WO2010123018A1 - Dérivé de diazaspiroalcane - Google Patents

Dérivé de diazaspiroalcane Download PDF

Info

Publication number
WO2010123018A1
WO2010123018A1 PCT/JP2010/057036 JP2010057036W WO2010123018A1 WO 2010123018 A1 WO2010123018 A1 WO 2010123018A1 JP 2010057036 W JP2010057036 W JP 2010057036W WO 2010123018 A1 WO2010123018 A1 WO 2010123018A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
diazaspiroalkane
acceptable salt
pharmaceutically acceptable
Prior art date
Application number
PCT/JP2010/057036
Other languages
English (en)
Japanese (ja)
Inventor
遠藤剛
高橋理恵
田中博人
國上敏浩
Original Assignee
日本ケミファ株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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 WO2010123018A1 publication Critical patent/WO2010123018A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to GPR119 agonists.
  • Diabetes mellitus 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), rapid-acting type Insulin secretion promoters (mitiglinide calcium hydrate) and the like are on the market.
  • 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
  • Non-Patent Document 1 GPR119 agonists have been found to increase plasma concentrations of Glucagon like peptide-1 (GLP-1), one of the incretins in in vivo action (Non-patent Document 2).
  • Non-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.
  • Patent Documents 7 and 8 mainly have an action as a Ca channel blocker, and there is also a description of GPR119 agonist action as well as action on TRPV1.
  • G G
  • H GPR119 agonist activity
  • compounds having the description of the same action are compounds of the present invention.
  • diazaspiroalkane derivative represented by the general formula (I) those corresponding to the nitrogen-containing heterocyclic moiety consisting of X, Z, N and Y are limited to benzene rings, and their action strength is weak It is.
  • Non-patent document 3 describes the following compound (J) and the like.
  • compound (J) is described as a synthetic intermediate of Melanostatin analog, there is no description that this compound is used as a GPR119 agonist.
  • An object of the present invention is to provide a diazaspiroalkane derivative represented by the following general formula (I) or (II) 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 diazaspiroalkane derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
  • a halogen atom as a substituent, a nitro group, a cyano group, hydroxy group, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 substituted with 1 to 3 halogen atoms An 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) 1-8) alkylsulfonyl radical (1-8 carbon atoms in the alkyl), amino group, C 1-8 alkylamino group, C 2-12
  • the nitrogen-containing heterocycle composed of T, nitrogen atom, U and carbon atom, and the nitrogen-containing heterocycle composed of V, carbon atom, W and nitrogen atom are each independently a 4- to 7-membered ring
  • R 3 represents a hydrogen atom, a C 1-8 alkyl group, or a C 1-8 alkyl group substituted with 1 to 3 halogen atoms.
  • Y and Z are the same or different substituents as a halogen atom, cyano group, C 1-8 alkyl group, C 1-8 alkoxy group, carboxyl group, C 1-8 alkyl substituted with 1 to 3 halogen atoms.
  • G is C (O) OR 4 , C (O) R 5 , SO 2 R 6 , C (O) NR 7 R 8 , CH 2 C (O) NR 9 R 10 , or a 5- or 6-membered ring.
  • R 4 to R 10 are a hydrogen atom, a C 1-8 alkyl group, a 3 to 7-membered cycloalkyl group, a C 1-4 alkyl group substituted with an aryl group, or 1 to 3 halogen atoms.
  • the heteroaryl group is bonded to the nitrogen atom of the nitrogen-containing heterocyclic ring consisting of Y, X, Z and N via the carbon atoms constituting the ring, and is a halogen atom, a nitro group, a cyano group, a hydroxy group, From 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 1-8 alkoxy group substituted with 1 to 3 halogen atoms It may have a selected substituent. )
  • the present invention also relates to a diazaspiroalkane derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof.
  • R 11 , R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy 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), (1-8 carbon atoms in the alkyl) alkyl
  • the nitrogen-containing heterocycle consisting of T 1 , nitrogen atom, U 1 and carbon atom, and the nitrogen-containing heterocycle consisting of V 1 , carbon atom, W 1 and nitrogen atom are each independently a 4 to 7-membered ring
  • B 1 represents a bond
  • a C ( O)
  • C ( O)
  • CR 14 R 15 or C 1-8 alkyl groups as substituents
  • C 1-8 alkyl group substituted with 1 to 3 halogen atoms Represents C 1-5 alkylene optionally having a selected one
  • R 14 and R 15 Y 1 and Z 1 represent the same or different hydrogen atom
  • C 1-8 alkyl, C 1-8 alkyl group substituted with 1 to 3 halogen atoms may be the same or Unlike a substituent, a halogen atom, a cyano group, a C 1-8 alkyl group, a C 1-8 alkoxy group, a carboxyl group, a C 1-8 alkyl group substituted
  • the present invention also relates to a therapeutic agent for diabetes containing the diazaspiroalkane derivative represented by the above general formula (I) or (II) or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, this invention relates to the GPR119 agonist which contains the diaza spiro alkane derivative represented by the said general formula (I) or (II), or its pharmaceutically acceptable salt as an active ingredient.
