JP7450610B2 - ピルビン酸キナーゼｒの活性化 - Google Patents
ピルビン酸キナーゼｒの活性化 Download PDFInfo
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- JP7450610B2 JP7450610B2 JP2021515149A JP2021515149A JP7450610B2 JP 7450610 B2 JP7450610 B2 JP 7450610B2 JP 2021515149 A JP2021515149 A JP 2021515149A JP 2021515149 A JP2021515149 A JP 2021515149A JP 7450610 B2 JP7450610 B2 JP 7450610B2
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- Prior art keywords
- alkyl
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- independently selected
- ring
- alkynyl
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- 102000013009 Pyruvate Kinase Human genes 0.000 title claims description 14
- 108020005115 Pyruvate Kinase Proteins 0.000 title claims description 14
- 230000004913 activation Effects 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 275
- 229910052757 nitrogen Inorganic materials 0.000 claims description 230
- 125000000623 heterocyclic group Chemical group 0.000 claims description 226
- 229910052760 oxygen Inorganic materials 0.000 claims description 226
- 229910052717 sulfur Inorganic materials 0.000 claims description 223
- 125000005842 heteroatom Chemical group 0.000 claims description 218
- 229910052736 halogen Inorganic materials 0.000 claims description 205
- 125000003118 aryl group Chemical group 0.000 claims description 184
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 161
- 125000000217 alkyl group Chemical group 0.000 claims description 130
- 150000002367 halogens Chemical class 0.000 claims description 122
- 125000001072 heteroaryl group Chemical group 0.000 claims description 101
- 150000003839 salts Chemical class 0.000 claims description 90
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 83
- 125000005843 halogen group Chemical group 0.000 claims description 83
- -1 chloro, methyl Chemical group 0.000 claims description 77
- 125000002619 bicyclic group Chemical group 0.000 claims description 71
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 68
- 125000002950 monocyclic group Chemical group 0.000 claims description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
- 125000003342 alkenyl group Chemical group 0.000 claims description 42
- 125000000304 alkynyl group Chemical group 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 36
- 125000001153 fluoro group Chemical group F* 0.000 claims description 32
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 28
- 125000004076 pyridyl group Chemical group 0.000 claims description 26
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 21
- 230000003213 activating effect Effects 0.000 claims description 20
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 14
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 101
- 239000000243 solution Substances 0.000 description 99
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 66
- 102100034170 Interferon-induced, double-stranded RNA-activated protein kinase Human genes 0.000 description 62
- 238000000034 method Methods 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 229920006395 saturated elastomer Polymers 0.000 description 48
- 229910052799 carbon Inorganic materials 0.000 description 47
- 235000019439 ethyl acetate Nutrition 0.000 description 47
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 47
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 41
- 238000006243 chemical reaction Methods 0.000 description 41
- 239000007787 solid Substances 0.000 description 38
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 37
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 37
- 239000003039 volatile agent Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 238000000746 purification Methods 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- 125000001424 substituent group Chemical group 0.000 description 25
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 125000004093 cyano group Chemical group *C#N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 239000002243 precursor Substances 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000012267 brine Substances 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 16
- 238000002953 preparative HPLC Methods 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 108700014121 Pyruvate Kinase Deficiency of Red Cells Proteins 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 230000035772 mutation Effects 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- XOHUEYCVLUUEJJ-UHFFFAOYSA-N 2,3-Bisphosphoglyceric acid Chemical compound OP(=O)(O)OC(C(=O)O)COP(O)(O)=O XOHUEYCVLUUEJJ-UHFFFAOYSA-N 0.000 description 10
- 101001091538 Homo sapiens Pyruvate kinase PKM Proteins 0.000 description 10
- 102100034911 Pyruvate kinase PKM Human genes 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 10
- 239000007821 HATU Substances 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 230000001960 triggered effect Effects 0.000 description 9
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 8
- 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 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- JVKRKMWZYMKVTQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JVKRKMWZYMKVTQ-UHFFFAOYSA-N 0.000 description 7
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 7
- 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 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 238000003556 assay Methods 0.000 description 7
