CN112010861A - 用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的pde9抑制剂 - Google Patents
用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的pde9抑制剂 Download PDFInfo
- Publication number
- CN112010861A CN112010861A CN202010907952.7A CN202010907952A CN112010861A CN 112010861 A CN112010861 A CN 112010861A CN 202010907952 A CN202010907952 A CN 202010907952A CN 112010861 A CN112010861 A CN 112010861A
- Authority
- CN
- China
- Prior art keywords
- imidazo
- compound
- pyrazin
- methyl
- pyran
- 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
- 238000011282 treatment Methods 0.000 title abstract description 26
- 229940076380 PDE9 inhibitor Drugs 0.000 title abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 16
- 201000010099 disease Diseases 0.000 title description 15
- 230000002093 peripheral effect Effects 0.000 title description 11
- IJYHVZICHKCLMQ-UHFFFAOYSA-N imidazo[4,5-d]triazin-4-one Chemical group O=C1N=NN=C2N=CN=C12 IJYHVZICHKCLMQ-UHFFFAOYSA-N 0.000 title description 8
- MPWOBEOETVOESI-UHFFFAOYSA-N imidazo[4,5-b]pyrazin-2-one Chemical group N1=CC=NC2=NC(=O)N=C21 MPWOBEOETVOESI-UHFFFAOYSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- OPPJESMUQLKXLM-UHFFFAOYSA-N 3-(4-fluorophenyl)-6-[(3-pyridin-4-yloxyazetidin-1-yl)methyl]-7h-imidazo[1,5-a]pyrazin-8-one Chemical compound C1=CC(F)=CC=C1C1=NC=C2C(=O)NC(CN3CC(C3)OC=3C=CN=CC=3)=CN12 OPPJESMUQLKXLM-UHFFFAOYSA-N 0.000 claims abstract description 15
- RXXATJXJQNATOK-UHFFFAOYSA-N 3-(oxan-4-yl)-6-[(3-pyridin-3-yloxyazetidin-1-yl)methyl]-7h-imidazo[1,5-a]pyrazin-8-one Chemical compound C=1N2C(C3CCOCC3)=NC=C2C(=O)NC=1CN(C1)CC1OC1=CC=CN=C1 RXXATJXJQNATOK-UHFFFAOYSA-N 0.000 claims abstract description 14
- GWGNPYYVGANHRJ-GDBMZVCRSA-N 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(oxan-4-yl)-7H-imidazo[1,5-a]pyrazin-8-one Chemical compound C[C@H]1[C@@H](CN(C1)CC1=NC=CC=N1)C=1NC(C=2N(C=1)C(=NC=2)C1CCOCC1)=O GWGNPYYVGANHRJ-GDBMZVCRSA-N 0.000 claims abstract description 10
- GWGNPYYVGANHRJ-HOCLYGCPSA-N 6-[(3R,4R)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(oxan-4-yl)-7H-imidazo[1,5-a]pyrazin-8-one Chemical compound C[C@@H]1[C@H](CN(C1)CC1=NC=CC=N1)C=1NC(C=2N(C=1)C(=NC=2)C1CCOCC1)=O GWGNPYYVGANHRJ-HOCLYGCPSA-N 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- KXXMSVLXMZUNBO-UHFFFAOYSA-N 2-[[3-(4-fluorophenoxy)azetidin-1-yl]methyl]-7-(oxan-4-yl)-1h-imidazo[5,1-f][1,2,4]triazin-4-one Chemical compound C1=CC(F)=CC=C1OC1CN(CC=2NN3C(C4CCOCC4)=NC=C3C(=O)N=2)C1 KXXMSVLXMZUNBO-UHFFFAOYSA-N 0.000 claims description 15
- 239000003085 diluting agent Substances 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 208000007056 sickle cell anemia Diseases 0.000 abstract description 26
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 abstract description 19
- GWGNPYYVGANHRJ-UHFFFAOYSA-N 6-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(oxan-4-yl)-7h-imidazo[1,5-a]pyrazin-8-one Chemical compound C1C(C=2NC(=O)C3=CN=C(N3C=2)C2CCOCC2)C(C)CN1CC1=NC=CC=N1 GWGNPYYVGANHRJ-UHFFFAOYSA-N 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
- 229910052717 sulfur Inorganic materials 0.000 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 77
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 76
- 239000011541 reaction mixture Substances 0.000 description 73
- 238000003786 synthesis reaction Methods 0.000 description 67
- 239000007787 solid Substances 0.000 description 66
- 230000015572 biosynthetic process Effects 0.000 description 65
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 61
- 239000000203 mixture Substances 0.000 description 61
- 238000005160 1H NMR spectroscopy Methods 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- 229910001868 water Inorganic materials 0.000 description 40
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- 239000012074 organic phase Substances 0.000 description 31
- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 description 26
- -1 cyclic nucleoside Chemical class 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 239000012043 crude product Substances 0.000 description 20
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 18
- 239000008346 aqueous phase Substances 0.000 description 18
- 239000012267 brine Substances 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 230000001965 increasing effect Effects 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 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
- 238000001816 cooling Methods 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical compound O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 7
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 7
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- RVEJWGYZBXCGGM-DNVCBOLYSA-N chembl2179094 Chemical compound C([C@H]([C@@H](C1)C=2NC(=O)C=3C=NN(C=3N=2)C2CCOCC2)C)N1CC1=CC=CC=C1 RVEJWGYZBXCGGM-DNVCBOLYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 229960001330 hydroxycarbamide Drugs 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 230000021164 cell adhesion Effects 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 101001117089 Drosophila melanogaster Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 Proteins 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000008499 blood brain barrier function Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- DVLGIQNHKLWSRU-UHFFFAOYSA-N methyl 1h-imidazole-5-carboxylate Chemical compound COC(=O)C1=CN=CN1 DVLGIQNHKLWSRU-UHFFFAOYSA-N 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 206010012289 Dementia Diseases 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 description 4
- 108010044495 Fetal Hemoglobin Proteins 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 238000013480 data collection Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 201000001881 impotence Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- TWIIRMSFZNYMQE-UHFFFAOYSA-N methyl pyrazine-2-carboxylate Chemical compound COC(=O)C1=CN=CC=N1 TWIIRMSFZNYMQE-UHFFFAOYSA-N 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 150000004682 monohydrates Chemical class 0.000 description 4
- 208000015122 neurodegenerative disease Diseases 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 210000002307 prostate Anatomy 0.000 description 4
- 150000003216 pyrazines Chemical class 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 210000001635 urinary tract Anatomy 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
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 3
- 241001439211 Almeida Species 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 3
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 208000010877 cognitive disease Diseases 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 229910052727 yttrium Inorganic materials 0.000 description 3
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 2
- IPLCSDCAWNDONJ-HTQZYQBOSA-N (3s,4s)-4-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(O)=O IPLCSDCAWNDONJ-HTQZYQBOSA-N 0.000 description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- NIHUZJPITMUICY-UHFFFAOYSA-N 1h-imidazo[5,1-f][1,2,4]triazin-4-one Chemical compound O=C1NC=NN2C=NC=C12 NIHUZJPITMUICY-UHFFFAOYSA-N 0.000 description 2
- MSFVEEFXECBJPG-UHFFFAOYSA-N 2-(chloromethyl)pyrimidine Chemical compound ClCC1=NC=CC=N1 MSFVEEFXECBJPG-UHFFFAOYSA-N 0.000 description 2
- JTPXVCKCLBROOJ-UHFFFAOYSA-N 2-amino-6-chloropyrazine Chemical compound NC1=CN=CC(Cl)=N1 JTPXVCKCLBROOJ-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- KAADYLCSXGRGRX-UHFFFAOYSA-N 2-phenylpyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1C1=CC=CC=C1 KAADYLCSXGRGRX-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- YESBKGNNQBDQKB-UHFFFAOYSA-N 3-[(2-phenylmethoxyacetyl)amino]imidazole-4-carboxamide Chemical compound NC(=O)C1=CN=CN1NC(=O)COCC1=CC=CC=C1 YESBKGNNQBDQKB-UHFFFAOYSA-N 0.000 description 2
- CXKUYRJNAIFRAY-UHFFFAOYSA-N 3-[(4-fluorophenyl)methoxy]azetidine Chemical compound C1=CC(F)=CC=C1COC1CNC1 CXKUYRJNAIFRAY-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- OQXAACOHEQDRSF-UHFFFAOYSA-N 4-fluoro-N-[(5-iodo-3-methoxypyrazin-2-yl)methyl]benzamide Chemical compound FC1=CC=C(C(=O)NCC2=NC=C(N=C2OC)I)C=C1 OQXAACOHEQDRSF-UHFFFAOYSA-N 0.000 description 2
- SGCMXKBMMUXENL-UHFFFAOYSA-N 5-amino-3-chloropyrazine-2-carbonitrile Chemical compound NC1=CN=C(C#N)C(Cl)=N1 SGCMXKBMMUXENL-UHFFFAOYSA-N 0.000 description 2
- VELFKJVIXURHDI-UHFFFAOYSA-N 5-amino-3-methoxypyrazine-2-carbonitrile Chemical compound COC1=NC(N)=CN=C1C#N VELFKJVIXURHDI-UHFFFAOYSA-N 0.000 description 2
- YEBDYUMXHLRMBW-UHFFFAOYSA-N 6-chloro-5-iodopyrazin-2-amine Chemical compound NC1=CN=C(I)C(Cl)=N1 YEBDYUMXHLRMBW-UHFFFAOYSA-N 0.000 description 2
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 2
- SLYRIXNICMCXFH-UHFFFAOYSA-N 7h-imidazo[1,5-a]pyrazin-8-one Chemical compound O=C1NC=CN2C=NC=C12 SLYRIXNICMCXFH-UHFFFAOYSA-N 0.000 description 2
- 206010065040 AIDS dementia complex Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- DWIPQNPJJVLVJZ-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CC(C1)OCc1ccc(F)cc1 Chemical compound CC(C)(C)OC(=O)N1CC(C1)OCc1ccc(F)cc1 DWIPQNPJJVLVJZ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- SWUPQAFIEWLDPO-UHFFFAOYSA-N Cl.C1NCC1Oc1cccnc1 Chemical compound Cl.C1NCC1Oc1cccnc1 SWUPQAFIEWLDPO-UHFFFAOYSA-N 0.000 description 2
- PQJDYBBWSGRZRS-UHFFFAOYSA-N Cl.N1CC(C1)OC1=CC=NC=C1 Chemical compound Cl.N1CC(C1)OC1=CC=NC=C1 PQJDYBBWSGRZRS-UHFFFAOYSA-N 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- KMVRIMZHQHWRQX-UHFFFAOYSA-N N-[(5-amino-3-methoxypyrazin-2-yl)methyl]-4-fluorobenzamide Chemical compound NC=1N=C(C(=NC=1)CNC(C1=CC=C(C=C1)F)=O)OC KMVRIMZHQHWRQX-UHFFFAOYSA-N 0.000 description 2
- CQKSOJHVPBBAMC-UHFFFAOYSA-N N-[(5-amino-3-methoxypyrazin-2-yl)methyl]oxane-4-carboxamide Chemical compound NC=1N=C(C(=NC=1)CNC(=O)C1CCOCC1)OC CQKSOJHVPBBAMC-UHFFFAOYSA-N 0.000 description 2
- NUKZDPLAVFZMLZ-UHFFFAOYSA-N N-[(5-iodo-3-methoxypyrazin-2-yl)methyl]oxane-4-carboxamide Chemical compound IC=1N=C(C(=NC=1)CNC(=O)C1CCOCC1)OC NUKZDPLAVFZMLZ-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- 229940127271 compound 49 Drugs 0.000 description 2
- 229940126545 compound 53 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 210000005226 corpus cavernosum Anatomy 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- GDZPWQCQDBQIJJ-TZMCWYRMSA-N ethyl (3s,4s)-1-benzyl-4-methylpyrrolidine-3-carboxylate Chemical compound C1[C@@H](C)[C@H](C(=O)OCC)CN1CC1=CC=CC=C1 GDZPWQCQDBQIJJ-TZMCWYRMSA-N 0.000 description 2