  • A is a halogen atom, nitro group, cyano group, hydroxy group, C 1-8 alkyl group, 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 3 halogen atoms, phenyloxy group, alkoxycarbonyl group (alkoxy has 1 to 8 carbon atoms), carboxyl group, carbamoyl group, acyl group (alkyl has 1 carbon atom) 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 (1-8 carbon
  • A represents a substituent as a halogen atom, a cyano 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, a C 1-8 alkylsulfonyl group
  • A is a phenyl group having at least one C 1-8 alkylsulfonyl group as a substituent or a 5- or 6-membered heteroaryl group, or a pharmaceutically acceptable salt thereof Acceptable salt.
  • T, U and V are CH 2 and W is CH 2 CH 2 , or pharmaceutically Acceptable salt.
  • a substituent in which the heteroaryl group of G is selected from a halogen atom, a C 1-8 alkyl group, a 3- to 7-membered cycloalkyl group, and a C 1-8 alkyl group substituted with 1 to 3 halogen atoms;
  • R 11 , R 12 and R 13 are the same or different and are a hydrogen atom, a halogen atom, a cyano 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.
  • a diazaspiroalkane derivative according to the above general formula (II) which is an alkyl group, a C 1-8 alkylsulfonyl group, a sulfamoyl group or a 5- or 6-membered heteroaryl group, or a pharmaceutically acceptable salt thereof.
  • T 1 , U 1 , V 1 and W 1 are all CH 2 , or the diazaspiroalkane derivative according to any one of (18) or (19) above or pharmaceutically acceptable Salt.
  • 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 3- to 7-membered 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 1-4 alkyl group substituted with an aryl group include a benzyl group.
  • examples of the 5- or 6-membered heteroaryl group which may have the substituent of A in the general formula (I) include a pyridyl group.
  • examples of the 5- or 6-membered heteroaryl group of G include a pyrimidyl group and an oxadiazolyl group.
  • the heteroaryl group of G 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 cyclopropyl group, a cyclopentyl group, a cyclohexyl group or the like.
  • the phenyl group of A or the 5- or 6-membered heteroaryl group of the substituent which the 5- or 6-membered heteroaryl group may have may be 1, 2, 4 -Triazolyl group, tetrazolyl group and the like.
  • A may have 1 to 5 substituents, preferably 1 to 3 in the case of a phenyl group, and 1 to 4 in the case of pyridine, preferably One or two.
  • examples of the 5- or 6-membered heteroaryl group of R 11 , R 12 and R 13 include a 1,2,4-triazolyl group and a tetrazolyl group.
  • pharmaceutically acceptable salts include organic acids or inorganic acids such as hydrochloride, sulfate, fumaric acid, oxalate, etc. And salts thereof.
  • the diazaspiroalkane derivatives represented by the above general formula (I) or (II) include racemates and optically active substances.
  • the diazaspiroalkane derivative represented by the above general formula (I) or (II) includes these hydrates and solvates.
  • the diazaspiroalkane derivative represented by the above general formula (I) in which B is alkylene can be produced by the following method A or method B.
  • PG represents a protecting group such as tert-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, and LG represents a halogen atom such as chlorine, bromine, iodine or the like, or trifluoromethanesulfonyloxy group, methanesulfonyloxy group.
  • R 0 represents a hydrogen atom or a C 1-8 alkyl group, a C 1-8 alkyl group substituted with 1 to 3 halogen atoms
  • B 2 represents C 1 as a substituent.
  • the starting material (a) can be synthesized by a known method (J. Burkhard et. Al., Org. Lett., 2008, 10, 3526, etc.) and a method analogous thereto.
  • the compound of the general formula (d) can be obtained by a method using trifluoroacetic acid or the like in a solvent such as dichloromethane or without solvent.
  • the protecting group is a benzyl group, palladium-carbon in a solvent that does not participate in the reaction such as 1,2-dichloroethane, a method using 1-chloroethyl chloroformate, or a solvent that does not participate in the reaction such as methanol or ethanol.
  • the compound of the general formula (d) can be obtained by a method of catalytic hydrogenation using, as a catalyst.
  • Step 3 Conversion of the compound of the general formula (d) to the compound of the general formula (f) is carried out in the presence of a catalyst such as acetic acid or p-toluenesulfonic acid in a solvent such as methanol or toluene. ) After condensation with the compound of (2), it can be obtained by reduction using sodium borohydride, sodium triacetoxyborohydride or the like.
  • the compound of the general formula (f) can also be produced by the following method B.
  • Step 1 Conversion of the compound of the general formula (d) into the compound of the general formula (f) is carried out in the presence of a base such as triethylamine or diisopropylethylamine in a solvent that does not participate in the reaction such as toluene or tetrahydrofuran or without solvent. Or it can carry out by making it react with the compound of general formula (g) in absence. In this case, the reaction temperature is from room temperature to 150 ° C. Further, the diazaspiroalkane derivative represented by the above general formula (I) in which B is a bond can be produced by the following method C.
