TWI695838B - 作爲ｐｄｅ１抑制劑之咪唑並吡酮 - Google Patents

Info

Publication number

TWI695838B

TWI695838B TW105113074A TW105113074A TWI695838B TW I695838 B TWI695838 B TW I695838B TW 105113074 A TW105113074 A TW 105113074A TW 105113074 A TW105113074 A TW 105113074A TW I695838 B TWI695838 B TW I695838B

Authority

TW

Taiwan

Prior art keywords

pyridine

methyl

imidazo

piperan

tetrahydro

Prior art date

2015-04-30

Links

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• Global Dossier
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• 229940121836 Phosphodiesterase 1 inhibitor Drugs 0.000 title abstract description 17
• MPWOBEOETVOESI-UHFFFAOYSA-N imidazo[4,5-b]pyrazin-2-one Chemical class N1=CC=NC2=NC(=O)N=C21 MPWOBEOETVOESI-UHFFFAOYSA-N 0.000 title abstract 2
• 238000011282 treatment Methods 0.000 claims abstract description 32
• 208000020016 psychiatric disease Diseases 0.000 claims abstract description 20
• 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 17
• -1 imidazo[1,5-a]pyridine -8(7H)-one Chemical compound 0.000 claims description 189
• 150000001875 compounds Chemical class 0.000 claims description 110
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 66
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
• 150000003839 salts Chemical class 0.000 claims description 39
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 33
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 27
• 208000028698 Cognitive impairment Diseases 0.000 claims description 19
• 208000010877 cognitive disease Diseases 0.000 claims description 19
• 239000008194 pharmaceutical composition Substances 0.000 claims description 17
• 239000003085 diluting agent Substances 0.000 claims description 12
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 11
• 208000024827 Alzheimer disease Diseases 0.000 claims description 10
• 208000018737 Parkinson disease Diseases 0.000 claims description 10
• 208000005793 Restless legs syndrome Diseases 0.000 claims description 10
• 201000003631 narcolepsy Diseases 0.000 claims description 10
• 201000000980 schizophrenia Diseases 0.000 claims description 10
• 208000023105 Huntington disease Diseases 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 9
• 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 4
• MLXWMEFKFOSOCP-UHFFFAOYSA-N imidazo[1,5-a]pyridine Chemical compound C1=CC=CC2=C=N[CH]N21 MLXWMEFKFOSOCP-UHFFFAOYSA-N 0.000 claims 52
• 239000003814 drug Substances 0.000 abstract description 7
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 425
• 239000000203 mixture Substances 0.000 description 412
• JMANUKZDKDKBJP-UHFFFAOYSA-N imidazo[1,5-a]pyridine Chemical compound C1=CC=CC2=CN=CN21 JMANUKZDKDKBJP-UHFFFAOYSA-N 0.000 description 223
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 221
• 238000000034 method Methods 0.000 description 203
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 188
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 185
• 239000000243 solution Substances 0.000 description 162
• 239000007787 solid Substances 0.000 description 133
• 238000005481 NMR spectroscopy Methods 0.000 description 126
• 239000011734 sodium Substances 0.000 description 120
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 100
• 239000012044 organic layer Substances 0.000 description 90
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 89
• 239000012267 brine Substances 0.000 description 88
• VLPWXHZDGMUMBR-UHFFFAOYSA-N 3-methoxy-5-methylpyridine Chemical compound COC1=CN=CC(C)=C1 VLPWXHZDGMUMBR-UHFFFAOYSA-N 0.000 description 80
• 235000019439 ethyl acetate Nutrition 0.000 description 71
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 69
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 64
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 64
• 238000006243 chemical reaction Methods 0.000 description 62
• 239000000706 filtrate Substances 0.000 description 57
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 54
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• 238000002953 preparative HPLC Methods 0.000 description 50
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
• 239000011541 reaction mixture Substances 0.000 description 46
• 229920006395 saturated elastomer Polymers 0.000 description 43
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 39
• 239000002904 solvent Substances 0.000 description 39
• 239000000741 silica gel Substances 0.000 description 36
• 229910002027 silica gel Inorganic materials 0.000 description 36
• 239000004698 Polyethylene Substances 0.000 description 35
• 238000003818 flash chromatography Methods 0.000 description 33
• 238000010898 silica gel chromatography Methods 0.000 description 33
• 239000003208 petroleum Substances 0.000 description 32
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 31
• 239000012043 crude product Substances 0.000 description 30