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N ethyl but-2-enoate Chemical compound CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 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
- 238000007913 intrathecal administration Methods 0.000 description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NRUFJPRJBNULNF-UHFFFAOYSA-N methyl 3-[(2-phenylmethoxyacetyl)amino]imidazole-4-carboxylate Chemical compound COC(=O)C1=CN=CN1NC(=O)COCC1=CC=CC=C1 NRUFJPRJBNULNF-UHFFFAOYSA-N 0.000 description 2
- BGPIJVLISHIDFQ-UHFFFAOYSA-N methyl 3-aminoimidazole-4-carboxylate Chemical compound COC(=O)C1=CN=CN1N BGPIJVLISHIDFQ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 238000000879 optical micrograph Methods 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 210000003899 penis Anatomy 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004648 relaxation of smooth muscle Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 210000001995 reticulocyte Anatomy 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 230000002739 subcortical effect Effects 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 2
- 229960000835 tadalafil Drugs 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 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 2
- RTDLUHDCAKPYDB-RKDXNWHRSA-N tert-butyl (3S,4S)-3-(2-bromoacetyl)-4-methylpyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C[C@H]([C@@H](C1)C)C(CBr)=O RTDLUHDCAKPYDB-RKDXNWHRSA-N 0.000 description 2
- RUMGUDRIHVNQDU-NXEZZACHSA-N tert-butyl (3S,4S)-3-[methoxy(methyl)carbamoyl]-4-methylpyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C[C@H]([C@@H](C1)C)C(N(C)OC)=O RUMGUDRIHVNQDU-NXEZZACHSA-N 0.000 description 2
- HREZTDIFTLSAQP-PSASIEDQSA-N tert-butyl (3s,4s)-3-acetyl-4-methylpyrrolidine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)=O HREZTDIFTLSAQP-PSASIEDQSA-N 0.000 description 2
- XRRXRQJQQKMFBC-UHFFFAOYSA-N tert-butyl 3-hydroxyazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(O)C1 XRRXRQJQQKMFBC-UHFFFAOYSA-N 0.000 description 2
- QVRCCEVVKRJINS-UHFFFAOYSA-N tert-butyl n-(5-cyano-6-methoxypyrazin-2-yl)carbamate Chemical compound COC1=NC(NC(=O)OC(C)(C)C)=CN=C1C#N QVRCCEVVKRJINS-UHFFFAOYSA-N 0.000 description 2
- BUQIFANLLOIOSK-UHFFFAOYSA-N tert-butyl n-[5-(aminomethyl)-6-methoxypyrazin-2-yl]carbamate Chemical compound COC1=NC(NC(=O)OC(C)(C)C)=CN=C1CN BUQIFANLLOIOSK-UHFFFAOYSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 210000003708 urethra Anatomy 0.000 description 2
- 210000003741 urothelium Anatomy 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- OCQAXYHNMWVLRH-QZTJIDSGSA-N (2r,3r)-2,3-dibenzoyl-2,3-dihydroxybutanedioic acid Chemical compound O=C([C@@](O)(C(=O)O)[C@](O)(C(O)=O)C(=O)C=1C=CC=CC=1)C1=CC=CC=C1 OCQAXYHNMWVLRH-QZTJIDSGSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- GRZHHTYDZVRPIC-UHFFFAOYSA-N (benzyloxy)acetic acid Chemical compound OC(=O)COCC1=CC=CC=C1 GRZHHTYDZVRPIC-UHFFFAOYSA-N 0.000 description 1
- IZXWCDITFDNEBY-UHFFFAOYSA-N 1-(chloromethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCl)C=C1 IZXWCDITFDNEBY-UHFFFAOYSA-N 0.000 description 1
- SLOLMQZWHOQIEZ-RKDXNWHRSA-N 1-O-tert-butyl 3-O-methyl (3S,4S)-4-methylpyrrolidine-1,3-dicarboxylate Chemical compound COC(=O)[C@@H]1CN(C[C@H]1C)C(=O)OC(C)(C)C SLOLMQZWHOQIEZ-RKDXNWHRSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- 239000002677 5-alpha reductase inhibitor Substances 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- SKTFQHRVFFOHTQ-UHFFFAOYSA-N 8-bromo-1,3-dimethyl-7h-purine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Br)=N2 SKTFQHRVFFOHTQ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010048554 Endothelial dysfunction Diseases 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241001313288 Labia Species 0.000 description 1
- 241000699729 Muridae Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 229940121836 Phosphodiesterase 1 inhibitor Drugs 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 108010016797 Sickle Hemoglobin Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010053648 Vascular occlusion Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- FDXOHKDMDYSTDN-UHFFFAOYSA-N [Cr](=O)(=O)([O-])[O-].[Ge+2] Chemical compound [Cr](=O)(=O)([O-])[O-].[Ge+2] FDXOHKDMDYSTDN-UHFFFAOYSA-N 0.000 description 1
- QPQGTZMAQRXCJW-UHFFFAOYSA-N [chloro(phenyl)phosphoryl]benzene Chemical compound C=1C=CC=CC=1P(=O)(Cl)C1=CC=CC=C1 QPQGTZMAQRXCJW-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000011953 bioanalysis Methods 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 239000010431 corundum Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000008694 endothelial dysfunction Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000000267 erythroid cell Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical class 0.000 description 1
- SJECIYLGISUNRO-UHFFFAOYSA-N o-diphenylphosphorylhydroxylamine Chemical compound C=1C=CC=CC=1P(=O)(ON)C1=CC=CC=C1 SJECIYLGISUNRO-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- RYGUCYSSMOFTSH-UHFFFAOYSA-N oxane-4-carbonyl chloride Chemical compound ClC(=O)C1CCOCC1 RYGUCYSSMOFTSH-UHFFFAOYSA-N 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill 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
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- JQXFBJIDTLTFNU-UHFFFAOYSA-N tert-butyl 3-methylpyrrolidine-1-carboxylate Chemical compound CC1CCN(C(=O)OC(C)(C)C)C1 JQXFBJIDTLTFNU-UHFFFAOYSA-N 0.000 description 1
- DUSRUWXLYFPEDE-UHFFFAOYSA-N tert-butyl N-[6-methoxy-5-[(oxane-4-carbonylamino)methyl]pyrazin-2-yl]carbamate Chemical compound COC1=C(N=CC(=N1)NC(OC(C)(C)C)=O)CNC(=O)C1CCOCC1 DUSRUWXLYFPEDE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 150000003527 tetrahydropyrans Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 201000002327 urinary tract obstruction Diseases 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Images
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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及PDE9抑制剂及其用于治疗良性前列腺增生和镰状细胞疾病的用途。该抑制化合物可选自:3‑(4‑氟苯基)‑6‑((3‑(吡啶‑4‑基氧基)氮杂环丁烷‑1‑基)甲基)咪唑并[1,5‑a]吡嗪‑8(7H)‑酮、6‑[3‑(吡啶‑3‑基氧基)‑氮杂环丁烷‑1‑基甲基]‑3‑(四氢‑吡喃‑4‑基)‑7H‑咪唑并[1,5‑a]吡嗪‑8‑酮、6‑(4‑甲基‑1‑嘧啶‑2‑基甲基‑吡咯烷‑3‑基)‑3‑(四氢‑吡喃‑4‑基)‑7H‑咪唑并[1,5‑a]吡嗪‑8‑酮、(3S,4S)‑6‑(4‑甲基‑1‑嘧啶‑2‑基甲基‑吡咯烷‑3‑基)‑3‑(四氢‑吡喃‑4‑基)‑7H‑咪唑并[1,5‑a]吡嗪‑8‑酮和(3R,4R)‑6‑(4‑甲基‑1‑嘧啶‑2‑基甲基‑吡咯烷‑3‑基)‑3‑(四氢‑吡喃‑4‑基)‑7H‑咪唑并[1,5‑a]吡嗪‑8‑酮。
Description
本申请是申请日为2016年7月6日,申请号为201680039418.0,发明名称为“用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的PDE9抑制剂”的申请的分案申请。
相关申请的引用
本申请要求以下DK临时专利申请的优先权:2015年7月7日提交的名称为“用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的PDE9抑制剂”的DK临时专利申请号PA201500393、2015年7月10日提交的名称为“用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的PDE9抑制剂”的DK临时专利申请号PA201500407和2016年4月7日提交的名称为“用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的PDE9抑制剂”的DK临时专利申请号PA201600209,这些申请中的每一个申请的内容通过引用的方式以其整体并入本文中。
技术领域
本发明涉及3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮或7H-咪唑并[1,5-a]吡嗪-8-酮形式的环单磷酸鸟苷(cGMP)特异性9型磷酸二酯酶抑制剂(下文称为PDE9抑制剂)及其作为用于治疗外周疾病的药物的用途。而且,本发明涉及包含3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮和7H-咪唑并[1,5-a]吡嗪-8-酮的药物组合物。
背景技术
磷酸二酯酶(PDE)是降解环核苷酸并因此调节遍及整个身体的第二信使的细胞水平的酶家族。PDE代表有吸引力的药物靶标,这已分别被进入临床试验和市场的多个化合物所证明。PDE由21个基因编码,这些基因在功能上被分成11个家族,这些家族在动力学性质、底物选择性、表达、定位模式、激活、调节因子和抑制剂敏感性方面有所不同。PDE的功能是降解环单磷酸核苷、环单磷酸腺苷(cAMP)和/或环单磷酸鸟苷(cGMP),它们是参与众多至关重要的过程(包括控制神经传递和平滑肌收缩和舒张)的重要细胞内调质。
PDE9是cGMP特异性(cAMP的Km是cGMP的1000多倍),并且已被假设为调整cGMP水平的关键物质,因为在这一核苷酸的PDE之间其具有最低的Km。PDE9在整个脑部以低水平表达,具有调整基底cGMP的潜能。
在外周,PDE9的表达在前列腺、肠、肾和造血细胞中达到峰值,开放了各种外周适应症的治疗潜能。
良性前列腺增生(Benign prostate hyperplasia,BPH)是老年男性群体最常见的状况之一,并代表了主要的健康问题(Ueckert S等人,Expert Rev ClinPharmacol.2013May;6(3):323-32)。BPH导致在前列腺的尿道周区域形成大的结节,这可导致尿路梗阻。BPH主要是基质增殖过程的结果,并且前列腺增大的重要成因是由平滑肌增殖造成的。目前对BPH的药物治疗包括α1肾上腺素能阻滞剂、5-α-还原酶抑制剂,以及最近的PDE5抑制剂他达拉非(tadalafil)。已知PDE5抑制剂经由增加的cGMP水平来介导平滑肌松弛。cGMP特异性PDE9在前列腺中以高水平表达,并且PDE9抑制因此可以对BPH提供潜在的抗增殖益处。
PDE9广泛分布在人下尿路的尿路上皮中,并且PDE9抑制在下尿路功能障碍上皮(lower urinary tract dysfunctional epithelium,LUDE)疾病中可能是有益的(Nagasaki等人,BJU Int.2012Mar;109(6):934-40)。功能障碍的下尿路上皮能影响女性的膀胱、尿道、阴唇或阴道口以及男性的前列腺管和尿道(Parsons LC et al.,2002)。
已表明在鼠科动物的阴茎海绵体中存在PDE9的表达,并且已证明长期PDE9抑制导致放大的NO-cGMP介导的海绵体响应并因此开放了在勃起功能障碍中的潜在益处(DaSilva等人,Int J Impot Res.2013Mar-Apr;25(2):69-73)。目前经批准的用于勃起功能障碍的治疗是PDE5抑制剂类型,增加在供应阴茎的阴茎海绵体的血管内层的平滑肌细胞中的cGMP。
已表明cGMP PDE抑制增强肌肉微脉管血液流动和对胰岛素的葡萄糖摄取响应(Genders等人,Am J Physiol Endocrinol Metab.2011Aug;301(2):E342-50)。靶向在肌肉和血管中表达的cGMP特异性PDE9可以为增强肌肉胰岛素敏感性提供有前景的途径,并因此有益于治疗2型糖尿病。
PDE9抑制可以代表对镰状细胞疾病(Sickle Cell Disease,SCD)(一种遗传病症,导致血管闭塞性过程,引起许多SCD患者死亡)的新型一线治疗。SCD疾病因血红蛋白(HBB)基因中的点突变产生异常的镰状血红蛋白(HbS)而引起的,该镰状血红蛋白聚合并形成僵硬且粘性的镰状红细胞。镰状红细胞导致慢性炎症、增多的细胞粘附、氧化应激、内皮功能障碍,在血管闭塞性过程中达到顶峰。
迄今为止尚不能治愈SCD。治疗选择包括输血和用抗癌剂羟基脲治疗。输血通过增加循环中正常的、非镰状红细胞的数量来矫正贫血。定期输血的疗法能帮助高风险的儿童预防中风复发。羟基脲已被批准用于治疗SCD并显示降低疼痛危象和住院治疗的频率。羟基脲改善SCD症状的假说机理是双重的:a)增加非镰状胎血红蛋白的生产;和b)减少细胞粘附。具体地说,羟基脲a)经由cGMP信号传导增加非镰状胎血红蛋白的生产,已表明这导致增加的血细胞存活;和b)增加氧化氮和cGMP水平,从而减少粘附并增加存活。总之,迄今为止的证据支持以下观点:羟基脲对SCD具有益处的两种机理都是经由增加的cGMP介导的。
PDE9具体是在人造血系统(包括中性粒细胞、网织红细胞、红系细胞和红白血病细胞)中表达。而且,SCD患者显示出明显且显著增多的PDE9在网织红细胞和中性粒细胞中的表达(Almeida等人,Br J Haematol.2008九月;142(5):836-44)。证据额外证明了PDE9和细胞粘附之间的联系,因为PDE9抑制导致SCD中性粒细胞的增强的粘附性能逆转(Miguel等人,Inflamm Res.2011七月;60(7):633-42)。已表明PDE9抑制减少细胞粘附的机理是经由增加的cGMP和减少的内皮黏附分子表达介导的。重要的是,在SCD动物模型中,PDE9抑制剂介导的细胞黏附减少具有增加细胞存活的功能性作用。除了证明与羟基脲相当的减少细胞粘附的作用之外,PDE9抑制导致增加的非镰状胎血红蛋白生产。最后,Almeida和同事们证明了在SCD小鼠模型中采用羟基脲联合PDE9抑制进行治疗导致PDE9抑制剂具有放大羟基脲的cGMP升高作用的额外益处(Almeida等人,Blood.2012十月4;120(14):2879-88)。总之,PDE9抑制既能调节胎血红蛋白生产的表达又能减少细胞粘附,这两种机理对于治疗SCD均是关键的。
WO 2013/053690公开了具有咪唑并吡嗪酮骨架的PDE9抑制剂,用作药物例如治疗患有认知损伤特别是与神经退行性疾病如皮质性痴呆(例如阿尔茨海默病)或皮质下痴呆(例如AIDS相关痴呆)相关的患者。
WO 2013/110768公开了具有咪唑并三嗪酮骨架的PDE9抑制剂,用作药物例如治疗患有认知损伤特别是与神经退行性疾病如皮质性痴呆(例如阿尔茨海默病)或皮质下痴呆(例如AIDS相关痴呆)相关的患者。
WO 2012/040230公开了具有咪唑并三嗪酮骨架的PDE9抑制剂,用作药物治疗PDE9相关疾病,包括CNS和神经退行性病症。
WO 2008/139293和WO 2010/084438均公开了为PDE9抑制剂的氨基-杂环化合物及其用于治疗神经退行性病症和认知障碍的用途。
发明内容
对于外周疾病良性前列腺增生(BPH)、尿路功能障碍上皮疾病、勃起功能障碍、2型糖尿病和镰状细胞疾病(SCD)的改进治疗具有持续的需求,就此目的而言,使用PDE9抑制剂可能是非常有用的。因为PDE9在整个脑部以低水平表达,潜在的基底cGMP,和因此信号传导级联显示调节突触传导,用于治疗外周疾病的PDE9抑制剂具有低血脑屏障穿透作用(BBB穿透作用)以避免潜在的中枢介导的副作用是明显重要的。
本发明提供了新型PDE9抑制剂,已表明其具有低血脑屏障穿透作用并因此可以特别用于治疗外周疾病,如良性前列腺增生(BPH)、尿路功能障碍上皮疾病、勃起功能障碍、2型糖尿病和镰状细胞疾病(SCD)。而且,本发明的PDE9抑制剂相比于PDE1抑制剂,是显著更强的PDE9抑制剂,这是重要的,因为PDE1在心脏和睾丸中表达,并且对这些PDE1同种型的抑制被认为是心血管和生殖系统副作用的潜在原因。
本发明涵盖以下化合物:
本发明的另一方面涉及P1、P2、P3和P4的合成。本发明的又一方面涉及化合物P3的对映选择合成,包括中间体化合物rac-35至(S,S)-35的转化。
附图说明
图1显示化合物P3对映异构体2一水合物的绝对立体化学。
图2A-2B是结晶批次的光学显微照片(图2A)和用于数据收集的晶体(图2B)。
图3是化合物P3对映异构体2一水合物的球棍图。
