US20230250092A1 - Glucagon-like peptide1 receptor agonists - Google Patents
Glucagon-like peptide1 receptor agonists Download PDFInfo
- Publication number
- US20230250092A1 US20230250092A1 US18/194,155 US202318194155A US2023250092A1 US 20230250092 A1 US20230250092 A1 US 20230250092A1 US 202318194155 A US202318194155 A US 202318194155A US 2023250092 A1 US2023250092 A1 US 2023250092A1
- Authority
- US
- United States
- Prior art keywords
- phenyl
- methyl
- fluoro
- compound
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 28
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 9
- 241000124008 Mammalia Species 0.000 claims description 19
- 239000008280 blood Substances 0.000 claims description 10
- 210000004369 blood Anatomy 0.000 claims description 10
- 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 claims description 9
- 239000008103 glucose Substances 0.000 claims description 9
- 201000001421 hyperglycemia Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
- 239000000203 mixture Substances 0.000 description 60
- 238000002360 preparation method Methods 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- 239000012141 concentrate Substances 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 239000007832 Na2SO4 Substances 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 23
- -1 erbumine salt Chemical class 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 20
- 239000011780 sodium chloride Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 238000005192 partition Methods 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 12
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 5
- 102000056448 human GLP1R Human genes 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
- GEPGBRNJFZVYFN-UHFFFAOYSA-N 4-[(6-bromopyridin-2-yl)oxymethyl]-3-fluorobenzonitrile Chemical compound BrC1=CC=CC(=N1)OCC1=C(C=C(C#N)C=C1)F GEPGBRNJFZVYFN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- CEYHKCZODRRMMV-VIFPVBQESA-N methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1 CEYHKCZODRRMMV-VIFPVBQESA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- COYPLDIXZODDDL-UHFFFAOYSA-M 3h-benzimidazole-5-carboxylate Chemical compound [O-]C(=O)C1=CC=C2N=CNC2=C1 COYPLDIXZODDDL-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QZQFEJHDNYVBKL-DEOSSOPVSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1C)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)O)C[C@H]1OCC1)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1C)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)O)C[C@H]1OCC1)F)F QZQFEJHDNYVBKL-DEOSSOPVSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 3
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001502 aryl halides Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000105 evaporative light scattering detection Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 238000002821 scintillation proximity assay Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-O tert-butylammonium Chemical compound CC(C)(C)[NH3+] YBRBMKDOPFTVDT-UHFFFAOYSA-O 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- YKJBUISQMKCZTM-UHFFFAOYSA-N (4-bromo-2-fluoro-3-methylphenyl)methanol Chemical compound Cc1c(F)c(CO)ccc1Br YKJBUISQMKCZTM-UHFFFAOYSA-N 0.000 description 2
- DIXAGUQFYRVLRS-UHFFFAOYSA-N (4-bromo-2-fluoro-5-methylphenyl)methanol Chemical compound CC1=CC(CO)=C(F)C=C1Br DIXAGUQFYRVLRS-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BJIDGKVVRDUBKM-UHFFFAOYSA-N 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile Chemical compound CC1=CC(CC#N)=C(F)C=C1Br BJIDGKVVRDUBKM-UHFFFAOYSA-N 0.000 description 2
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 2
- ZESZAIOGACKOMB-UHFFFAOYSA-N 4-(bromomethyl)-3-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC=C1CBr ZESZAIOGACKOMB-UHFFFAOYSA-N 0.000 description 2
- MKKJTADNAAPSQP-UHFFFAOYSA-N 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyridin-2-one Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(=O)N1 MKKJTADNAAPSQP-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- IDBFVWZXXQFWOE-VWLOTQADSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C(=C(C=C1)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)F)C)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C(=C(C=C1)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)F)C)F IDBFVWZXXQFWOE-VWLOTQADSA-N 0.000 description 2
- YTOVQJQUYNWGPW-SANMLTNESA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C=C(C=C1)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)C)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C=C(C=C1)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)C)F YTOVQJQUYNWGPW-SANMLTNESA-N 0.000 description 2
- OCUMKNALNCGCAR-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C=C(C=C1)CC(=O)O)C)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C=C(C=C1)CC(=O)O)C)F OCUMKNALNCGCAR-UHFFFAOYSA-N 0.000 description 2
- PCBJBDAPOPLMFF-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C=C(C=C1)CC(=O)OC)C)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C=C(C=C1)CC(=O)OC)C)F PCBJBDAPOPLMFF-UHFFFAOYSA-N 0.000 description 2
- PAQVEHHGZIEZPM-QHCPKHFHSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)F)F PAQVEHHGZIEZPM-QHCPKHFHSA-N 0.000 description 2
- YMWFCLIZOZYOIG-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)CC(=O)O)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)CC(=O)O)F)F YMWFCLIZOZYOIG-UHFFFAOYSA-N 0.000 description 2
- PEFDGJRIYDRHGL-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)CC(=O)OC)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)CC(=O)OC)F)F PEFDGJRIYDRHGL-UHFFFAOYSA-N 0.000 description 2
- DFAYRTODMDPGEC-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1)CC(=O)O)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1)CC(=O)O)F)F DFAYRTODMDPGEC-UHFFFAOYSA-N 0.000 description 2
- LIELJQNCABRACL-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1)CC(=O)OC)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1)CC(=O)OC)F)F LIELJQNCABRACL-UHFFFAOYSA-N 0.000 description 2
- TVSVJERBURYKIY-VWLOTQADSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)OC)C[C@H]1OCC1)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)OC)C[C@H]1OCC1)F)F TVSVJERBURYKIY-VWLOTQADSA-N 0.000 description 2
- YGZOMSRUZDPHKX-VWLOTQADSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1C)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1C)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)F)F YGZOMSRUZDPHKX-VWLOTQADSA-N 0.000 description 2
- QFLVWIAXMLWUIW-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1C)CC(=O)O)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1C)CC(=O)O)F)F QFLVWIAXMLWUIW-UHFFFAOYSA-N 0.000 description 2
- LEHWXXQVIBMMHB-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1C)CC(=O)OC)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C=C1C)CC(=O)OC)F)F LEHWXXQVIBMMHB-UHFFFAOYSA-N 0.000 description 2
- LBERDGQGLPFQKN-SANMLTNESA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC=C(C=C1)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC=C(C=C1)CC(=O)NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1)F LBERDGQGLPFQKN-SANMLTNESA-N 0.000 description 2
- DAFAYIUNERWMAJ-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC=C(C=C1)CC(=O)O)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC=C(C=C1)CC(=O)O)F DAFAYIUNERWMAJ-UHFFFAOYSA-N 0.000 description 2
- YLWUUDXJHNIKDF-UHFFFAOYSA-N CC1=C(C=CC(=C1F)CC(=O)OC)C2=NC(=CC=C2)OCC3=C(C=C(C=C3)C#N)F Chemical compound CC1=C(C=CC(=C1F)CC(=O)OC)C2=NC(=CC=C2)OCC3=C(C=C(C=C3)C#N)F YLWUUDXJHNIKDF-UHFFFAOYSA-N 0.000 description 2
- GZTOCYILDNMEOT-UHFFFAOYSA-N Cc1c(Br)ccc(CC#N)c1F Chemical compound Cc1c(Br)ccc(CC#N)c1F GZTOCYILDNMEOT-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- OYCJYMBJQDASQT-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C1=NC(=CC=C1)O)F)CC(=O)OC Chemical compound FC1=C(C(=CC(=C1)C1=NC(=CC=C1)O)F)CC(=O)OC OYCJYMBJQDASQT-UHFFFAOYSA-N 0.000 description 2
- FYFQCQDKLKYGHM-UHFFFAOYSA-N FC1=C(C=C(C(=C1)C1=NC(=CC=C1)O)C)CC(=O)OC Chemical compound FC1=C(C=C(C(=C1)C1=NC(=CC=C1)O)C)CC(=O)OC FYFQCQDKLKYGHM-UHFFFAOYSA-N 0.000 description 2
- MBKCFDNHVJOXSR-UHFFFAOYSA-N FC1=C(C=CC(=C1C)C1=NC(=CC=C1)O)CC(=O)OC Chemical compound FC1=C(C=CC(=C1C)C1=NC(=CC=C1)O)CC(=O)OC MBKCFDNHVJOXSR-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 238000013262 cAMP assay Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000008004 cell lysis buffer Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000003821 enantio-separation Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000010030 glucose lowering effect Effects 0.000 description 2
- 238000007446 glucose tolerance test Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 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 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- IBZQCHWAYCYBEB-UHFFFAOYSA-N methyl 2-(4-bromo-2,6-difluorophenyl)acetate Chemical compound C1=C(C(=C(C=C1Br)F)CC(=O)OC)F IBZQCHWAYCYBEB-UHFFFAOYSA-N 0.000 description 2
- MSRMSGOTPCGMCL-UHFFFAOYSA-N methyl 2-(4-bromo-2-fluoro-3-methylphenyl)acetate Chemical compound COC(=O)Cc1ccc(Br)c(C)c1F MSRMSGOTPCGMCL-UHFFFAOYSA-N 0.000 description 2
- FKTJIHHOCPOUQG-UHFFFAOYSA-N methyl 2-(4-bromo-2-fluoro-5-methylphenyl)acetate Chemical compound BrC1=CC(=C(C=C1C)CC(=O)OC)F FKTJIHHOCPOUQG-UHFFFAOYSA-N 0.000 description 2
- HTYWVEUBCLGQES-VIFPVBQESA-N methyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate Chemical compound [N+](=O)([O-])C1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1 HTYWVEUBCLGQES-VIFPVBQESA-N 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- 238000003653 radioligand binding assay Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010956 selective crystallization Methods 0.000 description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 2
- 238000004808 supercritical fluid chromatography Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- NFGJQVPDPIGBJE-UHFFFAOYSA-N 2-(4-boronophenyl)acetic acid Chemical compound OB(O)C1=CC=C(CC(O)=O)C=C1 NFGJQVPDPIGBJE-UHFFFAOYSA-N 0.000 description 1
- GBFFYYLXGIHKLU-UHFFFAOYSA-N 2-(4-bromo-2,6-difluorophenyl)acetic acid Chemical compound OC(=O)CC1=C(F)C=C(Br)C=C1F GBFFYYLXGIHKLU-UHFFFAOYSA-N 0.000 description 1
- RQOWDNZXQGUFQZ-UHFFFAOYSA-N 2-(4-bromo-2-fluoro-5-methylphenyl)acetic acid Chemical compound CC1=CC(CC(O)=O)=C(F)C=C1Br RQOWDNZXQGUFQZ-UHFFFAOYSA-N 0.000 description 1
- LHFFNLRLDVODNC-UHFFFAOYSA-N 2-(4-bromo-3-methylphenyl)acetic acid Chemical compound CC1=CC(CC(O)=O)=CC=C1Br LHFFNLRLDVODNC-UHFFFAOYSA-N 0.000 description 1
- ZIDIKYIZXMYHAW-UHFFFAOYSA-N 2-bromo-6-fluoropyridine Chemical compound FC1=CC=CC(Br)=N1 ZIDIKYIZXMYHAW-UHFFFAOYSA-N 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- YGAURRAHPYQHDC-UHFFFAOYSA-N 3-fluoro-4-(hydroxymethyl)benzonitrile Chemical compound OCC1=CC=C(C#N)C=C1F YGAURRAHPYQHDC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QGMGHALXLXKCBD-UHFFFAOYSA-N 4-amino-n-(2-aminophenyl)benzamide Chemical compound C1=CC(N)=CC=C1C(=O)NC1=CC=CC=C1N QGMGHALXLXKCBD-UHFFFAOYSA-N 0.000 description 1
- PIMDCUNZRUXGME-UHFFFAOYSA-N 4-bromo-2-fluoro-3-methylbenzoic acid Chemical compound CC1=C(Br)C=CC(C(O)=O)=C1F PIMDCUNZRUXGME-UHFFFAOYSA-N 0.000 description 1
- PJJJBQHQICIYJH-UHFFFAOYSA-N 4-bromo-2-fluoro-5-methylbenzoic acid Chemical compound CC1=CC(C(O)=O)=C(F)C=C1Br PJJJBQHQICIYJH-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OXRPXFQQZQQNGY-UHFFFAOYSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C(=C(C=C1)CC(=O)O)F)C)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C(=C(C=C1)CC(=O)O)F)C)F OXRPXFQQZQQNGY-UHFFFAOYSA-N 0.000 description 1