• 239000003921 oil Substances 0.000 description 28
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
• 239000002585 base Substances 0.000 description 27
• 235000019198 oils Nutrition 0.000 description 27
• RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 27
• 101001117089 Drosophila melanogaster Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 Proteins 0.000 description 23
• 238000004809 thin layer chromatography Methods 0.000 description 23
• LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 23
• 239000007821 HATU Substances 0.000 description 22
• 238000010828 elution Methods 0.000 description 22
• SCBZBMXPJYMXRC-UHFFFAOYSA-N 1-(bromomethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CBr)=C1 SCBZBMXPJYMXRC-UHFFFAOYSA-N 0.000 description 21
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 21
• RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 20
• 230000002829 reductive effect Effects 0.000 description 19
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 18
• 239000000460 chlorine Substances 0.000 description 18
• 125000001424 substituent group Chemical group 0.000 description 17
• MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 16
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• 239000012074 organic phase Substances 0.000 description 16
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• 239000011737 fluorine Substances 0.000 description 14
• 229910052731 fluorine Inorganic materials 0.000 description 14
• 229910052739 hydrogen Inorganic materials 0.000 description 14
• 239000001257 hydrogen Substances 0.000 description 14
• 239000007788 liquid Substances 0.000 description 14
• 229910000027 potassium carbonate Inorganic materials 0.000 description 14
• 235000011181 potassium carbonates Nutrition 0.000 description 13
• 238000012746 preparative thin layer chromatography Methods 0.000 description 13
• IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 12
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 11
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
• DVLGIQNHKLWSRU-UHFFFAOYSA-N methyl 1h-imidazole-5-carboxylate Chemical compound COC(=O)C1=CN=CN1 DVLGIQNHKLWSRU-UHFFFAOYSA-N 0.000 description 11
• 239000002253 acid Substances 0.000 description 10
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
• ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 10
• 229910052736 halogen Inorganic materials 0.000 description 10
• 150000002367 halogens Chemical class 0.000 description 10
• 239000000758 substrate Substances 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• 208000014644 Brain disease Diseases 0.000 description 9
• 229910000024 caesium carbonate Inorganic materials 0.000 description 9
• 125000004122 cyclic group Chemical group 0.000 description 9
• 201000010099 disease Diseases 0.000 description 9
• 238000000746 purification Methods 0.000 description 9
• 239000000725 suspension Substances 0.000 description 9
• OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 8
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
• 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 description 8
• 125000000217 alkyl group Chemical group 0.000 description 8
• 239000012230 colorless oil Substances 0.000 description 8
• 230000005764 inhibitory process Effects 0.000 description 8
• NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 8
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
• 108090000623 proteins and genes Proteins 0.000 description 8
• 230000001105 regulatory effect Effects 0.000 description 8
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
• 102000004190 Enzymes Human genes 0.000 description 7
• 108090000790 Enzymes Proteins 0.000 description 7
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 7
• 239000010410 layer Substances 0.000 description 7
• 235000009518 sodium iodide Nutrition 0.000 description 7
• 238000003756 stirring Methods 0.000 description 7
• 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 6
• 125000006163 5-membered heteroaryl group Chemical group 0.000 description 6
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
• 238000003556 assay Methods 0.000 description 6
• 239000011324 bead Substances 0.000 description 6
• 230000037396 body weight Effects 0.000 description 6
• 208000035475 disorder Diseases 0.000 description 6
• 230000000694 effects Effects 0.000 description 6
• 239000003480 eluent Substances 0.000 description 6
• 239000012065 filter cake Substances 0.000 description 6
• 235000019253 formic acid Nutrition 0.000 description 6
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
• 238000002360 preparation method Methods 0.000 description 6
• 239000000047 product Substances 0.000 description 6
• 239000011877 solvent mixture Substances 0.000 description 6
• 239000007858 starting material Substances 0.000 description 6
• 239000003826 tablet Substances 0.000 description 6
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 6
• 239000003643 water by type Substances 0.000 description 6
• PWRBCZZQRRPXAB-UHFFFAOYSA-N 3-chloropyridine Chemical compound ClC1=CC=CN=C1 PWRBCZZQRRPXAB-UHFFFAOYSA-N 0.000 description 5
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
• 101001117094 Homo sapiens Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C Proteins 0.000 description 5
• 229940076380 PDE9 inhibitor Drugs 0.000 description 5
• 239000004480 active ingredient Substances 0.000 description 5
• 150000001408 amides Chemical class 0.000 description 5
• 239000007864 aqueous solution Substances 0.000 description 5
• 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 5
• UUWSLBWDFJMSFP-UHFFFAOYSA-N bromomethylcyclohexane Chemical compound BrCC1CCCCC1 UUWSLBWDFJMSFP-UHFFFAOYSA-N 0.000 description 5
• 125000004432 carbon atom Chemical group C* 0.000 description 5
• 238000004440 column chromatography Methods 0.000 description 5
• 125000004093 cyano group Chemical group *C#N 0.000 description 5
• 150000004032 porphyrins Chemical class 0.000 description 5
• 235000018102 proteins Nutrition 0.000 description 5
• 102000004169 proteins and genes Human genes 0.000 description 5
• 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 5
• 230000001225 therapeutic effect Effects 0.000 description 5
• VCXIGSJESNXXLW-UHFFFAOYSA-N 3-bromo-6-methylimidazo[1,5-a]pyridine Chemical compound C1=C(C)C=CC2=CN=C(Br)N21 VCXIGSJESNXXLW-UHFFFAOYSA-N 0.000 description 4
• DBVWFKFSJSQZDG-UHFFFAOYSA-N 3-cyclopropylimidazo[1,5-a]pyridine Chemical compound C1(CC1)C1=NC=C2N1C=CC=C2 DBVWFKFSJSQZDG-UHFFFAOYSA-N 0.000 description 4
• CTQPCFFQBYXOAJ-UHFFFAOYSA-N 5-methoxypyridin-3-amine Chemical compound COC1=CN=CC(N)=C1 CTQPCFFQBYXOAJ-UHFFFAOYSA-N 0.000 description 4
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• LUSJGBUIEDXGJH-UHFFFAOYSA-N CC1=CN2C(Br)=NC=C2C=C1CC(C=C1)=CC=C1OC Chemical compound CC1=CN2C(Br)=NC=C2C=C1CC(C=C1)=CC=C1OC LUSJGBUIEDXGJH-UHFFFAOYSA-N 0.000 description 4
• SIQXBGQBGOQULZ-UHFFFAOYSA-N CC1=CN2C(Br)=NC=C2C=C1CC1=CC(F)=CC=C1 Chemical compound CC1=CN2C(Br)=NC=C2C=C1CC1=CC(F)=CC=C1 SIQXBGQBGOQULZ-UHFFFAOYSA-N 0.000 description 4
• CWAPMHHZPWBOKW-UHFFFAOYSA-N CC1C(CCO1)C2=NC=C3N2C=C(C(=C3)CC4=CC(=CC=C4)F)C Chemical compound CC1C(CCO1)C2=NC=C3N2C=C(C(=C3)CC4=CC(=CC=C4)F)C CWAPMHHZPWBOKW-UHFFFAOYSA-N 0.000 description 4
• OIERBJNRDMOCLU-UHFFFAOYSA-N CC1CC1C2=NC=C3N2C=C(C(=C3)CC4=CC(=CC=C4)F)C Chemical compound CC1CC1C2=NC=C3N2C=C(C(=C3)CC4=CC(=CC=C4)F)C OIERBJNRDMOCLU-UHFFFAOYSA-N 0.000 description 4
• 102100024317 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C Human genes 0.000 description 4
• AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
• 241000124008 Mammalia Species 0.000 description 4
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
• 150000001204 N-oxides Chemical class 0.000 description 4
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
• 239000007868 Raney catalyst Substances 0.000 description 4
• 229910000564 Raney nickel Inorganic materials 0.000 description 4
• NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
• 239000002671 adjuvant Substances 0.000 description 4
• 150000001347 alkyl bromides Chemical class 0.000 description 4
• 239000002168 alkylating agent Substances 0.000 description 4
• 229940100198 alkylating agent Drugs 0.000 description 4
• 239000003054 catalyst Substances 0.000 description 4
• 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 4
• 238000006880 cross-coupling reaction Methods 0.000 description 4
• 239000002552 dosage form Substances 0.000 description 4
• 239000000839 emulsion Substances 0.000 description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
• 238000009472 formulation Methods 0.000 description 4
• 239000012458 free base Substances 0.000 description 4
• 238000004128 high performance liquid chromatography Methods 0.000 description 4
• 150000002576 ketones Chemical class 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
• 238000004519 manufacturing process Methods 0.000 description 4
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
• FIDBZJWCHLENOB-UHFFFAOYSA-N methyl 3-(2-oxopropyl)imidazole-4-carboxylate Chemical compound COC(=O)C1=CN=CN1CC(C)=O FIDBZJWCHLENOB-UHFFFAOYSA-N 0.000 description 4
• 150000007522 mineralic acids Chemical class 0.000 description 4
• 125000002950 monocyclic group Chemical group 0.000 description 4
• 150000007524 organic acids Chemical class 0.000 description 4
• YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
• 238000004704 ultra performance liquid chromatography Methods 0.000 description 4
• 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
• GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 description 3
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