ES2462403T3 - Diceto azolopiperidinas y azolopiperazinas como agentes anti-VIH - Google Patents
Diceto azolopiperidinas y azolopiperazinas como agentes anti-VIH Download PDFInfo
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- ES2462403T3 ES2462403T3 ES09770927.3T ES09770927T ES2462403T3 ES 2462403 T3 ES2462403 T3 ES 2462403T3 ES 09770927 T ES09770927 T ES 09770927T ES 2462403 T3 ES2462403 T3 ES 2462403T3
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- alkyl
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- 239000002259 anti human immunodeficiency virus agent Substances 0.000 title description 4
- 229940124411 anti-hiv antiviral agent Drugs 0.000 title description 4
- WEXJJSPMIBHSKF-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-pyrrolo[2,3-b]pyrazine Chemical class N1CCNC2=C1C=CN2 WEXJJSPMIBHSKF-UHFFFAOYSA-N 0.000 title description 3
- BSGMHULECQOVGD-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-pyrrolo[3,2-b]pyridine Chemical class C1CCNC2=C1NC=C2 BSGMHULECQOVGD-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 209
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 238000006467 substitution reaction Methods 0.000 claims abstract description 31
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 26
- 150000002367 halogens Chemical class 0.000 claims abstract description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 13
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 10
- 125000002541 furyl group Chemical group 0.000 claims abstract description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 9
- 125000001715 oxadiazolyl group Chemical group 0.000 claims abstract description 9
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 9
- 125000001113 thiadiazolyl group Chemical group 0.000 claims abstract description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 9
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 9
- 125000001425 triazolyl group Chemical group 0.000 claims abstract description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 8
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 8
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 148
- 208000030507 AIDS Diseases 0.000 claims description 96
- 208000031886 HIV Infections Diseases 0.000 claims description 62
- 208000037357 HIV infectious disease Diseases 0.000 claims description 60
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 60
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 32
- 239000003112 inhibitor Substances 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- 239000012317 TBTU Substances 0.000 claims description 17
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 230000000840 anti-viral effect Effects 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 239000003443 antiviral agent Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 7
- 239000002955 immunomodulating agent Substances 0.000 claims description 7
- 229940121354 immunomodulator Drugs 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 229960005475 antiinfective agent Drugs 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 4
- 239000004599 antimicrobial Substances 0.000 claims description 4
- 230000002584 immunomodulator Effects 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 2
- 229940126154 HIV entry inhibitor Drugs 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- 238000002360 preparation method Methods 0.000 description 78
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 73
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- 238000004949 mass spectrometry Methods 0.000 description 64
- -1 bicyclic hydrocarbons Chemical class 0.000 description 62
- 238000005160 1H NMR spectroscopy Methods 0.000 description 57
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 52
- 239000011541 reaction mixture Substances 0.000 description 46
- 239000000243 solution Substances 0.000 description 45
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 32
- 229910002027 silica gel Inorganic materials 0.000 description 32
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 32
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- 238000004440 column chromatography Methods 0.000 description 31
- 230000014759 maintenance of location Effects 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- 239000002904 solvent Substances 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 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 29
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- 238000002953 preparative HPLC Methods 0.000 description 25
- 238000001953 recrystallisation Methods 0.000 description 25
- 229960002555 zidovudine Drugs 0.000 description 25
- 239000003814 drug Substances 0.000 description 23
- 239000008346 aqueous phase Substances 0.000 description 21
- 238000001665 trituration Methods 0.000 description 21
- 229940079593 drug Drugs 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 description 17
- 238000012512 characterization method Methods 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- AKRYBBWYDSDZHG-UHFFFAOYSA-N nitrosobis(2-oxopropyl)amine Chemical compound CC(=O)CN(N=O)CC(C)=O AKRYBBWYDSDZHG-UHFFFAOYSA-N 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- 235000019270 ammonium chloride Nutrition 0.000 description 14