- NTWPVHUSHHLTEN-DEOSSOPVSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C(=C(C=C1)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)O)C[C@H]1OCC1)F)C)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C(=C(C=C1)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)O)C[C@H]1OCC1)F)C)F NTWPVHUSHHLTEN-DEOSSOPVSA-N 0.000 description 1
- AHNWKZGQCCULJE-VWLOTQADSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C=C(C=C1)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)O)C[C@H]1OCC1)C)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=C(C=C(C=C1)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)O)C[C@H]1OCC1)C)F AHNWKZGQCCULJE-VWLOTQADSA-N 0.000 description 1
- YHWOWBZYTVVUQA-QFIPXVFZSA-N C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)O)C[C@H]1OCC1)F)F Chemical compound C(#N)C1=CC(=C(C=C1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)CC=1N(C2=C(N=1)C=CC(=C2)C(=O)O)C[C@H]1OCC1)F)F YHWOWBZYTVVUQA-QFIPXVFZSA-N 0.000 description 1
- BYBMBPGYOCDKOR-DEOSSOPVSA-N C(#N)C1=CC(=C(COC2=CC=CC(=N2)C2=CC(=C(CC3=NC4=C(N3C[C@H]3OCC3)C=C(C=C4)C(=O)O)C=C2)F)C=C1)F Chemical compound C(#N)C1=CC(=C(COC2=CC=CC(=N2)C2=CC(=C(CC3=NC4=C(N3C[C@H]3OCC3)C=C(C=C4)C(=O)O)C=C2)F)C=C1)F BYBMBPGYOCDKOR-DEOSSOPVSA-N 0.000 description 1
- WVSMCGPVNMVRDE-VWLOTQADSA-N C(#N)C1=CC(=C(COC2=CC=CC(=N2)C2=CC=C(CC3=NC4=C(N3C[C@H]3OCC3)C=C(C=C4)C(=O)O)C=C2)C=C1)F Chemical compound C(#N)C1=CC(=C(COC2=CC=CC(=N2)C2=CC=C(CC3=NC4=C(N3C[C@H]3OCC3)C=C(C=C4)C(=O)O)C=C2)C=C1)F WVSMCGPVNMVRDE-VWLOTQADSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 102400000325 Glucagon-like peptide 1(7-36) Human genes 0.000 description 1
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101500028772 Homo sapiens Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 101001072037 Homo sapiens cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A Proteins 0.000 description 1
- 206010022079 Injection site irritation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101001015515 Mus musculus Glucagon-like peptide 1 receptor Proteins 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- QDEFNAHLCTUWAH-BYPYZUCNSA-N [(2s)-oxetan-2-yl]methanamine Chemical compound NC[C@@H]1CCO1 QDEFNAHLCTUWAH-BYPYZUCNSA-N 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 238000006795 borylation reaction Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 102100036377 cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A Human genes 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- WIKQEUJFZPCFNJ-UHFFFAOYSA-N carbonic acid;silver Chemical compound [Ag].[Ag].OC(O)=O WIKQEUJFZPCFNJ-UHFFFAOYSA-N 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- IXTMWRCNAAVVAI-UHFFFAOYSA-N dofetilide Chemical compound C=1C=C(NS(C)(=O)=O)C=CC=1CCN(C)CCOC1=CC=C(NS(C)(=O)=O)C=C1 IXTMWRCNAAVVAI-UHFFFAOYSA-N 0.000 description 1
- 229960002994 dofetilide Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 229950005127 erbumine Drugs 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- MMANYAVWRYOHTI-UHFFFAOYSA-N methyl 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate Chemical compound C1=C(F)C(CC(=O)OC)=CC=C1B1OC(C)(C)C(C)(C)O1 MMANYAVWRYOHTI-UHFFFAOYSA-N 0.000 description 1
- FKMZNQQOPCCUTD-UHFFFAOYSA-N methyl 3-fluoro-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C(F)=C1 FKMZNQQOPCCUTD-UHFFFAOYSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
Definitions
- This invention relates to glucagon-like peptide-1 receptor agonists and therapeutic uses of the compounds to treat type II diabetes mellitus.
- Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by intestinal enteroendocrine L-cells. GLP-1 induces the release of insulin from beta cells in a glucose dependent manner. However, GLP-1 is rapidly metabolized so that only a small percentage of the GLP-1 can be utilized to induce insulin secretion. To offset this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion as a treatment for type II diabetes mellitus.
- GLP-1R GLP-1 receptor
- GLP-1R agonists that have been approved to treat type II diabetes mellitus are injectable agents. Patients often prefer orally administered drugs because of the drawbacks associated with injection such as inconvenience, pain, and the potential for injection site irritation.
- WO2018/109607 discloses certain benzimidazole derivatives, which are described as GLP-1R agonists.
- GLP-1R agonists which can be administered orally.
- GLP-1R agonists having improved potency, a favourable toxicology profile and/or a pharmacokinetic profile which supports once daily dosing.
- the present invention provides a compound of the formula:
- R 1 is H or F
- R 2 is H or F
- R 3 is H or CH 3 ; or a pharmaceutically acceptable salt thereof.
- Formula I includes all individual enantiomers, and mixtures thereof, as well as racemates, and pharmaceutically acceptable salts thereof.
- R 1 is H or F, or a pharmaceutically acceptable salt thereof.
- R 1 is H or F, or a pharmaceutically acceptable salt thereof.
- the compound is a compound of the formula:
- the compound is a compound of the formula:
- the compound is a compound of the formula:
- the compound is a compound of the formula:
- tert-butylamine salt also known as the erbumine salt
- R 2 is H or F, or a pharmaceutically acceptable salt thereof.
- R 2 is H or F, or a pharmaceutically acceptable salt thereof.
- the compound is a compound of the formula:
- the compound is a compound of the formula:
- the compound is a compound of the formula:
- the compound is a compound of the formula:
- Formula I encompasses Formulae Ia, Ib, II, IIa, IIb, III, Ma and Mb and reference to Formula I below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to each and all of these sub-formulae.
- a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.
- the pharmaceutically acceptable composition is formulated for oral administration.
- a method of treating a mammal for type II diabetes mellitus comprises administering to the mammal in need of treatment a pharmaceutically acceptable composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.
- the pharmaceutically acceptable composition is formulated for oral administration.
- the mammal is a human.
- a method of treating a mammal for type II diabetes mellitus comprises administering to the mammal in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
- the mammal is a human.
- a method of lowering blood glucose levels in a mammal comprises administering to the mammal in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
- the mammal is a human.
- a method of treating hyperglycemia in a mammal comprises administering to the mammal in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
- the mammal is a human.
- a compound of Formula I for use in the treatment of type II diabetes mellitus.
- a compound of Formula I for use in lowering blood glucose levels.
- a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of type II diabetes mellitus.
- the compound of Formula I is administered orally. In a preferred embodiment, the compound of Formula I is administered once daily. In another preferred embodiment, the therapeutic use is in a human.
- pharmaceutically acceptable salt refers a salt of a compound of the invention considered to be acceptable for clinical and/or veterinary use.
- pharmaceutically acceptable salts and common methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S. M. Berge, et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
- the pharmaceutically compositions can be formulated for oral administration.
- the pharmaceutical compositions are formulated as a tablet, capsule, or a solution.
- the tablet, capsule, or solution can include a compound of Formula I in an amount effective for treating a patient in need of treatment.
- an effective amount refers to the amount or dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.
- the attending physician as one skilled in the art, can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances.
- Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the species of mammal to be treated; its size, age, and general health; the degree of involvement or the severity of the disorder; the response of the individual mammal; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and other relevant circumstances.
- the compounds of the present invention are effective at a dosage per day that falls within the range of about 0.01 to about 15 mg/kg of body weight.
- treating refers to lowering, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition, such as hyperglycemia, which can include increasing insulin secretion.
- the compounds of Formula I can be formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable. Preferably, such compositions are for oral administration.
- Such pharmaceutical compositions and processes for preparing same are well known in the art (See, e.g., Remington, J. P., “Remington: The Science and Practice of Pharmacy”, L. V. Allen, Editor, 22 nd Edition, Pharmaceutical Press, 2012).
- Compounds of the present invention include:
- Individual enantiomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques, chiral chromatography (See for example, J. Jacques, et al., “ Enantiomers, Racemates, and Resolutions ”, John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen, “ Stereochemistry of Organic Compounds ”, Wiley-Interscience, 1994), or supercritical fluid chromatography (SFC) (See for example, T. A. Berger; “ Supercritical Fluid Chromatography Primer ,” Agilent Technologies, July 2015).
- SFC supercritical fluid chromatography
- a pharmaceutically acceptable salt of the compounds of the invention can be formed, for example, by reaction of a compound of Formula I and an appropriate pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (See, for example, Bastin, R. J., et al.; Org. Process. Res. Dev., 4, 427-435, 2000 and Berge, S. M., et al.; J. Pharm. Sci., 66, 1-19, 1977).
- a preferred salt is the tert-butyl amine (or erbumine) salt.
- ACN refers to acetonitrile
- ATP refers to adenosine triphosphate
- BSA Bovine Serum Albumin
- cAMP refers to cyclic adenosine-3′,5′-monophosphate
- DCM refers to dichloromethane or methylene chloride
- DIPEA refers to N,N-diisopropylethylamine
- DMF refers to N,N-dimethylformamide
- DMSO refers to dimethyl sulfoxide
- EC 50 refers to the concentration of an agent which produces 50% response of the target activity compared to a predefined positive control compound (absolute EC 50 ); “ES/MS
- the compounds of the present invention may be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below.
- the specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the invention, or salts thereof.
- the product of each step below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
- the reagents and starting materials are readily available to one of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers may be separated or resolved at any convenient point in the synthesis, by methods such as, selective crystallization techniques or chiral chromatography (See for example, J.
- Scheme 1 shows the synthesis of intermediate 6, which is used in the preparation of the compounds of Formula I.
- Benzoic acid 1 first undergoes reduction with borane dimethylsulfide complex in Step 1 to give alcohol 2.
- the alcohol is converted into a leaving group (LG, intermediate 3).
- the alcohol in intermediate 2 can be converted to a mesylate group using methanesulfonyl chloride at ⁇ 15° C. in Step 2, or it can be converted to a bromide using phosphorus tribromide at 0° C.
- Intermediate 3 is reacted with NaCN in Step 3 to give nitrile 4.
- Nitrile 4 is converted with KOH at elevated temperature in Step 4 to give acid 5, which is then esterified in Step 5 to give intermediate 6 using oxalyl chloride, DMF, and methanol.
