JP2014517021A5 - - Google Patents
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- Publication number
- JP2014517021A5 JP2014517021A5 JP2014515155A JP2014515155A JP2014517021A5 JP 2014517021 A5 JP2014517021 A5 JP 2014517021A5 JP 2014515155 A JP2014515155 A JP 2014515155A JP 2014515155 A JP2014515155 A JP 2014515155A JP 2014517021 A5 JP2014517021 A5 JP 2014517021A5
- Authority
- JP
- Japan
- Prior art keywords
- oxo
- piperidin
- dimethoxyphenyl
- pyrrolo
- pyrimidine
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 claims description 567
- -1 -C (O) NH 2 Chemical group 0.000 claims description 514
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 248
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 199
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 116
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 108
- 229910052739 hydrogen Inorganic materials 0.000 claims description 89
- 239000001257 hydrogen Substances 0.000 claims description 83
- 125000003545 alkoxy group Chemical group 0.000 claims description 82
- 150000003839 salts Chemical class 0.000 claims description 76
- 239000011737 fluorine Chemical group 0.000 claims description 71
- 229910052731 fluorine Chemical group 0.000 claims description 71
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 59
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 57
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 54
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical group 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 239000000460 chlorine Chemical group 0.000 claims description 26
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 229910052801 chlorine Inorganic materials 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 23
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 21
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 19
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 19
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 18
- 150000002431 hydrogen Chemical group 0.000 claims description 18
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 16
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 16
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 16
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 15
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 11
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 11
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 11
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 11
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 11
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 150000001721 carbon Chemical group 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 9
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical compound C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 claims description 8
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 8
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 5
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 3
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- GRILGPUHRHEJEX-UHFFFAOYSA-N NC(=O)c1cnc2cnc[nH]c12 Chemical compound NC(=O)c1cnc2cnc[nH]c12 GRILGPUHRHEJEX-UHFFFAOYSA-N 0.000 claims description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 2
- 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 8
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 8
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 claims 4
- 239000003119 guanylate cyclase activator Substances 0.000 claims 4
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 claims 4
- 208000030090 Acute Disease Diseases 0.000 claims 3
- 208000014085 Chronic respiratory disease Diseases 0.000 claims 3
- 230000001154 acute effect Effects 0.000 claims 3
- 239000002671 adjuvant Substances 0.000 claims 3
- 229940124125 5 Lipoxygenase inhibitor Drugs 0.000 claims 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 2
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims 2
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 2
- 229930003316 Vitamin D Natural products 0.000 claims 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims 2
- 239000000048 adrenergic agonist Substances 0.000 claims 2
- 229940126157 adrenergic receptor agonist Drugs 0.000 claims 2
- 239000003146 anticoagulant agent Substances 0.000 claims 2
- 229940127219 anticoagulant drug Drugs 0.000 claims 2
- 239000002876 beta blocker Substances 0.000 claims 2
- 229940097320 beta blocking agent Drugs 0.000 claims 2
- 230000003115 biocidal effect Effects 0.000 claims 2
- 239000000480 calcium channel blocker Substances 0.000 claims 2
- 239000000812 cholinergic antagonist Substances 0.000 claims 2
- 239000003246 corticosteroid Substances 0.000 claims 2
- 230000006806 disease prevention Effects 0.000 claims 2