  • Step 1 Conversion of the compound of the general formula (d) to the compound of the general formula (k) can be carried out by using N, N-dimethylformamide, dichloromethane, etc. in a solvent not involved in the reaction, such as N-methylmorpholine, triethylamine, etc.
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), 1-hydroxybenzotriazole and the like It can be obtained by condensation.
  • the diazaspiroalkane derivative represented by the general formula (I) or (II) can also be produced with reference to the production methods described in Patent Documents 1 to 8 and Non-Patent Document 3.
  • T and U are CH 2
  • X is CH
  • Y and Z are CH 2 CH 2
  • R 21 , R 22 , V, W, B, Q and R 23 is as shown in Table 1.
  • Y and Z are CH 2 CH 2 , and R 21 , R 22 , T, U, V, W, B, X, Q, and R 23 are as shown in Table 2.
  • R 22 is H
  • U and V are CH 2 CH 2
  • X is CH
  • Z is CH 2
  • R 21 , T, W, B, Y, Q and R 23 are as shown in Table 3.
  • V and W are CH 2
  • X is CH
  • Y and Z are CH 2 CH 2
  • Q is C (O) O
  • R 21 , R 22 , T , U, B and R 23 are as shown in Table 4.
  • T, V, W and B are CH 2
  • X is CH
  • Y and Z are CH 2 CH 2
  • R 21 , R 22 , U, Q and R 23 is as shown in Table 5.
  • T and B are CH 2
  • X is CH
  • Y and Z are CH 2 CH 2
  • R 21 , R 22 , U, V, W, Q and R 23 is shown in Table 6.
  • B is CH 2
  • Q is C (O) O
  • Ar, T, U, V, W, and R 23 are as shown in Table 7.
  • T and U are CH 2
  • Ar, V, W, B, Q, and R 23 are as shown in Table 8.
  • Q2 is the same as Q2 of Table 5
  • Q3 is the same as Q3 of Table 6.
  • 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.
  • 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. (Primers: tcctggatccatggaatcatctttctcatt (SEQ ID NO: 1), tcctggggcccctagcacatactactgagc (SEQ ID NO: 2)).
  • 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. Followinged 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%.
  • Example 5 exhibited an excellent GPR119 agonistic action. Accordingly, the diazaspiroalkane derivative of the above general formula (I) or (II) or a pharmaceutically acceptable salt thereof is expected as a therapeutic agent for diabetes because it has a GPR119 agonistic action. Adaptation to lifestyle-related diseases such as syndrome is also expected.
  • the diazaspiroalkane derivative of the above general formula (I) or (II), or a pharmaceutically acceptable salt thereof can also be used in combination with known antidiabetic drugs.
  • the diazaspiroalkane derivative of the above general formula (I) or (II) or a pharmaceutically acceptable salt thereof should be administered to humans 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.
  • it can be produced into 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 dosage is usually about 0.01 mg to about 0.01 mg / day of the diazaspiroalkane derivative of the above general formula (I) or (II), which is an active ingredient in an injection, or a pharmaceutically acceptable salt thereof, in an adult. 100 mg, 1 mg to 2000 mg per day by oral administration, but may be increased or decreased depending on age, symptoms, etc.
  • EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these.
  • IR (KBr, cm ⁇ 1 ): 2925, 1693, 1595, 1512, 1473, 1421, 1388, 1365, 1292, 1236, 1174, 1147, 1088, 1003, 964, 868, 814, 777, 575, 534.
  • IR (KBr, cm ⁇ 1 ): 2935, 2843, 1684, 1595, 1469, 1429, 1390, 1367, 1333, 1317, 1300, 1248, 1234, 1144, 1090, 958, 864, 829, 775, 596, 532 486.
  • IR (KBr, cm ⁇ 1 ): 2935, 1685, 1635, 1593, 1506, 1471, 1446, 1421, 1383, 1360, 1333, 1317, 1300, 1236, 1146, 1092, 1066, 1003, 974, 945, 866 , 827, 773, 731, 577, 536, 459.
  • IR (KBr, cm ⁇ 1 ): 2931, 1691, 1597, 1523, 1458, 1415, 1367, 1333, 1288, 1230, 1144, 1086, 947, 864, 818, 773, 741, 598, 526, 488.
  • IR (KBr, cm ⁇ 1 ): 2937, 2853, 1685, 1605, 1517, 1476, 1419, 1383, 1368, 1327, 1303, 1248, 1209, 1153, 1134, 1072, 1027, 971, 957, 866, 815 762,616,592,536,493.
  • the reaction mixture was concentrated under reduced pressure, anhydrous toluene (5 ml) and p-toluenesulfonic acid (catalytic amount) were added, and the mixture was heated to reflux for 2 days using a Dean-Stark trap. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in anhydrous dichloromethane (5 mL), sodium triacetoxyborohydride (60 mg, 0.283 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into saturated multistory water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • a crude product of [Ilmethyl] piperidine was obtained.
  • the obtained crude product was dissolved in acetonitrile (0.4 mL), and potassium carbonate (8.9 mg, 42.8 ⁇ mol) and 2-chloro-5-ethylpyrimidine (6.2 ⁇ L, 51.3 ⁇ mol) were added, and at room temperature. After stirring for 3 hours, the mixture was stirred at 100 ° C. for 15 hours.
  • the reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • 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%.
  • Experimental results Table 9 shows the experimental results.
  • Example 5 As is clear from Table 9, the compound described in Example 5 exhibited an excellent GPR119 agonistic action.
  • Pharmacological experiment 2 The amount of intracellular cAMP was measured by the same method as the pharmacological test method of Example 13. The test results are listed in Table 10.
  • Example 5 As is clear from Table 11, the compound described in Example 5 showed an excellent blood glucose lowering action.

