WO2012117996A1 - Agoniste de gpr119 - Google Patents

Agoniste de gpr119 Download PDF

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Publication number
WO2012117996A1
WO2012117996A1 PCT/JP2012/054721 JP2012054721W WO2012117996A1 WO 2012117996 A1 WO2012117996 A1 WO 2012117996A1 JP 2012054721 W JP2012054721 W JP 2012054721W WO 2012117996 A1 WO2012117996 A1 WO 2012117996A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
ylmethyl
pyridin
piperidin
methanesulfonylindol
Prior art date
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PCT/JP2012/054721
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English (en)
Japanese (ja)
Inventor
遠藤剛
高橋理恵
金久保紀子
高橋俊弘
國上敏浩
Original Assignee
日本ケミファ株式会社
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Application filed by 日本ケミファ株式会社 filed Critical 日本ケミファ株式会社
Publication of WO2012117996A1 publication Critical patent/WO2012117996A1/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
    • C07D401/14—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 three or more hetero rings
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to GPR119 agonists.
  • Diabetes a lifestyle-related disease
  • Treatment methods for diabetes can be divided into diet therapy, exercise therapy, and drug therapy (insulin injection, oral diabetes drug).
  • Oral diabetes drugs include ⁇ -glucosidase inhibitors (acarbose, voglibose), insulin resistance improvers (pioglitazone hydrochloride), biguanide preparations (metformin hydrochloride), sulfonylurea preparations (glibenclamide, glimepiride), accelerated rapid insulin secretion An agent (mitiglinide calcium hydrate) is commercially available.
  • GPR119 is a G protein-coupled receptor (GPCR) having N-Oleoylanolamide as an endogenous ligand, and has been reported as a receptor that enhances insulin secretion from pancreatic ⁇ cells.
  • GPCR G protein-coupled receptor
  • Patent Document 1 describes the following compound (A) and the like,
  • Patent Document 2 describes the following compound (B) and the like,
  • Patent Document 3 describes the following compound (C) and the like,
  • Patent Document 4 describes the following compound (D) and the like,
  • Patent Document 5 describes the following compound (E) and the like,
  • Patent Document 6 describes the following compound (F) and the like.
  • the compounds of the present invention represented by the following general formula (I) differ from the compounds (A) to (F) in that the carbon atom of a cyclic amine such as a piperidine ring and a pyridyl group are directly bonded. It is also different that indole or the like is bonded to the above-mentioned pyridyl group via A.
  • the present inventors have also studied GPR119 agonist and have applied for a patent (Patent Document 7). Recently, Patent Document 8 has been published internationally.
  • the compounds described in Patent Documents 7 and 8 and the compound represented by the following general formula (I) are bonded to a pyridyl group via A, and the former is a monocycle such as a phenyl group.
  • the latter is different in two-ring heterocycles such as indole.
  • it is important not only to have an action strength of hypoglycemic action but also to be a compound having excellent pharmacokinetic properties such as safety and metabolic stability, but among the known GPR119 agonists Some compounds have poor metabolic stability.
  • Patent Document 9 describes a compound (G) represented by the following formula.
  • Patent Document 9 when the Alzheimer's disease therapeutic drug is produced, the compound G is used as a synthetic intermediate, but there is no description that this compound has a GPR119 agonistic action.
  • An object of the present invention is to provide a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutic agent for diabetes containing these as active ingredients.
  • any one of T 1 , T 2 , T 3, and T 4 is N, and the remaining 3 represent the same or different CR 5 , or all four represent the same or different CR 5 ,
  • R 5 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a C 1-8 alkyl group, a C 1-8 alkoxy group, or a C 1-8 substituted with 1 to 3 halogen atoms.
  • alkyl group a C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, a phenyloxy group, an alkoxycarbonyl group (alkoxy has 1 to 8 carbon atoms), a carboxyl group, a carbamoyl group, an acyl group (an alkyl group) 1-8), alkylaminocarbonyl group (alkyl having 1-8 carbon atoms), dialkylaminocarbonyl group (alkyl having 2-12 carbon atoms), alkoxycarbonylmethylcarbonyl group (alkoxy having 1 carbon atom) To 8), alkylsulfonylmethyl group (the alkyl has 1 to 8 carbon atoms), amino group, C 1-8 alkylamino group, C 2-12 dial Killamino group, C 1-8 alkylsulfonylamino group, acylamino group (the alkyl has 1 to 8 carbon atoms), C 1-8 alkylsulfinyl group, C 1
  • X and Y are the same or different and are a halogen atom, a hydroxyl group, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group substituted with 1 to 3 halogen atoms, and 1 to 3 Represents an alkylene having 1 to 3 carbon atoms which may be substituted with a substituent selected from a C 1-8 alkoxy group substituted with a halogen atom of Z represents C (O) OR 6 , C (O) R 7 , C (O) SR 8 , C (O) NHR 9 , or a halogen atom, a C 1-8 alkyl group, a C 2-8 alkenyl group , C 1-8 alkoxy groups, one to three substituents selected from C 1-8 alkoxy group substituted with substituted C 1-8 alkyl group and 1 to 3 halogen atoms by a halogen atom
  • a 5- or 6-membered heteroaryl group which
  • R 1 and R 2 are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a C 1-8 alkyl group, a C 1-8 alkoxy group, or a C 1-8 substituted with 1 to 3 halogen atoms. It represents an alkyl group or a C 1-8 alkoxy group substituted with 1 to 3 halogen atoms.
