PH12014502280B1 - Indole and indazole compounds that activate ampk - Google Patents
Indole and indazole compounds that activate ampk Download PDFInfo
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- PH12014502280B1 PH12014502280B1 PH12014502280A PH12014502280A PH12014502280B1 PH 12014502280 B1 PH12014502280 B1 PH 12014502280B1 PH 12014502280 A PH12014502280 A PH 12014502280A PH 12014502280 A PH12014502280 A PH 12014502280A PH 12014502280 B1 PH12014502280 B1 PH 12014502280B1
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- Philippines
- Prior art keywords
- alkyl
- alkoxy
- hydroxy
- independently
- formula
- Prior art date
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title abstract description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title abstract description 4
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title abstract description 3
- 101100321932 Rattus norvegicus Prkaa2 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 327
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 518
- 229910052731 fluorine Inorganic materials 0.000 claims description 388
- 150000003839 salts Chemical class 0.000 claims description 310
- 229910052739 hydrogen Inorganic materials 0.000 claims description 276
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 191
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 52
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 51
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- HFTSUSPGKRQUGS-UHFFFAOYSA-N 6-chloro-5-[2-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1h-indole-3-carboxylic acid Chemical group C1=C2C(C(=O)O)=CNC2=CC(Cl)=C1C(C(=C1)F)=CC=C1C1(O)CCC1 HFTSUSPGKRQUGS-UHFFFAOYSA-N 0.000 claims 1
- VJRMUMYLSWYBNV-UHFFFAOYSA-N 6-chloro-5-[3-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1h-indole-3-carboxylic acid Chemical compound C1=C2C(C(=O)O)=CNC2=CC(Cl)=C1C(C=C1F)=CC=C1C1(O)CCC1 VJRMUMYLSWYBNV-UHFFFAOYSA-N 0.000 claims 1
- FHQXLWCFSUSXBF-UHFFFAOYSA-N 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1h-indole-3-carboxylic acid Chemical compound C1=C2C(C(=O)O)=CNC2=CC(Cl)=C1C(C=C1)=CC=C1C1(O)CCC1 FHQXLWCFSUSXBF-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 abstract description 30
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 abstract description 30
- 238000000034 method Methods 0.000 abstract description 17
- 230000004913 activation Effects 0.000 abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 12
- 230000001668 ameliorated effect Effects 0.000 abstract description 7
- UPJKSWLLCONYMW-UHFFFAOYSA-N 5'-Adenosine monophosphate Natural products COc1cc(O)c(C(=O)C)c(OC2OC(COC3OC(C)C(O)C(O)C3O)C(O)C(O)C2O)c1 UPJKSWLLCONYMW-UHFFFAOYSA-N 0.000 abstract description 6
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 abstract description 6
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 description 1172
- 125000003545 alkoxy group Chemical group 0.000 description 752
- 229910052736 halogen Inorganic materials 0.000 description 332
- 150000002367 halogens Chemical class 0.000 description 331
- 125000005843 halogen group Chemical group 0.000 description 315
- 125000004093 cyano group Chemical group *C#N 0.000 description 297
- 125000001424 substituent group Chemical group 0.000 description 285
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 247
- -1 1H-tetrazol-5-yl Chemical group 0.000 description 240
- 125000003118 aryl group Chemical group 0.000 description 193
- 125000000623 heterocyclic group Chemical group 0.000 description 183
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 168
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 168
- 239000000460 chlorine Chemical group 0.000 description 133
- 229910052801 chlorine Inorganic materials 0.000 description 133
- 239000011651 chromium Substances 0.000 description 127
- 125000000753 cycloalkyl group Chemical group 0.000 description 121
- 125000001072 heteroaryl group Chemical group 0.000 description 117
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 116
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 108
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 92
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 86
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 82
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 82
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 81
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 58
- 125000000000 cycloalkoxy group Chemical group 0.000 description 57
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 54
- 125000002393 azetidinyl group Chemical group 0.000 description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 54
