HRP20050593A2 - Tetrahydro-4h-pyrido[1,2-a]pyrimidines and related compounds useful as hiv integrase inhibitors - Google Patents
Tetrahydro-4h-pyrido[1,2-a]pyrimidines and related compounds useful as hiv integrase inhibitors Download PDFInfo
- Publication number
- HRP20050593A2 HRP20050593A2 HR20050593A HRP20050593A HRP20050593A2 HR P20050593 A2 HRP20050593 A2 HR P20050593A2 HR 20050593 A HR20050593 A HR 20050593A HR P20050593 A HRP20050593 A HR P20050593A HR P20050593 A2 HRP20050593 A2 HR P20050593A2
- Authority
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- Croatia
- Prior art keywords
- oxo
- hydroxy
- amino
- fluorobenzyl
- tetrahydro
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 113
- UBOXAHWUKQXQEH-UHFFFAOYSA-N 2,3,4,6-tetrahydro-1h-pyrido[1,2-a]pyrimidine Chemical class C1=CCN2CCCNC2=C1 UBOXAHWUKQXQEH-UHFFFAOYSA-N 0.000 title abstract description 3
- 229940099797 HIV integrase inhibitor Drugs 0.000 title description 4
- 239000003084 hiv integrase inhibitor Substances 0.000 title description 4
- 208000030507 AIDS Diseases 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 208000031886 HIV Infections Diseases 0.000 claims abstract description 24
- 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 22
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 108010002459 HIV Integrase Proteins 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 20
- -1 4-fluoro-3-methylbenzyl Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 10
- WBQCKUNNRLRPOG-UHFFFAOYSA-N n'-[2-[(4-fluorophenyl)methylcarbamoyl]-3-hydroxy-4-oxo-7,8,9,10-tetrahydro-6h-pyrimido[1,2-a]azepin-10-yl]-n,n,n'-trimethyloxamide Chemical compound CN(C)C(=O)C(=O)N(C)C1CCCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 WBQCKUNNRLRPOG-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- ZQDWKAJNPJBABY-UHFFFAOYSA-N n'-[2-[(4-fluorophenyl)methylcarbamoyl]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-9-yl]-n,n,n'-trimethyloxamide Chemical compound CN(C)C(=O)C(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 ZQDWKAJNPJBABY-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- MCDBKPBDTVBVTL-UHFFFAOYSA-N 9-[dimethylsulfamoyl(methyl)amino]-n-[(4-fluorophenyl)methyl]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound CN(C)S(=O)(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 MCDBKPBDTVBVTL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- BXGKUPHBJWLRPJ-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound N1=C2CCCCN2C(=O)C(O)=C1C(=O)NCC1=CC=C(F)C=C1 BXGKUPHBJWLRPJ-UHFFFAOYSA-N 0.000 claims description 3
- AGXRVRVEFKZWCP-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-9-morpholin-4-yl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound C1CCN2C(=O)C(O)=C(C(=O)NCC=3C=CC(F)=CC=3)N=C2C1N1CCOCC1 AGXRVRVEFKZWCP-UHFFFAOYSA-N 0.000 claims description 3
- FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical compound NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 claims description 3
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 2
- VMWJCFLUSKZZDX-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- MCPXZOOZEBNEGJ-UHFFFAOYSA-N n'-[2-[(4-fluoro-3-methylphenyl)methylcarbamoyl]-3-hydroxy-4-oxo-7,8,9,10-tetrahydro-6h-pyrimido[1,2-a]azepin-10-yl]-n,n,n'-trimethyloxamide Chemical compound CN(C)C(=O)C(=O)N(C)C1CCCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C(C)=C1 MCPXZOOZEBNEGJ-UHFFFAOYSA-N 0.000 claims 6
