WO2011078306A1 - Agoniste de gpr119 - Google Patents

Agoniste de gpr119 Download PDF

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Publication number
WO2011078306A1
WO2011078306A1 PCT/JP2010/073280 JP2010073280W WO2011078306A1 WO 2011078306 A1 WO2011078306 A1 WO 2011078306A1 JP 2010073280 W JP2010073280 W JP 2010073280W WO 2011078306 A1 WO2011078306 A1 WO 2011078306A1
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group
alkyl
acceptable salt
pharmaceutically acceptable
compound according
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PCT/JP2010/073280
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English (en)
Japanese (ja)
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遠藤剛
齊藤大祐
國上敏浩
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日本ケミファ株式会社
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Publication of WO2011078306A1 publication Critical patent/WO2011078306A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • 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

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
  • GPR119 agonists have been found to increase the plasma concentration of Glucagon like peptide-1 (GLP-1), which is one of the incretins, in the action in vivo (Non-patent document 1).
  • 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.
  • the compounds of the present invention represented by the following general formula (I), (II) or (III) and the above-mentioned compounds (A), (B) and (C) are clearly different in structure. That is, in the compound (A), an azabicyclo ring is bonded to a nitrogen atom of a 5-membered triazole ring, whereas in the compound of the present invention, an azabicyclo ring is bonded to a carbon atom such as a 6-membered pyridine ring. is doing.
  • an azabicyclo ring and a pyrimidine ring are bonded through an oxygen atom in the middle, whereas in the compound of the present invention, an azabicyclo ring and a pyridine ring are directly bonded.
  • a piperidine ring and a 5-membered thiazole ring are bonded, whereas in the compound of the present invention, an azabicyclo ring and a 6-membered pyridine ring are bonded.
  • Patent Document 4 It is described in Patent Document 4 that a compound represented by is useful as a GPR119 agonist. However, there is no specific description regarding the compound in which the pyridine ring and the azabicyclo ring are bonded in the compound of the present invention.
  • Patent Document 5 describes the following compound (D) in which an azabicyclo ring is bonded to a carbon atom of a pyridine ring.
  • the compound (D) is different from the compound of the present invention in the AB portion of the compound (I) of the present invention, and in Patent Document 4, the compound (D) is a synthetic intermediate of a renin inhibitor. However, there is no description that it has a GPR119 agonistic action.
  • An object of the present invention is to provide a compound represented by the following general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, and a therapeutic agent for diabetes containing these as active ingredients. is there.
  • the present invention relates to a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
  • Ar is a halogen atom, a nitro group, a cyano group, 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, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, phenyloxy group, alkoxycarbonyl group (alkoxy has 1 to 8 carbon atoms), carboxyl group, carbamoyl group, acyl group (alkyl carbon number is 1-8), alkylaminocarbonyl group (alkyl has 1 to 8 carbon atoms), dialkylaminocarbonyl group (alkyl has 2 to 12 carbon atoms), alkoxycarbonylmethylcarbonyl group (alkoxy has 1 to 8 carbon atoms) , alkylsulfonyl methyl group (the carbon number of alkyl is 1 to 8), an amino group, C 1-8 alkylamino
  • A is S, O or NR 6
  • B is not S, O or NR 8 .
  • One of U and V is N and the other is CR 9 or U and V are both N;
  • R 9 is a hydrogen atom, 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, or 1 to 3
  • R 9 represents a C 1-8 alkoxy group substituted with one halogen atom
  • R 1 and R 2 are the same or different and are a hydrogen atom, 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.
  • R 3 represents a hydrogen atom, a hydroxyl group, a halogen atom or a C 1-8 alkyl group
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1-8 alkyl group or a 3- to 6-membered cycloalkyl group
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are the same or different and represent (CR 10 R 11 ) p or a bond
  • R 10 and R 11 represent a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-8 alkyl group, a C 1-8 alkoxy group, or a 3- to 6-membered cycloalkyl group
  • p represents 1 or 2
  • Y is a single bond, a double bond
  • C NOR 12
  • C C (R 13 )
  • R 12 , R 13 , R 14 , R 15 , R 16 and R 17 represent a hydrogen atom, a C 1-8 alkyl group or a 3-6 membered cycloalkyl group, q represents an integer of 0-2.
