TWI499591B - 雙環嘧啶化合物 - Google Patents

雙環嘧啶化合物 Download PDF

Info

Publication number: TWI499591B
Authority: TW; Taiwan
Prior art keywords: dihydro; mmol; ylamino; pyrimidin; indol
Prior art date: 2013-01-11

Application number

TW102149122A

Other languages

English (en)

Chinese (zh)

Other versions

TW201437209A (zh

Inventor

Lance Allen Pfeifer

Spencer Brian Jones

Thomas James Beauchamp

Yen Dao

Bryan Hurst Norman

Original Assignee

Lilly Co Eli

Priority date (The priority date 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 date listed.)

2013-01-11

Filing date

2013-12-30

Publication date

2015-09-11

2013-12-30 Application filed by Lilly Co Eli filed Critical Lilly Co Eli

2014-10-01 Publication of TW201437209A publication Critical patent/TW201437209A/zh

2015-09-11 Application granted granted Critical

2015-09-11 Publication of TWI499591B publication Critical patent/TWI499591B/zh

Links

-1 Bicyclic pyrimidine compounds Chemical class 0.000 title description 25
150000001875 compounds Chemical class 0.000 claims description 118
150000003839 salts Chemical class 0.000 claims description 37
238000011282 treatment Methods 0.000 claims description 20
208000002193 Pain Diseases 0.000 claims description 18
201000008482 osteoarthritis Diseases 0.000 claims description 12
IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 10
238000004519 manufacturing process Methods 0.000 claims description 6
CSVAWVYVYHPRPU-UHFFFAOYSA-N N1C(CC2=CC=CC=C12)NC=1N=CC2=C(N1)CN(C2)C(COCCC=2N=NNC2)=O Chemical compound N1C(CC2=CC=CC=C12)NC=1N=CC2=C(N1)CN(C2)C(COCCC=2N=NNC2)=O CSVAWVYVYHPRPU-UHFFFAOYSA-N 0.000 claims description 5
239000003814 drug Substances 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
239000003085 diluting agent Substances 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
239000000546 pharmaceutical excipient Substances 0.000 claims description 2
238000002560 therapeutic procedure Methods 0.000 claims description 2
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 261
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 226
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
239000000243 solution Substances 0.000 description 105
235000019439 ethyl acetate Nutrition 0.000 description 95
230000015572 biosynthetic process Effects 0.000 description 89
238000003786 synthesis reaction Methods 0.000 description 85
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 80
239000000203 mixture Substances 0.000 description 70
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
238000002360 preparation method Methods 0.000 description 60
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
239000011541 reaction mixture Substances 0.000 description 37
239000000284 extract Substances 0.000 description 36
238000004440 column chromatography Methods 0.000 description 35
AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 31
WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 30
239000010410 layer Substances 0.000 description 30
239000012043 crude product Substances 0.000 description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
238000006243 chemical reaction Methods 0.000 description 26
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
239000007787 solid Substances 0.000 description 24
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
238000003756 stirring Methods 0.000 description 21
238000000034 method Methods 0.000 description 20
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 19
239000002904 solvent Substances 0.000 description 19
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 17
125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 16
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
102000005731 Glucose-6-phosphate isomerase Human genes 0.000 description 14
108010070600 Glucose-6-phosphate isomerase Proteins 0.000 description 14
230000003305 autocrine Effects 0.000 description 14
230000004899 motility Effects 0.000 description 14
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 13
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
239000012267 brine Substances 0.000 description 12
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 10
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 9