具体实施方式
发明实施方式
使用下列符号:本发明的实施方式被描述为Ei,其中i是表示实施方式编号的整数。详细说明先前列出的实施方式Ei的具体实施方式的实施方式Ei’被描述为Ei’(Ei),例如E2(E1)表示“在实施方式E1的实施方式E2中”。
当一个实施方式是两个实施方式的组合时,符号类似地为Ei”(Ei和Ei’),例如E3(E2和E1)表示“在E2和E1任一实施方式的实施方式E3中”。
当一个实施方式是多于两个实施方式的组合时,符号类似地为Ei”’(Ei、Ei’和Ei”),例如E4(E1、E2和E3)表示“在E1、E2和E3任一实施方式的实施方式E4中”。
在第一实施方式E1中,本发明涉及具有以下结构的化合物:
在实施方式E2(E1)中,当通过手性HPLC(柱:Chiralpak IA,250x 4.6mm x 5um;流动相:Hex/EtOH/DEA=70:30:0.2;流速为1.0mL/min)分离P3的外消旋混合物时,化合物P3的对映异构体纯变体是第一洗脱(eluding)化合物(P3对映异构体1)。
E3(E1和E2):E1和E2任一实施方式的化合物,用作药物。
E4:E1和E2任一实施方式的化合物或以下化合物,用于治疗良性前列腺增生或镰状细胞疾病:
E5:一种药物组合物,其包含治疗有效量的E1和E2的任何化合物或化合物P4,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
E6(E5):该药物组合物用于治疗良性前列腺增生或镰状细胞疾病。
E7:化合物P4或E1和E2的任何化合物用于制备用于治疗良性前列腺增生或镰状细胞疾病的药物的用途。
E8:一种治疗患有良性前列腺增生或镰状细胞疾病的患者的方法,其包括向有此需要的受试者施用治疗有效量的化合物P4或E1和E2的任何化合物。
E9:一种化合物,选自:3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)、6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)、(3S,4S)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体1)和(3R,4R)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体2)。
E10(E9):化合物(3S,4S)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体1)。
E11(E9):化合物(3R,4R)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体2)。
E12(E9、E10和E11):E9至E11任一实施方式的化合物,用作药物。
E13:选自以下的化合物:3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)、6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)、(3S,4S)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体1)、(3R,4R)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体2)和2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4),用于治疗良性前列腺增生或镰状细胞疾病。
E14:一种药物组合物,其包含治疗有效量的任何以下化合物以及一种或多种药学上可接受的载体、稀释剂或赋形剂:3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)、6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)、(3S,4S)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体1)、(3R,4R)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体2)和2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
E15(E14):该药物组合物用于治疗良性前列腺增生或镰状细胞疾病。
E16:任何以下化合物用于制备用于治疗良性前列腺增生或镰状细胞疾病的药物的用途:3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)、6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)、(3S,4S)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体1)、(3R,4R)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体2)和2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
E17:一种治疗患有良性前列腺增生或镰状细胞疾病的受试者的方法,其包括向有此需要的受试者施用治疗有效量的任何以下化合物:3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)、6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)、(3S,4S)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体1)、(3R,4R)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体2)和2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
PDE9抑制剂
在本发明的上下文中,如果达到三种PDE9同种型任一种的IC50水平所需的量为10微摩尔或更少,优选少于9微摩尔,如8微摩尔或更少,如7微摩尔或更少,如6微摩尔或更少,如5微摩尔或更少,如4微摩尔或更少,如3微摩尔或更少,更优选2微摩尔或更少,如1微摩尔或更少,特别是500nM或更少,化合物被认为是PDE9抑制剂。在优选的实施方式中,达到PDE9的IC50水平所需的PDE9抑制剂的所需量为400nM或更少,如300nM或更少,200nM或更少,100nM或更少,或甚至80nM或更少,如50nM或更少,例如25nM或更少。
在本申请的全文中,符号IC50和IC50可互换使用。
异构形式
当本发明的化合物含有一个或多个手性中心时,除非另有规定,对任何化合物的提及将涵盖对映异构体纯或非对映异构体纯的化合物以及以任何比率存在的对映异构体或非对映异构体的混合物。
药学上可接受的盐
本发明还包含化合物的盐,通常为药学上可接受的盐。这样的盐包括药学上可接受的酸加成盐。酸加成盐包括无机酸以及有机酸的盐。
合适的无机酸的代表性实例包括盐酸、氢溴酸、氢碘酸、磷酸、硫酸、氨基磺酸、硝酸等。合适的有机酸的代表性实例包括甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、苯甲酸、肉桂酸、柠檬酸、富马酸、乙醇酸、衣康酸、乳酸、甲磺酸、马来酸、苹果酸、丙二酸、扁桃酸、草酸、苦味酸、丙酮酸、水杨酸、琥珀酸、甲烷磺酸、乙磺酸、酒石酸、抗坏血酸、双羟萘酸、亚甲基双水杨酸(bismethylene salicylic)、乙二磺酸、葡糖酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、EDTA、羟基乙酸、对氨基苯甲酸、谷氨酸、苯磺酸、对甲苯磺酸、茶碱乙酸以及8-卤代茶碱(例如8-溴茶碱)等。药学上可接受的无机酸或有机酸加成盐的更多实例包括在以下文献中列出的药学上可接受的盐中:Berge,S.M.等人,J.Pharm.Sci.1977,66,2,该文献的内容通过引用的方式并入本文。
而且,本发明的化合物可以以未溶剂化的形式以及与药学上可接受的溶剂(如水、乙醇等)溶剂化的形式存在。一般地,就本发明的目的来说,溶剂化形式被认为等同于未溶剂化的形式。
药物组合物
本发明还提供了一种药物组合物,其包含治疗有效量的任何本发明化合物和药学上可接受的载体或稀释剂。本发明还提供了一种药物组合物,其包含治疗有效量的在本文实验部分中所公开的具体化合物之一以及药学上可接受的载体或稀释剂。
本发明的化合物可以以单剂量或多剂量单独地给药或与药学上可接受的载体、稀释剂或赋形剂联合地给药。根据常规技术如在以下文献中描述的那些技术可以将根据本发明的药物组合物与药学上可接受的载体或稀释剂以及任何其他已知的佐剂和赋形剂一起配制:Remington:The Science and Practice of Pharmacy(雷明顿:药剂学科学与实践),第22版,Gennaro,Ed.,Mack Publishing Co.,Easton,PA,2013。
药物组合物可以被具体配制成用于通过任何合适的途径给药,如口服、直肠、鼻、肺部、局部(包括口腔和舌下)、经皮、脑池内、腹膜内、阴道和肠胃外(包括皮下、肌内、鞘内、静脉内和皮肤内)途径。可以理解,该途径取决于待治疗的受试者的一般状况和年龄、待治疗的状况的性质和活性成分。
用于口服给药的药物组合物包括固体剂型如胶囊剂、片剂、糖衣丸、丸剂、锭剂、粉剂和颗粒剂。适当时,组合物可以被制备成具有包衣如肠溶包衣,或者其可以根据本领域已知的方法被配制成提供活性成分的控释如缓释或延释。用于口服给药的液体剂型包括溶液、乳剂、混悬液、糖浆剂和酏剂。
用于肠胃外给药的药物组合物包括无菌可注射的水溶液和非水溶液、分散液、混悬液或乳剂以及在使用前在无菌可注射的溶液或分散液中重构的无菌粉剂。其它合适的给药形式包括但不限于栓剂、喷雾剂、软膏剂、乳膏剂、凝胶剂、吸入剂、皮肤贴剂和植入物。
典型的口服剂量为每天约0.001至约100mg/kg体重。典型的口服剂量也可以为每天约0.01至约50mg/kg体重。典型的口服剂量还可以为每天约0.05至约10mg/kg体重。口服剂量一般以一次或多次剂量(通常为每天一至三次剂量)给药。确切的剂量将取决于给药频率和方式;被治疗的受试者的性别、年龄、体重和一般状况;被治疗的状况的性质和严重程度;以及待治疗的任何伴发疾病和其他对本领域技术人员来说是显然的因素。
通过本领域技术人员已知的方法也可以使制剂呈现为单位剂型。出于举例说明的目的,典型的用于口服给药的单位剂型可以含有约0.01至约1000mg、约0.05至约500mg或约0.5mg至约200mg。
对于肠胃外途径如静脉内、鞘内、肌内及类似的给药,典型的剂量大约为口服给药所用剂量的一半。
本发明还提供了用于制备药物组合物的方法,该方法包括将治疗有效量的本发明的化合物和至少一种药学上可接受的载体或稀释剂混合。在本发明的一个实施方案中,在前述方法中使用的化合物是本文实验部分中公开的具体化合物之一。
本发明的化合物通常作为游离物质或作为其药学上可接受的盐使用。以常规的方式通过用摩尔当量的药学上可接受的酸来处理本发明化合物的溶液或悬浮液来制备这样的盐。合适的有机酸和无机酸的代表性实例在上文描述。
对于肠胃外给药,可以使用本发明化合物在无菌水溶液、丙二醇水溶液、维生素E水溶液或芝麻油或花生油中的溶液。这样的水溶液在必要时应当进行适当的缓冲,并且液体稀释剂应当首先用足够的盐水或葡萄糖来使其等渗。水溶液特别适合用于静脉内、肌内、皮下和腹膜内给药。使用本领域技术人员已知的标准技术可以容易地将本发明化合物并入到已知的无菌水介质中。
适合的药物载体包括惰性固体稀释剂或填充剂、无菌水溶液和各种有机溶剂。固体载体的实例包括乳糖、石膏粉、蔗糖、环糊精、滑石粉、明胶、琼脂、果胶、阿拉伯树胶、硬脂酸镁、硬脂酸和纤维素的低级烷基醚。液体载体的实例包括但不限于糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯和水。类似地,载体或稀释剂可以包括单独的或与蜡混合的本领域中已知的任何缓释物质,如单硬脂酸甘油酯或二硬脂酸甘油酯。通过将本发明的化合物和药学上可接受的载体组合而形成的药物组合物则容易地以适合所公开的给药途径的各种剂型给药。通过制药领域中已知的方法可以方便地使制剂以单位剂型呈现。
适合口服给药的本发明制剂可以呈现为独立单元,如胶囊或片剂,其各自含有预定量的活性成分以及任选的适合的赋形剂。而且,可口服利用的制剂可以为粉剂或颗粒剂、在水或非水液体中的溶液或混悬液、或者水包油或油包水型液体乳剂的形式。
如果使用固体载体用于口服给药,则制剂可以被压片、以粉末或微丸形式置于硬明胶胶囊中,或者其可以为糖锭或锭剂的形式。固体载体的量可以变化很大,但将在每剂量单位约25mg至约1g的范围内。如果使用液体载体,则制剂可以为糖浆、乳剂、软明胶胶囊或无菌可注射液体如水或非水液体混悬液或溶液的形式。
本发明的药物组合物可以通过本领域的常规方法来制备。例如,片剂可以通过将活性成分与常用佐剂和/或稀释剂混合,并随后在常规压片机中压制混合物以制备片剂来制备。佐剂或稀释剂的实例包括:玉米淀粉、马铃薯淀粉、滑石、硬脂酸镁、明胶、乳糖、胶等。可以使用任何其他的常用于这样的目的的佐剂或添加剂,如着色剂、调味剂、防腐剂等,条件是它们与活性成分相容。
本发明的化合物
表1列出了本发明的化合物以及相应的IC50值(nM),该IC50值(nM)是如“PDE9抑制试验”部分中所述测定的。进一步地,列出了化合物在血浆和脑中的浓度,该浓度是如“血脑屏障穿透”部分中所述测定的。每个化合物均构成本发明的独立的实施方式:
表1:本发明的化合物、IC50值和血浆/脑浓度
实施例
实施例1.化合物的合成
本发明的化合物可以如下所述进行合成。
总体方案:
方案1:
方案2(化合物(P1)):
方案3(化合物(P2)):
方案4(化合物(P3)):
方案5(化合物(P4)):
合成步骤:
缩写列表
aq 水
NBS N-溴代丁二酰亚胺
Boc 叔丁氧羰基
℃ 摄氏度
CDI N,N-羰基二咪唑
δH 相对于四甲基硅烷在低场的化学位移,单位为百万分之一
DCM 二氯甲烷
DEAD 偶氮二甲酸二乙酯
Dppf 双(二苯基膦)二茂铁
DIPEA N,N-二异丙基乙胺
DMF N,N-二甲基甲酰胺
eq 当量
ESI 电喷雾电离
Et 乙基
EtOAc 乙酸乙酯
g 克
HPLC 高效液相色谱法
h 小时
Hz 赫兹
J 耦合常数(在NMR波谱中)
LCMS 液相色谱法-质谱法联用
LiHMDS 双(三甲基硅烷基)酰胺锂
μ 微
m 多重峰(光谱);米;毫
M+ 母分子离子
Me 甲基
MeCN 乙腈
MeOH 甲醇
MHz 兆赫兹
min 分钟
mL 毫升
MS 质谱法
MTBE 甲基叔丁基醚
N 当量浓度(当量每升)
NaOH 氢氧化钠
NBS N-溴代丁二酰亚胺
nm 纳米
NMR 核磁共振
PE 石油醚,沸点:60~90℃
rt 室温
s 单峰(波谱)
t 三重峰(波谱)
T 温度
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
TMS 四甲基硅烷
TMS-Cl 三甲基氯硅烷
Tol 甲苯
一般实验方法
在Bruker Avance III 400MHz和Bruker Fourier 300MHz上记录1H NMR谱图,并使用TMS作为内标。
LCMS在Agilent LC/MSD 1200系列(柱:ODS 2000(50×4.6mm,5μm)上在四极杆质谱仪上进行,以ES(+)或(-)电离模式操作;T=30℃;流速=1.5mL/min;检测波长:214nm。
6-氯-吡嗪-2-基胺(9)的合成
将化合物8(450.0g,3.02mol)在浓NH3水溶液(3.0L)中的溶液在10L密封压力容器中于135℃下搅拌过夜。TLC和LC/MS显示起始原料完全转化。将反应混合物冷却至室温,并过滤,得到白色固体。将该固体用水(200mL x 3)洗涤,然后干燥,得到为固体的化合物9(312g,收率为80%)。
1HNMR(400MHz,DMSO-d6):δ7.82(s,1H),7.12(s,1H),6.93(s,2H)。MS计算值:129MS实测值:130([M+H]+)。
6-氯-5-碘-吡嗪-2-基胺(10)的合成
在0℃下历经2小时向化合物9(312.0g,2.4mol)和K2CO3(664.0g,4.8mol)在MeOH(1.0L)中的混合物滴加ICl(704.0g,4.3mol在1.0L DCM中)。然后将反应混合物在室温下搅拌过夜。将反应用Na2SO3水溶液(2M,1.5L)淬灭。将混合物用DCM(1.0L x 3)萃取。合并的有机相经无水Na2SO4干燥,过滤并浓缩。粗产物经硅胶柱色谱法(PE/EA=10/1至4/1)纯化,得到为固体的化合物10(460g,收率为75%)。
1HNMR(400MHz,DMSO-d6):δ7.68(s,1H),7.07(s,2H)。MS计算值:255MS实测值:256([M+H]+)。
5-氨基-3-氯-吡嗪-2-甲腈(11)的合成
将化合物10(460.0g,1.8mol)和CuCN(177.0g,1.98mol)在DMF(2.0L)中的混合物在油浴上于150℃下搅拌2小时。LC/MS显示起始原料完全转化。将反应混合物冷却至室温,并倒入至EtOAc(1.5L)中。向得到的混合物中缓慢加入浓NH3水溶液(1.0L),然后将其用EtOAc(1.0L x 2)萃取。将合并的有机相用H2O(1.5L x 5)和盐水(1.5L)洗涤,并经无水Na2SO4干燥。将有机相过滤并浓缩,得到为固体的化合物11(232g,收率为84%)。
1HNMR(400MHz,DMSO-d6):δ8.12(s,2H),7.88(s,1H)。MS计算值:154;MS实测值:155([M+H]+)。
5-氨基-3-甲氧基-吡嗪-2-甲腈(12)的合成
在圆底烧瓶中将叔丁醇钾(168.0g,1.5mol)分份加入到甲醇(1.5L)中。将混悬液回流1小时。然后在N2气氛下加入化合物11(232.0g,1.5mol)。将得到的悬浮液回流1.5小时。冷却至室温后,将反应混合物在真空下浓缩,并用水(2.0L)稀释,然后用EtOAc(2.0L x5)萃取。将合并的有机相用Na2SO4干燥,过滤并浓缩,得到为固体的12(170g,收率为75%)。
1HNMR(300MHz,DMSO-d6):δ7.69(s,2H),7.51(s,1H),3.89(s,3H)。MS计算值:150;MS实测值:151([M+H]+)。
(5-氰基-6-甲氧基-吡嗪-2-基)-氨基甲酸叔丁酯(13)的合成
在室温下将4-二甲基氨基吡啶(1.0g,0.01mol)加入至化合物12(120.0g,0.8mol)在DCM(1.5L)中的混合物中。然后在10-20℃下2小时内滴加含二碳酸二叔丁酯(327g,1.5mol)的DCM(1.0L)。然后将反应在室温下搅拌过夜。使混悬液溶解,然后将反应溶液用2L水稀释。分离DCM相,并用硫酸钠干燥,过滤并在真空中浓缩。残余物经硅胶柱色谱法(PE/EtOAc=10:1)纯化,得到13(150g,收率为75%)。
1HNMR(300MHz,DMSO-d6):δ10.78(s,1H),8.70(s,1H),3.97(s,3H),1.49(s,9H)。MS计算值:250;MS实测值:251([M+H]+)。
(5-氨基甲基-6-甲氧基-吡嗪-2-基)-氨基甲酸叔丁酯(14)的合成
在室温下将Raney Ni(10.0g)加入至化合物13(30.0g,120mmol)在浓NH3的MeOH(500mL)溶液中的混合物。将混悬液在室温、1atm H2下搅拌过夜。将反应混合物用DCM/MeOH(1:1)的混合物稀释。将反应混合物过滤,并将滤液在真空中浓缩。将残余物用PE/EtOAc=2/1研磨,得到为固体的14(23g,收率为75%)。
1HNMR(300MHz,DMSO-d6):δ8.46(s,1H),3.87(s,3H),3.70(s,2H),3.17(s,3H),1.47(s,9H)。MS计算值:254;MS实测值:255([M+H]+)。
5-[(4-氟-苯甲酰基氨基)-甲基]-6-甲氧基-吡嗪-2-基-氨基甲酸叔丁酯(15)的
合成
向化合物14(4.52g,17.86mmol)在DCM(200mL)中的溶液中加入TEA(5.41g,58.53mmol),然后滴加4-氟苯甲酰氯(3.4g,21.42mmol)。将得到的反应混合物在室温下搅拌2小时。TLC检测反应完全。将反应用水(100mL)淬灭。分离有机相,并将水相用DCM(200mL×2)萃取。将合并的有机相经无水MgSO4干燥,过滤并在真空中浓缩。残余物经硅胶柱色谱法纯化,得到为固体的15(5.77g,收率为85.9%)。
1HNMR(400MHz,DMSO-d6):δ9.89(s,1H),8.81(t,J=5.6Hz,1H),8.46(s,1H),7.94(m,2H),7.29(m,2H),4.49(d,J=5.6Hz,2H),3.90(s,3H),1.47(s,9H)。MS计算值:376;MS实测值:377([M+H]+)。
N-(5-氨基-3-甲氧基-吡嗪-2-基甲基)-4-氟-苯甲酰胺(16)的合成
将化合物15(5.77g,15.33mmol)溶解于DCM(25mL)。加入TFA(25mL)。将反应在室温下搅拌过夜。TLC检测反应完全。除去溶剂。将残余物用DCM(100mL)和饱和NaHCO3水溶液(100mL)稀释。分离有机相,并将水相用DCM(100mL×2)萃取。合并的有机相经无水MgSO4干燥,过滤并在真空中浓缩。残余物经硅胶柱色谱法(用PE/EtOAc=6:1至1:1洗脱)纯化,得到为固体的16(3.9g,收率为92.2%)。
1HNMR(300MHz,CDCl3):δ7.90-7.85(m,2H),7.46(s,1H),7.40(t,J=6.0Hz,1H),7.11(m,2H),4.60(d,J=6.0Hz,2H),4.37(s,2H),3.93(s,3H)。MS计算值:276;MS实测值:277([M+H]+)。
4-氟-N-(5-碘-3-甲氧基-吡嗪-2-基甲基)-苯甲酰胺(17)的合成
将化合物16(3.9g,14.1mmol)溶解于无水THF(100mL)。在N2气氛下加入CuI(2.7g,14.1mmol),然后加入亚硝酸异戊酯(4.9g,42.3mmol)和CH2I2(3.8g,14.1mmol)。将反应混合物在75℃下加热3小时。然后使反应冷却至室温,并过滤。将滤液在真空中浓缩。残余物经硅胶柱色谱法(用PE/EtOAc5:1洗脱)纯化,得到为固体的17(2.0g,收率为37%)。
1HNMR(400MHz,CDCl3):δ8.34(s,1H),7.88(m,2H),7.36(t,J=4.4Hz,1H),7.14(m,2H),4.66(d,J=4.4Hz,2H),4.04(s,3H)。MS计算值:387;MS实测值:388([M+H]+)。
3-(4-氟-苯基)-6-碘-8-甲氧基-咪唑并[1,5-a]吡嗪(18)的合成
将化合物17(1.6g,4.13mmol)混悬于MeCNCH3CN(50mL)。在N2气氛下加入POCl3(6.3g,41.3mmol)和TEA(1.25g,12.39mmol),并将反应混合物在85℃下加热6小时。减压除去溶剂。将残余物用DCM(100mL)和冰水(30mL)稀释。然后加入饱和Na2CO3水溶液(100mL)。分离有机相,并将水相用DCM(100mL×2)萃取。将合并的有机相干燥,过滤并在真空中浓缩。残余物经硅胶柱色谱法(用PE/EtOAc=20:1至3:1洗脱)纯化,得到为固体的18(1.5g,收率为97.8%)。
1HNMR(300MHz,CDCl3):δ8.01(s,1H),7.82(s,1H),7.77-7.72(m,2H),7.28-7.23(m,2H),4.11(s,3H)。MS计算值:369;MS实测值:370([M+H]+)。
3-(4-氟-苯基)-8-甲氧基-咪唑并[1,5-a]吡嗪-6-羧酸甲酯(19)的合成
