EA026300B1 - Активаторы ampk и их применение в терапевтических целях - Google Patents

Info

Publication number

EA026300B1

EA026300B1 EA201500064A EA201500064A EA026300B1 EA 026300 B1 EA026300 B1 EA 026300B1 EA 201500064 A EA201500064 A EA 201500064A EA 201500064 A EA201500064 A EA 201500064A EA 026300 B1 EA026300 B1 EA 026300B1

Authority

EA

Eurasian Patent Office

Prior art keywords

chloro

pyridin

thieno

hydroxy

groups

Prior art date

2012-06-29

Links

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• Global Dossier
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• 239000012190 activator Substances 0.000 title abstract description 9
• 230000001225 therapeutic effect Effects 0.000 title description 4
• 101100321932 Rattus norvegicus Prkaa2 gene Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 126
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 26
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 21
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
• 208000008589 Obesity Diseases 0.000 claims abstract description 17
• 201000011510 cancer Diseases 0.000 claims abstract description 17
• 235000020824 obesity Nutrition 0.000 claims abstract description 17
• 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 16
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
• 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 13
• 208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 13
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims abstract description 13
• 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 12
• 206010020772 Hypertension Diseases 0.000 claims abstract description 12
• 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 12
• 208000019423 liver disease Diseases 0.000 claims abstract description 12
• 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 11
• 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 11
• 206010061218 Inflammation Diseases 0.000 claims abstract description 11
• 206010038923 Retinopathy Diseases 0.000 claims abstract description 11
• 208000006575 hypertriglyceridemia Diseases 0.000 claims abstract description 11
• 230000004054 inflammatory process Effects 0.000 claims abstract description 11
• 201000001119 neuropathy Diseases 0.000 claims abstract description 11
• 230000007823 neuropathy Effects 0.000 claims abstract description 11
• 150000003839 salts Chemical class 0.000 claims description 41
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 125000000217 alkyl group Chemical group 0.000 claims description 17
• 125000003545 alkoxy group Chemical group 0.000 claims description 15
• 125000005843 halogen group Chemical group 0.000 claims description 15
• 201000010099 disease Diseases 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
• 208000010706 fatty liver disease Diseases 0.000 claims description 11
• 208000017442 Retinal disease Diseases 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 8
• 239000012453 solvate Substances 0.000 claims description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims description 5
• 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 5
• KPNBBJGVCJQHBR-UHFFFAOYSA-N 2-chloro-4-hydroxy-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound C1=CC=2CCCCC=2C(O)=C1C(C=1C=2O)=C(Cl)SC=1NC(=O)C=2C1=CC=CC=C1 KPNBBJGVCJQHBR-UHFFFAOYSA-N 0.000 claims description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• 229920006395 saturated elastomer Polymers 0.000 claims description 4
• DTHWQIYDEOQRJM-UHFFFAOYSA-N 2-chloro-3-(2,3-dihydro-1h-inden-5-yl)-4-hydroxy-5-(4-methoxyphenyl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound C1=CC(OC)=CC=C1C(C(N1)=O)=C(O)C2=C1SC(Cl)=C2C1=CC=C(CCC2)C2=C1 DTHWQIYDEOQRJM-UHFFFAOYSA-N 0.000 claims description 3
• BROPJRWDUIFHJI-UHFFFAOYSA-N 2-chloro-4-hydroxy-3-(4-hydroxy-2,3-dihydro-1h-inden-5-yl)-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound OC1=C2CCCC2=CC=C1C(C=1C=2O)=C(Cl)SC=1NC(=O)C=2C1=CC=CC=C1 BROPJRWDUIFHJI-UHFFFAOYSA-N 0.000 claims description 3
• OVOGQBVANWWOJB-UHFFFAOYSA-N 2-chloro-4-hydroxy-5-pyridin-3-yl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound O=C1NC=2SC(Cl)=C(C=3C=C4CCCCC4=CC=3)C=2C(O)=C1C1=CC=CN=C1 OVOGQBVANWWOJB-UHFFFAOYSA-N 0.000 claims description 3