- 239000002934 diuretic Substances 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 239000002308 endothelin receptor antagonist Substances 0.000 claims 2
- 229960001123 epoprostenol Drugs 0.000 claims 2
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 claims 2
- 239000000938 histamine H1 antagonist Substances 0.000 claims 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims 2
- 229960003444 immunosuppressant agent Drugs 0.000 claims 2
- 230000001861 immunosuppressant effect Effects 0.000 claims 2
- 239000003018 immunosuppressive agent Substances 0.000 claims 2
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims 2
- 239000003580 lung surfactant Substances 0.000 claims 2
- 229960003073 pirfenidone Drugs 0.000 claims 2
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 229960004617 sapropterin Drugs 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 235000019166 vitamin D Nutrition 0.000 claims 2
- 239000011710 vitamin D Substances 0.000 claims 2
- 150000003710 vitamin D derivatives Chemical class 0.000 claims 2
- 229940046008 vitamin d Drugs 0.000 claims 2
- LTMHDMANZUZIPE-UHFFFAOYSA-N 3-[3-[5-[5-(4,5-dihydroxy-6-methyloxan-2-yl)oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-12,14-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]-2h-furan-5-one Chemical compound C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 claims 1
- 206010006458 Bronchitis chronic Diseases 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- 201000003883 Cystic fibrosis Diseases 0.000 claims 1
- 206010014561 Emphysema Diseases 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 208000029523 Interstitial Lung disease Diseases 0.000 claims 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims 1
- 208000006673 asthma Diseases 0.000 claims 1
- 239000012752 auxiliary agent Substances 0.000 claims 1
- 206010006451 bronchitis Diseases 0.000 claims 1
- 208000007451 chronic bronchitis Diseases 0.000 claims 1
- 229960001334 corticosteroids Drugs 0.000 claims 1
- 229940082657 digitalis glycosides Drugs 0.000 claims 1
- 230000001882 diuretic effect Effects 0.000 claims 1
- 229940030606 diuretics Drugs 0.000 claims 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims 1
- 229940066294 lung surfactant Drugs 0.000 claims 1
- 239000001294 propane Substances 0.000 claims 1
- 208000005069 pulmonary fibrosis Diseases 0.000 claims 1
- 208000002815 pulmonary hypertension Diseases 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 783
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 438
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 382
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 245
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 230
- 239000000203 mixture Substances 0.000 description 209
- 239000012071 phase Substances 0.000 description 172
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 171
- 239000007787 solid Substances 0.000 description 141
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 131
- 239000000741 silica gel Substances 0.000 description 128
- 229910002027 silica gel Inorganic materials 0.000 description 128
- 235000017557 sodium bicarbonate Nutrition 0.000 description 115
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 115
- 239000000243 solution Substances 0.000 description 115
- 229920006395 saturated elastomer Polymers 0.000 description 114
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 112
- 239000012044 organic layer Substances 0.000 description 106
- 230000002829 reductive effect Effects 0.000 description 104
- 239000011541 reaction mixture Substances 0.000 description 89
- 238000010828 elution Methods 0.000 description 88
- 125000000217 alkyl group Chemical group 0.000 description 81
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 78
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 76
- 238000003818 flash chromatography Methods 0.000 description 76
- 239000012074 organic phase Substances 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 59
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 56
- 235000019341 magnesium sulphate Nutrition 0.000 description 56
- 238000004108 freeze drying Methods 0.000 description 54
- 239000000725 suspension Substances 0.000 description 53
- 239000003480 eluent Substances 0.000 description 49
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 46
- 238000002953 preparative HPLC Methods 0.000 description 44
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 239000002904 solvent Substances 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 23
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
- 238000000746 purification Methods 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 239000003960 organic solvent Substances 0.000 description 18
