JP5208962B2 - 二環式ピリミジノンおよびその使用 - Google Patents
二環式ピリミジノンおよびその使用 Download PDFInfo
- Publication number
- JP5208962B2 JP5208962B2 JP2009541695A JP2009541695A JP5208962B2 JP 5208962 B2 JP5208962 B2 JP 5208962B2 JP 2009541695 A JP2009541695 A JP 2009541695A JP 2009541695 A JP2009541695 A JP 2009541695A JP 5208962 B2 JP5208962 B2 JP 5208962B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- hydroxy
- oxo
- carboxylic acid
- 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.)
- Expired - Fee Related
Links
- -1 Bicyclic pyrimidinones Chemical class 0.000 title claims description 76
- 150000001875 compounds Chemical class 0.000 claims description 171
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 32
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 208000036142 Viral infection Diseases 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- 230000009385 viral infection Effects 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 7
- 208000031886 HIV Infections Diseases 0.000 claims description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 208000037357 HIV infectious disease Diseases 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 241000287463 Phalacrocorax Species 0.000 claims 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 235
- 238000000034 method Methods 0.000 description 209
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 195
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 147
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
- 239000000047 product Substances 0.000 description 131
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
- 238000004128 high performance liquid chromatography Methods 0.000 description 99
- 239000000203 mixture Substances 0.000 description 74
- 239000000460 chlorine Substances 0.000 description 66
- 239000000243 solution Substances 0.000 description 57
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 52
- 230000008569 process Effects 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
- 238000004519 manufacturing process Methods 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 36
- 239000011734 sodium Substances 0.000 description 36
- 239000007787 solid Substances 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- IXHNFOOSLAWRBQ-UHFFFAOYSA-N (3,4-dichlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C(Cl)=C1 IXHNFOOSLAWRBQ-UHFFFAOYSA-N 0.000 description 22
- 238000001914 filtration Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000000872 buffer Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 14
- 229940002612 prodrug Drugs 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 13
- 230000035892 strand transfer Effects 0.000 description 13
- 241000725303 Human immunodeficiency virus Species 0.000 description 12
- 102100034343 Integrase Human genes 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 108010061833 Integrases Proteins 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 108020004414 DNA Proteins 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 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 8