向18(4.11g,11.13mmol)、CuI(640mg,3.34mmol)和Pd(dppf)2Cl2(930mg,1.11mmol)在MeOH(100mL)中的混合物溶液中加入TEA(14mL)。在CO气氛下(3.0MPa)将反应混合物加热至85℃,持续16小时。使反应混合物冷却至室温,并在真空中浓缩,得到粗产物。残余物经硅胶柱色谱法(用PE/EtOAc=1:1洗脱)纯化,得到19(2.3g,收率为75%),为固体。
1H NMR(400MHz,CDCl3):δ8.59(s,1H),7.87(s,1H),7.78(m,2H),7.28(m,2H),4.21(s,3H),3.96(s,3H)。MS计算值:301;MS实测值:302([M+H]+)。
[3-(4-氟-苯基)-8-甲氧基-咪唑并[1,5-a]吡嗪-6-基]-甲醇(20)的合成
将粉末状的无水CaCl2(4.23g,38.15mmol)和NaBH4(2.86g,76.3mmol)在THF(100mL)中的混合物在室温下搅拌1小时。加入化合物19(2.3g,7.63mmol)在THF(25mL)中的溶液,然后加入MeOH(25mL)。将反应混合物在室温下搅拌1.5小时。将混合物反应用水(50mL)淬灭。减压除去有机溶剂后,将得到的溶液溶解于EtOAc(200mL)和水(50mL)中。将分离的水相用EtOAc(3x 100mL)萃取。然后将合并的有机相减压浓缩。残余物经硅胶柱色谱法(用PE/EtOAc=2:1洗脱)纯化,得到期望的产物化合物20(1.93,收率为93%),为固体。
1H NMR(400MHz,CDCl3):δ7.81(s,1H),7.79-7.74(m,3H),7.25-7.22(m,2H),4.56(d,J=4.4Hz,2H),4.11(s,3H),2.41(t,J=4.4Hz,1H)。MS计算值:273;MS实测值:274([M+H]+)。
6-氯甲基-3-(4-氟-苯基)-8-甲氧基-咪唑并[1,5-a]吡嗪(21)的合成
在冰水浴上冷却的同时向20(1.88g,6.88mmol)在二氯甲烷(100mL)中的溶液滴加亚硫酰氯(4.5mL)。加入完成后,将混合物再搅拌2小时。将反应混合物用冰水淬灭,用盐水(20mL)洗涤,经Na2SO4干燥,并在真空中浓缩,得到为固体的21(2.01g,收率为100%)。
1H NMR(400MHz,CDCl3):δ7.87(s,1H),7.83-7.79(m,3H),7.30-7.27(m,2H),4.50(s,2H),4.12(s,3H)。MS计算值:291;MS实测值:292([M+H]+)。
6-氯甲基-3-(4-氟-苯基)-7H-咪唑并[1,5-a]吡嗪-8-酮(22)的合成
向21(1.87g,6.41mmol)在MeOH(50mL)中的溶液加入6N HCl水溶液,并将得到的溶液在70℃下搅拌1小时。将混合物浓缩,得到产物22(1.60g,收率为90%),为白色固体。
1H NMR(300MHz,DMSO-d6):δ11.29(s,1H),8.07(s,1H),7.83-7.87(m,2H),7.74(s,1H),7.46-7.50(m,2H),4.59(s,2H)。MS计算值:277;MS实测值:278([M+H]+)。
4-(氮杂环丁烷-3-基氧基)-吡啶盐酸盐(5)的合成
向3-羟基氮杂环丁烷-1-羧酸叔丁酯1(4.55g,26.3mmol)在THF(100mL)中的溶液加入吡啶-4-醇(2.0g,21.0mmol)、PPh3(6.89g,26.3mmol)和DEAD(4.57g,26.3mmol)。将得到的反应混合物在70℃下搅拌过夜。TLC表明反应完全。将反应混合物在真空下浓缩。将得到的油溶解于1.0M HCl水溶液(,20mL),并用DCM(50mL×3)萃取。将合并的有机相用HCl(aq)溶液(0.5M,150mL)洗涤。合并水溶液部分并用NaOH(1.0M)碱化至pH≈12,并用DCM(100mL×3)萃取。合并的有机相经无水Na2SO4干燥,过滤并在真空中浓缩。残余物经硅胶柱色谱法纯化,得到4(2.81g,收率为53%),为固体。
1HNMR(400MHz,DMSO-d6):δ8.41(d,J=6.0Hz,2H),6.88(d,J=6.0Hz,2H),5.07-5.09(m,1H),4.32-4.33(m,2H),3.80-3.82(m,2H),1.39(s,9H)。MS计算值:250;MS实测值:251([M+H]+)。
向4(2.81g,11.2mmol)在Et2O(100mL)中的溶液加入HCl的Et2O(20mL)溶液。将得到的反应混合物在室温下搅拌过夜。TLC表明反应完全。过滤反应混合物,并干燥固体,得到5(1.82g,收率为87%)。
1HNMR(300MHz,DMSO-d6):δ9.58(s,2H),8.77-8.79(m,2H),7.48-7.49(m,2H),5.40-5.45(m,1H),4.49-4.51(m,2H),4.07-4.11(m,2H)。MS计算值:150;MS实测值:151([M+H]+)。
3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]
吡嗪-8(7H)-酮(P1)的合成
向化合物22(1.5g,5.4mmol)和5(1.31g,7.0mmol)在MeCN(100mL)中的混合物加入DIPEA(6.96g,5.4mmol)。将反应混合物加热并回流过夜。在真空中除去溶剂。残余物经反相硅胶快速柱色谱法(用5%~95%的MeCN水溶液洗脱)纯化,得到期望的产物P1(1.28g,收率为62%),为固体。
1H NMR(400MHz,DMSO-d6):δ10.7(s,1H),8.37(d,J=6.0Hz,2H),7.85(s,1H),7.85-7.82(m,2H),7.42(m,2H),7.34(s,1H),6.86(d,J=6.0Hz,2H),4.93(m,1H),3.88-3.77(m,2H),3.42(s,2H),3.18-3.14(m,2H)。MS计算值:391;MS实测值:392([M+H]+)。
(6-甲氧基-5-{[(四氢-吡喃-4-羰基)-氨基]-甲基}-吡嗪-2-基)-氨基甲酸叔丁
酯(23)的合成
向化合物14(28.4g,0.11mol)在DCM(200mL)中的溶液加入TEA(49mL,0.34mol),然后滴加四氢吡喃-4-甲酰氯(17.5g,0.13mol)。将得到的反应混合物在室温下搅拌过夜。TLC表明反应完全。将反应用水(100mL)淬灭。分离有机相,并将水相用DCM(200mL x 2)萃取。合并的有机相经无水Na2SO4干燥,过滤并在真空中浓缩。残余物经硅胶柱色谱法(PE/EA=5/1至1/3)纯化,得到为固体的23(31g,收率为75%)。
1H NMR(DMSO-d6,400MHz):δ9.89(s,1H),8.47(s,1H),8.10-8.07(t,J=5.2Hz,1H),4.29-4.28(d,J=5.2Hz,2H),3.87(s,3H),3.85-3.82(m,2H),3.32-3.25(m,2H),2.45-2.43(m,1H),1.60-1.55(m,4H),1.48(s,9H)。MS计算值:366;MS实测值:367([M+H]+)。
四氢-吡喃-4-羧酸(5-氨基-3-甲氧基-吡嗪-2-基甲基)-酰胺(24)的合成
将化合物23(19.0g,0.08mol)溶解于DCM(100mL)。加入TFA(100mL)。将反应在室温下搅拌过夜。TLC表明反应完全。除去溶剂。将残余物用DCM(100mL)和饱和NaHCO3水溶液(100mL)稀释。将水相用DCM(100mL x 2)萃取。合并的有机相经无水Na2SO4干燥,过滤并在真空中浓缩。残余物经硅胶柱色谱法(PE/EA=6/1至1/1)纯化,得到为固体的24(19g,收率为85%)。
1H NMR(DMSO-d6,400MHz):δ7.87(t,J=4.8Hz,1H),7.36(s,1H),6.26(br.s,2H),4.16(d,J=4.8Hz,2H),3.86-3.82(m,2H),3.80(s,3H),3.30-3.24(m,2H),2.41(m,1H),1.59-1.54(m,4H)。MS计算值:266;MS实测值:267([M+H]+)。
四氢吡喃-4-羧酸(5-碘-3-甲氧基-吡嗪-2-基甲基)-酰胺(25)的合成
在N2气氛下向化合物24(15.5g,58.4mmol)、CH2I2(23.5,87.6mmol)和亚硝酸异戊酯(23.9g,204mmol)在THF(600mL)中的混合物加入CuI(11.3g,39.6mmol)。将反应混合物在80℃下搅拌7小时。过滤沉淀物。将滤液浓缩,并经柱色谱法(MeOH/DCM=1/20)纯化,得到粗产物,然后通过反相硅胶快速柱色谱法(用5%~95%MeCN的水溶液洗脱)纯化,得到期望的产物化合物25(4.5g,收率为20%),为固体。
1H NMR(DMSO-d6,300MHz):δ8.41(s,1H),8.16(t,J=5.4Hz,1H),4.28(d,J=5.4Hz,2H),3.92(s,3H),3.87-3.81(m,2H),3.30-3.24(m,2H),2.49(m,1H),1.60-1.56(m,4H)。MS计算值:377MS实测值:378([M+H]+)。
6-碘-8-甲氧基-3-(四氢-吡喃-4-基)-咪唑并[1,5-a]吡嗪(26)的合成
向化合物25(4.5g,16.9mmol)在MeCN(100mL)中的溶液加入POCl3(18g,118mmol)。在N2气氛下将反应在回流下搅拌过夜。减压除去溶剂。将残留物用冰水(30mL)和DCM(150mL)处理。用饱和Na2CO3溶液将pH调解至7~8。将分离的水相用DCM(100mL x 4)萃取。将合并的有机相减压浓缩,得到期望的26(4.2g,,收率为99%),为固体。
1H NMR(DMSO-d6,400MHz):δ8.46(s,1H),7.64(s,1H),3.98(s,3H),3.94(m,2H),3.53-3.47(m,3H),1.81-1.77(m,4H)。MS计算值:359;MS实测值:360([M+H]+)。
8-甲氧基-3-(四氢-吡喃-4-基)-咪唑并[1,5-a]吡嗪-6-羧酸甲酯(27)的合成
向化合物26(4.2g,11.7mmol)在MeOH(100mL)中的混悬液加入CuI(0.7g,3.0mmol)、Pd(dppf)2Cl2(1.0g,1.17mmol)和TEA(16mL)。在CO气氛(3MPa)下将反应混合物在设定为85℃的油浴上搅拌16小时。滤出沉淀物,并将滤液减压蒸发。残余物经柱色谱法(用EtOAc/PE=2/1至MeOH/DCM=1/20洗脱)纯化,得到期望的27(2.7g,收率为80%),为固体。
1H NMR(CDCl3,400MHz):δ8.32(s,1H),7.70(s,1H),4.17(s,3H),4.14(m,2H),3.98(s,3H),3.66-3.60(m,2H),3.31-3.26(m,1H),2.17-2.13(m,2H),1.93(m,2H)。MS计算值:291;MS实测值:292([M+H]+)。
[8-甲氧基-3-(四氢-吡喃-4-基)-咪唑并[1,5-a]吡嗪-6-基]-甲醇(28)的合成
在室温下在THF(100mL)中将粉末状无水CaCl2(2.4g,21.5mmol)和NaBH4(1.6g,42.9mmol)的混合物搅拌1小时。加入化合物27(2.4g,4.29mmol)在THF(25mL)中的溶液,然后加入MeOH(25mL)。将反应混合物在室温下搅拌1.5小时。将混合物反应用水(50mL)淬灭。减压除去有机溶剂后,使残余物在EtOAc(200mL)和水(50mL)之间分配。将分离的水相用EtOAc(100x 3mL)萃取。然后将合并的有机相减压浓缩。残余物经硅胶柱色谱法(用DCM/MeOH=100/1至30/1洗脱)纯化,得到期望的产物化合物28,为白色固体(1.87,收率为80%)。
1H NMR(CDCl3,400MHz):δ7.65(s,1H),7.43(s,1H),4.58(s,2H),4.13(d,J=12.0Hz,2H),4.07(s,3H),3.60(dd,J=10.4Hz,10.8Hz,2H),3.24-3.17(m,1H),2.60(m,1H),2.18-2.06(m,2H),1.90(d,J=12.8Hz,2H)。MS计算值:263;MS实测值:264([M+H]+)。
6-氯甲基-3-(四氢吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(30)的合成
在0℃下向化合物28(1.9g,7.11mmol)在DCM(100mL)中的溶液加入SOCl2(5mL),然后将反应混合物在室温下搅拌5小时。TLC和LC-MS显示起始原料已被消耗。然后浓缩混合物溶液,并将残余物溶解于HCl(aq.)溶液(6N,20mL)。将混合物反应在室温下搅拌10分钟。然后减压浓缩反应混合物,得到期望的产物化合物29(1.90g,收率为95%),为固体。
1H NMR(DMSO-d6,300MHz):δ11.49(s,1H),8.28(s,1H),8.00(s,1H),4.55(s,2H),3.97(dd,J=2.4Hz,2.8Hz,2H),3.53-3.43(m,3H),1.95-1.81(m,4H)。MS计算值:267MS实测值:268([M+H]+)。
3-(氮杂环丁烷-3-基氧基)-吡啶盐酸盐(7)的合成
以与制备胺5所用的步骤类似的步骤制备化合物7。
7的分析数据:1H NMR((DMSO-d6,400MHz):δ9.73(br d,2H),8.55(d,J=2.4Hz,2H),8.47(d,J=4.4Hz,2H),7.88-7.75(m,2H),5.28(t,J=5.6Hz,1H),4.50-4.43(m,2H),4.08-4.00(m,2H)。MS计算值:150,MS实测值:151([M+H]+)。
6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢吡喃-4-基)-7H-咪唑并
[1,5-a]吡嗪-8-酮(P2)的合成
向化合物30(550mg,2.05mmol)和7(500mg,2.67mmol)在MeCN(200mL)中的混合物加入DIPEA(2.7g,20.5mmol)。将反应混合物回流过夜。在真空中除去溶剂。粗产物通过反相硅胶快速柱色谱法(用5%~95%MeCN的水溶液洗脱)纯化,得到期望的产物P2(360mg,收率为46%),为固体。
1H NMR(CDCl3,300MHz):δ8.26(d,J=4.0Hz 1H),8.22(s,1H),8.20(d,J=2.8Hz,1H),7.91(s,1H),7.24-7.21(m,1H),7.07(d,J=2.8Hz,1H),6.79(s,1H),4.86(m,1H),4.13(m,2H),3.89(t,J=7.6Hz,2H),3.57(m,2H),3.50(s,2H),3.28(dd,J=2.4Hz,6.8Hz,2H),3.10-30.6(m,1H),2.14-2.08(m,2H),1.87(m,2H)。MS计算值:381;MS实测值:382([M+H]+)。
3H-咪唑-4-羧酸甲酯(32)的合成
向化合物31(25g,0.22mol)在MeOH(300mL)中的溶液加入H2SO4(24mL)。将混合物在回流下搅拌18小时。然后将反应溶液的pH调节至~7。在真空中浓缩反应混合物。将残余物溶解于100ml MeOH中并在室温下搅拌15分钟。过滤混合物溶液,并将滤液浓缩,得到为固体的粗产物32(28g,收率为100%),其不经进一步纯化用于下一步骤。
1H NMR(400MHz,DMSO-d6):δ7.80(s,2H),3.57(s,3H)。
3H-咪唑-4-羧酸甲酯(33)的合成
向化合物32(22g,0.18mol)在MeCN(500mL)中的溶液加入NBS(66g,0.37mol)。将混合物在70℃下搅拌4小时。在真空中浓缩反应混合物。粗产物经硅胶柱色谱法(用PE/EtOAc=5:1至1:1洗脱)纯化,得到为固体的化合物33(20g,收率为40%)。
1H NMR(400MHz,DMSO-d6):δ14.35(br,1H),3.81(s,3H)。
外消旋反式-1-苄基-4-甲基-吡咯烷-3-羧酸乙酯(35)的合成
向34(69g,0.29mol)的甲苯溶液加入丁-2-烯酸乙酯(50g,0.44mol)和TFA(25mL,0.32mol)。在N2下将得到的溶液在50℃下搅拌过夜。向反应混合物加入饱和NaHCO3水溶液(300mL),并将水相用EtOAc(500mL x 3)萃取。将合并的有机层用盐水(300mL)洗涤,经Na2SO4干燥,过滤并在真空中浓缩。粗产物经快速色谱法(PE/EA=20:1至6:1)纯化,得到期望的外消旋反式产物35(41g,收率为57%),为油状物。
(SS)-反式-1-苄基-4-甲基-吡咯烷-3-羧酸乙酯(SS)-(35)的合成
向Rac-35(37g,0.15mol)的4-甲基-2-戊酮溶液中加入(-)-二苯甲酰基-L-酒石酸(34.78g,0.65eq.),并将得到的反应混合物加热至72℃持续1小时,之后使其冷却至RT,并在RT下保持4小时。将得到的固体滤出,并将滤液用浓碳酸钠水溶液(55mL)洗涤。将水相用4-甲基-2-戊酮(15mL)萃取,并将合并的有机相用盐水(40mL)洗涤。然后将有机相用(+)-二苯甲酰基-D-酒石酸(32.16g)处理,并加热至72℃持续1小时。将反应混合物冷却至RT,并在该温度下维持4小时。将固体滤出并在滤器上干燥。然后通过加入MTBE-MeOH的混合物(2:1,270mL)使固体重结晶,加热至70℃持续1小时,并使产物在室温下沉淀4小时。将得到的固体滤出,用MTBE洗涤并干燥。按照相同的步骤再进行两次重结晶,得到纯产物,为(+)-二苯甲酰基-D-酒石酸盐(基于分离的游离碱为>98%ee)。
通过以下步骤释放游离碱:使滤出的固体在MTBE(250mL)和浓碳酸钠水溶液(250mL)之间分配,并将水相用MTBE(125mL)萃取。将合并的有机相用水(250mL)和盐水(50mL)洗涤,并蒸发,得到产物,为澄清油状物(13.79g,0.056mol)。
外消旋反式-4-甲基-吡咯烷-1,3-二羧酸1-叔丁酯3-甲酯rac-(36)的合成
向35(41g,0.17mol)和Boc2O(43g,0.20mol)在EtOH(500mL)中的溶液加入Pd/C(5%,10.0g)。在H2气氛(50Psi)下将反应混合物在50℃下搅拌48小时。过滤反应混合物,并在真空中浓缩。粗产物经快速色谱法(PE/EA=20/1)纯化,得到期望的外消旋反式36(20g,收率为46%),为油状物。
经由(S,S)-反式-4-甲基-吡咯烷-1,3-二羧酸1-叔丁酯3-甲酯(S,S)-(36)合成
(S,S)-反式-4-甲基-吡咯烷-1,3-二羧酸1-叔丁酯(S,S)-(37)
在N2-保护气氛下将(S,S)-35(12.80g,51.8mmol)和Boc2O(13.57g,1.2eq)在EtOH(150mL)中的溶液置于高压釜中,并加入Pd/C(5%,2.56g)。在搅拌下使反应混合物在45-50℃、15-20Bar H2压力下氢化,直到不再吸收氢气(48小时)。将反应混合物冷却至RT,并过滤,并将滤液用EtOH(50mL)洗涤。使滤液在<45℃下蒸发至大约25mL。加入水(10mL)和NaOH溶液(2mL),并将得到的反应混合物在RT下搅拌2小时(GC分析显示此时起始原料完全消失)。加入水(125mL),并将得到的混合物用MTBE(2x 50mL)萃取。将水相用2N HCl溶液处理以实现pH值为3-4(大约25mL),并将得到的溶液用MTBE(2x 150mL)萃取。将合并的有机萃取物用盐水(50mL)洗涤,并蒸发至大约20mL。加入正庚烷(40mL),并使得到的反应混合物在0℃下放置2小时,之后滤出固体并干燥,得到为固体的产物(S,S)-37(9.48g,41.7mmol)。在该步骤,ee经测定为97.5%。这一物质与下面描述的rac-37具有相同的NMR和LC/MS特性。
经由(S,S)-反式-4-甲基-吡咯烷-1,3-二羧酸1-叔丁酯3-甲酯(S,S)-(36)合成
(S,S)-反式-4-甲基-吡咯烷-1,3-二羧酸1-叔丁酯(S,S)-(37)
在N2-保护气氛下将(S,S)-35(12.80g,51.8mmol)和Boc2O(13.57g,1.2eq)在EtOH(150mL)中的溶液置于高压釜中,并加入Pd/C(5%,2.56g)。在搅拌下使反应混合物在45-50℃、15-20Bar H2压力下氢化,直到不再吸收氢气(48小时)。将反应混合物冷却至RT,并过滤,并将滤液用EtOH(50mL)洗涤。使滤液在<45℃下蒸发至大约25mL。加入水(10mL)和NaOH溶液(2mL),并将得到的反应混合物在RT下搅拌2小时(GC分析显示此时起始原料完全消失)。加入水(125mL),并将得到的混合物用MTBE(2x 50mL)萃取。将水相用2N HCl溶液处理以实现pH值为3-4(大约25mL),并将得到的溶液用MTBE(2x 150mL)萃取。将合并的有机萃取物用盐水(50mL)洗涤,并蒸发至大约20mL。加入正庚烷(40mL),并使得到的反应混合物在0℃下放置2小时,之后滤出固体并干燥,得到为固体的产物(S,S)-37(9.48g,41.7mmol)。在该步骤,ee经测定为97.5%。这一物质与下面描述的rac-37具有相同的NMR和LC/MS特性。
外消旋反式-4-甲基-吡咯烷-1,3-二羧酸1-叔丁酯(37)的合成
将化合物36(10.0g,39.1mmol)、NaOH(3.10g,78.2mmol)在甲醇/H2O(50/5mL)中的溶液在室温下搅拌2小时。将反应混合物浓缩并用EA(150mL)萃取。在0℃下用2M HCl将水相酸化至pH~5,并用EtOAc(150mL x 3)萃取。将合并的有机层用盐水洗涤,干燥并浓缩,得到为油状物的化合物37(8.0g,90%)。
1H NMR(400MHz,DMSO-d6):δ12.43(s,1H),3.55-3.51(m,2H),3.47-3.27(m,1H),2.85-2.78(m,1H),2.63-2.57(m,1H),2.34-2.28(m,1H),1.55(s,9H),1.03(d,J=4.8Hz,3H)。
经由(S,S)-反式-3-(甲氧基-甲基-氨基甲酰基)-4-甲基-吡咯烷-1-羧酸叔丁酯
(S,S)-(38)合成(S,S)-反式-3-乙酰基-4-甲基-吡咯烷-1-羧酸叔丁酯(S,S)-(39)
在10分钟内向(S,S)-37(5.0g,22.0mmol)在DCM(50mL)中的溶液加入CDI(4.25g,1.2eq),同时在整个过程中保持温度低于5℃。将反应混合物搅拌1小时,之后在大约10分钟内将N,O-二甲基羟胺盐酸盐(3.0g,1.4eq)分成小份加入,保持温度低于5℃。然后使反应加温至室温并搅拌12小时,此时起始原料已被完全消耗。加入水(50mL),分离各相,并用DCM(35mL)萃取水相。将合并的有机相用水(50mL)洗涤,并浓缩至大约5mL。加入THF(20mL),将得到的溶液蒸发至干,并在高真空中干燥。加入干燥的THF(50mL),将溶液冷却至0℃,并在N2气氛下在30分钟内滴加MeMgCl(3M,11.35mL,1.5eq),确保温度低于5℃。然后将反应混合物加热至RT并搅拌2小时(此时Weinreb酰胺已被完全转化)。在低于25℃的温度下滴加饱和氯化铵水溶液(50mL)以淬灭反应,并将得到的反应混合物用EtOAc(2x 50mL)萃取,将合并的有机萃取物用盐水(50mL)洗涤并蒸发至大约5mL。加入THF(25mL),并将得到的溶液在真空中蒸发至干,给出为油状物的产物(S,S)-39(4.91g,21.6mmol),为大约98%ee。所有的光谱特性均与rac-39的光谱特性相同。
外消旋反式-3-(甲氧基-甲基-氨基甲酰基)-4-甲基-吡咯烷-1-羧酸叔丁酯(38)
的合成