  • the present invention also relates to a therapeutic agent for diabetes containing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, this invention relates to the GPR119 agonist which contains the compound represented by the said general formula (I), or its pharmaceutically acceptable salt as an active ingredient.
  • T 1, T 2, T 3 any one of CR 5 and of T 4 C- (1- tetrazolyl) or C-(1,2,4-triazol-1-yl)
  • the above formula is (I) Or a compound of the above (1) or a pharmaceutically acceptable salt thereof.
  • Any one of CR 5 of T 1 , T 2 , T 3 and T 4 is C- (1-tetrazolyl) or C- (1,2,4-triazol-1-yl) and the remaining CR 5 is CH , C- (C 1-8 alkyl) or C- (halogeno), a compound represented by the above general formula (I), a compound described in (1) above, or a pharmaceutically acceptable salt thereof Salt.
  • (11) A compound represented by the above general formula (I), wherein Z is C (O) OR 6 , a compound described in the above (1) to (10), or a pharmaceutically acceptable salt thereof.
  • R 6 is C 1-8 alkyl, or a pharmaceutically acceptable salt thereof.
  • Z is a halogen atom, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms.
  • Z is a halogen atom, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms.
  • a compound represented by the above general formula (I) which is a pyrimidinyl group optionally having a substituent selected from a C 1-8 alkoxy group substituted by an atom, or the above (1) to (10) Or a pharmaceutically acceptable salt thereof.
  • examples of the halogen atom include a fluorine atom, a chlorine atom or a bromine atom
  • examples of the C 1-8 alkyl group include a methyl group, an ethyl group, a propyl group, i -Propyl group, butyl group, t-butyl group, pentyl group, neopentyl group, hexyl group and the like.
  • Examples of the C 3-8 cycloalkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.
  • Examples of the C 1-8 alkoxy group include a methoxy group, an ethoxy group, and a propoxy group.
  • Examples of the C 1-8 alkyl group substituted with 1 to 3 halogen atoms include a chloromethyl group, a fluoromethyl group, and a fluoromethyl group.
  • a C 1-8 alkoxy group substituted with 1 to 3 halogen atoms includes a fluoromethoxy group or a trifluoromethoxy group.
  • examples of the alkoxycarbonyl group include a methoxycarbonyl group or an ethoxycarbonyl group
  • examples of the acyl group (alkyl has 1 to 8 carbon atoms) include an acetyl group.
  • examples of the alkylaminocarbonyl group include a methylaminocarbonyl group and an ethylaminocarbonyl group.
  • the dialkylaminocarbonyl group (the alkyl has 2 to 12 carbon atoms) includes Examples thereof include a dimethylaminocarbonyl group and a diethylaminocarbonyl group.
  • alkoxycarbonylmethylcarbonyl group examples include a methoxycarbonylmethylcarbonyl group and an ethoxycarbonylmethylcarbonyl group.
  • alkylsulfonylmethyl group examples include a methanesulfonylmethyl group and an ethanesulfonylmethyl group.
  • a C 1-8 alkylamino group includes a methylamino group and an ethylamino group.
  • Examples of the C 2-12 dialkylamino group examples include a dimethylamino group and a diethylamino group.
  • Examples of the C 1-8 alkylsulfonylamino group include a methanesulfonylamino group and an ethanesulfonylamino group.
  • Examples of the acylamino group include an acetylamino group.
  • As the C 1-8 alkylsulfinyl group and the like methylsulfinyl group or ethylsulfinyl group.
  • Examples of the C 1-8 alkylsulfonyl group such as a methanesulfonyl group or an ethanesulfonyl group and the like, C 1-8 Examples of the alkylaminosulfonyl group include a methylaminosulfonyl group and an ethylaminosulfonyl group. Examples of the C 2-12 dialkylaminosulfonyl group include a dimethylaminosulfonyl group and a diethylaminosulfonyl group. Examples of the C 1-8 alkyl group substituted with a phenyl group include a benzyl group. Examples of the C 2-8 alkenyl group include a vinyl group and a propenyl group.
  • Examples of bicyclic heterocycles consisting of T 1 to T 4 and a 6-membered ring composed of 2 carbon atoms and a 5-membered ring containing nitrogen include indole, indoline, pyrrolo [2,3-b] pyridine and the like. It is done.
  • examples of the heteroaryl group represented by R 5 include a 1,2,4-triazolyl group and a tetrazolyl group.
  • a 5- or 6-membered heteroaryl group of Z (the heteroaryl ring has a carbon atom and a nitrogen atom as ring-constituting atoms, and further an oxygen atom or sulfur
  • the group which may have an atom and are bonded to the nitrogen atom of the cyclic amine via a carbon atom constituting the ring
  • pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloride and sulfate, or organic acids such as fumarate and mesylate. Salt.
  • the compound represented by the general formula (I) includes a racemate and an optically active substance.
  • the compound represented by the general formula (I) includes these hydrates and solvates.
  • Halo represents a halogen atom such as chlorine, bromine or iodine
  • L represents a halogen atom such as chlorine, bromine or iodine, or a leaving group such as a methanesulfonyloxy group or p-toluenesulfonyloxy group.
  • R 1 , R 2 , R 3 , R 4 , T 1 , T 2 , T 3 , T 4 and Z are the same as above.
  • the starting material (a) can be synthesized by a known method (such as M.V.Cheliah et.al., J. Med. Chem., 2007, 50, 5147), or a method analogous thereto.
  • the starting material (b) can be synthesized by a known method (G. Shyamali et.al., Can. J. Chem., 2006, 84, 555, WO2007081995, etc.) and a method according thereto. 2) Conversion of the compound of the general formula (c) by reaction of the starting material (a) with the starting material (b) in the first step is a solvent that does not participate in the reaction such as toluene, tetrahydrofuran, dioxane, N, N-dimethylformamide, etc.
  • Second Step The conversion of the compound of the general formula (c) into the compound of the general formula (d) is a method in which catalytic hydrogenation is carried out using palladium-carbon or the like as a catalyst in a solvent not involved in the reaction such as methanol and ethanol.
  • Step 3 Conversion of the compound of the general formula (d) to the compound of the general formula (e) is performed in the presence or absence of a base such as pyridine or triethylamine in a solvent such as toluene or dichloromethane. , Methanesulfonyl chloride, p-toluenesulfonyl chloride, thionyl chloride and the like can be reacted.
  • Step 4 Conversion of the compound of the general formula (e) to the compound of the general formula (g) is carried out by using potassium hydroxide, hydrogenation in a solvent such as toluene, N, N-dimethylformamide, acetone, etc.
  • the reaction can be carried out by reacting the compound of general formula (f) in the presence of a base such as sodium or potassium carbonate, in the presence or absence of an additive such as crown ether.
  • a base such as sodium or potassium carbonate
  • an additive such as crown ether.
  • the reaction temperature is from room temperature to 130 ° C.
  • the compound represented by general formula (g) can be manufactured also by the following B method. ⁇ Method B>
  • Halo represents a halogen atom such as chlorine, bromine or iodine
  • L represents a halogen atom such as chlorine, bromine or iodine, or a leaving group such as a methanesulfonyloxy group or p-toluenesulfonyloxy group.
  • R 1 , R 2 , R 3 , R 4 , T 1 , T 2 , T 3 , T 4 and Z are the same as above.
  • Step 2 Conversion of the compound of the general formula (h) to the compound of the general formula (i) can be carried out in the same manner as described in the method A above.
  • Step 3 Conversion of the compound of the general formula (i) to the compound of the general formula (j) can be performed in the same manner as described in the method A.
  • Step 4 Conversion of the compound of the general formula (j) to the compound of the general formula (g) can be performed in the same manner as described in the above-mentioned method A.
  • the compound represented by the general formula (I) can also be produced with reference to the above production method, examples described later, and the above-mentioned patent documents 1 to 9.
  • the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is expected as a therapeutic agent for diabetes because it has a GPR119 agonistic action and a blood glucose lowering action, and is further used for life such as obesity and metabolic syndrome. Adaptation to habitual diseases is also expected.
  • the compounds of the present invention the following compounds have excellent blood glucose lowering activity and excellent metabolic stability.
  • lactose, D-mannitol, crystalline cellulose, glucose and the like are used, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca) and the like, as the lubricant, magnesium stearate,
  • binders include talc and the like, hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.
  • Solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives and the like are used for the preparation of injections.
  • the compound of the above general formula (I), which is an active ingredient in an injection, or a pharmaceutically acceptable salt thereof is about 0.01 mg to 100 mg per day, orally 1 mg per day. It can be increased or decreased depending on age, symptoms, etc.
  • the mixture was stirred at room temperature for 1 hour, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 65 4- [2- [7-Fluoro-5- (tetrazol-1-yl) indol-1-ylmethyl] -3-methylpyridin-5-yl] piperidine-1-carboxylate
  • the title compound (28 mg, 82% yield) was obtained as a brown amorphous substance in the same manner as in Example 1.
  • IR (KBr, cm ⁇ 1 ): 2933, 2854, 1604, 1545, 1500, 1454, 1410, 1362, 1335, 1306, 1252, 1169, 1092, 1022, 972, 949, 876, 793, 768, 727, 658 613.
  • IR (KBr, cm ⁇ 1 ): 3153, 3051, 2924, 2848, 1579, 1529, 1504, 1415, 1360, 1306, 1242, 1211, 1161, 1126, 1093, 1016, 972, 951, 879, 848, 783 , 760, 725, 646, 613, 559, 511.
  • IR (KBr, cm ⁇ 1 ): 3116, 3001, 2933, 2908, 2860, 1734, 1614, 1529, 1471, 1414, 1365, 1329, 1307, 1242, 1223, 1165, 1130, 1093, 1024, 972, 891 , 849, 796, 756, 727, 688, 609, 582, 536, 482.
  • Example 88 and Example 102 were found to have an excellent hypoglycemic effect.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur un composé représenté par la formule générale (I), ledit composé étant un agoniste de GPR119, ou un sel de celui-ci qui est utilisable comme médicament antidiabétique. Dans la formule générale (I) : l'un de T1, T2, T3 et T4 représente N et les trois autres représentent CR5 ou T1, T2, T3 et T4 représentent tous CR5 ; R5 représente H, un atome d'halogène, un groupe alkyle en C1-8, un groupe alkylsulfonyle en C1-8, un groupe hétéroaryle à 5 ou 6 chaînons ou similaire ; R3 et R4 représentent chacun H ou un groupe alkyle en C1-8 ; --- représente une liaison simple ou une double liaison ; A représente (CH2)m ou similaire ; X et Y représentent chacun un groupe alkylène en C1-3 éventuellement substitué ; Z représente C(O)OR6, un groupe hétéroaryle à 5 ou 6 chaînons éventuellement substitué ou similaire ; et R1 et R2 représentent chacun H, un atome d'halogène ou similaire.
PCT/JP2012/054721 2011-02-28 2012-02-27 Agoniste de gpr119 WO2012117996A1 (fr)

Applications Claiming Priority (2)

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JP2011041386A JP2014094886A (ja) 2011-02-28 2011-02-28 Ｇｐｒ１１９作動薬
JP2011-041386 2011-02-28

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JP2017505808A (ja) * 2014-01-06 2017-02-23 ライゼン・ファーマシューティカルズ・エスアー 新規グルタミナーゼ阻害剤
US11143547B2 (en) 2018-04-11 2021-10-12 Exo Imaging, Inc. Asymmetrical ultrasound transducer array
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11313717B2 (en) 2018-04-11 2022-04-26 Exo Imaging, Inc. Imaging devices having piezoelectric transceivers
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11794209B2 (en) 2019-09-12 2023-10-24 Exo Imaging, Inc. Increased MUT coupling efficiency and bandwidth via edge groove, virtual pivots, and free boundaries
US11819881B2 (en) 2021-03-31 2023-11-21 Exo Imaging, Inc. Imaging devices having piezoelectric transceivers with harmonic characteristics
US11951512B2 (en) 2021-03-31 2024-04-09 Exo Imaging, Inc. Imaging devices having piezoelectric transceivers with harmonic characteristics
US11986350B2 (en) 2016-12-04 2024-05-21 Exo Imaging, Inc. Imaging devices having piezoelectric transducers
US11998950B2 (en) 2020-09-11 2024-06-04 Exo Imaging, Inc. Increased MUT coupling efficiency and bandwidth via edge groove, virtual pivots, and free boundaries

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WO2011093501A1 (fr) * 2010-02-01 2011-08-04 日本ケミファ株式会社 Agoniste du gpr119

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