WO2015046595A1 - アディポネクチン受容体活性化化合物 - Google Patents
アディポネクチン受容体活性化化合物 Download PDFInfo
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- WO2015046595A1 WO2015046595A1 PCT/JP2014/076185 JP2014076185W WO2015046595A1 WO 2015046595 A1 WO2015046595 A1 WO 2015046595A1 JP 2014076185 W JP2014076185 W JP 2014076185W WO 2015046595 A1 WO2015046595 A1 WO 2015046595A1
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- MGTFEKWKCLDVNN-UHFFFAOYSA-N CC(CN(Cc1ccccc1)CC1)C1N Chemical compound CC(CN(Cc1ccccc1)CC1)C1N MGTFEKWKCLDVNN-UHFFFAOYSA-N 0.000 description 1
- PFQXDUKLHMLEHY-UHFFFAOYSA-N CC(c1ccccc1)N(CC1)CCC1N Chemical compound CC(c1ccccc1)N(CC1)CCC1N PFQXDUKLHMLEHY-UHFFFAOYSA-N 0.000 description 1
- JDLDWQAGLANKKN-UHFFFAOYSA-N CC(c1ccccc1)N(CC1)CCC1NC(COc1ccc(C(F)(F)F)cc1)=O Chemical compound CC(c1ccccc1)N(CC1)CCC1NC(COc1ccc(C(F)(F)F)cc1)=O JDLDWQAGLANKKN-UHFFFAOYSA-N 0.000 description 1
- KXROTPXCYDXGSC-UHFFFAOYSA-N CC1SCCCS1 Chemical compound CC1SCCCS1 KXROTPXCYDXGSC-UHFFFAOYSA-N 0.000 description 1
- JLFGNJQBUIMOPL-UHFFFAOYSA-N CCC(c(cc1)ccc1OCC(NC1C(C)CN(Cc2ccccc2)CC1)=O)=O Chemical compound CCC(c(cc1)ccc1OCC(NC1C(C)CN(Cc2ccccc2)CC1)=O)=O JLFGNJQBUIMOPL-UHFFFAOYSA-N 0.000 description 1
- FBTYYZZUMRUNGH-UHFFFAOYSA-N CCC(c(cc1)ccc1OCC(O)=O)=O Chemical compound CCC(c(cc1)ccc1OCC(O)=O)=O FBTYYZZUMRUNGH-UHFFFAOYSA-N 0.000 description 1
- RAAISYQENRTMLJ-UHFFFAOYSA-N CCc(cc1)ccc1OCC(NC1CCN(Cc(cc2)cc(F)c2OC)CC1)=O Chemical compound CCc(cc1)ccc1OCC(NC1CCN(Cc(cc2)cc(F)c2OC)CC1)=O RAAISYQENRTMLJ-UHFFFAOYSA-N 0.000 description 1
- WVELHLIHMYYZAT-UHFFFAOYSA-N CCc(cc1)ccc1OCC(O)=O Chemical compound CCc(cc1)ccc1OCC(O)=O WVELHLIHMYYZAT-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N CN(CCC1)C1=O Chemical compound CN(CCC1)C1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- DTKJIYJVOIPGOX-UHFFFAOYSA-N COc(ccc(CN(CC1)CCC1N)c1)c1F Chemical compound COc(ccc(CN(CC1)CCC1N)c1)c1F DTKJIYJVOIPGOX-UHFFFAOYSA-N 0.000 description 1
- MBIMSLCBSQBMQC-UHFFFAOYSA-N COc1ccc(CN(CC2)CCN2C(CCNC(c(cc2)ccc2[N+]([O-])=O)=O)=O)cc1F Chemical compound COc1ccc(CN(CC2)CCN2C(CCNC(c(cc2)ccc2[N+]([O-])=O)=O)=O)cc1F MBIMSLCBSQBMQC-UHFFFAOYSA-N 0.000 description 1
- DOHKJEHZIZZYLD-UHFFFAOYSA-N COc1ccc(CN2CCNCC2)cc1F Chemical compound COc1ccc(CN2CCNCC2)cc1F DOHKJEHZIZZYLD-UHFFFAOYSA-N 0.000 description 1
- YBVVDCMQKWGTHH-UHFFFAOYSA-N NC(CC1)CCN1C(c(cccc1)c1F)=O Chemical compound NC(CC1)CCN1C(c(cccc1)c1F)=O YBVVDCMQKWGTHH-UHFFFAOYSA-N 0.000 description 1
- VHGVDCSTZAGLEX-UHFFFAOYSA-N O=C(COc(cc1)ccc1N(CCC1)C1=O)NC(CC1)CCN1C(c(cccc1)c1F)=O Chemical compound O=C(COc(cc1)ccc1N(CCC1)C1=O)NC(CC1)CCN1C(c(cccc1)c1F)=O VHGVDCSTZAGLEX-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N O=C([n]1cncc1)[n]1cncc1 Chemical compound O=C([n]1cncc1)[n]1cncc1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- ZJAZOQRDYBOLBW-UHFFFAOYSA-N OC(COc(cc1)ccc1N(CCC1)C1=O)=O Chemical compound OC(COc(cc1)ccc1N(CCC1)C1=O)=O ZJAZOQRDYBOLBW-UHFFFAOYSA-N 0.000 description 1
- NTBSLTKYEVAWEE-UHFFFAOYSA-N OC(COc1ccc(C(F)(F)F)cc1)=O Chemical compound OC(COc1ccc(C(F)(F)F)cc1)=O NTBSLTKYEVAWEE-UHFFFAOYSA-N 0.000 description 1
- PDTLZWITKYGYDN-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1C(NCCC(O)=O)=O)=O Chemical compound [O-][N+](c(cc1)ccc1C(NCCC(O)=O)=O)=O PDTLZWITKYGYDN-UHFFFAOYSA-N 0.000 description 1
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Definitions
- the present invention relates to a compound having an adiponectin receptor activating action or a salt thereof.
- Insulin resistance is a common feature of obesity and causes patients to have various pathologies including type 2 diabetes and cardiovascular disease.
- Adiponectin is an anti-diabetic and anti-atherogenic adipokine. Adiponectin levels in plasma decrease with obesity, insulin resistance, and type 2 diabetes (Non-Patent Document 1). In addition, administration of adiponectin is known to have a glucose lowering effect and improve insulin resistance in mice (Non-patent Documents 2-4). This insulin-sensitive effect of adiponectin is due, at least in part, to activation of AMP-activated protein kinase (AMPK) (Non-Patent Documents 5-7) and fatty acid oxidation via peroxisome proliferator-activated receptor (PPAR) ⁇ . (Non-patent Documents 8-9).
- AMPK AMP-activated protein kinase
- PPAR peroxisome proliferator-activated receptor
- AdipoR adiponectin receptor
- AdipoR1 In skeletal muscle, AdipoR1 is predominantly expressed (Non-Patent Document 11) and activates AMPK and PPAR ⁇ coactivator (PGC) -1 ⁇ and Ca 2+ signaling pathway, which are also activated by exercise.
- the Exercise has been reported to exert beneficial effects on obesity-related diseases such as type 2 diabetes, and can contribute to healthy longevity.
- AdipoRl and AdipoR2 are expressed in the liver, both of which play a role in the regulation of glucose and lipid metabolism, inflammation, and oxidative stress (Non-patent Document 10).
- a compound that activates AdipoR exhibits an adiponectin-like action, thereby causing a disease in which the AdipoR activation action is effective, such as reduced insulin sensitivity, diabetes, obesity, metabolic syndrome, dyslipidemia, mitochondrial dysfunction, artery It is effective for prevention, treatment or improvement of curing.
- a disease in which the AdipoR activation action is effective such as reduced insulin sensitivity, diabetes, obesity, metabolic syndrome, dyslipidemia, mitochondrial dysfunction, artery It is effective for prevention, treatment or improvement of curing.
- Patent Documents 1 to 5 Several compounds have been reported so far as compounds that activate the AMPK pathway in cells (Patent Documents 1 to 5), but the development of more effective drugs is desired.
- Hotta, K., et al. Plasmaconcentrations of a novel, adipose-specific protein, adiponectin, in type 2diabetic patients. Arterioscler. Thromb. Vasc. Biol. 20, 1595-1599 (2000). Yamauchi, T., et al., Thefat-derived hormone adiponectin reverses insulinresistance associated with bothlipoatrophy and obesity. Nature Med. 7, 941-946 (2001). Berg, A.H., Combs, T.P., Du, X., Brownlee, M., & Scherer, P.E., The adipocytesecretedprotein Acrp30 enhanceshepatic insulin action. Nature Med.
- Yamauchi, T., et al. Globularadiponectin protected ob / ob mice from diabetes and apoE deficient mice fromatherosclerosis. J. Biol. Chem. 278, 2461-2468 (2003). Yamauchi, T., et al., Targeteddisruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding andmetabolic actions. Nature Med. 13, 332-339 (2007). Iwabu, M., et al., Adiponectinand AdipoR1 regulate PGC-1alpha and mitochondria by Ca (2+) and AMPK / SIRT1.Nature 464, 1313-1319 (2010).
- the present invention relates to providing an activator of AdipoR that activates both AdipoR1 and AdipoR2.
- the present invention also relates to providing an agent for preventing or treating symptoms, diseases or disorders resulting from decreased production of adiponectin, decreased levels of adiponectin in blood, or decreased activity of reduced AdipoR.
- A represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aryloxy group, or a C 4 ⁇ 8 tertiary alkyl group or -NH 2
- Y 1 is, - (CHR 2) a - (.
- R 2 represents a hydrogen atom or a C 1 ⁇ 7 alkyl group, a is an integer of 0-2) or -CO- indicates, X represents CH or N; R 1 represents a C 1 ⁇ 7 alkyl group, a plurality of R 1 may optionally be the same or different m represents an integer of 0 to 4, Y 2 is, i) when X is CH, * —O—CH 2 —CONH—, —O—, * —CONH—, or (Wherein, R 3 represents a C 1 - 7 alkyl group, r 0 ⁇ an integer of 4, when p and q are independently an integer of 0 to 2 (r is 2 or greater R 3 may be the same or Which may be different), * indicates binding at this position to Z.) ii) when X is N, * —CONH— (CH 2 ) b —CO—, * —NHCO—Ar 1 —CH 2 —, * —NHCO— (CH 2 )
- a medicament comprising the compound of 1) above or a salt thereof, and a pharmaceutically acceptable carrier.
- An adiponectin receptor activator comprising the compound of 1) or a salt thereof as an active ingredient.
- a method for the prevention, amelioration, or treatment of a symptom or disease that develops with a decrease in adiponectin production or adiponectin receptor activity comprising administering the medicine of 2) above to a patient.
- the compound of 1) or a salt thereof used for activating the adiponectin receptor comprising the compound of 1) above or a salt thereof, and a pharmaceutically acceptable carrier.
- An adiponectin receptor activator comprising the compound of 1) or a salt thereof as an active ingredient.
- the compound of the present invention or a salt thereof has an activating action of AdipoR. Therefore, the compound of the present invention or a salt thereof is a symptom, disease, disorder or condition that develops with decreased AdipoR (AdipoR1 or AdipoR2) activity, such as hyperglycemia; impaired glucose tolerance; decreased insulin sensitivity (eg, insulin resistance) Type II diabetes; hypertension; arteriosclerosis, atherosclerotic effect, hyperlipidemia, dyslipidemia such as fatty liver; mitochondrial dysfunction; obesity; metabolic syndrome and lifestyle-related diseases; malignant tumors caused by lifestyle-related diseases; It is useful as a preventive, therapeutic or ameliorating agent.
- AdipoR1 or AdipoR2 AdipoR1 or AdipoR2
- hyperglycemia impaired glucose tolerance
- decreased insulin sensitivity eg, insulin resistance
- Type II diabetes hypertension
- arteriosclerosis atherosclerotic effect, hyperlipidemia, dyslipidemia such as fatty liver; mitochondrial dysfunction; obesity; metabolic syndrome and
- action with respect to glucose intolerance, insulin resistance, and dyslipidemia a to g; plasma compound concentration (a), body weight (b), food intake (c), plasma glucose (d, e, g), plasma insulin (d, e), and insulin resistance (f) Oral glucose tolerance test (OGTT) (1.0 g glucose / kg) in wild type (WT) and Adipor1 ⁇ / ⁇ Adipor2 ⁇ / ⁇ double knockout mice with or without oral administration of AdipoRon (50 mg / kg body weight) Body weight) (d, e) or insulin tolerance test (ITT) (0.5 U insulin / kg body weight) g) value.
- OGTT Oral glucose tolerance test
- h i, glucose infusion rate (GIR) of hyperinsulinemia normoglycemic clamp test in wild type and Adipor1 ⁇ / ⁇ Adipor2 ⁇ / ⁇ double knockout mice with or without oral administration of AdipoRon (50 mg / kg body weight), Endogenous glucose production (EGP) and glucose processing rate (Rd).
- j, k plasma triglycerides (j) and free fatty acids (FFA) in wild type and Adipor1 ⁇ / ⁇ Adipor2 ⁇ / ⁇ double knockout mice treated with or without AdipoRon (50 mg / kg body weight) (k ). All values are expressed as mean ⁇ sem.
- a to h Ppargc1a, Esrra, Tfam, mt-Co2, Tnni1, Acadm, and Sod2 mRNA levels (a), mitochondrial content as assessed by mitochondrial DNA copy number in skeletal muscle (b), exercise endurance ( c), Ppargc1a, Pck1, G6pc, Ppara, Acox1, Ucp2, Cat, Tnf, and Ccl2 mRNA levels (d), tissue triglyceride content (e), TBARS (f) in liver, Tnf, Il6, Ccl2, Emr1 , Itgax and Mrc1 mRNA levels (g) and TBARS in WAT (h).