向37(8.0g,34.9mmol)和O,N-二甲基羟胺(4.0g,41.9mmol)在DCM(50mL)中的溶液加入CDI(6.8g,41.9mmol)。将混合物反应在20℃下搅拌18小时。向该混合物溶液加入水(100mL),并用DCM(100mL x 3)萃取。将合并的有机层用盐水(30mL)洗涤,干燥,并在真空中浓缩。粗产物经快速色谱法(PE/EtOAc=20/1)纯化,得到为油状物的外消旋反式38(8.0g,收率为84%)。
1H NMR(400MHz,DMSO-d6):δ3.68(s,3H),3.60-3.48(m,2H),3.20-3.05(m,5H),2.84-2.73(m,1H),2.40-2.32(m,1H),1.39(s,9H),0.96(d,J=4.8Hz,3H)。
外消旋反式-3-乙酰基-4-甲基-吡咯烷-1-羧酸叔丁酯(39)的合成
在0℃下向38(8.0g,29.4mmol)在THF(60mL)中的溶液加入MeMgBr(3.0M,13mL,38.2mmol)。将反应混合物在室温下搅拌2小时。将混合物反应用饱和NH4Cl水溶液(200mL)淬灭,并用EtOAc(300mL x 3)萃取。将合并的有机层用盐水洗涤,干燥,并在真空中浓缩。粗产物经快速色谱法(PE/EtOAc=10/1)纯化,得到期望的外消旋反式39(6.0g,收率为94%),为油状物。
1H NMR(400MHz,DMSO-d6):δ3.66-3.51(m,1H),3.49-3.39(m,1H),3.34-3.24(m,1H),2.88-2.79(m,2H),2.34-2.30(m,1H),2.15(s,3H),1.36(s,9H),1.02-1.00(m,3H)。
外消旋反式-3-(2-溴-乙酰基)-4-甲基-吡咯烷-1-羧酸叔丁酯(40)的合成
在N2气氛、-78℃下将LiHMDS溶液(1M在THF中,40mL,40mmol)加入至39(6.0g,26.4mmol)在THF(100mL)中的溶液。将反应混合物在该温度下搅拌1小时。然后在-78℃下滴加TMSCl(10mL,26.4mmol),并使反应温度升高至0℃。1小时后,在0℃下加入PhMe3NBr3(11.0g,29.1mmol)。将混合物反应再搅拌1小时,然后在室温下搅拌过夜。将反应用水(200mL)淬灭,并用EtOAc(250mL x 3)萃取。将合并的有机层用盐水洗涤,干燥,并在真空中浓缩。粗产物经快速色谱法(PE/EtOAc=10/1)纯化,得到期望的外消旋反式40(4.5g,收率为56%),为油状物。
1H NMR(400MHz,CDCl3):δ4.05(s,2H),3.69-3.50(m,2H),3.36-3.30(m,1H),3.04-2.86(m,2H),2.51-2.43(m,1H),1.39(s,9H),1.10-1.05(m,3H)。
(S,S)-反式-3-(2-溴-乙酰基)-4-甲基-吡咯烷-1-羧酸叔丁酯(S,S)-(40)的合成
在N2气氛、-78℃下将LiHMDS溶液(1M在THF中,21.12mL,21.12mmol)滴加(S,S)-39(3.96g,17.4mmol)在THF(50mL)中的溶液。将反应混合物在该温度下搅拌1小时。然后在-78℃下滴加TMSBr(6.43g,42mmol),并使反应温度升温至0℃。1小时后,在0℃下将NBS(2.76g,15.5mmol)分成小份加入。TLC显示所有的起始原料已被消耗。滴加水(20mL),保持温度处于RT,并将得到的反应混合物搅拌30分钟。分离各相,并将水相用MTBE(2x 15mL)萃取。将合并的有机相用盐水洗涤,干燥,并在真空中浓缩。将残余物再溶解于MTBE(25mL),用水(3x10mL)和盐水(10mL)洗涤,并在真空中浓缩,得到为油状物的产物,其可经快速色谱法(PE/EtOAc=10/1)纯化,得到期望的(S,S)-40(6.4g,20.9mmol),为油状物。
外消旋反式-2,5-二溴-3-[2-(1-叔丁氧羰基-4-甲基-吡咯烷-3-基)-2-氧代-乙
基]-3H-咪唑-4-羧酸甲酯(41)的合成
向33(4.1g,14.7mmol)在DMF(30mL)中的溶液加入K2CO3(5.8g,42.5mmol)。搅拌15分钟后,将化合物40(4.5g,14.7mmol)加入到反应混合物中。在室温下搅拌反应5小时。将反应混合物用EtOAc(200mL)稀释,用盐水(200mL x 2)洗涤。然后将有机相干燥(Na2SO4),过滤,并在真空中浓缩。残余物经柱色谱法(PE/EtOAc=10/0~3/1)纯化,得到为固体的外消旋反式41(3.0g,收率为40%)。
1H NMR(400MHz,DMSO-d6):δ5.41(s,2H),3.78(s,3H),3.68-3.66(m,1H),3.48-3.45(m,1H),3.34-3.31(m,1H),3.20-3.25(m,1H),2.92-2.87(m,1H),2.50-2.46(m,1H),1.36(s,9H),1.07(m,3H)。
(S,S)-反式-2,5-二溴-3-[2-(1-叔丁氧羰基-4-甲基-吡咯烷-3-基)-2-氧代-乙
基]-3H-咪唑-4-羧酸甲酯(S,S)-(41)的合成
向33(2.78g,9.79mmol)在NMP(30mL)中的溶液加入Na2CO3(3.11g,26.2mmol)。搅拌15分钟后,将化合物(S,S)-40(4.5g,14.7mmol)加入到反应混合物中。在室温下搅拌反应5小时。将反应混合物用EtOAc(200mL)稀释,用盐水(200mL x 2)洗涤。然后将有机相干燥(Na2SO4),过滤,并在真空中浓缩。残余物经柱色谱法(PE/EtOAc=10/0~3/1)纯化,得到为粗固体的产物,将其从2-丙醇/正庚烷中重结晶,得到为固体的(S,S)-41(3.03g,收率为40%)。在该阶段物质的ee经测定为大于99%。所有的光谱数据与rac-41的光谱数据相同。
外消旋反式-3-(1,3-二溴-8-氧代-7,8-二氢-咪唑并[1,5-a]吡嗪-6-基)-4-甲
基-吡咯烷-1-羧酸叔丁酯(42)的合成
向41(3.0g,5.89mmol)在MeOH(150mL)中的溶液加入NH4OAc(9.07g,117.8mmol)。在压力容器中将反应混合物加热至130℃,持续15小时。将反应混合物过滤并浓缩,得到粗产物。残余物经柱色谱法(DCM/MeOH=100/1~10/1)纯化,得到为固体的外消旋反式42(2.2g,收率为80%)。
1H NMR(400MHz,DMSO-d6):δ10.98(br.s,1H),7.10(s,1H),3.63-3.54(m,2H),3.39-3.34(m,1H),2.84-2.77(m,2H),2.50(m,1H),1.41(s,9H),0.96(m,3H)。
(S,S)-反式-3-(1,3-二溴-8-氧代-7,8-二氢-咪唑并[1,5-a]吡嗪-6-基)-4-甲
基-吡咯烷-1-羧酸叔丁酯(S,S)-(42)的合成
向(S,S)-41(3.03g,5.9mmol)在2-丙醇(20mL)中的溶液加入NH4OAc(9.18g,118mmol)。将反应混合物在105-110℃下加热12小时,之后在搅拌下将其倒入水(60mL)中,并放置2小时。将反应混合物过滤并浓缩,得到粗产物。残余物经柱色谱法(DCM/MeOH=100/1~10/1)纯化并蒸发,得到为固体的(S,S)-42(2.1g,4.4mmol)。该物质经测定具有99.3%ee并具有与rac-42的光谱特性相似的光谱特性。
外消旋反式-3-[1-溴-3-(3,6-二氢-2H-吡喃-4-基)-8-氧代-7,8-二氢-咪唑并
[1,5-a]吡嗪-6-基]-4-甲基-吡咯烷-1-羧酸叔丁酯(43)的合成
向化合物42(2.2g,4.62mmol)和4-(4,4,5,5-四甲基-[1,3,2]二氧杂戊硼烷-2-基)-3,6-二氢-2H-吡喃(1.1g,5.08mmol)在THF(200mL)中的混合物加入磷酸钾(2.7g,13.86mmol)。通过用N2吹扫5min使反应混合物脱气,之后向该混合物加入Pd2(dba)3(0.8g,0.92mmol)和Xanthphos(1.0g,1.84mmol)。将得到的混悬液用N2脱气10分钟。然后在N2气氛下将混合物反应加热至80℃持续15小时。冷却至室温后,将反应混合物用EtOAc(250mL)稀释,并滤出沉淀物。浓缩滤液。粗残余物经硅胶柱色谱法(用EtOAc洗脱)纯化,得到为固体的43(1.3g,收率为60%)。
1H NMR(400MHz,DMSO-d6):δ10.80(m,1H),7.34(s,1H),6.42(s,1H),4.30-4.29(m,2H),3.92-3.80(m,2H),3.63-3.33(m,4H),2.87-2.71(m,2H),2.50(m,1H),1.41(s,9H),0.95(m,3H)。
(S,S)-反式-3-[1-溴-3-(3,6-二氢-2H-吡喃-4-基)-8-氧代-7,8-二氢-咪唑并
[1,5-a]吡嗪-6-基]-4-甲基-吡咯烷-1-羧酸叔丁酯(S,S)-(43)的合成
向化合物(S,S)-42(2.11g,4.42mmol)和4-(4,4,5,5-四甲基-[1,3,2]二氧杂戊硼烷-2-基)-3,6-二氢-2H-吡喃(0.975g,4.64mmol)在1,4-二氧六环(40mL)和水(10mL)中的混合物加入磷酸钾(2.57g,12.2mmol)。通过用N2吹扫5min使反应混合物脱气,之后向该混合物加入Pd2(dba)3(0.8g,0.9mmol)和Xanthphos(1.0g,1.8mmol)。将得到的混悬液用N2脱气10分钟。然后在N2气氛下将混合物反应加热至80℃持续15小时。冷却至室温后,将反应混合物用EtOAc(250mL)稀释,并通过硅藻土过滤除去固体。浓缩滤液。粗残余物经硅胶柱色谱法(用EtOAc洗脱)纯化,得到为固体的43(1.4g,2.92mmol)。在此阶段物质具有大于99%的ee。
外消旋反式-3-甲基-4-[8-氧代-3-(四氢-吡喃-4-基)-7,8-二氢-咪唑并[1,5-a]
吡嗪-6-基]-吡咯烷-1-羧酸叔丁酯(44)的合成
向43(1.3g,2.73mmol)在DMF(100mL)和甲醇(30mL)中的溶液加入10%Pd/C(0.8g)。使烧瓶充入氢气(50psi),并将混合物在50℃下搅拌过夜。冷却后,将反应混合物通过硅藻土过滤。减压浓缩滤液。粗产物经硅胶柱色谱法(用DCM/CH3OH=100/1-20/1洗脱)纯化,得到为固体的化合物44(0.99g,收率为90%)。
1H NMR(400MHz,CDCl3):δ10.80(br d,1H),7.86(s,1H),6.79(s,1H),4.13-4.10(m,2H),3.83-3.79(m,3H),3.63-3.49(m,2H),3.13-3.03(m,2H),2.77-2.75(m,2H),2.54-2.53(m,1H),2.11-2.06(m,2H),1.80-1.85(m,2H),1.48(m,9H),1.12(d,J=6.4Hz,3H)。
(S,S)-反式-3-甲基-4-[8-氧代-3-(四氢-吡喃-4-基)-7,8-二氢-咪唑并[1,5-a]
吡嗪-6-基]-吡咯烷-1-羧酸叔丁酯(S,S)-(44)的合成
在N2-保护性气氛下将(S,S)-43(1.15g,2.41mmol)在甲醇(50mL)中的溶液置于高压釜中,并在氮气气氛下加入10%Pd/C(0.8g)。在搅拌下使反应混合物在45-50℃、10-15Bar H2压力下氢化,直到不再吸收氢气(24小时)。冷却后,将反应混合物通过硅藻土过滤。减压浓缩滤液。粗产物经硅胶柱色谱法(用DCM/CH3OH=100/1-20/1洗脱)纯化,得到为固体的化合物44(0.97g,2.41mmol)。ee经测定为大于99%。
外消旋反式-6-(4-甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]
吡嗪-8-酮(45)的合成
向化合物44(0.99g,2.49mmol)在CH2Cl2(20mL)中的溶液加入HCl/Et2O溶液(20mL)。将得到的混合物在室温下搅拌2小时。在真空中浓缩反应,得到为固体的外消旋反式45盐酸盐(0.75g,收率为100%)。
1H NMR(400MHz,DMSO-d6):δ11.47(s,1H),9.93(s,2H),8.41(s,1H),7.92(s,1H),3.98-3.95(m,2H),3.85-3.80(m,1H),3.58-3.44(m,3H),2.97-2.88(m,2H),2.60-2.50(m,3H),1.98-1.78(m,4H),1.08(m,3H)。
(S,S)-反式-6-(4-甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]
吡嗪-8-酮(S,S)-(45)的合成
向化合物(S,S)-44(800mg,2.0mmol)的溶液中加入冷(0℃)的HCl的MeOH溶液(1.5M,10mL)中,并将得到的反应混合物搅拌,同时允许回到室温。搅拌2小时后,在真空中浓缩反应,得到为固体的(S,S)-45盐酸盐(0.60g,2.0mmol)。
1H NMR(400MHz,DMSO-d6):δ11.47(s,1H),9.93(s,2H),8.41(s,1H),7.92(s,1H),3.98-3.95(m,2H),3.85-3.80(m,1H),3.58-3.44(m,3H),2.97-2.88(m,2H),2.60-2.50(m,3H),1.98-1.78(m,4H),1.08(m,3H)。
外消旋反式-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-
7H-咪唑并[1,5-a]吡嗪-8-酮(P3)的合成
向化合物45(0.75g,2.49mmol)、2-氯甲基-嘧啶(0.49g,2.99mmol)在DMF(10mL)和CH3CN(30mL)中的溶液加入K2CO3(1.7g,12.5mmol)。将混合物在45℃下搅拌48小时。将反应混合物过滤,在真空中浓缩。残余物经快速柱色谱法(DCM到含15%MeOH的DCM溶液梯度洗脱)纯化,得到为固体的外消旋反式P3(580mg,收率为59%)。
1H NMR(400MHz,CD3OD):δ8.85(d,J=4.8Hz,2H),7.79(s,1H),7.42(t,J=4.8Hz,1H),7.36(s,1H),4.11-4.04(m,3H),3.93(d,J=15.2Hz,1H),3.684-3.62(m,2H),3.41-3.32(m,2H),3.16-3.13(m,1H),2.85~2.80(m,2H),2.44-2.40(m,1H),2.28-2.23(m,1H),2.04-1.86(m,4H),1.17(d,J=6.4Hz,3H)。MS计算值:394.5;MS实测值:395.8([M+H]+)。
通过手性HPLC(柱:Chiralpak IA,250x 4.6mm x 5um;流动相:Hex/EtOH/DEA=70:30:0.2)以1.0mL/min的流速分离P3的外消旋混合物(1.4g),得到P3对映异构体1((3S,4S)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮或6-[(3S,4S)-4-甲基-1-(嘧啶-2-基甲基)吡咯烷-3-基]-3-四氢吡喃-4-基-7H-咪唑并[1,5-a]吡嗪-8-酮)(0.52g,RT=9.98min)和P3对映异构体2((3R,4R)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮,与P3对映异构体1相对)(0.49g,RT=12.6min)。
(S,S)-反式-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-
7H-咪唑并[1,5-a]吡嗪-8-酮(S,S)-(P3)的合成
向化合物(S,S)-45(0.60g,2.0mmol)和2-氯甲基-嘧啶(0.40g,2.40mmol)在DCM(15mL)中的溶液加入DIPEA(3.1g,24mmol),并将混合物在RT下搅拌24小时(此时所有的起始原料都已被转化)。将反应混合物冷却至5℃,并加入去离子水(10mL)。通过添加盐酸(大约1mL)将水相的pH调节至pH6.0,同时保持混合物的温度为<25℃。使各相分离,并将有机相用盐水(3x 5mL)洗涤(将这些洗涤液丢弃)。将水相用二氯甲烷(10mL)萃取,并将来自该萃取的有机相用盐水(3x 5mL)洗涤。合并的有机相经硫酸钠(3g)干燥1小时,过滤并蒸发。对得到的残余物进行柱色谱法(如对rac-(P3)所述的),得到(S,S)-P3(580mg,收率为59%),蒸发后为固体。该物质具有大于99%的ee,并且在所有方面与P3对映异构体1(上文所述的)相同。
(氨基氧基)(二苯基)氧化膦(B)的合成
在-30℃、氮气气氛下在15分钟内向羟胺盐酸盐(73.5g,1.05mol)在二氯甲烷(500mL)中的混悬液加入DIPEA(136g,1.05mol)。加入后形成白色沉淀物。在该温度下搅拌1小时后,在60分钟内加入二苯基次膦酰氯A(50g,0.2mol)在二氯甲烷(100mL)中的溶液。在搅拌下在1小时内将混合物反应加温至0℃。通过在10分钟内加入水(200mL)淬灭反应。搅拌混合物0.5小时后,通过过滤收集沉淀物,并用水(100mL x 2)洗涤。然后减压干燥固体,得到粗产物。将粗产物用EtOH研磨,得到化合物B(27g,收率为56%),为白色固体。
1HNMR(400MHz,CD3OD):δ77.91-7.79(m,5H),7.62-7.50(m,7H)。
MS计算值:233;MS实测值:234([M+H]+)。
3-氨基-3H-咪唑-4-羧酸甲酯(46)的合成
在-78℃下在2小时内向化合物3H-咪唑-4-羧酸甲酯32(30.0g,0.24mol)在THF(1.0L)中的溶液滴加LiHMDS(239mL,10M在THF中,2.4mol)。然后将反应混合物在-78℃下再搅拌2小时,并使其加温至-10℃。在该温度下加入化合物B(60.0g,0.26mol)。然后将混合物反应在环境温度下搅拌过夜。在用水(250mL)淬灭后,浓缩反应混合物。粗产物经硅胶柱色谱法(DCM/MeOH=20/1)纯化,得到为固体的化合物46(24g,收率为73%)。
1H NMR(400MHz,DMSO-d6):δ7.82(s,1H),7.51(s,1H),6.20(s,2H),3.79(s,3H)。MS计算值:382;MS实测值:383([M+H]+)。MS计算值:141;MS实测值:142([M+H]+)。
3-(2-苄氧基-乙酰基氨基)-3H-咪唑-4-羧酸甲酯(47)的合成
在冰水浴上冷却的同时向化合物46(4.9g,30mmol)、苄氧基-乙酸(5.8g,30mmol)和DIPEA(18.6ml,90mmol)在DMF(100mL)中的溶液加入HATU(15.8g,36mmol)。然后将混合物在环境温度下搅拌过夜。除去溶剂后,残余物经硅胶柱色谱法(用PE/EtOAc=10:1至2:1洗脱)纯化,得到为油状物的化合物47(6.1g,收率为61%)。
1H NMR(400MHz,CDCl3):δ9.93(br.s,1H),7.74(s,1H),7.67(s,1H),7.39-7.33(m,5H),4.70(s,2H),4.23(s,2H),3.83(s,3H)。MS计算值:289;MS实测值:300([M+H]+)。
3-(2-苄氧基-乙酰基氨基)-3H-咪唑-4-羧酸酰胺(48)的合成
将化合物47(30.0g,100mmol)和浓氨水(300mL)合并在密封的试管中,并在微波辐射下加热至70℃,持续2小时。将得到的混合物在真空中浓缩,得到为固体的化合物48(26.3g,收率为96%)。MS计算值:274;MS实测值:275([M+H]+)。
2-苄氧基甲基-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(49)的合成
向化合物48(28.0g,100mmol)在EtOH(240mL)中的溶液滴加KOH(19.8g,300mmol)在水(200mL)中的溶液。将得到的溶液加热至回流,持续3小时。在真空中除去有机溶剂后,将混合物倒入到冰水中,并用1M HCl水溶液将pH调解至7.0。将混悬液过滤并干燥,得到为固体的化合物49(11.3g,收率为44.1%)。
1H NMR(400MHz,DMSO-d6):δ12.05(s,1H),8.45(s,1H),7.74(s,1H),7.39-7.29(m,5H),4.59(s,2H),4.36(s,2H)。MS计算值:256;MS实测值:257([M+H]+)。
2-苄氧基甲基-7-碘-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(50)的合成
在-78℃下向化合物49(10.0g,38.2mmol)在THF(240mL)中的溶液滴加n-BuLi(46mL),并将反应在低于-70℃的温度下搅拌1小时。在该温度下滴加碘(39.3g,153mmol)在THF(120mL)中的溶液,然后使反应温度缓慢升温至室温。将反应用饱和Na2SO3水溶液(120mL)淬灭,然后用EtOAc(150mL×3)萃取。合并的有机相经Na2SO4干燥,过滤,并在真空中浓缩,得到粗产物。残留物经硅胶柱色谱法(用PE/EtOAc=10:1至2:1洗脱)纯化,得到为固体的化合物50(4.75g,收率为32.5%)。
1H NMR(400MHz,DMSO-d6):δ12.16(br.s,1H),7.84(s,1H),7.42-7.29(m,5H),4.62(s,2H),4.40(s,2H)。MS计算值:382;MS实测值:383([M+H]+)。
2-苄氧基甲基-7-(3,6-二氢-2H-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-
酮(51)的合成
向化合物50(4.75g,10.0mmol)在二氧六环(80mL)中的溶液滴加Cs2CO3(9.88g,30mmol)在水(12mL)中的溶液,接着滴加Pd(PPh3)4(2.36g,2.00mmol)和4-(4,4,5,5-四甲基-[1,3,2]二氧杂戊硼烷-2-基)-3,6-二氢-2H-吡喃(3.86g,18.0mmol)。通过用N2吹扫15min使反应混合物脱气。然后将混合物加热至回流,持续16小时。在真空中除去溶剂后,残余物经硅胶柱色谱法(用PE/EtOAc=10:1至1:5洗脱)纯化,得到为固体的化合物51(2.1mg,收率为76%)。
1H NMR(400MHz,DMSO-d6):δ12.10(br.s,1H),7.78(s,1H),7.39-7.30(m,5H),7.25(s,1H),4.62(s,2H),4.41(s,2H),4.27(d,J=2.8Hz,2H),3.82(t,J=5.2Hz,2H),2.63(m,2H)。MS计算值:338;MS实测值:339([M+H]+)。
2-羟基甲基-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(52)的
合成
向化合物51(1.8g,5.0mmol)在MeOH(70mL)中的溶液加入Pd(OH)2(20%,在碳上(用大约50%水润湿),400mg)。将反应烧瓶充入氢气(50psi),并将混合物在加热至70℃的油浴上搅拌,直到LC/MS显示起始原料已被消耗。通过硅藻土过滤混悬液,并将滤液用MeOH(100mL×2)洗涤。将合并的有机相在真空中浓缩,得到为固体的化合物52(1.0g,收率为79%)。
1H NMR(400MHz,DMSO-d6):δ11.65(s,1H),7.68(s,1H),4.30(s,2H),3.96-3.92(m,2H),3.51-3.17(m,3H),1.88-1.81(m,4H)。MS计算值:250;MS实测值:251([M+H]+)。
2-氯甲基-7-(四氢吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(53)的合成
在冰水浴上冷却的同时向化合物52(1.0g,4mmol)在CH2Cl2(50mL)中的溶液滴加SOCl2(15mL)。然后将得到的混合物在环境温度下搅拌过夜。在真空中浓缩反应混合物,得到为固体的化合物53(1.07g,收率为100%)。
1H NMR(400MHz,DMSO-d6):δ12.50(br.s,1H),8.02(s,1H),4.57(s,2H),3.95(m,2H),3.57-3.48(m,3H),1.91-1.81(m,4H)。MS计算值:268;MS实测值:269([M+H]+)。
3-(4-氟-苄氧基)-氮杂环丁烷-1-羧酸叔丁酯(2)的合成
在冰水浴上冷却的同时向化合物3-羟基-氮杂环丁烷-1-羧酸叔丁酯1(5.30g,30mmol)在DMF(60mL)中的溶液加入NaH(1.80g,45mmol)。然后将混悬液在该温度下搅拌1小时,接着加入1-氯甲基-4-氟-苯(8.94g,60mmol)。将得到的混合物在环境温度下搅拌过夜。将反应混合物倒入到水(200mL)中,并用EtOAc(150mL×3)萃取。将合并的有机相经Na2SO4干燥,过滤,并在真空中浓缩,得到粗产物。残余物经硅胶柱色谱法(用PE/EtOAc=10:1至2:1洗脱)纯化,得到为油状物的化合物2(7.90g,收率为94%)。
1H NMR(300MHz,DMSO-d6):δ7.41-7.37(m,2H),7.21-7.14(m,2H),4.40(s,2H),4.33-4.29(m,1H),4.02-3.97(m,2H),3.68-3.66(m,2H),1.37(s,9H)。MS计算值:281;MS实测值:282([M+H]+)。
3-(4-氟-苄氧基)-氮杂环丁烷(3)的合成
在冰水浴下向化合物2(2.68g,9.30mmol)在二氧六环(30mL)中的溶液加入HCl/二氧六环(4M,9.25mL)。然后将反应混合物在环境温度下搅拌过夜。在真空中浓缩反应溶液,得到化合物3的盐酸盐(1.2g,收率为71%),为固体。
1H NMR(300MHz,DMSO-d6):δ7.36(m,2H),7.16(m,2H),4.35(s,2H),4.39(m,1H),3.47(t,J=7.5Hz,2H),3.38(t,J=7.2Hz,2H)。MS计算值:181;MS实测值:182([M+H]+)。
2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并
[5,1-f][1,2,4]三嗪-4-酮(P4)的合成
向化合物53(1.27mg,4.0mmol)和化合物3(1.8g,8.3mmol)在CH3CN(20mL)中的溶液加入DIPEA(2.61mL,20mmol)。将得到的溶液加热至70℃,持续2小时。TLC表明反应完全。在真空中浓缩反应。残余物经硅胶柱色谱法纯化(用DCM/MeOH 100:1至30:1洗脱),得到期望的产物P4(1.23g,收率为74%),为固体。
1H NMR(400MHz,DMSO-d6):δ11.70(br.s,1H),7.67(s,1H),7.37(m,2H),7.16(m,2H),4.38(s,2H),4.17(m,1H),3.95~3.92(m,2H),3.56(t,J=8.0Hz,2H),3.54~3.46(m,4H),3.37~3.35(m,1H),3.06~3.03(m,2H),1.86~1.80(m,4H)。MS计算值:413;MS实测值:414([M+H]+)。
实施例2.P3对映异构体2的X射线晶体结构
使用晶体生长在正交晶系,空间群为P212121下在100K下测定P3对映异构体2的单晶X-射线结构。在不对称单元中有一个化合物分子和一分子水。最终R1[I>2δ(I)]=3.09%。化合物的绝对立体化学在图1中示出。
P3对映异构体2一水合物
仪器和方法的详述
进行结晶实验以获得适合的晶体,以通过单晶X-射线衍射测定P3对映异构体2的结构和绝对构型。
X-射线粉末衍射(XRPD)
在使用Cu Kα辐射(40kV,40mA)、θ-2θ测角仪和V4散度和接收狭缝、一铬酸锗(Gemonochromate)和Lynxeye检测器的Bruker D8衍射仪上收集X-射线粉末衍射图谱。采用已被证明的Corundum标准(NIST 1976)对仪器进行性能检验。数据收集所用的软件为DiffracPlus XRD Commander v2.6.1,并使用Diffrac Plus EVA v15.0.0.0分析和显示数据。
使用收到的粉末作为平板试样在环境条件下运行样品。将样品轻轻地装入到在抛光的零背景(510)硅晶片中切割的腔中。在分析过程中使样品在其自己的平面中旋转。数据收集的细节为:角范围:2至42°2θ;步长尺寸:0.05°2θ;收集时间:0.5s/步。
单晶X-射线衍射(SCXRD)
在配备有Oxford Cryosystems Cobra冷却装置的Oxford DiffractionSupernova双源(零时为Cu)Atlas CCD衍射仪上收集数据。使用CuKα辐射收集数据。通常使用SHELXS或SHELXD程序解析结构,并用作为Bruker AXS SHELXTL套件(V6.10)的一部分的SHELXL程序精修。除非另有声明,与碳连接的氢原子按几何学放置,并允许用行驶各向同性位移参数(riding isotropic displacement parameter)精修。与杂原子连接的氢原子位于差分傅里叶合成中,并允许用各向同性位移参数自由精修。
偏振光显微镜技术(PLM)
在具有用于图像捕捉的与DS Camera控制单元DS-L2连接的数字视频摄像机的Nikon SMZ1500偏振光显微镜上研究样品。将少量的各样品置于载玻片上,安装在浸没油中,尽可能地使个体颗粒分离开。采用偶联到λ伪色滤光器中的适当的放大倍数和部分偏振光观察样品。
结晶屏幕
尝试使P3对映异构体2(5mg)在50℃下溶解于所选的溶剂中。将溶液放置下冰箱中于4℃下放置48小时。过滤混悬液,并将得到的母液也于4℃下放置。通过光学显微镜评估获得的任何晶体。
该物质在大多数所评估的溶剂系统中是可溶的,除了乙酸异丙酯和异丙基苯。在4℃下从一系列溶剂包括乙腈、四氢呋喃和1,4-二氧六环中获得了大的棱柱形晶体。使用通过在乙腈中冷却获得的晶体来解析P3对映异构体2的晶体结构。
单晶结构测定
通过将5mg供应的物质溶解于50μl乙腈并于4℃冷却获得P3对映异构体2的结晶样品。获得的晶体具有棱柱形态。通过单晶X-射线衍射分离出供分析用的具有足够的大小和质量的晶体,大致尺寸为0.25x0.15x0.11 mm。收到的晶体的光学显微照片和用于数据收集的单晶在图1中示出。
在100K下,在正交晶系,空间群为P212121中,以最终R1{I>2δ(I)]=3.09%,测定结构。化合物经鉴定为P3对映异构体2的一水合物,如图1和图3中所述。不对称单元含有全序化的P3对映异构体2分子和1分子水。在50%的概率水平下显示非氢原子的各向异性原子位移椭圆体。采用任意小的半径显示氢原子。
对于图1中显示的P3对映异构体2的绝对立体化学,C12和C13(该编号不是在IUPAC名称中使用的编号)为R构型,Flack参数=-0.03(4)。对于C12和C13为S构型的反转结构(P3对映异构体1),Flack参数=1.03(4)。
采用对Bijvoet差值的Bayesian统计方法测定绝对结构揭示了所显示的绝对结构是正确的概率是1.000,而绝对结构为成对的外消旋物或为错误的概率都是0.000。通过该程序计算Flack等值及其不确定性为-0.02(4)。该计算是基于1806个Bijvoet对,覆盖率为100%。
P3对映异构体2的构型分析显示嘧啶环是平面型,吡咯烷环是在氮上的信封型,并且四氢吡喃环是椅型。
实施例3.体外测试
PDE9抑制试验
可以例如如下进行PDE9试验:该试验在60μL样品中进行,所述样品含有固定量的相关PDE酶(足以转化20-25%的环核苷酸底物)、缓冲液(50mM HEPES7.6;10mM MgCl2;0.02%吐温20)、0.1mg/ml BSA、225pCi的3H-标记的环核苷酸底物、最终浓度为5nM的氚标记的cAMP以及不同量的抑制剂。通过添加环核苷酸底物而引发反应,并且使反应在室温下进行1个小时,然后通过与15μL 8mg/mL硅酸钇SPA珠(Amersham)混合而终止。将该珠在暗处静置1个小时,然后将板置于Wallac 1450Microbeta计数器中计数。测量的信号可被转化成相对于未被抑制的对照(100%)的活性,并且可以使用EXCEL的Xlfit扩展来计算IC50值。
在本发明中,该试验在60uL试验缓冲液(50mM HEPES pH 7.6;10mM MgCl2;0.02%吐温20)中进行,该试验缓冲液含有足以转化20-25%的10nM3H-cAMP的PDE9和不同量的抑制剂。孵育1小时后,通过添加15uL 8mg/mL硅酸钇SPA珠(Amersham)终止反应。将该珠在暗处静置1个小时,然后将板置于Wallac 1450Microbeta计数器中计数。通过使用XLfit(IDBS)的非线性回归计算IC50值。
实验结果表明,测试的本发明化合物抑制PDE9酶,IC50值低于100nM。
PDE1抑制试验
可以如下进行PDE1试验:该试验在60μL样品中进行,所述样品含有固定量的PDE1酶(足以转化20-25%的环核苷酸底物)、缓冲液(50mM HEPES pH 7.6;10mM MgCl2;0.02%吐温20)、0.1mg/ml BSA、15nM氚标记的cAMP以及不同量的抑制剂。通过添加环核苷酸底物而引发反应,并且使反应在室温下进行1个小时,然后通过与20μL(0.2mg)硅酸钇SPA珠(PerkinElmer)混合而终止。将该珠在暗处静置1个小时,然后将板置于Wallac1450Microbeta计数器中计数。
测量的信号可被转化成相对于未被抑制的对照(100%)的活性,并且可以使用XlFit(型号205,IDBS)来计算IC50值。
实施例4.体内测试
血脑屏障穿透
在开始实验之前,将雄性CD小鼠(20-24g)成对置于笼中,自由获取食物和水,适应期为3-7天。在给药之前,使动物空腹过夜。在测试期间,将小鼠保持在单独的笼子中。在以10mg/kg的剂量皮下给药测试化合物之后的30分钟和2小时(每个时间点n=3)评估脑-血浆分布。使用适当的溶媒来溶解每种测试化合物使给药体积为10ml/kg。在采样时,用异氟烷麻醉动物并通过心脏穿刺将体循环血液样品收集到含有肝素钠作为抗凝剂的血样采集容器(vacutainer)中。将血液在4℃下以3500rpm离心10分钟以获得血浆。断头后,剖出脑部,并转移至预先称重的容器中,之后进行组织重量测定。在-80℃下储存血浆和脑,直到采用LC-MS/MS进行定量生物分析。血浆样品的结果用ng/ml表示,脑样品的结果用ng/g表示。
Claims (10)
1.一种化合物,选自3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)、6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)和2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
2.根据权利要求1所述的化合物,其中所述化合物是3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)或6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)。
3.根据权利要求1所述的化合物,其中所述化合物是2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
4.一种药物组合物,包含治疗有效量的权利要求1中的任何化合物,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
5.根据权利要求4所述的化合物,其中所述化合物是3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)或6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)。
6.根据权利要求4所述的化合物,其中所述化合物是2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
7.化合物在制备用于治疗治疗良性前列腺增生或镰状细胞疾病的药物中的用途,所述化合物选自3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)、6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)和2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
8.根据权利要求7所述的用途,其中所述化合物是3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)或6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)。
9.根据权利要求7所述的用途,其中所述化合物是2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
10.化合物在制备用于治疗尿路功能障碍上皮疾病或勃起功能障碍的药物中的用途,所述化合物选自3-(4-氟苯基)-6-((3-(吡啶-4-基氧基)氮杂环丁烷-1-基)甲基)咪唑并[1,5-a]吡嗪-8(7H)-酮(P1)、6-[3-(吡啶-3-基氧基)-氮杂环丁烷-1-基甲基]-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P2)、(3S,4S)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体1)、(3R,4R)-6-(4-甲基-1-嘧啶-2-基甲基-吡咯烷-3-基)-3-(四氢-吡喃-4-基)-7H-咪唑并[1,5-a]吡嗪-8-酮(P3,对映异构体2)和2-[3-(4-氟-苯氧基)-氮杂环丁烷-1-基甲基]-7-(四氢-吡喃-4-基)-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(P4)。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA201500393 | 2015-07-07 | ||
DKPA201500393 | 2015-07-07 | ||
DKPA201500407 | 2015-07-10 | ||
DKPA201500407 | 2015-07-10 | ||
DKPA201600209 | 2016-04-07 | ||
DKPA201600209 | 2016-04-07 | ||
CN201680039418.0A CN107810187B (zh) | 2015-07-07 | 2016-07-06 | 用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的pde9抑制剂 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680039418.0A Division CN107810187B (zh) | 2015-07-07 | 2016-07-06 | 用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的pde9抑制剂 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112010861A true CN112010861A (zh) | 2020-12-01 |
Family
ID=56345156
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010907952.7A Pending CN112010861A (zh) | 2015-07-07 | 2016-07-06 | 用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的pde9抑制剂 |
CN201680039418.0A Active CN107810187B (zh) | 2015-07-07 | 2016-07-06 | 用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的pde9抑制剂 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680039418.0A Active CN107810187B (zh) | 2015-07-07 | 2016-07-06 | 用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的pde9抑制剂 |
Country Status (21)
Country | Link |
---|---|
US (4) | US10513524B2 (zh) |
EP (3) | EP3303339B1 (zh) |
CN (2) | CN112010861A (zh) |
AU (2) | AU2016289856B2 (zh) |
BR (1) | BR112018000254A2 (zh) |
CA (1) | CA2990521C (zh) |
DK (2) | DK3303339T3 (zh) |
ES (2) | ES2971969T3 (zh) |
FI (1) | FI3865484T3 (zh) |
HK (1) | HK1249903A1 (zh) |
HR (2) | HRP20240082T1 (zh) |
HU (2) | HUE065652T2 (zh) |
IL (2) | IL280619B2 (zh) |
LT (1) | LT3865484T (zh) |
MX (1) | MX2018000283A (zh) |
PL (1) | PL3865484T3 (zh) |
PT (1) | PT3865484T (zh) |
SI (2) | SI3865484T1 (zh) |
TN (1) | TN2017000507A1 (zh) |
WO (1) | WO2017005786A1 (zh) |
ZA (1) | ZA201708341B (zh) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI3865484T1 (sl) * | 2015-07-07 | 2024-05-31 | H. Lundbeck A/S | Zaviralec pde9 z imidazo pirazinonsko hrbtenico za zdravljenje perifernih bolezni |
BR112019000005A2 (pt) * | 2016-07-06 | 2019-04-16 | H. Lundbeck A/S | inibidores de pde9 para o tratamento de doenças periféricas |
TWI843393B (zh) | 2017-05-26 | 2024-05-21 | 美商卡杜隆製藥公司 | 製備和使用pde9抑制劑之方法 |
WO2018224455A1 (en) | 2017-06-07 | 2018-12-13 | Basf Se | Substituted cyclopropyl derivatives |
WO2018234488A1 (en) | 2017-06-23 | 2018-12-27 | Basf Se | SUBSTITUTED CYCLOPROPYL DERIVATIVES |
BR112020024019A2 (pt) * | 2018-05-25 | 2021-02-23 | Imara Inc. | monoidrato e formas cristalinas de 6-[(3s,4s)-4-metil-1-(pirimidin-2-ilmetil)pirrolidin-3-il]-3-tetra-hidropiran-4-il-7h-imidazo[1,5-a]pirazin-8-ona |
AU2019328299A1 (en) * | 2018-08-31 | 2021-04-22 | Cardurion Pharmaceuticals, Inc. | PDE9 inhibitors for treating sickle cell disease |
BR112021019876A2 (pt) * | 2019-04-05 | 2022-01-18 | Imara Inc | Inibidores de pde9 para tratar anemia falciforme |
EP3965768A1 (en) * | 2019-05-07 | 2022-03-16 | Imara Inc. | Pde9 inhibitors for treating thalassemia |
WO2022036111A1 (en) * | 2020-08-13 | 2022-02-17 | Imara Inc. | Methods and compositions for treating sickle cell disease |
CN112552339A (zh) * | 2020-12-10 | 2021-03-26 | 安徽昊帆生物有限公司 | 一种o-二苯基磷酰羟胺的制备方法 |
AU2022311952A1 (en) * | 2021-07-13 | 2024-01-25 | Relay Therapeutics, Inc. | PI3Kα INHIBITORS AND METHODS OF USE THEREOF |
CN115448864B (zh) * | 2022-08-26 | 2023-12-22 | 上海方予健康医药科技有限公司 | 3-氟-3-(1-羟乙基)吡咯烷-1-羧酸叔丁酯的制备方法 |
WO2024151930A1 (en) * | 2023-01-13 | 2024-07-18 | Relay Therapeutics, Inc. | Pi3k inhibitors and methods of making and using the same |
Family Cites Families (136)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB587992A (en) | 1944-12-11 | 1947-05-12 | Charles William Scaife | Improvements in and relating to the production of organic nitrogen compounds |
US3578687A (en) | 1968-01-30 | 1971-05-11 | Texaco Inc | Process for producing 4-nitroalkanoic acids |
US3819561A (en) | 1970-10-23 | 1974-06-25 | Aerojet General Co | Wetting agents for non-aqueous dispersions |
JPS5313608B2 (zh) | 1972-06-16 | 1978-05-11 | ||
JPS5318013B2 (zh) | 1973-03-19 | 1978-06-13 | ||
US4599430A (en) | 1981-12-21 | 1986-07-08 | The Standard Oil Company | Nitrogenation of hydrocarbons, including the production of maleimide |
JPS62132804A (ja) | 1985-12-05 | 1987-06-16 | Aguro Kanesho Kk | 植物生長調節剤 |