  • X 5 or X 6 is a bond
  • Y is not a double bond
  • X 5 and X 6 represent (CR 10 R 11 ) p .
  • Z represents C (O) OR 18 , C (O) R 19 , SO 2 R 20 , C (O) NR 21 R 22 or CH 2 C (O) N (R 23 ) (R 24 ) Or 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 a C 1 substituted with 1 to 3 halogen atoms
  • R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are C 1-8 alkyl, C 2-8 alkeny
  • any one of T 1 , T 2 , T 3 and T 4 represents C (R 25 ) or N, and the rest represents C (R 26 ).
  • R 25 and R 26 are 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 substituted with 1 to 3 halogen atoms.
  • alkyl group C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, phenyloxy group, alkoxycarbonyl group (alkoxy has 1 to 8 carbon atoms), carboxyl group, carbamoyl group, acyl group ( Alkyl has 1 to 8 carbon atoms, alkylaminocarbonyl group (alkyl has 1 to 8 carbon atoms), dialkylaminocarbonyl group (alkyl has 2 to 12 carbon atoms), alkoxycarbonylmethylcarbonyl group (alkoxy has carbon atoms) 1 to 8), an alkylsulfonyl radical (1-8 carbon atoms in the alkyl), amino group, C 1-8 alkylamino group, C 2 12 dialkylamino group, C 1-8 alkylsulfonylamino group, an acylamino group (1-8 carbon atoms in the alkyl), C 1-8 alkylsulfinyl group, C 1-8 alkylsulfin
  • a 01 is CH 2 or a bond
  • B 01 is not S, O, or NR 28 .
  • Either one of U 01 and V 01 is N and the other is CR 29 or U 01 and V 01 are both N;
  • R 29 is a hydrogen atom, 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, or 1 to 3
  • R 01 and R 02 are a hydrogen atom, 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, or 1 to 3 Represents a C 1-8 alkoxy group substituted with one halogen atom
  • Z 01 represents C (O) OR 30 ,
  • a 5- or 6-membered heteroaryl group optionally having a substituent selected from 8 alkoxy groups (the heteroaryl ring has a carbon atom and a nitrogen atom as ring-constituting atoms, and further an oxygen atom or a sulfur atom And may be bonded to the nitrogen atom of the azabicyclo ring through the carbon atoms constituting the ring),
  • R 30 , R 31 , R 32 , R 33 , R 34 , R 35 and R 36 are C 1-8 alkyl, C 2-8 alkenyl group, 3-6 membered cycloalkyl group, phenyl group or Represents a C 1-8 alkyl group substituted with a phenyl group, T represents 1 or 2.
  • the present invention also relates to a compound represented by the following general formula (III) or a pharmaceutically acceptable salt thereof.
  • R 07 , R 08 and R 09 are the same or different and each represents 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, 1 to 3 C 1-8 alkyl group substituted with a halogen atom, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, phenyloxy group, alkoxycarbonyl group (alkoxy has 1 to 8 carbon atoms), carboxyl Group, carbamoyl group, acyl group (alkyl has 1 to 8 carbon atoms), alkylaminocarbonyl group (alkyl has 1 to 8 carbon atoms), dialkylaminocarbonyl group (alkyl has 2 to 12 carbon atoms), alkoxycarbonyl methylcarbonyl group (number of carbon atoms in the alkoxy 1-8) alkylsulfonyl radical (1-8 carbon
  • a 02 is O, S or NR 38
  • B 02 is not O, S or NR 40 .
  • Any one of U 02 and V 02 is N and the other is CR 41 or U 0 and V 0 are both N;
  • R 41 is a hydrogen atom, 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, or 1 to 3
  • R 41 is a hydrogen atom, 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, or 1 to 3
  • Z 02 represents C (O) OR
  • a 5- or 6-membered heteroaryl group optionally having a substituent selected from 8 alkoxy groups (the heteroaryl ring has a carbon atom and a nitrogen atom as ring-constituting atoms, and further an oxygen atom or a sulfur atom And may be bonded to the nitrogen atom of the azabicyclo ring via a carbon atom constituting the ring),
  • R 42 , R 43 , R 44 , R 45 , R 46 , R 47 and R 48 are C 1-8 alkyl, C 2-8 alkenyl, 3- to 6-membered cycloalkyl, phenyl or Represents a C 1-8 alkyl group substituted with a phenyl group, And w represents 1 or 2.