- RNBGYGVWRKECFJ-ARQDHWQXSA-N beta-D-fructofuranose 1,6-bisphosphate Chemical compound O[C@H]1[C@H](O)[C@@](O)(COP(O)(O)=O)O[C@@H]1COP(O)(O)=O RNBGYGVWRKECFJ-ARQDHWQXSA-N 0.000 description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
- 125000002541 furyl group Chemical group 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- OJUDYRHHQXKVIO-MRXNPFEDSA-N CC(C)(C)OC(N1CC(CN(C2)C([C@@H](C3=CC=CC=C3)O)=O)=C2C1)=O Chemical compound CC(C)(C)OC(N1CC(CN(C2)C([C@@H](C3=CC=CC=C3)O)=O)=C2C1)=O OJUDYRHHQXKVIO-MRXNPFEDSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 108010044467 Isoenzymes Proteins 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- 239000013058 crude material Substances 0.000 description 6
- 239000006186 oral dosage form Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 125000003373 pyrazinyl group Chemical group 0.000 description 6
- OXUPNVQFTWUSGY-UHFFFAOYSA-N tert-butyl 2,3,4,6-tetrahydro-1h-pyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2=C1CNC2 OXUPNVQFTWUSGY-UHFFFAOYSA-N 0.000 description 6
- JJRPXOQSXGBENW-UHFFFAOYSA-N tert-butyl 2,3,4,6-tetrahydro-1h-pyrrolo[3,4-c]pyrrole-5-carboxylate;hydrochloride Chemical compound Cl.C1N(C(=O)OC(C)(C)C)CC2=C1CNC2 JJRPXOQSXGBENW-UHFFFAOYSA-N 0.000 description 6
- 125000000335 thiazolyl group Chemical group 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 5
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 5
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 5
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 5
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
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- 230000034659 glycolysis Effects 0.000 description 5
- 125000001624 naphthyl group Chemical group 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- QOBGYENMLPORNA-UHFFFAOYSA-N 5-pyridin-2-ylsulfonyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole Chemical compound N1=C(C=CC=C1)S(=O)(=O)N1CC=2CNCC=2C1 QOBGYENMLPORNA-UHFFFAOYSA-N 0.000 description 4
- 125000003627 8 membered carbocyclic group Chemical group 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000002393 azetidinyl group Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 4
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- DTBNBXWJWCWCIK-UHFFFAOYSA-K phosphonatoenolpyruvate Chemical compound [O-]C(=O)C(=C)OP([O-])([O-])=O DTBNBXWJWCWCIK-UHFFFAOYSA-K 0.000 description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- UZROEFJDKGOPPS-UHFFFAOYSA-N tert-butyl 5-pyridin-2-ylsulfonyl-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-2-carboxylate Chemical compound N1=C(C=CC=C1)S(=O)(=O)N1CC2=C(C1)CN(C2)C(=O)OC(C)(C)C UZROEFJDKGOPPS-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- BTGIKBSVYPIDAD-CYBMUJFWSA-N (2R)-2-hydroxy-2-phenyl-1-(2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)ethanone Chemical compound O[C@@H](C(=O)N1CC=2CNCC=2C1)C1=CC=CC=C1 BTGIKBSVYPIDAD-CYBMUJFWSA-N 0.000 description 3
- WNIURWXOEGKFLM-GOSISDBHSA-N (2R)-2-hydroxy-2-phenyl-1-(5-pyridin-2-ylsulfonyl-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrol-2-yl)ethanone Chemical compound O[C@@H](C(=O)N1CC=2CN(CC=2C1)S(=O)(=O)C1=NC=CC=C1)C1=CC=CC=C1 WNIURWXOEGKFLM-GOSISDBHSA-N 0.000 description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 3
- XOHUEYCVLUUEJJ-UHFFFAOYSA-I 2,3-Diphosphoglycerate Chemical compound [O-]P(=O)([O-])OC(C(=O)[O-])COP([O-])([O-])=O XOHUEYCVLUUEJJ-UHFFFAOYSA-I 0.000 description 3
- DVTYJMQWZHKOTG-UHFFFAOYSA-N 2-(Trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CN(C(=O)C(F)(F)F)CCC2=C1 DVTYJMQWZHKOTG-UHFFFAOYSA-N 0.000 description 3
- OLDNDGSKTPEWOV-UHFFFAOYSA-N 2-benzylsulfanyl-6-methylpyridine Chemical compound CC1=CC=CC(SCC=2C=CC=CC=2)=N1 OLDNDGSKTPEWOV-UHFFFAOYSA-N 0.000 description 3
- WSSYMNZDHDNKRI-UHFFFAOYSA-N 2-hydroxy-2-[2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinolin-7-yl]acetic acid Chemical compound C(C(=O)O)(C1=CC=C2CCN(CC2=C1)C(=O)OC(C)(C)C)O WSSYMNZDHDNKRI-UHFFFAOYSA-N 0.000 description 3
- ALEBBKYJGXLBQM-UHFFFAOYSA-N 2-pyridin-3-yl-1-(5-pyridin-2-ylsulfonyl-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrol-2-yl)ethanone Chemical compound C1=CC=NC(=C1)S(=O)(=O)N1CC2=C(C1)CN(C2)C(=O)CC1=CC=CN=C1 ALEBBKYJGXLBQM-UHFFFAOYSA-N 0.000 description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- LBDIVBPISBCDSE-UHFFFAOYSA-N 5-[4-(difluoromethoxy)phenyl]sulfonyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole hydrochloride Chemical compound Cl.FC(F)Oc1ccc(cc1)S(=O)(=O)N1CC2=C(CNC2)C1 LBDIVBPISBCDSE-UHFFFAOYSA-N 0.000 description 3
- YUWSYDYNEKIQLL-UHFFFAOYSA-N 6-methylpyridine-2-sulfonyl chloride Chemical compound CC1=CC=CC(S(Cl)(=O)=O)=N1 YUWSYDYNEKIQLL-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- DCVGMZPLNWAHKD-OAQYLSRUSA-N N-[2-fluoro-5-[[2-[(2R)-2-hydroxy-2-phenylacetyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrol-5-yl]sulfonyl]phenyl]acetamide Chemical compound FC1=C(C=C(C=C1)S(=O)(=O)N1CC=2CN(CC=2C1)C([C@@H](C1=CC=CC=C1)O)=O)NC(C)=O DCVGMZPLNWAHKD-OAQYLSRUSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 101150025052 Pklr gene Proteins 0.000 description 3
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- JOFHRALTEXLLIC-UHFFFAOYSA-N tert-butyl 6-bromo-2,3-dihydro-1,4-benzoxazine-4-carboxylate Chemical compound C1=C(Br)C=C2N(C(=O)OC(C)(C)C)CCOC2=C1 JOFHRALTEXLLIC-UHFFFAOYSA-N 0.000 description 1
- RUIBTNKXFPJXJR-UHFFFAOYSA-N tert-butyl 6-formyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate Chemical compound C1=C(C=O)C=C2N(C(=O)OC(C)(C)C)CCOC2=C1 RUIBTNKXFPJXJR-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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