US5412137A (en) | 1993-06-07 | 1995-05-02 | Sandoz Ltd. | Process for preparing phosphinyloxy propanaminium inner salt derivatives |
UA42779C2 (uk) | 1994-08-08 | 2001-11-15 | Дебіофарм С.А. | Фармацевтично стійкий препарат оксалату платини для парентерального застосування |
KR100463709B1 (ko) | 1994-10-13 | 2005-08-04 | 위민스 앤드 칠드런스 호스피털 애드레이드 | 변형된불포화지방산 |
US5919816A (en) | 1994-11-14 | 1999-07-06 | Bionumerik Pharmaceuticals, Inc. | Formulations and methods of reducing toxicity of antineoplastic agents |
US5741211A (en) | 1995-10-26 | 1998-04-21 | Medtronic, Inc. | System and method for continuous monitoring of diabetes-related blood constituents |
GB9618420D0 (en) | 1996-09-04 | 1996-10-16 | Scotia Holdings Plc | Fatty acid treatment |
US6187747B1 (en) | 1997-09-08 | 2001-02-13 | Panacea Biotech Limited | Pharmaceutical composition comprising cyclosporin |
GB9722520D0 (en) | 1997-10-24 | 1997-12-24 | Pfizer Ltd | Compounds |
WO1999022719A1 (fr) | 1997-10-30 | 1999-05-14 | Morishita Jintan Co., Ltd. | Preparation de capsule contenant un acide gras insature ou un derive de celui-ci, et procede de fabrication |
CU23063A3 (es) | 1997-11-12 | 2005-07-19 | Bayer Ag | Imidazotriazinonas 2-fenil sustituidas como inhibidores de fosfodiesterasas |
US7795246B2 (en) | 1998-08-06 | 2010-09-14 | Cephalon, Inc. | Particle-forming compositions containing fused pyrrolocarbazoles |
US6262029B1 (en) | 1998-08-14 | 2001-07-17 | Galenica Pharmaceuticals, Inc. | Chemically modified saponins and the use thereof as adjuvants |
SK10322001A3 (sk) | 1999-01-20 | 2002-07-02 | Arzneimittelwerk Dresden Gmbh | Spôsob prípravy imidazo [1,5-a]pyrido[3,2-e]pyrazínov, farmaceutické prostriedky obsahujúce takéto zlúčeniny a spôsob výroby farmaceutického prostriedku |
WO2000059855A1 (en) | 1999-04-01 | 2000-10-12 | Esperion Therapeutics, Inc. | Ether compounds, compositions, and uses thereof |
AU5319499A (en) | 1999-07-22 | 2001-02-13 | Ivan L. Cameron | Fatty acids to minimize cancer therapy side effects |
SE9903028D0 (sv) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
AUPQ291499A0 (en) | 1999-09-17 | 1999-10-07 | Women's And Children's Hospital Adelaide | Novel nitro and sulphur containing compounds |
US6346231B1 (en) | 1999-10-06 | 2002-02-12 | Joar Opheim | Flavored gelatin capsule and method of manufacture |
IL139456A0 (en) | 1999-11-08 | 2001-11-25 | Pfizer | Compounds for the treatment of female sexual dysfunction |
US20010037598A1 (en) | 1999-12-14 | 2001-11-08 | Suppes Galen J. | Process for producing cetane improvers from triglycerides |
MXPA02007915A (es) | 2000-02-16 | 2005-06-20 | Brigham & Womens Hospital | Mediador de lipido activado por aspirina. |
AR030416A1 (es) | 2000-04-13 | 2003-08-20 | Pharmacia Corp | COMPUESTO DERIVADO HALOGENADO DEL ACIDO 2-AMINO-3,4 HEPTENOICO, COMPOSICION FARMACEUTICA QUE LO COMPRENDE Y SU USO EN LA FABRICACION DE UN MEDICAMENTO uTIL COMO INHIBIDOR DE LA OXIDO NITRICO SINTETASA |
AR032318A1 (es) | 2000-04-13 | 2003-11-05 | Pharmacia Corp | Compuesto derivado halogenado del acido 2-amino-5,6 heptenoico; composicion farmaceutica que lo comprende y su uso en la fabricacion de un medicamento util como inhibidor de la oxido nitrico sintetasa |
AR034120A1 (es) | 2000-04-13 | 2004-02-04 | Pharmacia Corp | Compuesto derivado halogenado del acido 2-amino-4,5 heptenoico, composicion farmaceutica que lo comprende y el uso de dicho compuesto y dicha composicion en la fabricacion de un medicamento para inhibir o modular la sintesis de acido nitrico |
CA2412232C (en) | 2000-06-28 | 2010-03-30 | Zambon Group S.P.A. | Process for the preparation of nitroalkenes |
AR031129A1 (es) | 2000-09-15 | 2003-09-10 | Pharmacia Corp | Derivados de los acidos 2-amino-2-alquil-4-hexenoico y -hexinoico utiles como inhibidores de oxido nitrico sintetasa |
PT1368022E (pt) | 2001-03-02 | 2007-10-01 | Debiopharm Sa | Utilização de um frasco em vidro que contém uma solução de oxaliplatina |
EE200300510A (et) | 2001-04-18 | 2004-02-16 | Prometic Biosciences Inc. | Keskmise pikkusega ahelaga rasvhapped, glütseriidid ja nende analoogid kui neutrofiilide ellujäämis- ja aktiveerimisfaktorid |
US7105556B2 (en) | 2001-05-30 | 2006-09-12 | Bristol-Myers Squibb Company | Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method |
EP1407767A4 (en) | 2001-06-18 | 2007-01-24 | Yamada Sachiko | AGONIST MEDICINAL PREPARATIONS PPAR $ G (G) |
WO2003015704A2 (en) | 2001-08-17 | 2003-02-27 | University Of Pittsburgh | Administration of estradiol metabolites for the treatment or prevention of obesity, metabolic syndrome, diabetes, and vascular and renal disorders |
GB0123961D0 (en) | 2001-10-05 | 2001-11-28 | Astrazeneca Ab | Process and intermediates |
KR20040053210A (ko) | 2001-11-02 | 2004-06-23 | 화이자 프로덕츠 인크. | Pde9 억제제를 사용한 인슐린 저항 증후군 및 2형당뇨병의 치료 |
HN2002000317A (es) | 2001-11-02 | 2003-05-21 | Pfizer | Inhibidores de pde9 para tratamiento de trastornos cardiovasculares |
US20030166716A1 (en) | 2001-11-06 | 2003-09-04 | Serhan Charles N. | Lipoxins and aspirin-triggered lipoxins and their stable analogs in the treatment of asthma and inflammatory airway diseases |
GB2388111A (en) | 2002-05-01 | 2003-11-05 | Bayer Ag | Novel imidazotriazinone compounds |
US6684626B1 (en) | 2002-07-30 | 2004-02-03 | General Electric Company | Aircraft gas turbine engine with control vanes for counter rotating low pressure turbines |
US7759395B2 (en) | 2002-08-12 | 2010-07-20 | The Brigham And Women's Hospital, Inc. | Use of docosatrienes, resolvins and their stable analogs in the treatment of airway diseases and asthma |
EP1539129A4 (en) | 2002-08-20 | 2006-03-08 | Protemix Corp Ltd | DOSAGE FORMS AND RELEVANT THERAPIES |
EP1558237A4 (en) | 2002-09-27 | 2007-01-17 | Martek Biosciences Corp | IMPROVED GLYCEMIC REGULATION IN PREDIABETE AND / OR DIABETES TYPE II USING DOCOSAHEXAENOIC ACID |
US7326421B2 (en) | 2002-10-21 | 2008-02-05 | Kensey Nash Corporation | Device and methods for sequential, regional delivery of multiple cytotoxic agents and directed assembly of wound repair tissues |
US7166575B2 (en) | 2002-12-17 | 2007-01-23 | Nastech Pharmaceutical Company Inc. | Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity |
US20040220186A1 (en) | 2003-04-30 | 2004-11-04 | Pfizer Inc. | PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease |
WO2005016864A1 (en) | 2003-07-29 | 2005-02-24 | The Arizona Disease Control Research Commission | Conjugated nitro alkene anticancer agents based on isoprenoid metabolism |
US20050136103A1 (en) | 2003-09-17 | 2005-06-23 | Ben-Sasson Shmuel A. | Compositions capable of facilitating penetration across a biological barrier |
US7935365B2 (en) | 2003-10-22 | 2011-05-03 | Enzymotec, Ltd. | Glycerophospholipids for the improvement of cognitive functions |
BRPI0416118A (pt) | 2003-10-31 | 2007-01-02 | Pfizer Prod Inc | inibição da fosfodiesterase 9 como tratamento para estados relacionados com a obesidade |
EP1718602A4 (en) | 2004-01-30 | 2007-12-12 | Peplin Biolipids Pty Ltd | THERAPEUTIC AND CARRIER MOLECULES |
KR20070044805A (ko) | 2004-04-15 | 2007-04-30 | 키아스마, 인코포레이티드 | 생물학적 장벽 투과를 촉진시킬 수 있는 조성물 |
WO2005110396A2 (en) | 2004-04-28 | 2005-11-24 | Uab Research Foundation | Nitrated lipids and methods of making and using thereof |
UA103758C2 (ru) | 2004-07-19 | 2013-11-25 | Биокон Лимитед | Конъюгаты олигомеров инсулина, их композиции и применение |
AR053090A1 (es) | 2004-07-20 | 2007-04-25 | Osi Pharm Inc | Imidazotriazinas como inhibidores de proteina quinasas y su uso para la preparacion de medicamentos |
EP1772149A1 (en) | 2004-07-27 | 2007-04-11 | Kowa Company. Ltd. | Drug for prevention or treatment of diabetes |
BRPI0516803A (pt) | 2004-11-19 | 2008-09-23 | Martek Biosciences Corp | oxilipinas de ácidos graxos polinsaturados de cadeia longa e métodos de produção e uso dos mesmos |
WO2006058250A2 (en) | 2004-11-24 | 2006-06-01 | Spi Pharma, Inc. | Orally disintegrating compositions |
AU2011202664B2 (en) | 2004-12-08 | 2012-04-05 | Cedars-Sinai Medical Center | Methods for diagnosis and treatment of Crohn's disease |
US20070032420A1 (en) | 2005-02-09 | 2007-02-08 | Entelos, Inc. | Treating diabetes with glucagon-like peptide-1 secretagogues |
US7709468B2 (en) | 2005-09-02 | 2010-05-04 | Abbott Laboratories | Imidazo based heterocycles |
GB0522569D0 (en) | 2005-11-04 | 2005-12-14 | Univ Bath | Biocompatible drug delivery device |
TW200815436A (en) | 2006-05-30 | 2008-04-01 | Elbion Ag | 4-amino-pyrido[3,2-e]pyrazines, their use as inhibitors of phosphodiesterase 10, and processes for preparing them |
US9274129B2 (en) | 2006-05-31 | 2016-03-01 | Lpath, Inc. | Methods and reagents for detecting bioactive lipids |
WO2008008767A2 (en) | 2006-07-14 | 2008-01-17 | Cedars-Sinai Medical Center | Methods of using ppar-gamma agonists and caspase-dependent chemotherapeutic agents for the treatment of cancer |
US20100035989A1 (en) | 2006-07-19 | 2010-02-11 | Resolvyx Pharmaceuticals, Inc. | Compositions and methods for the treatment of mucositis |
US7947577B2 (en) | 2006-09-08 | 2011-05-24 | Tokuyama Corporation | Method and apparatus for producing group III nitride |
US8299080B2 (en) | 2006-12-13 | 2012-10-30 | Aska Pharmaceutical Co., Ltd. | Substituted imidazo[1,5-A] quinoxalines as a PDE9 inhibitor |
JPWO2008072778A1 (ja) | 2006-12-13 | 2010-04-02 | あすか製薬株式会社 | 尿路系疾患の処置剤 |
JP2010519311A (ja) | 2007-02-20 | 2010-06-03 | マーテック バイオサイエンシーズ コーポレーション | 長鎖多価不飽和脂肪酸由来のオキシリピンならびにその作製およびその使用方法 |
RS52166B (en) | 2007-05-11 | 2012-08-31 | Pfizer Inc. | AMINO-HETEROCYCLIC COMPOUNDS |
DE102007032349A1 (de) | 2007-07-11 | 2009-01-15 | Bayer Healthcare Ag | Imidazo-, Pyrazolopyrazine und Imidazotriazine und ihre Verwendung |
WO2009017802A1 (en) | 2007-08-01 | 2009-02-05 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Nitro-fattyacid modulation of type ii diabetes |
US20090137527A1 (en) | 2007-09-14 | 2009-05-28 | Resolvyx Pharmaceuticals, Inc. | Compositions and methods for modulating immune function |
CN102066924B (zh) | 2008-04-18 | 2013-03-27 | 犹他大学研究基金会 | 使用硝化脂质治疗脂质病症和肥胖以及与脂质和肥胖相关的病状 |
JP2011519373A (ja) | 2008-05-01 | 2011-07-07 | コンプレクザ インコーポレイテッド | ビニル置換脂肪酸 |
WO2009149496A1 (en) | 2008-06-10 | 2009-12-17 | Central Northern Adelaide Health Service | Treatment of diabetes and complications thereof and related disorders |
US20140024713A1 (en) | 2008-06-19 | 2014-01-23 | University Of Utah Research Foundation | Use of nitrated lipids for treatment of side effects of toxic medical therapies |