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• QACVLUHLIOSBJI-UHFFFAOYSA-M sodium;2-chloro-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-6-oxo-5-phenyl-7h-thieno[2,3-b]pyridin-4-olate Chemical compound [Na+].OC1=C2CCCCC2=CC=C1C(C=1C=2[O-])=C(Cl)SC=1NC(=O)C=2C1=CC=CC=C1 QACVLUHLIOSBJI-UHFFFAOYSA-M 0.000 claims description 3
• UGVUIHZLKYZUFU-UHFFFAOYSA-N 2-chloro-3-(2,3-dihydro-1h-inden-5-yl)-4-hydroxy-5-(3-methoxyphenyl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC=CC(C=2C(NC=3SC(Cl)=C(C=3C=2O)C=2C=C3CCCC3=CC=2)=O)=C1 UGVUIHZLKYZUFU-UHFFFAOYSA-N 0.000 claims description 2
• ZZIJTLCVZPHSRL-UHFFFAOYSA-N 2-chloro-3-(2,3-dihydro-1h-inden-5-yl)-4-hydroxy-5-(3-methylphenyl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound CC1=CC=CC(C=2C(NC=3SC(Cl)=C(C=3C=2O)C=2C=C3CCCC3=CC=2)=O)=C1 ZZIJTLCVZPHSRL-UHFFFAOYSA-N 0.000 claims description 2
• XERZDWSHUNNSJU-UHFFFAOYSA-N 2-chloro-3-(2,3-dihydro-1h-inden-5-yl)-4-hydroxy-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound O=C1NC=2SC(Cl)=C(C=3C=C4CCCC4=CC=3)C=2C(O)=C1C1=CC=CC=C1 XERZDWSHUNNSJU-UHFFFAOYSA-N 0.000 claims description 2
• PDXRFUXVYGWFJX-UHFFFAOYSA-N 2-chloro-3-(2,3-dihydro-1h-inden-5-yl)-4-hydroxy-5-pyridin-3-yl-7h-thieno[2,3-b]pyridin-6-one Chemical compound O=C1NC=2SC(Cl)=C(C=3C=C4CCCC4=CC=3)C=2C(O)=C1C1=CC=CN=C1 PDXRFUXVYGWFJX-UHFFFAOYSA-N 0.000 claims description 2
• RBELYHIQPKVNMM-UHFFFAOYSA-N 2-chloro-3-(2,3-dihydro-1h-inden-5-yl)-5-(4-fluorophenyl)-4-hydroxy-7h-thieno[2,3-b]pyridin-6-one Chemical compound O=C1NC=2SC(Cl)=C(C=3C=C4CCCC4=CC=3)C=2C(O)=C1C1=CC=C(F)C=C1 RBELYHIQPKVNMM-UHFFFAOYSA-N 0.000 claims description 2
• SLOWYHYYVJFROA-UHFFFAOYSA-N 2-chloro-4-hydroxy-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-5-(3-methylphenyl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound CC1=CC=CC(C=2C(NC=3SC(Cl)=C(C=3C=2O)C=2C(=C3CCCCC3=CC=2)O)=O)=C1 SLOWYHYYVJFROA-UHFFFAOYSA-N 0.000 claims description 2
• AFZAGQJTHUJQDD-UHFFFAOYSA-N 2-chloro-4-hydroxy-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-5-(4-methylphenyl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound C1=CC(C)=CC=C1C(C(N1)=O)=C(O)C2=C1SC(Cl)=C2C1=CC=C(CCCC2)C2=C1O AFZAGQJTHUJQDD-UHFFFAOYSA-N 0.000 claims description 2
• YYWARFMNDDMOMI-UHFFFAOYSA-N 2-chloro-4-hydroxy-5-phenyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound O=C1NC=2SC(Cl)=C(C=3C=C4CCCCC4=CC=3)C=2C(O)=C1C1=CC=CC=C1 YYWARFMNDDMOMI-UHFFFAOYSA-N 0.000 claims description 2
• MJIAXJHADPRYNY-UHFFFAOYSA-N 2-chloro-5-(2-fluorophenyl)-4-hydroxy-3-(4-hydroxy-2,3-dihydro-1h-inden-5-yl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound OC1=C2CCCC2=CC=C1C(C=1C=2O)=C(Cl)SC=1NC(=O)C=2C1=CC=CC=C1F MJIAXJHADPRYNY-UHFFFAOYSA-N 0.000 claims description 2
• XVNOTJOXPKDQGN-UHFFFAOYSA-N 2-chloro-5-(3-fluorophenyl)-4-hydroxy-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound C1=CC=2CCCCC=2C(O)=C1C(C=1C=2O)=C(Cl)SC=1NC(=O)C=2C1=CC=CC(F)=C1 XVNOTJOXPKDQGN-UHFFFAOYSA-N 0.000 claims description 2
• WVPFNPJRPTZIIS-UHFFFAOYSA-N 2-chloro-5-(3-fluorophenyl)-4-hydroxy-3-(4-hydroxy-2,3-dihydro-1h-inden-5-yl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound OC1=C2CCCC2=CC=C1C(C=1C=2O)=C(Cl)SC=1NC(=O)C=2C1=CC=CC(F)=C1 WVPFNPJRPTZIIS-UHFFFAOYSA-N 0.000 claims description 2
• CNVSWEKTKGMHEA-UHFFFAOYSA-N 2-chloro-5-(4-fluorophenyl)-4-hydroxy-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound C1=CC=2CCCCC=2C(O)=C1C(C=1C=2O)=C(Cl)SC=1NC(=O)C=2C1=CC=C(F)C=C1 CNVSWEKTKGMHEA-UHFFFAOYSA-N 0.000 claims description 2
• AFAWELPFAPAJAN-UHFFFAOYSA-N 2-chloro-5-(4-fluorophenyl)-4-hydroxy-3-(4-hydroxy-2,3-dihydro-1h-inden-5-yl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound OC1=C2CCCC2=CC=C1C(C=1C=2O)=C(Cl)SC=1NC(=O)C=2C1=CC=C(F)C=C1 AFAWELPFAPAJAN-UHFFFAOYSA-N 0.000 claims description 2
• 150000004683 dihydrates Chemical class 0.000 claims description 2
• YZTWYBVYYFTGLJ-UHFFFAOYSA-L disodium;2-chloro-3-(1-oxido-5,6,7,8-tetrahydronaphthalen-2-yl)-6-oxo-5-phenyl-7h-thieno[2,3-b]pyridin-4-olate Chemical compound [Na+].[Na+].C1=CC=2CCCCC=2C([O-])=C1C(C=1C=2[O-])=C(Cl)SC=1NC(=O)C=2C1=CC=CC=C1 YZTWYBVYYFTGLJ-UHFFFAOYSA-L 0.000 claims description 2
• 150000004682 monohydrates Chemical group 0.000 claims description 2
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
• LWVVLKOKCHODDJ-UHFFFAOYSA-M potassium 2-chloro-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-6-oxo-5-phenyl-7H-thieno[2,3-b]pyridin-4-olate Chemical compound [K+].Oc1c(ccc2CCCCc12)-c1c(Cl)sc2[nH]c(=O)c(-c3ccccc3)c([O-])c12 LWVVLKOKCHODDJ-UHFFFAOYSA-M 0.000 claims description 2