- YLIYNHWYALYMOQ-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-9-[methyl-(4-methylpiperazin-1-yl)sulfonylamino]-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound C1CN(C)CCN1S(=O)(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 YLIYNHWYALYMOQ-UHFFFAOYSA-N 0.000 claims 6
- GOIXPYWYXSSRFX-UHFFFAOYSA-N 9-[azetidin-1-ylsulfonyl(methyl)amino]-n-[(4-fluorophenyl)methyl]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound C1CCN1S(=O)(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 GOIXPYWYXSSRFX-UHFFFAOYSA-N 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- COUJNVGGWLUEHF-UHFFFAOYSA-N n'-[2-[(4-fluorophenyl)methylcarbamoyl]-3-hydroxy-8,8-dimethyl-4-oxo-7,9-dihydro-6h-pyrido[1,2-a]pyrimidin-9-yl]-n,n,n'-trimethyloxamide Chemical compound OC=1C(=O)N2CCC(C)(C)C(N(C)C(=O)C(=O)N(C)C)C2=NC=1C(=O)NCC1=CC=C(F)C=C1 COUJNVGGWLUEHF-UHFFFAOYSA-N 0.000 claims 2
- LUKWPQJBONDYSK-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-9-(6-methyl-1,1-dioxo-1,2,6-thiadiazinan-2-yl)-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound O=S1(=O)N(C)CCCN1C1C2=NC(C(=O)NCC=3C=CC(F)=CC=3)=C(O)C(=O)N2CCC1 LUKWPQJBONDYSK-UHFFFAOYSA-N 0.000 claims 2
- IUWUIPCTVGUKAL-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-9-[methyl(morpholin-4-ylsulfonyl)amino]-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound C1COCCN1S(=O)(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 IUWUIPCTVGUKAL-UHFFFAOYSA-N 0.000 claims 2
- SJWPTLITARZLER-UHFFFAOYSA-N 9-[[2-(dimethylsulfamoyl)acetyl]-methylamino]-n-[(4-fluoro-3-methylphenyl)methyl]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound CN(C)S(=O)(=O)CC(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C(C)=C1 SJWPTLITARZLER-UHFFFAOYSA-N 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- FHMHJNJYVZSGOD-UHFFFAOYSA-N n'-[2-[(3-chloro-4-methylphenyl)methylcarbamoyl]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-9-yl]-n,n,n'-trimethyloxamide Chemical compound CN(C)C(=O)C(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(C)C(Cl)=C1 FHMHJNJYVZSGOD-UHFFFAOYSA-N 0.000 claims 1
- QMHNSONWMFDIOU-UHFFFAOYSA-N n'-[2-[(3-chlorophenyl)methylcarbamoyl]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-9-yl]-n,n,n'-trimethyloxamide Chemical compound CN(C)C(=O)C(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=CC(Cl)=C1 QMHNSONWMFDIOU-UHFFFAOYSA-N 0.000 claims 1
- SJVFREKFBRXASI-UHFFFAOYSA-N n'-[2-[(4-fluoro-3-methylphenyl)methylcarbamoyl]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-9-yl]-n,n,n'-trimethyloxamide Chemical compound CN(C)C(=O)C(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C(C)=C1 SJVFREKFBRXASI-UHFFFAOYSA-N 0.000 claims 1
- GJDMGRQVNYSRDY-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-9-[methyl(pyrrolidin-1-ylsulfonyl)amino]-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound C1CCCN1S(=O)(=O)N(C)C1CCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 GJDMGRQVNYSRDY-UHFFFAOYSA-N 0.000 claims 1
- 239000003443 antiviral agent Substances 0.000 abstract description 12
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- 230000010076 replication Effects 0.000 abstract description 8
- 239000002955 immunomodulating agent Substances 0.000 abstract description 7
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- 229960005486 vaccine Drugs 0.000 abstract description 4
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940088710 antibiotic agent Drugs 0.000 abstract description 2
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- 229940042443 other antivirals in atc Drugs 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 66
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
- 239000000203 mixture Substances 0.000 description 55
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 47
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 39
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- 239000002904 solvent Substances 0.000 description 38
- 238000000034 method Methods 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 241000725303 Human immunodeficiency virus Species 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 102100034343 Integrase Human genes 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
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- 239000012043 crude product Substances 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- 239000012071 phase Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
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- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 150000004702 methyl esters Chemical class 0.000 description 9
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 9
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 8
- 101710203526 Integrase Proteins 0.000 description 8
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- 108020004414 DNA Proteins 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- XPNODRGEKBEUOO-UHFFFAOYSA-N methyl 3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C1CCCN2C(=O)C(O)=C(C(=O)OC)N=C21 XPNODRGEKBEUOO-UHFFFAOYSA-N 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- 125000003118 aryl group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
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- DTEOUDKGIWFDEO-UHFFFAOYSA-N methyl 3-hydroxy-9-(methylamino)-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound CNC1CCCN2C1=NC(C(=O)OC)=C(O)C2=O DTEOUDKGIWFDEO-UHFFFAOYSA-N 0.000 description 1
- RSNVSNOSNVCVTR-UHFFFAOYSA-N methyl 9-[benzyl(methyl)amino]-3-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxylate;hydrochloride Chemical compound Cl.C1CCN2C(=O)C(O)=C(C(=O)OC)N=C2C1N(C)CC1=CC=CC=C1 RSNVSNOSNVCVTR-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- PPOHPUOKXMNCCI-UHFFFAOYSA-N n-(3,4,5,6-tetrahydro-2h-azepin-7-yl)hydroxylamine Chemical compound ONC1=NCCCCC1 PPOHPUOKXMNCCI-UHFFFAOYSA-N 0.000 description 1
- HIOPZDBGXHDCMB-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-10-(methylamino)-4-oxo-7,8,9,10-tetrahydro-6h-pyrimido[1,2-a]azepine-2-carboxamide Chemical compound CNC1CCCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 HIOPZDBGXHDCMB-UHFFFAOYSA-N 0.000 description 1
- WZUWQZYLHJCNOO-OQHSHRKDSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-10-[methyl-[(1r)-1-phenylethyl]amino]-4-oxo-7,8,9,10-tetrahydro-6h-pyrimido[1,2-a]azepine-2-carboxamide Chemical compound CN([C@H](C)C=1C=CC=CC=1)C1CCCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 WZUWQZYLHJCNOO-OQHSHRKDSA-N 0.000 description 1
- WKDJVAMTCVRQSI-QRIPLOBPSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-4-oxo-10-[[(1r)-1-phenylethyl]amino]-7,8,9,10-tetrahydro-6h-pyrimido[1,2-a]azepine-2-carboxamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C1CCCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1 WKDJVAMTCVRQSI-QRIPLOBPSA-N 0.000 description 1
- XMIPAKWCYIZLFV-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-9-morpholin-4-yl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxamide;hydrochloride Chemical compound Cl.C1CCN2C(=O)C(O)=C(C(=O)NCC=3C=CC(F)=CC=3)N=C2C1N1CCOCC1 XMIPAKWCYIZLFV-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
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- KHPXUQMNIQBQEV-UHFFFAOYSA-L oxaloacetate(2-) Chemical compound [O-]C(=O)CC(=O)C([O-])=O KHPXUQMNIQBQEV-UHFFFAOYSA-L 0.000 description 1
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 108700004029 pol Genes Proteins 0.000 description 1
- 101150088264 pol gene Proteins 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 1
- 150000008518 pyridopyrimidines Chemical class 0.000 description 1
- IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical compound Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
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- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- XJBFPQUKNPHLBX-UHFFFAOYSA-N tert-butyl n-(5-cyanopentyl)-n-phenylmethoxycarbamate Chemical compound N#CCCCCCN(C(=O)OC(C)(C)C)OCC1=CC=CC=C1 XJBFPQUKNPHLBX-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US43683002P | 2002-12-27 | 2002-12-27 | |
| US52877603P | 2003-12-12 | 2003-12-12 | |
| PCT/GB2003/005543 WO2004058757A1 (fr) | 2002-12-27 | 2003-12-18 | Tetrahydro-4h-pyrido[1,2-a]pyrimidines et composes associes utilises en tant qu'inhibiteurs de l'integrase du vih |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20050593A2 true HRP20050593A2 (en) | 2006-03-31 |
Family
ID=32685467
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20050593A HRP20050593A2 (en) | 2002-12-27 | 2005-06-24 | Tetrahydro-4h-pyrido[1,2-a]pyrimidines and related compounds useful as hiv integrase inhibitors |
Country Status (20)
| Country | Link |
|---|---|
| US (2) | US7414045B2 (fr) |
| EP (1) | EP1578748B1 (fr) |
| JP (1) | JP4733986B2 (fr) |
| KR (1) | KR20050087865A (fr) |
| CN (1) | CN100343253C (fr) |
| AT (1) | ATE481401T1 (fr) |
| AU (2) | AU2003292436B2 (fr) |
| BR (1) | BR0317749A (fr) |
| CA (1) | CA2509554C (fr) |
| DE (1) | DE60334248D1 (fr) |
| EC (1) | ECSP055890A (fr) |
| HR (1) | HRP20050593A2 (fr) |
| IS (1) | IS7892A (fr) |
| MA (1) | MA27583A1 (fr) |
| MX (1) | MXPA05007010A (fr) |
| NO (1) | NO20053624L (fr) |
| NZ (1) | NZ540729A (fr) |
| PL (1) | PL377354A1 (fr) |
| RU (1) | RU2329265C2 (fr) |
| WO (2) | WO2004058756A1 (fr) |
Families Citing this family (58)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004062613A2 (fr) * | 2003-01-13 | 2004-07-29 | Bristol-Myers Squibb Company | Inhibiteurs d'integrase hiv |
| CA2542047A1 (fr) * | 2003-10-20 | 2005-05-12 | Merck & Co., Inc. | Composes pyridopyrrolopyrazine dione hydroxy utiles comme inhibiteurs de l'integrase du vih |
| AR046938A1 (es) * | 2003-12-12 | 2006-01-04 | Merck & Co Inc | Procedimiento para preparar hexahidropirimido[1,2-a]azepin-2-carboxilatos y compuetos similares |
| TW200526635A (en) * | 2003-12-22 | 2005-08-16 | Shionogi & Co | Hydroxypyrimidinone derivative having HIV integrase inhibitory activity |
| US7273859B2 (en) * | 2004-05-12 | 2007-09-25 | Bristol-Myers Squibb Company | HIV integrase inhibitors: cyclic pyrimidinone compounds |
| US7115601B2 (en) | 2004-05-18 | 2006-10-03 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| US7192948B2 (en) | 2004-05-28 | 2007-03-20 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| US7173022B2 (en) * | 2004-05-28 | 2007-02-06 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| US7157447B2 (en) | 2004-05-28 | 2007-01-02 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| US7176196B2 (en) * | 2004-05-28 | 2007-02-13 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| WO2006060225A2 (fr) * | 2004-11-23 | 2006-06-08 | Merck & Co., Inc. | Processus destine a la synthese asymetrique d'hexahydropyrimido[1,2-a] azepine-2-carboxamides et de composes correspondants |
| AU2005311714B2 (en) | 2004-12-03 | 2010-09-30 | Merck Sharp & Dohme Corp. | Pharmaceutical composition containing an anti-nucleating agent |
| UA87884C2 (uk) * | 2004-12-03 | 2009-08-25 | Мерк Энд Ко., Инк. | Безводна кристалічна калієва сіль інгібітора віл-інтегрази |
| RU2403066C2 (ru) * | 2004-12-03 | 2010-11-10 | Мерк Шарп Энд Домэ Корп | Применение атазанавира для улучшения фармакокинетики лекарственных средств, метаболизируемых ugt1a1 |
| ES2755273T3 (es) * | 2004-12-03 | 2020-04-22 | Merck Sharp & Dohme | Formulación farmacéutica de inhibidores de la carboxamida VIH integrasa que contienen una composición de control de la velocidad de liberación |
| EP1852434B1 (fr) * | 2005-02-21 | 2011-07-13 | Shionogi Co., Ltd. | Dérivé de carbamoylpyridone bicyclique ayant une activité d'inhibition de la vih intégrase |
| US7981879B2 (en) * | 2005-03-31 | 2011-07-19 | Instituto di Ricerchi di Biologia Molecolare P. Angeletti S.p.A. | HIV integrase inhibitors |
| WO2006116764A1 (fr) | 2005-04-28 | 2006-11-02 | Smithkline Beecham Corporation | Derive polycyclique de la carbamoylpyridone a activite inhibitrice sur l'integrase du vih |
| WO2007005404A1 (fr) | 2005-06-30 | 2007-01-11 | Wyeth | DÉRIVÉS D'IMIDAZOLONE PORTANT UN GROUPEMENT HÉTÉROARYLE À 6 CHAÎNONS EN POSITION 5 ET UN GROUPEMENT AMINO, ET LEUR EMPLOI DANS LA RÉGULATION DE LA β-SECRÉTASE |
| US7494984B2 (en) * | 2005-08-31 | 2009-02-24 | Bristol-Myers Squibb Company | Substituted imidazo[1,2-a]pyrimidines as HIV viral DNA integrase inhibitors |
| US7939537B2 (en) | 2005-10-04 | 2011-05-10 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | HIV integrase inhibitors |
| CA2626956A1 (fr) * | 2005-10-27 | 2007-05-03 | Shionogi & Co., Ltd. | Derive de carbamoylpyridone polycyclique ayant une activite d'inhibition sur l'integrase du vih |
| EP1942736A2 (fr) * | 2005-10-27 | 2008-07-16 | Merck & Co., Inc. | Inhibiteurs de l'integrase du vih |
| US7897592B2 (en) * | 2005-11-15 | 2011-03-01 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| WO2007058646A1 (fr) * | 2005-11-15 | 2007-05-24 | Bristol-Myers Squibb Company | Inhibiteurs d’integrase du vih : composes cycliques de la pyrimidinone |
| US7902182B2 (en) * | 2005-11-16 | 2011-03-08 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| US8039458B2 (en) * | 2005-11-17 | 2011-10-18 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| WO2007064316A1 (fr) * | 2005-11-30 | 2007-06-07 | Bristol-Myers Squibb Company | Heterocycles bicycliques en tant qu'inhibiteurs de l'integrase du vih |
| US20070129379A1 (en) * | 2005-12-01 | 2007-06-07 | Bristol-Myers Squibb Company | Hiv integrase inhibitors |
| US20090136570A1 (en) * | 2006-01-20 | 2009-05-28 | Bhagwant Rege | Taste-Masked Tablets and Granules |
| WO2007143446A1 (fr) * | 2006-05-30 | 2007-12-13 | Bristol-Myers Squibb Company | Composés hétérotricycliques spiro-condensés utilisés en tant qu'inhibiteurs de la vih intégrase |
| US7893055B2 (en) * | 2006-06-28 | 2011-02-22 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| US7763630B2 (en) * | 2007-06-06 | 2010-07-27 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| US8129398B2 (en) * | 2008-03-19 | 2012-03-06 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| JP4880097B1 (ja) * | 2008-10-06 | 2012-02-22 | メルク・シャープ・エンド・ドーム・コーポレイション | Ｈｉｖインテグラーゼ阻害剤 |
| MX2011006241A (es) * | 2008-12-11 | 2011-06-28 | Shionogi & Co | Sintesis de inhibidores de integrasa de vih de carbamoil-piridona e intermediarios. |
| US8143244B2 (en) * | 2009-02-26 | 2012-03-27 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
| MX2012000103A (es) * | 2009-07-02 | 2012-05-22 | Sanofi Sa | Nuevos derivados de 1,2,3,4-tetrahidro-pirimido (1,2-a) pirimidin-6-ona, su preparacion y su uso farmaceutica. |
| EP2488521B1 (fr) | 2009-10-13 | 2013-12-18 | Elanco Animal Health Ireland Limited | Inhibiteurs de l'intégrase macrocyclique |
| US8383639B2 (en) | 2009-10-15 | 2013-02-26 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| CA2777937C (fr) | 2009-10-26 | 2017-08-29 | Merck Sharp & Dohme Corp. | Compositions pharmaceutiques solides contenant un inhibiteur d'integrase |
| WO2011121105A1 (fr) | 2010-04-02 | 2011-10-06 | Tibotec Pharmaceuticals | Inhibiteurs de l'intégrase macrocyclique |
| UA112517C2 (uk) * | 2010-07-06 | 2016-09-26 | Новартіс Аг | Тетрагідропіридопіримідинові похідні |
| WO2013088404A1 (fr) | 2011-12-15 | 2013-06-20 | Novartis Ag | Utilisation d'inhibiteurs de l'activité ou de la fonction de pi3k |
| WO2014099586A1 (fr) | 2012-12-17 | 2014-06-26 | Merck Sharp & Dohme Corp. | Dérivés 4-pyridinonetriazines en tant qu'inhibiteurs de l'intégrase du vih |
| US9493479B2 (en) | 2013-04-16 | 2016-11-15 | Merck Sharp & Dohme Corp. | Substituted pyrido[1,2-a]pyrazines as HIV integrase inhibitors |
| ME02977B (fr) | 2013-05-17 | 2018-10-20 | Merck Sharp & Dohme | Composés hétérocycliques tricycliques fusionnés utiles en tant qu'inhibiteurs de l'intégrase du vih |
| EP3008044B1 (fr) | 2013-06-13 | 2018-11-21 | Merck Sharp & Dohme Corp. | Composés hétérocycliques tricycliques fusionnés utiles en tant qu'inhibiteurs de l'intégrase du vih |
| EA030695B1 (ru) | 2013-09-27 | 2018-09-28 | Мерк Шарп И Доум Корп. | Замещенные производные хинолизина, которые можно использовать как ингибиторы интегразы вич |
| WO2016187788A1 (fr) | 2015-05-25 | 2016-12-01 | Merck Sharp & Dohme Corp. | Composés hétérocycliques tricycliques fusionnés utiles pour traiter l'infection au vih |
| WO2017087257A1 (fr) | 2015-11-17 | 2017-05-26 | Merck Sharp & Dohme Corp. | Dérivés de pyridotriazine amido-substitués utiles en tant qu'inhibiteurs de l'intégrase du vih |
| WO2017106071A1 (fr) | 2015-12-15 | 2017-06-22 | Merck Sharp & Dohme Corp. | Dérivés de quinolizine spirocycliques utiles en tant qu'inhibiteurs de l'intégrase du vih |
| WO2017113288A1 (fr) | 2015-12-31 | 2017-07-06 | Merck Sharp & Dohme Corp. | Composés hétérocycliques tricycliques condensés utiles en tant qu'inhibiteurs de l'intégrase du vih |
| JP2020500866A (ja) | 2016-12-02 | 2020-01-16 | メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． | Ｈｉｖインテグラーゼ阻害剤として有用な三環式複素環化合物 |
| JOP20190130A1 (ar) | 2016-12-02 | 2019-06-02 | Merck Sharp & Dohme | مركبات حلقية غير متجانسة رباعية الحلقات مفيدة كمثبطات إنزيم مدمج لفيروس نقص المناعة البشرية (hiv) |
| EP3573984A4 (fr) | 2017-01-26 | 2020-07-29 | Merck Sharp & Dohme Corp. | Dérivés de quinolizine substitués utiles en tant qu'inhibiteurs de l'intégrase du vih |
| CR20230571A (es) | 2018-05-31 | 2024-01-22 | Shionogi & Co | DERIVADO POLICÍCLICO DE CARBAMOILPIRIDONA (divisional 2020-0644) |
| WO2019230857A1 (fr) | 2018-05-31 | 2019-12-05 | 塩野義製薬株式会社 | Dérivé de pyridone polycyclique |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6262055B1 (en) * | 1998-06-03 | 2001-07-17 | Merck & Co., Inc. | HIV integrase inhibitors |
| US6306891B1 (en) * | 1998-06-03 | 2001-10-23 | Merck & Co., Inc. | HIV integrase inhibitors |
| US6380249B1 (en) * | 1998-06-03 | 2002-04-30 | Merck & Co., Inc. | HIV integrase inhibitors |
| JP2003503386A (ja) | 1999-06-25 | 2003-01-28 | メルク エンド カムパニー インコーポレーテッド | １−（芳香族またはヘテロ芳香族置換）−３−（ヘテロ芳香族置換）−１，３−プロパンジオン類およびそれの使用 |
| AU2001275279B2 (en) * | 2000-06-07 | 2007-01-04 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
| GB0017676D0 (en) * | 2000-07-19 | 2000-09-06 | Angeletti P Ist Richerche Bio | Inhibitors of viral polymerase |
| CA2321348A1 (fr) * | 2000-09-27 | 2002-03-27 | Blaise Magloire N'zemba | Derives aromatiques ayant des proprietes inhibant l'integrase de l'hiv |
| WO2002030426A1 (fr) | 2000-10-12 | 2002-04-18 | Merck & Co., Inc. | Azanaphthalenylcarboxamides et polyazanaphthalenylcarboxamides utiles en tant qu'inhibiteurs de la vih integrase |
| US20050010048A1 (en) | 2000-10-12 | 2005-01-13 | Linghang Zhuang | Aza-and polyaza-naphthalenly ketones useful as hiv integrase inhibitors |
| CZ20031028A3 (cs) | 2000-10-12 | 2003-08-13 | Merck & Co., Inc. | Aza- a polyazanaftalenylkarboxamidy |
| ES2274913T3 (es) | 2000-10-12 | 2007-06-01 | MERCK & CO., INC. | Aza y poliaza-naftalenil carboxamidas utiles como inhibidores de vih integrada. |
| CN101513402B (zh) | 2001-08-10 | 2012-03-21 | 盐野义制药株式会社 | 抗病毒药 |
| BRPI0213522C1 (pt) * | 2001-10-26 | 2021-05-25 | St Di Ricerche Di Biologia Molecolare P Angeletti S P A | compostos derivados de hidroxipirimidinona, composição farmacêutica, e, uso de um composto |
| DE60218511T2 (de) | 2001-10-26 | 2007-10-25 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti S.P.A. | Dihydroxypyrimidin-carbonsäueramid-hemmer der hiv-integrase |
| JP4523281B2 (ja) | 2002-01-17 | 2010-08-11 | メルク・シャープ・エンド・ドーム・コーポレイション | Ｈｉｖインテグラーゼ阻害薬として有用なヒドロキシナフチリジノンカルボキサミド類 |
| US7109186B2 (en) * | 2002-07-09 | 2006-09-19 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| WO2004062613A2 (fr) * | 2003-01-13 | 2004-07-29 | Bristol-Myers Squibb Company | Inhibiteurs d'integrase hiv |
| US7037908B2 (en) * | 2003-04-24 | 2006-05-02 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| AR046938A1 (es) * | 2003-12-12 | 2006-01-04 | Merck & Co Inc | Procedimiento para preparar hexahidropirimido[1,2-a]azepin-2-carboxilatos y compuetos similares |
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- 2003-12-18 WO PCT/GB2003/005536 patent/WO2004058756A1/fr active Application Filing
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Also Published As
| Publication number | Publication date |
|---|---|
| NZ540729A (en) | 2008-03-28 |
| EP1578748B1 (fr) | 2010-09-15 |
| EP1578748A1 (fr) | 2005-09-28 |
| RU2005123807A (ru) | 2006-01-20 |
| AU2003292437A1 (en) | 2004-07-22 |
| WO2004058757A1 (fr) | 2004-07-15 |
| PL377354A1 (pl) | 2006-01-23 |
| NO20053624L (no) | 2005-09-26 |
| DE60334248D1 (de) | 2010-10-28 |
| NO20053624D0 (no) | 2005-07-26 |
| US20080176869A1 (en) | 2008-07-24 |
| ATE481401T1 (de) | 2010-10-15 |
| US20060046985A1 (en) | 2006-03-02 |
| US7414045B2 (en) | 2008-08-19 |
| JP2006513200A (ja) | 2006-04-20 |
| AU2003292436A1 (en) | 2004-07-22 |
| RU2329265C2 (ru) | 2008-07-20 |
| WO2004058756A1 (fr) | 2004-07-15 |
| CN100343253C (zh) | 2007-10-17 |
| MA27583A1 (fr) | 2005-10-03 |
| BR0317749A (pt) | 2005-11-22 |
| CA2509554A1 (fr) | 2004-07-15 |
| CA2509554C (fr) | 2011-02-01 |
| MXPA05007010A (es) | 2005-08-18 |
| US7968553B2 (en) | 2011-06-28 |
| AU2003292436B2 (en) | 2009-07-30 |
| IS7892A (is) | 2005-06-13 |
| KR20050087865A (ko) | 2005-08-31 |
| ECSP055890A (es) | 2005-09-20 |
| JP4733986B2 (ja) | 2011-07-27 |
| CN1753892A (zh) | 2006-03-29 |
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