- GHJORKVUGKXEEY-UHFFFAOYSA-N 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-5h-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid Chemical compound N1=CN=C2C(C(=O)O)=CNC2=C1C1=C2OCOC2=CC=C1OCC1CC1 GHJORKVUGKXEEY-UHFFFAOYSA-N 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 150000002430 hydrocarbons Chemical group 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- SIXISCAJFLMLLM-UHFFFAOYSA-N 5-(cyclopropylmethoxy)-1,3-benzodioxole Chemical compound C=1C=C2OCOC2=CC=1OCC1CC1 SIXISCAJFLMLLM-UHFFFAOYSA-N 0.000 description 12
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 12
- 125000002436 D-phenylalanyl group Chemical group N[C@@H](C(=O)*)CC1=CC=CC=C1 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 125000003709 fluoroalkyl group Chemical group 0.000 description 10
- MXRIRQGCELJRSN-UHFFFAOYSA-N O.O.O.[Al] Chemical compound O.O.O.[Al] MXRIRQGCELJRSN-UHFFFAOYSA-N 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
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| GB9306703D0 (en) | 1993-03-31 | 1993-05-26 | Fisons Plc | Inhalation device |
| IL111194A (en) | 1993-10-08 | 1998-02-08 | Fisons Plc | Process for the production of medicament formulations |
| SK283270B6 (sk) * | 1997-01-15 | 2003-04-01 | Altana Pharma Ag | Ftalazinóny, farmaceutické prostriedky s ich obsahom a ich použitie |
| SI1070056T1 (en) * | 1998-03-14 | 2004-12-31 | Altana Pharma Ag | Phthalazinone pde iii/iv inhibitors |
| ATE234604T1 (de) | 1998-08-04 | 2003-04-15 | Jago Res Ag | Medizinische aerosolformulierungen |
| US6397838B1 (en) | 1998-12-23 | 2002-06-04 | Battelle Pulmonary Therapeutics, Inc. | Pulmonary aerosol delivery device and method |
| DE60030103T2 (de) | 1999-04-23 | 2007-02-08 | Ventaira Pharmaceuticals, Inc., Columbus | Elektrostatisches versprühen mit transfer- hoher masse |
| EP1194244B1 (en) | 1999-04-23 | 2005-12-21 | Battelle Memorial Institute | Directionally controlled ehd aerosol sprayer |
| CN1471515A (zh) * | 2000-06-05 | 2004-01-28 | ��̹��ҽҩ��˾ | 作为β2-肾上腺素受体激动剂及PDE-4抑制剂的有效的化合物 |
| CN1635870A (zh) | 2000-10-09 | 2005-07-06 | 3M创新有限公司 | 药用气雾剂制剂 |
| NZ527424A (en) | 2001-02-15 | 2005-02-25 | Altana Pharma Ag | Phthalayinone-piperidino-derivatives as PDE4 inhibitors |
| EP1385848A2 (en) | 2001-04-25 | 2004-02-04 | ALTANA Pharma AG | Phtalazinones derivatives useful as pde4/7 inhibitors |
| US20060167001A1 (en) * | 2002-08-10 | 2006-07-27 | Sterk Jan G | Pyridazinone-derivatives as pde4 inhibitors |
| WO2004018449A1 (en) | 2002-08-10 | 2004-03-04 | Altana Pharma Ag | Piperidine-derivatives as pde4 inhibitors |
| HRP20050198A2 (hr) | 2002-08-10 | 2006-04-30 | Altana Pharma Ag | Piperidin-piridazoni i ftalazoni kao inhibitori pde4 |
| PL378247A1 (pl) * | 2003-01-14 | 2006-03-20 | Altana Pharma Ag | Inhibitory PDE4 w terapii nowotworów komórek limfoidalnych |
| EP1716133B1 (en) | 2004-02-04 | 2008-03-26 | Nycomed GmbH | 2-(piperidin-4-yl)-4,5-dihydro-2h-pyridazin-3-one derivatives as pde4 inhibitors |
| EP1720854A1 (en) | 2004-02-04 | 2006-11-15 | Altana Pharma AG | Phthalzinone derivatives as pde4 inhibitors |
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| AR077898A1 (es) * | 2009-08-26 | 2011-09-28 | Nycomed Gmbh | Metilpirrolopirimidincarboxamidas |
-
2012
- 2012-06-12 MX MX2013014888A patent/MX2013014888A/es not_active Application Discontinuation
- 2012-06-12 PH PH1/2013/502546A patent/PH12013502546A1/en unknown
- 2012-06-12 CA CA2837248A patent/CA2837248A1/en not_active Abandoned
- 2012-06-12 BR BR112013031791A patent/BR112013031791A2/pt not_active IP Right Cessation
- 2012-06-12 EA EA201400001A patent/EA023713B1/ru not_active IP Right Cessation
- 2012-06-12 KR KR1020147000392A patent/KR20140037195A/ko not_active Withdrawn
- 2012-06-12 WO PCT/EP2012/061084 patent/WO2012171900A1/en not_active Ceased
- 2012-06-12 JP JP2014515155A patent/JP5980318B2/ja not_active Expired - Fee Related
- 2012-06-12 ES ES12728453.7T patent/ES2564882T3/es active Active
- 2012-06-12 US US14/125,187 patent/US20140112945A1/en not_active Abandoned
- 2012-06-12 EP EP12728453.7A patent/EP2721030B1/en active Active
- 2012-06-12 AU AU2012269133A patent/AU2012269133A1/en not_active Abandoned
- 2012-06-12 PE PE2013002801A patent/PE20140648A1/es not_active Application Discontinuation
- 2012-06-12 AR ARP120102088A patent/AR086915A1/es unknown
- 2012-06-12 CN CN201280028413.XA patent/CN103582644B/zh not_active Expired - Fee Related
-
2013
- 2013-10-29 TN TNP2013000439A patent/TN2013000439A1/fr unknown
- 2013-12-11 EC ECSP13013076 patent/ECSP13013076A/es unknown
- 2013-12-11 CL CL2013003556A patent/CL2013003556A1/es unknown
- 2013-12-11 DO DO2013000298A patent/DOP2013000298A/es unknown
- 2013-12-13 CR CR20130656A patent/CR20130656A/es unknown
-
2014
- 2014-01-10 CO CO14004200A patent/CO6852074A2/es not_active Application Discontinuation
- 2014-01-16 MA MA36689A patent/MA35269B1/fr unknown
-
2015
- 2015-12-03 US US14/958,141 patent/US20160108049A1/en not_active Abandoned
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