• WQSWVILYSJZJQS-UHFFFAOYSA-K trisodium;2-chloro-3-(1-oxido-5,6,7,8-tetrahydronaphthalen-2-yl)-5-phenylthieno[2,3-b]pyridine-4,6-diolate Chemical compound [Na+].[Na+].[Na+].[O-]C1=NC=2SC(Cl)=C(C=3C(=C4CCCCC4=CC=3)[O-])C=2C([O-])=C1C1=CC=CC=C1 WQSWVILYSJZJQS-UHFFFAOYSA-K 0.000 claims description 2
• ODTPSVZPAACGKZ-UHFFFAOYSA-N 3-[2-chloro-3-(2,3-dihydro-1h-inden-5-yl)-4-hydroxy-6-oxo-7h-thieno[2,3-b]pyridin-5-yl]benzonitrile Chemical compound O=C1NC=2SC(Cl)=C(C=3C=C4CCCC4=CC=3)C=2C(O)=C1C1=CC=CC(C#N)=C1 ODTPSVZPAACGKZ-UHFFFAOYSA-N 0.000 claims 1
• UFJUAKAFXMCTNU-UHFFFAOYSA-N 3-[2-chloro-4-hydroxy-6-oxo-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-7h-thieno[2,3-b]pyridin-5-yl]benzonitrile Chemical compound O=C1NC=2SC(Cl)=C(C=3C=C4CCCCC4=CC=3)C=2C(O)=C1C1=CC=CC(C#N)=C1 UFJUAKAFXMCTNU-UHFFFAOYSA-N 0.000 claims 1
• 102100040055 Amyloid beta precursor like protein 1 Human genes 0.000 claims 1
• 101710168919 Amyloid beta precursor like protein 1 Proteins 0.000 claims 1
• 210000004204 blood vessel Anatomy 0.000 claims 1
• 102000014156 AMP-Activated Protein Kinases Human genes 0.000 abstract description 55
• 108010011376 AMP-Activated Protein Kinases Proteins 0.000 abstract description 55
• 230000004913 activation Effects 0.000 abstract description 23
• 230000001105 regulatory effect Effects 0.000 abstract description 6
• 208000035475 disorder Diseases 0.000 abstract description 2
• 206010019708 Hepatic steatosis Diseases 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
• 239000000203 mixture Substances 0.000 description 45
• 239000011541 reaction mixture Substances 0.000 description 45
• -1 hydroxy, methoxy, ethoxy, amino, diethylamino, diethylamino, methyl Chemical group 0.000 description 40
• 239000002904 solvent Substances 0.000 description 37
• 235000002639 sodium chloride Nutrition 0.000 description 35
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 28
• 239000003921 oil Substances 0.000 description 24
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• 239000002585 base Substances 0.000 description 22
• 230000000694 effects Effects 0.000 description 22
• 235000019198 oils Nutrition 0.000 description 22
• 238000006243 chemical reaction Methods 0.000 description 20
• 239000000741 silica gel Substances 0.000 description 20
• 229910002027 silica gel Inorganic materials 0.000 description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
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• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
• 239000004480 active ingredient Substances 0.000 description 18
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• 235000011152 sodium sulphate Nutrition 0.000 description 18
• 239000007787 solid Substances 0.000 description 18
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
• 239000012267 brine Substances 0.000 description 16
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
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• 238000000034 method Methods 0.000 description 13
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 12
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• 125000003118 aryl group Chemical group 0.000 description 12
• 239000008103 glucose Substances 0.000 description 12
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
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• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
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• 125000004390 alkyl sulfonyl group Chemical group 0.000 description 10
• 150000003857 carboxamides Chemical class 0.000 description 10
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• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 10
• RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 9
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 9
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• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
• 150000001412 amines Chemical class 0.000 description 8
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
• 125000004663 dialkyl amino group Chemical group 0.000 description 8
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
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