WO2012043505A1 - Nouveau dérivé de pipéridine et produit pharmaceutique l'incluant - Google Patents

Nouveau dérivé de pipéridine et produit pharmaceutique l'incluant Download PDF

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WO2012043505A1
WO2012043505A1 PCT/JP2011/071949 JP2011071949W WO2012043505A1 WO 2012043505 A1 WO2012043505 A1 WO 2012043505A1 JP 2011071949 W JP2011071949 W JP 2011071949W WO 2012043505 A1 WO2012043505 A1 WO 2012043505A1
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group
isoxazolo
methylsulfonyl
pyrimidin
carboxylate
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PCT/JP2011/071949
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English (en)
Japanese (ja)
Inventor
俊晴 森元
智章 越澤
玄 渡部
友昭 福田
忠明 扇谷
奈穂 山崎
訓之 井上
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興和株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a drug having an action of promoting insulin secretion from pancreatic ⁇ cells and preventing and / or treating diseases caused by hyperglycemia such as diabetes.
  • 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
  • pancreatic La Islet which is an endocrine cell, constitutes 1% of the entire pancreas and is mainly classified into four cells. That is, ⁇ cells that secrete glucagon, ⁇ cells that secrete insulin, ⁇ cells that synthesize and secrete somatostatin, and F cells that synthesize and secrete pancreatic polypeptides.
  • insulin secreted from ⁇ 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 ⁇ 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 hyperglycemia caused by insulin deficiency or lack of action. Diabetes mainly causes insulin-dependent diabetes mellitus (IDDM) caused by abnormal pancreatic insulin secretion due to autoimmune diseases, etc., and insulin secretion ability due to pancreatic exhaustion resulting from persistent high insulin state due to insufficient insulin action (insulin resistance) It is divided into two types of non-insulin dependent diabetes mellitus (NIDDM) caused by a decrease.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • 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.
  • ⁇ Exercise therapy, diet therapy, and drug therapy are used to treat diabetes.
  • the drug used for drug therapy include a drug that promotes insulin secretion from pancreatic ⁇ cells, a drug that improves insulin resistance, a drug that suppresses sugar absorption, and a drug that promotes the use of sugar.
  • 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), etc. are actually used in the field of diabetes treatment.
  • Non-Patent Document 3 the most commonly used SU drug in Japan stimulates pancreatic ⁇ -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 ⁇ cells is desired.
  • 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 condensed ring compounds (Patent Documents 7 and 8) related to GPR119 have been reported, the structure is different from the compounds of the present invention.
  • Patent Document 9 a compound having an FXR (Farneoside X receptor) inhibitory action
  • Patent Documents 10 and 11 a compound having an FXR (Farneoside X receptor) inhibitory action
  • Patent Document 12 and 13 a compound having an FXR (Farneoside X receptor) inhibitory action
  • Patent Document 14 a compound having an FXR (Farneoside X receptor) inhibitory action
  • An object of the present invention is to provide a compound having an action of promoting insulin secretion from pancreatic ⁇ cells and useful as a prophylactic or therapeutic drug for diseases caused by hyperglycemia such as diabetes.
  • the present inventors searched for a compound that promotes insulin secretion using a hamster pancreatic ⁇ cell line HIT-T15 cell.
  • the piperidine derivative represented by (1) was found to have an excellent effect of promoting insulin secretion from pancreatic ⁇ cells, and was useful as a therapeutic agent for diabetes, and the present invention was completed.
  • a and B each 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 ) — (where R 11
  • R 15 represents a C 1-6 alkyl group
  • 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 represents 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 which may have a substituent, a C 1 -1 which may be
  • a heterocycle formed by combining R 1 and R 11 or R 1 and R 12 together has the following formula:
  • 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 represent a C 1-6 alkyl group, C 3-6 8 represents a cycloalkyl group, and the wavy line represents an aromatic ring constituted by D and E]
  • 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 represent a C 1-6 alkyl group, C 3-6 8 represents a cycloalkyl group, and the wavy line represents an aromatic ring constituted by D and E]
  • a heterocycle formed by combining R 1 and R 11 or R 1 and R 12 together has the following formula:
  • R 1 is 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, or a solvate thereof object.
  • R 1 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, and R 2 to R 7 are the same as above)
  • a pharmaceutical composition comprising the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
  • An insulin secretion promoter comprising the compound or salt thereof according to any one of [1] to [7] or a solvate thereof as an active ingredient.
  • a hypoglycemic agent comprising the compound or salt thereof according to any one of [1] to [7] or a solvate thereof as an active ingredient.
  • a prophylactic and / or therapeutic agent for diabetes comprising the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof as an active ingredient.
  • a method for promoting insulin secretion comprising administering an effective amount of the compound according to any one of [1] to [7] 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 [1] to [7] or a salt thereof, or a solvate thereof.
  • a method for the prophylaxis and / or treatment of diabetes comprising administering an effective amount of the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof.
  • 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 ⁇ 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.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • 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 thereof 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.
  • 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
  • monofluoromethyl examples 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, or a 2,2,2-trifluoroethyl group.
  • 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.
  • 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).
  • examples of the “C 2-6 alkynyl group” include ethynyl group, prop-1-in-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.
  • 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.
  • examples of the “C 3-8 cycloalkyloxy group” include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyloxy group.
  • examples of the “C 2-6 alkenyloxy group” include a vinyloxy group, a prop-1-en-1-yloxy group (propenyloxy group), a prop-2-en-1-yloxy group (allyloxy group).
  • 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.
  • 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. .
  • the “di (C 1-6 alkyl) amino group” means the same or different groups in which two alkyl groups are bonded to a nitrogen atom.
  • a dimethylamino group a methylethylamino group , Diethylamino group, methylpropylamino group, ethylpropylamino group, dipropylamino group, diisopropylamino group, dibutylamino group and the like.
  • examples of the “C 6-10 aryl group” include a phenyl group, a naphthyl group, an azulenyl group, and the like.
  • substituted sulfonyl group refers to a “C 1-6 alkylsulfonyl group” in which an alkyl group is bonded via sulfonyl (—SO 2 —), and a “halo group in which a haloalkyl group is bonded via a sulfonyl group”.
  • 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-methylpentyls
  • 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.
  • examples of the “C 3-8 cycloalkylsulfonyl group” include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, a cycloheptylsulfonyl group, a cyclooctylsulfonyl group, and the like. Can be mentioned.
  • examples of the “C 2-6 alkenylsulfonyl group” include a vinylsulfonyl group, a propenylsulfonyl group, an allylsulfonyl group, a crotylsulfonyl group, and the like.
  • examples of the “C 2-6 alkynylsulfonyl group” include ethynylsulfonyl group, propargylsulfonyl group and the like.
  • 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.
  • examples of the “di (C 1-6 alkyl) sulfamoyl group” include a dimethylsulfamoyl group, a methylethylsulfamoyl group, a diethylsulfamoyl group, a dipropylsulfamoyl group, and a diisopropylsulfamoyl group.
  • a moyl group, a dibutylsulfamoyl group, etc. are mentioned.
  • examples of the “C 6-10 arylsulfonyl group” include a phenylsulfonyl group, a toluenesulfonyl group, a naphthylsulfonyl group, an azulenylsulfonyl group, and the like.
  • the “heterocycle” means a 4- to 10-membered saturated or unsaturated heterocycle which may have at least one nitrogen atom, oxygen atom or sulfur atom, for example, , Pyrrolidine, pyrroline, pyrrole, pyrrolidinone, pyrrolinone, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, indole, indoline, piperidine, piperidinone, dihydropyridine, dihydropyridinone, pyridine Morpholine, pyrimidine, thiophene, furan, benzofuran, benzothiophene, tetrahydropyran, tetrahydrofuran, oxetane and the like.
  • the “5- to 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, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl , 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,
  • the “saturated heterocyclic group” means a 4- to 6-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, for example, Examples include pyrrolidyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, indolinyl group, isoindolinyl group, morpholinyl group, tetrahydropyranyl group, tetrahydrofuryl group, oxetanyl group and the like.
  • 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.
  • 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, 5-10 membered heteroaryl group, saturated heterocyclic group and the like. These substituents may have 1 to 4 substituents.
  • the carbon number (C 2-7 ) of the alkoxycarbonyl group indicates a number including the carbonyl carbon.
  • a C 1-6 alkoxy group which may have a substituent a C 2-6 alkenyloxy group which may have a substituent, and a C 3-6 which may have a substituent
  • the “substituent” in the 8 cycloalkyloxy group include a halogen atom, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a mono (C 1-6 alkyl) amino group, and di (C 1- 1).
  • 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, 5-10 membered heteroaryl group, aliphatic heterocyclic group and the like.
  • substituents may have 1 to 4 substituents.
  • the carbon number (C 2-7 ) of the alkoxycarbonyl group indicates a number including the carbonyl carbon.
  • a C 6-10 aryl group which may have a substituent a 5-10 membered heteroaryl group which may have a substituent, and a C 6-10 aryloxy which may have a substituent
  • the “substituent” in the group, C 6-10 aryl C 1-6 alkoxy group which may have a substituent and heterocyclic oxy group which may have a substituent include, for example, 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, o
  • R 1 and R 3 are preferably a hydrogen atom, a halogen atom or a C 1-6 alkyl group, 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.
  • the halogen atom in R 1 and R 3 is preferably a fluorine atom.
  • 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.
  • 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 preferred.
  • R 4 , R 5 and R 6 are preferably hydrogen atoms.
  • R 7 includes —C (O) R 18 , —C (S) R 19 , —S (O) 2 R 20 , and optionally substituted C 6-10 aryl.
  • a 5- to 10-membered heteroaryl group which may have a group or a substituent is preferable, and —C (O) R 18 , —S (O) 2 R 20 or a 5- to 10-membered heteroaryl which may have a substituent
  • An aryl group is more preferred.
  • R 18 in -C (O) R 18 in R 7 which may have a substituent C 1-6 alkoxy group, an optionally substituted C 2-6
  • a C 1-6 alkoxy group, an optionally substituted heterocyclic oxy group, an optionally substituted 5-10 membered heteroaryl group or mono (C 1-6 alkyl) amino group is preferred.
  • a C 1-6 alkoxy group which may have a group is more preferable.
  • 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.
  • 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.
  • the 5-10 membered heteroaryl group in the 5-10 membered heteroaryl group which may have a substituent for R 7 is preferably a pyridyl group, a pyrimidinyl group, or an oxadiazole group.
  • 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, and a chlorine atom, an ethyl group Is more preferable.
  • the heterocyclic ring formed by combining R 1 and R 11 or R 1 and R 12 is represented by the following formula:
  • R 21 represents a hydrogen atom, a C 1-6 alkyl group, —C (O) R 22 or —S (O) 2 R 23 (wherein R 22 and R 23 are a C 1-6 alkyl group or C 3- 8 represents an cycloalkyl group, and the wavy line represents an aromatic ring containing D and E].
  • Preferred is a heterocycle selected from
  • R 11 or R 12 is preferably a hydrogen atom.
  • 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.
  • the C 6-10 aryl group which may have a substituent for R 13 or R 14 is preferably a phenyl group or a toluyl group, and more preferably a p-toluyl group.
  • the C 1-6 alkoxy group which may have a substituent for R 18 includes a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, a 2-fluoroethoxy group, 2- Methoxyethoxy group, (3-methyloxetane-3-yl) methoxy group, 1,1,1-trifluoro-2-methylpropan-2-yloxy group, 2,2,2-trifluoroethoxy group, 2,2, A 2-trichloroethoxy group is preferred.
  • the C 3-8 cycloalkyloxy group which may have a substituent for R 18 is C 3-6 cycloalkyloxy optionally substituted with 1 to 3 halogen atoms.
  • Group is preferable, and 4-fluorocyclohexyloxy group and 4,4-difluorocyclohexyloxy group are more preferable.
  • the C 2-6 alkenyloxy group which may have a substituent for R 18 is preferably a C 2-4 alkenyloxy group, and a prop-2-en-1-yloxy group (allyloxy). Group) is more preferred.
  • the C 6-10 aryloxy group for R 18 is preferably a phenyloxy group or a p-nitrophenyloxy group.
  • 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.
  • the 5-10 membered heteroaryl group which may have a substituent for R 18 is preferably a pyridyl group.
  • 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.
  • 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.
  • the C 1-6 alkyl group in R 20 is preferably a C 1-4 alkyl group, and more preferably an n-butyl group.
  • the halo C 1-6 alkyl group for R 20 is preferably a halo C 1-4 alkyl group, more preferably a trichloromethyl group.
  • the C 3-8 cycloalkyl group in R 20 is preferably a C 3-6 cycloalkyl group, more preferably a cyclopropyl group or a cyclohexyl group.
  • the C 6-10 aryl group which may have a substituent in R 20 is preferably a phenyl group which may have a substituent.
  • a halo C 1-6 alkyl group such as a trifluoromethyl group
  • a C 1-6 alkoxy group such as a methoxy group
  • the C 6-10 heteroaryl group which may have a substituent for R 20 is preferably a thienyl group.
  • 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.
  • D is preferably a nitrogen atom, CH or C-halogen, and more preferably CH.
  • E is preferably a nitrogen atom, CH or C-halogen, and more preferably CH.
  • X is preferably a nitrogen atom or an oxygen atom, and more preferably a nitrogen atom.
  • Y is preferably an oxygen atom, a sulfur atom, or a nitrogen atom, more preferably an oxygen atom or a nitrogen atom, and even more preferably an oxygen atom.
  • Z is preferably an oxygen atom, a sulfur atom, or a nitrogen atom, more preferably an oxygen atom or a nitrogen atom, and even more preferably a nitrogen atom.
  • the ring structure including D and E is more preferably a benzene ring (both D and E are CH).
  • the ring structure containing A, B, Y and Z includes the following structures:
  • the compounds represented by the following (1a) or (1b) are particularly preferable.
  • R 1 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, and R 2 to R 7 are the same as above)
  • tert-butyl 4- (7- (5- (methylsulfonyl) indoline-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) ), 3- (1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 3) ), 3- (1- (5-Bromopyrimidin-2-yl) piperidin-4-yl) -7- (5- (
  • the salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • alkali metal salt or alkaline earth metal salt such as sodium, potassium, magnesium, calcium
  • 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.
  • prodrugs are also included in the present invention.
  • examples of the group that forms a prodrug of the compound of the present invention include the 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”, Vol.
  • 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.
  • the reaction described below It can be manufactured according to the process.
  • functional groups other than the reaction site may be protected in advance as necessary, and may be deprotected at an appropriate stage.
  • a commonly used method for example, a method described in Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc., 1999) can be used.
  • reaction may be carried out by a commonly performed method (for example, the method described in Comprehensive Organic Transformation Second Edition, John Wiley & Sons, Inc; 1999), and isolation and purification are crystallized and recrystallized. 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]
  • Step A-1 is a step in which compound (2) is mixed with a dehydrating condensing agent such as hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP) in a solvent in the presence of a base.
  • a dehydrating condensing agent such as hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP) in a solvent in the presence of a base.
  • This is a step for producing a compound (3) by reacting with a sulfonylating agent such as methanesulfonyl chloride.
  • the base is not particularly limited.
  • alkali metal 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
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • the solvent is not particularly limited, and examples thereof include N, N-dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, propionitrile, chloroform, methylene chloride and the like, and these can be used alone or in combination.
  • Preferred is tetrahydrofuran alone or a mixed solvent of tetrahydrofuran and methylene chloride.
  • the reaction temperature is preferably 0 to 150 ° C., more preferably 10 to 30 ° C.
  • the reaction time is preferably 5 minutes to 48 hours, more preferably 10 minutes to 2 hours.
  • Step A-2 is a step for producing compound (1) by reacting compound (3) with compound (4) in the presence of a base in a solvent.
  • 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-butyllith
  • the reaction temperature is preferably 0 to 150 ° C, more preferably 50 to 100 ° C.
  • the reaction time is preferably 5 minutes to 48 hours, more preferably 10 minutes to 4 hours.
  • reaction Path Diagram 2 [Reaction Path Diagram 2]
  • Step B-1 comprises reacting compound (2) 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.
  • a halogenating agent such as phosphorus oxychloride (POCl 3 )
  • POCl 3 phosphorus oxychloride
  • 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.
  • N N-dimethylaniline, N, N-diethylaniline, N, N, N-diisopropylethylamine or the like can be used.
  • solvent dioxane, 1,2-dichloroethane and the like can be used.
  • the reaction temperature is preferably 0 to 150 ° C, more preferably 80 to 120 ° C.
  • the reaction time is preferably 10 minutes to 48 hours, more preferably 3 to 6 hours.
  • Step B-2 is a step of 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, the ligand, the base, and the reaction conditions are not particularly limited as long as they are reagents and conditions that are usually used in an amination reaction. R. Muci, S .; L. Buchwald, Top. Curr. Chem. , 219, 131-209, (2002), etc. can be used.
  • a method of an amination reaction performed in the presence or absence of a base and in the presence of a metal catalyst in a solvent or without a solvent can be applied. In that case, microwave irradiation may be performed.
  • the metal catalyst is not particularly limited.
  • 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.
  • the solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water and the like can be used alone 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.
  • R 24 is a C 1-6 alkyl group or C 6-10. Represents an aryl C 1-6 alkyl group.
  • Step C-1 is a step for producing compound (2) by reacting compound (6) with amidine derivative (7) or a salt thereof.
  • the solvent is not particularly limited, and for example, methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene and the like can be used. Ethanol is preferable.
  • the reaction temperature is preferably 40 to 120 ° C, more preferably 80 to 100 ° C.
  • the reaction time is preferably 1 hour to 5 days, more preferably 12 hours to 2 days.
  • Compound (2a-d) was also prepared according to Bioorg. Med. Chem. Lett. 2005, 15, 3900. , WO2001 / 047934 pamphlet, Liebigs Ann.
  • 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.
  • various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between 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.
  • a diastereomeric mixture can be divided
  • 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 an ordinary method. Moreover, it can also be set as the solvate and hydrate of solvents, such as a reaction solvent and a recrystallization solvent.
  • 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.
  • 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.
  • an excipient e.g., lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like.
  • binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like.
  • disintegrant examples include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • lubricant examples include purified talc, stearate, borax, and polyethylene glycol.
  • corrigent examples include sucrose, orange peel, citric acid, and tartaric acid.
  • a corrigent 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.
  • the corrigent those mentioned above may be used.
  • the buffer include sodium citrate
  • examples of the stabilizer include tragacanth, gum arabic, and gelatin.
  • 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.
  • the pH adjusting agent and buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
  • the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • local anesthetics include procaine hydrochloride and lidocaine hydrochloride.
  • isotonic agents include sodium chloride and glucose.
  • 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.
  • 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.
  • the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
  • the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like.
  • the compound represented by the general formula (1) can be converted into an inhalant, an eye drop, or a nasal drop by a conventional method.
  • the compound represented by the general formula (1) has an action of significantly promoting insulin secretion in hamster pancreatic ⁇ 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.
  • 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 patient's body weight, age, sex, symptoms, etc., but in the case of a normal adult, it is usually 0.01 to 1000 mg, preferably 0, as the compound represented by the general formula (1). It is preferable to administer 1 to 300 mg in 1 to 3 divided doses.
  • 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 radicals (360 mg, 2.32 mmol) were dissolved in chloroform (230 mL), and sodium hypochlorite / saturated aqueous sodium hydrogen carbonate 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 give the title compound (11.1 g, crude product) as a brown oily product.
  • 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 solution was filtered to obtain the title compound (7.70 g, 61%, 3 steps) as a white powder.
  • 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 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.
  • 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. did. Cool to 0 ° C. and slowly add triethylamine (0.1 mL).
  • Step 7 Preparation of ethyl 4-amino-3- (1- (tert-butoxycarbonyl) piperidin-4-yl) isoxazole-5-carboxylate
  • zinc (140 mg, 2.13 mmol) and ammonium chloride (280 mg) , 5.33 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours.
  • concentration under reduced pressure and drying over anhydrous sodium sulfate the resulting residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound (64.5 mg, 89%) as a yellow oil.
  • 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) are dissolved in ethanol and heated under reflux for 24 hours. It was. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform.
  • 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-benzo Triazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate (27.0 mg, 0.053 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL), triethylamine (10 ⁇ L) was added, and the mixture was stirred at room temperature for 1 hour.
  • 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.
  • Example 2 3- (1- (5-chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine
  • Production step 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) in ethyl acetate (0.5 mL) Then, 4N hydrochloric acid ethyl acetate (1.3 mL) was added under ice-cooling, and the mixture was stirred at room
  • 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- Dichloropyrimidine (2.7 mg, 0.018 mmol) is dissolved in anhydrous N, N-dimethylformamide (0.3 mL), N, N-diisopropylethylamine (7 ⁇ L, 0.036 mmol) is added, and the mixture is stirred at 80 ° C.
  • Example 3 (1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Preparation The reaction and treatment were conducted in a similar manner to Example 2 using 2-chloro-5-ethylpyrimidine instead of 2,5-dichloropyrimidine, and the title compound was obtained as an orange oil.
  • Example 4 (1- (5-Bromopyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production
  • the reaction and treatment were conducted in a similar manner to process 2 of example 2 using 5-bromo-2-chloropyrimidine in place of 2,5-dichloropyrimidine, and the title compound was obtained as a white solid.
  • Example 5 3- (1- (5-Fluoropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production
  • the reaction and treatment were conducted in a similar manner to process 2 of example 2 using 2-chloro-5-fluoropyrimidine in place of 2,5-dichloropyrimidine, and the title compound was obtained as a white solid.
  • Example 6 Ethyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxy Production of rate Using ethyl 2- (methylsulfinyl) pyrimidine-5-carboxylate instead of 2,5-dichloropyrimidine, the reaction and treatment were carried out in the same manner as in Step 2 of Example 2 to obtain the title compound as a pale yellow solid. It was.
  • Example 8 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5- d] Production of pyrimidine The reaction and treatment were conducted in the same manner as in Step 2 of Example 2 using 2- (methylsulfinyl) -5- (trifluoromethyl) pyrimidine in place of 2,5-dichloropyrimidine, and the title compound was palely prepared. Obtained as a yellow solid.
  • 2-chloro-5- (4,4,5,5-tetra instead of 2,5-dichloropyrimidine Methyl-1,3,2-dioxaborolan-2-yl) pyrimidine was used for the reaction and treatment in the same manner as in Step 2 of Example 2 to obtain the title compound as a yellow solid.
  • Step 2 2- (4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol
  • Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine -2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (13.4 mg, 0.023 mmol) was dissolved in THF (1 mL), 30% aqueous hydrogen peroxide (50 ⁇ L) was added, After stirring at room temperature for 4 hours, an aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform.
  • Example 10 3- (1- (5-methoxypyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine
  • Preparation 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol (10.
  • Example 11 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5-phenylpyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine
  • Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) under argon atmosphere -Yl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (14.7 mg, 0.024 mmol), iodobenzene (7.5 mg, 0.036 mmol), tetrakistriphenylphosphine Palladium (2.8 mg, 0.0024 mmol) is dissolved in N, N-dimethylformamide (0.4 mL) and water (0.1 mL
  • Preparation of pyrimidine The reaction and treatment were conducted in the same manner as in Step 2 of Example 2 using 2-chloro-5- (trifluoromethyl) pyridine in place of 2,5-dichloropyrimidine, and the title compound was converted to a pale yellow solid. Obtained.
  • Example 14 Preparation of ethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Chlorogy instead of isopropyl chloroformate Reaction and treatment were conducted in the same manner as in Example 13 using ethyl acid to obtain the title compound as a pale yellow solid.
  • Example 15 Preparation of 2-fluoroethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, the reaction and treatment were conducted in the same manner as in Example 13 using 2-fluoroethyl chloroformate to obtain the title compound as a pale yellow solid.
  • Example 17 Tetrahydro-2H-pyran-4-yl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate
  • the reaction and treatment were conducted in the same manner as in Example 13 using 4-nitrophenyl (tetrahydro-2H-pyran-4-yl) carbonate instead of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
  • Example 19 Preparation of tert-butyl 4- (7- (5 (methylsulfinyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- (Methylsulfonyl) )
  • the reaction and treatment were conducted in the same manner as in step 10 of Example 1 using 5- (methylsulfinyl) indoline instead of indoline to obtain the title compound as a yellow solid.
  • Step 1 Preparation of 7- (5- (methylsulfinyl) 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 instead of tert-butyl 4- (7- (5 (methylsulfinyl) indoline) -1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate was reacted and treated in the same manner as in Step 1 of Example 2 to obtain the title compound as a yellow solid. .
  • Step 2 7- (5- (Methylsulfinyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5- d]
  • pyrimidine 2-chloro-5- (trifluoromethyl) pyridine instead of 2,5-dichloropyrimidine
  • 7- (5- (methylsulfinyl) indoline-1-yl) -3 obtained in Step 1
  • the reaction and treatment were conducted in a similar manner to process 2 of example 2 using-(piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride to obtain the title compound as a yellow solid.
  • Example 21 2,2-Dimethyl-1- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) Production of propan-1-one
  • the reaction and treatment were conducted in the same manner as in Example 13 using pivaloyl chloride in place of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
  • Example 22 Preparation of tert-butyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5
  • the reaction and treatment were conducted in a similar manner to process 10 of example 1 using 2-fluoro-4- (methylsulfonyl) aniline in place of-(methylsulfonyl) indoline, and the title compound was obtained as a pale-yellow solid.
  • Step 2 N- (2-Fluoro-4- (methylsulfonyl) phenyl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5- d]
  • pyrimidine-7-amine 2- (methylsulfinyl) -5- (trifluoromethyl) pyrimidine instead of 2,5-dichloropyrimidine and N- (2-fluoro-4- ( Methylsulfonyl) phenyl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine hydrochloride was reacted and treated in the same manner as in Step 2 of Example 2 to obtain the title compound. Obtained as a pale yellow solid.
  • Example 26 2,2,2-trifluoroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1- Preparation of carboxylate 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate instead of 1,2,1-trifluoroethyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in the same manner as in Example 25 to obtain the title compound as a pale yellow amorphous.
  • Example 27 2,2,2-Trichloroethyl 4- (7-((2-Fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxy Production of rate The reaction and treatment were conducted in the same manner as in Example 13 using 2,2,2-trichloroethyl chloroformate instead of isopropyl chloroformate to obtain the title compound as a pale yellow solid.
  • Example 28 Preparation of neopentyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, the reaction and treatment were conducted in the same manner as in Example 13 using neopentyl chloroformate to obtain the title compound as a pale yellow solid.
  • Example 29 4,4-Difluorocyclohexyl 4- (7-((2-Fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate
  • Example 25 using 4,4-difluorocyclohexyl 1H-imidazole-1-carboxylate instead of 1H-imidazole-1-carboxylate The title compound was obtained as a yellow amorphous product.
  • Example 30 Preparation of Oxetan-3-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate
  • the reaction and treatment were conducted in a similar manner to Example 13 using 4-nitrophenyl oxetane-3-yl carbonate in place of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
  • Example 31 (3-Methyloxetane-3-yl) methyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine Preparation of -1-carboxylate The reaction and treatment were conducted in the same manner as in Example 13 using (3-methyloxetane-3-yl) methyl (4-nitrophenyl) carbonate instead of isopropyl chloroformate, and the title compound was pale yellow. Obtained as a solid.
  • Example 32 Preparation of phenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, phenyl chloroformate was used and reacted and treated in the same manner as in Example 13 to obtain the title compound as a pale yellow solid.
  • Example 33 Preparation of 4-nitrophenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate The reaction and treatment were conducted in a similar manner to Example 13 using 4-nitrophenyl chloroformate instead of isopropyl acid, and the title compound was obtained as a pale-yellow solid.
  • Example 35 Preparation of tert-butyl 4- (7- (4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate of 5- (methylsulfonyl) indoline Instead, 4- (methylsulfonyl) phenol was used for the reaction and treatment in the same manner as in Step 10 of Example 1 to obtain the title compound as a pale yellow oil.
  • Example 36 Preparation of tert-butyl 4- (7- (2-fluoro-4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- (Methyl).
  • the reaction and treatment were conducted in a similar manner to process 10 of example 1 using 2-fluoro-4- (methylsulfonyl) phenol in place of sulfonyl) indoline, and the title compound was obtained as a pale-yellow oil.
  • Example 37 Preparation of tert-butyl 4- (7- (4- (1H-tetrazol-1-yl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- ( The reaction and treatment were conducted in a similar manner to process 10 of example 1 using 4- (1H-tetrazol-1-yl) phenol in place of methylsulfonyl) indoline, and the title compound was obtained as a white solid.
  • Example 38 tert-butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) piperidine-1-carvone Production process of xylate 1: Production of tert-butyl 4- (methoxy (methyl) carbamoyl) piperidine-1-carboxylate 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (15.0 g, 65.4 mmol) N, O-dimethylhydroxylamine hydrochloride (8.3 g, 85.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (16.3 g, 85.0 mmol) in dichloromethane (400 mL) And triethylamine (13.7 mL, 98.1 mmol) and N, N- Dimethylaminopyridine (0.80 g, 6.
  • Step 2 Preparation of tert-butyl 4-acetylpiperidine-1-carboxylate tert-butyl 4- ⁇ methoxy (methyl) carbamoyl ⁇ piperidine-1-carboxylate (17.7 g, 65.0 mmol) under an argon atmosphere. It melt
  • Step 3 Preparation of tert-butyl 4- (4-ethoxy-3,4-dioxobutanoyl) piperidine-1-carboxylate tert-butyl 4-acetylpiperidine-1-carboxylate (1.20 g, 4.40 mmol) ) was dissolved in tetrahydrofuran (20 mL) under argon atmosphere, hexamethyldisilazane lithium (7.27 mL, 1.09 mol / L hexane solution) was added dropwise at -78 ° C, and the mixture was stirred at 0 ° C for 1 hour.
  • Step 4 Preparation of tert-butyl 4- (1-methyl-7-oxo-6,7-dihydro-1H-pyrazo [4,3-d] pyrimidin-3-yl) piperidine-1-carboxylate
  • tert-butyl (4-Ethoxy-3,4-dioxobutanoyl) piperidine-1-carboxylate 100 mg, 0.305 mmol
  • acetic acid 1 mL
  • sodium nitrite 23.2 mg, 0.336 mmol
  • Step 5 tert-Butyl 4- (7-((1H-benzo [d] [1,2,3] triazo-1-yl) oxy) -1-methyl-1H-pyrazolo [4,3-d] pyrimidine
  • -3-yl piperidin-1-carboxylate
  • tert-butyl 4- (1-methyl-7-oxo-6,7-dihydro-1H-pyrazo [4,3-d] pyrimidin-3-yl) piperidine 1-carboxylate (9.7 mg, 0.029 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (16.6 mg, 0.032 mmol) were dissolved in tetrahydrofuran (1 mL).
  • 1,8-diazabicyclo [5,4,0] -7-undecene (5.2 ⁇ L, 0.035 mmol) was added, and the mixture was stirred at room temperature for 1 hour. .
  • Step 6 tert-Butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) piperidine-1-carvone
  • xylate tert-butyl 4- (7-((1H-benzo [d] [1,2,3] triazo-1-yl) oxy) -1-methyl-1H-pyrazolo [4,3-d] Pyrimidin-3-yl) piperidine-1-carboxylate (7.6 mg, 0.017 mmol) and 5- (methylsulfonyl) indoline (4.5 mg, 0.023 mmol) in N, N-dimethylformamide (1 mL).
  • Test Example 1 Insulin Secretion Promoting Action Hamster pancreatic ⁇ cell line HIT-T15 cells are passaged using Ham's F-12K medium containing penicillin (100 units / mL), streptomycin (100 ⁇ g / 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 ⁇ M to 10 ⁇ M 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).
  • the compound of the present invention has a strong insulin secretion promoting effect.
  • 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.

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Abstract

Nouveau composé ayant pour effet de favoriser la sécrétion d'insuline par les cellules β pancréatiques et utile en tant qu'agent prophylactique et/ou thérapeutique contre les troubles ayant pour origine une hyperglycémie, tels que le diabète. Composé répondant à la formule générale (1), l'un de ses sels, ou un solvate dudit composé ou de son sel. Dans la formule, A ou B représente un atome d'azote et l'autre représente un atome d'azote ou CR8 ; X représente un atome d'oxygène, un atome de soufre, −(CH2)n−N(R11)− ou −(CH2)n−CH(R12)−; Z représente un atome d'azote si Y représente un atome d'oxygène ou un atome de soufre; Z représente un atome d'oxygène ou un atome de soufre si Y représente un atome d'azote; et les radicaux R1 à R7 représentent des atomes d'hydrogène ou d'autres substituants.
PCT/JP2011/071949 2010-09-28 2011-09-27 Nouveau dérivé de pipéridine et produit pharmaceutique l'incluant WO2012043505A1 (fr)

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US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma

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WO2009141238A1 (fr) * 2008-05-19 2009-11-26 F. Hoffmann-La Roche Ag Agonistes des récepteurs de gpr119
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US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma

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