CA2543533A1 - 2-cyanopyrrolidinecarboxamide compound - Google Patents

Info

Publication number

CA2543533A1

CA2543533A1 CA002543533A CA2543533A CA2543533A1 CA 2543533 A1 CA2543533 A1 CA 2543533A1 CA 002543533 A CA002543533 A CA 002543533A CA 2543533 A CA2543533 A CA 2543533A CA 2543533 A1 CA2543533 A1 CA 2543533A1

Authority

CA

Canada

Prior art keywords

compound

substituent

lower alkyl

azabicyclo

amino

Prior art date

2003-10-31

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• -1 2-cyanopyrrolidinecarboxamide compound Chemical class 0.000 title claims description 68
• 150000001875 compounds Chemical class 0.000 claims abstract description 362
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 145
• 125000001424 substituent group Chemical group 0.000 claims abstract description 135
• 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims abstract description 24
• 150000003839 salts Chemical class 0.000 claims abstract description 23
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 18
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 11
• 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims abstract 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 91
• 238000000034 method Methods 0.000 claims description 90
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 84
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
• 125000003545 alkoxy group Chemical group 0.000 claims description 44
• 125000001072 heteroaryl group Chemical group 0.000 claims description 41
• 238000006243 chemical reaction Methods 0.000 claims description 36
• 150000002367 halogens Chemical class 0.000 claims description 36
• 229910052736 halogen Inorganic materials 0.000 claims description 35
• 125000003118 aryl group Chemical group 0.000 claims description 32
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
• 125000001589 carboacyl group Chemical group 0.000 claims description 26
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 20
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
• 125000004043 oxo group Chemical group O=* 0.000 claims description 17
• 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 12
• 125000005419 heteroarylsulfonylamino group Chemical group 0.000 claims description 11
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 11
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 10
• 125000005241 heteroarylamino group Chemical group 0.000 claims description 10
• 125000000623 heterocyclic group Chemical group 0.000 claims description 10
• 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 10
• 125000003277 amino group Chemical group 0.000 claims description 9
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 8
• 239000003112 inhibitor Substances 0.000 claims description 8
• 241000282414 Homo sapiens Species 0.000 claims description 7
• 125000004104 aryloxy group Chemical group 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 125000001769 aryl amino group Chemical group 0.000 claims description 6
• 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 6
• 239000004480 active ingredient Substances 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 125000006239 protecting group Chemical group 0.000 claims description 5
• 230000002265 prevention Effects 0.000 claims description 4
• IXYABBFPMPPMPO-OWMZXZORSA-N (2s)-1-[(1r,4r,5r,7s)-4-hydroxy-6-azabicyclo[3.2.1]octane-7-carbonyl]pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.O=C([C@H]1N[C@@]2(C[C@]1(CC[C@H]2O)[H])[H])N1CCC[C@H]1C#N IXYABBFPMPPMPO-OWMZXZORSA-N 0.000 claims description 3
• BSTOTEXATQCDHE-WMYFGTORSA-N (2s)-1-[(1s,3s,4s,5r)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carbonyl]pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.O=C([C@@H]1[C@]2([H])CC[C@@](C[C@H]2O)(N1)[H])N1CCC[C@H]1C#N BSTOTEXATQCDHE-WMYFGTORSA-N 0.000 claims description 3
• 125000003342 alkenyl group Chemical group 0.000 claims description 3
• HIFIXNJGFRGAKV-AFFIPDDESA-N (2s)-1-[(1s,2s,4s,5r,6s)-5,6-dihydroxy-3-azabicyclo[2.2.2]octane-2-carbonyl]pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.O=C([C@@H]1[C@]2([H])CC[C@@]([C@H]([C@H]2O)O)(N1)[H])N1CCC[C@H]1C#N HIFIXNJGFRGAKV-AFFIPDDESA-N 0.000 claims description 2
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 241001465754 Metazoa Species 0.000 claims 3
• AUEFMDKGVXZKPL-BUMIUHBFSA-N (2s)-1-[(1r,2s,4r,5r)-5-amino-3-azabicyclo[2.2.1]heptane-2-carbonyl]pyrrolidine-2-carbonitrile;dihydrochloride Chemical compound Cl.Cl.O=C([C@H]1N[C@@]2([H])[C@H](N)C[C@@]1(C2)[H])N1CCC[C@H]1C#N AUEFMDKGVXZKPL-BUMIUHBFSA-N 0.000 claims 1
• UTSAVWUDUPXYMN-AFLYGPLOSA-N (2s)-1-[(1s,2s,4r,5r)-5-(2-hydroxyethoxy)-3-azabicyclo[2.2.1]heptane-2-carbonyl]pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.O=C([C@H]1N[C@@]2([H])[C@H](OCCO)C[C@@]1(C2)[H])N1CCC[C@H]1C#N UTSAVWUDUPXYMN-AFLYGPLOSA-N 0.000 claims 1
• 125000003302 alkenyloxy group Chemical group 0.000 claims 1
• RROXAYBIBLKEOP-WZJFGBDDSA-N n-[(1s,2s,4r,5r)-2-[(2s)-2-cyanopyrrolidine-1-carbonyl]-3-azabicyclo[2.2.1]heptan-5-yl]acetamide;hydrochloride Chemical compound Cl.O=C([C@H]1N[C@@]2([H])[C@H](NC(C)=O)C[C@@]1(C2)[H])N1CCC[C@H]1C#N RROXAYBIBLKEOP-WZJFGBDDSA-N 0.000 claims 1
• 230000000694 effects Effects 0.000 abstract description 10
• 230000001404 mediated effect Effects 0.000 abstract description 4
• 230000002401 inhibitory effect Effects 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 234
• 238000005160 1H NMR spectroscopy Methods 0.000 description 147
• 239000000203 mixture Substances 0.000 description 147
• 239000000243 solution Substances 0.000 description 118
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
• 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 107
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 104
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 99
• 101150041968 CDC13 gene Proteins 0.000 description 95
• 230000008569 process Effects 0.000 description 78
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 56
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
• 239000002904 solvent Substances 0.000 description 44
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 41
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
• 239000012267 brine Substances 0.000 description 40
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 40
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 239000012044 organic layer Substances 0.000 description 39
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
• 239000011541 reaction mixture Substances 0.000 description 37
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
• FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 34
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
• 239000000741 silica gel Substances 0.000 description 26
• 229910002027 silica gel Inorganic materials 0.000 description 26
• 239000007787 solid Substances 0.000 description 26
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
• 229920006395 saturated elastomer Polymers 0.000 description 23
• 239000007858 starting material Substances 0.000 description 22
• 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 21
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
• 229910052938 sodium sulfate Inorganic materials 0.000 description 21
• 235000011152 sodium sulphate Nutrition 0.000 description 21
• NEAPKZHDYMQZCB-UHFFFAOYSA-N N-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]ethyl]-2-oxo-3H-1,3-benzoxazole-6-carboxamide Chemical compound C1CN(CCN1CCNC(=O)C2=CC3=C(C=C2)NC(=O)O3)C4=CN=C(N=C4)NC5CC6=CC=CC=C6C5 NEAPKZHDYMQZCB-UHFFFAOYSA-N 0.000 description 20
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
• 238000001816 cooling Methods 0.000 description 17
• 238000010898 silica gel chromatography Methods 0.000 description 17
• 235000017557 sodium bicarbonate Nutrition 0.000 description 17
• 239000000843 powder Substances 0.000 description 16
• 239000012074 organic phase Substances 0.000 description 15
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
• 239000011780 sodium chloride Substances 0.000 description 14
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
• 239000000706 filtrate Substances 0.000 description 12
• LLQHSBBZNDXTIV-UHFFFAOYSA-N 6-[5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-4,5-dihydro-1,2-oxazol-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC1CC(=NO1)C1=CC2=C(NC(O2)=O)C=C1 LLQHSBBZNDXTIV-UHFFFAOYSA-N 0.000 description 11
• 239000003921 oil Substances 0.000 description 11
• 239000003795 chemical substances by application Substances 0.000 description 10
• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 10
• 239000010410 layer Substances 0.000 description 10
• 239000003960 organic solvent Substances 0.000 description 10
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
• 238000005481 NMR spectroscopy Methods 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 239000002585 base Substances 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 239000012230 colorless oil Substances 0.000 description 9
• 239000013078 crystal Substances 0.000 description 9
• 229910052739 hydrogen Inorganic materials 0.000 description 9
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
• 150000001412 amines Chemical class 0.000 description 8
• 239000012298 atmosphere Substances 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 230000035484 reaction time Effects 0.000 description 8
• 238000003756 stirring Methods 0.000 description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
• 238000007796 conventional method Methods 0.000 description 7
• 229960004132 diethyl ether Drugs 0.000 description 7
• 238000007429 general method Methods 0.000 description 7
• 239000001257 hydrogen Substances 0.000 description 7
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Substances 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 7
• 229910000489 osmium tetroxide Inorganic materials 0.000 description 7
• 238000000746 purification Methods 0.000 description 7
• 238000010992 reflux Methods 0.000 description 7
• 239000011734 sodium Substances 0.000 description 7
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 206010012601 diabetes mellitus Diseases 0.000 description 6
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 6
• 239000012285 osmium tetroxide Substances 0.000 description 6
• 239000002244 precipitate Substances 0.000 description 6
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
• 238000012360 testing method Methods 0.000 description 6
• 238000005406 washing Methods 0.000 description 6
• NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 description 5
• 239000005977 Ethylene Substances 0.000 description 5
• AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 5
• 230000002378 acidificating effect Effects 0.000 description 5
• 230000003197 catalytic effect Effects 0.000 description 5
• GFFCSDRCCRGJKW-XBVQOTNRSA-N ethyl (1r,2s,4s)-3-[(1r)-1-phenylethyl]-3-azabicyclo[2.2.2]oct-5-ene-2-carboxylate Chemical compound C1([C@@H](C)N2[C@@]3([H])CC[C@](C=C3)([C@H]2C(=O)OCC)[H])=CC=CC=C1 GFFCSDRCCRGJKW-XBVQOTNRSA-N 0.000 description 5
• 238000001914 filtration Methods 0.000 description 5
• 238000005984 hydrogenation reaction Methods 0.000 description 5
• 229910052757 nitrogen Inorganic materials 0.000 description 5
• 235000009518 sodium iodide Nutrition 0.000 description 5
• ARWLIMOJIMFGRX-KDXUFGMBSA-N (1s,2s,4r,5r)-5-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[2.2.1]heptane-2-carboxylic acid Chemical compound C1[C@@H](O)[C@]2([H])N(C(=O)OC(C)(C)C)[C@H](C(O)=O)[C@@]1([H])C2 ARWLIMOJIMFGRX-KDXUFGMBSA-N 0.000 description 4
• FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 4
• SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 4
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• 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
• 229920002554 vinyl polymer Polymers 0.000 description 1
• 238000009736 wetting Methods 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1