  • the present invention also relates to a therapeutic agent for diabetes containing the compound represented by the above general formula (I), (II) or (III), 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), (II) or (III), or its pharmaceutically acceptable salt as an active ingredient.
  • At least one of the substituents of Ar is a cyano group, an alkoxycarbonyl group (the alkoxy has 1 to 8 carbon atoms), a C 1-8 alkylsulfonyl group, a 3- to 6-membered cycloalkylsulfonyl group, a sulfamoyl group, a phenylsulfonyl group And a phenyl group, a pyridyl group, an indolyl group, an indolinyl group or a pyrrolopyridyl group substituted with 1 to 3 identical or different substituents selected from 5- or 6-membered heteroaryl groups.
  • Ar is a cyano group, an alkoxycarbonyl group (the alkoxy has 1 to 8 carbon atoms), a C 1-8 alkylsulfonyl group, a 3- to 6-membered cycloalkylsulfonyl group, a sulfamoyl group, a phenylsulfonyl group, and a 5- or 6-membered ring.
  • at least one of the substituents of Ar is a phenyl group, pyridyl group, indolyl group, indolinyl group or pyrrolopyridyl group substituted with 1 to 3 identical or different substituents which are C 1-8 alkylsulfonyl groups.
  • I) or a pharmaceutically acceptable salt thereof thereof.
  • Ar is C 1-8 alkylsulfonyl group and a C 1-8 alkyl group or any one of the two is substituted with a substituent a phenyl group substituents of a halogen atom, a pyridyl group, an indolyl group, indolinyl group or pyrrolopyridyl group A compound represented by the above general formula (I), or a pharmaceutically acceptable salt thereof.
  • the compound represented by the said general formula (I) which is a group, an indolyl group, an indolinyl group or a pyrrolopyridyl group, or a pharmaceutically acceptable salt thereof.
  • (22) Z is a 3-C 1-8 alkyl-1,2,4-oxadiazol-5-yl group, a 5-C 1-8 alkyl-1,2,4-oxadiazol-3-yl group or 5-
  • a compound represented by the above general formula (I) which is a C 1-8 alkylpyrimidin-2-yl group, a compound described in the above (1) to (19), or a pharmaceutically acceptable salt thereof.
  • (23) Compounds represented by the above general formula (I), wherein either one of R 1 and R 2 is a hydrogen atom and the other is a hydrogen atom, C 1-8 alkyl or halogen atom, or the above (1) to (22) Or a pharmaceutically acceptable salt thereof.
  • R 25 and R 26 are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a C 1-8 alkyl group, an alkoxycarbonyl group (alkoxy has 1 to 8 carbon atoms), a C 1-8 alkylsulfonyl group, 3 to 6
  • Any one of T 1 , T 2 , T 3 and T 4 is C (1-tetrazolyl group) or C (1,2,4-triazol-1-yl group).
  • T 1 , T 2 , T 3 and T 4 is C (1-tetrazolyl group) or C (1,2,4-triazol-1-yl group), and any one of the remaining is C ( C 1-8 alkyl group) or C (halogen atom) represented by the above general formula (II), or a pharmaceutically acceptable salt thereof.
  • Z 01 is a 3-C 1-8 alkyl-1,2,4-oxadiazol-5-yl group, a 5-C 1-8 alkyl-1,2,4-oxadiazol-3-yl group, or 5
  • a compound represented by the above general formula (II) which is a —C 1-8 alkylpyrimidin-2-yl group, a compound described in the above (24) to (32), or a pharmaceutically acceptable salt thereof.
  • R 07 , R 08 and R 09 are the same or different, a hydrogen atom, a halogen atom, a cyano group, a C 1-8 alkyl group, an alkoxycarbonyl group (the alkoxy has 1 to 8 carbon atoms), a C 1-8 alkylsulfonyl group,
  • Any one of R 07 , R 08 and R 09 is a C 1-8 alkylsulfonyl group, and the remaining one is a C 1-8 alkyl group or a halogen atom, and is represented by the above general formula (III) A compound, or a pharmaceutically acceptable salt thereof.
