membered heteroaryl group which may have a group or a substituent is preferable, and 5-10 membered heteroaryl which may have —C (O) R ¹⁸ , —S (O) ₂ R ²⁰ or a substituent An aryl group is more preferred.

In the general formula (1), as the R ¹⁸ in -C (O) R ¹⁸ in R ^7, C _1-6 alkoxy, halo C _1-6 alkoxy group, C _6-10 aryl C _1-6 alkoxy group or A mono (C _1-6 alkyl) amino group is preferred, and a C _1-6 alkoxy group is more preferred.

In the general formula (1), as the R ¹⁹ in -C (S) R ¹⁹ in R ^7, C _1-6 alkoxy, halo C _1-6 alkoxy group, C _6-10 aryl C _1-6 alkoxy group or A mono (C _1-6 alkyl) amino group is preferred, and a mono (C _1-6 alkyl) amino group is more preferred.

In the general formula (1), as the R ²⁰ in -S (O) ₂ R ²⁰ in R ^7, C _1-6 alkyl, halo C _1-6 alkyl group, C _3-8 cycloalkyl group, a substituent A C _6-10 aryl group which may have or a 5-10 membered heteroaryl group which may have a substituent is preferable.

In the general formula (1), the 5-10 membered heteroaryl group in the 5-10 membered heteroaryl group which may have a substituent in R ⁷ is preferably a pyridyl group, a pyrimidinyl group, or an oxadiazole group. Further, the substituent moiety is preferably a halogen atom, a C _1-6 alkyl group or a halo C _1-6 alkyl group, more preferably a chlorine atom, an ethyl group, an isopropyl group or a trifluoromethyl group, a chlorine atom, an ethyl group. Is more preferable.

In the general formula (1), the heterocyclic ring formed by combining R ¹ and R ¹¹ or R ¹ and R ¹² may be represented by the following formula:

[Where:
R ²¹ represents a hydrogen atom, a C _1-6 alkyl group, —C (O) R ²² or —S (O) ₂ R ²³ (where R ²² and R ²³ are each a C _1-6 alkyl group or C _{3− 8 represents a} cycloalkyl group, and the wavy line represents an aromatic ring containing D and E]

Preferred is a heterocycle selected from

Is more preferred,

Is more preferable.

In general formula (1), R ¹¹ or R ¹² is preferably a hydrogen atom.

In the general formula (1), the C _1-6 alkyl group in R ¹³ or R ¹⁴ is preferably a C _1-4 alkyl group, and more preferably a methyl group.

In the general formula (1), the C _6-10 aryl group which may have a substituent in R ¹³ or R ¹⁴ is preferably a phenyl group or a toluoyl group, and more preferably a p-toluyl group.

In general formula (1), the C _1-6 alkoxy group in R ¹⁸ is preferably a C _1-4 alkoxy group, more preferably a methoxy group, an ethoxy group, an isopropoxy group, or a tert-butoxy group, and a tert-butoxy group. Is more preferable.

In general formula (1), the C _6-10 aryl C _1-6 alkoxy group in R ¹⁸ is preferably a phenyl C _1-6 alkoxy group, more preferably a benzyloxy group.

In general formula (1), the 5-10 membered heteroaryl group which may have a substituent for R ¹⁸ is preferably a pyridyl group.

In the general formula (1), the mono (C _1-6 alkyl) amino group in R ¹⁸ is preferably a mono (C _1-4 alkyl) amino group, and more preferably a tert-butylamino group.

In the general formula (1), the mono (C _1-6 alkyl) amino group in R ¹⁹ is preferably a mono (C _1-4 alkyl) amino group, and more preferably a tert-butylamino group.

In the general formula (1), the C _1-6 alkyl group in R ²⁰ is preferably a C _1-4 alkyl group, and more preferably an n-butyl group.

In general formula (1), the halo C _1-6 alkyl group in R ²⁰ is preferably a halo C _1-4 alkyl group, more preferably a trichloromethyl group.

In the general formula (1), the C _3-8 cycloalkyl group in R ²⁰ is preferably a C _3-6 cycloalkyl group, and more preferably a cyclopropyl group or a cyclohexyl group.

In general formula (1), the C _6-10 aryl group which may have a substituent in R ²⁰ is preferably a phenyl group which may have a substituent. As the substituent portion, a halo C _1-6 alkyl group (such as a trifluoromethyl group) or a C _1-6 alkoxy group (such as a methoxy group) is preferable.

In general formula (1), the C _6-10 heteroaryl group which may have a substituent for R ²⁰ is preferably a thienyl group.

  In general formula (1), as A and B, when A and B are nitrogen atoms, when A is a nitrogen atom and B is CH, the case where A is CH and B is a nitrogen atom is more preferable, More preferably, A and B are nitrogen atoms.

  In general formula (1), as D, a nitrogen atom, CH or C-halogen is preferable, and CH is more preferable.

  In general formula (1), as E, a nitrogen atom, CH, or C-halogen is preferable, and CH is more preferable.

  In general formula (1), as X, a nitrogen atom or an oxygen atom is preferable, and a nitrogen atom is more preferable.

  In general formula (1), Y is preferably an oxygen atom, a sulfur atom, or a nitrogen atom, more preferably an oxygen atom or a nitrogen atom, and still more preferably an oxygen atom.

  In general formula (1), as Z, an oxygen atom, a sulfur atom, or a nitrogen atom is preferable, an oxygen atom or a nitrogen atom is more preferable, and a nitrogen atom is more preferable.

As a more preferable compound of the condensed pyridine or the condensed pyrimidine derivative represented by the general formula (1),
tert-butyl 4- (7- (5- (methylsulfonyl) indolin-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate (Example 1),
3- (1- (5-chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 2) ), And 3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine ( Example 3)
A compound selected from the group consisting of:

  When geometrical isomers or optical isomers exist in the compound of the present invention, these isomers are also included in the scope of the present invention. These isomers are separated by a conventional method.

  The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. When the compound is treated as an acidic compound, for example, alkali metal salt or alkaline earth metal salt such as sodium, potassium, magnesium, calcium; trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N- And salts with organic bases such as methylmorpholine. When treating a compound as a basic compound, for example, acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, Examples include acid addition salts of organic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate. It is done.

  Examples of the solvate of the compound represented by the general formula (1) or a salt thereof include, but are not limited to, hydrates and the like.

  It should be noted that all compounds that are metabolized in vivo and converted into the compound represented by the general formula (1), so-called prodrugs, are also included in the present invention. Examples of the group that forms a prodrug of the compound of the present invention include groups described in “Progress in Medicine”, Life Science Medica, 1985, Vol. 5, pages 2157-2161. Examples include the groups described in Yodogawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163-198.

The compound represented by the above general formula (1), a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited. For example, the reaction described below It can be manufactured according to the process. Moreover, when performing the following reaction, functional groups other than the reaction site may be protected in advance as necessary, and may be deprotected at an appropriate stage. The protection and deprotection conditions can be carried out with reference to commonly used methods (for example, the method described in Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc., 1999). Further, in each step, the reaction may be carried out by a usual method (for example, the method described in Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc; 1999), and isolation and purification are performed by crystallization and recrystallization. Ordinary methods such as chromatography may be appropriately selected or combined.
(Method for producing the compound represented by the general formula (1))
The compound represented by the general formula (1) of the present invention can be produced by the method shown in the following reaction pathway diagram 1.
[Reaction Path Diagram 1]

(In the formula, A, B, D, E, X, Y, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are the same as those in the general formula (1). And W ¹ represents a leaving group.)

(A-1) In the step A-1, the compound (2) is mixed with a dehydrating condensing agent such as hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP) in the presence of a base in a solvent. This is a step for producing a compound (3) by reacting with a sulfonylating agent such as methanesulfonyl chloride. Although there is no restriction | limiting in particular as a base, For example, alkali carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2,2,2] octane (DABCO), triethylamine, N, N-diisopropylethylamine, N, N -Organic bases such as diisopropylpentylamine and trimethylamine can be used. 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) is preferred. Although there is no restriction | limiting in particular as a solvent, For example, they are N, N- dimethylformamide, a dioxane, tetrahydrofuran, acetonitrile, propionitrile, chloroform, a methylene chloride etc., These can be used individually or in combination. Preferred is tetrahydrofuran alone or a mixed solvent of tetrahydrofuran and methylene chloride. 0-150 degreeC of reaction temperature is preferable, More preferably, it is 10-30 degreeC. The reaction time is preferably 5 minutes to 48 hours, more preferably 10 minutes to 2 hours.