Abstract

L'invention porte sur un dérivé de diazaspiroalcane représenté par la formule générale (II) [dans laquelle R11, R12 et R13 représentent indépendamment un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1-8, un groupe alcoxy en C1-8, un groupe alkyle en C1-8 qui est substitué par 1 à 3 atomes d'halogène, un groupe alkylsulfonyle en C1-8 ou similaire ; T1, U1, V1 et W1 représentent indépendamment une liaison ou un groupe alcoylène en C1-5 qui peut avoir un substituant ; B1 représente C(=O), un groupe alcoylène en C1-5 qui peut avoir un substituant ou similaire ; Y1 et Z1 représentent indépendamment un groupe alcoylène en C1-3 qui peut avoir un substituant ; et R représente un groupe alkyle en C1-8 ou similaire], qui est un agoniste de GPR119 ou un sel pharmaceutiquement acceptable de celui-ci. Le dérivé de diazaspiroalcane ou le sel pharmaceutiquement acceptable de celui-ci peut être utilisé comme agent thérapeutique pour le diabète.
PCT/JP2010/057036 2009-04-24 2010-04-21 Dérivé de diazaspiroalcane WO2010123018A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009105760A JP2012136439A (ja) 2009-04-24 2009-04-24 ジアザスピロアルカン誘導体
JP2009-105760 2009-04-24

Publications (1)

Publication Number Publication Date
WO2010123018A1 true WO2010123018A1 (fr) 2010-10-28

Family

ID=43011135

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/057036 WO2010123018A1 (fr) 2009-04-24 2010-04-21 Dérivé de diazaspiroalcane

Country Status (2)