239000003112 inhibitor Substances 0.000 description 9
RESRVDFIMBPWDM-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine Chemical compound C1NCCC2=NC(NC3CC4=CC=CC=C4C3)=NC=C21 RESRVDFIMBPWDM-UHFFFAOYSA-N 0.000 description 9
239000012044 organic layer Substances 0.000 description 9
230000008569 process Effects 0.000 description 9
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 8
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
239000000047 product Substances 0.000 description 8
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 7
229960001231 choline Drugs 0.000 description 7
239000001257 hydrogen Substances 0.000 description 7
229910052739 hydrogen Inorganic materials 0.000 description 7
230000001404 mediated effect Effects 0.000 description 7
229910052938 sodium sulfate Inorganic materials 0.000 description 7
235000011152 sodium sulphate Nutrition 0.000 description 7
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
239000006260 foam Substances 0.000 description 6
229910052943 magnesium sulfate Inorganic materials 0.000 description 6
235000019341 magnesium sulphate Nutrition 0.000 description 6
IXAXVYMFIJYCSG-UHFFFAOYSA-N pentan-1-one Chemical compound CCCC[C]=O IXAXVYMFIJYCSG-UHFFFAOYSA-N 0.000 description 6
RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 5
MEOFLLJBCMLPOK-UHFFFAOYSA-N 3-azido-2,2-dimethylundecane Chemical compound CC(C(CCCCCCCC)N=[N+]=[N-])(C)C MEOFLLJBCMLPOK-UHFFFAOYSA-N 0.000 description 5
CYAAYHGVCOJQTP-UHFFFAOYSA-N CC(CCCCCCCCC)(C)C.[N-]=[N+]=[N-] Chemical compound CC(CCCCCCCCC)(C)C.[N-]=[N+]=[N-] CYAAYHGVCOJQTP-UHFFFAOYSA-N 0.000 description 5
KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 5
239000002253 acid Substances 0.000 description 5
150000001412 amines Chemical class 0.000 description 5
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
238000011534 incubation Methods 0.000 description 5
230000005764 inhibitory process Effects 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
229910052707 ruthenium Inorganic materials 0.000 description 5
208000024891 symptom Diseases 0.000 description 5
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
DKFVEDKCRIZEEM-UHFFFAOYSA-N 3-(1h-imidazol-5-yl)propan-1-ol Chemical compound OCCCC1=CNC=N1 DKFVEDKCRIZEEM-UHFFFAOYSA-N 0.000 description 4
229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
VIBWIDAXCFYRFX-UHFFFAOYSA-N O=C(COCCC1=CNN=N1)N(CC1)CC2=C1N=C(NC1NC3=CC=CC=C3C1)N=C2 Chemical compound O=C(COCCC1=CNN=N1)N(CC1)CC2=C1N=C(NC1NC3=CC=CC=C3C1)N=C2 VIBWIDAXCFYRFX-UHFFFAOYSA-N 0.000 description 4
UTIHNMCZTVCQCH-UHFFFAOYSA-N OC1=C(C(=O)O)N=NN1CC1=CC=CC=C1 Chemical compound OC1=C(C(=O)O)N=NN1CC1=CC=CC=C1 UTIHNMCZTVCQCH-UHFFFAOYSA-N 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 4
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
238000003556 assay Methods 0.000 description 4
239000012131 assay buffer Substances 0.000 description 4
230000001684 chronic effect Effects 0.000 description 4
LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 4
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
229910000027 potassium carbonate Inorganic materials 0.000 description 4
UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 4
229910052708 sodium Inorganic materials 0.000 description 4
239000011734 sodium Substances 0.000 description 4
239000012312 sodium hydride Substances 0.000 description 4
229910000104 sodium hydride Inorganic materials 0.000 description 4
125000001424 substituent group Chemical group 0.000 description 4
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
HYLYCAORDRXIHX-UHFFFAOYSA-N 3-azido-2,2-dimethyldecane Chemical compound C(C)(C)(C)C(CCCCCCC)N=[N+]=[N-] HYLYCAORDRXIHX-UHFFFAOYSA-N 0.000 description 3
JJNHCVLGDXAMEW-UHFFFAOYSA-N 3-chloropropyl 2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C2CN(C(=O)OCCCCl)CC2=N1 JJNHCVLGDXAMEW-UHFFFAOYSA-N 0.000 description 3
UXIGAUJZNRUQSO-UHFFFAOYSA-N 3-chloropropyl 2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidine-6-carboxylate Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C(CN(C(=O)OCCCCl)CC2)C2=N1 UXIGAUJZNRUQSO-UHFFFAOYSA-N 0.000 description 3
SHHMZGODDGYBRU-UHFFFAOYSA-N 5-(1h-1,2,4-triazol-5-yl)pentanoic acid Chemical compound OC(=O)CCCCC1=NN=CN1 SHHMZGODDGYBRU-UHFFFAOYSA-N 0.000 description 3