- FIG. 1 Plasma glucose level after intraperitoneal injection of adiponectin (30 ⁇ g / 10 g body weight) (left) or oral administration of AdipoRon (50 mg / kg body weight) (intermediate).
- the area under the curve (AUC) in the left figure and the middle figure is shown in the right figure.
- body weight (b), food intake (c), liver weight (d), WAT weight (e), plasma glucose (f, left, g), plasma insulin (f, intermediate), and insulin resistance Sex index (f, right), oral glucose tolerance test (OGTT) (1.0 g glucose / kg body weight) (f) or insulin tolerance test (ITT) (0.75 U insulin / kg body weight (g)
- OGTT oral glucose tolerance test
- ITT insulin tolerance test
- plasma triglycerides h
- FFA free fatty acids
- a to h Ppargc1a, Esrra, Tfam, mt-Co2, Tnni1, Acadm, and Sod2 mRNA levels (a), and mitochondrial content (b), tissue triglyceride content (c), and skeleton as assessed by mitochondrial DNA copy number TBARS (d), Ppargc1a, Pck1, G6pc, Ppara, Acox1, Ucp2, Cat, Tnf, and Ccl2 mRNA levels in muscle (t), tissue triglyceride content (f), and TBARS (g) in the liver, and Levels of Tnf, Il6, Ccl2, Emr1, Itgax, and Mrc1 mRNA in WAT (h).
- examples of the “C 1-7 alkyl group” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a hexyl group. And a C 1-7 alkyl group such as a heptyl group.
- a C 1-4 alkyl group is preferable, and a methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, s-butyl group, t-butyl group, isobutyl group and the like are more preferable. It is done.
- aryl group examples include C 6-14 aryl groups such as phenyl group, naphthyl group, indenyl group and anthryl group, preferably C 6-10 aryl group, more preferably phenyl group. It is done.
- heteroaryl group examples include 5- to 14-membered heteroaryl groups such as a furyl group, a thienyl group, an oxazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a benzofuranyl group, and a benzooxadiazolyl group.
- a 5- or 6-membered heteroaryl group more preferably a furyl group, a pyridyl group, or a benzofuranyl group.
- aryl in the “aryloxy group” the same aryl groups as those described above can be mentioned, and a phenoxy group is preferable.
- arylene group examples include a group excluding one hydrogen atom bonded to the aromatic ring of the aryl group, and a phenylene group and a naphthylene group are more preferable.
- Examples of the group that can be substituted with the aryl group, heteroaryl group, aryloxy group, and arylene group include a C 1-4 alkyl group (for example, a methyl group, an ethyl group, a propyl group, an n-butyl group, an s-butyl group).
- halo C 1-4 alkyl group eg chloromethyl group, dichloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, pentachloroethyl group etc.
- halogen Atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
- C 1-4 alkoxy group eg, methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, t-butoxy group, isobutoxy group, etc.
- hydroxyl group and the like hydroxyl group and the like.
- C 3-7 cycloalkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
- Examples of the “C 2-4 alkenyl group” include a vinyl group and a propenyl group.
- C 2-4 alkynyl group examples include an ethynyl group, a propynyl group, a butynyl group and the like, and a 2-propynyl group and a 2-butynyl group are preferable.
- the aryl group represented by A is preferably a phenyl group.
- a heteroaryl group a furyl group, a thienyl group, a pyridyl group, a benzofuranyl group, a benzooxadiazolyl group and the like are preferable.
- the aryloxy group a phenoxy group is preferable. Examples of the group which can be substituted with an aryl group, heteroaryl group or aryloxy group include a C 1-4 alkyl group (for example, methyl group, ethyl group, propyl group, n-butyl group, s-butyl group, t-butyl group).
- halo C 1-4 alkyl group eg trifluoromethyl group, chloromethyl group, dichloromethyl group, fluoromethyl group, difluoromethyl group etc.
- halogen atom eg fluorine atom, chlorine atom, Bromine atom, iodine atom, etc.
- C 1-4 alkoxy group for example, methoxy group, ethoxy group, propoxy group, butoxy group, etc.
- Examples of the substituted aryl group, the substituted heteroaryl group or the substituted aryloxy group include an aryl group, a heteroaryl group and an aryloxy group which are substituted by 1 to 3 with the substituent.
- A is more preferably a phenyl group or a phenyl group substituted by 1 to 3 with the above substituent.
- R 2 is a hydrogen atom or a C 1-3 alkyl group (preferably a methyl group or an ethyl group), and a is preferably 1.
- Preferred is —CH 2 — or —CH (CH 3 ) —.
- the C 1 ⁇ 7 alkyl group represented by R 1, C 1-4 alkyl group e.g., methyl group, ethyl group, propyl group, isopropyl group, n- butyl group, s- butyl, t- butyl group, Isobutyl group and the like are preferable, and a methyl group and an ethyl group are more preferable.
- M is preferably 0 or 1.
- the group represented by (A) is preferably in the the other is 1 p and q are both 0 or one is 0, the C 1 ⁇ 7 alkyl group represented by R 3, C 1 -4 alkyl groups (for example, a methyl group, an ethyl group, a propyl group, etc.) are preferred, and r is preferably 0 or 1. Further, when r is 2 or more, R 3 may be the same or different.
- Examples of (A) include the following groups.
- Y 2 is * —CONH— (CH 2 ) b —CO—, * —NHCO—Ar 1 —CH 2 —, * —NHCO— (CH 2 ) b — or —CO—.
- * —CONH— (CH 2 ) b —CO— or * —NHCO—Ar 1 —CH 2 — is preferred, and * —CONH— (CH 2 ) b —CO— is preferred. Is more preferable, and b is preferably 2.
- Cyclic group represented by Z is an aryl group, and a heteroaryl group, or C 3 ⁇ 7 cycloalkyl group is preferably from these aryl groups is preferably from further phenyl group or a naphthyl group, a phenyl group Is more preferable.
- n ⁇ is a group that can be substituted with the cyclic group represented by Z, and when n is 2 or more, B may be the same or different. n is preferably 0, 1 or 2.
- R 4 is preferably a C 1-4 alkyl group (preferably a methyl group, an ethyl group, a propyl group, etc.), a phenyl group, Examples thereof include a phenyl group and a pyridyl group which are substituted by 1 to 2 with a halogen atom.
- —O—R 4 is more preferable, specifically, a C 1-4 alkoxy group (preferably a methoxy group, an ethoxy group, a propoxy group, etc.); a phenoxy group; a halogen atom (preferably chlorine).
- a phenoxy group substituted by 1 or 2 with a nitro group or the like; a pyridyloxy group (2-pyridyloxy group, 3-pyridyloxy group, 4-pyridyloxy group) can be exemplified.
- R 5 is a hydrogen atom, a C 3 ⁇ 7 cycloalkyl group preferably a hydrogen atom, C 1 ⁇ 7 alkyl group, C 2 ⁇ 4 alkenyl group preferably as R 6, R 5 and R 6 are preferably both hydrogen atoms.
- R 5 as the Ar 2 of Ar 2 -C 1 ⁇ 4 alkyl group, a phenyl group, a furyl group, a pyrazolyl group, a pyridyl group, etc. are preferred, and C 1 ⁇ 2 alkyl as C 1 ⁇ 4 alkyl preferably .
- the C 1-4 alkoxy C 1-4 alkyl group is preferably a methoxyethyl group, an ethoxyethyl group, or an ethoxypropyl group.
- the C 1 ⁇ 7 alkyl group represented by B preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, n- butyl group, s- butyl, t- butyl group, isobutyl group and the like.
- Halo C 1 ⁇ 7 alkyl group represented by B chloromethyl group, dichloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group and the like, preferably trifluoromethyl group.
- halogen atom represented by B examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- the C 3 ⁇ 7 cycloalkyl group represented by B, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group are preferable.
- Preferred examples of the compound represented by the formula (1) of the present invention include those represented by the following (1a) and (1b).
- R 7 represents a C 1-4 alkyl group (for example, a methyl group, an ethyl group, a propyl group, an n-butyl group, s-butyl group, t-butyl group, isobutyl group, etc.), halo C 1-4 alkyl group (eg trifluoromethyl group, chloromethyl group, dichloromethyl group, fluoromethyl group, difluoromethyl group etc.), halogen atom (Eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-4 alkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, etc.), hydroxyl group, and s is 0-3 An integer (R 7 may be the same or different when s is 2 or more). ]
- the compound represented by the formula (1) of the present invention includes all stereoisomers such as geometric isomers such as cis isomer and trans isomer and optical isomers such as d isomer and l isomer. It may be a mixture containing the body in any proportion.
- the compound represented by the general formula (1) can form an acid, a base and an acid addition salt, or a base addition salt.
- the acid addition salt include salts with mineral acids such as hydrochloric acid and sulfuric acid; formic acid , Salts with organic carboxylic acids such as acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, maleic acid; methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid Examples of salts with sulfonic acids such as sodium and potassium; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts, trimethylamine, triethylamine, Butylamine, pyridine, N, N-dimethylaniline, N-methyl-D (-)-glucamine, N-
- the compound represented by the formula (1) or a salt thereof can exist not only as an unsolvated form but also as a hydrate or a solvate. Accordingly, in the present invention, all crystal forms and hydrates or solvates thereof are included.
- the compound represented by the formula (1) and the salt thereof of the present invention can be produced, for example, by the method shown below.
- Y 1 , A, B, Z, m and n are the same as defined above, and Y 2a represents * —O—CH 2 —, a single bond, or Y 2b represents * —CONH— (CH 2 ) b — or a single bond (wherein R 3 , r, p, q, b and * are as defined above).
- the compound (1A) or (1B) can be obtained by a condensation reaction of the carboxylic acid of the compound (2A) or (2B) and the amine of the compound (3A) or (3B).
- This reaction may be carried out according to a conventional method in the presence of a condensing agent using an equivalent amount of carboxylic acid (compound (2A) or (2B)) and amine (compound (3A) or (3B)) or an excess of one. .
- condensing agent examples include N, N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC or WSC), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), carbonyldiimidazole (CDI), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) 4-methylmorpholinium Chloride (DMTMM), 2- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) and the like can be preferably used. These condensing agents are used in an equivalent amount or an excess amount relative to the carboxylic acid.
- DCC N-dicyclohexylcarbodiimide
- EDC or WSC
- solvents not involved in the reaction such as N, N-dimethylformamide (DMF), dioxane, water, methanol, ethanol, tetrahydrofuran (THF), dichloromethane, dichloroethane, diethyl ether, chloroform, dimethoxyethane (DME), acetic acid.
- solvents not involved in the reaction such as N, N-dimethylformamide (DMF), dioxane, water, methanol, ethanol, tetrahydrofuran (THF), dichloromethane, dichloroethane, diethyl ether, chloroform, dimethoxyethane (DME), acetic acid.
- Ethyl, toluene, acetonitrile, dimethyl sulfoxide (DMSO), a mixed solvent thereof or the like can be used, but it is preferable to select appropriately depending on the raw materials and the type of condensing agent.
- the above reaction is usually carried out from cooling to room temperature, but depending on the conditions of the condensation reaction, the reaction can be carried out under heating.
- Compound (1A) or (1B) can also be produced by a method in which a carboxylic acid is led to an active derivative and then condensed with an amine. In this case, the reaction is carried out using an equivalent amount of carboxylic acid (compound (2A) or (2B)) and amine (compound (3A) or (3B)) or an excess of one.
- Active derivatives of carboxylic acid include phenolic compounds such as p-nitrophenol, or 1-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 7-aza-1-hydroxybenzotriazole (HOAt), etc.
- Examples thereof include acid mixed acid anhydrides, acid azides obtained by sequentially reacting esters with hydrazine and alkyl nitrites, acid halides such as acid chlorides or acid fluorides, and target acid anhydrides.
- the activating reagent used in the synthesis of the active derivative of carboxylic acid is carried out using an equivalent amount or an excess amount relative to the carboxylic acid (compound (2A) or (2B)). In addition to the reaction conditions in this case, any reaction can be used as long as it is a reaction that forms an amide bond.
- the carboxylic acid (compound (2A) or (2B)) and amine (compound (3A) or (3B)) used as raw materials are known compounds in the literature and should be produced by a known synthesis method. In addition, commercially available products can also be used.
- the compound represented by the formula (1) of the present invention thus produced can be used as a free compound or as a salt thereof in a conventional chemical operation in the art such as extraction, precipitation, fractional chromatography, fractional crystallization. , And can be isolated and purified by recrystallization or the like.
- the salt of the said compound can be manufactured by attaching
- an optical isomer exists when the compound of the present invention has an asymmetric carbon. These optical isomers can be converted into diastereomeric salts with optically active acids or bases, followed by fractional crystallization, optical resolution by conventional methods such as color chromatography, or optically active raw material compounds. Can be produced by a method of synthesis.
- the compound represented by the formula (1) of the present invention or a salt thereof increases phosphorylation of AMPK in C2C12 cells expressing AdipoR1, as shown in Test Examples to be described later, and this is due to the suppression of AdipoR1 by specific siRNA. It is greatly reduced (Test Example 1). That is, the compound of the present invention or a salt thereof increases AMPK phosphorylation via AdipoR.
- the compounds of the present invention bind to both AdipoR1 and AdipoR2, and activate the AMPK and PPAR ⁇ pathways in mice fed a high fat (HF) diet, improving insulin resistance and glucose intolerance, etc. It has an adiponectin-like effect.
- the compound of the present invention improves diabetes and prolongs the short life span of db / db mice by HF diet in db / db mice, which are rodent models of hereditary obesity (Test Examples 2 and 3). Therefore, the compound of the present invention or a salt thereof prevents, treats or improves symptoms, diseases, disorders or conditions that develop as adiponectin production decreases, blood adiponectin concentration decreases, and AdipoR (AdipoR1 or AdipoR2) activity decreases. It is useful as an agent and can be used for prevention, treatment or amelioration of the symptom, disease, disorder or condition.
- hyperglycemia impaired glucose tolerance; decreased insulin sensitivity (eg, insulin resistance); type II diabetes; hypertension; arteriosclerosis, atherosclerotic effect, hyperlipidemia, fatty lipids such as fatty liver Mitochondrial dysfunction; obesity; metabolic syndrome and lifestyle-related diseases; useful as a medicament for the prevention or treatment of malignant tumors and the like caused by lifestyle-related diseases.
- parenteral administration such as injection, rectal administration, transdermal administration, oral administration in solid, semi-solid or liquid form It can be formulated as a composition together with a pharmaceutically acceptable carrier for administration and the like.
- forms of the composition according to the invention for injection include pharmaceutically acceptable sterile water, non-aqueous solutions, suspensions or emulsions.
- suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
- adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
- These compositions are sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. be able to.
- solid preparations for oral administration include capsules, tablets, pills, troches, powders, granules and the like.
- the compound of the present invention is generally mixed with at least one inert diluent such as sucrose, lactose, starch and the like.
- This formulation can also include additional substances other than inert diluents, such as lubricants (eg, magnesium stearate), in a conventional formulation.
- lubricants eg, magnesium stearate
- Tablets and pills can be further provided with an enteric coating.
- Liquid preparations for oral administration include inert diluents commonly used by those skilled in the art, such as pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. that combine water. It is done.
- adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and flavoring agents can be added to the composition.
- excipients such as cocoa butter and suppository wax in addition to the compound of the present invention.
- the dose of the compound represented by the formula (1) of the present invention or a salt thereof depends on the properties of the compound to be administered, the administration route, the desired treatment period, and other factors, but generally in the case of intravenous administration. About 0.01 to 100 mg / kg per day, about 0.05 to 500 mg / kg per day for intramuscular administration, and about 0.1 to 1000 mg / kg for oral administration are preferable. If desired, this daily dose can be divided into 2 to 4 doses.
- Examples of administration subjects include humans who develop or are likely to develop various symptoms, diseases, or disorders associated with adiponectin production decrease, blood adiponectin concentration decrease, and AdipoR activity decrease.
- hyperglycemia impaired glucose tolerance; decreased insulin sensitivity (eg, insulin resistance); type II diabetes; hypertension; arteriosclerosis, atherosclerotic effect, hyperlipidemia, dyslipidemia such as fatty liver; mitochondrial function Obesity; metabolic syndrome and lifestyle-related diseases; patients suffering from malignant tumors caused by lifestyle-related diseases.
- % means “% by mass”.
- a vial was charged with carboxylic acid (347 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (313 mg, 1 eq).
- EDC was added (269 mg, 1.21 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the vial was charged with carboxylic acid (356 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (300 mg, 1 eq).
- EDC was added (276 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (333 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (319 mg, 1 eq).
- EDC was added (293 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the vial was charged with carboxylic acid (335 mg, 1.2 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (348 mg, 1 eq).
- EDC was added (275 mg, 1.32 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the vial was charged with carboxylic acid (373 mg, 1.2 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (305 mg, 1 eq).
- EDC was added (306 mg, 1.32 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (290 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (350 mg, 1 eq).
- EDC was added (254 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (314 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (331 mg, 1 eq).
- EDC was added (275 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (283 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (355 mg, 1 eq).
- EDC was added (248 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial is charged with carboxylic acid (302 mg, 1.1 eq), solvent (1 mL solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (397 mg, 1 eq), and further triethylamine (169 mg, 1.2 equivalents) was added.
- EDC was added (262 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated.
- a vial was charged with carboxylic acid (311 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (342 mg, 1 eq).
- EDC was added (269 mg, 1.21 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (325 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (307 mg, 1 eq).
- EDC was added (236 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (339 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (294 mg, 1 eq).
- EDC was added (246 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (307 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (324 mg, 1 eq).
- EDC was added (223 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (354 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (268 mg, 1 eq).
- EDC was added (224 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (345 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (279 mg, 1 eq).
- EDC was added (218 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the vial was charged with carboxylic acid (248 mg, 1.0 eq), 1 mL solvent (3.4 g imidazole in 200 mL dry DMF), and amine (387 mg, 1.0 eq.)
- the quinoline was added to the stirred reaction mixture. (443 mg, 1.2 eq.) Was added, the solution was kept at room temperature for 72 hours, the reaction mixture was carefully diluted with 2% hydrochloric acid and then allowed to stand for 24 hours, after which the reaction mixture was sonicated.
- the vial was left overnight, after which the aqueous layer was removed and 2-propanol (1 mL) was added to cause crystallization, or sodium carbonate was added in portions to the aqueous solution to effect amide crystallization.
- a vial was charged with carboxylic acid (329 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (339 mg, 1 eq).
- EDC was added (312 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the vial was charged with carboxylic acid (277 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (384 mg, 1 eq).
- EDC was added (278 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (348 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (319 mg, 1 eq).
- EDC was added (270 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the vial was charged with carboxylic acid (326 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (321 mg, 1 eq).
- EDC was added (253 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the carboxylic acid (348 mg, 1 equivalent) and dry DMF (1 mL) were added to the vial.
- Amine (271 mg, 1 eq) was then added, the vial was closed tightly and the reaction mixture was stirred.
- the reaction vial was placed in a water bath and left at 100 ° C. for 1 hour.
- the reaction mixture was cooled to room temperature and water was added until the vial was full.
- the vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the vial was charged with carboxylic acid (299 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (359 mg, 1 eq).
- EDC was added (260 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the carboxylic acid (338 mg, 1.1 eq) and dry DMF (1 mL) were added to the vial.
- Amine 320 mg, 1 eq was then added, the vial was closed tightly and the reaction mixture was stirred.
- the reaction vial was placed in a water bath and left at 100 ° C. for 1 hour.
- the reaction mixture was cooled to room temperature and water was added until the vial was full.
- the vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (320 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (311 mg, 1 eq).
- EDC was added (260 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (319 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (310 mg, 1 eq).
- EDC was added (259 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (383 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (270 mg, 1 eq).
- EDC was added (267 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (375 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (284 mg, 1 eq).
- EDC was added (261 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the carboxylic acid (330 mg, 1 equivalent) and dry DMF (1 mL) were added to the vial.
- N, N-carbodiimidazole (218 mg, 1 eq) was added to the stirred reaction mixture.
- Amine 280 mg, 1 eq
- the reaction vial was placed in a water bath and left at 100 ° C. for 1 hour.
- the reaction mixture was cooled to room temperature and water was added until the vial was full.
- the vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (315 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (314 mg, 1 eq).
- EDC was added (260 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (293 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (334 mg, 1 eq).
- EDC was added (241 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial is charged with carboxylic acid (348 mg, 1 eq), solvent (1 mL solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (370 mg, 1 eq), and further triethylamine (339 mg, 2. 4 equivalents) was added.
- EDC was added (238 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated.
- a vial is charged with carboxylic acid (341 mg, 1 eq), solvent (1 mL solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (397 mg, 1 eq), and further triethylamine (364 mg, 2. 4 equivalents) was added.
- EDC was added (256 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated.
- a vial was charged with carboxylic acid (319 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (320 mg, 1 eq).
- EDC was added (239 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial is charged with carboxylic acid (366 mg, 1 eq), solvent (1 mL solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (357 mg, 1 eq), and further triethylamine (327 mg, 2. eq.). 4 equivalents) was added.
- EDC was added (230 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled.
- a vial was charged with carboxylic acid (352 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (267 mg, 1 eq).
- EDC was added (221 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (287 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (336 mg, 1 eq).
- EDC was added (215 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the carboxylic acid (322 mg, 1 equivalent) and dry DMF (1 mL) were added to the vial.
- Amine (289 mg, 1 eq) was then added, the vial was closed tightly and the reaction mixture was stirred.
- the reaction vial was placed in a water bath and left at 100 ° C. for 1 hour.
- the reaction mixture was cooled to room temperature and water was added until the vial was full.
- the vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (299 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (308 mg, 1 eq).
- EDC was added (223 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (343 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (274 mg, 1 eq).
- EDC was added (246 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial is charged with carboxylic acid (312 mg, 1 eq), solvent (1 mL solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (357 mg, 1 eq), and further triethylamine (159 mg, 1. eq). 2 equivalents) was added.
- EDC was added (224 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled.
- a vial was charged with carboxylic acid (310 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (318 mg, 1 eq).
- EDC was added (222 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial was charged with carboxylic acid (323 mg, 1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (304 mg, 1 eq).
- EDC was added (232 mg, 1.1 eq). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- a vial is charged with carboxylic acid (386 mg, 1.1 eq), solvent (1 mL solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (383 mg, 1 eq), followed by more triethylamine (350 mg, 2.4 equivalents) was added.
- EDC was added (271 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated.
- a vial was charged with carboxylic acid (371 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (286 mg, 1 eq).
- EDC was added (260 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated. If a crystalline precipitate formed, the vial was sent for filtration.
- the vial is charged with carboxylic acid (133 mg, 1.1 eq), solvent (1 g solution of 200 g N-oxybenzotriazole in 1 L DMF), and amine (215 mg, 1 eq), and further triethylamine (193 mg, 2.4 equivalents) was added.
- EDC was added (149 mg, 1.21 equiv). If the reaction mixture became very viscous, a little more DMF was added. If the reaction mixture was a homogeneous solution, it was kept at room temperature for 72 hours. Otherwise, the reaction mixture was sonicated at room temperature for 5 days. The reaction mixture was diluted with 1% aqueous sodium phosphate until the vial was filled. The vial was then sonicated.
- Acid 10a is charged into a 10 ml flask (0.285 g, 1.0 eq), carbodiimidazole 3a (0.213 g, 1.15 eq) is added, and 1 ml DMFA is added. The reaction mixture is heated to 70 ° C. for 1 hour until dissolved. Amine 2a (0.236 g, 1.0 eq) is then added to the reaction mixture and stored at 100 ° C. for an additional 2 hours. The reaction mixture is cooled and 8 ml of water is added. The precipitate is ground with a spatula, filtered and washed with 50% water / isopropanol. Drying (without further purification) gave 0.33 g of compound 74.
- Test Example 1 Measurement of AMPK Phosphorylation Capacity in Human AdipoR1-Expressing Cell Line
- the AMPK phosphorylation capacity of the compound of the present invention was measured using differentiated C2C12 cells or HEK293T cells.
- 1. Measurement of phosphorylation ability of AMPK (Assay 1) (1) Cell culture i) Evaluation using HEK293T cells HEK293T cells (ATCC; CRL-3216, Medium; DMEM, Fetal Bovine Serum (FBS)) were cultured to 100% confluent in 12 or 24 wells plate. (37C, 5% CO 2) . After Starvation, the test compounds listed in Tables 10 to 11 (concentrations: 25 ⁇ M, 50 ⁇ M) were added, and after 10 minutes, Medium was discarded and frozen in liquid nitrogen.
- C2C12 cells (ATCC; CRL-1772, Medium; DMEM, 10% FBS) were cultured in 12 or 24 wells plate until they became 100% confluent (37C, 5% CO 2 ). .
- the medium was changed to DMEM, 2.5% Horse Serum (HS), and differentiation was started.
- the medium (DMEM, 2.5% HS) was changed every two days. After Starvation, the test compound (concentration: 10 ⁇ M) shown in Table 12 was added, and after 10 minutes, the medium was discarded and frozen in liquid nitrogen.
- sample buffer 280 mM Tris-HCl (pH 6.9), 40% Glycerol, 10% ⁇ -mercaptoethanol, 13% SDS, a small amount of bromophenol blue
- 1 ⁇ sample buffer was added according to the concentration of each sample to adjust the protein concentration.
- PVDF membrane (GE; Hybond-P) is immersed in methanol for several minutes, and then immersed in 1 ⁇ Transfer buffer.
- 1 ⁇ Transfer buffer 10% 10 ⁇ Transfer buffer, 20% Me-OH, 70% distilled water
- 10 ⁇ Transfer buffer 479 mM Tris-HCl, 386 mM Glycine, 0.37% SDS
- HEK293T cells (Medium; the DMEM, 10% FBS) at 24 wells plate, and cultured until 60% confluent (37C, 5% CO 2).
- Lipofectamine RNAiMAX 1 ⁇ L and 50 ⁇ L OPTI-MEM, and 5 ⁇ M siRNA (sense siRNA sequence: GAGAUGGGCAACAUUCGAGACAtt (SEQ ID NO: 1)) and 50 ⁇ L OPTI-MEM were mixed and placed at room temperature for 5 minutes.
- Lipofectamine RNAiMAX 1 ⁇ L / 50 ⁇ L OPTI-MEM and 5 ⁇ M siRNA / 50 ⁇ l OPTI-MEM were mixed, placed at room temperature for 10 minutes, and added to the cells. After 5 minutes, the medium (DMEM, 10% FBS) was changed, and the next day after Starvation, the test compounds described in Tables 10 to 11 were added. After 10 minutes, the medium was discarded and frozen in liquid nitrogen.
- C2C12 cells (ATCC; CRL-1772, Medium; DMEM, 10% Fetal Bovine Serum (FBS)) were cultured in 12 or 24 wells plate until reaching 100% confluent (37C, 5% CO 2).
- Medium was changed to DMEM, 2.5% Horse Serum (HS), and differentiation was started. Two days after the start of differentiation, the medium (DMEM, 2.5% HS) was changed. Two more days later, the medium (DMEM, 2.5% HS) was changed.
- Lipofectamine RNAiMAX and 50 ⁇ LOPTI-MEM were mixed for 5 minutes at room temperature.
- Lipofectamine RNAiMAX 1 ⁇ L / 50 ⁇ L OPTI-MEM and 5 ⁇ M siRNA / 50 ⁇ L OPTI-MEM were mixed, placed at room temperature for 10 minutes, and added to the cells. After 5 minutes, the medium (DMEM, 2.5% HS) was changed, and the test compound described in Table 12 was added the next day after Starvation. After 10 minutes, the medium was discarded and frozen in liquid nitrogen.
- Test Example 2 Affinity for AdipoR1 and AdipoR2 As shown below, the surface plasmon resonance (SPR) was used to measure the affinity for Compound 73 of the present invention (hereinafter referred to as “AdipoRon”), both AdipoR1 and AdipoR2. .
- SPR surface plasmon resonance
- Method Surface plasmon resonance measurement was performed with BIAcore X100 system (GE Healthcare) and sensor chip SA (GE Healthcare). Human AdipoR1 and AdipoR2 were expressed by the baculovirus system and purified to homogeneity.
- AdipoR1 and AdipoR2 were reconstituted with egg phosphatidylcholine liposomes (Avanti) containing biotinyl phosphatidylethanolamine as described in the literature a.
- Mouse full length adiponectin was generated as described in literature references b, c, d, e .
- AdipoR1 and AdipoR2 were immobilized on sensor chip SA at a level of 2500-3000 reaction units (RU) using a standard immobilization protocol (GE Healthcare). Rhodopsin receptor was used as a control and it was confirmed that AdipoRon did not actually react with rhodopsin receptor at all.
- Test Example 3 Various Pharmacological Actions of the Compound of the Present Invention The results of various pharmacological tests conducted on Compound 73 (AdipoRon) and Compound 74 (No. 112254) are summarized below. 1. Materials and Methods (1) Mice Original Adipol1 +/ ⁇ / Adipo2 +/ ⁇ mice (mixed background of C57BL / 6 and 129 / Sv) a was backcrossed more than 7 times with C57B1 / 6 mice. All experiments in this study were performed on male littermates. Mice were 6-10 weeks old at the time of the experiment. Mice were housed in cages and managed with a 12 hour light / dark cycle. For the experiments shown in FIG. 4 and FIG.
- C2C12 cells Mouse C2C12 myoblasts (ATCC, CRL-1772) were grown in 90% Dulbecco's modified high glucose eagle medium containing 10% (v / v) fetal calf serum. When cells reach 80% confluence, myoblasts are replaced by low serum differentiation medium (98% Dulbecco's modified high glucose eagle medium, 2.5% (v / v) horse serum, changed daily) was induced to differentiate into myotubes.
- low serum differentiation medium 98% Dulbecco's modified high glucose eagle medium, 2.5% (v / v) horse serum, changed daily
- the optimal precursor ion pair for AdipoRon was m / z 429.251 ⁇ 91.057.
- the optimal MS parameters were as follows: ion spray: 4000 V, vaporizer temperature: 530 ° C., sheath gas pressure: 50 psi, auxiliary gas pressure: 5 psi, capillary temperature: 270 ° C. Impact pressure: 1.5 mTorr. Peak areas were automatically integrated using LC quan Version 4.5.6 (Thermo Fisher).
- Hepatocytes were isolated from 8-week-old male mice by collagenase perfusion methods a and b with some modifications. Cells were plated at 3.75 ⁇ 10 5 cells / ml in Williams Medium E supplemented with 10% (v / v) fetal calf serum, 10 nM dexamethasone, 10 nM insulin on collagen I-coated plates.
- Yamauchi, T., et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectinbinding and metabolic actions.Nature Med. 13, 332-339 (2007).
- Isolated muscle For analysis of insulin signaling and AMPK phosphorylation, isolated gastrocnemius muscle was isolated from Krebs Ringer bicarbonate (KRB) buffer containing 2 mM pyruvate (117 mM NaCl, 2.5 mM CaCl 2). , 1.2mM KH 2 PO 4, 1.2mM MgSO 4, in 24.6mM NaHCO 3), was pre-incubated 50 min at 37 ° C., a stimulated 10 minutes in the presence or absence of 100nM insulin.
- KRB Krebs Ringer bicarbonate
- JC et al.
- Respiratory chain complex I activity The respiratory chain complex I assay was performed as previously described ac , with minor modifications.
- mitochondria 0.5 mg / ml
- Tris-HCl pH 7.2
- Complex I activity was evaluated by the oxidation rate of NADH (absorbance at 340 nm measured with a spectrophotometer) after adding 100 ⁇ M decylubiquinone as an electron acceptor.
- AMPK phosphorylation in vivo Evaluation of AMPK phosphorylation in vivo was performed by intravenously injecting 50 mg of AdipoRon per kg body weight through a inferior vena cava catheter a .
- Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.Nature Med. 8, 1288-1295 (2002).
- Real-time PCR was performed according to methods a, b and c described in the literature.
- Total RNA was prepared from cells or tissues by Trizol (Invitrogen) according to the manufacturer's instructions. MRNA was quantified using a real-time PCR method with some modifications 19 .
- Immunoblots were performed by cryo-clamping liver, muscle or white adipose tissue in situ in liquid nitrogen by methods described in the literature b, d, e . Immunoprecipitation and immunoblotting were performed by literature methods a, f .
- muscle or liver or cell lysate was incubated with 60 ⁇ l of protein G Sepharose (Merck Millipore) conjugated to an antibody against phosphotyrosine (4G10).
- the beads were then washed and boiled in sample buffer for 5 minutes and the immunoprecipitate was subjected to immunoblotting.
- AMPK ⁇ Cell signaling # 2535, # 2532
- 1R ⁇ Upstate 05-321, Santa Cruz sc-711
- AKT Cell signaling # 9271, # 9272
- GSK3 Cell signaling # 5558, # 9315
- tubulin RB-9281-PO from NeoMarkers
- the level of lipid peroxidation in tissue homogenate and plasma was measured in terms of the amount of TBARS using the LPO test (Wako Pure Chemical Industries, Ltd.).
- [ 14 C] CO 2 production from [1- 14 C] palmitic acid was measured using liver and skeletal muscle as described in references d and e .
- Plasma glucose levels were determined using the glucose B test (Wako Pure Chemical Industries, Ltd.).
- Plasma insulin was measured by an insulin immunoassay (Shiba Goat Co., Ltd.).
- Plasma NEFA (Wako Pure Chemical Industries, Ltd.) was assayed by enzymatic method. All measurements were performed blind.
- Insulin tolerance index Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were carried out as described in literature references a and b with slight modifications.
- the insulin resistance index was calculated from the product of the area of glucose and insulin ⁇ 10 ⁇ 2 in the glucose tolerance test. Results are expressed as a percentage of control litter values.
- Yamauchi, T., et al. Thefat-derived hormone adiponectin reverses insulin resistance associated withboth lipoatrophy and obesity.Nature Med.
- mice administered AdipoRon significantly reduced fasting plasma glucose and insulin levels and glucose and insulin responses during the oral glucose tolerance test (OGTT) (FIG. 2d).
- a decrease in glucose levels despite a decrease in plasma insulin levels indicates improved insulin sensitivity (FIGS. 2d, f).
- HF diet-induced hyperglycemia and hyperinsulinemia could not be improved (FIGS. 2e and f).
- compound 74 No. 112254 can improve glucose intolerance and insulin resistance as well as AdipoRon (FIGS. 7c to f).
- AdipoR1-AMPK-PGC-1 ⁇ pathway Activation of the AdipoR1-AMPK-PGC-1 ⁇ pathway in skeletal muscle
- Mitochondria such as Pparc1a and estrogen-related receptor ⁇ (Esra) in WT mouse skeletal muscle administered orally (50 mg / kg body weight) with AdipoRon Genes involved in neoplasia, genes involved in mitochondrial DNA replication / translation such as mitochondrial transcription factor A (Tfam), genes involved in oxidative phosphorylation (OXPHOS) such as cytochrome c oxidase subunit II (mt-Co2) Expression was increased (Figure 3a). AdipoRon also increased the mitochondrial DNA content in the skeletal muscle of WT mice (FIG. 3b).
- AdipoRon also increased the level of Troponin I (slow) (Tnni1), a type I fiber marker.
- Adipor1 / r2 double knockout mice did not increase.
- administration of AdipoRon significantly increased exercise endurance in WT mice. No increase in Adipo1 / r2 double knockout mice fed the HF diet (FIG. 3c).
- AdipoRon also significantly increased genes involved in fatty acid oxidation, such as medium chain acyl-CoA dehydrogenase (Acadm) (FIG. 3a). This is related to a decrease in TG content in skeletal muscle of WT mice and not to Adipo1 / r2 double knockout mice fed the HF diet.
- AdipoRon significantly increases the expression level of oxidative stress detoxification genes such as manganese superoxide dismutase (Sod2) (FIG. 3a) in WT mouse skeletal muscle, and thiobarbituric acid reactive substances (TBARS) and the like Oxidative stress markers were reduced (Figure 3h). This effect was not observed in Adipo1 / r2 double knockout mice fed with HF diet.
- Activation of the AdipoR1-AMPK and AdipoR2-PPAR ⁇ pathways in the liver involves Pparc1a, phosphoenolpyruvate carboxykinase 1 (Pck1), and glucose-6-phosphatase ( It has been reported to reduce the expression of genes involved in hepatic gluconeogenesis such as G6pc).
- AdipoRon significantly reduced the expression of Pparg1a and G6pc in the liver of WT mice (FIG. 3d). However, this effect was not observed in Adipo1 / r2 double knockout mice fed the HF diet (FIG. 3d).
- AdipoR2 Activation of AdipoR2 can increase PPAR ⁇ levels and activate the PPAR ⁇ pathway, resulting in increased fatty acid oxidation and reduced oxidative stress.
- AdipoRon is a gene that encodes PPAR ⁇ (Ppar ⁇ ) in the liver of WT mice and its target gene, such as acyl-CoA oxidase (Acox1), which is involved in fatty acid combustion, uncoupling protein 2 (Ucp2), etc.
- Cox1 acyl-CoA oxidase
- Ucp2 uncoupling protein 2
- AdipoRon reduced the expression level of genes encoding inflammatory cytokines such as TNF ⁇ (Tnf) and MCP-1 (Ccl2) in the liver of WT mice (FIG. 3d). In contrast, this effect was not observed in Adipo1 / r2 double knockout mice fed the HF diet (FIG. 3d).
- AdipoRon reduced the expression level of genes encoding proinflammatory cytokines such as Tnf, IL-6 (Il6), and Ccl2 in WAT of WT mice. In contrast, this effect was not observed in Adipo1 / r2 double knockout mice fed with HF diet (FIG. 3g).
- AdipoRon is classically activated in the WAT of WT mice fed the HF diet (FIG. 3g), in particular the levels of macrophage markers such as TBARS (FIG. 3h), F4 / 80 (Emr1), especially CD11c (Itgax).
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Abstract
Description
細胞中のAMPK経路を活性化する化合物として、これまでに幾つか報告がなされているが(特許文献1~5)、より効果の高い薬剤の開発が望まれている。
1)下記一般式(1):
Aは、置換又は非置換のアリール基、置換又は非置換のヘテロアリール基、置換又は非置換のアリールオキシ基、又はC4~8第3級アルキル基又は-NH2を示し、
Y1は、-(CHR2)a-(ここで、R2は水素原子又はC1~7アルキル基を示し、aは0~2の整数を示す。)又は-CO-を示し、
Xは、CH又はNを示し、
R1は、C1~7アルキル基を示し、複数のR1は同一又は異なっていてもよい
mは0~4の整数を示し、
Y2は、
i)XがCHである場合、
*-O-CH2-CONH-、-O-、*-CONH-、又は
ii)XがNである場合、
*-CONH-(CH2)b-CO-、*-NHCO-Ar1-CH2-、*-NHCO-(CH2)b-又は-CO-(ここで、Ar1は置換基又は非置換のアリーレン基を示し、bは1~3の整数を示し、*はこの位置でZと結合すること示す。)を示し、
Zは、アリール基、ヘテロアリール基及びC3~7シクロアルキル基から選ばれる環状基を示し、
Bは、Zで示される環状基に置換し得る基であり、-CO-R4若しくは-O-R4(ここで、R4はC1~7アルキル基、又は置換又は非置換のフェニル基、置換又は非置換のピリジル基を示す)、-CONR5R6(ここで、R5は水素原子、C3~7シクロアルキル基、C1~4アルコキシC1~4アルキル基、ノルボルネニルC1~4アルキル基、又はAr2-C1~4アルキル基(Ar2は置換又は非置換のアリール又はヘテロアリール基を示す)を示し、R6は水素原子、C1~7アルキル基、C2~4アルケニル基又はC2~4アルキニル基を示す)、C1~7アルキル基、C3~7シクロアルキル基、ハロC1~7アルキル基、フェニル基、ハロゲン原子、-NO2、又は以下で示される基:
nは0~3の整数(nが2以上の場合Bは同一又は異なっていてもよい。)を示す。〕
で表される化合物。
3)上記1)の化合物又はその塩を有効成分とするアディポネクチン受容体活性化剤。
4)上記2)の医薬を患者に投与することを含む、アディポネクチンの産生低下又はアディポネクチン受容体の活性低下に伴って発症する症状又は疾患の予防、改善又は治療方法。
5)アディポネクチンの産生低下又はアディポネクチン受容体の活性低下に伴って発症する症状又は疾患の予防、改善又は治療のために使用される、上記1)の化合物又はその塩。
6)アディポネクチン受容体活性化のため使用される、上記1)の化合物又はその塩。
アリール基、ヘテロアリール基又はアリールオキシ基に置換し得る基としては、C1-4アルキル基(例えば、メチル基、エチル基、プロピル基、n-ブチル基、s-ブチル基、t-ブチル基、イソブチル基等)、ハロC1-4アルキル基(例えば、トリフルオロメチル基、クロロメチル基、ジクロロメチル基、フルオロメチル基、ジフルオロメチル基等)、ハロゲン原子(例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子等)、Cl-4アルコキシ基(例えば、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基等)、水酸基等が挙げられる。置換アリール基、置換ヘテロアリール基又は置換アリールオキシ基としては、当該置換基で1~3置換されたアリール基、ヘテロアリール基又はアリールオキシ基が挙げられる。
Aは、より好適には、フェニル基又は上記置換基で1~3置換されたフェニル基である。
また、mは、0又は1であるのが好ましい。
Bで示される、-CO-R4若しくは-O-R4において、R4としては、好適にはC1~4アルキル基(好適にはメチル基、エチル基、プロピル基等)、フェニル基、ハロゲン原子で1~2置換されたフェニル基、ピリジル基等が挙げられる。
このうち、-O-R4であるのがより好ましく、具体的にはC1~4アルコキシ基(好適には、メトキシ基、エトキシ基、プロポキシ基等);フェノキシ基;ハロゲン原子(好ましくは塩素原子、フッ素原子等)、ニトロ基等で1又は2置換されたフェノキシ基;ピリジルオキシ基(2-ピリジルオキシ基、3-ピリジルオキシ基、4-ピリジルオキシ基)を例示することができる。
また、R5において、Ar2-C1~4アルキル基のAr2としては、フェニル基、フリル基、ピラゾリル基、ピリジル基等が好ましく、C1~4アルキルとしてはC1~2アルキルが好ましい。
Bで示されるC1~7アルキル基としては、好ましくはメチル基、エチル基、プロピル基、イソプロピル基、n-ブチル基、s-ブチル基、t-ブチル基、イソブチル基等が挙げられる。
Bで示されるハロC1~7アルキル基としては、クロロメチル基、ジクロロメチル基、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基等が挙げられ、好ましくはトリフルオロメチル基である。
Bで示されるハロゲン原子としては、好適にはフッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
Bで示されるC3~7シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基等が好ましい。
本反応はカルボン酸(化合物(2A)又は(2B))とアミン(化合物(3A)又は(3B))とを当量或いは一方を過剰量用いて、縮合剤の存在下、常法に従って行えばよい。
縮合剤としては、例えばN,N-ジシクロヘキシルカルボジイミド(DCC),1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(EDC又はWSC)、O-ベンゾトリアゾール-1-イル-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロホスフェート(HBTU),カルボニルジイミダゾール(CDI)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)4-メチルモルホリニウムクロリド(DMTMM)、2-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロホスフェート(HATU)等を好適に用いることができる。これら縮合剤は、カルボン酸に対して当量、或いは過剰量用いて行われる。
カルボン酸の活性誘導体を合成する際の活性化試薬はカルボン酸(化合物(2A)又は(2B))に対して当量又は、過剰量用いて実施される。この場合の反応条件以外でも、アミド結合を形成する反応であれば、いずれの反応も用いることができる。
また、本発明の化合物は、AdipoR1及びAdipoR2の両方に結合し、高脂肪(HF)食を与えたマウスにおけるAMPK及びPPARα経路の活性化、インスリン抵抗性及びグルコース不耐性の改善等、筋肉及び肝臓でアディポネクチン様の作用を有する。また、本発明の化合物は、遺伝性肥満の齧歯類モデルであるdb/dbマウスにおいて、糖尿病を改善し、HF食によるdb/dbマウスの短い寿命を延ばす(試験例2、3)。
従って、本発明の化合物又はその塩は、アディポネクチンの産生低下や、血中アディポネクチン濃度の低下、AdipoR(AdipoR1又はAdipoR2)活性低下に伴って発症する症状、疾患、障害又は状態の予防、治療又は改善剤として有用であり、当該症状、疾患、障害又は状態の予防、治療又は改善のために使用できる。具体的には、高血糖症;耐糖能障害;インスリン感受性低下(例えばインスリン抵抗性);II型糖尿病;高血圧症;動脈硬化、アテローム性動脈効果、高脂血症、脂肪肝などの脂質異常症、ミトコンドリア機能障害;肥満;メタボリックシンドロームおよび生活習慣病;生活習慣病に起因する悪性腫瘍等の予防又は治療のため医薬として有用である。
注射剤のための本発明による組成物の形態としては、製薬上許容し得る無菌水、非水溶液、懸濁液又は乳濁液が挙げられる。適当な非水担体、希釈剤、溶媒又はビヒクルの例としては、プロピレングリコール、ポリエチレングリコール、オリーブ油等の植物油、オレイン酸エチル等の注射可能な有機エステルが挙げられる。このような組成物は、防腐剤、湿潤剤、乳化剤、分散剤等の補助剤をも合有することができる。これらの組成物は、例えば細菌保持フィルターによる濾過により、又は使用直前に滅菌水あるいは若干の他の滅菌注射可能な媒質に溶解し得る無菌固形組成物の形態で滅菌剤を混入することにより滅菌することができる。
以下に、実施例を挙げて本発明をさらに具体的に説明する。なお、特に記載がない限り%は、質量%を意味する。
13C-NMR(150MHz,DMSO-d6):δ194.4、166.2、161.5、138.6、137.7、132.2、132.0、129.8、129.3、128.7、128.5、128.1、126.8、114.6、66.9、62.1、51.9、46.1、31.4。
本発明化合物が有するAMPKのリン酸化能を、分化したC2C12細胞又はHEK293T細胞を用いて測定した。
1.AMPKのリン酸化能の測定(Assay 1)
(1)細胞培養
i)HEK293T細胞を用いた評価
HEK293T細胞(ATCC;CRL-3216,Medium;DMEM, Fetal Bovine Serum(FBS))を12又は24 wells plateにて、100% confluentになるまで培養した(37C,5% CO2)。
Starvation後、表10~11に記載の試験化合物(濃度;25μM、50μM)を添加し、10分後、Mediumをdiscardし、液体窒素にて凍結した。
C2C12細胞(ATCC;CRL-1772,Medium;DMEM,10%FBS)を12又は24 wells plateにて、100% confluentになるまで培養した(37C,5% CO2)。
培地をDMEM,2.5%Horse Serum(HS)に変更し、分化をスタートした。2日おきに培地(DMEM,2.5%HS)を交換した。
Starvation後、表12に記載の試験化合物(濃度;10μM)を添加し、10分後、培地をdiscardし、液体窒素にて凍結した。
i)サンプルの調製
凍結した12又は24 wellの細胞プレートに、各100又は150μLのCell lysis buffer pH7.4(50mM HEPES(pH7.4)、2mM オルトバナジン酸ナトリウム、10mM ピロリン酸ナトリウム、10mM NaF、2mM EDTA、2mM EGTA、0.1%(v/v) NP-40、0.2mM PMSF)を加え、セルスクレーパーで細胞をかき取り、懸濁し、マイクロ遠心チューブに移した。次いで、ソニケーターにより超音波破砕した(1秒×3回)。15,000 rpm、4℃で15分間遠心し、上清を新しいチューブに回収した。
100μLの上清に対して25μLの5×サンプルバッファー(280mM Tris-HCl(pH6.9)、40%Glycerol、10%β-メルカプトエタノール、13%SDS、ブロモフェノールブルー少量)を加え、混和した。残りの上清を用いて、タンパク質定量を行い、各サンプルの濃度に応じて1×サンプルバッファーを加え、タンパク質濃度を揃えた。
泳動槽に1×SDS buffer(25mM Tris-HCl、250mM Glycine、0.1%SDS)を満たし、ポリアクリルアミドゲルのウェルにサンプルをアプライした。サンプル中のブロモフェノールブルーがゲルの下端に到達するまで電気泳動を行った。
PVDFメンブレン(GE;Hybond-P)を数分間メタノールに浸した後、1×Transfer bufferに浸しておく。
1×Transfer buffer;10% 10×Transfer buffer、20%Me-OH、70%蒸留水
10×Transfer buffer; 479mM Tris-HCl、386mM Glycine、0.37%SDS
1×Transfer bufferに濾紙を十分に浸し、その上にPVDFメンブレン、泳動後のゲルの順に重ね、さらに上に1×Transfer bufferを十分に浸した濾紙を重ね、空気を抜いて、セミドライ式トランスファー装置にセットし転写した(7V、35分間)。
ブロットしたメンブレンから不要な部分をカットし、速やかにブロッキングバッファー(5%スキムミルク in Rinse buffer)に浸し、室温で3時間、40rpmで振とうした。
Rinse buffer; 10mM Tris-HCl (pH7.5)、0.1mM EDTA、10%Triton X-100、150mM NaCl
ブロッキング終了後、Rinse bufferにメンブレンを移し、振とうしながら室温で10分間洗浄した。メンブレンを1次抗体溶液(AMPKalpha Antibody(Cell signaling; #2532)1/1,000 in Rinse buffer、Phospho-AMPKalpha(Thr172)(40H9) antibody(Cell signaling;#2535)1/1,000 in Rinse buffer)に浸し、4℃でover night、40rpmで振とうした。
Rinse bufferにメンブレンを移し、振とうしながら、室温で45分間洗浄した(3~5分ごとにRinse bufferを交換)。
メンブレンを2次抗体溶液(goat anti-rabbit IgG-HRP Antibody(Santa Cruz;sc-2030)1/2,000 in Rinse buffer)に浸し、室温で1時間、40rpmで振とうした。
メンブレンを1次抗体反応後と同様に45分間洗浄した後、化学発光反応液(ECL Western Blotting Detection Reagents,GE Healthcare)に1分間程度浸した。余分な反応液を除いて、透明フィルムにメンブレンを並べて挟み、暗室中でX線フィルムに感光させ(数秒~60秒程度)、フィルムを現像した。
vii)定量
X線フィルムをスキャンして、画像を取り込み、画像解析ソフト「Image J」にて、バンドを測定し、pAMPK及びAMPK量を求めた。
本発明の化合物は、AMPKのリン酸化を促進し、AMPKを活性化した(表10~12)。
(1)細胞培養
i)HEK293T細胞を用いた評価
HEK293T細胞(Medium;DMEM,10%FBS)を24 wells plateにて、60%confluentになるまで培養した(37C,5% CO2)。
Lipofectamine RNAiMAX 1μLと50μL OPTI-MEM、また、5μM siRNA(センスsiRNA配列:GAGACUGGCAACAUCUGGACAtt(配列番号1))と50μL OPTI-MEMを混合し、室温で5分間置いた。Lipofectamine RNAiMAX 1μL/50μL OPTI-MEMと5μM siRNA/50μl OPTI-MEMを混合し、室温で10分間置き、これらを細胞に添加した。
5分後、培地(DMEM,10% FBS)を交換し、翌日、Starvation後、表10~11に記載の試験化合物を添加した。10分後、培地をdiscardし、液体窒素にて凍結した。
C2C12 cells(ATCC;CRL-1772,Medium;DMEM,10% Fetal Bovine Serum(FBS))を12又は24 wells plateにて、100%confluentになるまで培養した(37C,5% CO2)。MediumをDMEM,2.5%Horse Serum(HS)に変更し、分化をスタートした。分化スタート2日後に、培地(DMEM,2.5%HS)を交換した。さらに2日後に、培地(DMEM,2.5%HS)を交換した。
培地交換した翌日、Lipofectamine RNAiMAX 1μLと50μLOPTI-MEM、また、5μM siRNA(センスsiRNA配列:GAGACUGGCAACAUCUGGACAtt(配列番号1))と50μLOPTI-MEMを混合し、室温で5分間置いた。Lipofectamine RNAiMAX 1μL/50μL OPTI-MEMと5μM siRNA/50μL OPTI-MEMを混合し、室温で10分間置き、これらを細胞に添加した。
5分後、培地(DMEM,2.5% HS)を交換し、翌日、Starvation後、表12に記載の試験化合物を添加した。10分後、培地をdiscardし、液体窒素にて凍結した。
上記Assay 1と同様にして、pAMPK及びAMPK量を求めた。
本発明の化合物によるAMPKリン酸化の促進は、AdipoR1に特異的に作用するsiRNAの添加により、大きく低減された(表10~12)。したがって、本発明化合物は、AdipoR1を介してAMPKリン酸化を増加させたことを示す。
以下に示すように、表面プラズモン共鳴(SPR)を使用し、本発明の化合物73(以下「AdipoRon」と称する)、AdipoR1及びAdipoR2の両方に対する親和性を測定した。
i)方法
表面プラズモン共鳴測定を、BIAcore X100システム(GE Healthcare)及びセンサーチップSA(GE Healthcare)によって行った。ヒトAdipoR1及びAdipoR2を、バキュロウイルス系によって発現させ、均一になるまで精製した。次いで、AdipoR1及びAdipoR2のサンプルを、文献記載aのようにビオチニルホスファチジルエタノールアミンを含有する卵ホスファチジルコリンリポソーム(Avanti)で再構成した。マウス完全長アディポネクチンを、文献記載b,c,d,eのように生成した。AdipoR1及びAdipoR2を、標準固定プロトコル(GE Healthcare)を用いて2500~3000反応単位(RU)のレベルでセンサーチップSAに固定した。対照としてロドプシン受容体を使用し、AdipoRonが実際にはロドプシン受容体と全く反応しないことを確認した。
実験は、AdipoRon(0.49μM~31.25μM)及びアディポネクチン(1.5ng~3.75μg)を用い、泳動バッファー(20mM Hepes(pH7.4)、200mM NaCl、10%グリセロール、0.05%(v/v)界面活性剤P20)を用いて25℃で行った。Biacore X100評価ソフトウェアを用いて、化合物又はタンパク質の平衡解離定数(KD)を決定した。
<文献>
a)Hino, T., et al. , G-protein-coupledreceptor inactivation by an allosteric inverse-agonist antibody. Nature 482,237-240 (2012).
b)Yamauchi, T., et al., Globularadiponectin protected ob/ob mice from diabetes and apoE deficient mice fromatherosclerosis. J. Biol. Chem. 278, 2461-2468 (2003).
c)Iwabu, M., et al., Adiponectin and AdipoR1regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 464,1313-1319 (2010).
d)Yamauchi, T., et al., The fat-derivedhormone adiponectin reverses insulin resistance associated with bothlipoatrophy and obesity. Nature Med. 7, 941-946 (2001).
e)Yamauchi, T., et al., Adiponectinstimulates glucose utilization and fatty-acid oxidation by activatingAMP-activated protein kinase. Nature Med. 8, 1288-1295 (2002).
ii)結果
図1j、kに示すとおり、KD 1.8及び3.1μM、Rmax 14.6及び8.6RUであり、AdipoRonは、AdipoR1及びAdipoR2の両方に親和性を有していた。
化合物73(AdipoRon)及び化合物74(No.112254)について行った各種薬理試験の結果を、以下にまとめて示す。
1.材料及び方法
(1)マウス
オリジナルAdipor1+/-/Adipor2+/-マウス(C57BL/6及び129/Svの混合バックグラウンド)aは、C57Bl/6マウスと7回を超えて戻し交雑した。本研究の全ての実験を雄性同腹子に対して行った。
マウスは実験時に6週齢~10週齢であった。マウスをケージに収容し、12時間の明暗サイクルで管理した。図4及び図5に示す実験については、以下の組成を有する標準固形飼料(CE-2、日本クレア株式会社)である食餌を使用した:25.6%(wt/wt)のタンパク質、3.8%の食物繊維、6.9%の灰分、50.5%の炭水化物、4%の脂肪及び9.2%の水。他の全ての実験については、25.5%(wt/wt)のタンパク質、2.9%の食物繊維、4.0%の灰分、29.4%の炭水化物、32%の脂肪及び6.2%の水からなる高脂肪食32(日本クレア株式会社)を使用した。
雄性Lepr-/-(6週齢~10週齢)はJ、ackson Laboratoryから購入した。同じ遺伝子型のマウスに異なる処理を施し、処理群に無作為に割り当てた。
a)Yamauchi, T., et al., Targeteddisruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding andmetabolic actions. Nature Med. 13, 332-339 (2007).
マウスC2C12筋芽細胞(ATCC、CRL-1772)を、10%(v/v)ウシ胎仔血清を含有する90%ダルベッコ改変高グルコースイーグル培地で成長させた。細胞が80%コンフルエントに達した時点で、培地を低血清分化培地(98%ダルベッコ改変高グルコースイーグル培地、2.5%(v/v)ウマ血清、毎日交換する)に置き換えることによって筋芽細胞を筋管に分化するように誘導した。
体重1kg当たり50mgのAdipoRonを経口投与したC57BL/6マウスにおけるAdipoRonの血漿濃度を、HPLC及びTSQ Quantum Ultra(ThermoFisher)によって測定した。定量分析のために、20μlの血漿をアセトニトリルと混合した。混合物を30秒間激しく混合した後、4℃、10000rpmで3分間遠心分離した。上清のアリコートを定量LC/MSシステムに注入した。定量分析を、Accela HPLCシステム(ThermoFisher)を用いて行った。液体クロマトグラフ分離を、syncronis C18(150×2.1mm、3μm)を用いて行った。カラム温度は40℃に保持した。流量は0.2ml/分とした。溶出溶媒Aは水中の0.1%ギ酸からなるものであり、溶媒Bはメタノール中の0.1%ギ酸からなるものであった。クロマトグラフ条件は以下のとおりとした:0分~5分 45%のA/55%のB;5分~6.5分 5%のA/95%のB、6.5分~10分 45%のA/55%のB。典型的な注入量は3μlであった。定量分析を、TSQ Quantum Ultra三段四重極質量分析計を用いて行った。陽イオンモードのエレクトロスプレーイオン化(ESI+)をイオン化に用い、選択反応モニタリング(SRM)モードを検出に選んだ。AdipoRonの最適前駆イオン対は、m/z429.251→91.057であった。最適MSパラメーターは以下のとおりであった:イオンスプレー:4000V、気化器温度:530℃、シースガス圧:50psi、補助ガス圧:5psi、キャピラリー温度:270℃。衝突圧:1.5mTorr。ピーク面積を、LC quan Version 4.5.6(Thermo Fisher)を用いて自動的に積分した。
肝細胞を、8週齢の雄性マウスから若干の変更を加えたコラゲナーゼ灌流法a,bによって単離した。細胞を3.75×105細胞/mlでコラーゲンIコーティングプレートの10%(v/v)ウシ胎仔血清、10nMデキサメタゾン、10nMインスリンを添加したウィリアム培地E中にプレーティングした。
a)Yamauchi, T., et al.,Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectinbinding and metabolic actions. Nature Med. 13, 332-339 (2007).
b)Tsuchida, A., et al.,Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors andadiponectin sensitivity. J. Biol. Chem. 279, 30817-30822 (2004).
インスリンシグナル伝達及びAMPKのリン酸化の分析のために、単離腓腹筋を、2mMピルビン酸塩を含有するクレブスリンガー重炭酸塩(KRB)バッファー(117mM NaCl、2.5mM CaCl2、1.2mM KH2PO4、1.2mM MgSO4、24.6mM NaHCO3)中、37℃で50分間プレインキュベートし、100nMインスリンの存在下又は非存在下で10分間刺激したa。
a)Bruning, J.C., et al., A muscle-specific insulin receptor knockoutexhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance.Mol. Cell 2, 559-569 (1998).
呼吸鎖複合体Iアッセイを、若干の変更を加えて以前の記載a~cのように行った。複合体Iアッセイのために、ミトコンドリア(0.5mg/ml)を、1mM EGTA、20mM Tris-HCl(pH7.2)溶液中、500μM NADH及び5mM KCNの存在下でインキュベートした。複合体I活性を、電子受容体として100μMデシルユビキノンを添加した後のNADHの酸化率(分光光度計で340nmでの吸光度を測定する)によって評価した。
a)Brunmair, B., et al.,Thiazolidinediones, like metformin, inhibit respiratory complex I: a commonmechanism contributing to their antidiabetic actions? Diabetes 53, 1052-1059(2004).
b)El-Mir, M.Y., et al.,Dimethylbiguanide inhibits cell respiration via an indirect effect targeted onthe respiratory chain complex I. J. Biol. Chem. 275, 223-228 (2000).
c)Hinke, S.A., et al.,Methyl succinate antagonises biguanide-induced AMPK-activation and death ofpancreatic beta-cells through restoration of mitochondrial electron transfer.Br. J. Pharmacol. 150, 1031-1043 (2007).
ミトコンドリア含量アッセイは、若干の変更を加えて文献記載a,bのように行った。ミトコンドリア含量の定量化のために、mtDNAを文献記載cのように使用した。
a)Iwabu, M., et al.,Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) andAMPK/SIRT1. Nature 464, 1313-1319 (2010).
b)Civitarese, A.E. et al.,Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab. 4,75-87 (2006).
c)Heilbronn, L.K., et al.,Glucose tolerance and skeletal muscle gene expression in response to alternateday fasting. Obes. Res. 13, 574-581 (2005).
in vivoでのAMPKリン酸化の評価は、体重1kg当たり50mgのAdipoRonをマウスに下大静脈カテーテルを通して静脈注射することにより行ったa。
a)Yamauchi, T., et al.,Adiponectin stimulates glucose utilization and fatty-acid oxidation byactivating AMP-activated protein kinase. Nature Med. 8, 1288-1295 (2002).
リアルタイムPCRは、文献記載の方法a,b,cに従って行った。全RNAを、Trizol(Invitrogen)によりメーカーの使用説明書に従って細胞又は組織から調製した。若干の変更を加えたリアルタイムPCR法を用いてmRNAを定量化した19。
免疫ブロットは、文献記載の方法により、肝臓、筋肉又は白色脂肪組織を液体窒素中でin situに凍結クランプすることにより行ったb,d,e。
免疫沈降及び免疫ブロットは、文献記載の方法により行ったa,f。すなわち、筋又は肝臓又は細胞溶解物を、ホスホチロシンに対する抗体(4G10)に結合したプロテインGセファロース(Merck Millipore)60μlと共にインキュベートした。次いで、ビーズを洗浄し、サンプルバッファー中で5分間煮沸し、免疫沈降物を免疫ブロットに供した。AMPKα(Cell signalingの#2535、#2532)、1Rβ(Upstateの05-321、Santa Cruzのsc-711)、AKT(Cell signalingの#9271、#9272)、GSK3(Cell signalingの#5558、#9315)及びチューブリン(NeoMarkersのRB-9281-PO)のリン酸化及び/又はタンパク質レベルを、文献記載a,g,hのように決定した。2回~5回の独立実験の内の1つの代表的なデータを示した。
a)Yamauchi, T., et al.,Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectinbinding and metabolic actions. Nature Med. 13, 332-339 (2007).
b)Kubota, N., et al.,Pioglitazone ameliorates insulin resistance and diabetes by bothadiponectin-dependent and -independent pathways. J. Biol. Chem. 281, 8748-8755(2006).
c)Yamauchi, T., et al.,Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.Nature 423, 762-769 (2003).
d)Kamei, N., et al.,Overexpression of MCP-1 in adipose tissues causes macrophage recruitment andinsulin resistance. J. Biol. Chem. 281, 26602-26614 (2006).
e)Yamauchi, T., et al., Thefat-derived hormone adiponectin reverses insulinresistance associatedwith both lipoatrophy and obesity. Nature Med. 7, 941-946 (2001).
f)Kubota, N., et al.,Dynamic functional relay between insulin receptor substrate 1 and 2 in hepaticinsulin signaling during fasting and feeding. Cell Metab. 8, 49-64 (2008).
g)Iwabu, M., et al.,Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) andAMPK/SIRT1. Nature 464, 1313-1319 (2010).
h)Cross, D.A., et al.,Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinaseB. Nature 378, 785-789 (1995).
骨格筋ホモジネートを抽出し、組織のトリグリセリド含量を幾らか変更を加えて文献記載a~cのように行った。酸化ストレスが増大したか否かを調査するために、文献記載4のように血漿チオバルビツール酸反応性物質(TBARS)によって表される酸化損傷のマーカーである脂質過酸化を測定した。簡潔に述べると、組織サンプルを50mM Tris-HCl(pH7.4)及び1.15%KClを含有するバッファー溶液中でホモジナイズした後、遠心分離した。上清をアッセイに使用した。組織ホモジネート及び血漿における脂質過酸化のレベルを、LPO試験(和光純薬工業株式会社)を用いてTBARS量の点から測定した。
[1-14C]パルミチン酸からの[14C]CO2生成の測定を、肝臓及び骨格筋を用いて文献記載d,eのように行った。
血漿グルコースレベルを、グルコースB試験(和光純薬工業株式会社)を用いて決定した。血漿インスリンを、インスリンイムノアッセイ(株式会社シバヤギ)によって測定した。血漿NEFA(和光純薬工業株式会社)を酵素法によってアッセイした。
全ての測定を盲検で行った。
a)Wu, H., et al., MEF2responds to multiple calcium-regulated signals in the control of skeletalmuscle fiber type. EMBO J. 19, 1963-1973 (2000).
b)Westfall, M.V. &Sayeed, M.M., Effect of Ca2(+)-channel agonists and antagonists on skeletalmuscle sugar transport. Am. J. Physiol. 258, R462-468 (1990).
c)Merrill, G.F., Kurth,E.J., Hardie, D.G., & Winder, W.W., AICA riboside increases AMP-activatedprotein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am. J.Physiol. 273, E1107-1112 (1997).
d)Yamauchi, T., et al.,Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectinbinding and metabolic actions. Nature Med. 13, 332-339 (2007).
e)Iwabu, M., et al., Adiponectinand AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1.Nature 464, 1313-1319 (2010).
経口グルコース負荷試験(OGTT)及びインスリン負荷試験(ITT)を、若干の変更を加えて文献記載a,bのように行った。
グルコース及びインスリンの曲線面積を、グルコース値(1mg/ml=1cm)及びインスリン値(1ng/ml=1cm)のそれぞれの累加平均高さに時間(60分=1cm)を乗算することによって算出したc,a。インスリン耐性指数を、グルコース負荷試験におけるグルコース及びインスリンの面積×10-2の積から算出した。結果を対照同腹子の値に対するパーセンテージとして表す。
a)Yamauchi, T., et al., Thefat-derived hormone adiponectin reverses insulin resistance associated withboth lipoatrophy and obesity. Nature Med. 7, 941-946 (2001).
b)Yamauchi, T., et al.,Adiponectin stimulates glucose utilization and fatty-acid oxidation byactivating AMP-activated protein kinase. Nature Med. 8, 1288-1295 (2002).
c)Yamauchi, T., et al.,Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectinbinding and metabolic actions. Nature Med. 13, 332-339 (2007).
クランプ試験を、若干の変更を加えて文献記載a,bのように行った。試験の2日~3日前に、ペントバルビタールナトリウムによる全身麻酔下で右頸静脈に注入カテーテルを挿入した。試験は、6時間の絶食後に意識のあるストレスのない条件下でマウスに対して行った。インスリン(Humulin R、Lilly)のプライミング後(primed)、持続注入し(10.0ミリ単位/kg/分)、5分間隔でモニタリングした。血中グルコース濃度を、120分間のグルコース([6,6-2H2]グルコース(Sigma)で20%まで富化した10ml当たり5gのグルコース)の投与によって120mg/dlに維持した。血液を90分、105分及び120分の時点で尾端出血によりサンプリングし、グルコース消失率(Rd)を決定した。Rdを非定常状態方程式に従って算出し、Rdと外因性グルコース注入速度との差として内因性グルコース産生(EGP)を算出したa,b,c。
a)Kubota, N., et al.,Pioglitazone ameliorates insulin resistance and diabetes by bothadiponectin-dependent and -independent pathways. J. Biol. Chem. 281, 8748-8755(2006).
b)Kamei, N., et al.,Overexpression of MCP-1 in adipose tissues causes macrophage recruitment andinsulin resistance. J. Biol. Chem. 281, 26602-26614 (2006)
c)Iwabu, M., et al.,Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) andAMPK/SIRT1. Nature 464, 1313-1319 (2010).
トレッドミル運動負荷試験計画は15m/分で20分間とした。運動持久力を、マウスが電気ショックを回避することができない回数で20分を除算することによって評価した。
結果は、平均±s.e.m.と表される。2つの群の間の差を、独立両側t検定を使用して評価した。3つ以上の群に関するデータを、分散分析(ANOVA)により評価した。
(1)マウスの骨格筋及び肝臓におけるAMPKのリン酸化の誘導
AdipoRonをマウスに静脈内投与(50mg/kg体重)した場合、野生型(WT)マウスの骨格筋及び肝臓でAMPKのリン酸化を有意に誘導した。これに対し、Adiporl/r2ダブルノックアウトマウスではAMPKのリン酸化は誘導されなかった(図1l、m)。これはAdipoRonが、AdipoR1/R2を介して骨格筋及び肝臓でAMPKを活性化できたことを示している。
i)50mg/kgのAdipoRonをC57B6 WTマウスに経口投与後、AdipoRonの血漿中濃度を測定した。最大血中濃度(Cmax)は11.8μMであった(図2a)。
ii)高脂肪(HF)食誘導肥満マウスを用い、AdipoRonを10日間経口投与(50mg/kg体重)して、インスリン抵抗性を測定した。尚、HF食の摂取は、マウスの体重(図2b)及び食物摂取(図2c)に著しい影響を及ぼさなかった。
その結果、AdipoRonを投与したマウス(WTマウス)では、空腹時血漿グルコース及びインスリンレベル並びに経口グルコース耐性試験(OGTT)中のグルコース及びインスリン応答を著しく低減した(図2d)。血漿中インスリンレベルの低減にも関わらずグルコースレベルが減少したことは、インスリン感受性が改善したことを示す(図2d、f)。
また、Adipor1/r2ダブルノックアウトマウスを用いた同様の試験では、HF食誘導高血糖症及び高インスリン血症を改善できなかった(図2e、f)。
尚、化合物74(No.112254)についても、AdipoRonと同様に、グルコース不耐性を改善することができ、かつインスリ抵抗性を改善することができることが確認された(図7c~f)
iii)更に、10日間の化合物投与の後に、HF食を与えたマウスにおいて高インスリン型正常血糖クランプを行った。AdipoRonを投与したWTマウスにおいて、グルコース注入率(GIR)は著しく増大し(図2h、左)、内因性グルコース産生(EGP)は著しく抑制され(図2h、中)、グルコース処理率(Rd)は著しく増大した(図2h、右)。これらのパラメーターはいずれも、Adipor1/r2ダブルノックアウトマウスにおいてAdipoRonにより改善されなかった(図2i)。
AdipoRonの10日間経口投与(50mg/kg体重)は、HF食を与えたWTマウスにおけるトリグリセリド(TG)及び遊離脂肪酸(FFA)の血漿中濃度を低減させ(図2j、k)、これはAdipor1/r2ダブルノックアウトマウスでは観察されなかった(図2j、k)。
i)AdipoRonを経口投与(50mg/kg体重)したWTマウスの骨格筋では、Ppargc1a及びエストロゲン関連受容体α(Esrra)などのミトコンドリア新生に関与する遺伝子、ミトコンドリア転写因子A(Tfam)などのミトコンドリアDNA複製/翻訳に関与する遺伝子、シトクロームcオキシダーゼサブユニットII(mt-Co2)などの酸化的リン酸化(OXPHOS)に関与する遺伝子の発現を増加させた(図3a)。また、AdipoRonは、WTマウスの骨格筋中のミトコンドリアDNA含量も増加させた(図3b)。これらの作用は、Adipor1/r2ダブルノックアウトマウスでは全体的に消失していた(図3a、b)。
また、AdipoRonは、I型線維マーカーであるTroponin I(slow)(Tnni1)のレベルを増加させた。これに対し、Adipor1/r2ダブルノックアウトマウス(図3a)では増加させなかった。
また、HF食を与えたマウスに、トレッドミルランニングによる強制的な身体運動を行わせ、次いで筋持久力を評価したところ、AdipoRonの投与により、WTマウスにおいては運動持久力を著しく増大させたが、HF食を与えたAdipor1/r2ダブルノックアウトマウス(図3c)では増大させなかった。
ii)また、AdipoRonは、中鎖アシル-CoAデヒドロゲナーゼ(Acadm)などの脂肪酸酸化に関与する遺伝子を著しく増加させた(図3a)。これはWTマウスの骨格筋中のTG含量の低下したことに関連したものであって、HF食を与えたAdipor1/r2ダブルノックアウトマウスに関連したものではない。
iii)また、AdipoRonは、WTマウスの骨格筋ではマンガンスーパーオキシドジスムターゼ(Sod2)(図3a)などの酸化ストレス解毒遺伝子の発現レベルを著しく増大させ、チオバルビツール酸反応性物質(TBARS)などの酸化ストレスマーカーを低下させた(図3h)。当該作用は、HF食を与えたAdipor1/r2ダブルノックアウトマウスでは認められなかった。
i)肝臓のAdipoR1-AMPK経路の活性化は、Ppargc1a、ホスホエノールピルビン酸カルボキシキナーゼ1(Pck1)、及びグルコース-6-ホスファターゼ(G6pc)などの肝グルコース新生に関与する遺伝子の発現を低減させることが報告されている。
AdipoRonは、WTマウスの肝臓において、Ppargc1a及びG6pcの発現を著しく低下させた(図3d)。しかし、当該作用は、HF食を与えたAdipor1/r2ダブルノックアウトマウス(図3d)では認められなかった。
ii)AdipoR2の活性化は、PPARαレベルを増大させかつPPARα経路を活性化させることができ、その結果、脂肪酸の酸化が増大しかつ酸化ストレスが低減する。
AdipoRonは、WTマウスの肝臓において、PPARα(Pparα)をコードする遺伝子、及びその標的遺伝子であってアシル-CoAオキシダーゼ(Acox1)などの脂肪酸燃焼に関与する遺伝子、脱共役タンパク質2(Ucp2)などのエネルギー散逸に関与する遺伝子、及びカタラーゼ(Cat)などの酸化ストレス解毒酵素をコードする遺伝子を含めた遺伝子の発現レベルを増大させた(図3d)。しかし、HF食を与えたAdipor1/r2ダブルノックアウトマウス(図3d)では増大させなかった。また、実際、AdipoRonは、TBARS(図3f)の測定により、TG含量(図3e)及び酸化ストレスをWTマウスの肝臓で著しく低減させた。これに対し、HF食を与えたAdipor1/r2ダブルノックアウトマウスでは当該作用は認められなかった(図3e、f)。
AdipoRonは、TNFα(Tnf)及びMCP-1(Ccl2)などの炎症性サイトカインをコードする遺伝子の発現レベルをWTマウス(図3d)の肝臓では低減させた。これに対し、HF食を与えたAdipor1/r2ダブルノックアウトマウス(図3d)では当該作用は認められなかった。
AdipoRonは、Tnf、IL-6(Il6)、及びCcl2などの炎症誘発性サイトカインをコードする遺伝子の発現レベルをWTマウスのWATで低減させた。これに対し、HF食を与えたAdipor1/r2ダブルノックアウトマウスでは当該作用は認められなかった(図3g)。
AdipoRonは、HF食を与えたWTマウス(図3g)のWATにおいて、TBARS(図3h)、F4/80(Emr1)などのマクロファージマーカーのレベル、特に、CD11c(Itgax)などの古典的に活性化させたM1マクロファージに関するマーカーのレベルを低減させたが、CD206(Mrc1)などの代替的に活性化されたM2マクロファージに関するマーカーのレベルに対しては影響を与えなかった。また、これらの変化は、Adipor1/r2ダブルノックアウトマウス(図3g、h)では認められなかった。
遺伝的に肥満の齧歯類モデルであるLepr-/-(「db/db」とも呼ばれる。)マウスに対して、AdipoRonを2週間経口投与(50mg/kg体重)した場合、アディポネクチンをdb/dbマウスへの腹腔内(IP)投与した場合と同様に、血漿中アディポネクチン濃度が低下し、血漿中グルコースレベルを低下させた(図4a、左、右)。また、体重、食物摂取、肝重量、及びWAT重量に影響を及ぼすことなく(図4b~e)、グルコース不耐性、インスリン抵抗性、及び異脂肪血症を著しく改善した(図4f~i)。
AdipoRonを経口投与したdb/dbマウスにおいては、骨格筋では、ミトコンドリア発生機能及びDNA含量(図5a、b)に関与する遺伝子のレベルと、Acadm及びSod2(図5a)のレベルが著しく増加した。これらはそれぞれ低下したTG含量及びTBARS(図5c、b)に関連したものであった。
肝臓において、AdipoRonは、Ppargc1a、Pck1、及びG6pcの発現を著しく低下させ(図5e)、Pparα及びその標的遺伝子の発現を増加させたが(図5e)、これらは、著しく低減したTG含量(図5f)及び酸化ストレス(図5g)と、炎症誘発性サイトカインをコードする遺伝子の発現レベルの低下とに関連するものであった。
WATでは、AdipoRonは、炎症誘発性サイトカインをコードする遺伝子、マクロファージマーカーの発現レベル、特に古典的に活性化されたM1マクロファージに関するマーカーのレベルを低下させたが、代替的に活性化されたM2マクロファージに関するマーカーのレベルはそうではなかった(図5h)。
通常の固形飼料(a)(それぞれn=50、32、29、及び35)、又は高脂肪食(b)(それぞれn=47、33、35、及び31)を摂取した、野生型、Adipor1-/-、Adipor2-/-、及びAdipor1-/-Adipor2-/-ノックアウトマウスの生存率を毎日記録し、生存曲線を、Kaplan-Meier法を使用してプロットした。その結果、Adipor1/r2ダブルノックアウトマウスが、通常の固形飼料及び高脂肪食の両方の下でWTマウスと比較して短い寿命を示した(図6a及びb)。
HF食は寿命を短くすることが報告されていることから、AdipoRonの経口投与により、HF食により短くなった寿命を延ばすことができるか否かを、検討した。
すなわち、db/dbマウスをランダムに3つの群:通常の固形飼料群(通常の固形飼料、n=20)、高脂肪食群(高脂肪食、n=20)、及び高脂肪食にAdipoRonを加えた群(高脂肪食+AdipoRon、n=20)に分け、これらを日用量30mg kg-1体重のAdipoRonで処置し、生存率を毎日記録した。
その結果、HF食によるdb/dbマウスの寿命は、通常の固形飼料による場合に比べて明らかに短くなり、AdipoRonは、HF食によるdb/dbマウスの短い寿命を著しく回復させた(図6c)。
Claims (12)
- 下記一般式(1):
Aは、置換又は非置換のアリール基、置換又は非置換のヘテロアリール基、置換又は非置換のアリールオキシ基、又はC4~8第3級アルキル基又は-NH2を示し、
Y1は、-(CHR2)a-(ここで、R2は水素原子又はC1~7アルキル基を示し、aは0~2の整数を示す。)又は-CO-を示し、
Xは、CH又はNを示し、
R1は、C1~7アルキル基を示し、複数のR1は同一又は異なっていてもよい
mは0~4の整数を示し、
Y2は、
i)XがCHである場合、
*-O-CH2-CONH-、-O-、*-CONH-、又は
ii)XがNである場合、
*-CONH-(CH2)b-CO-、*-NHCO-Ar1-CH2-、*-NHCO-(CH2)b-又は-CO-(ここで、Ar1は置換基又は非置換のアリーレン基を示し、bは1~3の整数を示し、*はこの位置でZと結合すること示す。)を示し、
Zは、アリール基、ヘテロアリール基及びC3~7シクロアルキル基から選ばれる環状基を示し、
Bは、Zで示される環状基に置換し得る基であり、-CO-R4若しくは-O-R4(ここで、R4はC1~7アルキル基、又は置換又は非置換のフェニル基、置換又は非置換のピリジル基を示す)、-CONR5R6(ここで、R5は水素原子、C3~7シクロアルキル基、C1~4アルコキシC1~4アルキル基、ノルボルネニルC1~4アルキル基、又はAr2-C1~4アルキル基(Ar2は置換又は非置換のアリール又はヘテロアリール基を示す)を示し、R6は水素原子、C1~7アルキル基、C2~4アルケニル基又はC2~4アルキニル基を示す)、C1~7アルキル基、C3~7シクロアルキル基、ハロC1~7アルキル基、フェニル基、ハロゲン原子、-NO2、又は以下で示される基:
nは0~3の整数(nが2以上の場合Bは同一又は異なっていてもよい。)を示す。〕
で表される化合物。 - XがCHでY2が-O-CH2-CONH-であるか、又はXがNでY2が-CONH-(CH2)b-CO-である、請求項1記載の化合物又はその塩。
- 請求項1又は2記載の化合物又はその塩、及び医薬上許容され得る担体を含有する医薬。
- アディポネクチンの産生低下又はアディポネクチン受容体の活性低下に伴って発症する症状又は疾患を予防、改善又は治療するための請求項3記載の医薬。
- アディポネクチンの産生低下又はアディポネクチン受容体の活性低下に伴って発症する症状又は疾患が、II型糖尿病、高血圧症、脂質異常症、ミトコンドリア機能障害、生活習慣病、生活習慣病に起因する悪性腫瘍、又は肥満である請求項4記載の医薬。
- 請求項1又は2記載の化合物又はその塩を有効成分とするアディポネクチン受容体活性化剤。
- アディポネクチン受容体が、AdipoR1及びAdipoR2である請求6記載のアディポネクチン受容体活性化剤。
- 請求項3記載の医薬を患者に投与することを含む、アディポネクチンの産生低下又はアディポネクチン受容体の活性低下に伴って発症する症状又は疾患の予防、改善又は治療方法。
- アディポネクチンの産生低下又はアディポネクチン受容体の活性低下に伴って発症する症状又は疾患が、II型糖尿病、高血圧症、脂質異常症、ミトコンドリア機能障害、生活習慣病、生活習慣病に起因する悪性腫瘍、又は肥満である請求項8記載の予防、改善又は治療方法。
- アディポネクチンの産生低下又はアディポネクチン受容体の活性低下に伴って発症する症状又は疾患の予防、改善又は治療のために使用される、請求項1又は2記載の化合物又はその塩。
- アディポネクチンの産生低下又はアディポネクチン受容体の活性低下に伴って発症する症状又は疾患が、II型糖尿病、高血圧症、脂質異常症、ミトコンドリア機能障害、生活習慣病、生活習慣病に起因する悪性腫瘍、又は肥満である請求項10記載の化合物又はその塩。
- アディポネクチン受容体活性化のため使用される、請求項1又は2記載の化合物又はその塩。
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DATABASE REGISTRY [online] 13 October 2008 (2008-10-13), "BENZAMIDE, 3-CHLORO-4-[[1-[(2-FLUORO-4-METHOXYPHENYL)METHYL]-4- PIPERIDINYL]OXY]-N-(2-METHOXYETHYL)- (CA INDEX NAME)", XP055353898, retrieved from STN Database accession no. 1060425-92-4 * |
DATABASE REGISTRY [online] 13 October 2008 (2008-10-13), "BENZAMIDE, 3-CHLORO-N-(2-METHOXYETHYL)-4-[[1-[(5-METHYL-2-THIENYL)METHYL]- 4-PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353905, retrieved from STN Database accession no. 1060378-36-0 * |
DATABASE REGISTRY [online] 13 October 2008 (2008-10-13), "BENZAMIDE, 3-CHLORO-N-CYCLOPENTYL-4-[[1-[[5-(METHOXYMETHYL)-2- FURANYL]METHYL]-4-PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055332820, retrieved from STN Database accession no. 1060428-05-8 * |
DATABASE REGISTRY [online] 13 October 2008 (2008-10-13), "BENZAMIDE, 4-[[1-(3-FURANYLMETHYL)-4-PIPERIDINYL]OXY]-N-(4- PYRIDINYLMETHYL)- (CA INDEX NAME)", XP055353895, retrieved from STN Database accession no. 1060384-26-0 * |
DATABASE REGISTRY [online] 14 October 2008 (2008-10-14), "BENZAMIDE, 3-CHLORO-4-[[1-(2,2-DIMETHYLPROPYL)-4-PIPERIDINYL]OXY]-N-(3- ETHOXYPROPYL)- (CA INDEX NAME)", XP055353888, retrieved from STN Database accession no. 1061037-69-1 * |
DATABASE REGISTRY [online] 14 October 2008 (2008-10-14), "BENZAMIDE, 4-[[1-[(2-METHYLPHENYL)METHYL]-4-PIPERIDINYL]OXY]-N-(2- PYRIDINYLMETHYL)- (CA INDEX NAME)", XP055353909, retrieved from STN Database accession no. 1060938-35-3 * |
DATABASE REGISTRY [online] 16 April 2009 (2009-04-16), "BENZAMIDE, N-(1-METHYLETHYL)-N-[(1-METHYL-1H-PYRAZOL-4-YL)METHYL]-4-[[1-(2- PYRIDINYLMETHYL)-4-PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353919, retrieved from STN Database accession no. 1135318-71-6 * |
DATABASE REGISTRY [online] 2 November 2008 (2008-11-02), "BENZAMIDE, 3-CHLORO-4-[[1-[(2-FLUORO-5-METHOXYPHENYL)METHYL]-4- PIPERIDINYL]OXY]-N-(2-METHOXYETHYL)- (CA INDEX NAME)", XP055353893, retrieved from STN Database accession no. 1069855-00-0 * |
DATABASE REGISTRY [online] 2 November 2008 (2008-11-02), "BENZAMIDE, 3-CHLORO-4-[[1-[(4-ETHOXYPHENYL)METHYL]-4-PIPERIDINYL]OXY]-N-(2- METHOXYETHYL)- (CA INDEX NAME)", XP055353912, retrieved from STN Database accession no. 1069626-66-9 * |
DATABASE REGISTRY [online] 2 November 2008 (2008-11-02), "BENZAMIDE, 3-CHLORO-N-CYCLOPENTYL-4-[[1-(3-FURANYLMETHYL)-4- PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353942, retrieved from STN Database accession no. 1069620-31-0 * |
DATABASE REGISTRY [online] 2 November 2008 (2008-11-02), "BENZAMIDE, 3-CHLORO-N-CYCLOPENTYL-4-[[1-[(2-METHOXYPHENYL)METHYL]-4- PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353957, retrieved from STN Database accession no. 1069517-18-5 * |
DATABASE REGISTRY [online] 2 November 2008 (2008-11-02), "BENZAMIDE, N-(2-FURANYLMETHYL)-N-2-PROPYN-1-YL-4-[[1-(2-PYRIDINYLMETHYL)-4- PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353944, retrieved from STN Database accession no. 1069716-06-8 * |
DATABASE REGISTRY [online] 2 November 2008 (2008-11-02), "BENZAMIDE, N-2-BUTYN-1-YL-N-(2-FURANYLMETHYL)-4-[[1-(2-PYRIDINYLMETHYL)-4- PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353961, retrieved from STN Database accession no. 1069611-11-5 * |
DATABASE REGISTRY [online] 21 March 2010 (2010-03-21), "BENZAMIDE, N-[2-(1R,2R,4R)-BICYCLO[2.2.1]HEPT-5-EN-2-YLETHYL]-4-[[1-(2- PYRIDINYLMETHYL)-4-PIPERIDINYL]OXY]-, REL- (CA INDEX NAME)", XP055353924, retrieved from STN Database accession no. 1212101-72-8 * |
DATABASE REGISTRY [online] 24 October 2008 (2008-10-24), "BENZAMIDE, 3-CHLORO-4-[[1-(2,2-DIMETHYLPROPYL)-4-PIPERIDINYL]OXY]-N-[2-(4- PYRIDINYL)ETHYL]- (CA INDEX NAME)", XP055353914, retrieved from STN Database accession no. 1065611-82-6 * |
DATABASE REGISTRY [online] 24 October 2008 (2008-10-24), "BENZAMIDE, 3-CHLORO-N-(2-METHOXYETHYL)-4-[[1-(1-METHYL-2-PHENOXYETHYL)-4- PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353900, retrieved from STN Database accession no. 1065552-59-1 * |
DATABASE REGISTRY [online] 27 October 2008 (2008-10-27), "BENZAMIDE, 3-CHLORO-N-CYCLOPENTYL-4-[[1-[(3-HYDROXYPHENYL)METHYL]-4- PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353921, retrieved from STN Database accession no. 1066883-94-0 * |
DATABASE REGISTRY [online] 27 October 2008 (2008-10-27), "BENZAMIDE, N-[2-(4-CHLOROPHENYL)ETHYL]-4-[[1-(2-PYRIDINYLMETHYL)-4- PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353928, retrieved from STN Database accession no. 1066995-66-1 * |
DATABASE REGISTRY [online] 31 July 2002 (2002-07-31), "METHANONE, (3,4-DIMETHOXYPHENYL)[4-[[4-(TRIFLUOROMETHYL)PHENYL]METHYL]-1- PIPERAZINYL]- (CA INDEX NAME)", XP055353970, retrieved from STN Database accession no. 441314-59-6 * |
DATABASE REGISTRY [online] 4 November 2008 (2008-11-04), "BENZAMIDE, 3-CHLORO-4-[[1-[(4-ETHYLPHENYL)METHYL]-4-PIPERIDINYL]OXY]-N-(2- METHOXYETHYL)- (CA INDEX NAME)", XP055353967, retrieved from STN Database accession no. 1070474-65-5 * |
DATABASE REGISTRY [online] 4 November 2008 (2008-11-04), "BENZAMIDE, 3-CHLORO-N-CYCLOPENTYL-4-[[1-[(6-METHYL-2-PYRIDINYL)METHYL]-4- PIPERIDINYL]OXY]- (CA INDEX NAME)", XP055353964, retrieved from STN Database accession no. 1070722-55-2 * |
DATABASE REGISTRY [online] 4 November 2008 (2008-11-04), "BENZAMIDE, 4-[[1-(2,1,3-BENZOXADIAZOL-4-YLMETHYL)-4-PIPERIDINYL]OXY]-3- CHLORO-N-(2-METHOXYETHYL)- (CA INDEX NAME)", XP055353949, retrieved from STN Database accession no. 1070742-57-2 * |
DATABASE REGISTRY [online] 4 November 2008 (2008-11-04), "BENZAMIDE, 4-[[1-(2-BENZOFURANYLMETHYL)-4-PIPERIDINYL]OXY]-3-CHLORO-N-(2- METHOXYETHYL)- (CA INDEX NAME)", XP055353939, retrieved from STN Database accession no. 1070688-89-9 * |
DATABASE REGISTRY [online] 7 June 2012 (2012-06-07), "1-PIPERAZINEPROPANAMIDE, N-CYCLOPROPYL-4-(3-METHOXYBENZOYL)- (CA INDEX NAME)", XP055353973, retrieved from STN Database accession no. 1376314-21-4 * |
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CN104906094A (zh) * | 2015-05-18 | 2015-09-16 | 中国药科大学 | N-(1-苄基哌啶-4-氨基)-2-(4-苯甲酰苯氧基)乙酰胺的新用途 |
CN104906094B (zh) * | 2015-05-18 | 2017-06-09 | 中国药科大学 | N‑(1‑苄基哌啶‑4‑氨基)‑2‑(4‑苯甲酰苯氧基)乙酰胺的用途 |
WO2019159925A1 (ja) | 2018-02-14 | 2019-08-22 | 学校法人東京理科大学 | 軟骨細胞増殖促進剤、軟骨細胞増殖促進方法、及び軟骨細胞増殖促進剤のスクリーニング方法 |
JPWO2019159925A1 (ja) * | 2018-02-14 | 2021-03-04 | 学校法人東京理科大学 | 軟骨細胞増殖促進剤、軟骨細胞増殖促進方法、及び軟骨細胞増殖促進剤のスクリーニング方法 |
JP7266307B2 (ja) | 2018-02-14 | 2023-04-28 | 学校法人東京理科大学 | 軟骨細胞増殖促進剤及び軟骨細胞増殖促進方法 |
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Publication number | Publication date |
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EP3053911B1 (en) | 2020-01-22 |
EP3053911A1 (en) | 2016-08-10 |
JP6664632B2 (ja) | 2020-03-13 |
EP3053911A4 (en) | 2017-04-12 |
US20170298051A1 (en) | 2017-10-19 |
JPWO2015046595A1 (ja) | 2017-03-09 |
US20160214967A1 (en) | 2016-07-28 |
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