(A-2) Step A-2 is a step of producing compound (1) by reacting compound (3) with compound (4) in the presence of a base in a solvent. Although there is no restriction | limiting in particular as a base, For example, Alkali metal hydrides, such as lithium hydride, sodium hydride, potassium hydride; Alkali metals, such as metallic lithium, metallic sodium, metallic potassium; Lithium hydroxide, Hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc. can be used. . Sodium hydride is preferable. Although there is no restriction | limiting in particular as a solvent, For example, they are N, N- dimethylformamide, a dioxane, tetrahydrofuran, acetonitrile, propionitrile, etc., These can be used individually or in combination. N, N-dimethylformamide is preferred. 0-150 degreeC of reaction temperature is preferable, More preferably, it is 50-100 degreeC. The reaction time is preferably 5 minutes to 48 hours, more preferably 10 minutes to 4 hours.

Apart from the method described above, the compound represented by the general formula (1) of the present invention can also be produced by the method described in the following reaction pathway diagram 2.
[Reaction Path Diagram 2]

(In the formula, A, B, D, E, X, Y, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are the same as those in the general formula (1). And is synonymous and W ² represents a leaving group.)

(B-1) In the step B-1, compound (2) is reacted with a halogenating agent such as phosphorus oxychloride (POCl ₃ ) in the presence or absence of a solvent, in the presence or absence of a base. In this step, compound (5) is produced. The halogenating agent to be used is not particularly limited, and for example, phosphorus oxychloride, phosphorus oxychloride / phosphorus pentachloride, N, N-dimethylformamide / oxalyl chloride and the like can be used. Preferred is phosphorus oxychloride. As the base, N, N-dimethylaniline, N, N-diethylaniline, N, N, N-diisopropylethylamine or the like can be used. As the solvent, dioxane, 1,2-dichloroethane and the like can be used. 0-150 degreeC of reaction temperature is preferable, More preferably, it is 80-120 degreeC. The reaction time is preferably 10 minutes to 48 hours, more preferably 3 to 6 hours.

(B-2) Step B-2 is a step for producing a compound represented by the general formula (1) by reacting compound (5) with compound (4) by an amination reaction using a metal catalyst. . The metal catalyst, ligand, base, and reaction conditions are not particularly limited as long as they are reagents and conditions that are usually used in amination reactions. For example, AR Muci, SL Buchwald, Top. Curr. Chem., 219, 131- 209, (2002) can be used. In the step B-2, a method of an amination reaction performed in a solvent or in the absence of a solvent in the presence or absence of a base and in the presence of a metal catalyst can also be applied. In that case, microwave irradiation may be performed. The metal catalyst is not particularly limited. For example, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0 ), Palladium complexes such as tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium, or Monovalent copper reagents such as cuprous iodide, cuprous bromide, cuprous cyanide may be used alone, but (2-biphenyl) di-tert-butylphosphine, (2-biphenyl) dicyclohexylphosphine , Tricyclohexylphosphine, 1,3-bis (phenylphospho ) Propane, 2,2′-bis (diphenylphosphanyl) -1,1′-binaphthyl, 2- (dicyclohexylphosphono) biphenyl, 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, A combination of ligands such as tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, and N-methylglycine can also be used. Although there is no restriction | limiting in particular as a base, For example, Alkali metal hydrides, such as lithium hydride, sodium hydride, potassium hydride; Alkali metals, such as metallic lithium, metallic sodium, metallic potassium; Lithium hydroxide, Hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc. can be used. . Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, toluene, a dioxane, N, N- dimethylformamide, N-methylpyrrolidone, a dimethylsulfoxide, water etc. can be used individually or in combination. The reaction temperature is preferably 0 to 200 ° C, more preferably 100 ° C to 150 ° C. The reaction time is preferably 1 minute to 5 days, more preferably 30 minutes to 6 hours.

(Method for producing piperidine derivative represented by general formula (2))
Next, among the compounds represented by the general formula (2) used in the above reaction, the compounds (2a-d) in which A and B are both nitrogen atoms can be produced by the method shown in the following reaction route diagram 3. it can.
[Reaction route diagram 3]

(In the formula, Y, Z, R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as those in the general formula (1), and R ²⁴ is a C _1-6 alkyl group or C _{6-10. Represents} an aryl C _1-6 alkyl group.)