JOMRZAVGSLQILC-UHFFFAOYSA-N 5-[3-[(2-methylpropan-2-yl)oxycarbonyl]imidazol-4-yl]pentanoic acid Chemical compound CC(C)(C)OC(=O)N1C=NC=C1CCCCC(O)=O JOMRZAVGSLQILC-UHFFFAOYSA-N 0.000 description 3
108010000659 Choline oxidase Proteins 0.000 description 3
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 3
102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 description 3
108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 description 3
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
VOLGDVHQHHLZNI-UHFFFAOYSA-N OC1=CN=NN1CC1=CC=CC=C1 Chemical compound OC1=CN=NN1CC1=CC=CC=C1 VOLGDVHQHHLZNI-UHFFFAOYSA-N 0.000 description 3
230000001154 acute effect Effects 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
239000012298 atmosphere Substances 0.000 description 3
UDLLFLQFQMACJB-UHFFFAOYSA-N azidomethylbenzene Chemical compound [N-]=[N+]=NCC1=CC=CC=C1 UDLLFLQFQMACJB-UHFFFAOYSA-N 0.000 description 3
125000004744 butyloxycarbonyl group Chemical group 0.000 description 3
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 3
KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
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208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
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IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
229910000041 hydrogen chloride Inorganic materials 0.000 description 3
239000000463 material Substances 0.000 description 3
MDUPGSVZADYURN-UHFFFAOYSA-N methyl 5-(1h-1,2,4-triazol-5-yl)pentanoate Chemical compound COC(=O)CCCCC1=NN=CN1 MDUPGSVZADYURN-UHFFFAOYSA-N 0.000 description 3
RAMSXSXXFQDNLE-UHFFFAOYSA-N n-pent-4-ynylimidazole-1-carboxamide Chemical compound C#CCCCNC(=O)N1C=CN=C1 RAMSXSXXFQDNLE-UHFFFAOYSA-N 0.000 description 3
208000004296 neuralgia Diseases 0.000 description 3
239000003921 oil Substances 0.000 description 3
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230000009467 reduction Effects 0.000 description 3
230000002829 reductive effect Effects 0.000 description 3
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MTBKGWHHOBJMHJ-UHFFFAOYSA-N tert-butyl imidazole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CN=C1 MTBKGWHHOBJMHJ-UHFFFAOYSA-N 0.000 description 3
NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 3
230000001225 therapeutic effect Effects 0.000 description 3
RBZRMBCLZMEYEH-UHFFFAOYSA-N 1h-pyrazol-1-ium-1-carboximidamide;chloride Chemical compound Cl.NC(=N)N1C=CC=N1 RBZRMBCLZMEYEH-UHFFFAOYSA-N 0.000 description 2
NMCUEAHFJHOFMQ-UHFFFAOYSA-N 2,3-dihydro-1H-indol-2-amine hydrochloride Chemical compound Cl.C1=CC=C2NC(N)CC2=C1 NMCUEAHFJHOFMQ-UHFFFAOYSA-N 0.000 description 2
NUYJLLQGQBOLRE-UHFFFAOYSA-N 2,3-dihydro-1h-indol-2-amine Chemical compound C1=CC=C2NC(N)CC2=C1 NUYJLLQGQBOLRE-UHFFFAOYSA-N 0.000 description 2
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GMGOBQAMJNTCPN-UHFFFAOYSA-N tert-butyl 2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound N1=C(Cl)N=C2CN(C(=O)OC(C)(C)C)CC2=C1 GMGOBQAMJNTCPN-UHFFFAOYSA-N 0.000 description 1
ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
GUKSBFFJBYAIJI-UHFFFAOYSA-N tert-butyl 5-(5-oxo-5-phenylmethoxypent-1-ynyl)imidazole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=NC=C1C#CCCC(=O)OCC1=CC=CC=C1 GUKSBFFJBYAIJI-UHFFFAOYSA-N 0.000 description 1
SGGIGUOZCHNGIW-UHFFFAOYSA-N tert-butyl N-[2-(2H-triazol-4-yl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCc1cn[nH]n1 SGGIGUOZCHNGIW-UHFFFAOYSA-N 0.000 description 1
RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
JDYFOQOAKDWNBE-UHFFFAOYSA-N tert-butyl n-but-3-ynyl-n-[2-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-2-oxoethyl]carbamate Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C(CN(C(=O)CN(CCC#C)C(=O)OC(C)(C)C)CC2)C2=N1 JDYFOQOAKDWNBE-UHFFFAOYSA-N 0.000 description 1
VBUWHAJDOUIJMV-UHFFFAOYSA-N tert-butyl n-propylcarbamate Chemical compound CCCNC(=O)OC(C)(C)C VBUWHAJDOUIJMV-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
238000010257 thawing Methods 0.000 description 1
229910052723 transition metal Inorganic materials 0.000 description 1
150000003624 transition metals Chemical class 0.000 description 1
GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1

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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Rheumatology (AREA)
Pain & Pain Management (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Immunology (AREA)
Orthopedic Medicine & Surgery (AREA)
Physical Education & Sports Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Epidemiology (AREA)

TW102149122A 2013-01-11 2013-12-30 雙環嘧啶化合物 TWI499591B (zh)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US201361751363P	2013-01-11	2013-01-11
US201361777201P	2013-03-12	2013-03-12

Publications (2)

Publication Number	Publication Date
TW201437209A TW201437209A (zh)	2014-10-01
TWI499591B true TWI499591B (zh)	2015-09-11

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TW102149122A TWI499591B (zh)	2013-01-11	2013-12-30	雙環嘧啶化合物

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Country	Link
US (1)	US8969555B2 (2)
EP (1)	EP2943494B1 (2)
JP (1)	JP6285461B2 (2)
KR (1)	KR101757997B1 (2)
CN (1)	CN104903327B (2)
AU (1)	AU2014205642B2 (2)
BR (1)	BR112015015812A2 (2)
CA (1)	CA2893253C (2)
EA (1)	EA025106B1 (2)
ES (1)	ES2636248T3 (2)
MX (1)	MX2015008971A (2)
TW (1)	TWI499591B (2)
WO (1)	WO2014110000A1 (2)

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US20220081400A1 (en) *	2018-07-16	2022-03-17	The Scripps Research Institute	Opioid haptens, conjugates, vaccines, and methods of generating antibodies
WO2020156459A1 (zh)	2019-02-01	2020-08-06	湖北生物医药产业技术研究院有限公司	吡咯并嘧啶衍生物及其用途
AU2020342202B2 (en) *	2019-09-06	2023-07-06	Wuhan Humanwell Innovative Drug Research and Development Center Limited Company	Pyrimidine compound and preparation method therefor
KR20220100858A (ko) *	2019-09-17	2022-07-18	비알 - 알&디 인베스트먼츠, 에스.에이.	치환된 이미다졸 카르복사미드, 및 질병의 치료에서의 이의 용도
CN112778334B (zh) *	2019-11-07	2022-04-15	广州市恒诺康医药科技有限公司	芳杂环化合物、其药物组合物及其应用
TW202128682A (zh) *	2019-12-11	2021-08-01	大陸商四川海思科製藥有限公司	含氮雜環類自分泌運動因子抑制劑及其組合物和用途
CN113943296B (zh) *	2020-07-16	2025-07-04	武汉人福创新药物研发中心有限公司	吡咯并嘧啶衍生物及其应用
CN113943295B (zh) *	2020-07-16	2025-08-12	武汉人福创新药物研发中心有限公司	吡咯并嘧啶类化合物及其用途
US20230312582A1 (en) *	2020-07-28	2023-10-05	Wuhan Humanwell Innovative Drug Research and Development Center Limited Company	Salts Of Nitrogen-Containing Heterocyclic Compound, And Solid Forms Of Salts, Pharmaceutical Composition And Use Thereof
TW202214644A (zh) *	2020-07-28	2022-04-16	大陸商武漢人福創新藥物研發中心有限公司	含氮雜環化合物的固體形式及其藥物組合物和用途

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- 2013-12-30 TW TW102149122A patent/TWI499591B/zh active
2014
- 2014-01-07 CN CN201480004482.6A patent/CN104903327B/zh not_active Expired - Fee Related
- 2014-01-07 KR KR1020157018295A patent/KR101757997B1/ko not_active Expired - Fee Related
- 2014-01-07 CA CA2893253A patent/CA2893253C/en not_active Expired - Fee Related
- 2014-01-07 BR BR112015015812A patent/BR112015015812A2/pt not_active IP Right Cessation
- 2014-01-07 EP EP14702336.0A patent/EP2943494B1/en active Active
- 2014-01-07 AU AU2014205642A patent/AU2014205642B2/en not_active Ceased
- 2014-01-07 ES ES14702336.0T patent/ES2636248T3/es active Active
- 2014-01-07 MX MX2015008971A patent/MX2015008971A/es unknown
- 2014-01-07 JP JP2015552726A patent/JP6285461B2/ja not_active Expired - Fee Related
- 2014-01-07 WO PCT/US2014/010400 patent/WO2014110000A1/en not_active Ceased
- 2014-01-07 EA EA201591098A patent/EA025106B1/ru not_active IP Right Cessation
- 2014-01-07 US US14/148,775 patent/US8969555B2/en active Active

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Also Published As

Publication number	Publication date
AU2014205642A1 (en)	2015-07-02
TW201437209A (zh)	2014-10-01
EP2943494A1 (en)	2015-11-18
CN104903327A (zh)	2015-09-09
CA2893253A1 (en)	2014-07-17
CN104903327B (zh)	2016-09-07
US20140200231A1 (en)	2014-07-17
JP6285461B2 (ja)	2018-02-28
KR20150092761A (ko)	2015-08-13
EP2943494B1 (en)	2017-02-22
KR101757997B1 (ko)	2017-07-13
US8969555B2 (en)	2015-03-03
MX2015008971A (es)	2015-09-28
JP2016505010A (ja)	2016-02-18
EA201591098A1 (ru)	2015-11-30
ES2636248T3 (es)	2017-10-05
EA025106B1 (ru)	2016-11-30
AU2014205642B2 (en)	2016-02-25
WO2014110000A1 (en)	2014-07-17
CA2893253C (en)	2017-11-28
BR112015015812A2 (pt)	2017-07-11

Publication	Publication Date	Title
TWI499591B (zh)	2015-09-11	雙環嘧啶化合物
JP6133491B2 (ja)	2017-05-24	ジヒドロピリドピリミジン化合物
JP6611799B2 (ja)	2019-11-27	新規化合物
CA2900956C (en)	2017-11-28	Imidazo pyridine compounds
US9029392B2 (en)	2015-05-12	Quinoline derivatives as kinase inhibitors
JP2017528504A (ja)	2017-09-28	線維性疾患などの治療のためのαｖβ６インテグリンアンタゴニストとしてのナフチリジン誘導体
CN103534258A (zh)	2014-01-22	酪氨酸激酶抑制剂
JP2011526295A (ja)	2011-10-06	５員および６員複素環化合物
EP1347980A1 (en)	2003-10-01	Compounds specific to adenosine-a1,-a2a, and- a3-receptor and uses thereof
AU2002248151A1 (en)	2003-02-13	Compounds specific to adenosine A1, A2A, and A3 receptor and uses thereof
WO2017092413A1 (zh)	2017-06-08	一种二氨基嘧啶化合物及包含该化合物的组合物
JP7413346B2 (ja)	2024-01-15	ピロロピラゾール誘導体
WO2024051720A1 (zh)	2024-03-14	靶向抑制clk2的5-吡啶-1h-吲唑类化合物及其应用
EA043636B1 (ru)	2023-06-07	АНТИБАКТЕРИАЛЬНЫЕ 3,4-ДИГИДРО-1Н-[1,8]НАФТИРИДИНОНЫ, ЗАМЕЩЕННЫЕ ЦИКЛОПЕНТА[с]ПИРРОЛОМ