- 239000007822 coupling agent Substances 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 235000017550 sodium carbonate Nutrition 0.000 description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 13
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 13
- 239000012267 brine Substances 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 11
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 208000007766 Kaposi sarcoma Diseases 0.000 description 10
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 10
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 229960001355 tenofovir disoproxil Drugs 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 102100034343 Integrase Human genes 0.000 description 8
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 229910052738 indium Inorganic materials 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 229960001936 indinavir Drugs 0.000 description 7
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 6
- 229960004748 abacavir Drugs 0.000 description 6
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 6
- 229910000397 disodium phosphate Inorganic materials 0.000 description 6
- 235000019800 disodium phosphate Nutrition 0.000 description 6
- 229960003804 efavirenz Drugs 0.000 description 6
- 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 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 235000019799 monosodium phosphate Nutrition 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000002777 nucleoside Substances 0.000 description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 6
- 229910000162 sodium phosphate Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 6
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 6
- 235000019801 trisodium phosphate Nutrition 0.000 description 6
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 5
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 5
- 229940126656 GS-4224 Drugs 0.000 description 5
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 5
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 5
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 5
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 5
- 125000004104 aryloxy group Chemical group 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
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Classifications
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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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- 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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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- AIDS & HIV (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (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 |
|---|---|---|---|
| US7537408P | 2008-06-25 | 2008-06-25 | |
| US75374P | 2008-06-25 | ||
| PCT/US2009/048427 WO2009158394A1 (en) | 2008-06-25 | 2009-06-24 | Diketo azolopiperidines and azolopiperazines as anti-hiv agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2462403T3 true ES2462403T3 (es) | 2014-05-22 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES09770927.3T Active ES2462403T3 (es) | 2008-06-25 | 2009-06-24 | Diceto azolopiperidinas y azolopiperazinas como agentes anti-VIH |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US7960406B2 (https=) |
| EP (1) | EP2303876B1 (https=) |
| JP (1) | JP5433690B2 (https=) |
| CN (1) | CN102131810B (https=) |
| ES (1) | ES2462403T3 (https=) |
| WO (1) | WO2009158394A1 (https=) |
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| AP2673A (en) | 2006-02-03 | 2013-05-23 | Grt Inc | Continuous process for converting natural gas to liquid hydrocarbons |
| WO2012142080A1 (en) * | 2011-04-12 | 2012-10-18 | Bristol-Myers Squibb Company | Thioamide, amidoxime and amidrazone derivatives as hiv attachment inhibitors |
| WO2013033061A1 (en) * | 2011-08-29 | 2013-03-07 | Bristol-Myers Squibb Company | Fused bicyclic diamine derivatives as hiv attachment inhibitors |
| ES2798289T3 (es) | 2012-01-25 | 2020-12-10 | Novartis Ag | Compuestos heterocíclicos y métodos para su uso |
| EA024872B1 (ru) | 2012-02-08 | 2016-10-31 | Бристол-Майерс Сквибб Компани | Способы получения пиперазинового пролекарства - ингибитора присоединения вич |
| JO3407B1 (ar) | 2012-05-31 | 2019-10-20 | Eisai R&D Man Co Ltd | مركبات رباعي هيدرو بيرازولو بيريميدين |
| EP2895472B1 (en) * | 2012-08-09 | 2016-11-23 | VIIV Healthcare UK (No.5) Limited | Tricyclic alkene derivatives as HIV attachment inhibitors |
| WO2014160689A1 (en) * | 2013-03-27 | 2014-10-02 | Bristol-Myers Squibb Company | Piperazine and homopiperazine derivatives as hiv attachment inhibitors |
| US9586957B2 (en) * | 2013-03-27 | 2017-03-07 | VIIV Healthcare UK (No.5) Limited | 2-keto amide derivatives as HIV attachment inhibitors |
| GB201321748D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| CA2971104A1 (en) * | 2014-12-18 | 2016-06-23 | ViiV Healthcare UK (No.4) Limited | A process for preparing halogenated azaindole compounds using boroxine |
| CA2971096A1 (en) * | 2014-12-18 | 2016-06-23 | ViiV Healthcare UK (No.4) Limited | A process for preparing halogenated azaindole compounds using pybrop |
| WO2016109684A2 (en) * | 2014-12-30 | 2016-07-07 | Novira Therapeutics, Inc. | Derivatives and methods of treating hepatitis b infections |
| US10153966B1 (en) * | 2015-03-12 | 2018-12-11 | Alarm.Com Incorporated | Hybrid mesh network monitoring signaling environment |
| CN108473495B (zh) | 2015-11-20 | 2022-04-12 | 福马治疗有限公司 | 作为泛素-特异性蛋白酶1抑制剂的嘌呤酮 |
| JP7014736B2 (ja) * | 2016-05-24 | 2022-02-01 | ジェネンテック， インコーポレイテッド | がんの処置のためのピラゾロピリジン誘導体 |
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|---|---|---|---|---|
| US4354924A (en) * | 1980-06-25 | 1982-10-19 | Chevron Research Company | Dual component chromia silicate cracking catalyst |
| US4812462A (en) * | 1986-04-01 | 1989-03-14 | Warner-Lambert Company | 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity |
| US6469006B1 (en) | 1999-06-15 | 2002-10-22 | Bristol-Myers Squibb Company | Antiviral indoleoxoacetyl piperazine derivatives |
| US6476034B2 (en) | 2000-02-22 | 2002-11-05 | Bristol-Myers Squibb Company | Antiviral azaindole derivatives |
| US6573262B2 (en) | 2000-07-10 | 2003-06-03 | Bristol-Myers Sqibb Company | Composition and antiviral activity of substituted indoleoxoacetic piperazine derivatives |
| US20040110785A1 (en) | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| EP1363705B9 (en) | 2001-02-02 | 2012-11-07 | Bristol-Myers Squibb Company | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| US6825201B2 (en) | 2001-04-25 | 2004-11-30 | Bristol-Myers Squibb Company | Indole, azaindole and related heterocyclic amidopiperazine derivatives |
| US20030236277A1 (en) | 2002-02-14 | 2003-12-25 | Kadow John F. | Indole, azaindole and related heterocyclic pyrrolidine derivatives |
| US20040063744A1 (en) | 2002-05-28 | 2004-04-01 | Tao Wang | Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides |
| US7348337B2 (en) * | 2002-05-28 | 2008-03-25 | Bristol-Myers Squibb Company | Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides |
| US20040106104A1 (en) | 2002-06-11 | 2004-06-03 | Pin-Fang Lin | Viral envelope mediated fusion assay |
| US6900206B2 (en) | 2002-06-20 | 2005-05-31 | Bristol-Myers Squibb Company | Indole, azaindole and related heterocyclic sulfonylureido piperazine derivatives |
| US20040063746A1 (en) | 2002-07-25 | 2004-04-01 | Alicia Regueiro-Ren | Indole, azaindole and related heterocyclic ureido and thioureido piperazine derivatives |
| US20050054716A1 (en) | 2002-11-08 | 2005-03-10 | Gogate Uday Shankar | Pharmaceutical compositions and methods of using taxane derivatives |
| US20050075364A1 (en) * | 2003-07-01 | 2005-04-07 | Kap-Sun Yeung | Indole, azaindole and related heterocyclic N-substituted piperazine derivatives |
| EA200600225A1 (ru) | 2003-08-14 | 2006-08-25 | Пфайзер Инк. | Производные пиперазина для лечения вич инфекций |
| US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
| US20050215544A1 (en) | 2004-03-24 | 2005-09-29 | Pin-Fang Lin | Methods of treating HIV infection |
| US7776863B2 (en) | 2004-03-24 | 2010-08-17 | Bristol-Myers Squibb Company | Methods of treating HIV infection |
| US20050215543A1 (en) | 2004-03-24 | 2005-09-29 | Pin-Fang Lin | Methods of treating HIV infection |
| DE102004020908A1 (de) * | 2004-04-28 | 2005-11-17 | Grünenthal GmbH | Substituierte 5,6,7,8,-Tetrahydro-pyrido[4,3-d]pyrimidin-2-yl- und 5,6,7,8,-Tetrahydro-chinazolin-2-yl-Verbindungen |
| US7449476B2 (en) * | 2004-05-26 | 2008-11-11 | Bristol-Myers Squibb Company | Tetrahydrocarboline antiviral agents |
| WO2005121094A1 (en) | 2004-06-09 | 2005-12-22 | Pfizer Limited | Piperazine and piperidine derivatives as anti-hiv-agents |
| US7396830B2 (en) | 2005-10-04 | 2008-07-08 | Bristol-Myers Squibb Company | Piperazine amidines as antiviral agents |
| US7851476B2 (en) | 2005-12-14 | 2010-12-14 | Bristol-Myers Squibb Company | Crystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-YL)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-C]pyridin-3-YL]-1,2-dioxoethyl]-piperazine |
| US20070259879A1 (en) | 2006-03-06 | 2007-11-08 | Trimeris, Inc. | Piperazine and piperidine biaryl derivatives |
| US7807671B2 (en) | 2006-04-25 | 2010-10-05 | Bristol-Myers Squibb Company | Diketo-piperazine and piperidine derivatives as antiviral agents |
| US7504399B2 (en) | 2006-06-08 | 2009-03-17 | Bristol-Meyers Squibb Company | Piperazine enamines as antiviral agents |
-
2009
- 2009-06-24 WO PCT/US2009/048427 patent/WO2009158394A1/en not_active Ceased
- 2009-06-24 CN CN200980133292.3A patent/CN102131810B/zh not_active Expired - Fee Related
- 2009-06-24 JP JP2011516575A patent/JP5433690B2/ja not_active Expired - Fee Related
- 2009-06-24 EP EP09770927.3A patent/EP2303876B1/en not_active Not-in-force
- 2009-06-24 US US12/490,714 patent/US7960406B2/en active Active
- 2009-06-24 ES ES09770927.3T patent/ES2462403T3/es active Active
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2011
- 2011-05-05 US US13/101,591 patent/US8124615B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009158394A1 (en) | 2009-12-30 |
| CN102131810B (zh) | 2014-02-26 |
| US7960406B2 (en) | 2011-06-14 |
| JP2011526283A (ja) | 2011-10-06 |
| EP2303876A1 (en) | 2011-04-06 |
| US8124615B2 (en) | 2012-02-28 |
| CN102131810A (zh) | 2011-07-20 |
| US20100009993A1 (en) | 2010-01-14 |
| EP2303876B1 (en) | 2014-03-19 |
| US20110212971A1 (en) | 2011-09-01 |
| JP5433690B2 (ja) | 2014-03-05 |
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