(C-1) Step C-1 is a step for producing compound (2) by reacting compound (6) with amidine derivative (7) or a salt thereof. Although there is no restriction | limiting in particular as a solvent, For example, methanol, ethanol, ether, tetrahydrofuran, 1, 4- dioxane, benzene, toluene etc. can be used. Ethanol is preferable. The reaction temperature is preferably 40 to 120 ° C, more preferably 80 ° C to 100 ° C. The reaction time is preferably 1 hour to 5 days, more preferably 12 hours to 2 days. In addition, compound (2a-d) can be obtained from Bioorg. Med. Chem. Lett., 2005, 15, 3900., WO2001 / 047934 pamphlet, Liebigs Ann. Chem., 1979, 10, 1534., Indian J. Chem, Sec B., 1994, 33B, 436., and WO2006 / 047516 pamphlet can also be used for production. As the compound (7) used in the above reaction, an available compound can be used as it is, or it can be appropriately produced by a known method, but it is not limited thereto.

(Method for producing piperidine derivative represented by general formula (2))
Next, among the compounds represented by the general formula (2) used in the above reaction, the compound (2e-j) in which either A or B is a nitrogen atom is produced by the method shown in the following reaction route diagram 4. be able to.
[Reaction route diagram 4]

(In the formula, Y, Z, R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as those in the general formula (1), and R ²⁴ is a C _1-6 alkyl group or C _6-10. Aryl C _1-6 alkyl group, W ³ represents a halogen atom, a hydroxyl group or an amino group.

(D-1) The compound (2e-h) shown above can be synthesized with reference to US2001 / 0007867 pamphlet. The raw material (6) can be produced with reference to WO2006 / 047516 pamphlet, Bioorg. Med. Chem. Lett., 2004, 14, 5543., Liebigs Ann. Chem., 1979, 10, 1534.
Compounds (2e, f) and (2i, j) can also be produced by the methods of WO2005 / 007658 (E-1) and EP0778277 (F-1), respectively. As the compounds (6), (7), and (8) used in the above reaction, those that are available can be used as they are, or can be appropriately produced by known methods, but are not limited thereto.

  Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.

  Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between the isomers. The racemic mixture is optically purified by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to isomers. Moreover, a diastereomeric mixture can be divided | segmented by fractional crystallization or various chromatography, for example. An optically active compound can also be produced by using an appropriate optically active raw material.

  The obtained compound (1) can be converted into a salt by a usual method. Moreover, it can also be set as the solvate and hydrate of solvents, such as a reaction solvent and a recrystallization solvent.

  As a medicament containing the compound represented by the general formula (1) of the present invention or a salt thereof, or a solvate thereof as an active ingredient, this active ingredient may be used alone, but it is usually pharmaceutically acceptable. It is used in the form of a pharmaceutical composition by blending carriers, additives and the like. The administration form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, patches and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by known formulation methods.

  When preparing an oral solid preparation, the compound represented by the general formula (1) is mixed with an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a corrigent and the like. After the addition, tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. The additive may be one commonly used in the art. Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, and tartaric acid.

  When preparing an oral liquid preparation, add a corrigent, a buffer, a stabilizer, a corrigent, etc. to the compound represented by the general formula (1), and add an oral solution, syrup, elixir, etc. Can be manufactured. As the corrigent, those mentioned above may be used. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and subcutaneous, muscle and Intravenous injections can be manufactured. Examples of the pH adjusting agent and buffer include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  When preparing a suppository, a carrier for a suppository known to the compound represented by the general formula (1), such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and Tween (registered trademark) as necessary. After adding a surfactant, etc., it can be produced by a conventional method.

  When preparing an ointment, bases, stabilizers, wetting agents, preservatives, etc., which are usually used for the compound represented by the general formula (1) are blended as necessary, and mixed and formulated by conventional methods. It becomes. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of preservatives include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and the like.

  In addition to the above, the compound represented by the general formula (1) can be converted into an inhalant, eye drop, or nasal drop by a conventional method.

  As shown in Examples described later, the compound represented by the general formula (1) has an effect of significantly promoting insulin secretion in the hamster pancreatic β cell line HIT-T15 cells. Therefore, the compound represented by the general formula (1), or an acid addition salt thereof, or a solvate thereof is used as a hypoglycemic agent and for prevention of diseases caused by hyperglycemia in mammals including humans such as diabetes. Or it is useful as a therapeutic agent. Here, as diabetes, non-insulin dependent diabetes mellitus (NIDDM) is mentioned in more detail.

  The compound represented by the general formula (1) of the present invention is administered by oral administration or parenteral administration. The dose of the medicament of the present invention varies depending on the weight, age, sex, symptoms, etc. of the patient, but in the case of a normal adult, it is 0.01 to 1000 mg per day as a compound represented by the general formula (1), preferably 0 It is preferable to administer 1 to 300 mg in 1 to 3 divided doses.

EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these Examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: doublet
t: triplet
q: quartet
quintet: quintet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl ₃ : deuterated chloroform d ₆ -DMSO: deuterated dimethyl sulfoxide CD ₃ OD: deuterated methanol
¹ H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum

Example 1 Preparation of tert-butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate Step 1: tert Preparation of 4-butyl 4-hydroxymethylpiperidine-1-carboxylate 4-piperidinemethanol (4.6 g, 40 mmol) was dissolved in tetrahydrofuran (40 mL) and water (40 mL), and di-tert-butyl dicarbonate (9.6 mL) was dissolved. g, 44 mmol) and sodium carbonate (5.1 g, 48 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (12.9 g) as a crude product.

Step 2: Preparation of tert-butyl 4-formylpiperidine-1-carboxylate tert-butyl-4-hydroxymethylpiperidine (10.0 g, 46.4 mmol) and 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (360 mg, 2.32 mmol) was dissolved in chloroform (230 mL), and sodium hypochlorite / saturated aqueous sodium bicarbonate solution (1/1, 94 mL) was added over 1 hour so that the internal temperature did not exceed 1 ° C. And dripped. After completion of the dropwise addition, sodium thiosulfate was added to the reaction solution to stop the reaction, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (11.1 g, crude product) as a brown oily product.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.83-1.94 (2H, m), 2.36-2.45 (1H, m), 2.87-2.98 (2H, m), 3.93-4.03 (2H, m), 9.66 (1H, s).

Step 3: Preparation of tert-butyl 4- (1-hydroxy-2-nitroethyl) piperidine-1-carboxylate tert-butyl 4-formylpiperidine-1-carboxylate (11.1 g, crude product) and potassium fluoride ( 540 mg, 9.28 mmol) was dissolved in isopropanol (50 mL), nitromethane (14.2 g, 232 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, diethyl ether was added to the resulting residue, and the suspension was filtered to obtain the title compound (7.70 g, 61%, 3 steps) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.24-1.39 (2H, m), 1.46 (9H, s), 1.58-1.65 (2H, m), 1.77-1.84 (1H, m), 2.57-2.62 (1H, m), 2.62-2.74 (2H, m), 4.09-4.24 (3H, m), 4.44 (1H, dd, J = 8.5, 13.4 Hz), 4.50 (2H, dd, J = 2.9, 13.2 Hz).

Step 4: Preparation of tert-butyl 4- (2-nitroacetyl) piperidine-1-carboxylate tert-Butyl 4- (1-hydroxy-2-nitroethyl) piperidine-1-carboxylate (7.70 g, 28.1 mmol) was prepared. It was dissolved in methylene chloride (140 mL), Dess-Martin periodinane (14.3 g, 33.7 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. A sodium thiosulfate aqueous solution and a saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to give the title compound (6.83 g, 89%) Was obtained as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.60-1.64 (2H, m), 1.84-1.87 (2H, m), 2.61-2.67 (1H, m), 2.80-2.83 (2H, m), 4.07-4.30 (2H, m), 5.36 (2H, s).

Step 5: Preparation of tert-butyl 4- (1- (hydroxyimino) -2-nitroethyl) piperidine-1-carboxylate tert-butyl 4- (2-nitroacetyl) piperidine-1-carboxylate (2.00 g, 7.34 mmol) and hydroxyamine sulfate (1.81 g, 11.0 mmol) were dissolved in ethanol / toluene = 1/1 (36 mL), and the mixture was refluxed for 4 and a half hours. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (945 mg, 45%) as an E / Z mixture as a yellow solid.

Step 6: Preparation of ethyl 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4-nitroisoxazole-5-carboxylate tert-butyl 4- (1- (hydroxyimino) under argon atmosphere 2-Nitroethyl) piperidine-1-carboxylate (100 mg, 0.348 mmol) was dissolved in anhydrous tetrahydrofuran (3.5 mL), ethyl chloroglyoxylate (95 mg, 0.696 mmol) was added, and the mixture was heated at 60 ° C. for 6 hours. . Cool to 0 ° C. and slowly add triethylamine (0.1 mL). Water and saturated brine were added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (38.6 mg, 30%) as a colorless oil. Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 1.76 (1H, dd, J = 4.1, 12.0 Hz), 1.82 (1H, dd, J = 4.4, 11.7 Hz), 1.96-2.03 (2H, m), 2.82-2.96 (2H, m), 3.27 (1H, dddd, J = 4.0, 4.0, 11.6, 11.6 Hz), 4.14-4.26 (2H, m ), 4.52 (2H, q, J = 7.2 Hz).

Step 7: Preparation of ethyl 4-amino-3- (1- (tert-butoxycarbonyl) piperidin-4-yl) isoxazole-5-carboxylate Ethyl 3- (1- (tert-butoxycarbonyl) piperidine-4- Yl) -4-nitroisoxazole-5-carboxylate (78.8 mg, 0.213 mmol) dissolved in ethanol / water = 1/1 (2 mL), zinc (140 mg, 2.13 mmol) and ammonium chloride (280 mg) , 5.33 mmol) at 0 ° C. and stirred for 4 hours at room temperature. After concentration under reduced pressure and drying over anhydrous sodium sulfate, the obtained residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound (64.5 mg, 89%) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 1.74-1.87 (2H, m), 1.90-1.98 (2H, m), 2.79 (1H , dddd, J = 4.0, 4.0, 11.6, 11.6 Hz), 2.84-2.96 (2H, m), 4.11-4.24 (4H, m), 4.41 (2H, q, J = 7.2 Hz).

Step 8: Preparation of tert-butyl 4- (7-hydroxyisoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate ethyl 4-amino-3- (1- (tert-butoxy) Carbonyl) piperidin-4-yl) isoxazole-5-carboxylate (32.5 mg, 0.081 mmol) and formamidine acetate (26.0 mg, 0.243 mmol) were dissolved in ethanol and heated under reflux for 24 hours. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1 → chloroform: methanol = 9: 1) to give the title compound (17.9 mg, 69%) as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.94 (1H, dd, J = 3.9, 12.2 Hz), 2.00 (1H, dd, J = 4.1, 12.2 Hz), 2.07-2.16 (2H , m), 2.88-3.03 (2H, m), 3.28 (1H, J = 4.0, 4.0, 11.6, 11.6 Hz, dddd), 4.11-4.29 (2H, m), 8.07 (1H, s), 8.24 (1H , d, J = 14.1 Hz).

Step 9: tert-Butyl 4- (7-((1H-benzo [d] [1,2,3] triazol-1-yl) oxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- Preparation of 1-carboxylate tert-butyl 4- (7-hydroxyisoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (14.1 mg. 0.044 mmol) and 1H-benzotriazole- 1-yloxytripyrrolidinephosphonium hexafluorophosphate (27.0 mg, 0.053 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL), triethylamine (10 μL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (7.1 mg, 37%) as a cloudy oil. Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.98-2.12 (2H, m), 2.15-2.24 (2H, m), 2.91-3.08 (2H, m), 3.44 (1H, dddd, J = 4.0, 4.0, 11.2, 11.2 Hz), 4.14-4.33 (2H, m), 7.48-7.53 (2H, m), 7.57-7.62 (1H, m), 8.17 (1H, dd, J = 1.2, 8.0 Hz), 8.64 (1H, s).

Step 10: Preparation of tert-butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate under argon atmosphere 5- (Methylsulfonyl) indoline (2.5 mg, 0.013 mmol) and tert-butyl 4- (7-((1H-benzo [d] [1,2,3] triazol-1-yl) oxy) isoxazolo [4 5-d] pyrimidin-3-yl) piperidine-1-carboxylate (7.1 mg, 0.016 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.3 mL) and sodium hydride (1.0 mg, 0.020 mmol) was dissolved. The mixture was further stirred at 70 ° C. for 10 minutes. Water was added and extracted with chloroform. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 50: 1) to give the title compound (1.6 mg, 25%) as a brown solid Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.98 (1H, dd, J = 3.9, 12.2 Hz), 2.04 (1H, dd, J = 3.9, 11.7 Hz), 2.13-2.23 (2H , m), 2.97-3.12 (2H, m), 3.07 (3H, s), 3.33-3.49 (1H, m), 3.45 (2H, t, J = 8.5 Hz), 4.16-4.31 (2H, m), 4.83 (2H, t, J = 8.8 Hz), 7.83 (1H, s), 7.88 (1H, d, J = 8.8 Hz), 8.78 (1H, s), 8.82 (1H, d, J = 8.8 Hz).

Example 2 3- (1- (5-chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production Process 1: Production of 7- (5- (methylsulfonyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride tert-butyl 4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate (5.8 mg, 0.012 mmol) was dissolved in ethyl acetate (0.5 mL). Under ice cooling, 4N hydrochloric acid ethyl acetate (1.3 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. Concentration under reduced pressure gave the title compound (5.8 mg, crude product) as an orange solid.

Step 2: 3- (1- (5-Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride (5.3 mg, crude) and 2,5-dichloro Pyrimidine (2.7 mg, 0.018 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.3 mL), N, N-diisopropylethylamine (7 μL, 0.036 mmol) was added, and the mixture was stirred at 80 ° C. for 4 hours. Water was added and extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 80: 1) to give the title compound (2.8 mg, 46%) as a yellow solid Obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.04-2.13 (2H, m), 2.23-2.31 (2H, m), 3.07 (3H, s), 3.16-3.23 (2H, m), 3.42-3.53 (1H, m), 3.44 (2H, t, J = 8.5 Hz), 4.79-4.86 (4H, m), 7.83 (1H, s), 7.88 (1H, dd, J = 2.0, 8.8 Hz), 8.24 (2H, s ), 8.78 (1H, s), 8.82 (1H, d, J = 8.8 Hz).

Example 3 of 3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production The reaction and treatment were conducted in the same manner as in Example 2 using 2-chloro-5-ethylpyrimidine instead of 2,5-dichloropyrimidine, and the title compound was obtained as an orange oil.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.6 Hz), 2.06-2.12 (2H, m), 2.27-2.30 (2H, m), 2.48 (2H, q, J = 7.5 Hz ), 3.07 (3H, s), 3.15-3.18 (2H, m), 3.40-3.53 (2H, m), 4.77-4.89 (2H, m), 4.82 (2H, t, J = 8.8 Hz), 7.82 ( 1H, s), 7.88 (1H, d, J = 8.8 Hz), 8.20 (2H, s), 8.78 (1H, s), 8.82 (1H, d, J = 8.8 Hz).

  The compounds obtained by the above examples are shown in Table 1.

Test Example 1 Insulin Secretion Promoting Action Hamster pancreatic β cell line HIT-T15 cells were transferred using Ham's F-12K medium containing penicillin (100 units / mL), streptomycin (100 μg / mL) and 10% fetal bovine serum. Subcultured. Cells were seeded in a 24-well culture plate, cultured for 48 hours at 37 ° C., and then washed with a KRBH buffer containing 0.1% albumin. Subsequently, it left still at 37 degreeC with the same buffer for 1 hour. Glucose was added to this to a final concentration of 2 mM, and the compound of the present invention dissolved in dimethyl sulfoxide at a concentration 1000 times the concentration (from 0.0001 μM to 10 μM at a common ratio of 10) was added to the buffer. It was added under the condition of 0.1% by volume. After adding the compound of the present invention, the mixture was allowed to stand at 37 ° C. for 1 hour, and then the insulin concentration contained in the supernatant was measured with an insulin kit (Setty Medical Co., Ltd.). As the standard solution, a hamster insulin standard solution (Shiba Goat Co., Ltd.) was used. A control to which only dimethyl sulfoxide was added was used. The results are shown in Table 2 as 50% effective concentration (EC ₅₀ value, 50% effect concentration) of each test compound. The EC ₅₀ value was calculated using a statistical analysis program, SAS preclinical package Ver 5.0 (SAS institute Japan Co., Tokyo).

  From the above, it can be seen that the compound of the present invention has a strong insulin secretion promoting effect.

  Since the piperidine derivative represented by the general formula (1) of the present invention or a salt thereof, or a solvate thereof has an excellent insulin secretion promoting action and is useful for the prevention and / or treatment of diabetes, Has industrial applicability.