US8686038B2 (en) | 2008-06-19 | 2014-04-01 | The Univsersity of Utah Research Foundation | Use of nitrated lipids for treatment of side effects of toxic medical therapies |
US8518930B2 (en) | 2008-07-29 | 2013-08-27 | Nerviano Medical Sciences S.R.L. | Therapeutic combination comprising a CDKS inhibitor and an antineoplastic agent |
PL2350043T3 (pl) | 2008-10-09 | 2014-09-30 | Tekmira Pharmaceuticals Corp | Ulepszone aminolipidy i sposoby dostarczania kwasów nukleinowych |
CN102307464A (zh) | 2008-12-31 | 2012-01-04 | 尼特罗米加公司 | 含有硝基脂肪酸的营养制品 |
US8937194B2 (en) | 2008-12-31 | 2015-01-20 | Nitromega Corp. | Topical compositions containing nitro fatty acids |
TWI404721B (zh) | 2009-01-26 | 2013-08-11 | Pfizer | 胺基-雜環化合物 |
US20100286272A1 (en) | 2009-05-08 | 2010-11-11 | Perricone Nicholas V | Methods Of Use Of Nitroalkene Compositions In Dermatologic Applications |
US20100286257A1 (en) | 2009-05-08 | 2010-11-11 | Perricone Nicholas V | Methods Of Use Of Nitroalkane Compositions In Dermatologic Applications To Prevent or Treat Skin Aging |
US20100286271A1 (en) | 2009-05-08 | 2010-11-11 | Perricone Nicholas V | Nitro-alkyl Compound Compositions |
US20110082147A1 (en) | 2009-07-24 | 2011-04-07 | Concert Pharmaceuticals, Inc. | Substituted imidazotriazines |
US20120136057A1 (en) | 2009-07-29 | 2012-05-31 | Phenomenome Discoveries Inc. | Hydroxy fatty acid compounds and uses thereof for disease treatment and diagnosis |
JP2013500966A (ja) | 2009-07-31 | 2013-01-10 | ユニバーシティー オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケーション | 抗炎症剤としての脂肪酸 |
US9260432B2 (en) | 2009-09-02 | 2016-02-16 | Concert Pharmaceuticals, Inc. | Substituted derivatives of bicyclic [4.3.0] heteroaryl compounds |
WO2011030351A2 (en) | 2009-09-03 | 2011-03-17 | Rubicon Research Private Limited | Taste - masked pharmaceutical compositions |
EP2483233A4 (en) | 2009-10-02 | 2013-08-14 | Complexa Inc | HETEROATOMA CONTAINING SUBSTITUTED FATTY ACIDS |
AU2010315946A1 (en) | 2009-11-09 | 2012-05-31 | Medivir Ab | Novel 1,3-oxazolidine compounds and their use as renin inhibitors |
WO2011098746A1 (en) | 2010-02-09 | 2011-08-18 | Pulmagen Therapeutics (Inflammation) Limited | Crystalline acid addition salts of ( 5r) -enanti0mer of pioglitazone |
RU2567049C2 (ru) | 2010-03-15 | 2015-10-27 | Ульрих ДИТЦ | Применение нитрокарбоновых кислот для лечения, диагностики и профилактики агрессивных форм заживления |
JP2013526865A (ja) | 2010-05-13 | 2013-06-27 | ニトロメガ コーポレーション | ニトロ脂肪酸、神経保護および/または認識減退の抑制 |
CA2804144A1 (en) | 2010-06-28 | 2012-01-12 | Complexa, Inc. | Multi-component pharmaceuticals for treating diabetes |
AR083058A1 (es) | 2010-09-20 | 2013-01-30 | Envivo Pharmaceuticals Inc | Compuestos de estructura de imidazotriazinona |
US8809345B2 (en) | 2011-02-15 | 2014-08-19 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
WO2013028501A1 (en) | 2011-08-19 | 2013-02-28 | The University Of Utah Research Foundation | Combination therapy with nitrated lipids and inhibitors of the renin-angiotensin-aldosterone system |
ES2568015T3 (es) | 2011-10-07 | 2016-04-27 | Eisai R&D Management Co., Ltd. | Derivado de pirazoloquinolina como inhibidores de PDE9 |
EP2906562B1 (en) | 2011-10-10 | 2016-10-05 | H. Lundbeck A/S | Pde9i with imidazo pyrazinone backbone |
US9271952B2 (en) | 2011-10-11 | 2016-03-01 | Complexa, Inc. | Compositions and methods for treating nephropathy |
DE102012008730A1 (de) | 2011-12-02 | 2013-06-06 | Dr. Budz GmbH | Orale Zusammensetzungen mit ungesättigten C18-Fettsäuren und ihre Verwendung |
CN104093720B (zh) | 2012-01-26 | 2017-04-12 | H.隆德贝克有限公司 | 具有咪唑并三嗪酮骨架的pde9抑制剂 |
ES2681027T3 (es) | 2012-02-01 | 2018-09-11 | City Of Hope | Inhibidores de la ribonucleótida reductasa y métodos de uso |
JP2015508065A (ja) | 2012-02-03 | 2015-03-16 | ユニバーシティ オブ ピッツバーグ オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション | 抗炎症薬としての脂肪酸 |
US10435367B2 (en) | 2013-03-14 | 2019-10-08 | City Of Hope | Indirubin derivatives, and uses thereof |
EP2828262A4 (en) | 2012-03-19 | 2015-09-23 | Forum Pharmaceuticals Inc | IMIDAZOTRIAZINONVERBINDUNGEN |
WO2013170069A1 (en) | 2012-05-09 | 2013-11-14 | Massachusetts Institute Of Technology | Medicament, method, and drug delivery device for treatment of ovarian cancer |
SG11201501424SA (en) | 2012-08-31 | 2015-03-30 | Taris Biomedical Llc | Drug delivery systems and methods for treatment of bladder cancer comprising oxaliplatin |
US20140271844A1 (en) | 2013-03-15 | 2014-09-18 | Nitromega Corp. | Compositions containing nitro fatty acids |
ES2762555T3 (es) | 2013-04-10 | 2020-05-25 | Massachusetts Inst Technology | Dispositivos y métodos de administración local de fármacos para el tratamiento del cáncer |
EP2994165A4 (en) | 2013-05-10 | 2017-01-04 | Nitromega Corp. | Nutritional or dietary supplements containing fatty acids and nitrite |
WO2014204872A2 (en) | 2013-06-14 | 2014-12-24 | Complexa, Inc. | Composition and method for inhibition of pkng from mycobacterium tuberculosis |
US10369340B2 (en) | 2013-08-12 | 2019-08-06 | Nanomedical Systems, Inc. | Device and method for sustained release of low water solubility therapeutic agent in solubilizer |
WO2015073527A1 (en) | 2013-11-12 | 2015-05-21 | Complexa, Inc. | Nitroalkene tocopherols and analogs thereof for use in the treatment and prevention of inflammation related conditions |
WO2015185499A1 (en) | 2014-06-06 | 2015-12-10 | H. Lundbeck A/S | Pde9 inhibitors with 1-benzyl-2,5,6,8-tetrahydro-3-oxo-2,7-naphthyridine-4-carbonitrile backbone |
EP3194386A2 (en) | 2014-09-17 | 2017-07-26 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
WO2016161285A1 (en) | 2015-04-02 | 2016-10-06 | Aobiome Llc | Production of nitro-fatty acids and nitro-hydrocarbons by ammonia oxidizing bacteria |
SI3865484T1 (sl) | 2015-07-07 | 2024-05-31 | H. Lundbeck A/S | Zaviralec pde9 z imidazo pirazinonsko hrbtenico za zdravljenje perifernih bolezni |
AU2016331314A1 (en) | 2015-10-02 | 2018-05-17 | Complexa, Inc. | Prevention, treatment and reversal of disease using therapeutically effective amounts of activated fatty acids |
US9771366B2 (en) | 2016-02-19 | 2017-09-26 | Phoenix Molecular Design | Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamides as RSK inhibitors |
BR112019000005A2 (pt) | 2016-07-06 | 2019-04-16 | H. Lundbeck A/S | inibidores de pde9 para o tratamento de doenças periféricas |
TWI843393B (zh) | 2017-05-26 | 2024-05-21 | 美商卡杜隆製藥公司 | 製備和使用pde9抑制劑之方法 |
BR112020024019A2 (pt) | 2018-05-25 | 2021-02-23 | Imara Inc. | monoidrato e formas cristalinas de 6-[(3s,4s)-4-metil-1-(pirimidin-2-ilmetil)pirrolidin-3-il]-3-tetra-hidropiran-4-il-7h-imidazo[1,5-a]pirazin-8-ona |
AU2019328299A1 (en) | 2018-08-31 | 2021-04-22 | Cardurion Pharmaceuticals, Inc. | PDE9 inhibitors for treating sickle cell disease |
BR112021019876A2 (pt) | 2019-04-05 | 2022-01-18 | Imara Inc | Inibidores de pde9 para tratar anemia falciforme |
EP3965768A1 (en) | 2019-05-07 | 2022-03-16 | Imara Inc. | Pde9 inhibitors for treating thalassemia |
WO2022036111A1 (en) | 2020-08-13 | 2022-02-17 | Imara Inc. | Methods and compositions for treating sickle cell disease |
KR20230128450A (ko) | 2020-10-27 | 2023-09-05 | 카듀리온 파마슈티칼스, 인크. | 심부전 치료를 위한 pde9 억제제 |
-
2016
- 2016-07-06 SI SI201631793T patent/SI3865484T1/sl unknown
- 2016-07-06 BR BR112018000254A patent/BR112018000254A2/pt not_active Application Discontinuation
- 2016-07-06 US US15/742,086 patent/US10513524B2/en active Active
- 2016-07-06 ES ES20217833T patent/ES2971969T3/es active Active
- 2016-07-06 FI FIEP20217833.1T patent/FI3865484T3/fi active
- 2016-07-06 SI SI201631145T patent/SI3303339T1/sl unknown
- 2016-07-06 WO PCT/EP2016/065964 patent/WO2017005786A1/en active Application Filing
- 2016-07-06 MX MX2018000283A patent/MX2018000283A/es unknown
- 2016-07-06 CA CA2990521A patent/CA2990521C/en active Active
- 2016-07-06 ES ES16734707T patent/ES2869939T3/es active Active
- 2016-07-06 LT LTEP20217833.1T patent/LT3865484T/lt unknown
- 2016-07-06 HU HUE20217833A patent/HUE065652T2/hu unknown
- 2016-07-06 IL IL280619A patent/IL280619B2/en unknown
- 2016-07-06 CN CN202010907952.7A patent/CN112010861A/zh active Pending
- 2016-07-06 EP EP16734707.9A patent/EP3303339B1/en active Active
- 2016-07-06 PL PL20217833.1T patent/PL3865484T3/pl unknown
- 2016-07-06 AU AU2016289856A patent/AU2016289856B2/en active Active
- 2016-07-06 HR HRP20240082TT patent/HRP20240082T1/hr unknown
- 2016-07-06 DK DK16734707.9T patent/DK3303339T3/da active
- 2016-07-06 EP EP23208076.2A patent/EP4335497A3/en active Pending
- 2016-07-06 PT PT202178331T patent/PT3865484T/pt unknown
- 2016-07-06 TN TNP/2017/000507A patent/TN2017000507A1/en unknown
- 2016-07-06 CN CN201680039418.0A patent/CN107810187B/zh active Active
- 2016-07-06 HU HUE16734707A patent/HUE053968T2/hu unknown
- 2016-07-06 DK DK20217833.1T patent/DK3865484T3/da active
- 2016-07-06 EP EP20217833.1A patent/EP3865484B1/en active Active
-
2017
- 2017-12-06 IL IL256143A patent/IL256143B/en active IP Right Grant
- 2017-12-08 ZA ZA2017/08341A patent/ZA201708341B/en unknown
-
2018
- 2018-07-19 HK HK18109354.1A patent/HK1249903A1/zh unknown
-
2019
- 2019-11-04 US US16/673,709 patent/US20200062770A1/en not_active Abandoned
-
2020
- 2020-12-08 US US17/115,108 patent/US11608342B2/en active Active
-
2021
- 2021-02-25 AU AU2021201227A patent/AU2021201227B2/en active Active
- 2021-04-06 HR HRP20210543TT patent/HRP20210543T1/hr unknown
-
2023
- 2023-02-10 US US18/167,411 patent/US20230183255A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107810187B (zh) | 用于治疗外周疾病的具有咪唑并三嗪酮骨架和咪唑并吡嗪酮骨架的pde9抑制剂 | |
US11634422B2 (en) | Inhibitors of activin receptor-like kinase | |
IL257886A (en) | History of imidazo [5,4-c] quinoline and imidazo [5,4-c] [5,1] naphthyridine as lrrk2 inhibitors | |
EP3169325B1 (en) | Therapeutic inhibitory compounds | |
WO2017071516A1 (zh) | 一种蛋白激酶抑制剂及其制备方法和医药用途 | |
TW202309020A (zh) | KEAP1-Nrf2蛋白-蛋白交互作用抑制劑 | |
CN112689637B (zh) | 咪唑并吡啶酮化合物 | |
KR20200058599A (ko) | 삼환형 화합물 및 포스포다이에스터라제 억제제로서 이의 용도 | |
CN113493453B (zh) | 稠合芳香环类衍生物、其制备方法及其在医药上的应用 | |
CA3056027A1 (en) | Cyclic substituted imidazo[4,5-c]quinoline derivatives | |
CN110248946B (zh) | Menin-MLL相互作用的氮杂环庚烷抑制剂 | |
CA3104357A1 (en) | Amino-pyrimidonyl derivatives, a process for their preparation and pharmaceutical compositions containing them | |
CN112778273A (zh) | 环酮并吡啶酮类化合物及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40041434 Country of ref document: HK |