  • Any one of R 07 , R 08 and R 09 is a 1-tetrazolyl group or a 1,2,4-triazol-1-yl group, and any one of the remaining is a C 1-8 alkyl group or a halogen atom
  • examples of the halogen atom include a fluorine atom, a chlorine atom or a bromine atom
  • the C 1-8 alkyl group includes a methyl group.
  • 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 methanesulfonyl group or ethanesulfonyl group, and 3-6 membered
  • Examples of the cycloalkylsulfonyl group in the ring include a cyclopropylsulfonyl group and a cyclohexylsulfonyl group.
  • Examples of the C 1-8 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 the 3- to 6-membered cycloalkyl group include a cyclopropyl group and a cyclohexyl group.
  • a compound represented by the above general formula (I) a substituent which the phenyl group, pyridyl group, indolyl group, indolinyl group or pyrrolopyridyl group of Ar may have, a compound represented by the above general formula (II) R 25 , R 26 and R 07 , R 08 , R 09 of the compound represented by the above general formula (III) as the 5- or 6-membered heteroaryl group include a 1-tetrazolyl group or 1,2,4 -Triazol-1-yl group and the like.
  • the 5- or 6-membered heteroaryl group of Z, Z 01 and Z 02 is a halogen atom such as a fluorine atom, a C 1-8 alkyl group such as a methyl group, an ethyl group, a propyl group or an i-propyl group, a cyclo Having a substituent such as a C 1-8 alkyl group substituted with 1 to 3 halogen atoms such as a cycloalkyl group having 3 to 7 members such as a propyl group, a cyclopentyl group or a cyclohexyl group, and a trifluoromethyl group; May be.
  • a halogen atom such as a fluorine atom
  • a C 1-8 alkyl group such as a methyl group, an ethyl group, a propyl group or an i-propyl group
  • a cyclo Having a substituent such as a C 1-8 alkyl
  • the phenyl group, pyridyl group, indolyl group, indolinyl group, or pyrrolopyridyl group of Ar may have 1 to 3 substituents.
  • the azabicyclo ring includes 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, 2-azabicyclo [2. 2.1] heptane and 3-oxa-9-azabicyclo [3.3.1] nonane are preferred.
  • pharmaceutically acceptable salts include hydrochlorides, salts with inorganic acids such as sulfates, fumarate, mesyl And salts with organic acids such as acid salts.
  • the compound represented by the general formula (I), (II) or (III) includes a racemate and an optically active substance.
  • the compound represented by the general formula (I), (II) or (III) includes these hydrates and solvates.
  • a 01 is CH 2 and B 01 is a bond manufacturing method, but other similar compounds can be manufactured by the same method.
  • 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 01 , R 02 , R 03 , R 04 , T 1 , T 2 , T 3 , T 4 , U 01 , V 01 , Z 01 , and t 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.
  • 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)
  • the reaction of the starting material (a) and the starting material (b) in the first step is carried out in a solvent not involved in the reaction such as toluene, tetrahydrofuran, dioxane, N, N-dimethylformamide, potassium carbonate, cesium carbonate, sodium carbonate, etc.
  • Step 2 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 performed using palladium-carbon or the like as a catalyst in a solvent such as methanol or ethanol that does not participate in the reaction. It can be carried out.
  • 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 01 , R 02 , R 03 , R 04 , T 1 , T 2 , T 3 , T 4 , U 01 , V 01 , Z 01 , and t are the same as above
  • 1) First Step Conversion of the starting material (a) into the compound of the general formula (h) can be carried out in the same manner as described in the above Method A.
  • Step 2 Conversion of the compound of the general formula (h) to the compound of the general formula (i) can be performed in the same manner as described in the above-mentioned method A.
  • 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.
  • Fourth Step The conversion of the compound of the general formula (j) into the compound of the general formula (g) can be performed in the same manner as described in the method A.