- Scheme 2 depicts the preparation of key intermediate 12 for the preparation of the compounds of Formula I via two routes.
- aryl halide 6 undergoes a one-pot Miyura borylation/Suzuki coupling: using bis(pinacolato)diboron, Pd(dppf)Cl 2 , and potassium acetate at elevated temperature, aryl halide 6 is converted in Step 1a to boronic ester 7, whereupon bromopyridine 8 and K 2 CO 3 are added to the reaction (Step 2a) giving intermediate 12.
- Step 1b Suzuki coupling of aryl halide 6 with 6-hydroxypyridine-2-boronic acid pinacol ester 9 using Pd(dppf)Cl 2 and K 2 CO 3 at elevated temperature
- Step 1b provides intermediate 10
- Step 2b alkylated with 4-(bromomethyl)-3-fluorobenzonitrile 6 using Ag 2 CO 3 at elevated temperature
- Step 2b Ester hydrolysis of intermediate 12 in Step 3 using LiOH yields acid intermediate 13.
- key intermediates 12 and 13 can be prepared according to Scheme 3, coupling bromopyridine 8 with boronic ester 7 or boronic acid 14 using Pd(dppf)Cl 2 and potassium carbonate at elevated temperature.
- Scheme 4 shows the conversion of key intermediate 13 to compounds of Formula I.
- Amide coupling in Step 1 using HATU and dianiline 15 gives intermediate 16.
- Cyclization (Step 2) is accomplished by heating intermediate 16 in acetic acid to give benzimidazole 17.
- Step 3 the compounds of Formula I are obtained by hydrolysis of 17 using LiOH.
- LC-ES/MS is performed on an AGILENT® HP1200 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and/or negative mode) are performed on a Mass Selective Detector quadrupole mass spectrometer interfaced to an HPLC which may or may not have an ELSD.
- the X-ray powder diffraction (XRPD) patterns of crystalline solids are obtained on a Bruker D4 Endeavor X-ray powder diffractometer, equipped with a CuK ⁇ source and a Vantec detector, operating at 35 kV and 50 mA.
- the sample is scanned between 4 and 40 2 ⁇ °, with a step size of 0.008 2 ⁇ ° and a scan rate of 0.5 seconds/step, and using 1.0 mm divergence, 6.6 mm fixed anti-scatter, and 11.3 mm detector slits.
- the dry powder is packed on a quartz sample holder and a smooth surface is obtained using a glass slide.
- the crystal form diffraction patterns are collected at ambient temperature and relative humidity.
- Crystal peak positions are determined in MDI-Jade after whole pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.774 2 ⁇ °. It is well known in the crystallography art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly.
- peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard.
- a peak position variability of ⁇ 0.2 2 ⁇ ° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.
- a prepared sample of the title compound is characterized by an XRD pattern using CuK ⁇ radiation as having diffraction peaks (2-theta values) as described in Table 1 below, and in particular having peaks at 6.9 in combination with one or more of the peaks selected from the group consisting of 16.3 and 22.5; with a tolerance for the diffraction angles of 0.2 degrees.
- the hGLP-1R receptor expressing cells are treated with compound (20 point concentration-response curve in DMSO, 2.75-fold Labcyte Echo direct dilution, 384 well plate Corning Cat #3570) in DMEM (Gibco Cat #31053) supplemented with 1 ⁇ GlutaMAXTM (Gibco Cat #35050), 0.1% bovine casein (Sigma C4765-10ML), 250 IBMX (3-Isobutyl-1-methylxanthine, Acros Cat #228420010) and 20 mM HEPES (Gibco Cat #15630) in a 20 ⁇ L assay volume (final DMSO concentration is 0.5%).
- cAMP levels within the cell are detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 ⁇ L) followed by the antibody anti-cAMP-Eu 3+ -Cryptate, also in cell lysis buffer (10 The resulting competitive assay is incubated for at least 60 min at RT, then detected using a PerkinElmer Envision® instrument with excitation at 320 nm and emission at 665 nm and 620 nm.
- Envision units (emission at 665 nm/620 nm*10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using a cAMP standard curve.
- the amount of cAMP generated (nM) in each well is converted to a percent of the maximal response observed with human GLP-1(7-36)NH 2 .
- a relative EC 50 value and percent top (E max ) are derived by non-linear regression analysis using the percent maximal response vs. the concentration of compound added, fitted to a four-parameter logistic equation.
- the EC 50 and E max data when the compounds of Examples 1-6 are tested in the cAMP assay described above using HEK293 cells expressing 581 and 104 fmol/mg GLP-1R are shown in Tables 2 and 3, respectively. These data indicate that the compounds of Examples 1-6 are agonists of the human GLP-1 receptor.
- mice expressing the human GLP-1R NCBI accession number NP_002053 from the mouse Glp-1r genetic locus (Jun, L. S., et al., PLoS One. 2014 9:e93746).
- mice expressing the human GLP-1R NCBI accession number NP_002053 from the mouse Glp-1r genetic locus (Jun, L. S., et al., PLoS One. 2014 9:e93746).
- Overnight fasted mice are orally administered the test compound solubilized in10% Kolliphor® (HS15) in Polyetheylene Glycol 400 (PEG400).
- PEG400 Polyetheylene Glycol 400
- One hour post-dose the animals are administered glucose by intraperitoneal injection (2 g/kg), and blood glucose levels are measured intermittingly over the next two hours using glucometers.
- a dose range of the test compound is delivered, and area under the curve calculations for each dose group are determined and fit to a four-parameter logistic model for calculating in vivo potency as an ED50 with a 95% confidence interval.
- the compounds of Examples 1-3 exhibit potency to lower the concentration of blood glucose in mice expressing the human GLP-1R with ED50 (and 95% confidence interval) values as shown in Table 4, which indicates that these compounds are orally available potent GLP-1R agonists in mice.
- test compound is administered to fasted male cynomolgus monkeys intravenously (IV) at 0.5 mg/kg (using a dose volume of 1 mL/kg).
- IV intravenously
- Serial blood samples are collected at 0.08, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post dose for IV bolus.
- plasma is obtained by centrifugation and stored at ⁇ 70° C. until analysis by LC-MS/MS.
- Test article concentration is determined in plasma.
- Noncompartmental analysis is used to calculate plasma clearance and steady-state volume of distribution.
- Table 5 shows the pharmacokinetic data on the compounds of Examples 1-3 in this assay. These data, in part, are used to inform human mechanistic PK projections which suggest a human pharmacokinetic profile to support once daily dosing.
- Phosphodiesterase 10 (PDE10) Enzyme Activity Assay
- PDE10A1 phosphodiesterase 10A1
- GenBank ID AAD32595.1 a full-length PDE10A1 clone corresponding to GenBank ID AAD32595.1 is cloned into pFastBac1 (Invitrogen).
- the PDE10A1 protein with a C-terminal FLAG-tag is expressed by baculoviral infection of insect cells and purified using anti-FLAG M2-agarose (Sigma) and size exclusion chromatography on a Superdex 200 column (GE Healthcare) and stored at ⁇ 80° C. in small aliquots (20 mM Tris-HCl, Ph 7.5, 150 mM NaCl, 10% Glycerol).
- PDE10A1 enzyme activities are measured with a yittrium silicate based scintillation proximity assay (SPA) that detects radioactive nucleotide monophosphates but not cyclic monophosphates.
- the assay buffer is composed of 50 mM Tris-HCl pH 7.5, 8 mM MgCl 2 , 3.4 mM EDTA, and 0.1% BSA (Sigma).
- Assays are conducted in 384 well plates (3706, Corning) in a total volume of 50 ⁇ l: comprised of 24 ⁇ l PDE10A1 enzyme, 1 ⁇ l test compound and 25 ⁇ l of cyclic nucleotide.
- Test compounds are diluted in pure DMSO using ten-point concentration response curves with a 3-fold dilution factor and 1 ⁇ l is acoustically dispensed into assay plates using the Echo555 (LabCyte).
- 24 ⁇ l PDE10A1 protein is incubated with 1 ⁇ l compound for 30 min before the reaction is started by the addition of [8-3H]-cGMP substrate (6.5 Ci/mmol, Perkin Elmer).
- Final concentration of components is 70 ⁇ M PDE10A1, 80 nM ( 3 H -cGMP), and 2% DMSO in assay buffer. Maximal compound concentration in the reaction mixture is 10 ⁇ M.
- Table 6 shows the activity of the compounds of Examples 1 ⁇ 4 in this assay. These data show that the compounds of Examples 1 to 4 have weak binding affinity to PDE10A, which indicates a reduced toxicity risk.
- the affinity of compounds for the human hERG K + channel in transfected HEK-293 cells is evaluated in a radioligand binding assay as described herein.
- Cell membrane homogenates (about 40 ⁇ g protein) are incubated for 60 min at 22° C. with 3 nM [ 3 H]dofetilide in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 10 mM KCl and 1 mM MgCl 2 .
- the assay is carried out in a 96-well plate format with a volume of 200 containing a maximum of 1% DMSO from initial solubilization of test compound.
Abstract
In an embodiment, the present invention provides a compound of the formula:or a pharmaceutically acceptable salt thereof, and methods of using this compound for treating type II diabetes mellitus.
Description
- This invention relates to glucagon-like peptide-1 receptor agonists and therapeutic uses of the compounds to treat type II diabetes mellitus.
- Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by intestinal enteroendocrine L-cells. GLP-1 induces the release of insulin from beta cells in a glucose dependent manner. However, GLP-1 is rapidly metabolized so that only a small percentage of the GLP-1 can be utilized to induce insulin secretion. To offset this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion as a treatment for type II diabetes mellitus.
- The majority of GLP-1R agonists that have been approved to treat type II diabetes mellitus are injectable agents. Patients often prefer orally administered drugs because of the drawbacks associated with injection such as inconvenience, pain, and the potential for injection site irritation.
- WO2018/109607 discloses certain benzimidazole derivatives, which are described as GLP-1R agonists.
- However, there is a need for alternative GLP-1R agonists. In particular, there is a need for GLP-1R agonists which can be administered orally. There is especially a need for GLP-1R agonists having improved potency, a favourable toxicology profile and/or a pharmacokinetic profile which supports once daily dosing.
- Accordingly, the present invention provides a compound of the formula:
- wherein
- R3 is H or CH3;
or a pharmaceutically acceptable salt thereof. - Formula I includes all individual enantiomers, and mixtures thereof, as well as racemates, and pharmaceutically acceptable salts thereof.
- In an embodiment, there is a provided a compound of the formula:
- or a pharmaceutically acceptable salt thereof.
- In an embodiment, there is provided a compound of the formula:
- wherein R1 is H or F, or a pharmaceutically acceptable salt thereof.
- In an embodiment, there is provided a compound of the formula:
- wherein R1 is H or F, or a pharmaceutically acceptable salt thereof.
- In one embodiment, the compound is a compound of the formula:
- or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the compound is a compound of the formula:
- or a pharmaceutically acceptable salt thereof.
- In one embodiment, the compound is a compound of the formula:
- or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the compound is a compound of the formula:
- or a pharmaceutically acceptable salt thereof. In a particularly preferred embodiment, there is provided the tert-butylamine salt (also known as the erbumine salt) of:
- In an embodiment, there is provided a compound of the formula:
- wherein R2 is H or F, or a pharmaceutically acceptable salt thereof.
- In an embodiment, there is provided a compound of the formula:
- wherein R2 is H or F, or a pharmaceutically acceptable salt thereof.