Claims (14)

The following general formula (1):

[Where:
One of A and B represents a nitrogen atom and the other is a nitrogen atom or CR ⁸ (where R ⁸ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, or Nitro group)
D represents a nitrogen atom or CR ⁹ (wherein R ⁹ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group or a nitro group);
E represents a nitrogen atom or CR ¹⁰ (wherein R ¹⁰ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group or a nitro group);
X is an oxygen atom, a sulfur atom, — (CH ₂ ) n—N (R ¹¹ ) — or — (CH ₂ ) n—CH (R ¹² ) — (wherein R ¹¹ and R ¹² are each a hydrogen atom; Or a C _1-6 alkyl group, and n represents 0 or 1);
When Y is an oxygen atom or a sulfur atom, Z represents a nitrogen atom;
When Y is a nitrogen atom, Z represents an oxygen atom or a sulfur atom;
R ¹ and R ³ each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group or a nitro group,
Alternatively, R ¹ and R ¹¹ or R ¹ and R ¹² may be combined to form a heterocycle;
R ² is a hydrogen atom, —S (O) R ¹³ , —S (O) ₂ R ¹⁴ , —CO ₂ R ¹⁵ or —CONR ¹⁶ R ¹⁷ , an aryl group, a heteroaryl group (where R ¹³ and R ¹⁴ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, an optionally substituted C _6-10 aryl group, an amino group, respectively. A mono (C _1-6 alkyl) amino group or a di (C _1-6 alkyl) amino group, R ¹⁵ represents a C _1-6 alkyl group, and R ¹⁶ and R ¹⁷ are each independently A hydrogen atom or a C _1-6 alkyl group which may have a substituent);
R ⁴ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group or an amino group;
R ⁵ and R ⁶ each independently represent a hydrogen atom or a C _1-6 alkyl group;
R ⁷ is a C _1-6 alkyl group, —C (O) R ¹⁸ , —C (S) R ¹⁹ , —S (O) ₂ R ²⁰ , an optionally substituted C _6-10 aryl group Or a 5- to 10-membered heteroaryl group which may have a substituent (wherein R ¹⁸ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _6-10 aryl C _1-6 alkoxy group, A 5- to 10-membered heteroaryl group or mono (C _1-6 alkyl) amino group which may have a substituent, wherein R ¹⁹ and R ²⁰ are a C _1-6 alkyl group and a halo C _1-6 alkyl, respectively; Group, C _3-8 cycloalkyl group, mono (C _1-6 alkyl) amino group, _optionally substituted C _6-10 aryl group or _optionally substituted 5-10 membered heteroaryl Show group)]
Or a salt thereof, or a solvate thereof. A heterocycle formed by combining R ¹ and R ¹¹ or R ¹ and R ¹² together has the following formula:

[Where:
R ²¹ is a hydrogen atom, a C _1-6 alkyl group, —C (O) R ²² or —S (O) ₂ R ²³ (where R ²² and R ²³ are each a C _1-6 alkyl group, C _{3- 8 represents a} cycloalkyl group, and the wavy line represents an aromatic ring constituted by D and E].
The compound or its salt of Claim 1 selected from these, or those solvates. The following compound groups:
tert-Butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate, 3- (1- (5- Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indolin-1-yl) isoxazolo [4,5-d] pyrimidine, and 3- (1- (5-ethylpyrimidine) 2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine or a compound thereof according to claim 1 or 2 Salts, or solvates thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.   The insulin secretion promoter which uses the compound in any one of Claims 1-3, its salt, or those solvates as an active ingredient.   The hypoglycemic agent which uses the compound in any one of Claims 1-3, its salt, or those solvates as an active ingredient.   The preventive and / or therapeutic agent of diabetes which uses the compound in any one of Claims 1-3, its salt, or those solvates as an active ingredient.   A method for promoting insulin secretion, comprising administering an effective amount of the compound according to any one of claims 1 to 3 or a salt thereof, or a solvate thereof.   A method for lowering blood glucose, comprising administering an effective amount of the compound according to any one of claims 1 to 3 or a salt thereof, or a solvate thereof.   A method for preventing and / or treating diabetes, comprising administering an effective amount of the compound according to any one of claims 1 to 3 or a salt thereof, or a solvate thereof.   The compound according to any one of claims 1 to 3, or a salt thereof, or a solvate thereof, for promoting secretion of insulin.   The compound according to any one of claims 1 to 3, or a salt thereof, or a solvate thereof, for lowering blood glucose.   The compound according to any one of claims 1 to 3, or a salt thereof, or a solvate thereof, for preventing and / or treating diabetes.   Use of the compound or a salt thereof, or a solvate thereof according to any one of claims 1 to 3, for producing an insulin secretion promoter, a hypoglycemic agent, or a preventive and / or therapeutic agent for diabetes.