  • the manufacturing method of the compound represented by the said general formula (III) or its pharmacologically acceptable salt is shown below. In the following, a production method in which A 02 is O and B 02 is CH 2 is exemplified, but other similar compounds can be produced by the same method.
  • the starting material (k) can be synthesized in the same manner as described in the above method A.
  • Step 1 Conversion of the compound of the general formula (k) into the compound of the general formula (m) can be carried out in a solvent that does not participate in the reaction such as tetrahydrofuran, dioxane, toluene, and the like, such as diethyl azodicarboxylate, diisopropyl azodicarboxylate
  • the reaction can be carried out by reacting the azodicarboxylic acid ester with the phenol represented by the general formula (1) or heteroaryl alcohol in the presence of triphenylphosphine or the like. In this case, the reaction temperature is 0 ° C. to 80 ° C.
  • the conversion of the compound of the general formula (k) into the compound of the general formula (m) can also be performed by the following method D. ⁇ Method D>
  • L represents a halogen atom such as chlorine, bromine and iodine, or a leaving group such as a methanesulfonyloxy group and a p-toluenesulfonyloxy group, and R 05 , R 06 , R 07 , R 08 , R 09 , Q, U 02 , V 02 , Z 02 , and w are the same as above.
  • 1) First Step Conversion of the compound of general formula (k) to the compound of general formula (n) can be carried out in the same manner as described in the above-mentioned method A.
  • Step 2 Conversion of the compound of the general formula (n) to the compound of the general formula (m) can be carried out by using sodium hydride, potassium carbonate, etc. in a solvent not involved in the reaction such as N, N-dimethylformamide, acetone, etc.
  • the reaction can be carried out by reacting the phenol represented by the general formula (l) and a heteroaryl alcohol.
  • the reaction temperature is 0 ° C. to 80 ° C.
  • the compound represented by general formula (m) can be manufactured also by the following E method. ⁇ Method E>
  • 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. represents, R 05, R 06, R 07, R 08, R 09, Q, U 02, V 02, Z 02, and w are as defined above.
  • the starting material (o) can be synthesized in the same manner as described in the above method A.
  • the conversion of the starting material (o) of the first step into the compound of the general formula (p) can be carried out in the same manner as described in the method D above.
  • R 42 , R 43 , R 44 , R 45 , R 46 , A, B, U, V, Q and R 41 are as described in Tables 1 to 3.
  • the GPR119 agonistic effect was examined by measuring the effect of increasing the intracellular cAMP level of the test compound in cells into which human GPR119 was introduced.
  • the test method is shown below.
  • (1) Construction of human GPR119 constant expression cells The human GPR119 gene (NM_178471) was purchased from ATCC (ATCC No. 10807349), and PCR amplification was performed so that a BamHI site was formed on the 5 ′ side and an Apa I site was formed on the 3 ′ side.
  • PCR conditions are as follows. Single-stranded DNA in which double-stranded DNA was heat denatured at 98 ° C. for 10 seconds per cycle using DNA polymerase (KOD-Plus-Ver.2; TOYOBO # KOD-211) and primer was denatured at 55 ° C. for 30 seconds. followeded by DNA elongation at 68 ° C. for 1 minute 15 seconds. This was repeated for 35 cycles.
  • the PCR product was inserted as an insert into plasmid pcDNA5 / FRT / TO (Invitrogen # V6520-20), and the resulting plasmid was introduced into Flp-in T-Rex-293 cells (invitrogen # R78007).
  • the introduction method was performed according to the product protocol.
  • the amount of intracellular cAMP was measured using a commercially available kit (HitHunter TM cAMP XS + Assay (GE Healthcare # 90007503)) and a measuring machine (FLUOstar Optima: BMG LABTECH).
  • the test compound was dissolved in 100% DMSO and added at a final concentration of 1%.
  • the compound represented by the above general formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof has a GPR119 agonistic action and a blood glucose lowering action, it is used as a therapeutic agent for diabetes. It is also expected to be applied to lifestyle-related diseases such as obesity and metabolic syndrome.
  • the compound represented by the above general formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof can also be used in combination with a known therapeutic agent for diabetes.
  • the compound represented by the above general formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof is administered to a human by an appropriate administration method such as oral administration or parenteral administration. can do. It can also be used in combination with other therapeutic agents for diabetes.