- In one embodiment, the compound is a compound of the formula:
- or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the compound is a compound of the formula:
- or a pharmaceutically acceptable salt thereof.
- In one embodiment, the compound is a compound of the formula:
- or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the compound is a compound of the formula:
- or a pharmaceutically acceptable salt thereof.
- Formula I encompasses Formulae Ia, Ib, II, IIa, IIb, III, Ma and Mb and reference to Formula I below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to each and all of these sub-formulae.
- In another embodiment, there is provided a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient. In a preferred embodiment, the pharmaceutically acceptable composition is formulated for oral administration.
- In another embodiment, there is provided a method of treating a mammal for type II diabetes mellitus, the method comprises administering to the mammal in need of treatment a pharmaceutically acceptable composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the pharmaceutically acceptable composition is formulated for oral administration. Preferably, the mammal is a human.
- In another embodiment, there is provided a method of treating a mammal for type II diabetes mellitus, the method comprises administering to the mammal in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the mammal is a human.
- In another embodiment, there is provided a method of lowering blood glucose levels in a mammal, the method comprises administering to the mammal in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the mammal is a human.
- In another embodiment, there is provided a method of treating hyperglycemia in a mammal, the method comprises administering to the mammal in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the mammal is a human.
- In an embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.
- In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes mellitus.
- In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.
- In another embodiment, there is also provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating hyperglycemia.
- In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of type II diabetes mellitus.
- In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for lowering blood glucose levels.
- In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hyperglycemia.
- In a preferred embodiment, the compound of Formula I is administered orally. In a preferred embodiment, the compound of Formula I is administered once daily. In another preferred embodiment, the therapeutic use is in a human.
- The term “pharmaceutically acceptable salt” as used herein refers a salt of a compound of the invention considered to be acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S. M. Berge, et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
- Examples of pharmaceutical compositions and processes for their preparation can be found in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012. In one embodiment, the pharmaceutically compositions can be formulated for oral administration. Preferably the pharmaceutical compositions are formulated as a tablet, capsule, or a solution. The tablet, capsule, or solution can include a compound of Formula I in an amount effective for treating a patient in need of treatment.
- The term “effective amount” refers to the amount or dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. The attending physician, as one skilled in the art, can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances. Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the species of mammal to be treated; its size, age, and general health; the degree of involvement or the severity of the disorder; the response of the individual mammal; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and other relevant circumstances. The compounds of the present invention are effective at a dosage per day that falls within the range of about 0.01 to about 15 mg/kg of body weight.
- As used herein, the terms “treating”, “to treat”, or “treatment”, refers to lowering, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition, such as hyperglycemia, which can include increasing insulin secretion.
- The compounds of Formula I can be formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable. Preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing same are well known in the art (See, e.g., Remington, J. P., “Remington: The Science and Practice of Pharmacy”, L. V. Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012).
- The compounds of Formula I and the pharmaceutically acceptable salts thereof are useful in the therapeutic uses of the invention, with certain configurations being preferred.
- Compounds of the present invention include:
- or pharmaceutically acceptable salts thereof.
- Further compounds of the present invention include:
- or pharmaceutically acceptable salts thereof.
- Further compounds of the present invention include:
- or pharmaceutically acceptable salts thereof.
- Although the present invention contemplates all individual enantiomers, mixtures thereof, and racemates, compounds of Formula Ia, IIa and IIIa, and pharmaceutically acceptable salts thereof, are particularly preferred.
- Individual enantiomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques, chiral chromatography (See for example, J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994), or supercritical fluid chromatography (SFC) (See for example, T. A. Berger; “Supercritical Fluid Chromatography Primer,” Agilent Technologies, July 2015).
- A pharmaceutically acceptable salt of the compounds of the invention can be formed, for example, by reaction of a compound of Formula I and an appropriate pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (See, for example, Bastin, R. J., et al.; Org. Process. Res. Dev., 4, 427-435, 2000 and Berge, S. M., et al.; J. Pharm. Sci., 66, 1-19, 1977). A preferred salt is the tert-butyl amine (or erbumine) salt.
- Certain abbreviations used herein are defined according to Daub G. H., et al., “The Use of Acronyms in Organic Chemistry” Aldrichimica Acta, 1984, 17(1), 6-23. Certain abbreviations are defined as follows: “ACN” refers to acetonitrile; “ATP” refers to adenosine triphosphate; “BSA” refers to Bovine Serum Albumin; “cAMP” refers to cyclic adenosine-3′,5′-monophosphate; “DCM” refers to dichloromethane or methylene chloride; “DIPEA” refers to N,N-diisopropylethylamine; “DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “EC50” refers to the concentration of an agent which produces 50% response of the target activity compared to a predefined positive control compound (absolute EC50); “ES/MS” refers to electrospray mass spectrometry; “EtOAc” refers to ethyl acetate; “HATU” refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; “HEK” refers to human embryonic kidney; “HEPES” refers to 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; “h” refers to hours or hour, respectively; “MeOH” refers to methanol or methyl alcohol; “min” refers to minute or minutes; “Pd(dppf)Cl2” refers to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); “RT” refers to room temperature; and “THF” refers to tetrahydrofuran.
- The compounds of the present invention may be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the invention, or salts thereof. The product of each step below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers may be separated or resolved at any convenient point in the synthesis, by methods such as, selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). Without limiting the scope of the invention, the following preparations, and examples are provided to further illustrate the invention.
- Scheme 1 shows the synthesis of intermediate 6, which is used in the preparation of the compounds of Formula I. Benzoic acid 1 first undergoes reduction with borane dimethylsulfide complex in Step 1 to give alcohol 2. The alcohol is converted into a leaving group (LG, intermediate 3). For example, the alcohol in intermediate 2 can be converted to a mesylate group using methanesulfonyl chloride at −15° C. in Step 2, or it can be converted to a bromide using phosphorus tribromide at 0° C. Intermediate 3 is reacted with NaCN in Step 3 to give nitrile 4. Nitrile 4 is converted with KOH at elevated temperature in Step 4 to give acid 5, which is then esterified in Step 5 to give intermediate 6 using oxalyl chloride, DMF, and methanol.
- Scheme 2 depicts the preparation of key intermediate 12 for the preparation of the compounds of Formula I via two routes. In the first route, aryl halide 6 undergoes a one-pot Miyura borylation/Suzuki coupling: using bis(pinacolato)diboron, Pd(dppf)Cl2, and potassium acetate at elevated temperature, aryl halide 6 is converted in Step 1a to boronic ester 7, whereupon bromopyridine 8 and K2CO3 are added to the reaction (Step 2a) giving intermediate 12. In the second route, a two-step process is employed: Suzuki coupling of aryl halide 6 with 6-hydroxypyridine-2-boronic acid pinacol ester 9 using Pd(dppf)Cl2 and K2CO3 at elevated temperature (Step 1b) provides intermediate 10, which is then alkylated with 4-(bromomethyl)-3-fluorobenzonitrile 6 using Ag2CO3 at elevated temperature (Step 2b) to give intermediate 12. Ester hydrolysis of intermediate 12 in Step 3 using LiOH yields acid intermediate 13.
- Alternatively, key intermediates 12 and 13 can be prepared according to Scheme 3, coupling bromopyridine 8 with boronic ester 7 or boronic acid 14 using Pd(dppf)Cl2 and potassium carbonate at elevated temperature.
- Scheme 4 shows the conversion of key intermediate 13 to compounds of Formula I. Amide coupling in Step 1 using HATU and dianiline 15 gives intermediate 16. Cyclization (Step 2) is accomplished by heating intermediate 16 in acetic acid to give benzimidazole 17. Finally, in Step 3 the compounds of Formula I are obtained by hydrolysis of 17 using LiOH.
- LC-ES/MS is performed on an AGILENT® HP1200 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and/or negative mode) are performed on a Mass Selective Detector quadrupole mass spectrometer interfaced to an HPLC which may or may not have an ELSD. LC-ES/MS conditions (low pH): column: PHENOMENEX® GEMINI® NX C18 2.0×50 mm 3.0 μm, 110 Å; gradient: 5-95% B in 1.5 min, then 95% B for 0.5 min column temperature: 50° C.+/−10° C.; flow rate: 1.2 mL/min; 1 μL injection volume; Solvent A: deionized water with 0.1% HCOOH; Solvent B: ACN with 0.1% formic acid; wavelength 200-400 nm and 212-216 nm. If the HPLC is equipped with an ELSD the settings are 45° C. evaporator temperature, 40° C. nebulizer temperature, and 1.6 SLM gas flow rate. Alternate LC-MS conditions (high pH): column: Waters xBridge® C18 column 2.1×50 mm, 3.5 μm; gradient: 5-95% B in 1.5 min, then 95% B for 0.50 min; column temperature: 50° C.+/−10° C.; flow rate: 1.2 mL/min; 1 μL injection volume; Solvent A: 10 mM NH4HCO3 pH 9; Solvent B: ACN; wavelength: 200-400 nm and 212-216 nm; if had ELSD: 45° C. evaporator temp, 40° C. nebulizer temp, and 1.60 SLM gas flow rate.
- The X-ray powder diffraction (XRPD) patterns of crystalline solids are obtained on a Bruker D4 Endeavor X-ray powder diffractometer, equipped with a CuKα source and a Vantec detector, operating at 35 kV and 50 mA. The sample is scanned between 4 and 40 2θ°, with a step size of 0.008 2θ° and a scan rate of 0.5 seconds/step, and using 1.0 mm divergence, 6.6 mm fixed anti-scatter, and 11.3 mm detector slits. The dry powder is packed on a quartz sample holder and a smooth surface is obtained using a glass slide. The crystal form diffraction patterns are collected at ambient temperature and relative humidity. Crystal peak positions are determined in MDI-Jade after whole pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.774 2θ°. It is well known in the crystallography art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of ±0.2 2θ° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.
-
- To a flask add: 4-bromo-2-fluoro-5-methylbenzoic acid (100 g, 421 mmol), THF (200 mL) and borane (dimethyl sulfide complex, 2 mol/L solution in THF, 210 mL, 10 mmol). Stir the mixture at RT overnight. Quench the reaction mixture with HCl (1.0 N aqueous solution, 50 mL) and filter the mixture. Concentrate the filtrate in-vacuo and partition the residue between EtOAc (400 mL) and water (400 mL). Wash the organics with saturated aqueous NaCl (400 mL), dry over Na2SO4, filter, and concentrate to give the title compound as solid (93.5 g, 99%). 1H-NMR (400 MHz, CDCl3) δ 7.29 (d, J=7.9 Hz, 1H), 7.26 (d, J=9.1 Hz, 1H), 4.69 (s, 2H), 2.38 (s, 3H).
-
- Prepare the title compound essentially as described in Preparation 1 using 4-bromo-2-fluoro-3-methylbenzoic acid. Purify the product by silica gel chromatography using a gradient of 10 to 35% EtOAc in hexanes. LC-ES/MS peak retention time: 1.01 min.
-
- Dissolve (4-bromo-2-fluoro-5-methylphenyl)methanol (92 g, 420 mmol) in DCM (500 mL) and add triethylamine (120 mL, 861 mmol). Cool the mixture to −15° C. and add a solution of methanesulfonyl chloride (40 mL, 517 mmol) in DCM (30 mL) dropwise to the reaction mixture. Stir the mixture for 30 min at RT. Partition the reaction mixture between DCM (500 mL) and water (500 mL). Wash the organics with saturated aqueous NaCl (500 mL), dry over Na2SO4, filter, and concentrate. Dissolve the residue in DMF (400 mL) and cool the mixture with an ice bath. Add NaCN (21.0 g, 429 mmol) in one portion to the reaction mixture and stir at RT overnight. Partition the mixture between EtOAc (400 mL) and water (500 mL). Wash the organics with saturated aqueous NaCl (500 mL), dry over Na2SO4, filter, and concentrate. Purify the residue by silica gel chromatography using a gradient of 10 to 30% EtOAc in hexanes to give the title compound (47.0 g, 48%) as an oil. 1H-NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 3.71 (s, 2H), 2.41 (s, 3H).