- 125000001425 triazolyl group Chemical group 0.000 description 54
- 125000004193 piperazinyl group Chemical group 0.000 description 53
- 125000003386 piperidinyl group Chemical group 0.000 description 53
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 51
- 229910052702 rhenium Inorganic materials 0.000 description 49
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 48
- 229910052757 nitrogen Inorganic materials 0.000 description 48
- 125000004076 pyridyl group Chemical group 0.000 description 48
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 46
- 241000124008 Mammalia Species 0.000 description 41
- 125000003396 thiol group Chemical class [H]S* 0.000 description 35
- 125000004414 alkyl thio group Chemical group 0.000 description 29
- 206010012601 diabetes mellitus Diseases 0.000 description 16
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 16
- 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 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
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- RTRQQBHATOEIAF-UUOKFMHZSA-N acadesine Chemical compound NC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RTRQQBHATOEIAF-UUOKFMHZSA-N 0.000 description 7
- 229960003000 acadesine Drugs 0.000 description 7
- 125000004104 aryloxy group Chemical group 0.000 description 7
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 7
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- 125000005553 heteroaryloxy group Chemical group 0.000 description 7
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- 125000005129 aryl carbonyl group Chemical group 0.000 description 6
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 208000030761 polycystic kidney disease Diseases 0.000 description 6
- 229910052684 Cerium Inorganic materials 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- MCTFEMGZCDYRSE-UHFFFAOYSA-N 5-(4-bromophenyl)-1h-indole-3-carboxamide Chemical compound C1=C2C(C(=O)N)=CNC2=CC=C1C1=CC=C(Br)C=C1 MCTFEMGZCDYRSE-UHFFFAOYSA-N 0.000 description 4
- 229910014585 C2-Ce Inorganic materials 0.000 description 4
- 208000032928 Dyslipidaemia Diseases 0.000 description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 description 4
- 125000005138 alkoxysulfonyl group Chemical group 0.000 description 4
- 125000004419 alkynylene group Chemical group 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 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 4
- 208000020832 chronic kidney disease Diseases 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 208000030159 metabolic disease Diseases 0.000 description 4
- IDPDUOKTSMTTTI-UHFFFAOYSA-N 5-[4-(2,6-dihydroxyphenyl)phenyl]-1h-indole-3-carboxamide Chemical compound C1=C2C(C(=O)N)=CNC2=CC=C1C(C=C1)=CC=C1C1=C(O)C=CC=C1O IDPDUOKTSMTTTI-UHFFFAOYSA-N 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 125000004450 alkenylene group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- 229960003105 metformin Drugs 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 210000000557 podocyte Anatomy 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 2
- 102000011690 Adiponectin Human genes 0.000 description 2
- 108010076365 Adiponectin Proteins 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 2
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
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- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical class C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- MPLLLQUZNJSVTK-UHFFFAOYSA-N 5-[3-[4-[2-(4-fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1CCCC(C=C1)=CC=C1OCCC1=CC=C(F)C=C1 MPLLLQUZNJSVTK-UHFFFAOYSA-N 0.000 description 1
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- 102000004070 NADPH Oxidase 4 Human genes 0.000 description 1
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- 108010002998 NADPH Oxidases Proteins 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
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| ES2912657T3 (es) | 2017-08-02 | 2022-05-26 | Vertex Pharma | Procesos para preparar compuestos de pirrolidina |
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- 2014-10-09 PH PH12014502280A patent/PH12014502280B1/en unknown
- 2014-10-09 NI NI201400121A patent/NI201400121A/es unknown
- 2014-10-10 GT GT201400215A patent/GT201400215A/es unknown
- 2014-10-10 CO CO14225646A patent/CO7091185A2/es active IP Right Grant
- 2014-10-20 US US14/518,165 patent/US20150038484A1/en not_active Abandoned
- 2014-12-01 EC ECIEPI201426271A patent/ECSP14026271A/es unknown
-
2017
- 2017-08-07 CY CY20171100844T patent/CY1119194T1/el unknown
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