IL179455A - Bicyclic heterocycles as hiv integrase inhibitors - Google Patents

Info

Publication number

IL179455A

IL179455A IL179455A IL17945506A IL179455A IL 179455 A IL179455 A IL 179455A IL 179455 A IL179455 A IL 179455A IL 17945506 A IL17945506 A IL 17945506A IL 179455 A IL179455 A IL 179455A

Authority

IL

Israel

Prior art keywords

oxo

oxazine

methyl

hydroxy

fluoro

Prior art date

2004-05-28

Links

• Espacenet
• Global Dossier
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• 229940099797 HIV integrase inhibitor Drugs 0.000 title claims description 14
• 239000003084 hiv integrase inhibitor Substances 0.000 title claims description 14
• 125000002618 bicyclic heterocycle group Chemical group 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 366
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 304
• 239000000203 mixture Substances 0.000 claims description 177
• JROPBYGZSRBHDV-UHFFFAOYSA-N oxazine-2-carboxamide Chemical compound NC(=O)N1OC=CC=C1 JROPBYGZSRBHDV-UHFFFAOYSA-N 0.000 claims description 149
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 122
• 229910052739 hydrogen Inorganic materials 0.000 claims description 121
• -1 C^aUcyl Chemical group 0.000 claims description 112
• 208000030507 AIDS Diseases 0.000 claims description 83
• LDSKYBVNIGKJHA-UHFFFAOYSA-N 2h-1,4-oxazine-2-carboxamide Chemical compound NC(=O)C1OC=CN=C1 LDSKYBVNIGKJHA-UHFFFAOYSA-N 0.000 claims description 72
• 239000003112 inhibitor Substances 0.000 claims description 64
• 208000031886 HIV Infections Diseases 0.000 claims description 59
• 208000037357 HIV infectious disease Diseases 0.000 claims description 58
• 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 58
• 150000003839 salts Chemical class 0.000 claims description 39
• 239000001257 hydrogen Substances 0.000 claims description 38
• 239000003814 drug Substances 0.000 claims description 37
• 239000012453 solvate Substances 0.000 claims description 35
• 239000003795 chemical substances by application Substances 0.000 claims description 34
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 31
• 239000002777 nucleoside Substances 0.000 claims description 29
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 26
• 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 25
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
• 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 17
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 15
• 125000000217 alkyl group Chemical group 0.000 claims description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
• 238000011282 treatment Methods 0.000 claims description 14
• 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 13
• 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims description 11
• 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims description 11
• 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 11
• 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 11
• 230000034303 cell budding Effects 0.000 claims description 11
• 208000015181 infectious disease Diseases 0.000 claims description 11
• 230000035800 maturation Effects 0.000 claims description 11
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
• 239000004030 hiv protease inhibitor Substances 0.000 claims description 10
• 150000002148 esters Chemical class 0.000 claims description 9
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 8
• 239000002835 hiv fusion inhibitor Substances 0.000 claims description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 5
• 125000001475 halogen functional group Chemical group 0.000 claims description 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
• 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 claims description 4
• 101100203602 Hypocrea jecorina (strain QM6a) sor7 gene Proteins 0.000 claims description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• 101100134925 Gallus gallus COR6 gene Proteins 0.000 claims description 3
• 230000004927 fusion Effects 0.000 claims description 3
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
• 125000000304 alkynyl group Chemical group 0.000 claims description 2
• 230000001225 therapeutic effect Effects 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
• 239000002850 integrase inhibitor Substances 0.000 claims 2
• 229940124524 integrase inhibitor Drugs 0.000 claims 2
• DHXDFVUOYMUPPL-UHFFFAOYSA-N 3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazine-2-carboxamide Chemical compound CC1(C)OC=CN2C1=NC(C(N)=O)=C(O)C2=O DHXDFVUOYMUPPL-UHFFFAOYSA-N 0.000 claims 1
• CKUVWMOMSIPZMI-UHFFFAOYSA-N 9,9-diethyl-n-[(4-fluoro-2-methylsulfonylphenyl)methyl]-3-hydroxy-4-oxo-6,7-dihydropyrimido[2,1-c][1,4]oxazine-2-carboxamide Chemical compound CCC1(CC)OCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1S(C)(=O)=O CKUVWMOMSIPZMI-UHFFFAOYSA-N 0.000 claims 1
• MWXPELHYKUPTBS-UHFFFAOYSA-N n-[[4-fluoro-2-(2-oxopiperidin-1-yl)phenyl]methyl]-3-hydroxy-9,9-dimethyl-4-oxo-6,7-dihydropyrimido[2,1-c][1,4]oxazine-2-carboxamide Chemical compound CC1(C)OCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1N1CCCCC1=O MWXPELHYKUPTBS-UHFFFAOYSA-N 0.000 claims 1
• YPGPHKYNAXOSJE-UHFFFAOYSA-N n-[[4-fluoro-2-(2-oxopyrrolidin-1-yl)phenyl]methyl]-3-hydroxy-9,9-dimethyl-4-oxo-6,7-dihydropyrimido[2,1-c][1,4]oxazine-2-carboxamide Chemical compound CC1(C)OCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1N1CCCC1=O YPGPHKYNAXOSJE-UHFFFAOYSA-N 0.000 claims 1
• ZOOCBHIGFRTPKD-UHFFFAOYSA-N n-[[4-fluoro-2-(methylcarbamoyl)phenyl]methyl]-3-hydroxy-10,10-dimethyl-4-oxo-7,8-dihydro-6h-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide Chemical compound CNC(=O)C1=CC(F)=CC=C1CNC(=O)C1=C(O)C(=O)N(CCCOC2(C)C)C2=N1 ZOOCBHIGFRTPKD-UHFFFAOYSA-N 0.000 claims 1