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 108010002459 HIV Integrase Proteins 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- UQBKNQILGHFDMC-UHFFFAOYSA-N dichloro(phenyl)methanamine Chemical compound NC(Cl)(Cl)C1=CC=CC=C1 UQBKNQILGHFDMC-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 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 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- NKGXGEHGPYWBDK-BQYQJAHWSA-N dimethyl (e)-2,3-diacetyloxybut-2-enedioate Chemical compound COC(=O)C(\OC(C)=O)=C(/OC(C)=O)C(=O)OC NKGXGEHGPYWBDK-BQYQJAHWSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- URRAAZTVXPABJD-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]pyrimidine-2-carboxamide Chemical compound C1=CC(F)=CC=C1CNC(=O)C1=NC=CC=N1 URRAAZTVXPABJD-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 230000001566 pro-viral effect Effects 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 description 4
- FQDUAJNUWPKMQN-UHFFFAOYSA-N 3-hydroxy-4-oxo-7-[(2,2,2-trifluoroacetyl)amino]pyrido[1,2-a]pyrimidine-2-carboxylic acid Chemical compound C1=CC(NC(=O)C(F)(F)F)=CN2C(=O)C(O)=C(C(=O)O)N=C21 FQDUAJNUWPKMQN-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 241001494479 Pecora Species 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 229960003586 elvitegravir Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 229940124524 integrase inhibitor Drugs 0.000 description 4
- 239000002850 integrase inhibitor Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 229960004742 raltegravir Drugs 0.000 description 4
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 description 3
- VUDWKWROVMHUAY-UHFFFAOYSA-N 3-hydroxy-7-methyl-2-(5-phenyl-1,3-oxazol-2-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound OC=1C(=O)N2C=C(C)C=CC2=NC=1C(O1)=NC=C1C1=CC=CC=C1 VUDWKWROVMHUAY-UHFFFAOYSA-N 0.000 description 3
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 3
- ACYSKLGOADDKAI-UHFFFAOYSA-N 5-morpholin-4-ylpyridin-2-amine Chemical compound C1=NC(N)=CC=C1N1CCOCC1 ACYSKLGOADDKAI-UHFFFAOYSA-N 0.000 description 3
- LSONAJPRAKFMHX-UHFFFAOYSA-N 7-[(3-chloro-2-fluorophenyl)methyl]-3-hydroxy-4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid Chemical compound C=1N2C(=O)C(O)=C(C(=O)O)N=C2C=CC=1CC1=CC=CC(Cl)=C1F LSONAJPRAKFMHX-UHFFFAOYSA-N 0.000 description 3
- TXKBNPIGEGMVST-UHFFFAOYSA-N 7-chloro-n-[(4-fluorophenyl)methyl]-3-hydroxy-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound N1=C2C=CC(Cl)=CN2C(=O)C(O)=C1C(=O)NCC1=CC=C(F)C=C1 TXKBNPIGEGMVST-UHFFFAOYSA-N 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- QZUIWCRNRQXGNQ-UHFFFAOYSA-N COC(C(N=C(C=CC(N1CCOCC1)=C1)N1C1=O)=C1O)=O Chemical compound COC(C(N=C(C=CC(N1CCOCC1)=C1)N1C1=O)=C1O)=O QZUIWCRNRQXGNQ-UHFFFAOYSA-N 0.000 description 3
- 239000005973 Carvone Substances 0.000 description 3
- 241000283086 Equidae Species 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- XCULJYKHRJHSSE-UHFFFAOYSA-N N-[(3,4-dichlorophenyl)methyl]pyrimidine-2-carboxamide Chemical compound ClC=1C=C(CNC(=O)C2=NC=CC=N2)C=CC1Cl XCULJYKHRJHSSE-UHFFFAOYSA-N 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
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- AAGMZFHZMIWMAH-UHFFFAOYSA-N methyl 3-[tert-butyl(dimethyl)silyl]oxy-7-iodo-4-oxopyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C1=CC(I)=CN2C(=O)C(O[Si](C)(C)C(C)(C)C)=C(C(=O)OC)N=C21 AAGMZFHZMIWMAH-UHFFFAOYSA-N 0.000 description 1
- URCPKQIWJAHFIE-UHFFFAOYSA-N methyl 3-acetyloxy-4-oxo-10-(2-piperazin-1-ylethyl)pyrimido[1,2-a]benzimidazole-2-carboxylate Chemical compound C12=CC=CC=C2N2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CCN1CCNCC1 URCPKQIWJAHFIE-UHFFFAOYSA-N 0.000 description 1
- SNLPYJHBTDXBHM-UHFFFAOYSA-N methyl 3-bromo-6-hydroxy-7-oxo-1h-pyrazolo[1,5-a]pyrimidine-5-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)N=C2C(Br)=CNN21 SNLPYJHBTDXBHM-UHFFFAOYSA-N 0.000 description 1
- RWKXREANMRDGBP-UHFFFAOYSA-N methyl 3-cyano-6-hydroxy-7-oxo-1h-pyrazolo[1,5-a]pyrimidine-5-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)N=C2C(C#N)=CNN21 RWKXREANMRDGBP-UHFFFAOYSA-N 0.000 description 1
- OCFZUWWBQKLHLV-UHFFFAOYSA-N methyl 3-hydroxy-10-morpholin-4-yl-4-oxo-6h-pyrimido[1,2-b]indazole-2-carboxylate Chemical compound C1=CC=C2NN3C(=O)C(O)=C(C(=O)OC)N=C3C2=C1N1CCOCC1 OCFZUWWBQKLHLV-UHFFFAOYSA-N 0.000 description 1
- PBBIAXDLQWMXAV-UHFFFAOYSA-N methyl 3-hydroxy-4-oxo-6h-pyrimido[1,2-b]indazole-2-carboxylate Chemical compound C12=CC=CC=C2NN2C1=NC(C(=O)OC)=C(O)C2=O PBBIAXDLQWMXAV-UHFFFAOYSA-N 0.000 description 1
- DKAVFQFNEGXHNC-UHFFFAOYSA-N methyl 3-hydroxy-4-oxo-7-piperidin-1-ylpyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C=1N2C(=O)C(O)=C(C(=O)OC)N=C2C=CC=1N1CCCCC1 DKAVFQFNEGXHNC-UHFFFAOYSA-N 0.000 description 1
- UMQIBBMRUPMYGM-UHFFFAOYSA-N methyl 3-hydroxy-4-oxopyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C1=CC=CN2C(=O)C(O)=C(C(=O)OC)N=C21 UMQIBBMRUPMYGM-UHFFFAOYSA-N 0.000 description 1
- FDKCHZTZLLYDST-UHFFFAOYSA-N methyl 3-hydroxy-4-oxopyrimido[1,2-b][1,2]benzoxazole-2-carboxylate Chemical compound C12=CC=CC=C2ON2C1=NC(C(=O)OC)=C(O)C2=O FDKCHZTZLLYDST-UHFFFAOYSA-N 0.000 description 1
- OGZXKGFOTRIXGD-UHFFFAOYSA-N methyl 3-hydroxy-6-methyl-10-morpholin-4-yl-4-oxopyrimido[1,2-b]indazole-2-carboxylate Chemical compound C1=CC=C2N(C)N3C(=O)C(O)=C(C(=O)OC)N=C3C2=C1N1CCOCC1 OGZXKGFOTRIXGD-UHFFFAOYSA-N 0.000 description 1
- XJHOUZCUSHZUJA-UHFFFAOYSA-N methyl 3-hydroxy-6-methyl-4-oxopyrimido[1,2-b]indazole-2-carboxylate Chemical compound C12=CC=CC=C2N(C)N2C1=NC(C(=O)OC)=C(O)C2=O XJHOUZCUSHZUJA-UHFFFAOYSA-N 0.000 description 1
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- CPXYMXNMRWTCPM-UHFFFAOYSA-N methyl 6-(2,2-dimethylpropanoyloxy)-5-oxo-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxylate Chemical compound O=C1C(OC(=O)C(C)(C)C)=C(C(=O)OC)N=C2SC=CN21 CPXYMXNMRWTCPM-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| AU2006907283A AU2006907283A0 (en) | 2006-12-22 | Bicyclic pyrimidinones and uses thereof | |
| AU2006907283 | 2006-12-22 | ||
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| AU2007904114A AU2007904114A0 (en) | 2007-07-31 | Bicyclic pyrimidinones and uses thereof (4) | |
| AU2007904114 | 2007-07-31 | ||
| PCT/AU2007/001980 WO2008077188A1 (en) | 2006-12-22 | 2007-12-21 | Bicyclic pyrimidinones and uses thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011526248A (ja) * | 2008-07-02 | 2011-10-06 | アベキサ・リミテッド | 抗ウイルス特性を有する化合物 |
| JP2011526246A (ja) * | 2008-07-02 | 2011-10-06 | アベキサ・リミテッド | チアゾピリミジノンおよびその使用 |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2291377B1 (en) * | 2008-07-02 | 2015-02-18 | Avexa Limited | Imidazopyrimidinones and uses thereof |
| CN102336751A (zh) * | 2010-07-16 | 2012-02-01 | 爱维艾珂瑟有限公司 | 新型抗病毒剂 |
| KR102323515B1 (ko) | 2013-09-12 | 2021-11-05 | 얀센 바이오파마, 인코퍼레이트. | 아자-피리돈 화합물 및 이의 용도 |
| EP3082820B1 (en) * | 2013-12-19 | 2022-07-20 | PTC Therapeutics, Inc. | Methods for modulating the amount of rna transcripts |
| MX383931B (es) | 2015-03-11 | 2025-03-14 | Janssen Biopharma Inc | Compuestos de aza-piridona y usos de estos. |
| US10668171B2 (en) | 2015-05-30 | 2020-06-02 | Ptc Therapeutics, Inc. | Methods for modulating RNA splicing |
| CN113750101A (zh) | 2015-12-10 | 2021-12-07 | Ptc医疗公司 | 用于治疗亨廷顿病的方法 |
| EA201991309A1 (ru) | 2016-11-28 | 2019-11-29 | Способы модуляции сплайсинга рнк | |
| US11407753B2 (en) | 2017-06-05 | 2022-08-09 | Ptc Therapeutics, Inc. | Compounds for treating Huntington's disease |
| CN111372611A (zh) | 2017-06-14 | 2020-07-03 | Ptc医疗公司 | 修饰rna剪接的方法 |
| EP3645121B8 (en) | 2017-06-28 | 2025-06-18 | PTC Therapeutics, Inc. | Methods for treating huntington's disease |
| CA3067591A1 (en) | 2017-06-28 | 2019-01-03 | Ptc Therapeutics, Inc. | Methods for treating huntington's disease |
| KR20210005559A (ko) | 2018-03-27 | 2021-01-14 | 피티씨 테라퓨틱스, 인크. | 헌팅턴병 치료 화합물 |
| US11685746B2 (en) | 2018-06-27 | 2023-06-27 | Ptc Therapeutics, Inc. | Heteroaryl compounds for treating Huntington's disease |
| WO2020005877A1 (en) | 2018-06-27 | 2020-01-02 | Ptc Therapeutics, Inc. | Heteroaryl compounds for treating huntington's disease |
| LT3814357T (lt) | 2018-06-27 | 2024-06-25 | Ptc Therapeutics, Inc. | Heterocikliniai ir heteroarilų junginiai, skirti hantingtono ligos gydymui |
| MX2022006700A (es) | 2019-12-02 | 2022-09-02 | Storm Therapeutics Ltd | Compuestos poliheterociclicos como inhibidores de mettl3. |
| US12070445B2 (en) * | 2021-08-27 | 2024-08-27 | Wisconsin Alumni Research Foundation | System and assay for monitoring production/release of membrane-lytic toxins in bacteria and compounds for modulating same |
Family Cites Families (7)
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|---|---|---|---|---|
| ES2233708T3 (es) | 2000-09-20 | 2005-06-16 | Schering Corporation | Imidazoles sustituidos como agonistas o antagonistas duales de la histamina h1 y la h3. |
| DE60329318D1 (de) | 2002-11-20 | 2009-10-29 | Japan Tobacco Inc | 4-oxochinolinverbindungen und deren verwendung als hiv-integrase-inhibitoren |
| AR046971A1 (es) | 2003-12-18 | 2006-01-04 | Tibotec Pharm Ltd | Aminobenzoimidazoles y benzoimidazoles como inhibidores de la replicacion del virus sincitial respiratorio |
| TW200526635A (en) | 2003-12-22 | 2005-08-16 | Shionogi & Co | Hydroxypyrimidinone derivative having HIV integrase inhibitory activity |
| WO2006040520A1 (en) | 2004-10-12 | 2006-04-20 | Astrazeneca Ab | Quinazoline derivatives |
| EP1866313A1 (en) * | 2005-03-31 | 2007-12-19 | Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. | Hiv integrase inhibitors |
| JP5094725B2 (ja) * | 2005-10-04 | 2012-12-12 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・エルレ・エルレ | Hivインテグラーゼ阻害剤 |
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2007
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- 2007-12-21 NZ NZ577491A patent/NZ577491A/en not_active IP Right Cessation
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2010
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2012
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011526248A (ja) * | 2008-07-02 | 2011-10-06 | アベキサ・リミテッド | 抗ウイルス特性を有する化合物 |
| JP2011526246A (ja) * | 2008-07-02 | 2011-10-06 | アベキサ・リミテッド | チアゾピリミジノンおよびその使用 |
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