  • a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like by a conventional method in the technical field of formulation.
  • usual excipients, disintegrants, binders, lubricants, pigments and the like are used.
  • 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 represented by the above general formula (I), (II) or (III), which is an active ingredient in an injection, or a pharmaceutically acceptable salt thereof is about 0. 01 mg to 100 mg, orally 1 mg to 2000 mg per day, but may be increased or decreased depending on age, symptoms, etc.
  • Pharmacological experiment 1 (1) Construction of human GPR119 constant expression cell
  • the human GPR119 gene (NM_178471) was purchased from ATCC (ATCC No. 10807349), and PCR amplification was performed so that a BamHI site was formed on the 5 ′ side and an ApaI site was formed on the 3 ′ side.
  • PCR conditions are as follows. Single-stranded DNA in which double-stranded DNA was heat denatured at 98 ° C.
  • the amount of intracellular cAMP was measured using a commercially available kit (HitHunter TM cAMP XS + Assay (GE Healthcare # 90007503)) and a measuring machine (FLUOstar Optima: BMG LABTECH).
  • the test compound was dissolved in 100% DMSO and added at a final concentration of 1%.

Abstract

La présente invention concerne un composé représenté par la formule générale (I), qui est un agoniste de GPR119, ou un sel de celui-ci qui est utilisé en tant que médicament antidiabétique. Dans la formule générale (I), Ar représente un groupe phényle, un groupe pyridyle, etc. ; A représente O, une liaison, etc. ; B représente (C(R7)H)n, une liaison, etc. ; l'un de U et V représente N et l'autre représente CR9, ou U et V représentent tous deux N ; R1 et R2 représentent un atome d'hydrogène, un atome d'halogène, etc. ; R3 représente un atome d'hydrogène, un atome d'halogène, etc. ; R4 et R5 représentent un atome d'hydrogène, un groupe alkyle en C1-8, etc. ; X1, X2, X3, X4, X5 et X6 représentent (CR10R11)p ou une liaison ; Y représente une simple liaison, C(R15)(R16), etc. ; et Z représente C(O)OR18, etc., ou un groupe hétéroaryle de 5 ou 6 chaînons.
PCT/JP2010/073280 2009-12-24 2010-12-24 Agoniste de gpr119 WO2011078306A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors

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WO2008083238A2 (fr) * 2006-12-28 2008-07-10 Metabolex Inc. Agonistes de récepteur hétérocyclique pour le traitement du diabète et de troubles métaboliques
WO2009014910A2 (fr) * 2007-07-19 2009-01-29 Metabolex, Inc. Agonistes de recepteurs heterocycliques a liaison n utilises dans le traitement du diabete et des troubles metaboliques
WO2009055331A2 (fr) * 2007-10-22 2009-04-30 Schering Corporation Dérivés hétérocycliques bicycliques et leurs procédés d'utilisation
WO2010008739A2 (fr) * 2008-06-20 2010-01-21 Metabolex, Inc. Agonistes des récepteurs gpr119 aryles et utilisations associées
WO2010013849A1 (fr) * 2008-08-01 2010-02-04 日本ケミファ株式会社 Agoniste de gpr119

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Publication number Priority date Publication date Assignee Title
WO2008083238A2 (fr) * 2006-12-28 2008-07-10 Metabolex Inc. Agonistes de récepteur hétérocyclique pour le traitement du diabète et de troubles métaboliques
WO2009014910A2 (fr) * 2007-07-19 2009-01-29 Metabolex, Inc. Agonistes de recepteurs heterocycliques a liaison n utilises dans le traitement du diabete et des troubles metaboliques
WO2009055331A2 (fr) * 2007-10-22 2009-04-30 Schering Corporation Dérivés hétérocycliques bicycliques et leurs procédés d'utilisation
WO2010008739A2 (fr) * 2008-06-20 2010-01-21 Metabolex, Inc. Agonistes des récepteurs gpr119 aryles et utilisations associées
WO2010013849A1 (fr) * 2008-08-01 2010-02-04 日本ケミファ株式会社 Agoniste de gpr119

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors

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