Country Link
JP (1) JP2012136439A (fr)
WO (1) WO2010123018A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
US8293729B2 (en) 2009-06-24 2012-10-23 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
WO2012173174A1 (fr) * 2011-06-17 2012-12-20 大正製薬株式会社 Composé azaspiroalcane
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001030780A2 (fr) * 1999-10-27 2001-05-03 Cor Therapeutics, Inc. Composes spirocycliques pyridiles inhibiteurs de l'agregation plaquettaire dependant des fibrinogenes
WO2006053024A2 (fr) * 2004-11-10 2006-05-18 Incyte Corporation Composes de lactame et leur utilisation en temps que substances pharmaceutiques
WO2007016496A2 (fr) * 2005-08-02 2007-02-08 Neurogen Corporation Dipipérazinyl cétones et analogues apparentés
WO2008008887A2 (fr) * 2006-07-13 2008-01-17 Smithkline Beecham Corporation Composés chimiques
WO2008033460A2 (fr) * 2006-09-15 2008-03-20 Schering Corporation Procédé de traitement de la douleur, du diabète et des troubles du métabolisme lipidique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001030780A2 (fr) * 1999-10-27 2001-05-03 Cor Therapeutics, Inc. Composes spirocycliques pyridiles inhibiteurs de l'agregation plaquettaire dependant des fibrinogenes
WO2006053024A2 (fr) * 2004-11-10 2006-05-18 Incyte Corporation Composes de lactame et leur utilisation en temps que substances pharmaceutiques
WO2007016496A2 (fr) * 2005-08-02 2007-02-08 Neurogen Corporation Dipipérazinyl cétones et analogues apparentés
WO2008008887A2 (fr) * 2006-07-13 2008-01-17 Smithkline Beecham Corporation Composés chimiques
WO2008033460A2 (fr) * 2006-09-15 2008-03-20 Schering Corporation Procédé de traitement de la douleur, du diabète et des troubles du métabolisme lipidique

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8293729B2 (en) 2009-06-24 2012-10-23 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
WO2012173174A1 (fr) * 2011-06-17 2012-12-20 大正製薬株式会社 Composé azaspiroalcane
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

Also Published As

Publication number Publication date
JP2012136439A (ja) 2012-07-19

Similar Documents

Publication Publication Date Title
CN113227068B (zh) Glp-1r激动剂及其用途
AU2012323085B2 (en) PDE9i with imidazo pyrazinone backbone
EP2592933B1 (fr) Inhibiteurs mif et leurs utilisations
WO2011093501A1 (fr) Agoniste du gpr119
RU2405783C2 (ru) Гетеробициклические ингибиторы вируса гепатита с (hcv)
JP2022527607A (ja) Ｇｌｐ－１ｒアゴニスト及びその使用
KR101689421B1 (ko) 치환된 이미다조피리디닐-아미노피리딘 화합물
EP2696682B1 (fr) Facteurs d'inhibition de la migration des macrophages (mif) et leurs utilisations
AU2003267098B2 (en) Dihydroxypyridopyrazine-1,6-dione compounds useful as HIV integrase inhibitors
JPWO2010013849A1 (ja) Ｇｐｒ１１９作動薬
EP2474540A1 (fr) Agoniste du gpr119
JP2016029069A (ja) Ｃｘｃｒ４受容体アンタゴニスト
WO2010128425A1 (fr) Modulateurs de gpr119
JP2010531849A (ja) オレキシン受容体アンタゴニストとしてのイミダゾ［１，２−ｃ］ピリミジン−２−イルメチルピペリジン誘導体
EP2427448A1 (fr) Modulateurs du gpr119
JP2006077023A (ja) 多環式グアニン誘導体ホスホジエステラーゼｖ阻害剤
WO2012117996A1 (fr) Agoniste de gpr119
WO2018018986A1 (fr) Composé de diphénylaminopyrimidine et de triazine, composition pharmaceutique et utilisation de celui-ci
JP2020511452A (ja) ソマトスタチンモジュレータとその使用
WO2017071516A1 (fr) Inhibiteur de kinase et procédé pour sa préparation et utilisation pharmaceutique correspondante
US20120295845A1 (en) Imidazo-pyrazoles as gpr119 inhibitors
JP2023506357A (ja) 核内受容体に対して活性の化合物
WO2010123018A1 (fr) Dérivé de diazaspiroalcane
EP2480551A1 (fr) Modulateurs de gpr 119
JP2022529466A (ja) 二環式及び三環式化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10767075

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10767075

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP