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WO2018160024A1 - Dérivé de pipéridine-aryle ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et composition pharmaceutique contenant celui-ci en tant que principe actif - Google Patents

Dérivé de pipéridine-aryle ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et composition pharmaceutique contenant celui-ci en tant que principe actif Download PDF

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Publication number
WO2018160024A1
WO2018160024A1 PCT/KR2018/002508 KR2018002508W WO2018160024A1 WO 2018160024 A1 WO2018160024 A1 WO 2018160024A1 KR 2018002508 W KR2018002508 W KR 2018002508W WO 2018160024 A1 WO2018160024 A1 WO 2018160024A1
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Prior art keywords
piperidin
methoxy
methyl
ethylpyrimidin
biphenyl
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PCT/KR2018/002508
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English (en)
Korean (ko)
Inventor
안진희
배은정
이인규
전재한
강승규
이규명
정관령
장윤경
김광록
이상달
배명애
김효진
Original Assignee
한국화학연구원
경북대학교 산학협력단
경북대학교병원
광주과학기술원
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Publication of WO2018160024A1 publication Critical patent/WO2018160024A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone

Definitions

  • the present invention provides a piperidine-aryl derivative having a G protein-coupled receptor 119 (hereinafter referred to as 'GPR119') hyperactivity, or a pharmaceutically acceptable salt thereof; Its preparation method; And it relates to a pharmaceutical composition containing it as an active ingredient.
  • 'GPR119' G protein-coupled receptor 119
  • Diabetes mellitus is a hyperglycemia that causes high levels of blood glucose as a pancreas, a chronic disease in which the pancreas secretes little or no insulin or the body does not effectively utilize insulin. ) Can cause serious complications including cardiovascular disorders, blindness, and renal failure.
  • the number of diabetics estimated at 180 million worldwide, is expected to double by 2030, with approximately 90-95% of those with type 2 diabetes.
  • Type 2 diabetes is a process of decreasing insulin secretion mainly due to hepatic glucose overproduction, insulin resistance, and pancreatic ⁇ -cell dysfunction of insulin-releasing pancreas. Onset through.
  • Representative methods for treating type 2 diabetes include non-drug therapies such as diet and exercise therapy, and are broadly classified as pharmacological therapy except the non-drug therapy.
  • Medications usually begin when non-drug therapies, such as diet and exercise therapy, fail to achieve glycemic control goals, and widely prescribed oral medications can be classified according to the mechanism of action and structural features of the drug, with limitations and potential risks. It is reported to show.
  • Metformin is a biguanide-based drug that acts primarily through the suppression of glucose overproduction and reduced insulin resistance in the liver, and generally has no side effects, but it can induce lactic acidosis as a potential side effect. Is being reported.
  • the thiazolidinedione family of drugs includes rosiglitazone and pioglitazone as PPAR ⁇ agonists that act through enhanced insulin sensitization and edema. It has been reported to have side effects such as weight gain, hepatotoxicity, and heart failure.
  • Sulfonyl urea (sulfonylurea) drugs act in a glucose-independent manner to promote insulin secretion of the beta cells of the pancreas, causing hypoglycemia and may cause weight gain.
  • Meglitinide-based drugs also have similar mechanisms of action and side effects as sulfonylureas.
  • Alpha-glucosidase inhibitors are used to suppress sugar spikes after meals, with side effects in the intestines.
  • Insulin and insulin analogues are commonly used in combination therapy with oral drugs and have side effects such as hypoglycemia and weight gain and limitations as injections.
  • Glucagon-like peptide 1 receptor agonists such as exenatide mimic GLP-1, which is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).
  • DPP-IV dipeptidyl peptidase-IV
  • Analog (GLP-1 mimetics) which promotes glucose-dependent insulin secretion, inhibits glucagon secretion, gasstrc emptying, and appetite without being rapidly degraded by DPP-IV, and protects beta cells It is a drug that shows the effect of GLP-1. Therefore, it does not cause hypoglycemia, shows weight loss effect, shows HbA1c lowering effect, but has side effects such as intestinal side effects and pancreatitis and limitations as injections.
  • DPP-IV inhibitors such as sitagliptin and vildagliptin are oral drugs that act by inhibiting the degradation of GLP-1 and are similar to GLP-1 receptor agonists. It shows a HbA1c lowering effect but no weight loss effect.
  • GPR119 is a protein consisting of 335 amino acids expressed in the beta cells of the pancreatic islet and in the gastrointestinal tract.
  • the protein belongs to a receptor family coupled to the G-protein, and several candidates have been proposed as endogenous ligands, including oleoylethanolamide (OEA), N-oleleoyldopamine and olvanil.
  • OOA oleoylethanolamide
  • N-oleoyldopamine N-oleoyldopamine
  • olvanil oleoylethanolamide
  • GPR119 plays a role in sugar-dependent secretion of insulin, and the targeting potential of GPR119 receptors for the treatment of diabetes is supported by numerous studies in cell lines and animals. Activation of the GPR119 receptor by lysophosphatidylcholine raises glucose-dependent insulin secretion in mouse pancreatic beta cell lines, which can be blocked using GPR119-specific siRNA.
  • GPR119 is a promising target for the development of type 2 diabetes treatment, which has been the subject of intensive research and development by major pharmaceutical companies.
  • GPR119 is mainly expressed in the pancreas and intestinal tract, similar to the GLP-1 receptor, increases glucose-dependent insulin secretion upon activation in pancreatic beta cells and intestinal GLP-1 and / or GIP (glucose-) dependent insulinotropic peptide) It is known to increase the secretion of the corresponding incretin upon activation in secretory cells.
  • GLP-1 receptor which is a peptide ligand
  • GPR119 is potent and not selective but lipid.
  • GPR119 is an action point with the possibility of realizing the efficacy of GLP-1 receptor adjuvants as an oral drug.
  • APD-668 compound Ortho-McNeil, Arena
  • GPR119 agonists such as APD-597 compound (Ortho-McNeil, Arena), PSN-821 compound (OSI), MBX-2982 compound (Sanofi-Aventis, Metabolex), and GSK-1292263A compound (GSK) have entered the clinic.
  • PSN-821 compound (OSI), MBX-2982 compound (Sanofi-Aventis, Metabolex), and GSK-1292263A compound (GSK) have entered clinical phase II [Thomson Reuters Integrity].
  • the present inventors have made efforts to develop a type 2 diabetes therapeutic agent that ensures efficacy and safety, to prepare a novel piperidine-aryl derivative and its pharmaceutically acceptable salts having GPR119 anti-inflammatory activity, and as an active ingredient
  • the present invention has been completed by providing a therapeutic agent for diseases related to GPR119 anti-inflammatory activity.
  • Another object of the present invention is to provide a method for preparing the piperidine-aryl derivative.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of diseases associated with GPR119 anti-inflammatory activity containing the piperidine-aryl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the piperidine-aryl derivative of the present invention is a novel compound and has excellent GPR119 anti-inflammatory activity, and thus can be usefully used without side effects as an effective prophylactic and therapeutic agent for diseases related to GPR119 anti-inflammatory activity, especially diabetes or diabetic complications. .
  • the present invention provides a novel compound having excellent GPR119 anti-inflammatory activity, piperidine-aryl derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen or (C 1 -C 10 ) alkyl
  • R 2 is hydrogen, (C 1 -C 10 ) alkyl or (C 3 -C 7 ) cycloalkyl;
  • R 3 is (C 1 -C 10 ) alkyl or (C 3 -C 7 ) cycloalkyl;
  • R 4 to R 8 are each independently hydrogen, halogen or (C 1 -C 10 ) alkyl
  • Z is a single bond, (C 6 -C 20 ) arylene or (C 3 -C 20 ) heteroarylene;
  • L is a single bond, -O- (CR'R ") n -,-(CR'R") n -O- or NR 9- (CR'R ”) n- ;
  • R 9 is hydrogen, (C 1 -C 10 ) alkyl or (C 3 -C 7 ) cycloalkyl;
  • n is an integer of 0 or 1;
  • W is a single bond, (C 6 -C 20 ) arylene or (C 3 -C 20 ) heteroarylene;
  • Y is (C 1 -C 10 ) alkylcarbonyl, (C 1 -C 10 ) alkoxycarbonyl, (C 3 -C 7 ) cycloalkylcarbonyl, (C 3 -C 7 ) cycloalkoxycarbonyl, (C 3 -C 20 ) heteroaryl, (C 3 -C 20 ) heteroarylcarbonyl, SO 2 R 10 , (C 6 -C 20 ) aryl, (C 6 -C 20 ) arylcarbonyl or ego;
  • R 10 is (C 1 -C 10 ) alkyl, (C 3 -C 7 ) cycloalkyl or (C 6 -C 20 ) aryl;
  • R 11 and R 12 are each independently hydrogen or (C 1 -C 10 ) alkyl
  • the heteroarylene and heteroaryl include one or more heteroatoms selected from N, O and S.
  • the present invention also provides a method for preparing a piperidine-aryl derivative represented by Chemical Formula 1.
  • the present invention by confirming the excellent GPR119 anti-binding activity for the piperidine-aryl derivative represented by the formula (1), GPR119 containing the piperidine-aryl derivative or a pharmaceutically acceptable salt thereof as an active ingredient
  • GPR119 containing the piperidine-aryl derivative or a pharmaceutically acceptable salt thereof as an active ingredient Provided is a pharmaceutical composition for preventing or treating a disease associated with anti-inflammatory activity.
  • the present invention provides a piperidine-aryl derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen or (C 1 -C 10 ) alkyl
  • R 2 is hydrogen, (C 1 -C 10 ) alkyl or (C 3 -C 7 ) cycloalkyl;
  • R 3 is (C 1 -C 10 ) alkyl or (C 3 -C 7 ) cycloalkyl;
  • R 4 to R 8 are each independently hydrogen, halogen or (C 1 -C 10 ) alkyl
  • Z is a single bond, (C 6 -C 20 ) arylene or (C 3 -C 20 ) heteroarylene;
  • L is a single bond, -O- (CR'R ") n -,-(CR'R") n -O- or NR 9- (CR'R ”) n- ;
  • R 9 is hydrogen, (C 1 -C 10 ) alkyl or (C 3 -C 7 ) cycloalkyl;
  • n is an integer of 0 or 1;
  • W is a single bond, (C 6 -C 20 ) arylene or (C 3 -C 20 ) heteroarylene;
  • Y is (C 1 -C 10 ) alkylcarbonyl, (C 1 -C 10 ) alkoxycarbonyl, (C 3 -C 7 ) cycloalkylcarbonyl, (C 3 -C 7 ) cycloalkoxycarbonyl, (C 3 -C 20 ) heteroaryl, (C 3 -C 20 ) heteroarylcarbonyl, SO 2 R 10 , (C 6 -C 20 ) aryl, (C 6 -C 20 ) arylcarbonyl or ego;
  • R 10 is (C 1 -C 10 ) alkyl, (C 3 -C 7 ) cycloalkyl or (C 6 -C 20 ) aryl;
  • R 11 and R 12 are each independently hydrogen or (C 1 -C 10 ) alkyl
  • the heteroarylene and heteroaryl include one or more heteroatoms selected from N, O and S.
  • the piperidine-aryl derivative of the formula (1) according to the present invention is a novel compound, which has excellent GPR119 anti-inflammatory activity and is useful as a therapeutic agent and a preventive agent for diseases related to GPR119 anti-inflammatory activity, in particular diabetes or diabetic complications.
  • the piperidine-aryl derivative of Chemical Formula 1 may be represented by the following Chemical Formula 1-1, Chemical Formula 1-2, or Chemical Formula 1-3.
  • R 1 , X, Y and A rings are the same as defined in Formula 1;
  • Z is (C 6 -C 20 ) arylene or (C 3 -C 20 ) heteroarylene;
  • L is -O- (CR'R ") n -,-(CR'R") n -O- or -NR 9- (CR'R ") n- ;
  • R 9 is hydrogen, (C 1 -C 10 ) alkyl or (C 3 -C 7 ) cycloalkyl;
  • R 'and R are each independently hydrogen or (C 1 -C 10 ) alkyl;
  • n is an integer of 0 or 1;
  • W is (C 6 -C 20 ) arylene or (C 3 -C 20 ) heteroarylene;
  • the arylene or heteroarylene of Z and W is each independently halogen, (C 1 -C 10 ) alkyl, halo (C 1 -C 10 ) alkyl, (
  • R 1 is hydrogen or (C 1 -C 10 ) alkyl
  • X is ego
  • R 2 is hydrogen or (C 1 -C 10 ) alkyl
  • R 3 is (C 1 -C 10 ) alkyl or (C 3 -C 7 ) cycloalkyl
  • R 4 to R 8 are each independently hydrogen, halogen or (C 1 -C 10 ) alkyl
  • Z is a single bond, (C 6 -C 20 ) arylene or (C 3 -C 20 ) heteroarylene
  • L is a single bond, -O- (CR'R ") n -,-(CR'R") n -O- or NR 9- (CR'R ") n-
  • R 9 is hydrogen or (C 1 -C 10 ) alkyl
  • R 9 is hydrogen or (C 1 -C 10 )
  • the piperidine-aryl derivative of Formula 1 Can be selected from the following structures:
  • R 13 and R 14 are each independently hydrogen, halogen or (C 1 -C 10 ) alkyl; R 9 is hydrogen or (C 1 -C 10 ) alkyl; n is an integer of 0 or 1.)
  • R 1 is hydrogen or methyl
  • X is ego
  • R 2 is hydrogen, methyl, ethyl, i-propyl, t-butyl or cyclohexyl
  • R 3 is methyl, ethyl, i-propyl, t-butyl or cyclohexyl
  • a ring ego
  • R 4 , R 5 , R 6 ' , R 6 " , R 7 and R 8 are each independently hydrogen, fluoro or methyl
  • Z is a single bond, pyridinylene, phenylene, pyrimidinylene, thieno [ 3,2-d] pyrimidinylene ( ) Or benzooxazolylene
  • Pyridinylene, phenylene, pyrimidinylene, thieno [3,2-d] pyrimidinylene and benzooxazolylene of Z are each independently chloro, bromo, fluoro or methyl
  • R 1 is hydrogen or methyl
  • X is ego
  • R 3 is methyl, ethyl, i-propyl, t-butyl or cyclohexyl
  • a ring ego
  • R 4 ′ , R 4 ′′ , R 5 ′ , R 5 ′′ , R 6 ′ , R 6 ′′ , R 7 and R 8 are each independently hydrogen, fluoro or methyl
  • Z is a single bond, pyridinylene, Phenylene, pyrimidinylene, thieno [3,2-d] pyrimidinylene or benzooxazolylene;
  • pyridinylene, phenylene, pyrimidinylene, thieno [3,2-d] pyrides of Z Midinylene and benzooxazolylene are each independently further substituted with one or more substituents selected from the group consisting of chloro, bromo, fluoro,
  • the piperidine-aryl derivative of Chemical Formula 1 is
  • Piperidine-aryl derivatives represented by Formula 1 according to the present invention may form a hydrate or solvate with water or other organic solvents. Such hydrates or solvates are likewise included within the scope of the present invention.
  • the present invention provides a method for preparing a piperidine-aryl derivative of Chemical Formula 1.
  • Schemes 1 to 8 are illustrated as a method for preparing a piperidine-aryl derivative of Formula 1 of the present invention, and the following preparation method limits a method for preparing a piperidine-aryl derivative of Formula 1 according to the present invention.
  • the modifications of the following preparation methods will be apparent to those skilled in the art, and unless otherwise stated, the definitions of the substituents in the following schemes are the same as those in the formula (1).
  • the first step of the present invention is the general conditions of Suzuki coupling reaction [Armin de Meijere and Francois Diederich, Metal-Catalyzed Cross-Coupling Reactions, 2nd Ed. Vol. 1, Chapter 2, 2004], and the second step of the present invention is carried out through the condensation reaction of the prepared carbonyl derivative of formula 4 with hydroxylamine of formula 5 or
  • the second step is to prepare the ferridine-aryl derivative.
  • hydroxylamine (Formula 5 or Formula 6) is used in an amount of 2.0 to 10 equivalents, wherein the base used is an inorganic base (for example, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, etc.) or an organic base.
  • triethylamine, diisopropylamine, pyridine, rutidine, etc. can be used, and sodium acetate is preferably used.
  • the solvent used alcohols such as methanol, ethanol, and propanol are used.
  • a solvent such as dichloromethane may be mixed.
  • the reaction temperature is 100 ° C. at room temperature, and the reaction time is preferably 1 to 48 hours.
  • the amine compound represented by Chemical Formula 4-H may be reacted with a derivative including Boc (t-butoxycarbonyl) represented by Chemical Formula 4-Boc under Scheme 5 under conventional deprotection conditions.
  • a derivative including Boc (t-butoxycarbonyl) represented by Chemical Formula 4-Boc under Scheme 5 under conventional deprotection conditions.
  • Piperidine-aryl derivatives represented by the general formula (1) through condensation reaction with hydroxylamine (Formula 5 or 6) after introduction of an electrophile to obtain a conventional alkylation reaction (except when Y is Boc) Can be prepared.
  • R 13 and R 14 are each independently hydrogen, halogen or (C 1 -C 10 ) alkyl; R 2 , R 3 , X, Y and n are the same as defined in Formula 1 above.]
  • R 13 and R 14 are each independently hydrogen, halogen or (C 1 -C 10 ) alkyl; R 2 , R 3 , R 4 , R 5 , X, Y and n are the same as defined in Formula 1 above.]
  • a nitro group is reduced to an amino group using a palladium catalyst under hydrogen (amino derivative of Formula 17), Reaction with an aldehyde derivative of 18 to synthesize the benzoxazole derivative of the formula (19).
  • a carboxyl ester derivative of Chemical Formula 20 was prepared by introducing a carboxyl ester group using a palladium catalyst, and then reduced to synthesize an aldehyde derivative of Chemical Formula 21. Such methods are generally synthesized by well-known methods.
  • the condensation reaction of the benzoxazole aldehyde derivative of Formula 21 with hydroxylamine for preparing the piperidine-aryl derivative of Formula 1D is the same as the method defined in Scheme 1.
  • R 4 and R 5 are each independently hydrogen, halogen or (C 1 -C 10 ) alkyl; R 1 , R 2 , R 3 , X, Y and n are the same as defined in Formula 1 above.]
  • the first step of preparing a carbonyl derivative of Formula 24 by reacting the thiazole chloride derivative of Formula 22 and the aryl alcohol derivative of Formula 23 under conventional alkylation reaction conditions; And a second step of condensing the carbonyl derivative of Formula 24 prepared with a hydroxylamine derivative of Formula 5 or Formula 6 to produce a piperidine-aryl derivative of Formula 1E.
  • the first step of the present invention is thiazole methyl chloride (1 to 3 equivalents of cesium carbonate, 1 to 3 equivalents of potassium iodide) 22) 1 equivalent is reacted at 90 DEG C in acetonitrile solvent and the reaction time is preferably 2 to 12 hours.
  • the second step of the present invention consists of a second step of preparing the piperidine-aryl derivative of Formula 1E through a condensation reaction of the prepared carbonyl derivative of Formula 24 with hydroxylamine of Formula 5 or Formula 6 .
  • hydroxylamine (Formula 5 or Formula 6) is used in an amount of 2.0 to 10 equivalents, wherein the base used is an inorganic base (for example, sodium acetate, potassium acetate, sodium carbonate, posium carbonate, etc.) or Organic bases (for example triethylamine, diisopropylamine, pyridine, rutidine and the like) can be used, preferably potassium acetate is used.
  • the solvent used at this time uses alcohols, such as methanol, ethanol, and propanol, and when the solubility is low according to a compound, you may mix and use solvents, such as dichloromethane.
  • the reaction temperature is room temperature, and the reaction time is preferably 48 hours.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease associated with GPR119 anti-inflammatory activity comprising the piperidine-aryl derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the disease associated with GPR119 hyperactivity is diabetes or diabetic complications.
  • diabetes is meant a chronic disease characterized by a relative or absolute lack of insulin resulting in glucose-intolerance.
  • Diabetes that is prevented or treated with the compositions of the present invention includes all types of diabetes, including, for example, type 1 diabetes, type 2 diabetes and hereditary diabetes.
  • Type 1 diabetes is insulin dependent diabetes, mainly caused by the destruction of ⁇ -cells
  • type 2 diabetes is insulin independent diabetes, caused by insufficient insulin secretion or insulin resistance after meals.
  • diabetes complication refers to any disease in which diabetes affects its onset, progression or treatment sensitivity, for example obesity, coronary artery disease, ischemic stroke, peripheral vascular disease, intermittent claudication, myocardial infarction, postprandial lipids
  • Hyperglycemia symptoms of impaired glucose tolerance, symptoms of impaired fasting glucose, metabolic acidosis, ketoneosis, arthritis, osteoporosis, hypertension, congestive heart failure, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic nerve Pathology, angina, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, foot ulcers, ulcerative colitis and endocardial insufficiency Including, but not limited to, all diseases known in
  • compositions in the present invention may be prepared by conventional methods in the art, for example, with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like.
  • inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like.
  • Salts formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin Salts with organic acids such as), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid, ethanesulfonic acid And salts with sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, metal salts by reaction with alkali metals such as sodium and potassium, salts with ammonium ions and the like.
  • the pharmaceutical composition of the present invention is added to the piperidine-aryl derivatives represented by the formula (1) or pharmaceutically acceptable salts thereof by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient, etc.
  • Oral preparations such as tablets, capsules, troches, liquids, suspensions or the like for parenteral administration or preparations for parenteral administration, for the treatment of diseases related to the GPR119 anti-inflammatory activity, in particular diabetes or diabetic complications Can be used.
  • Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like.
  • lactose for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, alginate, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
  • the dosage of the piperidine-aryl derivative represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and the weight is 70 kg
  • the weight is 70 kg
  • based on an adult patient is 0.01 mg to 5,000 mg per day, may be divided into once or several times a day at regular intervals according to the judgment of the doctor or pharmacist.
  • Example 1 (E) -t-butyl 4-(((6- (4-(( Methoxyimino ) methyl ) Phenyl) pyridin-3-yl) Oxy Methyl) piperidine-1-carboxylate ((E) -tert-butyl 4-((((6- (4-((methoxyimino) methyl) phenyl) pyridin-3-yl) oxy) methyl) piperidine-1 -carboxylate, Preparation of Compound 1)
  • Example 6 (E) -4 '-((1- ( Cyclohexylsulfonyl Piperidin-4-yl) Methoxy ) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-carbaldehyde oxime ((E) -4'-((1- (cyclohexylsulfonyl) piperidin-4-yl) Preparation of methoxy) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-carbaldehyde oxime, compound 6)
  • Example 7 (E) -2,3 ', 5'- Trifluoro -4 '-((1- (3- Isopropyl -1,2,4- Oxadiazole -5-yl) piperidin-4-yl) methoxy)-[1,1'-biphenyl] -4-carbaldehyde O-ethyl oxime ((E) -2,3 ', 5'-trifluoro- 4 '-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy)-[1,1'-biphenyl] -4-carbaldehyde O-ethyl oxime , Compound 7)
  • Example 8 (Z) -N-((4 '-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) methanamine oxide ((Z) -N-((4'-((1- ( Preparation of 5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) methanamine oxide, compound 55)
  • Example 9 (Z) -N-((4 '-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) propan-2-amine oxide ((Z) -N-((4'-(( 1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) propan-2-amine oxide, compound 56) Produce
  • Example 10 (Z) -N-((4 '-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) -2-methylpropan-2-amine oxide ((Z) -N-((4 '-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -2,3', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene)- 2-methylpropan-2-amine oxide, compound 57) Produce
  • Example 11 (Z) -N-((4 '-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) cyclohexaneamine oxide ((Z) -N-((4'-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) cyclohexanamine oxide, compound 58) Produce
  • Example 12 (Z) -N-((4 '-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -3,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) propan-2-amine oxide ((Z) -N-((4'-(( 1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -3,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) propan-2-amine oxide, compound 59) Produce
  • Example 13 (Z) -N-((2,3 ', 5'-trifluoro-4'-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) pi Ferridin-4-yl) methoxy)-[1,1'-biphenyl] -4-yl) methylene) propan-2-amine oxide ((Z) -N-((2,3 ', 5'- trifluoro-4 '-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy)-[1,1'-biphenyl] -4-yl) methylene) propan-2-amine oxide, compound 60)
  • Example 14 (E) -4- (5-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -3-fluoropyridin-2-yl) -2,6-difluorobenzaldehyde O- methyl Oxime ((E) -4- (5-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -3-fluoropyridin-2-yl) -2,6-difluorobenzaldehyde O-methyl oxime, compound 61)
  • Example 15 ( Z) -N- (4- (5-((1- (t- Butoxycarbonyl Piperidin-4-yl) Methoxy ) -3- Fluoropyridine -2-yl) -3-fluorobenzylidene) methanamine oxide ((Z) -N- (4- (5-((1- (tert-butoxycarbonyl) piperidin-4-yl) methoxy) -3-fluoropyridin -2-yl) -3-fluorobenzylidene) methanamine oxide, compound 62)
  • 6-bromo-5-fluoropyridin-3-ol (1005 mg, 5.23 mmol), t-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (1227 mg, 5.23 mmol) and triphenyl Phosphine (1495 mg, 5.23 mmol) was dissolved in THF (50 mL) and diisopropyl azodicarboxylate (1.3 mL) was added dropwise at room temperature and stirred for 12 hours. The reaction mixture was extracted with ethyl acetate and purified by column chromatography to give the title compound 62-a as a white solid (1821 mg, 89%).
  • Example 16 (Z) -N- (4- (5-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -3-fluoropyridin-2-yl) -3-fluorobenzylidene) methanamine oxide ((Z) -N- (4- (5-((1- (5-ethylpyrimidin-2-yl) piperidin Preparation of -4-yl) methoxy) -3-fluoropyridin-2-yl) -3-fluorobenzylidene) methanamine oxide, compound 63)
  • 6-bromo-5-fluoropyridin-3-ol (504 mg, 2.62 mmol), (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methyl methanesulfonate (988 mg, 3.30 mmol) and cesium carbonate (1280 mg, 3.93 mmol) were added to DMF (10 mL) and then stirred at 90 ° C. for 2 hours. The reaction mixture was added with saturated ammonium chloride solution, extracted with ethyl acetate and separated by column chromatography to obtain the target compound 63-a as a white solid (825 mg, 80%).
  • Example 17 (Z) -N-((4 '-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -3,3 ', 5,5'-tetrafluoro- [1,1'-biphenyl] -4-yl) methylene) propan-2-amine oxide ((Z) -N-((4'- ((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -3,3 ', 5,5'-tetrafluoro- [1,1'-biphenyl] -4-yl) methylene) propan -2-amine oxide, compound 86 of Produce
  • Example 18 (Z) -N-((3,3 ', 5,5'-tetrafluoro-4'-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl ) Piperidin-4-yl) methoxy)-[1,1'-biphenyl] -4-yl) methylene) propan-2-amine oxide ((Z) -N-((3,3 ', 5 , 5'-tetrafluoro-4 '-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy)-[1,1'-biphenyl] -4- Preparation of yl) methylene) propan-2-amine oxide, Compound 94)
  • Example 19 (Z) -N-((4 '-(((1- (t- Butoxycarbonyl Piperidin-4-yl) methyl ) ( methyl ) Amino) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) methanamine oxide ((Z) -N-((4'-((( 1- (tert-butoxycarbonyl) piperidin-4-yl) methyl) (methyl) amino) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) methanamine oxide, compound 139) Manufacturing
  • Example 20 (Z) -N-((4 '-(((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) methyl ) ( methyl ) Amino) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) methanamine oxide ((Z) -N-((4'-((( 1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methyl) (methyl) amino) -2,3 ', 5'-trifluoro- [1,1'-biphenyl] -4-yl) methylene) methanamine oxide, compound 143)
  • Example 21 (Z) -N-((4 '-(((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) methyl ) Amino) -3,3 ', 5,5'-tetrafluoro- [1,1'-biphenyl] -4-yl) methylene) methanamine oxide ((Z) -N-((4'-( ((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methyl) amino) -3,3 ', 5,5'-tetrafluoro- [1,1'-biphenyl] -4-yl) methylene ) methanamine oxide, compound 150)
  • Example 22 (Z) -N-((2- (4-((1- (5-ethylpyrimidin-2-yl) Piperidin-4-yl) Methoxy ) -3,5-difluorophenyl) benzo [d] oxazol-5-yl) methylene) methanamine oxide ((Z) -N-((2- (4-((1- (5-ethylpyrimidin- 2-yl) piperidin-4-yl) methoxy) -3,5-difluorophenyl) benzo [d] oxazol-5-yl) methylene) methanamine oxide, compound 120) Produce
  • reaction mixture was extracted with saturated NaHCO 3 aqueous solution and ethyl acetate, followed by concentration under reduced pressure and the resulting residue was separated and purified by column chromatography to obtain the objective compound 120-c (0.5 g, 42 %).
  • Example 23 (Z) -N- (4- (5- (1- (5-ethylpyrimidin-2-yl) Piperidin-4-yl) Benzo [d] oxazole -2-yl) -3-fluorobenzylidene) methanamine oxide ((Z) -N- (4- (5- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) benzo [d ] oxazol-2-yl) -3-fluorobenzylidene) methanamine oxide, compound 124)
  • Example 24 (Z) -N- (4-((2- (1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) thiazol-4-yl) methoxy) -3-fluorobenzylidene) methanamine oxide ((Z) -N- (4-((2- (1 Preparation of-(5-ethylpyrimidin-2-yl) piperidin-4-yl) thiazol-4-yl) methoxy) -3-fluorobenzylidene) methanamine oxide, compound 167)
  • Example 25 (E) -1- (5- (4-((1- (5- Ethylpyrimidine -2-yl) piperidin-4-yl) Methoxy ) -3,5-Difluorophenyl) -3-fluoropyridin-2-yl) -N-isopropylmethaneimine oxide ((E) -1- (5- (4-((1- (5- Preparation of ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -3,5-difluorophenyl) -3-fluoropyridin-2-yl) -N-isopropylmethanimine oxide, compound 181)
  • Compounds 1 to 180 were prepared by the methods of Examples 1 to 25, and the structures and the 1 H NMR data of the compounds 1 to 182 are shown in Tables 1 to 44.
  • the GPR119 expression vector first extracted total RNA from RNA extract solution (Invitrogen, USA) from Caco-2 cells, synthesized cDNA using cDNA synthesis kit (Bioneer, Korea), and then prepared primer (forward ( forward): GTAAGTGAAGTCCTGCCACTTCG SEQ ID NO: 1, reverse: PCR was performed using TGAAATTCTCTGCCCTTACCG SEQ ID NO: 2) and cloned into pTARGET vector (Promega, USA). To see the effects of GPR119, CRE reporter vector (Promega, USA) and pTARGET GPR119 vector were introduced into CHO-K1 using lipofectamine (Invitogen, USA).
  • C2-C5 clone cells showing good activity against AR231453 among the surviving cells after introduction of the two vectors and screened with 50 ⁇ g / ml G418 (USB, USA) and 200 ⁇ g / ml Hygromycine B (Invitrogen, USA) Obtained.
  • GPR119 agonists were selected using CHO-K1-GPR119-C2-C5 cells (hereinafter referred to as 'clonal cells') and EC 50 of the agonists was obtained.
  • Clonal cells were maintained in RPMI (Giboco, USA), 10% FBS (Gibco. USA), penicillin / streptomycin (Gibco. USA) cultures.
  • the method is as follows. First, 30,000 clones / well were put into a 96 well plate, and then cultured for 24 hours. Clonal cells treated with the compounds of the present invention were cultured for 24 hours, and after 6 hours, the medium was discarded, treated with a reproter lysis buffer (Promega, USA), and stored at -70 ° C for 30 minutes. After storage, thawing at room temperature, the activity of the GPR 119 agonist was measured using a luciferase assay kit using a Luminoskan instrument (Luminoskan instrument, Thermo Scientific, USA). The measured value was calculated as the fold value of each of the control cells treated with DMSO only control group was calculated as fold value to calculate the activity of GPR119. EC 50 values were obtained using the Prism 4 (Prism4, GraphPad Inc. USA) program by entering the calculated activity fold values and concentrations.
  • the piperidine-aryl derivatives prepared in the Examples of the present invention have a skeleton that is different from those of the existing compounds, and the abnormal blood glucose level is determined by confirming the anti-inflammatory activity showing an EC 50 value of several ⁇ M or less through GPR119 anti-inflammatory activity experiment. It can be used as an effective pharmaceutical composition for the treatment of diabetes in the visible state.
  • Piperidine-aryl derivatives represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following formulation examples are merely illustrative of the formulation examples containing the piperidine-aryl derivative according to the present invention as an active ingredient, but are not limited thereto.
  • piperidine-aryl derivative represented by Chemical Formula 1 of the present invention is sieved, and then mixed and pressurized with 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate to prepare a conventional tablet. It was made into tablets according to the method.
  • piperidine-aryl derivative represented by Chemical Formula 1 of the present invention was sieved, and then 16.0 mg of lactose and 4.0 mg of starch were mixed.
  • 0.3 mg of polysorbate 80 was dissolved in pure water, then an appropriate amount of this solution was added to the mixture to atomize. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets according to the conventional method for preparing tablets.
  • piperidine-aryl derivative represented by Formula 1 of the present invention was sieved, and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.
  • piperidine-aryl derivative represented by Chemical Formula 1 of the present invention As an active ingredient, 100 mg of piperidine-aryl derivative represented by Chemical Formula 1 of the present invention is contained, and in addition, 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O, and 2974 mg of distilled water are used for the conventional injection. According to the preparation method, an injection was prepared.
  • the present invention provides a piperidine-aryl derivative and a pharmaceutically acceptable salt thereof as a novel compound having a GPR119 anti-tumor activity, and a method for preparing the same.
  • a new antidiabetic agent was provided by confirming the activity of the level of several ⁇ M or less.

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Abstract

La présente invention concerne : un dérivé de pipéridine-aryle ayant une activité agoniste vis-à-vis du récepteur couplé à la protéine G (G-protein-coupled receptor 119 ; GPR119), ou un sel pharmaceutiquement acceptable de celui-ci ; son procédé de préparation ; et une composition pharmaceutique le contenant en tant que principe actif.
PCT/KR2018/002508 2017-02-28 2018-02-28 Dérivé de pipéridine-aryle ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et composition pharmaceutique contenant celui-ci en tant que principe actif WO2018160024A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2009106565A1 (fr) * 2008-02-27 2009-09-03 Biovitrum Ab (Publ) Agonistes du gpr119
KR20090097184A (ko) * 2006-12-06 2009-09-15 스미스클라인 비참 코포레이션 비시클릭 화합물 및 항당뇨병제로서의 용도
WO2012041158A1 (fr) * 2010-09-29 2012-04-05 上海恒瑞医药有限公司 Composé tricyclique, procédé de préparation et utilisation pharmaceutique associés
KR20130139176A (ko) * 2012-06-12 2013-12-20 주식회사 종근당홀딩스 Ｇｐｒ１１９ 활성의 효능제로서의 피페리딘 유도체

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DE10359508B4 (de) * 2003-12-18 2007-07-12 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Verfahren und Vorrichtung zum Magnetronsputtern
US8063071B2 (en) * 2007-10-31 2011-11-22 GlaxoSmithKline, LLC Chemical compounds

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KR20090097184A (ko) * 2006-12-06 2009-09-15 스미스클라인 비참 코포레이션 비시클릭 화합물 및 항당뇨병제로서의 용도
WO2009106565A1 (fr) * 2008-02-27 2009-09-03 Biovitrum Ab (Publ) Agonistes du gpr119
WO2012041158A1 (fr) * 2010-09-29 2012-04-05 上海恒瑞医药有限公司 Composé tricyclique, procédé de préparation et utilisation pharmaceutique associés
KR20130139176A (ko) * 2012-06-12 2013-12-20 주식회사 종근당홀딩스 Ｇｐｒ１１９ 활성의 효능제로서의 피페리딘 유도체

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