• QOZUICSVLJMIDW-UHFFFAOYSA-N n-[[4-fluoro-2-(methylcarbamoyl)phenyl]methyl]-3-hydroxy-9,9-dimethyl-4-oxo-6,7-dihydropyrimido[2,1-c][1,4]oxazine-2-carboxamide Chemical compound CNC(=O)C1=CC(F)=CC=C1CNC(=O)C1=C(O)C(=O)N(CCOC2(C)C)C2=N1 QOZUICSVLJMIDW-UHFFFAOYSA-N 0.000 claims 1
• RQOGKHGPSHFOKR-UHFFFAOYSA-N n-[[4-fluoro-2-(morpholine-4-carbonyl)phenyl]methyl]-3-hydroxy-9,9-dimethyl-4-oxo-6,7-dihydropyrimido[2,1-c][1,4]oxazine-2-carboxamide Chemical compound CC1(C)OCCN(C(C=2O)=O)C1=NC=2C(=O)NCC1=CC=C(F)C=C1C(=O)N1CCOCC1 RQOGKHGPSHFOKR-UHFFFAOYSA-N 0.000 claims 1
• 239000000543 intermediate Substances 0.000 description 549
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 359
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 250
• 101150041968 CDC13 gene Proteins 0.000 description 240
• 125000003118 aryl group Chemical group 0.000 description 168
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 152
• 238000005481 NMR spectroscopy Methods 0.000 description 151
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 142
• 239000007787 solid Substances 0.000 description 142
• 239000000243 solution Substances 0.000 description 139
• 238000005160 1H NMR spectroscopy Methods 0.000 description 131
• 238000000034 method Methods 0.000 description 118
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 99
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 96
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 95
• 229910001868 water Inorganic materials 0.000 description 91
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 74
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 71
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 71
• 239000011541 reaction mixture Substances 0.000 description 67
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 65
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 55
• 235000019441 ethanol Nutrition 0.000 description 51
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 50
• 239000002904 solvent Substances 0.000 description 48
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
• 239000003921 oil Substances 0.000 description 41
• 239000012267 brine Substances 0.000 description 40
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 40
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 39
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• 230000015572 biosynthetic process Effects 0.000 description 35
• 238000003786 synthesis reaction Methods 0.000 description 35
• 238000006243 chemical reaction Methods 0.000 description 34
• 241000725303 Human immunodeficiency virus Species 0.000 description 33
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 32
• 229940079593 drug Drugs 0.000 description 32
• MTYYIWGKIVFIMX-UHFFFAOYSA-N oxazine-2-carboxylic acid Chemical compound OC(=O)N1OC=CC=C1 MTYYIWGKIVFIMX-UHFFFAOYSA-N 0.000 description 32
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
• 239000000741 silica gel Substances 0.000 description 30
• 229910002027 silica gel Inorganic materials 0.000 description 30
• 239000000843 powder Substances 0.000 description 28
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
• 230000000694 effects Effects 0.000 description 26
• 239000000706 filtrate Substances 0.000 description 25
• 239000013078 crystal Substances 0.000 description 24
• 239000000284 extract Substances 0.000 description 23
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 23
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
• 230000014759 maintenance of location Effects 0.000 description 22
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• 238000004440 column chromatography Methods 0.000 description 20
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• 230000002829 reductive effect Effects 0.000 description 20
• 238000001914 filtration Methods 0.000 description 19
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• 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 19
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• 238000003818 flash chromatography Methods 0.000 description 16
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• PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 14
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• 238000003756 stirring Methods 0.000 description 14
• 150000001408 amides Chemical class 0.000 description 13
• 150000001412 amines Chemical class 0.000 description 13
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
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• 235000011152 sodium sulphate Nutrition 0.000 description 13
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
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• GNNGREMVIPKSKL-UHFFFAOYSA-N 2h-1,4-oxazine-2-carboxylic acid Chemical compound OC(=O)C1OC=CN=C1 GNNGREMVIPKSKL-UHFFFAOYSA-N 0.000 description 10
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• 108010032976 Enfuvirtide Proteins 0.000 description 10
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
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• WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 9
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• NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 9
• 229910052757 nitrogen Inorganic materials 0.000 description 9
• 239000012074 organic phase Substances 0.000 description 9
• COEOZBBXBIAOHC-UHFFFAOYSA-N pyrimido[2,1-c][1,4]oxazine-2-carboxamide Chemical compound O1C=CN2C=CC(C(=O)N)=NC2=C1 COEOZBBXBIAOHC-UHFFFAOYSA-N 0.000 description 9
• 239000012312 sodium hydride Substances 0.000 description 9
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
• 125000001424 substituent group Chemical group 0.000 description 9
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