-
- Mix together (4-bromo-2-fluoro-3-methyl-phenyl)methanol (1.90 g, 8.67 mmol) and DCM (20 mL). Cool the mixture to 0° C., then add phosphorus tribromide (1.0 mL, 11 mmol) dropwise. Stir the mixture at 0° C. for 15 min, then basify the mixture with saturated aqueous NaHCO3 (10 mL). Extract the mixture with DCM (40 mL). Wash the organics with brine (30 mL), dry over (Na2SO4), filter and concentrate to give a solid. Dissolve the solid in DMSO (10 mL), then add NaCN (0.60 g, 13.0 mmol) and stir for 1 h. Partition the mixture between EtOAc (50 mL) and water (50 mL). Wash the organics with brine (50 mL), dry over Na2SO4, filter and concentrate to give the product as solid (1.3 g, 64%). LC-ES/MS peak retention time: 1.17 min
-
- To a flask add: 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile (1.20 g, 5.10 mmol), ethanol (5 mL), water (3 mL), and potassium hydroxide (0.90 g, 16 mmol). Heat the mixture at 90° C. overnight. Cool the mixture with an ice bath and acidify with 1.0 M HCl to pH 4-5, then partition the mixture between EtOAc (30 mL) and water (30 mL). Wash the organics with saturated aqueous NaCl (30 mL), dry over Na2SO4, filter, and concentrate to give 2-(4-bromo-2-fluoro-5-methyl-phenyl)acetic acid as solid. Dissolve this in DCM (10 mL), then add DMF (0.05 mL, 0.6 mmol) and oxalyl chloride (0.5 mL, 6 mmol) at RT. Stir the mixture RT for 30 min, then add MeOH (2 mL, 49.4 mmol) dropwise. After 30 min, remove the solvent in-vacuo and partition the residue between EtOAc (40 mL) and 5% NaHCO3 (30 mL). Wash the organics with saturated aqueous NaCl (40 mL), dry over Na2SO4, filter, and concentrate to give the title compound as an oil (1.1 g, 80%). ES/MS m/z (79Br,81Br) 278,280 (M+NH4 +).
-
- Prepare the title compound essentially as described in Preparation 5 using 2-(4-bromo-2-fluoro-3-methyl-phenyl)acetonitrile. LC-ES/MS peak retention time: 1.22 min.
-
- Mix 4-bromo-2,6-difluorophenylacetic acid (3.30 g, 12.5 mmol), DCM (20 mL), DMF (0.05 mL, 0.6 mmol), and oxalyl chloride (1.3 mL, 15 mmol). Stir the mixture at RT for 30 min, then add MeOH (1.5 mL, 37 mmol, 100 mass %) dropwise. Concentrate the mixture and partition between EtOAc (30 mL) and saturated aqueous NaHCO3 (15 mL). Wash the organics with saturated aqueous NaCl (30 mL), dry over Na2SO4, filter, and concentrate to give the title compound as an oil (3.41 g, quantitative yield), which is used without further purification in Preparation 10. ES/MS m/z (79Br,81Br) 265,267 (M+H).
-
- Dissolve 2-bromo-6-fluoropyridine (2.50 g, 13.8 mmol) and 3-fluoro-4-(hydroxymethyl)benzonitrile (2.15 g, 13.8 mmol) in 1,4-dioxane (25 mL) and add a solution of potassium tert-butoxide (20 wt % in THF, 10.0 mL, 16.6 mmol) dropwise over 12 min at RT. Heat the reaction mixture at 40° C. for 30 min. Pour the mixture into aqueous K2CO3 (1M) and extract twice with EtOAc. Wash the organics with water and saturated aqueous NaCl, dry over Na2SO4, filter, and concentrate. Dry the residue in a vacuum oven at 50° C. to give the title compound (4.23 g, 95%) as a light yellow solid. ES/MS m/z (79Br,81Br) 307,309 (M+H).
-
- To a flask add 6-hydroxypyridine-2-boronic acid pinacol ester (1.6 g, 6.9 mmol), methyl 2-(4-bromo-2-fluoro-5-methyl-phenyl)acetate (2.2 g, 8.4 mmol), THF (15 mL), water (1 mL), and potassium carbonate (2.0 g, 14 mmol). Purge the mixture with nitrogen for 10 min, then add Pd(dppf)Cl2 (0.26 g, 0.35 mmol) and heat at 75° C. for 2 h. Partition the mixture between EtOAc (30 mL) and water (30 mL). Wash the organics with saturated aqueous NaCl (30 mL), dry over Na2SO4, filter and concentrate to give the title compound (1.4 g, 74%) as a solid. ES/MS m/z 276 (M+H), 274 (M−H).
-
- Prepare the title compound essentially as described in Preparation 9 using methyl 2-(4-bromo-2,6-difluorophenyl)acetate, heating the reaction at 75° C. overnight. ES/MS m/z 280 (M+H).
-
- Prepare the title compound essentially as described in Preparation 9 using methyl 2-(4-bromo-2-fluoro-3-methyl-phenyl)acetate, heating the reaction at 75° C. overnight (18 h). ES/MS m/z 276 (M+H), 274 (M−H).
-
- Dissolve 2-(4-bromo-3-methylphenyl)acetic acid (10.7 g, 45.8 mmol) in DCM (50 mL). Cool the mixture in an ice/water bath, and then add oxalyl chloride (4.8 mL, 55 mmol) and DMF (0.1 mL). Remove ice/water bath and stirred at RT for 2 h. Add MeOH (6.0 mL) dropwise over 2 min and stirred at RT for 1 h. Concentrate the reaction mixture in-vacuo and dissolve the residue in EtOAc. Wash the organics with saturated aqueous NaHCO3 and saturated aqueous NaCl. Dry the organics over Na2SO4, then filter and concentrate. To the residue add bis(pinacolato)diboron (12.8 g, 50.4 mmol) and potassium acetate (13.6 g, 137 mmol). Bubble nitrogen through the reaction mixture for 15 min, then add Pd(dppf)Cl2 (complex with DCM, 1.13 g, 1.37 mmol). Heat the reaction under nitrogen at 85° C. for 15 h in an oil bath, then remove the reaction flask from the oil bath. Dissolve potassium carbonate (9.49 g, 68.7 mmol) in water (60 mL), bubble nitrogen through the solution for 10 min, and then add this solution to the reaction mixture followed by 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (14.1 g, 45.8 mmol). Bubble nitrogen through the entire reaction mixture for 5 min and heat under nitrogen at 85° C. for 6 h. Cool the reaction to near RT and concentrate in-vacuo to remove most of the 1,4-dioxane. Dilute this mixture with EtOAc (200 mL) and wash with water and saturated aqueous NaCl. Dry the organics over Na2SO4, then filter and concentrate. Purify the crude product by silica gel chromatography using a gradient of 5 to 50% EtOAc in hexanes to give the title compound (13.3 g, 70%) as a light yellow solid. ES/MS m/z 391 (M+H).
-
- To a flask add methyl 2-[2-fluoro-4-(6-hydroxy-2-pyridyl)-5-methyl-phenyl]acetate (1.40 g, 5.09 mmol), 1,4-dioxane (35 mL), silver carbonate (1.7 g, 6.2 mmol), and 4-(bromomethyl)-3-fluorobenzonitrile (1.4 g, 6.2 mmol). Heat the mixture at 60° C. overnight. Filter off the solid and concentrate the filtrate. Purified the residue by silica gel chromatography using 12 to 55% EtOAc in hexanes to give the title compound (1.60 g, 77%) as a solid. ES/MS m/z 409 (M+H), 407 (M−H).
-
- Charge a flask with 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (2.02 g, 6.58 mmol), methyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (2.99 g, 9.88 mmol), K2CO3 (2.30 g, 16.5 mmol), 1,4-dioxane (30 mL) and water (10 mL). Bubble nitrogen through the mixture for 10 min. Add Pd(dppf)Cl2 DCM complex (492 mg, 0.658 mmol) to the mixture and heat to 80° C. under nitrogen for 5 h. Cool the reaction mixture, dilute with EtOAc (75 mL) and filter through a pad of Celite®. Wash the filtrate with water and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. Purify the resulting residue by silica gel chromatography with a gradient of 5 to 90% EtOAc in hexanes to obtain the title compound (2.68 g, 94%). ES/MS m/z 395 (M+H).
-
- Prepare the title compound essentially as described in Preparation 13 using methyl 2-[2,6-difluoro-4-(6-hydroxy-2-pyridyl)phenyl]acetate, heating the reaction at 80° C. overnight. ES/MS m/z 413 (M+H).
-
- Prepare the title compound essentially as described in Preparation 13 using methyl 2-[2-fluoro-4-(6-hydroxy-2-pyridyl)-3-methyl-phenyl]acetate, heating the reaction at 80 ° C. for 3 h. ES/MS m/z 409 (M+H).
-
- To a flask add methyl 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-methyl-phenyl]acetate (1.20 g, 3.07 mmol), ACN (20 mL), water (10 mL), and lithium hydroxide (0.35 g, 15 mmol). Heat the mixture at 45° C. for 3 h. Cool the mixture with an ice bath and acidify with 1.0 M HCl to pH=4-5. Partition the mixture between EtOAc (30 mL) and water (30 mL). Wash the organics with brine (30 mL), dry over Na2SO4, filter, and concentrate to give the title compound (1.1 g, 95%) as solid. ES/MS m/z 377 (M+H).
-
- To a vial add methyl 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]acetate (1.6 g, 3.9 mmol), ACN (20 mL), water (6 mL), and lithium hydroxide (0.45 g, 19 mmol). Heat the mixture at 45° C. for 2 h, cool the mixture with an ice bath, and acidify with 1.0 M HCl to pH=4-5. Partition the mixture between EtOAc (50 mL) and water (50 mL). Wash the organics with saturated aqueous NaCl (50 mL), dry over Na2SO4, filter and concentrated to give the title compound (1.55 g, 100%) as solid. ES/MS m/z 395 (M+H).
-
- Dissolve methyl 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]acetate (2.68 g, 6.25 mmol) in THF (50 mL), then add lithium hydroxide (797 mg, 32.9 mmol) and water (20 mL). After stirring at RT for 5 h, adjust the pH of the reaction mixture to 5 with aqueous HCl (1M). Remove volatile solvents in-vacuo to give an aqueous slurry. Filter and dry the solid to obtain the title compound (2.24 g, 88%). ES/MS m/z 381 (M+H).
-
- Prepare the title compound essentially as described in Preparation 18 using methyl 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,6-difluoro-phenyl]acetate. ES/MS m/z 399 (M+H).
-
- Prepare the title compound essentially as described in Preparation 17 using methyl 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-3-methyl-phenyl]acetate. ES/MS m/z 395 (M+H).
-
- Mix together 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (0.70 g, 2.3 mmol) and 2-(4-boronophenyl)acetic acid (0.64 g, 3.4 mmol), THF (15 mL), water (5 mL) and potassium carbonate (0.63 g, 4.6 mmol). Purge the mixture with nitrogen for 10 min, then add Pd(dppf)Cl2 (0.085 g, 0.11 mmol) and heat the mixture at 75° C. for 8 h. Acidify the mixture to pH 4-5 with aqueous HCl (1 M). Partition the mixture between EtOAc (50 mL) and water (50 mL). Wash the organics with brine (50 mL), dry over (Na2SO4), then filter and concentrate. Purify the residue by silica gel chromatography using a gradient of 25 to 65% EtOAc in hexanes to give the title compound (800 mg, 97% yield) as solid. ES/MS m/z 363.0 (M+H).
-
- To a solution of methyl 3-fluoro-4-nitro-benzoate (2.0 g, 10 mmol) in THF (10 mL) and DMF (10 mL) add triethylamine (3.1 mL, 22 mmol) at RT. To the slightly yellow solution add [(2S)-oxetan-2-yl]methanamine (Austin Chemical Company, 1.0 g, 11 mmol) and stir the rust-colored solution overnight. Dilute the reaction with EtOAc (100 mL) and water (50 mL). Separate the organic layer and then back-extract the aqueous layer with EtOAc (2×50 mL). Combine the organics and wash with saturated aqueous NaCl. Dry the organics over Na2SO4, filter, concentrate, and dry the residue under high vacuum. This gives crude methyl 4-nitro-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (2.8 g, 10 mmol) as a yellow solid (ES/MS m/z 267 (M+H)).
- Next, dissolve methyl 4-nitro-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (2.8 g, 10 mmol) in THF (50 mL) and add palladium on carbon (5% pre-wetted with water, 0.5 g). Vacuum purge the reaction mixture with hydrogen then stir under a balloon of hydrogen at RT for 2 h, during which time the yellow color vanishes. Filter the mixture through Celite® and concentrate to give the title compound (2.4 g, 99%). ES/MS m/z 237 (M+H).
-
- To a vial add 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-methyl-phenyl]acetic acid (1.10 g, 2.92 mmol), DMF (10 mL), HATU (1.4 g, 3.6 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (0.76 g, 3.2 mmol), and DIPEA (1.5 mL, 8.6 mmol). Stir the mixture at RT for 30 min, then partition between EtOAc (30 mL) and water (30 mL). Wash the organics with saturated aqueous NaCl (30 mL), then dry over Na2SO4, filter, and concentrate. Purify the residue by silica gel chromatography using a gradient of 10 to 35% EtOAc in DCM to give the title compound (1.2 g, 69%) as solid. ES/MS m/z 595 (M+1), 593 (M−1).
-
- To a flask add: 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]acetic acid (1.20 g, 3.04 mmol), DMF (15 mL), HATU (1.2 g, 3.1 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (0.80 g, 3.4 mmol) and DIPEA (1.5 mL, 8.6 mmol). Stir the mixture at RT for 30 min, then partition between EtOAc (30 mL) and water (30 mL). Wash the organics with saturated aqueous NaCl (30 mL), then dry over Na2SO4, filter and concentrate. Purify the residue by silica gel chromatography using a gradient of 10 to 35% EtOAc in DCM to give the title compound as solid (1.20 g, 64%). ES/MS m/z 613 (M+1), 611 (M−H).
-
- To a round-bottom flask add 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]acetic acid (205 mg, 0.540 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (116 mg, 0.490 mmol), HATU (224 mg, 0.589 mmol), DIPEA (0.26 mL, 1.5 mmol), and DMF (5 mL). After stirring at RT for 3.5 h, dilute the reaction mixture with EtOAc (30 mL) and wash with water and saturated aqueous NaCl. Dry the organics over Na2SO4, filter, and concentrate. Purify the residue by silica gel chromatography using a gradient of 0 to 10% MeOH in DCM to obtain the intermediate amide (326 mg). ES/MS m/z 599 (M+H).
- Heat the intermediate amide with acetic acid (5 mL) at 50° C. for 15 h. Concentrate the reaction mixture in-vacuo and dissolve the remaining residue in EtOAc (25 mL). Wash the organics with saturated aqueous NaHCO3 and saturated aqueous NaCl. Dry the organics over Na2SO4, filtered and concentrate. Purify the resulting by silica gel chromatography using a gradient of 20 to 100% EtOAc in hexanes to obtain the title compound (152 mg, 52%). ES/MS m/z 581 (M+H).
-
- Prepare the title compound essentially as described in Preparation 24 using 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,6-difluoro-phenyl]acetic acid. Collect the product which precipitates during the aqueous workup by filtration and use without further purification. ES/MS m/z 617 (M+H), 615 (M−H).
-
- Prepare the title compound essentially as described in Preparation 24 using 2-[4-15 [6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-3-methyl-phenyl]acetic acid. ES/MS m/z 613 (M+H), 611 (M−H).
-
- Prepare the title compound essentially as described in Preparation 25 using 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]phenyl]acetic acid. ES/MS m/z 581.0 (M+H), 579.0 (M−H).
-
- To a vial add methyl 4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-methyl-phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (1.2 g, 2.0 mmol) and acetic acid (6 mL). Heat the mixture at 80° C. for 2 h, then remove the solvent in-vacuo. Partition the residue between EtOAc (30 mL) and aqueous NaHCO3(5%, 20 mL). Wash the organics with saturated aqueous NaCl (30 mL), dry over Na2SO4, filter, and concentrate. Dissolve the residue in ACN (5 mL) and water (3 mL), then add to the mixture LiOH (0.22 g, 9.2 mmol) and stir at 50° C. for 2 h. Remove the solvent in-vacuo. Purify the residue by reverse-phase flash chromatography using a gradient of 20 to 35% ACN in 5% aqueous NH4HCO3 to give the title compound (900 mg, 79%) as a solid. ES/MS m/z 563 (M+H), 561 (M−H).
-
- To a vial add methyl 4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (1.20 g, 1.96 mmol) and acetic acid (15 mL), then heat the mixture at 80° C. for 2 h. Remove the solvent in-vacuo. Partition the residue between EtOAc (30 mL) and aqueous NaHCO3(5%, 20 mL). Wash the organics with saturated aqueous NaCl (30 mL), dry over Na2SO4, filter, and concentrate. Dissolve the residue in ACN (10 mL) and water (4 mL), then add to the mixture LiOH (0.24 g, 10 mmol) and stir at 50° C. for 2 h. Acidify the mixture with saturated aqueous citric acid to pH=4-5. Remove the solvent in-vacuo. Purify the residue by reverse-phase flash chromatography using a gradient of 20 to 35% ACN in 5% aqueous NH4HCO3 to give the title compound (745 mg, 66%) as a solid. ES/MS m/z 581 (M+H), 579 (M−H).
-
- Method 1—Preparation without Seed Crystals
- Suspend 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (555 mg, 0.96 mmol) in acetone (6 mL) while stirring at 800 rpm at 50° C., giving a slurry of white solid. Add tert-butylamine (115 μL, 1.09 mmol, 1.14 eq) observing a brief clarification of the mixture followed by precipitation of a white solid. Stir this slurry at 50° C. for 1 h, then turn off heating and allow the sample to stir as it comes to RT. Filter off the solid by vacuum filtration and dry in place for 15 min under a stream of nitrogen, then dry in-vacuo at 50° C. for 1 h to give the title compound (612 mg, 98%).
- Method 2—Preparation with Seed Crystals
- Mix together 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (50 g, 86.1 mmol), acetone (658 mL), and water (42 mL), and heat the mixture 50° C. Filter the mixture over GF/F paper and rinse with 94:6 v:v acetone:water (25 mL). Heat the resulting solution at 50° C. Prepare a solution of tert-butylamine (10 mL, 94.7 mmol, 1.1 eq) and 94:6 v:v acetone:water (25 mL). Add a portion of the tert-butylamine solution (7 mL) followed by seed crystals of tert-butylammonium;2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (50 mg). Add the remaining tert-butylamine solution over approximately 1 h via syringe pump at a rate of 0.47 mL/min. Heat the resulting suspension at 50° C. for 2 h, then cool the mixture to ambient temperature overnight. Filter the slurry and rinse with acetone (2×100 mL). Dry the wetcake at 50° C. in-vacuo to a constant weight to give the title compound (51.8 g, 92%) as a pale yellow solid.
- A prepared sample of the title compound is characterized by an XRD pattern using CuKα radiation as having diffraction peaks (2-theta values) as described in Table 1 below, and in particular having peaks at 6.9 in combination with one or more of the peaks selected from the group consisting of 16.3 and 22.5; with a tolerance for the diffraction angles of 0.2 degrees.
-
TABLE 1 X-ray powder diffraction peaks of tert-butylammonium; 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxyl-2-pyridyl]- 2-fluoro-5-methyl-phenyl]methyl]-3-[[(2S)- oxetan-2-yl]methyl]benzimidazole-5-carboxylate Angle (°2-Theta) Relative Intensity Peak +/−0.2° (% of most intense peak) 1 5.5 26.20% 2 6.9 64.90% 3 11.2 49.20% 4 16.3 100.00% 5 17.1 34.70% 6 19.6 53.00% 7 21.8 43.10% 8 22.5 93.80% 9 27.3 41.10% 10 28.0 37.90% -
- Dissolve methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (152 mg, 0.256 mmol) in THF (6 mL), then add lithium hydroxide (31 mg, 1.26 mmol) and water (2 mL). Stir the mixture at RT for 16 h, then adjust the pH to 6 with aqueous HCl (1N). Remove the THF in-vacuo and collect the remaining solid by filtration. Purify by reverse-phase flash chromatography using a gradient of 10 to 40% ACN in aqueous NH4HCO3 (10 mM, pH 10) to obtain the title compound (60 mg, 41%). ES/MS m/z 567 (M+H).
-
- Prepare the title compound essentially as described in Example 1 using methyl 4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,6-difluoro-phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate. Purify the product by reverse-phase flash chromatography using a gradient of 30 to 50% ACN in aqueous NH4HCO3 (10 mM, pH 10). ES/MS m/z 585 (M+H), 583 (M−H).
-
- Prepare the title compound essentially as described in Example 2 using methyl 4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-3-methyl-phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate. Purify the product by reverse-phase flash chromatography using a gradient of 5 to 40% ACN in 5% aqueous NH4HCO3. ES/MS m/z 581 (M+H), 579 (M−H).
-
- Prepare the title compound essentially as described in Example 1 using methyl 4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-ylmethyl]amino]benzoate. Purify the crude product by reverse-phase flash chromatography using a gradient of 20 to 35% ACN in 5% aqueous NH4HCO3. ES/MS m/z 549.0 (M+H), 547.1 (M−H).
- Biological Assays
- Human GLP-1 Receptor HEK293 Cell cAMP Assay
- GLP-1 Receptor functional activity is determined using cAMP formation in an HEK293 clonal cell line expressing human GLP-1R (NCBI accession number NP_002053) at an expression density of 581±94 (n=6) and 104±12 (n=5) fmol/mg protein (determined using [125I]GLP-1(7-36)NH2 homologous competition binding analysis). The hGLP-1R receptor expressing cells are treated with compound (20 point concentration-response curve in DMSO, 2.75-fold Labcyte Echo direct dilution, 384 well plate Corning Cat #3570) in DMEM (Gibco Cat #31053) supplemented with 1×GlutaMAX™ (Gibco Cat #35050), 0.1% bovine casein (Sigma C4765-10ML), 250 IBMX (3-Isobutyl-1-methylxanthine, Acros Cat #228420010) and 20 mM HEPES (Gibco Cat #15630) in a 20 μL assay volume (final DMSO concentration is 0.5%). After a 30 min incubation at 37° C., the resulting increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ). Briefly, cAMP levels within the cell are detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 μL) followed by the antibody anti-cAMP-Eu3+-Cryptate, also in cell lysis buffer (10 The resulting competitive assay is incubated for at least 60 min at RT, then detected using a PerkinElmer Envision® instrument with excitation at 320 nm and emission at 665 nm and 620 nm. Envision units (emission at 665 nm/620 nm*10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using a cAMP standard curve. The amount of cAMP generated (nM) in each well is converted to a percent of the maximal response observed with human GLP-1(7-36)NH2. A relative EC50 value and percent top (Emax) are derived by non-linear regression analysis using the percent maximal response vs. the concentration of compound added, fitted to a four-parameter logistic equation. The EC50 and Emax data when the compounds of Examples 1-6 are tested in the cAMP assay described above using HEK293 cells expressing 581 and 104 fmol/mg GLP-1R are shown in Tables 2 and 3, respectively. These data indicate that the compounds of Examples 1-6 are agonists of the human GLP-1 receptor.
-
TABLE 2 HEK293 cell line with 581 fmol/mg expression density of GLP-1R, intracellular cAMP response Example EC50 (nM) ± SEM (n) Emax (%) ± SEM (n) 1 9.33 ± 1.36 (n = 6) 99.5 ± 2.53 (n = 6) 2 1.14 ± 0.315 (n = 6) 104 ± 4.35 (n = 6) 3 3.08 ± 0.379 (n = 5) 99 ± 3.69 (n = 5) 4 3.99 ± 0.378 (n = 3) 99.2 ± 4 (n = 3) 5 6.45 ± 0.934 (n = 3) 105 ± 2.43 (n = 3) 6 20 ± 6.51 (n = 4) 101 ± 3.42 (n = 4) -
TABLE 3 HEK293 cell line with 104 fmol/mg expression density of GLP-1R, intracellular cAMP response Example EC50 (nM) ± SEM (n) Emax (%) ± SEM (n) 1 20 ± 3.25 (n = 6) 71.4 ± 2.26 (n = 6) 2 3.97 ± 0.61 (n = 6) 79.2 ± 3.2 (n = 6) 3 10 ± 2.3 (n = 5) 81.7 ± 3.86 (n = 5) 4 9.59 ± 2.36 (n = 3) 78.3 ± 5.1 (n = 3) 5 23.6 ± 5.43 (n = 3) 76.7 ± 3.88 (n = 3) 6 47.7 ± 17.9 (n = 4) 80.3 ± 3.1 (n = 4) - The potency of the exemplified compounds to lower the concentration of blood glucose in vivo is determined using mice expressing the human GLP-1R (NCBI accession number NP_002053) from the mouse Glp-1r genetic locus (Jun, L. S., et al., PLoS One. 2014 9:e93746). Overnight fasted mice are orally administered the test compound solubilized in10% Kolliphor® (HS15) in Polyetheylene Glycol 400 (PEG400). One hour post-dose, the animals are administered glucose by intraperitoneal injection (2 g/kg), and blood glucose levels are measured intermittingly over the next two hours using glucometers. A dose range of the test compound is delivered, and area under the curve calculations for each dose group are determined and fit to a four-parameter logistic model for calculating in vivo potency as an ED50 with a 95% confidence interval. When tested in the in vivo intraperitoneal glucose tolerance test described above, the compounds of Examples 1-3 exhibit potency to lower the concentration of blood glucose in mice expressing the human GLP-1R with ED50 (and 95% confidence interval) values as shown in Table 4, which indicates that these compounds are orally available potent GLP-1R agonists in mice.
-
TABLE 4 Blood glucose lowering efficacy in mice expressing human GLP-1R Blood glucose lowering 95% confidence Example ED50 (mg/kg) interval 1 0.09 0.0301-0.2592 2 0.07 0.0246-0.1808 3 0.06 0.013-0.246 - The test compound is administered to fasted male cynomolgus monkeys intravenously (IV) at 0.5 mg/kg (using a dose volume of 1 mL/kg). Serial blood samples are collected at 0.08, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post dose for IV bolus. After treatment with an EDTA coagulant, plasma is obtained by centrifugation and stored at −70° C. until analysis by LC-MS/MS. Test article concentration is determined in plasma. Noncompartmental analysis is used to calculate plasma clearance and steady-state volume of distribution. Table 5 shows the pharmacokinetic data on the compounds of Examples 1-3 in this assay. These data, in part, are used to inform human mechanistic PK projections which suggest a human pharmacokinetic profile to support once daily dosing.
-
TABLE 5 Cynomolgous monkey pharmacokinetic data Plasma clearance Volume of Example (mL/min/kg) distribution (L/kg) Vehicle* 1 13 1.2 A 2 11 1.1 A 3 6 1.1 B *Vehicle A—5% DMSO and 95% (20% CAPTISOL ® (w/v) in water; Vehicle B—20% captisol (w/v) in water + 1 mole equivalent NaOH - To generate phosphodiesterase 10A1 (PDE10A1) protein, a full-length PDE10A1 clone corresponding to GenBank ID AAD32595.1 is cloned into pFastBac1 (Invitrogen). The PDE10A1 protein with a C-terminal FLAG-tag is expressed by baculoviral infection of insect cells and purified using anti-FLAG M2-agarose (Sigma) and size exclusion chromatography on a Superdex 200 column (GE Healthcare) and stored at −80° C. in small aliquots (20 mM Tris-HCl, Ph 7.5, 150 mM NaCl, 10% Glycerol).
- PDE10A1 enzyme activities are measured with a yittrium silicate based scintillation proximity assay (SPA) that detects radioactive nucleotide monophosphates but not cyclic monophosphates. The assay buffer is composed of 50 mM Tris-HCl pH 7.5, 8 mM MgCl2, 3.4 mM EDTA, and 0.1% BSA (Sigma). Assays are conducted in 384 well plates (3706, Corning) in a total volume of 50 μl: comprised of 24 μl PDE10A1 enzyme, 1 μl test compound and 25 μl of cyclic nucleotide. Test compounds are diluted in pure DMSO using ten-point concentration response curves with a 3-fold dilution factor and 1 μl is acoustically dispensed into assay plates using the Echo555 (LabCyte). 24 μl PDE10A1 protein is incubated with 1 μl compound for 30 min before the reaction is started by the addition of [8-3H]-cGMP substrate (6.5 Ci/mmol, Perkin Elmer). Final concentration of components is 70 μM PDE10A1, 80 nM (3H -cGMP), and 2% DMSO in assay buffer. Maximal compound concentration in the reaction mixture is 10 μM. Reactions are incubated for 60 min at RT before quenching and the addition of 400 mg/per well SPA beads (RPNQ0150, Perkin Elmer). Bead bound radioactivity (product) is quantified 12 h later with a Microbeta counter (Perkin Elmer). Data is normalized to % inhibition and IC50 values are calculated using the 4 parameter logistic equation as described (Campbell, R M.; Dymshitz, J.; Eastwood, B. J.; et al. “Data Standardization for Results Management.” In: Sittampalam, G S.; Grossman, A.; Brimacombe, K.; et al.; eds. Assay Guidance Manual. Bethesda (Md.): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004). Table 6 shows the activity of the compounds of Examples 1˜4 in this assay. These data show that the compounds of Examples 1 to 4 have weak binding affinity to PDE10A, which indicates a reduced toxicity risk.
- Human hERG K+ Channel Affinity Radioligand Binding Assay
- The affinity of compounds for the human hERG K+channel in transfected HEK-293 cells is evaluated in a radioligand binding assay as described herein. Cell membrane homogenates (about 40 μg protein) are incubated for 60 min at 22° C. with 3 nM [3H]dofetilide in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 10 mM KCl and 1 mM MgCl2. The assay is carried out in a 96-well plate format with a volume of 200 containing a maximum of 1% DMSO from initial solubilization of test compound. Following incubation, the samples are filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl, 10 mM KCl and 1 mM MgCl2 using a 96-sample cell harvester (Unifilter, Packard). The filters are dried and then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). Table 7 shows the activity of Examples 1-3 in this assay, expressed as a percent inhibition of the control radioligand specific binding. These data show that the compounds of Examples 1 to 3 have weak hERG inhibitory activity, which indicates a reduced toxicity risk.
-
TABLE 7 Human hERG K+ channel affinity radioligand percent inhibition Percent inhibition (%) at Example 100 μM compound concentration, n = 1 1 0 2 54 3 37
Claims (12)
1-20. (canceled)
25. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 21 and at least one pharmaceutically acceptable carrier, diluent, or excipient.
26. A method of treating type II diabetes mellitus in a mammal comprising administering to the mammal an effective amount of a compound according to claim 21 , or a pharmaceutically acceptable salt thereof.
27. The method according to claim 26 , wherein the compound is administered orally.
28. A method of lowering blood glucose levels in a mammal comprising administering an effective amount of a compound according to claim 21 , or a pharmaceutically acceptable salt thereof.
29. The method according to claim 28 , wherein the compound is administered orally.
30. A method of treating hyperglycemia in a mammal comprising administering to the mammal an effective amount of a compound according to claim 21 , or a pharmaceutically acceptable salt thereof.
31. The method according to claim 30 , wherein the compound is administered orally.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/194,155 US20230250092A1 (en) | 2019-06-28 | 2023-03-31 | Glucagon-like peptide1 receptor agonists |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962868117P | 2019-06-28 | 2019-06-28 | |
US201962904906P | 2019-09-24 | 2019-09-24 | |
US16/906,063 US11655242B2 (en) | 2019-06-28 | 2020-06-19 | Glucagon-like peptide1 receptor agonists |
US18/194,155 US20230250092A1 (en) | 2019-06-28 | 2023-03-31 | Glucagon-like peptide1 receptor agonists |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/906,063 Continuation US11655242B2 (en) | 2019-06-28 | 2020-06-19 | Glucagon-like peptide1 receptor agonists |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230250092A1 true US20230250092A1 (en) | 2023-08-10 |
Family
ID=71575804
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/906,063 Active 2040-11-06 US11655242B2 (en) | 2019-06-28 | 2020-06-19 | Glucagon-like peptide1 receptor agonists |
US18/194,155 Pending US20230250092A1 (en) | 2019-06-28 | 2023-03-31 | Glucagon-like peptide1 receptor agonists |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/906,063 Active 2040-11-06 US11655242B2 (en) | 2019-06-28 | 2020-06-19 | Glucagon-like peptide1 receptor agonists |
Country Status (27)
Country | Link |
---|---|
US (2) | US11655242B2 (en) |
EP (2) | EP3989972B1 (en) |
JP (1) | JP7256300B2 (en) |
KR (1) | KR20220012924A (en) |
CN (1) | CN114008033A (en) |
AU (1) | AU2020309064B2 (en) |
BR (1) | BR112021023923A2 (en) |
CA (1) | CA3144055C (en) |
CL (1) | CL2021003419A1 (en) |
CO (1) | CO2021017433A2 (en) |
CR (1) | CR20210599A (en) |
DK (1) | DK3989972T3 (en) |
DO (1) | DOP2021000273A (en) |
EC (1) | ECSP21093576A (en) |
FI (1) | FI3989972T3 (en) |
HR (1) | HRP20231586T1 (en) |
IL (1) | IL288479A (en) |
JO (1) | JOP20210337A1 (en) |
LT (1) | LT3989972T (en) |
MX (1) | MX2021015328A (en) |
PE (1) | PE20220590A1 (en) |
PL (1) | PL3989972T3 (en) |
PT (1) | PT3989972T (en) |
RS (1) | RS64940B1 (en) |
SI (1) | SI3989972T1 (en) |
TW (1) | TWI751585B (en) |
WO (1) | WO2020263695A1 (en) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10954221B2 (en) | 2019-04-12 | 2021-03-23 | Qilu Regor Therapeutics Inc. | GLP-1R agonists and uses thereof |
JP2022552735A (en) | 2019-10-25 | 2022-12-19 | ギリアード サイエンシーズ, インコーポレイテッド | GLP-1R modulating compounds |
US20230051318A1 (en) * | 2019-12-02 | 2023-02-16 | Hyundai Pharm Co., Ltd. | Glp-1 receptor agonist |
CN115698003A (en) | 2020-02-07 | 2023-02-03 | 加舒布鲁姆生物公司 | Heterocyclic GLP-1 agonists |
US20230165846A1 (en) * | 2020-02-13 | 2023-06-01 | Gasherbrum Bio, Inc. | Heterocyclic glp-1 agonists |
KR102563111B1 (en) * | 2020-03-18 | 2023-08-04 | 주식회사 엘지화학 | Glp-1 receptor agonists, pharmaceutical composition comprising the same and method for preparing the same |
PE20230175A1 (en) * | 2020-03-18 | 2023-02-01 | Lg Chemical Ltd | GLP-1 RECEPTOR AGONIST, PHARMACEUTICAL COMPOSITION INCLUDING THE SAME, AND METHOD FOR PREPARING THE SAME |
WO2022028572A1 (en) | 2020-08-06 | 2022-02-10 | Gasherbrum Bio, Inc. | Heterocyclic glp-1 agonists |
WO2022042691A1 (en) | 2020-08-28 | 2022-03-03 | Gasherbrum Bio, Inc. | Heterocyclic glp-1 agonists |
US11851419B2 (en) | 2020-11-20 | 2023-12-26 | Gilead Sciences, Inc. | GLP-1R modulating compounds |
CA3200245A1 (en) * | 2020-11-27 | 2022-06-02 | Junjun Wu | Benzimidazole derivative and preparation method therefor and medical use thereof |
WO2022184849A1 (en) | 2021-03-04 | 2022-09-09 | Les Laboratoires Servier | Glp-1r agonists, uses and pharmaceutical compositions thereof |
EP4317145A1 (en) | 2021-03-24 | 2024-02-07 | Shionogi & Co., Ltd | Pharmaceutical composition containing glp-1 receptor agonist having fused ring |
JP2024514259A (en) * | 2021-04-08 | 2024-03-29 | エルジー・ケム・リミテッド | GLP-1 receptor agonist, pharmaceutical composition containing the same, and method for producing the same |
JP2024514009A (en) | 2021-04-21 | 2024-03-27 | ギリアード サイエンシーズ, インコーポレイテッド | Carboxy-benzimidazole GLP-1R modulating compound |
CA3217720A1 (en) * | 2021-05-03 | 2022-11-10 | Xiaohui Du | Benzimidazoyl glp-1 receptor agonists, pharmaceutical compositions comprising the same, and methods for their use |
TW202310838A (en) | 2021-05-20 | 2023-03-16 | 美商美國禮來大藥廠 | Glucagon-like peptide 1 receptor agonists |
WO2023038039A1 (en) | 2021-09-08 | 2023-03-16 | 塩野義製薬株式会社 | Medicine for prevention and treatment of diseases linked to anti-obesity activity |
WO2023057414A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators |
WO2023057427A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain 2,5-diazabicyclo[4.2.0]octanes as glp-1 receptor modulators |
WO2023057429A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain 2,5-diazabicyclo[4.2.0]octanes and octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators |
WO2023111145A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
WO2023111144A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
WO2023169436A1 (en) * | 2022-03-08 | 2023-09-14 | 广州市联瑞制药有限公司 | Benzo bicyclic compound, and preparation method and application thereof |
WO2024041609A1 (en) * | 2022-08-24 | 2024-02-29 | 广州市联瑞制药有限公司 | Benzo bicyclic compound, preparation method therefor, and use thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20200325121A1 (en) * | 2019-04-12 | 2020-10-15 | Qilu Regor Therapeutics Inc. | Glp-1r agonists and uses thereof |
US20210171499A1 (en) * | 2019-10-25 | 2021-06-10 | Gilead Sciences, Inc. | Glp-1r modulating compounds |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102466418B1 (en) * | 2016-12-16 | 2022-11-14 | 화이자 인코포레이티드 | Glp-1 receptor agonists and uses thereof |
TWI707683B (en) | 2018-06-13 | 2020-10-21 | 美商輝瑞股份有限公司 | Glp-1 receptor agonists and uses thereof |
FI3806855T3 (en) | 2018-06-15 | 2023-05-04 | Pfizer | Glp-1 receptor agonists and uses thereof |
AU2019382642A1 (en) | 2018-11-22 | 2021-06-10 | Qilu Regor Therapeutics Inc. | GLP-1R agonists and uses thereof |
AU2020256647A1 (en) * | 2019-04-12 | 2021-11-18 | Qilu Regor Therapeutics Inc. | GLP-1R agonists and uses thereof |
WO2021018023A1 (en) | 2019-08-01 | 2021-02-04 | 济南泰达领创医药技术有限公司 | Small molecule glp-1 receptor modulator |
CN114728940A (en) | 2019-11-15 | 2022-07-08 | 日东制药株式会社 | GLP-1 receptor agonists and uses thereof |
US20230051318A1 (en) | 2019-12-02 | 2023-02-16 | Hyundai Pharm Co., Ltd. | Glp-1 receptor agonist |
CA3168543A1 (en) | 2020-01-29 | 2021-08-05 | Gilead Sciences, Inc. | Glp-1r modulating compounds |
US20230165846A1 (en) | 2020-02-13 | 2023-06-01 | Gasherbrum Bio, Inc. | Heterocyclic glp-1 agonists |
PE20230175A1 (en) | 2020-03-18 | 2023-02-01 | Lg Chemical Ltd | GLP-1 RECEPTOR AGONIST, PHARMACEUTICAL COMPOSITION INCLUDING THE SAME, AND METHOD FOR PREPARING THE SAME |
TW202144340A (en) | 2020-04-03 | 2021-12-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | Fused imidazole derivatives, preparation method and medical use thereof |
JP2023524493A (en) | 2020-04-29 | 2023-06-12 | ガシャーブラム・バイオ・インコーポレイテッド | heterocyclic GLP-1 agonists |
-
2020
- 2020-06-17 TW TW109120333A patent/TWI751585B/en active
- 2020-06-19 KR KR1020217042363A patent/KR20220012924A/en not_active Application Discontinuation
- 2020-06-19 FI FIEP20739523.7T patent/FI3989972T3/en active
- 2020-06-19 BR BR112021023923A patent/BR112021023923A2/en unknown
- 2020-06-19 CN CN202080046428.3A patent/CN114008033A/en active Pending
- 2020-06-19 EP EP20739523.7A patent/EP3989972B1/en active Active
- 2020-06-19 LT LTEPPCT/US2020/038617T patent/LT3989972T/en unknown
- 2020-06-19 JO JOP/2021/0337A patent/JOP20210337A1/en unknown
- 2020-06-19 CA CA3144055A patent/CA3144055C/en active Active
- 2020-06-19 DK DK20739523.7T patent/DK3989972T3/en active
- 2020-06-19 MX MX2021015328A patent/MX2021015328A/en unknown
- 2020-06-19 WO PCT/US2020/038617 patent/WO2020263695A1/en active Application Filing
- 2020-06-19 PL PL20739523.7T patent/PL3989972T3/en unknown
- 2020-06-19 AU AU2020309064A patent/AU2020309064B2/en active Active
- 2020-06-19 US US16/906,063 patent/US11655242B2/en active Active
- 2020-06-19 PT PT207395237T patent/PT3989972T/en unknown
- 2020-06-19 EP EP23206307.3A patent/EP4302826A3/en active Pending
- 2020-06-19 SI SI202030314T patent/SI3989972T1/en unknown
- 2020-06-19 HR HRP20231586TT patent/HRP20231586T1/en unknown
- 2020-06-19 CR CR20210599A patent/CR20210599A/en unknown
- 2020-06-19 JP JP2021577551A patent/JP7256300B2/en active Active
- 2020-06-19 RS RS20231184A patent/RS64940B1/en unknown
- 2020-06-19 PE PE2021002176A patent/PE20220590A1/en unknown
-
2021
- 2021-11-28 IL IL288479A patent/IL288479A/en unknown
- 2021-12-20 CL CL2021003419A patent/CL2021003419A1/en unknown
- 2021-12-20 CO CONC2021/0017433A patent/CO2021017433A2/en unknown
- 2021-12-23 DO DO2021000273A patent/DOP2021000273A/en unknown
- 2021-12-28 EC ECSENADI202193576A patent/ECSP21093576A/en unknown
-
2023
- 2023-03-31 US US18/194,155 patent/US20230250092A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20200325121A1 (en) * | 2019-04-12 | 2020-10-15 | Qilu Regor Therapeutics Inc. | Glp-1r agonists and uses thereof |
US20210171499A1 (en) * | 2019-10-25 | 2021-06-10 | Gilead Sciences, Inc. | Glp-1r modulating compounds |
Non-Patent Citations (1)
Title |
---|
Patani et al. Chem. Rev. 1996, 96, 3147-3176 (Year: 1996) * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11655242B2 (en) | Glucagon-like peptide1 receptor agonists | |
JP6917988B2 (en) | Heteroarylcarboxamide derivative as a plasma kallikrein inhibitor | |
US11939319B2 (en) | Pyridinyl and pyrazinyl-(asa)indolsulfonamides | |
US9738626B2 (en) | Antagonists of prostaglandin EP3 receptor | |
EP3055300B1 (en) | Antagonists of prostaglandin ep3 receptor | |
TW201130814A (en) | Pyrazine derivatives | |
US20220298112A1 (en) | N-(PHENYL)-Indole-3-Sulfonamide Derivatives And Related Compounds As GPR17 Modulators For Treating CNS Disorders Such As Multiple Sclerosis | |
JP2017522350A (en) | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity | |
TW201713629A (en) | A novel benzimidazole compound and the medical use thereof | |
KR20160071384A (en) | Compositions for the treatment of hypertension and/or fibrosis | |
CN115803321A (en) | 4- (2, 6-difluorophenoxy) -6- (trifluoromethyl) pyrimidin-2-amine derivatives as enhancers of the HMRGX1 receptor for the treatment of pain | |
JP7214053B2 (en) | 6-Methoxy-3,4-dihydro-1H-isoquinoline compounds useful for treating diabetes | |
EA045067B1 (en) | GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONISTS | |
RU2799321C2 (en) | Pyridinil- and pyrazinyl(aza)indolsulfonamides | |
TW201136938A (en) | Spiropiperidine benzylamines as beta-tryptase inhibitors | |
US9604969B2 (en) | Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof | |
WO2022246019A1 (en) | Macrocyclic glucagon-like peptide 1 receptor agonists | |
WO2023111144A1 (en) | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ELI LILLY AND COMPANY, INDIANA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:COATES, DAVID ANDREW;FIELDS, TODD;HO, JOSEPH DANIEL;AND OTHERS;SIGNING DATES FROM 20200512 TO 20200513;REEL/FRAME:063201/0761 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |