WO2016068453A1 - Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component - Google Patents
Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component Download PDFInfo
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- WO2016068453A1 WO2016068453A1 PCT/KR2015/007715 KR2015007715W WO2016068453A1 WO 2016068453 A1 WO2016068453 A1 WO 2016068453A1 KR 2015007715 W KR2015007715 W KR 2015007715W WO 2016068453 A1 WO2016068453 A1 WO 2016068453A1
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- piperidin
- propoxy
- oxadiazole
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- 0 Cc1n[o]c(*)n1 Chemical compound Cc1n[o]c(*)n1 0.000 description 2
- JMSHLHCXCZDIAY-UHFFFAOYSA-N CC(C)c1n[o]c(N2CCC(CCCOc3cc(F)c(C4=NC(C)CO4)c(F)c3)CC2)n1 Chemical compound CC(C)c1n[o]c(N2CCC(CCCOc3cc(F)c(C4=NC(C)CO4)c(F)c3)CC2)n1 JMSHLHCXCZDIAY-UHFFFAOYSA-N 0.000 description 1
- YEOPJAMZSDTMIL-UHFFFAOYSA-N CCc1cnc(N2CCC(CCCOc3cc(F)c(C(OC)=O)c(F)c3)CC2)nc1 Chemical compound CCc1cnc(N2CCC(CCCOc3cc(F)c(C(OC)=O)c(F)c3)CC2)nc1 YEOPJAMZSDTMIL-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to a compound having a GPR119 agonistic activity, a method for preparing the same, and a pharmaceutical composition including the same as an effective component.
- a metabolic disease refers to a syndrome accompanied by risk factors such as obesity, diabetes, hypertriglyceridemia, hypertension, other cardiovascular diseases and a hemostatic disorder.
- a diagnosis of the metabolic syndrome may be made: ® abdominal obesity, given as waist circumference of 40 inches (102 cm) or more in men, and 35 inches (88 cm) or more in women, (2) hypertriglyceridemia, given as triglycerides of 150 mg/dL or more, (3) HDL cholesterol of 40 mg/dL or less in men, and 50 mg/dL or less in women, ⁇ hypertension, given as blood pressure of 130/85 mmHg or more, and ⁇ fasting glucose of 1 10 mg/dL or more.
- Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating, which include Glucagon-like peptide 1 (GLP-1) and
- GLP-1 glucose-dependent insulinotropic peptide
- GLP-1 is a peptide hormone with a short half-life of less than 2 minutes, which is secreted by stimulation of L-cells of small intestine upon nutrient ingestion, thereby inducing insulin secretion in pancreatic beta cells.
- GPCRs G protein-coupled receptors
- GPR1 19 Activating G protein-coupled receptor 119 leads to the secretion of gut peptides including GLP-1 (Ahren B., Diabet Obes Metab, 2011(13): 158-166).
- GPR1 19 is a member of class A GPCR and therefore is a druggable target for the development of small molecule ligands, as compared with class B.
- GPR1 19 agonists have been reported to promote secretion of GLP-1 in small intestines, and directly or indirectly increase insulin secretion in pancreatic beta cells (Lauffer LM. et al., Diabetes, 2009(58): 1058- 1066; Chu ZL. et al., Endocrinology, 2008(149):2038-2047; Yoshida S. et al., Biochem Biophys Res
- GPR1 19 has an important function in recognizing the concentration of fat introduced from the outside in small intestinal epithelial cells to maintain homeostasis of in vivo fat (Schwartz TW. et al, Trends in Pharmacological Sciences, 2012 in press, doi.10.1016/j .tips.2012.03.014).
- GPR1 19 activation leads to the suppression of fat absorption in a small intestine, and the improvement of lipid metabolism, indicating that the GPR1 19 agonist has a therapeutic potential on dyslipidemia (Brown K. et al., 631-P and Nunez DJ. et al., 1084-P in 72 nd Scientific Session of American Diabetes Association, Philadelphia, PA).
- Hu YW, et al. GPR1 19 has been reported to play an important role in
- the present invention has been made in an effort to provide a novel compound having a GPRl 19 agonistic activity.
- the present invention has been made in an effort to provide a method for preparing the novel compound having a GPRl 19 agonistic activity.
- the present invention has been made in an effort to provide a pharmaceutical composition including the novel compound as an effective component, and being useful for treatment or prevention of a metabolic disease.
- An exemplary embodiment of the present invention provides a compound represented by following Chemical Formula 1 :
- A is oxadiazole, dihydrooxazole, thiazole or thiadiazole, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 straight chain or branched chain alkyl and C1 -C6 alcohol, the alkyl or alcohol group being optionally substituted by hydrogen, halogen or a C1-C6 alkoxy group;
- B is pyridine, pyrimidine, pyrazine or oxadiazole, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 straight chain or branched chain alkyl, C1 -C6 alcohol, C 1-C6 alkoxy and oxadiazole groups, the alkyl, alcohol, alkoxy or oxadiazole group being optionally substituted by hydrogen, halogen or a C1-C6 alkyl or C1-C6 alkoxy group; and
- X is independently F, CI, Br or I, preferably F; or an isomer thereof, or a
- Rj to R 6 are independently one or more substituents selected from the group consisting of hydrogen, halogen, C 1-C6 straight chain or branched chain alkyl and C 1-C6 alcohol, the alkyl or alcohol group being optionally substituted by hydrogen, halogen or a C1-C6 alkoxy group.
- R 7 to Ri are optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 straight chain or branched chain alkyl, C1 -C6 alcohol, C1-C6 alkoxy and oxadiazole groups, the C1 -C6 alkyl, C1 -C6 alcohol, C1-C6 alkoxy or oxadiazole group being optionally substituted by hydrogen, halogen, C1 -C6 alkyl or C1 -C6 alkoxy group.
- the compound wherein in the Chemical Formula 1 A is C1-C6 alkyl, for example, oxadiazole substituted by an isopropyl group; B is pyrimidine substituted by C1-C6 alkyl, for example, an ethyl group; and X is halogen, for example F; or the isomer thereof, or the
- 'halogen' refers to fluorine, chlorine, bromine or iodine.
- alkyl refers to a straight chain or branched chain
- C1-C6 alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.
- alkoxy' as used herein includes an alkyl-oxygen radical having alkyl as defined above, unless otherwise stated.
- the examples of the C1-C6 alkoxy include methoxy, ethoxy, propoxy, butoxy, pentoxy, and the like.
- heterocycle' or 'heterocyclic' refers to a 5 to 13 membered heteroaromatic or non-aromatic compound including 1 to 3 hetero atoms selected from the group consisting of N, O and S, unless otherwise stated.
- the compound represented by the above Chemical Formula 1 may be selected from the group consisting of following compounds:
- the compound represented by the Chemical Formula 1 may have an asymmetric carbon center, and if having the asymmetric carbon center, may exist as an optical isomer, a diastereomer or a recemate, and all forms of isomers including these may be also within the scope of the compound according to one embodiment of the present invention.
- Chemical Formula 1 or a pharmaceutically acceptable salt of the isomers of the compound represented by the Chemical Formula 1 may be also within the scope of the compound of the above described one embodiment.
- pharmaceutically acceptable salt of the compound represented by the Chemical Formula 1 or the isomer thereof may include a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; a salt with an organic carboxylic acid such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, or a salt with a sulfonic acid such as methane sulfonic acid or p-toluene sulfonic acid; a salt with an alkali metal such as sodium, potassium or lithium; a salt with various acids known to be capable of forming other pharmaceutically acceptable salts, or the like.
- an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid
- an organic carboxylic acid such as acetic acid, trifluoro
- the compound within the scope of the compound of the above Chemical Formula 1 may represent an excellent GPR1 19 agonistic activity, and accordingly represent a
- hypoglycemic action and a positive effect on pancreatic beta cells thereby being more effectively used to treat various metabolic diseases.
- the present inventors newly synthesized the compound of the Chemical Formula 1 having a GPR1 19 agonistic activity, and a pharmaceutical composition including the compound having a G protein-coupled receptor (GPR1 19) agonistic activity may have an effective hypoglycemic action and a positive effect on pancreatic beta cells, and also represent an effect of improving lipid metabolism which is a chronic cardiovascular risk factor, thereby being effective in the treatment and/or prevention of a metabolic disease.
- GPR1 19 G protein-coupled receptor
- the agonistic activity to GPR1 19 may increase secretion of glucagon-like peptide (GLP-1) or stability of secreted GLP-1 to represent anti-obesity and anti-diabetic efficacy mediated by the action of endogenous incretin.
- GLP-1 glucagon-like peptide
- another embodiment of the present invention provides a pharmaceutical composition including the above compound, the isomer thereof or the pharmaceutically acceptable salt thereof as an effective component.
- the pharmaceutical composition may be for treatment or prevention of a metabolic disease.
- the metabolic disease may be selected from the group consisting of diabetes, obesity,
- hypertension hypertension, a cardiovascular disease, a hemostatic disorder and dyslipidemia.
- a pharmaceutical composition including the compound represented by the Chemical Formula 1 , the isomer thereof or the pharmaceutically used salt thereof, as an effective component may be used in the form of a general medicinal preparation.
- the medicinal preparation may be administered in various formulations such as oral and parenteral formulation, and the formulation may be variously determined depending on usage.
- composition is formulated into various oral and parenteral formulations, it may be prepared using a generally used excipient such as a filler, a diluent, a bulking agent, a binder, a wetting agent, a disintergrating agent, a surfactant.
- a generally used excipient such as a filler, a diluent, a bulking agent, a binder, a wetting agent, a disintergrating agent, a surfactant.
- a solid preparation for oral administration may include tablets, pills, powders, granules, capsules, and the like, and the solid preparation may be prepared by mixing the compound represented by the Chemical Formula 1 , the isomer thereof, or the
- a pharmaceutically acceptable salt thereof with at least one excipient for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like.
- excipient for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like.
- a lubricant such as magnesium stearate and talc may be used.
- a liquid preparation for oral administration may be suspensions, oral liquids, emulsions, syrups, and the like, and include various excipients, for example, a wetting agent, a sweetener, an aromatic, a preservative, and the like, in addition to water and liquid paraffin which are a simple diluent to be commonly used.
- the preparation for parenteral administration includes a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a freeze-dried preparation, a suppository and the like.
- non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, a vegetable oil such as an olive oil, injectable ester such as ethyl oleate, and the like may be used.
- a base of the suppository witepsol, microgol, tween 61, cacao butter, laurin butter, glycerogelatin, and the like may be used.
- the pharmaceutical composition of the present invention including the compound represented by the Chemical Formula 1 , the isomer thereof or a pharmaceutically acceptable salt thereof as an effective component may have an effective amount in a dosage range of about 0.1 to about 1 ,000 mg.
- a dosage or dose may be administered in various dosages and methods, for example, in divided dosages from once to several times a day depending on a patient's weight, age, sex, a health condition, diet, administration time, an administration method, an excretion rate, and severity of a disease.
- yet another embodiment of the present invention provides a method for preparing the compound of Chemical Formula 1 of the above described one embodiment, including introducing a B group to a nitrogen group of piperidine of a compound of following Chemical Formula 2 to prepare a compound of following Chemical Formula 4; and introducing a compound of following Chemical Formula 12 to a hydroxyl group of the compound of the Chemical Formula 4:
- A is oxadiazole, dihydrooxazole, thiazole or thiadiazole, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1 -C6 straight chain or branched chain alkyl and C1-C6 alcohol, the alkyl or alcohol group being optionally substituted by hydrogen, halogen or a C1-C6 alkoxy group;
- B is pyridine, pyrimidine, pyrazine or oxadiazole, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 straight chain or branched chain alkyl, C1 -C6 alcohol, C1 -C6 alkoxy and an oxadiazole group, the alkyl, alcohol, alkoxy or oxadiazole group being optionally substituted by hydrogen, halogen or a C 1 -C6 alkyl or C 1 -C6 alkoxy group; and
- X is independently F, CI, Br or I.
- a reaction order of the step to introduce a B group to a nitrogen group of piperidine of a compound of the Chemical Formula 2, and the step to introduce the compound of the Chemical Formula 12 to a hydroxyl group of the compound of the Chemical Formula 4 is not limited, and thus, the compound of the Chemical Formula 12 may be introduced first to the hydroxyl group of the compound of the Chemical Formula 2, and the B group may be introduced first to the nitrogen group of piperidine.
- the step to introduce the compound of the Chemical Formula 12 to the hydroxyl group of the compound of the Chemical Formula 4 may include reacting the compound of the Chemical Formula 4 and a compound of following Chemical Formula 12a; and converting A' into A:
- A' is a cyano group, a carboxyl group, an ester group, a ketone group or halogen. More preferably, the step to react the compound of the Chemical Formula 4 and the compound of the Chemical Formula 12a may include introducing a methane sulfonyl group to the hydroxyl group of the Chemical Formula 4; and reacting the compound of the Chemical Formula 4 to which the methane sulfonyl group is introduced with the compound of the Chemical Formula 12a.
- Chemical Formula 4 may include reacting the compound of the Chemical Formula 4 with a compound selected from the group consisting of methane sulfonyl chloride, p-toluene sulfonyl chloride and trichloromethane sulfonyl chloride.
- a methane sulfonyl group may be introduced to the hydroxyl group of the Chemical Formula 4, and more preferably, methane sulfonyl chloride may be used.
- reaction temperature and reaction time may be appropriately controlled depending on an amount of the reactants, ambient conditions, and the like, however, the methane sulfonyl group may be more efficiently introduced by for example, a reaction at a temperature of -10 to 10°C, or at about 0°C for 10 minutes to 3 hours under a solvent of dichlororomethane (MC).
- MC dichlororomethane
- the compound of the Chemical Formula 4 to which the methane sulfonyl group is introduced may be reacted with the compound of the Chemical Formula 12a.
- the compound of the Chemical Formula 4 in which the methane sulfonyl group is introduced to the hydroxyl group in the previous step may be subjected to a coupling reaction with the hydroxyl group of the compound of the Chemical Formula 12a, thereby carrying out a reaction with the compound of the Chemical Formula 12a.
- the coupling reaction may be carried out in the presence of one or more bases selected from the group consisting of sodium carbonate, calcium carbonate, potassium carbonate and cesium carbonate; and one or more solvents selected from the group consisting of methyl sulfoxide, dimethyl formamide, N-methylpyrrolidin-2-on, tetrahydrofuran and
- reaction temperature and the reaction time of the coupling reaction may be appropriately controlled depending on an amount of the reactants, ambient conditions, and the like, however, for example, may be carried out at a temperature range of 50°C to 100°C for 5 to 24 hours.
- A' of the Chemical Formula 12a may be converted into A.
- the conversion step may be carried out using an appropriate process depending on the kind of A, and more specifically, using the following process.
- the compound wherein A is may be prepared by a method
- the oxidation step may be carried in methyl alcohol, ethyl alcohol, tetrahydrofuran, 1 ,4-dioxane or the like as a solvent, by using an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution or the like, and the reaction may be carried out at 0°C to 80°C for 1 to 5 hours. Thereafter, acidification with an aqueous HC1 solution is carried out.
- reaction with the aminoethanol may be carried out in methyl alcohol, ethyl alcohol, tetrahydrofuran, 1,4-dioxane or the like as a solvent, by adding
- the cyclization step may be carried out by reacting triphenylphosphine and 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone at 10 to 40°C for 0 minute to 3 hours under a dichloromethane (MC) solvent.
- MC dichloromethane
- the compound wherein A is may be prepared by a method comprising:
- R 2 is identical to R 2 of the Chemical Formula 1 ; and LG is a leaving group.
- the reaction with hydroxylamine may be carried out in methyl alcohol, ethyl alcohol, tetrahydrofuran or 1 ,4-dioxane as a solvent, at 80 to 150°C for 1 to 10 hours.
- reaction with the compound of the Chemical Formula 16 may be carried out by performing a first reaction at 10 to 40°C for 10 minutes to 3 hours under a
- the compound wherein A is may be prepared by a method comprising:
- R 3 is as defined in the Chemical Formula 1.
- the oxidation step may be carried in methyl alcohol, ethyl alcohol, tetrahydrofuran, 1 ,4-dioxane or the like as a solvent, by using an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution or the like, and the reaction may be carried out at 0°C to 80°C for 1 to 5 hours. Thereafter, acidification with an aqueous HC1 solution is carried out.
- the reaction with the hydrazine may be carried out in dichloromethane (MC) as a solvent, by adding l -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and hydroxybenzotriazole to perform a reaction at 10 to 40°C for 5 minutes to 3 hours, and then adding hydrazine to perform a reaction at 10 to 40°C for 1 to 10 hours.
- MC dichloromethane
- EDC.HCl l -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
- hydroxybenzotriazole hydroxybenzotriazole
- reaction step with the compound of the Chemical Formula 18 may be carried out by adding a reactant obtained from the previous step to the solution of the
- Chemical Formula 18 to perform a reaction at 100 to 200°C for 1 to 10 hours and the reaction step with the compound of the Chemical Formula 19 may be carried out by dissolving the compound of the Chemical Formula 17 obtained in the previous step in an aqueous solution, and then adding triefhylamine and the compound of the Chemical Formula 19 to perform a reaction at 100 to 200°C for 1 to 12 hours.
- the compound wherein A is may be prepared by a method comprising:
- R 5 is as defined in the Chemical Formula 1.
- the oxidation step may be carried in methyl alcohol, ethyl alcohol, tetrahydrofuran, 1 ,4-dioxane or the like as a solvent, by using an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution or the like, and the reaction may be carried out at 0°C to 80°C for 1 to 5 hours. Thereafter, acidification with an aqueous HC1 solution is carried out.
- the reaction step with the hydrazide may be carried out in dichloromethane (MC) as a solvent, by adding l -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
- reaction step with the compound of the Chemical Formula 21 may be carried out by dissolving the compound of the Chemical Formula 20 obtained in the previous step in xylene, and then adding the compound of the Chemical Formula 21 to perform a reaction at 100 to 200°C for 10 minutes to 2 hours.
- the compound wherein A is may be prepared by a method comprising:
- R 6 is identical to R of the Chemical Formula 1 ; and LG is a leaving group.
- the oxidation step may be carried in methyl alcohol, ethyl alcohol, tetrahydrofuran, 1 ,4-dioxane or the like as a solvent, by using an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution or the like, and the reaction may be carried out at 0°C to 80°C for 1 to 5 hours. Thereafter, acidification with an aqueous HC1 solution is carried out.
- the step to introduce the compound of the Chemical Formula 22 may be carried out by adding thionyl chloride under a dichloromethane solvent at 0°C to 80°C for 1 to 5 hours
- the step to introduce the compound of the Chemical Formula 23 may be carried out at 10 to 40°C for 1 to 3 hours by dissolving the compound of the Chemical Formula 21 obtained in the previous step in benzene, and then adding sodium hydroxide and ammonium chloride.
- the step to introduce the compound of the Chemical Formula 24 may be carried out by dissolving the compound of the Chemical Formula 23 obtained in the previous step in tetrahydrofuran, and then adding the compound of the Chemical Formula 21 thereto, to perform a reaction at 10 to 60°C for 1 to 3 hours.
- reaction step with the compound of the Chemical Formula 25 may be carried out by dissolving the compound of the Chemical Formula 24 obtained in the previous step in ethanol, and then adding the compound of the Chemical Formula 25 thereto, to perform a reaction at 70 to 100°C for 1 to 6 hours.
- A' may be converted into various A groups through conventional processes in the art, which are shown specifically in the following Examples.
- the step to introduce the B group to the nitrogen group of piperidine of the compound of the Chemical Formula 2 may be carried out by reacting the nitrogen group of piperidine with a suitable intermediate compound such as halogen-substituted pyrimidine, halogen-substituted pyridine, or a cyano group, and synthesizing the desired B group through a conventional process in the art.
- a suitable intermediate compound such as halogen-substituted pyrimidine, halogen-substituted pyridine, or a cyano group
- the novel compound, the isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention represents a GPRl 19 agonistic activity, and thus, may be used in the treatment and/or prevention of a metabolic disease such as diabetes usefully. More specifically, through the GPRl 19 agonistic activity, effective hypoglycemic action and a positive effect on pancreatic beta cells may be generated, and also lipid metabolism which is a chronic cardiovascular risk factor may be improved.
- an example of the method for preparing the compound of the Chemical Formula 1 including introducing the B group to the nitrogen group of piperidine of the compound of the Chemical Formula 2 to prepare the compound of the Chemical Formula 4, and introducing the compound of the Chemical Formula 12 to the hydroxyl group of the compound of the Chemical Formula 4, is as summarized in following Reaction Formulae 1 to 3.
- Step 1-1 Preparation of 4-(3-hydroxypropyl)piperidine-l-carbonitrile (Chemical Formula 3) 3-(Piperidin-4-yl)propan-l -ol hydrochloride of the Chemical Formula 2 (10 g, 69.8 mmol) was dissolved in a mixed solution of dichloromethane (MC, 75.0 ml) and water (55.0 ml); sodium bicarbonate (NaHC0 3 , 16.36 g, 195.0 mmol) was added thereto; then cyanic bromide (6.48 g, 61.2 mmol) was added thereto; and stirring was carried out at room temperature for 15 hours.
- MC dichloromethane
- MC dichloromethane
- sodium bicarbonate NaHC0 3 , 16.36 g, 195.0 mmol
- Step 1 -4 Preparation of 3-(l -(3-isopropyl-l ,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl methane sulfonate
- Triethylamine (89.1 ml, 0.64 mol) and methane sulfonyl chloride (39.7 ml, 0.51 mol) were slowly dropped to the reaction solution.
- the reaction solution was stirred at room temperature
- 2,6-difluoro-4-(3-(l-(3-isopropyl-l,2,4-oxadiazol-5-yl)propoxy)benzoate (88.9 g, 0.21 mol) was dissolved in a 1 ,4-dioxane solvent (1.5 L), and then a 2N aqueous NaOH solution (312 ml, 0.62 mol) was slowly dropped thereto.
- the reaction solution was stirred at 80°C for 3 hours, and then diluted with water, and a 2N aqueous HC1 solution (800 ml) was added thereto, to acidify the solution.
- Step 2-6 Preparation of 3-(l-(5-(5-isobutyl-l ,2,4-oxadiazol-3-yl)pyrimidin-2-yl) piperidi -4-yl)propyl methane sulfonate
- Step 2-7 Preparation of 2,6-difluoro-4-(3-(l-(5-(5-isobutyl-h2,4-oxadiazol-3-yl) pyrimidi -2-yl)piperidin-4-yl)propoxy)benzonitrile
- Step 2-9) Preparation of 3-(2.6-difluoro-4-(3-(l-(5-(5-isobutyl-1.2.4-oxadiazol-3-yl) pyrimidi -2-yl)piperidin-4-yl)propoxy)phenyl)-5-methyl- 1 ,2,4-oxadiazole (Example 2)
- Methyl 2,6-difluoro-4-hydroxybenzoate (1.72 g, 9.16 mmol) was dissolved in N,N-dimethyl formamide (DMF, 30 ml), and then
- Step 3-4 Preparation of 2-(4-(3-(l-(5-ethylpyrimidin-2-ynpiperidin-4-yl)propoxy) -2,6-difluorophenyl)-5-methyl-l ,3,4-oxadiazole (Preparation Example 3)
- isobutyrohydrazide (37.8 mg, 0.37 mmol) was dropped thereto, and stirring was carried out for 18 hours. After completion of the reaction, the reactant was filtered through celite, and then concentrated under reduced pressure to obtain the desired form of the compound, 4-(3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluoro-N'-isobutyrylbenzohydra zide in a yield of 88%.
- Step 4-2 Preparation of 2-(4-(3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy) -2,6-difluorophenyl)-5-isopropyl-l ,3,4-thiadiazole (Preparation Example 4)
- Step 5-4 Preparation of 4-ethyl-2-(4-(3-(l -(5-ethylpyrimidin-2-yl)piperidin-4-vn propoxy)-2,6-difluorophenyl)thiazole (Preparation Example 5)
- reaction solution was concentrated under reduced pressure, then the residue was purified with silica gel column chromatography, and further ether was added thereto, then filtering was carried out, thereby obtaining the desired form of the compound, 3,5-difluoro-4-(5-isopropyl-l ,2,4-oxadiazol-3-yl)phenol in a yield of 48%.
- Step 6-5 Preparation of 3-(4-(3-(l -(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy) -2,6-difluorophenyl)-5-isopropyl-l ,2,4-oxadiazole (Preparation Example 6)
- reaction solution was stirred at 65 °C for 17 hours, and then diluted with water, and extracted with EA. Moisture was removed from an organic layer with MgS0 4 , the organic layer was filtered and concentrated under reduced pressure, and then the residue was purified with silica gel column chromatography, thereby obtaining the desired form of the compound,
- Human GPR119 was temporarily expressed on cells, thereby quantifying the amount of cyclic adenosine 3 ',5 '-monophosphate (cAMP) increased upon activating GPR1 19 by the compound of the present invention, using the product from Cysbio, by a method of HTRF (homogeneous time resolved fluorescence), and such quantification was used to refer to efficacy on GPR1 19 activation.
- cAMP cyclic adenosine 3 ',5 '-monophosphate
- Human GPR1 19 expression vector (Origene) was overexpressed in hamster renal epithelial cells (HEK293) (ATCC), and the cells were stabilized for 48 hours.
- HEK293 hamster renal epithelial cells
- IBMX 3-isobutyl-l-methylxanthine which is a phosphodiesterase inhibitor being added to a KRBH (Krebs-Ringer Bicarbonate HEPES; Hou ZQ. et al., Mol Cell Endocrinol, 2008(291):71-78) buffer
- KRBH Krebs-Ringer Bicarbonate HEPES; Hou ZQ. et al., Mol Cell Endocrinol, 2008(291):71-78
- the cells were pre-treated for 10 minutes. Thereafter, the cells were treated with the same solution containing a drug for 60 minutes, then the supernatant was removed, and the increase in cAMP in cells was quantified using a Cysbio cAMP HiRange
- the glucose tolerance improvement effect of the above compounds was evaluated in 7-week male laboratory mouse (C57BL/6 mouse), as the effect of improving postprandial glycemic control ability.
- the laboratory mouse was fasted from the day before the experiment for 16-17 hours.
- the compound of the present invention was orally administered 30 minutes before administrating glucose, and after 30 minutes, a glucose solution (2 g/kg/10 ml) was orally administered.
- a drug was prepared by suspending in a 10% Gelucire solution.
- the whole blood glucose levels was measured from tail vein using a blood glucose meter (AccuChek Active, Roche Diagnostics), and the area under the curve of a temporal blood glucose curve was calculated.
- the novel compounds synthesized in Examples 1 to 67, the isomers thereof, or the pharmaceutically acceptable salts thereof have agonistic activities to the GPR1 19. Furthermore, the excellent glucose tolerance improvement effect was confirmed in many compounds of the Examples on which the experiment was carried out. Accordingly, the above compounds of the Examples are expected to have a high treatment effect or prevention effect on metabolic diseases such as obesity, diabetes, hypertension, cardiovascular diseases, a hemostatic disorder, dyslipidemia and the like.
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201580055671.0A CN107074838B (en) | 2014-10-27 | 2015-07-24 | Compound having GPR119 agonist activity, method for preparing the same, and pharmaceutical composition comprising the same as an effective ingredient |
NZ729455A NZ729455A (en) | 2014-10-27 | 2015-07-24 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
ES15854218T ES2758981T3 (en) | 2014-10-27 | 2015-07-24 | Compound having GPR119 agonist activity, method for preparing the same, and pharmaceutical composition including the same as an effective component |
JP2017522671A JP6470408B2 (en) | 2014-10-27 | 2015-07-24 | COMPOUND HAVING GPR119 ACTIVITY, PROCESS FOR PRODUCING THE SAME AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AS AN EFFECTIVE |
AU2015337407A AU2015337407B2 (en) | 2014-10-27 | 2015-07-24 | Compound having GPR119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
US15/521,090 US10428055B2 (en) | 2014-10-27 | 2015-07-24 | Substituted piperidines having GPR119 agonistic activity |
RU2017112728A RU2670197C1 (en) | 2014-10-27 | 2015-07-24 | Compound having agonistic activity against gpr119, method for its preparation, and pharmaceutical composition containing it as an effective component |
EP15854218.3A EP3212640B1 (en) | 2014-10-27 | 2015-07-24 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
SG11201701347WA SG11201701347WA (en) | 2014-10-27 | 2015-07-24 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
CA2959714A CA2959714C (en) | 2014-10-27 | 2015-07-24 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
BR112017007692A BR112017007692A2 (en) | 2014-10-27 | 2015-07-24 | compound having gpr119 agonist activity, method for preparing it and pharmaceutical composition comprising the same as an effective component |
MX2017005055A MX2017005055A (en) | 2014-10-27 | 2015-07-24 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component. |
PL15854218T PL3212640T3 (en) | 2014-10-27 | 2015-07-24 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
IL251456A IL251456A0 (en) | 2014-10-27 | 2017-03-29 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
SA517381341A SA517381341B1 (en) | 2014-10-27 | 2017-04-17 | Compound Having GPR119 Agonistic Activity, Method for Preparing The Same, and Pharmaceutical Composition Including The Same as Effective Component |
PH12017500795A PH12017500795B1 (en) | 2014-10-27 | 2017-04-27 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2014-0146462 | 2014-10-27 | ||
KR20140146462 | 2014-10-27 | ||
KR1020150090708A KR101726819B1 (en) | 2014-10-27 | 2015-06-25 | Compound having agonistic activity to gpr119, method for preparation thereof and pharmaceutical compositon comprising the same |
KR10-2015-0090708 | 2015-06-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2016068453A1 true WO2016068453A1 (en) | 2016-05-06 |
WO2016068453A8 WO2016068453A8 (en) | 2017-03-16 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2015/007715 WO2016068453A1 (en) | 2014-10-27 | 2015-07-24 | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
Country Status (1)
Country | Link |
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WO (1) | WO2016068453A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20190092763A1 (en) * | 2014-10-27 | 2019-03-28 | Dong-A St Co., Ltd. | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaecutical composition including the same as effective component |
US20220047591A1 (en) * | 2018-09-12 | 2022-02-17 | Dong-A St Co., Ltd. | Pharmaceutical composition for preventing or treating nonalcoholic fatty liver disease, containing gpr119 ligand as active ingredient |
US11279702B2 (en) | 2020-05-19 | 2022-03-22 | Kallyope, Inc. | AMPK activators |
US11407768B2 (en) | 2020-06-26 | 2022-08-09 | Kallyope, Inc. | AMPK activators |
EP4098261A4 (en) * | 2020-03-11 | 2024-02-28 | Dong A St Co Ltd | Pharmaceutical composition for prevention or treatment of nonalcoholic steatohepatitis |
EP4098262A4 (en) * | 2020-03-11 | 2024-02-28 | Dong A St Co Ltd | Pharmaceutical composition for prevention or treatment of diabetes and metabolic diseases associated therewith |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0435381A1 (en) * | 1989-12-26 | 1991-07-03 | Janssen Pharmaceutica N.V. | Antipicornaviral pyridazinamines |
WO2010004347A1 (en) * | 2008-07-10 | 2010-01-14 | Prosidion Limited | Heterocyclic gpcr agonists |
US8299241B2 (en) * | 2006-12-05 | 2012-10-30 | Arena Pharmaceuticals, Inc. | Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof |
-
2015
- 2015-07-24 WO PCT/KR2015/007715 patent/WO2016068453A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0435381A1 (en) * | 1989-12-26 | 1991-07-03 | Janssen Pharmaceutica N.V. | Antipicornaviral pyridazinamines |
US8299241B2 (en) * | 2006-12-05 | 2012-10-30 | Arena Pharmaceuticals, Inc. | Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof |
WO2010004347A1 (en) * | 2008-07-10 | 2010-01-14 | Prosidion Limited | Heterocyclic gpcr agonists |
Non-Patent Citations (2)
Title |
---|
GIERCZYK, B. ET AL.: "Synthesis of Substituted 1,3,4-thiadiazoles Using Lawesson' s reagent", ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, vol. 37, no. 3, 2005, pages 213 - 222, XP009144134 * |
UGARKAR, A. G. ET AL.: "Extracting structural requirements for activity of GPR119 agonists: a hologram quantitative structure activity relationship (HQSAR) study", CANADIAN JOURNAL OF CHEMISTRY, vol. 92, no. 7, July 2014 (2014-07-01), pages 670 - 676, XP009500753 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20190092763A1 (en) * | 2014-10-27 | 2019-03-28 | Dong-A St Co., Ltd. | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaecutical composition including the same as effective component |
US10428055B2 (en) * | 2014-10-27 | 2019-10-01 | Dong-A St Co., Ltd. | Substituted piperidines having GPR119 agonistic activity |
US20220047591A1 (en) * | 2018-09-12 | 2022-02-17 | Dong-A St Co., Ltd. | Pharmaceutical composition for preventing or treating nonalcoholic fatty liver disease, containing gpr119 ligand as active ingredient |
RU2768943C1 (en) * | 2018-09-12 | 2022-03-25 | Тон-А Ст Ко., Лтд. | Pharmaceutical composition for preventing or treating non-alcoholic fatty liver infiltration, containing gpr119 ligand as active ingredient |
AU2019337286B2 (en) * | 2018-09-12 | 2022-07-14 | Dong-A St Co., Ltd. | Pharmaceutical composition for preventing or treating nonalcoholic fatty liver disease, containing GPR119 ligand as active ingredient |
EP4098261A4 (en) * | 2020-03-11 | 2024-02-28 | Dong A St Co Ltd | Pharmaceutical composition for prevention or treatment of nonalcoholic steatohepatitis |
EP4098262A4 (en) * | 2020-03-11 | 2024-02-28 | Dong A St Co Ltd | Pharmaceutical composition for prevention or treatment of diabetes and metabolic diseases associated therewith |
US11279702B2 (en) | 2020-05-19 | 2022-03-22 | Kallyope, Inc. | AMPK activators |
US11851429B2 (en) | 2020-05-19 | 2023-12-26 | Kallyope, Inc. | AMPK activators |
US11407768B2 (en) | 2020-06-26 | 2022-08-09 | Kallyope, Inc. | AMPK activators |
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